ScienceBased Health provides a number of educational resources, including our monthly Staying Healthy Newsletter, monthly EduFacts scientific write-ups, nutrient glossary and scientific detail sheets (monographs) on our products. Browse these resources below.
In the news: Tune into the ‘Med Diet’ for Better Health in the New Year
Med Diet Associated with Lower AMD Risk
Over the past decade, many studies have shown that following a Mediterranean (Med) style diet can have powerful heart health benefits. It’s a diet rich in fresh fruits and veggies, seafood, whole-grains and monounsaturated fats (the type in olive oil), and relatively low in meats, sweets and dairy.
According to growing evidence – the newest published in November, 2016 in the journal Ophthalmology – adopting the Med style of eating may also be protective against age-related macular degeneration (AMD), a leading cause of vision loss in those of us aged 50 and older.
In the latest study , researchers used a Med diet score to assess adherence to the diet and prevalence of AMD in over 4,750 participants 65 and older from 7 study centers across Northern and Southern Europe.
Compared to those with the lowest Med diet scores, people who were best at sticking with the diet had a 47% reduced risk of advanced AMD.
Below is the Mediterranean Diet Pyramid (from the Aug. 2008 Staying Healthy entitled Mediterranean Diet Gains Momentum), which canserve as a model to help get started. Here’s to good visual health in the New Year!
Handful of Nuts Daily Lowers CVD & Chronic Disease Risk
Several of the intervention studies that have evaluated the effect of the Med diet on cardiovascular disease (CVD) risk, have shown that adding some nuts daily to the diet confers protection against developing CVD. Nuts contain many bioactive compounds and are high in magnesium, fiber and polyunsaturated fats. Walnuts and pecans in particular are good sources of antioxidant nutrients.
A new analysis of 20 studies that examined nut consumption and risk of CVD as well as other chronic diseases was conducted by university researchers from the UK and Norway. The studies included in the analysis involved over 800,000 participants and included many thousands of cases of heart disease, stroke, CVD and cancer.
The analysis found a consistent reduction in risk across many different diseases with nut consumption. One serving (28 grams or 1 oz.) per day increase in nut intake was associated with a reduction in risk of 29% for coronary heart disease, 21% for CVD, 15% for total cancer, and 22% reduction in risk of all-cause mortality. The results were similar for tree nuts (such as walnuts) and peanuts.
The take home message is clear: add a handful of nuts daily to the heart- and possibly eye-healthy Mediterranean style of eating.
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Brain Health Part I: Tips for Keeping Your Mind Sharp
Brain Protecting Basics and New Research
Studies have shown that some basic health habits can help prevent cognitive decline and reduce the risk of dementia: Healthy eating, staying physically active, not smoking, sleeping well, limiting alcohol intake, and maintaining good social connections. Challenging the brain with mental exercise is also thought to help maintain brain cells and stimulate signaling between them. This issue of Staying Healthy takes a look at recent insights into brain protective practices and key strategies for boosting mental function (part II will focus on culinary culprits in brain health).
Get a Good Night’s Sleep.
All of us can attest to the refreshing feeling that a good night’s sleep provides (and to the mental fuzziness that can result from inadequate or poor quality sleep). But in addition to renewing energy and consolidating memories, brain-protective processes with long-term implications also appear to be at work when we sleep.
In a series of animal studies , researchers found that while asleep the brain is busy cleaning out cellular “trash” and toxins that accumulate during waking hours, including proteins (beta amyloid and tau) associated with Alzheimer’s and other types of dementia. While more research needs to be conducted in humans, it appears that insufficient or disturbed sleep impairs the brain’s ability to get rid of this neural waste. Experts suggest 7-9 hours of sleep nightly.
Choose Brain-Boosting Beverages.
Coffee, green tea and cocoa seem to top the list. Coffee (caffeinated) may improve memory according to new findings . While caffeine is known to support mental performance, it has been thought to have little or no effect on longer-term memory retention. Researchers showed that volunteers given caffeine right after standard recognition memory tasks, per-formed better at similar tasks the next day versus those given a placebo.
Two cups of cocoa daily for a month was shown to improve cognitive function and blood flow in the brain among those with impaired neurovascular coupling – a measure of blood flow in the brain in relation to nerve cells. Other studies have shown that flavonols found in cocoa help maintain the elasticity of blood vessels, which is important for normal brain blood flow.A number of recent studies are stimulating interest in green tea’s potential to protect brain cells and promote brain performance. In one study , researchers used magnetic resonance imaging (MRI) to observe the brains of people during tests of working memory – memory that allows the brain to process and store information at the same time. Compared to those getting a placebo, participants given green tea extract had increased activity in an area of the brain where working memory is processed.
Go Mediterranean
Many individual nutrients contribute to maintaining good mental function as we age, including B-vitamins, antioxidants, flavonoids and omega-3 fatty acids. But examining the influence of an overall eating pattern on cognition instead of a single or a few nutrients allows us to study the synergy among these nutrients.
One way of eating that emphasizes brain-supporting nutrients is the Mediterranean diet (Med diet). It includes olive oil as the main dietary fat, and is high in plant-based foods (fruits, nuts, vegetables, beans and minimally processed or whole grains). It also includes ample amounts of fish and seafood, while dairy and meat are eaten more sparingly.
The results of a recent randomized trial found that the Med diet improves long-term mental function in older individuals . Study participants assigned to a Med diet plus extra virgin olive oil or nuts fared significantly better on a battery of cognitive tests after 6 ½ years than did those on a low fat diet.
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Young hearts & omega-3s; Antioxidants & Stroke Risk; Diet & genetic risk of AMD
Omega-3s & Heart Health in Young Women
The cardiovascular health benefits of omega-3 fatty acids are well-documented in men and older men and women. But whether a fish-rich diet is important for heart health in younger women is an area that – until recently – has received little attention.
Now, the first study to focus exclusively on women of child-bearing age reports that diets plentiful in omega-3s may help protect younger women’s hearts too .
The research team analyzed data from nearly 49,000 initially healthy pregnant women (average age of 30), whose dietary habits were assessed at 3 intervals over an 8 year period. The women were then followed by checking hospital records for cardiovascular-related admissions. Because very few of these women were found to take fish oil supplements, those that did were excluded from the analyses.
Women who rarely or never ate fish had 50% more cardiovascular problems than those who consumed fish regularly. And compared to women who ate fish high in omega-3s weekly, the risk of cardiovascular disease (CVD) was 90% higher for those who rarely ate these omega-3 fish sources. Because they saw a strong association with CVD in women who were still in their late 30’s, the team advises younger women to eat fish as a main meal at least twice a week.
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Fish Tip: Concerned about which fish are environmentally safe to eat? Print a Seafood Watch pocket guide from Monterey Bay Aquarium’s website to help you choose ocean-friendly seafood wherever you live or travel. |
Dietary Antioxidants & Stroke Risk in Women
In more good news for women, Swedish researchers have found a link between a diet high in fruits, veggies and whole grains (antioxidant rich foods) and the risk of stroke . The researchers used dietary information from more than 31,000 women without heart disease and 5,000 with a history of CVD to determine the women’s total antioxidant capacity – the power of the food’s antioxidants to reduce free radicals in cells.
Healthy women with the highest antioxidant intake had a 17% risk reduction for all forms of stroke (hemorrhagic and ischemic) compared to those with the lowest intake. A 57% lower risk of hemorrhagic stroke was seen in women with a history of CVD who fell within the highest ¾ of antioxidant intake.
Reducing the Genetic Risk of Early AMD
Can younger people with an inherited genetic risk for age-related macular degeneration (AMD) delay or even prevent this vision-disabling condition with the right diet? Science has no conclusive answer to this question yet, though higher intakes of lutein/zeaxanthin, as well as EPA/DHA have been linked to AMD risk reduction in a number of studies.
Dutch researchers have also found a strong link between dietary zinc, antioxidants (beta-carotene and lutein/zeaxanthin) and omega-3s, and AMD development in people who carry two of the more common gene forms (variants) known to increase susceptibility to this disease .
Carriers of one or both of these genetic variants who consumed more of these nutrients had a significantly reduced risk of developing early AMD. Researchers estimate that, together, these variants probably contribute to late AMD in more than 80% of cases.
The study’s authors urge younger people with family members who have AMD – to consume diets that provide good intakes of these nutrients. In addition to choosing cold water fish for EPA/DHA, zinc can be found in fortified cereals, meats, dairy products, nuts and seeds. Dark green leafy veggies such as spinach and kale, and orange veggies like pumpkin and carrots, are good sources of lutein and beta-carotene.
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Tackling Health Risks in Teens & Young Adults
Hypertension on the Rise in Younger People
Traditionally, high blood pressure has been considered an adult disease, not a condition common among young adults or teens. However a new study reports that nearly 1 in 5 younger adults have blood pressure readings that meet the definition of hypertension. Alarmingly, only about ¼ of those with high blood pressure in the study were aware that they had it.
Researchers from the University of North Carolina analyzed data on more than 14,000 younger adults aged 24-32, and found that 19% had blood pressure readings higher than 140/90. Previous estimates were about 4% in this age group. The study authors believe that the obesity epidemic is behind their findings, because hypertension is strongly associated with overweight. Due to the huge increase in obesity among children and teens, many experts warn that high blood pressure is now a significant health concern for them as well.
Tips for Fighting Overweight
One of the key reasons that many kids & teens carry around extra pounds is lack of physical activity, plain and simple. Of course the right eating plan can pay big dividends too. Have an overweight young person in your family? Here are some resources that can help:
Also keep in mind that teens can benefit from a calcium, magnesium and vitamin D supplement, if they’re not meeting recommended intakes from food alone. And although the evidence for fish oil reducing blood pressure is preliminary, a fish oil supplement is probably a good idea for those who shy away from fish.
Higher Protein Breakfast May Cut Snacking
While everyone knows that eating breakfast is important, it’s estimated that 60% of teens regularly skip this meal. A recent study that monitored brain signals associated with motivation and eating behavior among obese teen girls, found differences in those signals 3 hours after eating a high protein breakfast.
Passing up breakfast has been associated with unhealthy snacking, overeating and weight gain. These findings provide more evidence that a higher intake of protein at this meal can be a valuable strategy to help control appetite and regulate food intake.
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Eat Well & Help the Environment Too!
Healthy Food, Healthy Planet
A healthy diet also benefits the planet according to a scientific study presented this month by an Italian think tank group, The Barilla Center for Food and Nutrition (BCFN) .
Based on data from a wide variety of sources, the group computed the environmental impact of various foods in terms of how their production effects the generation of greenhouse gases (Carbon Footprint), consumption of water resources (Water Footprint) and use of territory (Ecological Footprint).
The BCFN emphasized that the world’s food supply is becoming a more costly and precious commodity, and that today’s challenge is to increase productivity with fewer resources and less pollution.
Dual Goals: Better Health & Environmental Protection
The scientists presented a “double food pyramid”, using a modernized version of the well known Mediterranean Food Pyramid alongside a new nutritional-environmental food pyramid. The double pyramid graphically shows not only how foods impact health, but also their influence on the environment.
The double pyramid depicts how the foods we should eat most frequently are those with the least environmental impact. Eat-often foods like whole-grains at the base of the food pyramid were found to have a lower impact on the environment than meat, poultry, fish, dairy, and eggs towards the top of the pyramid, as well as fats, oils and sweets.
The study concluded that reducing meat and dairy consumption, eating fewer fatty and sugary foods, and wasting less food are the three changes to our eating habits that will have the biggest effect on making diets more sustainable.
The Need to Improve our Food Selections
If making healthy and environmentally friendly nutrition choices is a shared goal, then we as Americans have room for big improvements. New research suggests that nearly the entire US population is failing to eat a diet in line with the Dietary Guidelines .
Researchers from the National Cancer Institute and the National Center for Nutrition Policy and Promotion examined government data which included the dietary habits of over 16,000 individuals.
They found that more than 80% of those aged 71 and older, and more than 90% of all other groups of both sexes, consumed too many calories that come from fats, added sugars and alcohol. And nearly everyone failed to meet recommendations for dark green and orange vegetables, and whole grains.
In view of the current obesity epidemic, increasing rates of diet-related chronic diseases and the need to support a more sustainable food supply, the double pyramid may prove to be a very useful tool in helping us make better food choices.
Graphic courtesy of Barilla Center for Nutrition.
View the interactive pyramid graphic at www.barillacfn.com
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Mediterranean Diet Gains Momentum
Science is Strong for the Med Style of Eating
A flood of studies over the past year have increased support for the Mediterranean (Med) style of eating. Some of the most recent findings include:
In Head-to-Head Test, Med Diet Promotes Weight Loss and is Best for Diabetics
Results from a 2-year trial comparing weight loss with a low-carb, Med-style or low-fat diet, made the news last month. In this tightly controlled experiment, 322 overweight people were assigned to 1 of 3 types of diet: a low-fat diet based on American Heart Association guidelines, a low-carb diet based on the Atkins plan, and a Med style diet.
The biggest weight loss happened in the first 5 months, with people in all 3 groups regaining some of the lost weight as time went on. At the end of 2 years, the low-fat dieters lost about 6 pounds while the Med and low-carb groups both lost about 10 pounds.
While the weight loss was modest, it resulted in improved health markers, and there were subtle differences in the 3 diets studied. Men seemed to do better on the low-carb diet, losing 11 pounds versus about 9 on the Med diet. Women fared best on the Med diet, losing about 14 pounds compared with about 5 pounds on the low-carb eating plan. For all dieters, the ratio of good to bad cholesterol improved. But among the 36 diabetic participants, the Med diet had the most favorable effect on glycemic control. Diabetics had better blood glucose and insulin levels.
What is the Med Style Diet?
The med diet is rich in cereals, wine, fruits, vegetables, nuts, beans, whole grains, fish and olive oil - foods which provide carotenoids, vitamins A, C and E, polyphenols, essential minerals, and the omega-3 fats.
Common foods include pasta, bread (whole grain is best), rice and couscous, olives, avocados, grapes, eggplant, tomatoes, peppers, nuts and beans, cheese and yogurt. Moderate consumption of fish and poultry is encouraged, while red meat is advised only a few times per month.
If you're not yet following the Med style of eating, the Mediterranean Pyramid, endorsed by the Harvard School of Public Health and the World Health Organization, can serve as a model to help you get started.
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Nutrition News Bites: Vitamin D for Lung Health, Omega-3s for Healthier Hearts
Vitamin D for Stronger Lungs
Research continues to uncover new benefits of vitamin D, which has been linked to everything from bone strength to reductions in the risk of prostate and colon cancers. A study now reports that higher blood levels of this vitamin support better lung function.
Using data collected from over 14,000 adults who took part in a US National Health and Nutrition Examination Survey, investigators divided the participants into 5 groups based on their blood levels of vitamin D. They then compared how well the groups had done on tests of lung function. FEV (forced expiratory volume) measures how much air you can exhale in a second, while forced vital capacity (FVC) determines the amount of air you can rapidly blow out after taking a deep breath.
People with the highest vitamin D levels had considerably stronger FEV scores and better FEC rates, even after adjusting for factors such as smoking and exercise. The study also found more vitamin D naturally occurring in men than in women, and that the older and more obese a person was, the less vitamin D was present. The researchers think that vitamin D may be helping the remodeling of tissues in the lung.
While the study showed a "definite relationship between vitamin D and lung function", the study's lead author cautioned that it isn't clear whether increases in vitamin D can favorably affect lung function in people who already have chronic respiratory diseases.
The body's capacity to produce vitamin D from sunlight exposure declines with age, and many experts believe that older adults need even higher levels of this vitamin than the currently recommended daily dose of 400 IU for those over 50 and 600 IU for those 70 years and older.
Omega-3s and Healthier Heart Rates
Many epidemiologic and clinical trials have documented the heart-protective effects of the omega-3 fatty acids found in cold-water fish.
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In recent years, studies have found that consuming more omega-3s reduces the risk for sudden death in people with coronary heart disease. Sudden death occurs when the heart stops abruptly, a condition also known as cardiac arrest. Most cardiac arrest occurs when electrical impulses in the heart become rapid and/or chaotic. The omega-3 fats are believed to fight against sudden death by regulating the heartbeat and preventing irregular rhythms.
A new study designed to explore the possible mechanisms in which fish oil protects against the risk of sudden death has shown that supplementation with omega-3 fatty acids significantly decreases heart rate while at rest, and accelerates its return to normal after exercise.
In this well-controlled but small study, men with a history of heart attack took omega-3 fatty-acid supplements (about 800 mg daily) or placebo for 4 months, then switched to the alternate treatment for another 4 months. Resting heart rate significantly decreased with the omega-3 supplement, and heart rate returned to normal much faster after the men completed a stress test. The decrease in heart rate at 1 minute post-exercise was 19% greater with omega-3s.
"This decrease in heart rate could help explain the decreased risk in sudden death with omega-3 fatty acids", noted the lead author, "because there is a relationship between resting heart rate and the risk of sudden death: The higher the rate, the higher the risk."
| While this study focused on people who had already experienced a heart attack, the omega-3s may help others too. In 2003, researchers reported that healthy men who regularly ate fish had lower average heart rates - a sign of a much healthier heart. |  Photo courtesy of www.cfsan.fda.gov |
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Embracing the Mediterranean-Style Diet
Chances are that we all know someone who has been diagnosed with coronary heart disease (CHD). It is, after all, one of the most common chronic diseases. Diet is a first line defense for preventing and treating this condition, yet evidence suggests that the benefits of following the Mediterranean diet may outweigh those of low-fat diets often prescribed for people with CHD. In the Lyon Diet Heart Study, for example, the Mediterranean style dietary approach was found to be better than the older American Heart Association's low-fat diet in preventing heart attacks in people with heart disease. It was also more protective against certain cancers.
What is The Mediterranean Diet?
This eating pattern is based on the traditional diets of Greece, Crete and southern Italy. The pattern is similar but varies a bit in the 16 countries that border the Mediterranean Sea due to cultural differences. But here's what the overall pattern looks like: lots of vegetables and fruit, whole grain breads, unrefined cereals and dairy daily, with olive oil as the main source of added fat. It calls for fish, poultry and nuts weekly, with very moderate intake of sweets, eggs and potatoes. Red meat is eaten sparingly, about once a week, but moderate red wine is consumed daily.
Why is This Diet Heart-Healthy?
The fats you get from the Mediterranean diet are important. At least some of the diet's cardio-protective effects are due to the omega-3 fats found in fish. Fish oils have been shown to reduce the rate of heart attack and stroke over the long term. The diet contains a moderate amount of fat, with more coming from fish and less from red meat. It also relies on fats from heart-healthy nuts and olive (or canola) oil as the primary added fat. This type of fat has a more favorable effect on triglycerides and the "good" HDL cholesterol compared to the more typical low-fat diet. Another important benefit comes from whole grains and unrefined cereals. They offer lots of fiber and essential nutrients, as do vegetables and fruits.
Embracing the Mediterranean style diet doesn't mean you have to follow it exactly. For one thing, the number of servings will vary depending on body size, level of activity and overall calorie needs. Including foods from your own culinary heritage can be important too. Certain Asian patterns of eating are actually similar to the Mediterranean diet in that they focus on eating less red meat and more plant-based sources of fat and protein. If you use the pyramid as a general guide, here are a few things to keep in mind:
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A Guide to Reading Supplement Labels
How Do You Read a Supplement Label? The sample below will help you become more familiar with the basic information on most supplement labels.
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In the news:Lower Vitamin D Linked with NIU; More Evidence that Multis Support Memory
Lower Vitamin D Levels Linked to NIU
Non-infectious uveitis (NIU) is an inflammatory ocular disorder characterized by inflammation of the uvea – the pigmented, middle layer of the eye comprised of the iris, ciliary body, and choroid. NIU can be a sight-threatening disease over time if untreated.
Vitamin D plays a critical role in modulating immune response, and recent publications have linked serum vitamin D levels with the development, inflammatory activity, and remission of NIU. One study reported that individuals with hypovitaminosis D were 2.53 times more likely to develop NIU.
Nevertheless, a vitamin D and NIU relationship is still inconclusive, leading researchers to conduct a systematic review and meta-analysis of observational studies to further assess the potential association of low vitamin D levels and NIU.
The meta-analysis included 5 observational studies with a total of 6,082 participants. Three of the studies were conducted in the US, 1 in Germany and 1 in Turkey. The participants either had NIU at baseline or developed the condition during follow-up.
Overall, the investigators found that patients with vitamin D deficiency exhibited an OR of 2.04 (P < 0.00001) for developing NIU compared to controls.
In subgroup analyses of studies that measured vitamin D levels prior to NIU onset, those who developed the condition had lower initial vitamin D levels than those who remained NIU free. Overall, potential sources of bias were low across most studies.
Current evidence supports a significant association between hypovitaminosis D and the development of NIU, according to the study authors. However, the number of studies analyzed was relatively small and further research is necessary to confirm these conclusions.
3rd Major Analysis of COSMOS Suggests Daily Multi Protects the Aging Brain
The results of the first and second Cocoa Supplement and Multivitamins Outcome Study (COSMOS) cognitive trials were discussed in earlier issues of EduFacts (sbh.com, volumes 25 and 27).
First, the COSMOS-Mind trial reported that daily use of a multi was associated with improved memory and slower cognitive decline in older individuals compared to those assigned to placebo. The daily multi group had a 60% slowing of global cognitive aging vs. placebo.
The second major COSMOS study, the COSMOS-Web study, which included 3500 participants 60 or older, looked at performance on a novel web-based assessment of memory and cognition annually over 3 years. The multi group did significantly better than the placebo group on memory tests and word recall – a benefit that was first seen at 1 year and was sustained across the 3- year period.
The current paper describes two sets of data. The first is the COSMOS -Clinic which administered in person cognitive assessments in 573 people. In this data set, significant benefit of a daily multi for episodic memory was seen, but not for executive function or attention.
The second data set is a meta-analysis of three separate studies within COSMOS combined (COSMOS -MIND, -Web and -Clinic) with no patient overlap. Significant benefits were observed in both global cognition and memory in the meta-analysis.
The authors estimate that, overall, the multivitamin-mineral supplementation slowed global aging by the equivalent of 2 years versus placebo.
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In the news: Higher B1 Intake Lowers Late AMD Risk? Stress-induced inflammation Drives MetS
Higher B1 Intake May Lower Late AMD Risk
According to growing observational study findings, increased intakes of various vitamins and minerals are related to slower development of age-related macular degeneration (AMD) or to the delay of its progression to intermediate or late stages.
One nutrient of interest is vitamin B1 (thiamine), which is an important cofactor for a wide variety of enzymes that are engaged in important metabolic processes, especially in the metabolism of carbohydrates and amino acids.
There is mounting evidence that thiamin also has antioxidant properties, and that it may help protect retinal tissues from radical oxygen species (ROS). With its strong oxygen metabolism, retinal tissue produces abundant ROS, leaving it vulnerable to oxidative injury. It’s established that oxidative stress is a major contributing factor to AMD pathogenesis.
Thiamine’s potential relevance to ocular health led researchers to assess the association between the vitamin and the prevalence of late AMD in a representative US sample – participants in the National Health and Nutrition Examination Survey (NHANES).
This cross-sectional study included over 5,000 individuals aged 40 years or older with dietary intake data. Fundus photographs from NHANES were used to classify early and advanced AMD.
After fully adjusting for numerous potential confounding variables, the investigators found an inverse association between B1 intake and late AMD. Compared with a lower intake, higher thiamine consumption correlated with a 38% lower risk for late AMD ((OR = 0.62). No link between thiamine and early AMD was observed.
The investigators concluded that further randomized clinical trials among multiple centers are warranted to investigate the longitudinal and causal relationship between vitamin B1 intake and late AMD.
How Stress May Drive Metabolic Syndrome
According to the findings of Ohio State researchers, stress may contribute to a state of chronic, low-grade inflammation that leads to metabolic dysregulation. The investigators suggest that affordable and relatively easy stress management techniques may be one means of improving the health of those with metabolic syndrome (MetS) – a condition affecting an estimated 1 in 3 US adults.
Metabolic syndrome, also referred to as insulin resistance syndrome, is defined as having at least three of five risk factors for heart disease, type 2 diabetes, and stroke. The risk factors include excess abdominal fat, hypertension, low HDL, high fasting blood glucose, and elevated triglycerides.
A link between stress and health is established, but few studies have looked specifically at the involvement of inflammation in the connection of stress to metabolic syndrome.
The study, supported by the National Institutes of Aging, used data from 648 participants in the Midlife in the US Study which provided measures of perceived stress, inflammatory biomarkers C-reactive protein, interleukin-6, E-selectin, fibrinogen, intracellular adhesion molecule-1 and metabolic health markers.
Statistical modeling demonstrated that stress was linked to metabolic dysregulation through inflammation (p < .001). Inflammation explained a large proportion – about 61% – of that connection.
These results suggest that inflammatory biomarkers are a viable explanatory pathway for the relationship between perceived stress and metabolic health consequences, according to the authors. Reducing stress may be one option to mitigate inflammatory health risks.
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In the news: Studies Highlight Key Nutrients in Maintaining Cognitive Function
Three newly published studies lend credence to previous findings that dietary intake of flavonoids, omega-3 fatty acids, and select vitamins and minerals play an important role in preserving cognition or slowing cognitive decline with age.
Omega-3 Blood Levels & All Cause Dementia
The largest study to date examining the relationship between omega-3 biomarkers and dementia tapped the UK Biobank, a prospective, population-based cohort of approximately 500,000 people. In that study – with available data on omega-3 and incident dementia in 102,722 participants – both plasma DHA and total omega-3 were linked to a significantly lower risk of incident dementia.
With the recent release of additional metabolic data from 157,000 UK Biobank participants, the researchers updated those associations. They confirmed the favorable relationships between DHA and dementia risk and found evidence that non-DHA omega-3 (e.g. EPA, DPA) may also be beneficial.
Comparing the highest vs. lowest levels of total omega-3 showed a 13% lower risk of Alzheimer’s and a 21% decrease in risk of all-cause dementia.
According to the authors, the stronger association seen for non-DHA omega-3 vs. DHA suggests that the effect of omega-3 is likely greater for non-Alzheimer’s dementias, such as vascular dementia, Lewy body dementia, and frontotemporal dementia.
Stronger associations were also observed for men compared to women; and for those over age 60 at baseline compared to those in their 50s. Thus, this research helps better define groups who might gain the greatest cognitive benefits in omega-3-based interventions.
Nutrients & Cognitive Function in AREDS 1&2
Numerous large-scale studies provide evidence that certain dietary patterns and nutrients support cognition as we grow older. A study published in 2020, for example, reported that participants in AREDS 1 and 2 who adhered most closely to the Mediterranean (Med) diet had a significantly lower risk of cognitive impairment, though not a slower decline in cognitive function. Fish intake was also associated with higher cognitive function.
The AREDS research group recently published a study analyzing associations between nutrients and altered function or decline. Echoing the findings from the Med diet investigation, some nutrients were linked with lower risk of cognitive impairment or higher cognitive function scores, but not slower cognitive decline.
Nutrients with the strongest and most consistent favorable associations included: Vitamins A, C, E and several B-vitamins. The minerals copper, magnesium, selenium, and zinc. The carotenoids lutein, zeaxanthin, beta-carotene and lycopene, as well as the lipids DHA, EPA, and fiber. Nutrients with harmful associations included MUFA, oleic and saturated fatty acids, as well as diets with a high glycemic index or load.
Higher Flavonoid Intake & MCI / Dementia Risk
Previous research has reported a link between cognition and flavonoid intake. [See SBH.com, EduFacts Vol. 26, Flavonols May Slow Memory Decline]. Briefly, a newly published meta-analysis of 13 observational studies reports that higher flavonoid intake was associated with a 17% lower risk of cognitive impairment/dementia.
The dose-response analysis indicated a lower dementia risk with higher total flavonoid intake up to about 250 mg daily. For individual flavonoid types, anthocyanins (-27%) and flavones (-23%) had the highest impact on risk reduction. Anthocyanins are abundant in berries, grapes, currants, and red to purplish leafy vegetables. Flavones are found in herbs, teas and many fruits and vegetables.
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In the news: Ocular Blood Flow & Glaucoma Progression Vitamin E May Help Fight Fatty Liver Disease
Ocular Blood Flow & Glaucoma Progression
Compromised ocular blood flow has been established as a contributing factor in the onset and development of open-angle glaucoma (OAG). Lacking, however, are larger, long-terms studies investigating whether ocular blood flow biomarkers are predictive of disease progression.
A newly published study now suggests that specific retinal capillary blood flow biomarkers may predict glaucoma progression after five years.
Researchers evaluated 112 early to moderate OAG patients at baseline and every 6 months for 5 years. Biomarkers of retinal capillary blood flow were assessed by Heidelberg retinal flowmetry. Functional changes were monitored by Humphrey Visual Field exams. Structural progression, reflected by decreases in retinal nerve fiber layer thickness and/or increases in cup to disc ratio, was tracked with OCT and Heidelberg retinal tomograph.
The results showed that lower retinal capillary blood flow in the superior retina was significantly associated with structural progression (p = 0.0009).
In this study structural and functional progression occurred even with lowered IOP over 5 years, confirming that glaucoma can progress in many patients despite well-controlled IOP.
Future research should focus on identifying and translating vascular insufficiency into actionable targets of research and clinical care in glaucoma, according to the authors. One research direction has attempted to identify neuroprotection measures. Certain antioxidants, for example, have been shown to increase biomarkers of ocular blood flow including superior retinal capillary blood flow.
Vitamin E Useful in Fatty Liver Disease
Non-alcoholic fatty liver disease (NAFLD), a build-up of fat in the liver, is the most common liver problem in the US. About 25% of adults are estimated to have the condition, and rates have been steadily climbing over the past three decades. About 20% of those with NAFLD progress to NASH (or nonalcoholic steatohepatitis). NASH in turn may lead to cirrhosis or even liver cancer.
NAFLD has recently undergone a name change to Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). The name now emphasizes the metabolic origins of the condition, as certain genes and metabolic disorders such as obesity, diabetes and high blood pressure raise the risk for MASLD.
The first line of treatment for MASLD and NASH is weight loss through calorie restriction, exercise and healthy eating. According to the results of a recent meta-analysis, vitamin E may also compliment these lifestyle changes.
The meta-analysis of 12 randomized controlled trials looked at the effect of vitamin E supplementation on blood levels of the liver enzymes alanine aminotransferase (ALT) and aspartate amino-transferase (AST) in 794 adults and children with MASLD / NASH. Elevated levels of these liver enzymes are associated with MASLD / NASH.
In 7 of the trials, vitamin E was accompanied by lifestyle modification in both vitamin E and placebo groups. The trials ranged from 4 to 96 weeks in length.
Vitamin E, ranging from 400 to 800 IU daily, consistently reduced serum ALT (-13.06 IU/L) and AST (-6.00 IU/L) levels compared with a placebo.
The beneficial effect of vitamin E seemed to be independent of ethnicity, whether the participants were adults or children, whether or not vitamin E was combined with interventions to improve overall dietary intake and increase physical activity, or whether the duration of the trials was less than 24 weeks or 48 weeks or more.
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In the news: Isometric Exercise for Lowering Blood Pressure; Could Vitamin D Reduce AFib Risk?
Isometric Exercise for Hypertension
Close to half of US adults have hypertension, defined as a systolic blood pressure greater than 130 mmHg or a diastolic blood pressure greater than 80 mmHg, or are taking medication for hypertension. Since the prevalence is high and the potential health effects (heart attack, stroke, retinal vessel damage) are consequential, research into effective ways to control this condition is ongoing.
Regular exercise is one of the pillars of treating hypertension, along with weight reduction, eating the DASH diet, reducing sodium, and lowering stress. Current recommendations call for at least a half an hour of exercise (aerobic) most days of the week. While many forms of exercise can be beneficial, is there a particular mode of exercise that is optimal for reducing high blood pressure?
To address this question, UK researchers conducted a meta-analysis , analyzing data from 270 randomized controlled trials that included more than 15,800 people. Included trial protocols were stratified as aerobic exercise training (AET), resistance training (RT), combined training (CT), high-intensity interval training (HIIT) and isometric exercise training (IET).
These categories were then further stratified into subgroups: AET included walking, running, and cycling, HIIT included sprint interval and aerobic interval training, and IET included isometric leg extension and wall squats.
While the analysis showed that all modes of exercises were effective at reducing both systolic and diastolic blood pressure, the isometric (IET) was the best. IET showed reductions (in mm Hg) of 8.24/4 compared with 4.49/2.253 for aerobic, 4.55/3.04 for resistance, 6.04/2.54 for combined, and 4.08/2.50 for high-intensity interval training.
All exercise modes significantly reduced systolic pressure in normal blood pressure cohorts, while reductions were larger in those with hypertension.
The study authors conclude that these findings should inform future exercise guideline recommendations for the prevention and treatment of arterial hypertension.
Isometric exercise involves increasing tension in a muscle without moving any surrounding joints. Wall squats involve slowly moving into a squat as the back is pushed against a wall, the position held, then coming back up. Examples of other isometric exercises are side planks, calf raises, low squats v-sits, and glute bridges – exercises that can be seen demonstrated on YouTube, for example.
Vitamin D & Risk of New AFib
Epidemiological studies have linked vitamin D deficiency with increased risk of atrial fibrillation (AFib), but very few randomized trials have looked at the effect of supplemental vitamin D on the incidence of this condition in healthy individuals.
Finnish university researchers conducted a post hoc analysis from a study that examined the effects of vitamin D on CVD and cancer incidence in nearly 2.500 healthy older participants who received either 1600 IU or 3,200 IU vitamin D or placebo daily. The participants were, for the most part, vitamin D sufficient.
AFib developed in 190 participants over an average 4-year follow-up period. The group receiving the lower dose vitamin D had a 27% reduction in AFib risk (HR 0.73, p= .03), while those in the higher dose vitamin D had a non-significant risk reduction.
The risk for AFib was reduced by 30% when both vitamin D dose groups combined were compared with the placebo group. (HR 0.70) p=.02)
The authors point out that the findings should be interpreted cautiously as AFib was not a prespecified primary outcome of the Finnish Vitamin D Trial (FIND), that was analyzed post-hoc.
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In the news: What Can MPOD in 1 relatives of AMD patients Tell Us? Vitamin B12 Linked to Lower Parkinson’s Risk
Is MPOD in Close Relatives of AMD Patients an Early Diagnostic Biomarker of AMD?
Studies have found a strong correlation between family history of AMD and development of the disease. It has been shown that AMD risk Is increased by up to 16 times in those having an affected first-degree family member (parents, siblings, children).
Genetic background is also an important determinant of macular pigment optical density (MPOD). Macular pigment is not completely determined genetically, however, so it's possible that MPOD may be modified by dietary intake of lutein and zeaxanthin for protective purposes.
Against this setting, researchers examined how the MPOD in first degree relatives of AMD patients compared with MPOD in healthy controls.
The study included 128 healthy first-degree relatives of AMD patients (group 1) and 74 healthy controls (group 2). The right eyes of all cases were included. MPOD was measured using heterochromatic flicker photometry. Central foveal thickness and subfoveal choroidal thickness were measured with spectral domain OCT.
The demographics of the two groups was similar, though the mean age of the first-degree relatives was slightly higher (49 vs. 42 years).
Mean MPOD values of subjects who were first-degree relatives of patients with AMD were significantly lower than healthy control group (0.43 v. 0.47 respectively, p=.0.048)
Mean central foveal thickness were 208 and 216 mm in group 1 and group 2 respectively (p=0.014), and mean subfoveal choroidal thickness were 232 and 250 mm respectively (p=0.002).
The authors suggest that reduced retinal thickness in subjects without any signs of AMD is likely to reflect possible photoreceptor degeneration due to genetic predisposition to AMD. Also, lower MPOD in Group 1 could be partly a reflection of the lower central foveal thickness in this group.
Further, “choroidal thinning in first-degree relatives may be related to the genetic tendency to atrophy of the microstructure of underlying capillaries and medium-sized vessels”.
According to the authors, theirs is the first study in the literature investigating MPOD values in first-degree relatives of AMD patients. Large, prospective studies are needed to clarify whether lower MPOD values have benefit as a diagnostic biomarker in this population. Such future studies should also measure dietary intake of lutein and zeaxanthin, as well as blood levels of these carotenoids.
Vitamin B12 May Be Protective Against Parkinson’s
Preclinical studies have linked folate, and vitamins B6 and B12. to risk of Parkinson’s disease (PD). B-vitamins have been associated with lower neurotoxicity, better dopamine production, and positively influencing a kinase enzyme (LRRK2) associated with PD.
A new study examining the relationship of long-term intake of these 3 B-vitamins to PD risk in the large-scale Nurses’ Health Study and the Health Professionals Follow-up study, failed to find a link between folate and B6 and PD. However, the highest intake of B12 was associated with a lower risk of PD.
Interestingly, a newly published paper indicates that OCT scans will someday be used by ophthalmologists to screen for Parkinson’s long before symptoms appear.
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In the news: Vitamin A & Dark Adaptation in AMD; Circulating Omega-3 Linked to Lung Function
Moderate Dose Vitamin A May Improve Dark Adaptation in iAMD Over Time
Previous studies have reported that high dose vitamin A (50,000 IU) may improve impaired dark adaptation (ability of the retina to transition from the light-adapted or photopic state to the dark adapted or scotopic state) in those with intermediate stage age-related macular degeneration (iAMD).
A small but potentially meaningful new study from the National Eye Institute now suggests that a lower dose of vitamin A (16,000 IU) can also significantly improve dysfunctional dark adaptation, though not in patients with reticular pseudodrusen – RPD, district lesions that occur in the subretinal space.
In the study, five patients with iAMD and with no RPD (AMD group) and seven with RPD (RPD group) received 16,000 IU of Vitamin A palmitate for 8 weeks. Patients were assessed at baseline, 4, 8 and 12 weeks on scotopic thresholds, dark adaptation, best-corrected and low luminance visual acuities and the low-luminance quality of life questionnaire.
Rod intercept time – which measures the amount of time it takes for eyes to adapt to darkness – improved significantly in the AMD group, with a mean change of -1.1 minute after 4 weeks and -2.2 minutes after 8 weeks of supplementation (p<0.001 for both time points).
The DA cone plateau also significantly improved (specifically, a more sensitive cone threshold) at 4 weeks (p=0.026 and at 8 weeks (p=0.001). The improvements in dark adaptation function seen at 4 and 8 weeks remained significant at 12 weeks.
In contrast, none of the measures improved significantly at any time point in the RPD group despite blood levels of vitamin A increasing during the study.
The authors postulate that in the iAMD group, “photoreceptors may be amenable to treatment and that dysfunction can be at least partially reversed”, while in the RPD group “the dysfunction could be due to a loss of photoreceptors or alterations that are beyond rescue.”
The authors point out that the RPD group in this study had significantly lower rod intercept time values at baseline, and showed no improvement after three months of vitamin A supplementation. The researchers also indicated that the higher variability observed in the functional parameters for this group may also contribute to the lack of improvement.
Omega-3 May Help Protect Lung Function
According to a two-part study, higher blood levels of omega-3 fatty acids, particularly DHA, are associated with a slower rate of lung function decline.
In the first part of the study – a longitudinal analysis of over 15,000 participants from the National Health Lung and Blood Institute Pooled Cohorts Study – higher DHA levels were also linked with a lower likelihood of restricted airflow from the lungs.
One standard deviation higher DHA blood level correlated with counteracting about 25% of the additional restricted airflow annual decline in current smokers vs. non-smokers and nearly all the additional decline in former smokers. The DHA blood level associated with counteracting this decline is achievable with a high-fish diet or omega-3 supplements.
The second analysis used a technique called Mendelian randomization to examine a causal relationship between omega-3 blood levels and lung health. Overall, the genetics-based analysis, which involved 500,000 United Kingdom Biobank participants, supported the observations from the longitudinal analysis that DHA was associated with slower lung function decline.
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In the news: Lowering IOP with Relaxation; Daily Multi Helps Preserve Cognitive Health
Relaxation Methods Lower IOP in Glaucoma
EduFacts has previously featured a small trial showing that in glaucoma patients, mindfulness meditation significantly lowers intraocular pressure (IOP) while upregulating neuroprotective genes and downregulating pro-inflammatory genes. (SBH.com, Vol. 24).
A newly published systematic review and meta-analysis now reports that various relaxation techniques may significantly reduce IOP – findings that suggest these techniques may be beneficial as an adjunctive treatment for glaucoma patients.
Twelve articles (596 subjects) were included for qualitative analysis and 5 articles (332 subjects) for quantitative analysis. The findings show that:
a) meditation consistently caused long-term reductions in IOP, even after practicing for only 3 weeks. b) Autogenic relaxation exercises showed a trend toward reducing IOP acutely and a significant reduction in the long-term. c) Ocular relaxation exercises combined with visual imagery of aqueous humour drainage showed both acute and long-term reductions in IOP. d) yoga ocular exercises were associated with long-term reductions in IOP. (Note, however, that the effects of yoga on IOP seem to depend on the positions being practiced. Yoga exercises with a head-down position may cause an increase in IOP).
Percentage reduction in IOP with the various techniques were as follows:
a) 31.8% from baseline occurred at 3 weeks after mindful meditation. b) 22% at 6 weeks after yoga ocular exercises, c) 15.3% at 16 weeks after autogenic relaxation exercises, ocular relaxation exercises, and visual imagination of aqueous humour drainage.
Mindful meditation programs are increasingly offered at colleges, in various medical settings, and online, making this technique relatively easy to find and access by interested patients.
Daily Multi Again Shows Slower Cognitive Aging
A second COSMOS (Cocoa Supplement and Multi-vitamins Outcome Study) trial has shown a benefit of a daily multi-vitamin/mineral (multi) on memory and cognition
The earlier COSMOS-Mind trial, a collaboration of Harvard Medical School and Wake Forest researchers, reported that daily use of a multi was associated with improved memory and slower cognitive decline in older individuals compared to those assigned to placebo. (SBH.com, Vol. 25). The multi group had a 60% slowing of global cognitive aging vs. placebo in this study funded by the National Institute on Aging and published in Alzheimer’s and Dementia in Sept, 2022.
The current and second major COSMOS study, this time a collaboration of Harvard and Columbia University, included 3500 participants 60 or older and looked at performance on a novel web-based assessment of memory and cognition annually over three years.
The multi group did significantly better than the placebo group on memory tests and word recall, a finding that was estimated as the equivalent of slowing age-related memory loss by about 3 years. The benefit was first seen at 1 year and was sustained across the 3 years.
Dr. JoAnn Manson, a co-author of COSMOS points out that poor status of various nutrients important for brain health such as vitamin B12, thiamin, other B vitamins, lutein, magnesium and zinc may accelerate cognitive decline. “Overall, the finding that a daily multivitamin improved memory and slowed cognitive decline in two separate COSMOS randomized trials is exciting” commented Dr. Manson.
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In the news: Omega-3 May Improve Cognition in Elderly; Supplemental Carotenoids in Pregnancy
Can Omega-3s Benefit Cognition in Elderly?
According to the results of a meta-analysis conducted by university researchers in China, supplemental omega-3s improve cognition in those with mild cognitive impairment (MCI) – often an early sign of Alzheimer’s disease.
Although there are previous meta-analyses looking at the relationship between the omega-3s and cognition, most of them did not focus on MCI. The current meta-analysis included 12 randomized trials with 1,224 participants 60 years or older with MCI.
The studies were conducted in China, the UK, Spain, Italy, Malaysia, and Iran, and all the studies had an intervention with DHA alone or combined with EPA, and placebo.
In trials examining DHA alone, the dose ranged from 800 to 2,000 mg daily, while the dose of total EPA plus DHA in trials testing both fatty acids varied from 300-1,800 mg daily. The interventions lasted from 2 to 24 months. The trials assessed global cognitive function, memory, and symptoms of depression as outcome measures.
The researchers report that supplementation with omega-3 fatty acids versus placebo benefited global cognition, a measure of overall cognitive function [Standardized Mean Difference= 0.51, p= 0.01]. No significant differences were observed between the intervention group and placebo on language fluency, executive functions, and depression.
The authors note the omega-3 fatty acid supple-mentation may also reduce the level of blood amyloid-beta and related biomarkers as well as some inflammatory factors (e.g., Il-6 and -10). However only two of the twelve studies measured these biomarkers, so no conclusions can be drawn.
Supplemental Carotenoids in Pregnancy
Evidence suggests that carotenoids play a functional and protective role in infant visual and cognitive development. In the third trimester of pregnancy, mothers transfer their store of nutrients via the placenta to support the baby’s central nervous system development, potentially putting mothers at risk of systemic and ocular carotenoid depletion.
Including the carotenoids lutein (L) and zeaxanthin (Z) in prenatal micronutrient supplement formulations has been promoted to enhance infant visual and neural development and to maintain maternal health. However, these claims are not yet supported by a compelling prospective trial.
Researchers at the Moran Eye Institute, University of Utah set out to investigate the effects of supplemental L and Z on maternal and infant ocular health. They hypothesized that supplementation with L and Z would improve carotenoid status in mother and infant, and that infants with the highest systemic and ocular carotenoid status would have a more mature foveal structure at birth. The first report from this trial is now published. It suggests that prenatal L and Z may have health benefits for women and their babies.
Forty-seven first trimester pregnant subjects were randomly allocated to receive standard-of-care prenatal vitamins plus a 10 mg L and 2 mg Z softgel (Carotenoid Group) or standard-of-care prenatal vitamins with a placebo (Controls) for 6 to 8 months.
A significant increase was seen in maternal serum L+Z concentrations, serum total carotenoid concentrations, and skin carotenoid status (p < 0.001, for all) in the Carotenoid Group v the Controls at all time points.
Similarly, infants whose mothers received carotenoids had a 5-fold increase in cord blood L+Z concentrations, over a 3-fold increase in cord blood total carotenoids, and a 38% increase in skin carotenoids compared to the Control Group (p < 0.0001, for all). Also, there was a strong positive correlation between postpartum maternal and infants’ systemic carotenoid status (p < 0.0001). Ocular effects of this intervention in the mothers and their children will be addressed in a forthcoming report.
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In the news: Identifying New Risk Factors for CVD
Newly Identified CVD Risk Factors
Eye care professionals have a two-way relationship with cardiovascular health. Eye exams can reveal potential signs of cardiovascular disease (CVD) such as vascular changes in retinal vessels due to hypertension, development of cholesterol around the eyes with hypercholesterolemia, or temporary vision loss due to a transient ischemic attack.
At the same time, CVD may influence ocular health. For example, stroke can lead to distorted or lost vision, and evidence suggests that CVD may increase the risk of retinal artery occlusion and vision loss due to age-related macular degeneration.
Familiar, widely studied CVD risk factors include obesity, smoking, sedentary lifestyle, diabetes, high cholesterol levels and high blood pressure. But despite efforts to prevent and treat these risk factors, the mortality and burden of disease attributed to CVD remains high.
New coronary risk factors have emerged in recent years because of gaps that remain in assessing and treating CVD. An editorial published in The American Journal of Medicine identifies and discusses the role of the new risk factors – a few of which are unusual, some that are not fully understood.
According to the author, recognizing the presence of one or more of these newly identified risk factors could trigger attempts by clinicians to minimize more traditional major risk factors.” Some of the newer risk factors include:
Systemic Inflammation
Several diseases characterized by systemic inflammation are among the new risk factors: • Gout – having a recent flare of gout increases the risk of an acute CV event such as heart attack or stroke • Rheumatoid arthritis, systemic lupus erythematosus, or both show higher odds for premature coronary artery disease (CAD) • Inflammatory bowel disease (Crohn’s, ulcerative colitis) increases the chance for developing CAD • Psoriasis patients are up to 50% more likely to develop CVD
Environmental Factors
An increased incidence of CAD has been related to two environmental factors that may themselves be connected: • Low socioeconomic status characterized by increased psychosocial stress and limited educational and economic opportunities may be causative factors in enhanced CAD • Air pollution, estimated to have caused 9 million deaths in 2019 worldwide, 62% due to CVD (CAD= 31.7% and stroke = 27.7%). Transient exposure to a variety of pollutants may trigger the onset of an acute coronary syndrome
Lifestyle Factors
• Long working hours by those who have had a first heart attack raises the risk for a recurrent event (likely due work stressors). • Skipping breakfast has been linked to increased cardiovascular and all-cause mortality. • Prolonged intake of sugary and artificially sweet-ened drinks containing sugar is also associated with increased CV mortality.
Maternal and Childhood Factors
• These maternal and childhood factors raise the risk of developing CAD: gestational diabetes, pre-eclampsia, delivering a child of low birth weight, preterm delivery, and premature or surgical menopause. How each condition is linked to higher CAD risk isn’t known, but may be due to increased cytokine and oxidative stress. • A yet unexplained association has been observed between migraine headaches with aura in women and incident CVD • Transgender patients receiving gender-affirming care are at increased CV risk, perhaps related to high rates of depression and anxiety • Early life trauma and the risk of adverse CV outcomes in the young and middle-aged with a history of heart attack is also of interest
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In the news: Lower Risk of DR with Higher omega-3; Metformin Lowers B12 Levels
Higher Blood Omega-3 Linked to Lower DR
Inflammation is associated with the development and progression of diabetic retinopathy (DR). Previous studies have shown that omega-3 polyunsaturated fatty acids (omega-3s) have anti-inflammatory properties and modulate capillary integrity and neovascularization.
Few studies, however, have examined the association of individual circulating levels of omega-3 with diabetic retinopathy.
In the current study, a research team determined the associations between the omega-3s EPA and DHA and the prevalence and severity of DR in a combined cohort of diabetic participants from the Multi-Ethnic Study of Atherosclerosis (MESA) and Genetics of Latino Diabetic Retinopathy (GOLDR).
The investigators found that individuals with blood levels of DHA in the top 25% (4th quartile) of DHA were 17% less likely to have retinopathy compared to the lowest 25% or first quartile (p=0.009).
Secondary analysis revealed 38% lower severity of retinopathy in individuals in the fourth compared to the first quartile of EPA + DHA combined and DHA alone (p=0.004 and p=0.006, respectively). No significant associations were observed between EPA alone and retinopathy.
Overall, the current findings are in line with those of the PEDIMED trial – the largest dietary intervention trial to assess the effects of the Mediterranean diet on cardiovascular disease. In PEDIMED, those who consumed at least 500 mg/day showed a 46% decreased risk in sight-threatening DR versus those consuming less.
Collectively, the results of the present study suggest that circulating levels of omega-3, particularly DHA, may be protective against developing or worsening DR. Further studies are warranted to see whether consuming more omega-3 is a viable DR prevention option in those with type 2 diabetes.
Metformin & Vitamin B12: New Insights
Decreased vitamin B12 levels is now considered to be a relatively common side effect in people taking metformin, especially for those receiving a higher dose or treated longer, or those with existing risk factors for B12 deficiency such as family history, Crohn’s, infections, vegan diets, and older age.
There are several ways that metformin could affect B12 status. The most common theory is that the drug reduces B12 absorption due to interference with the calcium-dependent binding of the intrinsic factor- vitamin B12 complex. It has also been suggested that gut microbes play a role. A newly published study exploring this theory found that metformin helps certain gut bacteria accumulate their own B12 (making less B12 available to the host) by increasing transporter genes.
A recent systematic review asked whether B12 supplementation could be effective in raising serum B12 levels, reducing homocysteine levels, and in reducing neuropathy in diabetics taking metformin.
The results support vitamin B12 supplementation for metformin-receiving type 2 patients. Out of 7 included studies in the review, the 5 that measured B12 found a significant increase in serum vitamin B12 level after supplementation and 2 of them showed a decrease in serum homocysteine levels. The effects on neuropathy symptoms were less clear, with 2 studies reporting improvements and 1 finding no significant effect.
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In the news:Vitamin D May Benefit Prediabetics; Obesity Impairs Vitamin D Metabolsm
Vitamin D Cuts Diabetes Risk in Prediabetes
A new systemic review and meta-analysis from researchers at Tufts Medical Center and published in the journal Annals of Internal Medicine has found that a higher vitamin D intake by individuals with prediabetes is associated with a 15% reduced risk of developing type 2 diabetes. People with prediabetes – estimated to be 1 of 3 Americans – have blood glucose levels higher than normal, but not high enough to be diagnosed with type 2.
Vitamin D also increased the likelihood of reverting back to normal glucose regulation by 30% - a finding with ophthalmic implications since an excess prevalence of retinopathy has been reported in prediabetes.
Three randomized trials were included that were specifically designed to test the effects of vitamin D vs. placebo on new-onset diabetes. The trials tested different vitamin D doses: 20,000 IU (500 mcg) cholecalciferol weekly; 4,000 IU (100 mcg) cholecalciferol daily; or 0.75 mcg eldecalcitol daily.
Vitamin D reduced the risk for diabetes by 15%, with a 3-year absolute risk reduction of 3.3%. The effect of vitamin D did not differ in prespecified subgroups.
For participants assigned to the vitamin D group who maintained a mean serum vitamin D level during the trial of at least 125 nmol/L compared with 50 to 74 nmol/L during follow-up, cholecalciferol reduced risk for diabetes by 76% with a 3-year absolute reduction of 18%.
In the analysis, no difference was seen in adverse events (including kidney stones, high blood or urine calcium levels) between those taking vitamin D and placebo takers. However, an accompanying editorial urges caution about high dose vitamin D in the general population.
According to the authors, the optimal level of vitamin D in the blood needed to reduce diabetes risk could be higher than the Institute of Medicine (IOM) committee recommendation of 400-800 IU daily.
The authors write that vitamin D blood levels needed to optimally reduce diabetes risk may be closer to the range corresponding to the tolerable upper intake level (UL) of 4,000 IU/d set for vitamin D. The benefit to risk ratio for vitamin D would depend on the target population and medical condition.
The investigators mention other strategies to combat prediabetes: Intensive lifestyle modification which has resulted in a 58% lower risk, and taking the drug metformin that has been shown to lower risk by 31%.
Obesity Impairs Response to Vitamin D
The large-scale VITAL Trial overall showed no benefits to those randomized to receive 2,000 IU vitamin D vs. placebo in terms of primary endpoints of cancer or major cardiovascular disease outcomes. However, prespecified secondary analyses showed that normal weight individuals (BMI < 25 Kg/m2) did indeed benefit significantly from supplementation, with 24% lower cancer incidence, 42% lower cancer mortality, and 22% lower autoimmune disease incidence.
To clarify whether weight was really driving these disparate results, researchers analyzed baseline and follow-up vitamin D related serum biomarkers.
They found that serum vitamin D and other biomarkers were incrementally lower with higher BMI at baseline, and at 2 years of follow-up serum vitamin D levels were also significantly lower at high BMI categories (P < 0,001 for all treatment effect interactions).
The leading theory for why obesity would blunt the response to supplementation is that more adipose (fat) tissue and fat storage capacity results in greater removal of fat-soluble vitamin D from the circulation. More research is needed to determine what doses might be necessary to overcome this phenomenon.
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In the news: MIND Diet Lowers Glaucoma Risk; Riboflavin Deficit in Keratoconus
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MIND Diet Linked to Lower Glaucoma Risk
Not long ago, the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet was developed as a strategy to promote healthy cognitive aging and neuroprotection. It’s a combination of the “Med” diet and the DASH diet (Dietary Approaches to Stop Hypertension). The MIND diet has recently been associated with a reduced incidence of Alzheimer’s and slower cognitive decline in several large-scale studies.
The MIND diet incorporates many individual dietary components that have been linked to a lower IOP level (green leafy vegetables) and to lower glaucoma incidence: produce with antioxidants and flavonoids which are anti-inflammatory and neuroprotective. One third to one half of eyes with glaucoma have no elevated IOP, suggesting that neurodegeneration is an important contributor to the disease.
The authors of a new study also point out that the eye and brain have a shared embryonic origin, and that glaucoma and Alzheimer’s share multiple common biochemical and pathological changes. Taken together, these factors led the authors to assess the association between adherence to the MIND diet, the Med diet, the Dutch dietary guidelines and incidence of open angle glaucoma (iOAG).
The study evaluated participants in the Rotterdam Study, who were followed since 1991 at 5-year intervals for iOAG. One hundred seventy participants developed glaucoma during follow-up.
Greater adherence to the MIND diet was associated with a 20% lower risk of iOAG for each 10% increase in adherence. A higher intake of green leafy vegetables, berries and fish tended to be protective for iOAG. No significant associations were seen with the Med diet or the Dutch guidelines and iOAG.
Since none of the three examined diets were linked to IOP, this diet may be particularly relevant for protection against neurodegeneration in the eye.
Low Riboflavin a Keratoconus Risk Factor?
Keratoconus (KC) is a degenerative disorder of the eye in which structural changes within the cornea cause it to thin and change to a more conical shape than its normal gradual-curved shape.
Studies are ongoing to learn more about how certain metabolic, genetic, and environmental factors might affect the development of KC. One research team recently compared blood levels of vitamin D, vitamin B12, riboflavin, homocysteine, folic acid and arginine in KC patients with progressive and non-progressive disease with normal controls.
Noting that every substance could directly or indirectly play a role in KC development, they found that only vitamin D levels were significantly lower in both KC groups vs. controls. Decreased vitamin D levels significantly increased nonprogressive KC probability 1.23 times and progressive KC probability 1.29 times more than the control group (P = 0.002, P= 0.001, respectively).
In a newly published prospective study, a second research team compared blood levels of B12, folic acid riboflavin and homocysteine in 100 KC patients vs. 200 healthy controls. They found that the mean riboflavin level in the KC group (84 +-21/8 g/L) was significantly lower than in the healthy group (183.6 +-&4.3 g/L), P <0.001.
Low levels of riboflavin, an essential part of two coenzymes that play major roles in energy production, cellular function, growth and development, may be a possible risk factor in the pathogenesis of KC according to the authors. Longitudinal studies are needed and warranted to further explore whether low levels of vitamin D and/or riboflavin contribute to the progression of KC.
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In the news: Flavonols May Slow Memory Decline; Caffeine Unlikely a Risk for DED
The last edition of EduFacts for 2022 covers recent findings on flavonoids and cognition, caffeine and dry eye. Best wishes for a happy, healthful holiday season from all of us at ScienceBased Health!
Dietary Flavonols May Slow Memory Decline
Higher intake of total flavonols and certain types of flavonols may slow the rate of cognitive decline according to a study published in Neurology.
Flavonols, which have anti-inflammatory and antioxidant properties, are one type of flavonoid found in various fruits, vegetables, tea, and wine. This study focuses on flavonols as a group and on the major individual flavonols: kaempferol, quercetin, myricetin and isorhamnetin.
The study included 961 participants (60-100 years) with no signs of dementia who were followed for an average of 7 years. Diet was assessed yearly using a validated semi-quantitative food frequency questionnaire. Cognitive performance was also assessed annually with a battery of 19 standardized tests such as recalling lists of words, and remembering numbers and putting them in correct order.
An overall global cognition score summarizing the 19 tests was used to determine rates of cognitive decline. The average score ranged from 0.5 for those with no cognitive impairment to 0.2 for mild impairment to -0.5 for those with Alzheimer’s.
After adjusting for an array of confounding factors including APOE-ɛ4, the global cognitive score for those consuming the most total flavonols (about 15 mg a day) declined 0.4 units per decade more slowly than those who consumed the least flavonols (about 5 mg daily). The highest intake was associated with less decline in multiple cognitive domains: episodic memory, semantic memory, perceptual speed, and working memory.
For individual flavonols, the highest vs. lowest intake of kaempferol resulted in a 0.4 units per decades lower rate of cognitive decline. For quercetin the rate was 0.2 units slower. A 0.3 units per decade slower rate of decline was observed for myricetin, while isorhamnetin was not associated with global cognition.
While these findings do not prove that flavonols directly cause slowing of cognitive decline, they are consistent with previous research reporting a link between cognition and flavonoids. Additionally, flavonols are known to be cytoprotective, including neurons. Thus, an impact of these bioactive plant compounds on cognition is plausible.
Caffeine Not Likely a Risk Factor for DED
Should curtailing caffeine be included as one of the modifiable risk factors for DED? While the literature has been unclear about the effects of caffeine on the ocular surface, caffeine stimulates the CNS by antagonizing adenosine receptors – receptors that are present in the eye and could possibly affect lacrimal gland secretion.
The results of the first large cohort study to examine the relationship between caffeine intake and DED suggest that caffeine is not a DED risk factor in the general public.
DED was assessed in 85,302 participants (59% females) using the Women’s Health Study defined criteria. Dietary caffeine was calculated from the intake of coffee, tea, cola, and energy drinks.
The mean caffeine intake was 285 mg/day. After adjusting for demographics, BMI, smoking status, and alcohol intake, higher caffeine intake was associated with a 3% decreased risk of a clinical diagnosis of DED per 100 mg caffeine daily (p < 0.0005).
When also adjusting for 48 comorbidities of DED, no significant effect of caffeine was observed.
None of the beverages were significantly linked with the risk of DED, when correcting for intake of other caffeinated beverages, demographics, smoking status, alcohol intake, and all comorbidities.
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In the news: Overview: Nutritional Optic Neuropathies; State of Omega-3s & Corneal Nerve Health
Nutritional Deficits & Optic Neuropathies
Nutritional deficiency is an under-recognized cause of optic neuropathy. Deficits of certain nutrients have long been thought to be common only in developing countries. However, they are showing up more often in the US with the advent of bariatric surgery, restrictive/selective diets, and the upswing in alcohol dependence. According to a national survey, for example, excessive and binge drinking increased by 21% during the COVID-19 pandemic.
Although nutritional optic neuropathy can cause severe and debilitating vision loss, it is often reversible when it is diagnosed and treated in a timely manner.
A new review on the topic from the Warren Alpert Medical School of Brown University, Department of Neurology, aims to raise awareness of how to identify, diagnose, and manage causes of nutritional optic neuropathies.
The authors provide an extensive overview of how patients with these optic neuropathies present, such as painless bilateral vision loss with distinctive visual field scotomas (blind spot or partial loss of vision in a normal visual field), and anatomic changes in the fundus.
The most common nutritional deficiencies associated with optic neuropathy are highlighted, including vitamin B12, B1 (thiamine) and folic acid. The authors also provide recommendations for the steps in diagnosing and managing these deficiencies, as well as identifying individuals who would benefit from early screening.
The authors point out that loss of visual acuity, color desaturation, and a relative afferent pupillary defect (RAPD) is common for all forms of optic neuropathies. Successful treatment algorithms have evolved from better imaging modalities such as OCT, refined MRI protocols for accurate diagnosis, and the availability of specific biomarkers.
This informative review can be downloaded in full -text PDF from ResearchGate: https://www.researchgate.net/publication/270963605_Approach_to_diagnosis_and_management_of_optic_neuropathy
Omega-3s & Corneal Nerve Health
Another review article worth reading focuses on the topic of omega-3 polyunsaturated fatty acids (PUFAs) and corneal nerve health.
The authors, a team from the University of Melbourne and the New Zealand National Eye Centre, University of Auckland, review the current evidence for the role of omega-3s in maintaining ocular surface health and summarize the potential applications of these PUFAs in managing ocular and systemic conditions that cause corneal nerve damage.
The cornea is the most densely innervated tissue in the body and plays a critical role in maintaining ocular surface integrity. Corneal nerve damage, from local or systemic conditions, can lead to ocular discomfort, pain, impaired wound healing, and if poorly managed, neurotrophic keratopathy – the degenerative disease of the corneal epithelium resulting from impaired corneal innervation.
The authors highlight the neuroprotective properties of these fatty acids. They also discuss their ability to reduce corneal epithelial nerves loss and to promote corneal nerve regeneration in diabetes, as well as their potential role in promoting corneal nerve recovery following corneal surgery.
The abstract and excerpts from the review are available at: https://www.sciencedirect.com/science/article/abs/pii/S1542012422000921?via%3Dihub
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In the news: Plant-Based Diet for Eye Health? Clinical Trials to Watch
Pescatarian Diet May Lower AMD, Cataract Risk
An increased risk of age-related eye diseases has been observed in those eating unbalanced diets, while a plant-based diet has been linked to lower risk. But is there a simple answer for patients who ask what kind of diet might best help them retain ocular health as they age?
Results of a systematic review and meta-analysis by Canadian university researchers sheds some light on how that question might be approached. The investigators sought to characterize the relationship between plant-based diets and age-related ocular outcomes among adults. To do so, they chose studies that focused on observed visual changes due to a reduced intake of animal products.
Twenty-one studies met the screening criteria: 15 studies (n= 51,695) assessed the impact of fish consumption, 8 studies (n=28,753) analyzed the effect of red meat intake, and 3 studies (n=7,723) assessed omitting skim milk, poultry, and non-meat animal products, on age-related macular degeneration (AMD) or cataract development.
Meta-analysis indicated that regular fish intake reduced the risk of the risk of age-related eye disease development by 30% (OR 0.70), as did the consumption of skim milk, poultry, and non-meat animal products (OR 0.70). In contrast, consumption of red meat increased that risk by 41% (OR 1.41).
The authors conclude that a pescatarian diet is associated with the most favorable visual outcomes, while consuming red meat negatively affects ocular health. The Mediterranean diet is very similar to a pescatarian diet, in that it emphasizes eating seafood, fish, eggs and dairy, vegetables, fruits, whole grains, healthy fats and nuts. It differs in that it allows for minimal red meat and poultry intake. A reasonable patient recommendation might be to follow the Mediterranean diet (also found to lower the risk of AMD), but to eat red meat infrequently.
New Trials Examine Issues of Interest
Vitamin D Deficient / marginal vitamin D blood levels have been linked to the risk of chronic health conditions, although the VITAL trial (the largest randomized clinical trial in the world) did not show reductions in major health outcomes except for autoimmune disease and advanced cancer.
Vitamin D has anti-inflammatory effects as evidenced by the reduction in autoimmune diseases seen in VITAL and recent insights from Purdue University and the NIH into how vitamin D functions to reduce inflammation caused by immune cells. Thus, the question has been raised whether vitamin D could be beneficial in reducing the severity of COVID illness, the need for hospitalization, and long COVID.
A new intervention trial (Vitamin D for COVID or VIVID trial), led by Dr. JoAnn Manson of Harvard is designed to address those questions. Now underway, the study is testing a dose of > 3,000 IU vitamin D/day in over 2,000 participants. The results should be available by the end of this year or early next year.
Genetic Testing and Lifestyle Behaviors for AMD Risk Although the American Academy of Ophthalmology currently does not recommend routine genetic testing for complex diseases such as AMD, some prevention-minded researchers have asked whether testing might have a role in helping prevent the disease. Would informing people of their genetic risk be incentive to improve their behaviors related to eye health?
Led by Dr. Paul Bernstein of the University of Utah, a new study (The Moran AMD Genetic Testing Assess-ment Study or MAGENTA) will assess the impact of genetic testing for AMD on lifestyle behaviors as measured by systemic and ocular carotenoid status. Of the anticipated 80 healthy participants, one group will have genetic testing results disclosed immediately, while the other group won’t receive results until the end of the one year study. The study is estimated to be completed by the end of August, 2024.
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In the news:Omega-3 & Blood Pressure Vitamin A & Dark Adaptation in AMD
A Clearer Picture of Optimal ω3 Intake for Blood Pressure Reduction
Current evidence generally supports the use of omega-3 (ω3) fatty acids EPA and DHA in lowering blood pressure, but the shape of the dose response relationship has been unclear – linear or non-linear?
Previous meta-analyses examining the association between ω3 intake and blood pressure have been unable to reveal a significant dose-response relationship or have shown conflicting trends.
Using a recently developed model for dose- response meta-analyses, researchers included 71 trials, involving 4973 individuals to look for the optimal fish oil dose lowering blood pressure. The studies included examined the effects of DHA, EPA or both from whole foods and supplements at doses of 1-5 grams daily.
A J-shaped curve was found, with the optimal combined intake of ω3 fatty acids for blood pressure lowering between 2 and 3 grams per day for the general population. At 2-3 grams daily of ω3 fatty acids, the mean decrease was -2.61 mmHg for systolic blood pressure and -1.64 to -1.80 mmHg for diastolic. For those with hypertension, 3 grams daily was associated with a mean decrease in systolic pressure of 4.5 mmHg.
Looking at pre-specified subgroups, the researchers found a stronger and nearly linear dose-response of ω3 fatty acids among hypertensive, hyperlipidemic and older individuals. The authors concluded that ω3 fatty acid intake above the recommended 3 grams daily may be associated with additional benefits in blood pressure-lowering among groups at high risk for cardiovascular diseases.
Pilot Study: Functional Impact of Low Dose Vitamin A in AMD
Dark adaptation refers to the capability to see in low light or darkness after exposure to bright light. How the eyes adapt to darkness can be a key indicator of retinal health, and dark adaptation can be altered in certain ocular diseases such as age-related macular degeneration (AMD). Dark adaptation occurs over a large range of luminance and involves both cone and rod photoreceptors. One reliable measure of rod response and dark adaption response is the rod-intercept time (RIT) – the time required for rod sensitivity to recover by 3 log units after exposure to bright light (called bleaching).
Using RIT and other measures, researchers from the National Eye Institute examined the functional impact of oral vitamin A on dark adaptation in a small number of participants with AMD separated into those without and with reticular pseudodrusen (associated with more severe disease). Both the AMD and RPD groups received 15,000 IU vitamin A palmitate supplements daily for 8 weeks and were followed another 4 weeks after stopping supplementation.
RIT improved significantly in the AMD group (-1.1 min after 4 weeks and -2.2 min after 8 weeks), both p<0.001. The improvement to RIT declined after vitamin A supplementation ceased, but a residual treatment effect could be measured.
In contrast, no significant improvement with vitamin A was seen in the RPD group.
According to the researchers, the result supports a mechanism where a diseased Bruch’s membrane serves as a barrier between the systemic circulation and the photoreceptors. Increasing systemic vitamin A availability through supplementation is thought to partially overcome that barrier in less severely affected eyes and improve dark adaptation. The authors stress that this is a pilot study, and more research is required to determine long-term effects of vitamin A.
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In the news: 20-20-20 Rule Aids Computer Users Omega-3 for Dry AMD & Stargardt?
Testing 20-20-20 Rule in Digital Eye Strain
Prolonged computer use can cause vision problems, particularly for young people who often have ‘nonstop’ screen time. The estimated prevalence of computer-related vision problems among young adults is 74-77%.
Grouped under the term digital eye strain (DES), symptoms can include those associated with dry eye, and those linked to accommodative and/or binocular vision such as eye strain, headache, back and neck pain, double vision and trouble refocusing.
To minimize DES symptoms, frequent screen users are often advised to blink regularly and follow the visual ergonomic 20-20-20 rule: every 20 minutes look at something 20 feet away for 20 seconds. The 20-20-20 rule is widely recommended although only one study has looked at this approach, reporting benefit but providing no evidence of compliance.
To further evaluate the effect of the 20-20-20 rule, researchers developed software using a laptop webcam to assess user breaks, eye gaze and blinking, and prompting users with reminders to rest every 20 minutes. The software was downloaded onto the laptops of 29 young, symptomatic computer users. DES, binocular vision, and dry eye were assessed before and after 2 weeks of using the program and 1 week after the intervention’s end.
Following the rule reminders increased the number of breaks taken daily (p < 0.015), with participants taking fewer longer breaks and averaging shorter periods of continuous computer use. Binocular accommodative facility improved (p = 0.010), as did dry eye symptoms and DES (p < 0.045), despite there being no change in the blink rate of participants. The improvement in DES and dry eye symptoms was not fully maintained 1 week after stopping the rule reminders.
The authors concluded that the 20-20-20 rule is an effective strategy for reducing DES and dry eye symptoms, although 2 weeks was not enough to considerably improve binocular vision (other than accommodative facility) or dry eye signs.
Role for Omega-3 in Dry AMD & Stargardt?
Preliminary data presented at the ARVO annual meeting, suggest a potential role for omega-3 fatty acids in dry age-related macular degeneration (AMD) and Stargardt disease (SD).
Researchers randomly assigned 21 participants with dry AMD or SD and best-corrected visual acuity (BCVA) between 21-55 ETDRS letters to receive either 3.7 grams omega-3 fatty acids (3,000 mg EPA; 660 mg DHA) or placebo daily for 24 weeks.
The primary endpoint of the study was the number of letters gained in BCVA from baseline at 12 and 24 weeks and change in the ratio of the omega-6 fatty acid arachidonic acid (AA) to the omega-3 EPA. Participants also completed a questionnaire on perceived vision at 12 and 24 weeks.
In the omega-3 group, mean BCVA increased from 40.93 letters at screening to 46.93 letters at week 24 (p = 0.003) while no significant increase was seen in the placebo group. There was a significant difference between the two groups for letters gained at 12 and 24 weeks. (p = 0.002). The ratio of AA/EPA decreased significantly only in the omega-3 group.
Although the mean questionnaire score was similar between the two groups at week 12, the score was higher in the omega-3 group than placebo takers at the end of 24 weeks (9.38 vs 7.28 respectively).
Omega-3 fatty acids can improve objective and subjective vision in dry AMD and SD patients, the authors concluded. Longer and larger studies are needed to confirm these results, though it’s promising to note that they are consistent with previous work in animals by the same researchers.
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In the news: Antioxidants, Vitamin C Linked to Lower Risk of Diabetic Retinopathy
Antioxidant Vitamins Linked to DR Risk
The development of diabetic retinopathy (DR) is predominantly a metabolically driven process, and vitamins and minerals play an important role in maintaining metabolic homeostasis. However, there is little information guiding clinical practice in the role these micronutrients may play in DR.
A team of Australian and Chinese researchers set out to investigate the associations between circulating vitamins A, C, D, E, and carotenoids and the risk of DR by conducting a cross-sectional study in participants of the U.S. National Health and Nutrition Examination Survey (NHANES) and a meta-analysis of relevant studies published from 1990 through 2020 .
In brief, the NHANES study found that a higher serum vitamin C level was associated with a 40% lower risk of DR in the diabetic population. No significant associations were observed between DR and serum levels of vitamins A, D, E or carotenoids.
The meta-analysis confirmed the significantly lower circulating vitamin C levels in DR participants compared with controls. Lower serum levels of vitamins D and E, however, were also significantly associated with a higher DR risk in the meta-analysis.
The NHANES study included 517 diabetics aged 40 years and older. The presence of DR was determined based on non-mydriatic fundus photographs. The meta-analysis included 35 studies, comparing 1,056 participants with DR to 920 controls, diabetics without DR.
Of the 517 included participants in the NHANES analysis, DR was identified in 159 (25.17%). After adjusting for multiple confounders, only serum vitamin C was associated with a lower risk of DR (odds ratio [OR]: 0.60).
In the meta-analysis, the pooled weighted mean difference (WMD) of circulating vitamin C was 11.01. For vitamins D and E, the pooled WMD was 3.06 and -3.03 respectively. No associations were identified between DR and vitamin A or carotenoids, including alpha carotene, beta carotene and lutein/zeaxanthin.
Perhaps the most prominent finding in this study is the inverse association seen between circulating antioxidant vitamin C and DR. That association has been consistently reported in previous studies, and oxidative stress has been implicated as a key underlying mechanism for DR.
A recently published meta-analysis found that across most studies, vitamin C levels are at least 30% lower among people with type 2 diabetes.
That meta-analysis of randomized, controlled trials investigated the efficacy of oral vitamin C supplementation in improving glycemic control, cardiovascular risk factors, and oxidative stress in people with type 2 diabetes. In the 28 included studies, participants took 200-3,000 mg of vitamin C per day for 14 days to 1 year.
The main findings were that vitamin C resulted in statistically significant, clinically meaningful decreases in blood pressure and HbA1c. Based on the GRADE system there was less certainty with HbA1c effect, though the effect size increased in longer and larger studies. HbA1c was lowered by 0.54% (as reference, Metformin lowers HbA1c by a little more than 1%). The results of this systematic review and meta-analysis suggest that vitamin C may benefit type 2 diabetics in general.
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In the news: Good News from AREDS Reports Nos. 28 & 29!
Benefit of AREDS2 Formula Confirmed for Slowing AMD: AREDS Report No. 28
The results of a new report analyzing 10 years of AREDS2 data shows that the AREDS2 formula “is not only safer, but actually better at slowing AMD progression” according to lead author of the study report Emily Chew MD.
In AREDS2, the beta-carotene formulation was compared to one containing lutein/zeaxanthin. The beta-carotene-containing formula was only given to participants who had never smoked or who had quit smoking.
At the end of the 5-year AREDS2 study period, the research group concluded that lutein/ zeaxanthin did not increase lung cancer risk, and that the new AREDS2 formulation could reduce the risk of AMD progression by about 26%.
The new analysis collected information from 3,883 of the original 4,203 AREDS2 participants on whether they had developed lung cancer and whether their AMD had progressed to late disease (validated with medical records) over the next 5 years of post-AREDS2 follow-up.
Even though all participants had switched to the lutein/zeaxanthin-containing formula at the end of the AREDS2 study, the follow-up continued to show that beta carotene nearly doubled lung cancer risk among former smokers. In contrast, there was no increased risk for lung cancer in those receiving lutein/zeaxanthin.
Importantly, after 10 years, those assigned to receive lutein/zeaxanthin had an additional 20% lower risk for progression to late AMD compared to those assigned to receive beta-carotene.
The follow-up also confirmed that receiving fish oil (omega-3 fatty acid) conferred no additional benefit beyond the AREDS supplement, and that there was no apparent difference between higher (80 mg) vs. lower (25 mg) in terms of developing late AMD However, the NEI continues to recommend an 80mg dose of zinc in the AREDS2 formula. That is because AREDS2 did not include a placebo control, and results from AREDS, a placebo-controlled trial, are still considered the gold standard.
Components of Med Diet May Impact Dry AMD Progression: AREDs Report No. 29
Researchers from the National Eye Institute and the University of Wisconsin School of Medicine and Public Health teamed to investigate how adherence to the Mediterranean diet affected the rate of geographic atrophy (GA) enlargement among a subset of 850 participants (1,155 eyes) in the AREDS2 study population.
Geographic atrophy area was measured from color fundus photographs at annual visits. An alternative Mediterranean Diet index (aMedi) was calculated for each participant by food frequency questionnaire.
Over a mean follow-up of 3.1 years, GA enlargement was significantly slower in those with higher aMedi scores (0.256, 0.290, and 0.298 mm/year, P = 0.008 for aMedi tertiles 3, 2, and 1, respectively).
Of the 9 aMedi components considered separately, significant differences in enlargement rate were seen for four of them. Enlargement was slower in those with higher whole fruit, lower red meat, moderate alcohol, and higher monounsaturated fatty acid: saturated fatty acid intake (P = 0.0004, P = 0.0002, P = 0.006, and P =0.040), respectively). No association was observed with fish intake.
The authors conclude that a Mediterranean-type diet is associated with slower GA enlargement. Diet patterns like this may therefore lead to clinically meaningful delays in vision loss. The good news is that diet can make a difference, even for those with GA.
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In the news: Can Microbiota Influence Ocular Health? Vitamin D + Mg Improves Vitamin D Status
Gut Microbiota and the Ocular Surface
The potential of the microbiota to influence ocular health is gaining more attention as a promising field of research. Recent studies, for example, have found an association of gut bacteria such as Bacteroides and Eysipelotrichi and AMD, with lower AMD risk in those whose microbiota is enriched with those bacteria.
A study published this month provides some insight into the potential role of gut microbiota in maintaining ocular surface homeostasis, with implications for dry eye syndrome.
The Baylor University team, who authored the study, are interested in investigating the potential role of microbially produced molecules in mediating the interaction between the intestinal microbiota and the ocular surface. One such molecule is butyrate, a short‐chain fatty acid produced by certain members of the gut microbiota through fermentation of dietary fiber. Butyrate in the gut can enter the bloodstream and has been shown to modulate inflammatory responses in the gut and elsewhere in the body.
Using a mouse model, the team showed, among other findings, that a short-chain fatty acid transporter (SLC5A8) is expressed in vivo in mice conjunctival and corneal epithelium, which suggests that circulating butyrate may directly interact with cells at the ocular surface.
Significantly, they found that pretreatment with butyrate in mice undergoing desiccating stress reduced ocular surface inflammation – an effect which involves SLC5A8 transporter.
Taken together, the findings indicate that butyrate originating in the gut can suppress inflammatory responses at the ocular surface.
Magnesium + Vitamin D May Be Better Than Vitamin D Alone for Some
Inadequate vitamin D levels have been associated with heightened cardiovascular disease, diabetes,and cancer risks. Studies suggest that vitamin D may play a protective role in ocular health as well.
Poor vitamin D status is often observed in over-weight and obese individuals. Magnesium, a cofactor in vitamin D metabolism, is also frequently found to be low in this population group. This led researchers to investigate the effects of a combined magnesium and vitamin D supplement regimen on raising serum vitamin D levels and cardiometabolic outcomes.
This 12-week, placebo-controlled trial randomized 95 overweight or obese participants into one of three treatments arms: magnesium (360 mg daily) plus vitamin D (1000 IU daily), vitamin D alone (1000 IU), or placebo. Serum vitamin D, serum PTH, inflammatory markers and blood pressure were measured at base-line and at the study’s conclusion.
Those in the combined magnesium and vitamin D group had the greatest increase in serum vitamin D concentrations (6.3 + 8.36 ng/mL, p < 0.05). For participants who were vitamin D insufficient and deficient at baseline, the increase in serum vitamin D was significantly higher in the combo group vs. the vitamin D-alone group.
There was also a decrease in systolic blood pressure (- 7.5 + 8.26 mmHg p < 0.05) for individuals in the combined nutrient group who started the trial with systolic blood pressure of at least 132 mmHg.
The authors conclude that combining vitamin D with magnesium may be more effective in raising serum vitamin D than vitamin D alone in overweight and obese individuals.
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In the news: Higher Plasma DHA & EPA + DHA Tied to Lower Risk of Early AMD
Background: DHA, EPA and Early AMD
Over the last two decades, there has been increasing interest in the role of the long-chain fatty acids DHA and EPA in the development and prevention of age-related macular degeneration (AMD). DHA is a major structural component of retinal photoreceptor membranes as well as retinal vascular tissue, and ocular tissue from deceased donors with a history of AMD has shown a significant reduction in DHA compared to age-matched controls.
Additionally, several case-control, cross-sectional, and large cohort studies have reported an association between dietary DHA and EPA and reduced risk for developing AMD and/or AMD progression.
Despite this large body of evidence, the Age-Related Eye Disease Study 2 (AREDS 2) found no risk reduction (beyond that of the AREDS 1 formula) for progression to advanced AMD with DHA and EPA supplementation. AREDS2, however, included only people with intermediate AMD in both eyes or intermediate AMD in one eye and advanced AMD in the other.
The relationship of the omega-3 fatty acids and early AMD remains unclear.
To shed more light on this relationship, researchers from the University of Minnesota, University of Wisconsin and Wake Forest School of Medicine examined the association between DHA and EPA and AMD in a multi-ethnic population.
Notably, the study represents the first to show a link between omega-3 fatty acids and AMD risk in a racially diverse population.
Design and Methods
This prospective study was conducted among participants of the Multi-ethnic Study of Atherosclerosis (MESA). MESA is a multi-center, cohort study designed to identify risk factors for cardiovascular disease in four ethnic groups: white, African American, Hispanic/Latino, and Chinese descent aged 45 – 84 years, and without cardio-vascular disease.
The study population included all MESA participants with baseline polyunsaturated fatty acid (PUFA) measurements and retinal photography at exam 5 (n = 3,772). Fundus photographs were assessed for AMD using a standard grading protocol. Relative risk regression determined associations between PUFA levels and AMD.
Results
Two hundred fourteen participants were determined to have early AMD, of which 46% were non-white.
The researchers found a significant association between increasing plasma DHA levels and increasing DHA + EPA levels with reduced risk for early AMD. EPA levels alone were not significantly associated with AMD.
Specifically, individuals in the two highest quartiles for DHA levels had a 40 – 50% risk reduction for early AMD, and AMD risk declined with increasing quartiles of DHA. Similarly for DHA+EPA, the highest two quartiles showed a risk reduction ranging from 41 – 53% for early AMD.
Comment
Several aspects of this study lend credence to its findings. First, most prior studies on DHA/EPA and AMD have relied on dietary intake estimates (often underestimated), rather than direct plasma measurements of PUFAs (more accurate). Additionally, the multi-ethnic make-up of the participants makes the findings more applicable to the general population.
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In the news: COSMOS: Promising CVD Effects of Cocoa, Multivitamins Tied to Cognitive Benefits
The COSMOS and COSMOS-Mind Trials
The Cocoa Supplement and Multivitamin Outcomes Study (COSMOS) is a large-scale trial conducted by researchers from Harvard and the Fred Hutchinson Cancer Center and designed to assess the effects of a cocoa flavanol extract and/or a multivitamin on cardiovascular disease (CVD) and cancers.
The study results, published this month, suggest that cocoa flavanols may offer protective cardiovascular effects.
Trial Design & Results from COSMOS
COSMOS is randomized, double-blind, placebo-controlled trial of 21,442 U.S. adults (12,666 women aged ≥ 65 years and 8776 men aged ≥ 60 years) free of major CVD and recently diagnosed cancer. Using a 2 x2 factorial design, participants received either 500 mg/day of cocoa extract flavanols and a daily ‘multi’, the cocoa extract and placebo, the ‘multi’ and placebo, or two placebos. The median follow-up was 3.6 years.
Neither supplement reduced the risk of the primary endpoint, a composite of total cardiovascular (CV) events. However, the cocoa flavanol group had a significant 27% reduction in death from CVD, a secondary endpoint.
Further, when looking at participants who took their treatment pills regularly (per-protocol analyses), the cocoa extract group showed a 15% reduction in total CV events and a 39% reduction for CVD death.
Neither supplement reduced the primary endpoint of total invasive cancer, although it is unlikely that the study period was long enough to detect an impact on cancer risk.
COSMOS-Mind Trial
COSMOS-Mind is an ancillary cognitive study led by Wake Forest School of Medicine investigators in collaboration with Harvard to examine whether cocoa flavanols and/or multivitamins benefit cognitive function in older adults.
COSMOS-Mind preliminary results, presented late last year at the 14th Clinical Trials on Alzheimer’s Disease conference, indicate that a daily multi-vitamin may slow cognitive aging, particularly in those with CVD.
The sub-study included 2262 COSMOS participants aged 65 and older (mean age of 73 at baseline) who were free of dementia. Participants underwent cognitive testing at baseline and annually for 3 yrs. Cognitive scores were similar between groups at the study’s start.
The researchers saw no effect of cocoa extract vs placebo on Global Cognitive Function composite score, the primary outcome. However, the multivitamin was associated with a 60% slowing of cognitive aging, the secondary outcome.
The findings were similar for the multivitamin group with respect to memory composite scores and executive function composite scores, two additional outcomes. Looking at treatment effects for prespecified subgroups, multivitamins had a more pronounced benefit on cognitive aging in those with a history of CVD. Participants with previous CVD taking placebo continued to show cognitive decline.
More Ancillary Studies to Come
The research team is planning additional COSMOS sub-studies such as assessing the effect of these supplements on falls, cognitive decline, and biomarkers of aging. One ancillary study underway, COSMOS-Eye, is examining whether the cocoa extract or multivitamin reduces the risk of cataract and AMD, two leading causes of visual impairment in US men and women.
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In the news: In the news: VITAL Study: Vitamin D Lowers Autoimmune Disease Risk in Middle-Aged & Older
Can Autoimmune Disease Rates be Reduced?
Autoimmune diseases (AD) affect up to 23.5 million Americans according to the National Institutes of Health – and prevalence is rising. Autoimmune conditions are common in older adults and are a leading cause of morbidity as well as mortality among women, in economically developed countries. Effective treatments for AD are lacking, with treatments focused on managing symptoms and controlling immune responses. Thus, finding ways to lower the risk of developing AD is important.
A newly published study conducted by Harvard researchers offers the first direct evidence that daily supplementation with vitamin D or vitamin D and omega-3 fatty acids may lower the rate of AD in middle-aged and older adults.
The VITAL Trial: Background
The current investigation was a pre-planned ancillary study of the large-scale vitamin D and omega-3 trial (VITAL). VITAL is a randomized placebo-controlled trial of 25,871 racially diverse men and women aged 50 and older (average age of 67 years.
VITAL Participants received either 2000 IU vitamin D with 1,000 mg omega-3 fatty acids; vitamin D with a placebo; omega-3 with a placebo; or two placebos daily, for a median 5.2 years. Vitamin D supplement-ation from outside sources was limited to 800 IU per day for participants, who also had to forego the use of supplemental fish oil.
Current Study
Participants self-reported all incident AD during the study period, which were confirmed by extensive medical record review. The primary endpoint was all incident AD (rheumatoid arthritis, psoriasis, polymyalgia rheumatica, autoimmune thyroid disease, inflammatory bowel disease and all others).
The Harvard team chose to study the effects of vitamin D on AD because the vitamin regulates a wide array of genes involved in inflammation and immunity. Vitamin D has also been associated, though inconsistently, with reduced risk of several AD (particularly multiple sclerosis) in observational studies. Marine omega-3s have been shown to reduce systemic inflammation and improve symptoms in some AD.
Results
The research team found that vitamin D – with or without omega-3 fatty acids – reduced AD by 22% compared to placebo (p=0.05). That rate fell to 39% after at least two years of supplementation (p=0.005).
Omega-3 fats, with or without vitamin D, reduced disease rate by 15%, though this was not statistically significant. When participants with probable AD were included in the analysis, the rate was 18%.
In pre-specified secondary analyses, no specific AD was statistically significant (possibly because of the small number of participants with individual disease) although the hazard ratios favored supplementation for almost all diseases. Rheumatoid arthritis incidence was about 40% lower in the supplementation groups than in the placebo group.
Comments
The authors note that “the clinical importance of the trial is high because these are well tolerated, non-toxic supplements”. Additionally, they saw consistent results across autoimmune diseases and increasing effects with time. The researchers are, in fact, extending the study 2 years to see whether further risk reductions accrue.
The authors also point to the need for studies in younger people who experience AD earlier if life. Interestingly, the effects seen in the study were more pronounced in those with a family history of AD and in those with lower vs. higher BMI. It’s also worth noting that this was not a study in those with vitamin D deficiency – only 13% began the study with deficient vitamin D levels (<20 ng/mL).
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In the news: Olive Oil Contributes to Longevity
Can Olive Oil Lower Mortality Risk?
Nutritionists have long touted the benefits of extra virgin olive oil for heart health. Further, current dietary guidelines call for replacing some saturated fats with olive oil and unsaturated vegetable oils for overall health.
Much of the evidence for olive oil’s benefits, how-ever, are based on research like the Spanish PREDIMED study where the Mediterranean diet was supplemented with extra virgin olive oil. Until now, no large prospective study has examined the link between olive oil intake and all-cause and cause-specific mortality in a U.S. population – a population whose olive oil use is far lower than in Mediterranean countries.
A new study strengthens support for these dietary recommendations, and reports novel findings regarding olive oil and Alzheimer’s, respiratory, and other diseases.
Harvard researchers evaluated whether olive oil intake is associated with total and cause-specific mortality in two prospective cohorts of U.S. men and women followed for 28 years.
The study included 60,582 women (Nurses’ Health Study, 1990-2018) and 31,801 men (Health Professionals Follow-up Study, 1990-2018) who were free of cardiovascular disease (CVD) or cancer at baseline. The average age at the study’s start was 56 years. Diet was assessed by a food frequency questionnaire every 4 years.
Compared with those who never or rarely consumed olive oil, those with the highest consumption of olive oil – greater than ½ tablespoon per day (7 g/day) – had a 19% lower risk of all-cause mortality.
Higher olive intake was additionally associated with a lower risk of dying from: • CVD – 19% lower risk • Cancer – 17% lower risk • Neurogenerative disease (including Parkinson’s, Alzheimer’s and multiple sclerosis) – 29% lower risk • Respiratory disease (e.g. chronic obstructive pulmonary disease) – 18%
The researchers estimate that replacing 10 g/day of margarine, butter, mayonnaise, or dairy fat with the same amount of olive oil is associated with an 8%-34% lower risk of death from various causes.
Finally, no decrease in mortality was observed when the researchers substituted olive oil for vegetable oil in analyses, which suggests that vegetable oils might offer similar health benefits. However, the researchers did not distinguish between virgin/extra-virgin olive oil and refined/processed olive oil which may have made a difference. Virgin and extra virgin olive oils contain polyphenols and antioxidant components while refined or processed olive oil contains few phytochemicals.
An accompanying editorial emphasizes that olive oil is not a ‘silver bullet’ but should be part of an overall plant-based diet and a healthy lifestyle – one which includes physical activity.
As for the link between olive oil intake and neuro-degenerative diseases, the editorial notes that “in a sensitivity analysis, the authors found a significant 27% reduction in risk of dementia-related mortality for those in the highest vs lowest category of olive oil consumption. Considering the lack of preventive strategies for Alzheimer’s disease and the high morbidity and mortality related to this disease, this finding, if confirmed, is of great public health importance”.
The editorial also addressed the association of olive oil consumption with risk of respiratory disease mortality. “Because the mechanism behind this association is unclear and residual confounding from smoking cannot be ruled out, this finding is tentative and requires confirmation in a study that is less susceptible to confounding, such as a randomized trial.”
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In the news: Do Coffee + Tea Act Synergistically to Lower Stroke & Dementia Risk?
Coffee & Tea Lowers Stroke & Dementia Risk
While previous studies have reported significant health benefits from moderate intake of coffee and tea separately, few have investigated the effect of drinking both.
Researchers from Tianjin Medical University and Yale School of Public Health have now examined the effects of coffee or tea, or their combined intake on stroke and dementia – two conditions of increasing global health concern, and both of which can impact vision.
The study included 365,682 participants (50 to 74 years old) from the UK Biobank who reported their coffee and tea consumption. Participants were recruited for the study from 2006 to 2010 and were followed until 2020.
During a median follow-up of 11.4 years for new onset disease, 5,079 participants developed dementia, and10,053 participants experienced stroke.
After adjusting for confounders, coffee intake of 2 - 3 cups/day or tea intake of 3 - 5 cups/day or their combined intake of 4 - 6 cups/day were linked to a reduced risk of incident stroke and dementia.
The benefits were greatest for those who drank both coffee and tea. Compared with those who did not drink tea and coffee, drinking 2 to 3 cups of coffee and 2 to 3 cups of tea daily was associated with a 32% lower risk of stroke (P < 0.001) and a 28% lower risk of dementia (P = 0.002).
Drinking both beverages was also tied to a lower risk of ischemic stroke and vascular dementia, Again, their combined consumption provided greater benefit than coffee or tea alone.
Importantly, the combination of tea and coffee was associated with a lower risk of poststroke dementia. Those who have had a stroke have a far greater risk of developing dementia than those who have not.
For participants who experienced a stroke during the follow-up period, drinking 2-3 cups of coffee daily was linked to a 20% lower risk for poststroke dementia (P = .04) while drinking both beverages (3 to 6 cups of coffee and tea daily) lowered the risk of post stroke dementia by 48% (P = .007).
No significant association between coffee and tea consumption and risk for hemorrhagic stroke or Alzheimer’s disease was observed.
“These findings highlight a potential beneficial relationship between coffee and tea consumption and risk of stroke, dementia, and poststroke dementia, though causality cannot be inferred” wrote the authors.
Coffee contains caffeine and is a rich source of antioxidants and other bioactive compounds, while tea provides catechin polyphenols, and flavonoids. Coffee and tea are distinct beverages with overlapping components such as caffeine, but also different biologically active constituents with different target molecules and therefore different biological effects. The findings of this study suggest a possible synergistic effect of these common beverages relevant to stroke and dementia.
In terms of mechanisms, a new study from UC Irvine shows that compounds in green and black tea relax blood vessels by activating ion channel proteins in the vessel wall – a discovery that helps explain the anti-hypertensive properties of tea. This is relevant because individuals with high blood pressure are more likely to have a stroke than those with normal blood pressure.
Caffeine might help counter dementia. One theory is that hypoxia (which leads to cognitive impairment) triggers the release of adenosine, which in turn causes a chain reaction of enzymes leading to inflammation. Caffeine interferes with this by blocking the cells' ability to recognize adenosine, reducing inflammation.
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In the news: Education lags for AREDS2 Supplement Use; Multi-vitamins Tied to Better Cognitive Aging
Many with AMD Do Not Use AREDS Supplements
The AREDS trial – and the subsequent AREDS2 study to evaluate lutein and omega-3 fats – showed that a specific high dose dietary supplement can reduce the progression of intermediate stage age-related macular degeneration (AMD) to the advanced stage of the disease.
However, past surveys of patients in retinal clinics conducted between 2003-2014 revealed that wide-spread adoption of AREDS formula for eligible patients has fallen short. paragraph
Researchers from Wilmer Eye Institute at John Hopkins recently revisited this issue, looking at whether AMD patients use dietary supplements and what type, whether home monitoring for non-neovascular (dry) AMD is used, and the prevalence of genetic testing.
Assessment of the completed self-administered questionnaires showed that over 90% of patients were taking vitamins and a little more than 60% reported taking AREDS or AREDS2 vitamins.
Unfortunately, nearly 38% of the AMD patients who were eligible candidates for AREDS2 supplements (intermediate or advanced AMD in one or both eyes) did not take them.
Similarly, despite AREDS2 data published in 2014 supporting the benefit of home monitoring for eyes with intermediate AMD at risk of conversion to neovascular AMD, only 61% did some type of home monitoring. Just 1.1% reported undergoing genetic testing for AMD – testing which remains controversial.
According to the authors, the significant gap in usage provides further support for improving education about AREDS2 supplements and home monitoring.
RCT Ties ‘Multi’ Use with Slower Brain Aging
Researchers from Wake Forest University presented findings from a large-scale study at the 14th Clinical Trials on Alzheimer’s Disease conference this month. The investigators reported that daily multivitamin-mineral supplementation for 3 years was associated with a 60% (1.8 years) slowing of cognitive aging.
The placebo-controlled trial (COSMOS-Mind) is an ancillary study of the COcoa Supplement and Multivitamin Outcomes Study or COSMOS – a randomized, controlled trial of a cocoa extract sup-plement and a multivitamin supplement to reduce the risk of cardiovascular disease and cancer in 21,000 older participants.
COSMOS-mind included 2,262 men and women with a mean age of 73 who were dementia-free at baseline and who underwent baseline cognitive testing and annually for 3 years. The study examined whether the cocoa extract supplement or the multivitamin sup-plement improves cognitive function and reduces risk of cognitive impairment vs. placebo.
Baseline cognitive scores were similar between study groups. While there was no effect of cocoa on global cognitive function, there was a significant difference between the multi-supplement and placebo groups for global cognitive function composite, memory composite and executive function composite scores.
The study outcomes included the impact of multivitamins and cocoa extract on prespecified subgroups, including those with a history of CVD. The effect of the multivitamins was particularly pronounced in CVD patients.
Those with CVD had lower cognitive scores at baseline. However, after an initial bump due to the ‘practice effect’ at year one, the CVD group continued to benefit from multivitamins while those assigned to placebo continued to decline over time, according to the lead researcher. Still to come are results on the effects of multivitamins on Alzheimer’s disease prevalence and progression.
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In the news: Low HDL3 Cholesterol Associated with a Higher Risk of Glaucoma
What is High Density Lipoprotein 3 (HDL3)?
A new study ePublished in the journal Ophthalmology reports that lower levels of HDL3 cholesterol is associated with a higher risk of primary open angle glaucoma (POAG).
As background, LDL and HDL particles carry cholesterol in the blood. LDL particles are the major carriers, but they can be ingested by macrophages and then be trapped in blood wall vessels and contribute to atherosclerosis. In contrast, HDL particles transport cholesterol back to the liver for excretion through reverse cholesterol transport. HDLs remove cholesterol from macrophage foam cells, smooth muscle cells and endothelial cells in vessel walls.
HDLs can be separated into two major subfractions: larger, more-buoyant HDL2 particles and smaller, less-buoyant, HDL3 particles. HDL particles, especially small and dense HDL3, have a protective effect on vascular endothelium through anti-oxidative, anti-inflammatory, and anti-thrombotic activities.
Lipoproteins and Age-Related Diseases
Recent findings underscore the importance of lipo-protein structure, composition, and function in age-related diseases. A recent meta-analysis, for example, showed that free cholesterol in small HDL was associated with a lower risk of dementia and Alzheimer’s disease. Further, phospholipids and total lipids within extra-large HDL, and cholesterol in small VLDL (very large dense lipoprotein) particles were associated with age-related macular degeneration.
In terms of glaucoma, several epidemiological studies have reported that plasma lipid concentrations and hyperlipidemia have a significant association with the risk of POAG. However, the effects of plasma lipids or subfractions and the risk of POAG are still unclear. This uncertainty coupled with recent findings led researchers to investigate the relationship between lipoprotein particles, lipid sub-fractions and POAG.
Study Details and Results
The researchers analyzed blood lipids in a cohort of patients from the Singapore Epidemiology of Eye Disease study. A total of 130 blood lipid-related metabolites were quantified using an NMR metabolomics platform. To investigate whether/which lipid-related particles were directly linked with POAG, they used regression analyses followed by Bayesian network modelling. To assess whether any causal relationship existed between any identified lipid-related metabolite and POAG they conducted mendelian randomization and genome-wide association studies.
The results were as follows: • Only HDL3 was directly associated with POAG, with higher blood levels of total HDL3 cholesterol significantly associated with lower odds of POAG independently of age, gender, IOP, BMI, education, systolic blood pressure, axial length, and statin medication. • None of the routine lipids (blood total, HDL, or LDL cholesterol) were associated with POAG, suggesting the specificity of HDL3
Study participants with POAG had lower blood levels of total HDL3 vs those without POAG. The authors theorize that the low HDL3evels may indicate a less efficient transport of cholesterol through the reverse cholesterol transport. The absence of a link between OAG & routine lipids, and the mendelian randomization analysis suggest the causality of this association, although further studies are needed.
Lifestyle Approaches to Raising HDL3?
Should more research confirm this link, the question becomes can HDL3 levels be raised? Physical activity and weight loss, while healthy mainstays, primarily raise HDL2 and not HDL3. It has been reported that higher HDL3 is associated with both moderate alcohol intake and lower carbohydrate intake. In one random-ized trial, HDL-3 decreased in abstainers but not in drinkers, and the resumption of alcohol increased HDL3 without affecting HDL2. Another study found that replacing dietary carbohydrates with fat significantly increased HDL3 concentrations. In general, however, research regarding the impact of diet patterns on glaucoma development or progression is scarce.
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In the news: Flavonoids, Especially Anthocyanins, May Improve Blood Pressure
Dietary Flavonoids Linked to Improved Blood Pressure, Partially via Gut Bacteria
Strong epidemiological evidence ties intake of the anthocyanin flavonoids with a reduced risk for cardiovascular disease and coronary heart disease. However, its effects on blood pressure in human studies has been less consistent.
A newly published study evaluated the relationship between consuming flavonoid-rich foods and blood pressure. and examined the association between the consumption of those foods and gut bacteria diversity.
The results suggest that flavonoids have a positive effect on blood pressure, and that this association is at least partially explained by characteristics of the gut microbiome.
Design and Methods
Researchers from Queen’s University Belfast analyzed data from over 900 men and women from Germany’s PopGen biobank in this population-based study. Participants’ intake of flavonoid-rich food was evaluated over time using food frequency question-naires.
Systolic and diastolic blood pressure (BP) was consistently measured 3 times at 3-minute intervals after an initial 5-minute rest period. Gut microbiome composition was sequenced from 16S ribosomal RNA genes.
Results
The highest intake of flavonoid-rich foods (specifically the polymer subclass) was associated with lower systolic BP (P=0.01). These foods included berries, red wine, pears, and apples. Participants in the highest intake bracket vs. the lowest also had greater gut microbiome diversity.
The data suggest that up to 15.2% of the link between flavonoid-rich foods and systolic BP could be explained by the gut microbiome, which plays a key role in metabolizing flavonoids to bioactive and bioavailable compounds.
Specifically, higher berry intake (1.6 servings daily with a serving = 1 cup, and containing an estimated 112 mg of anthocyanins) was associated with 4.1 mm Hg lower systolic BP. About 12% of this association could be explained by higher alpha and beta diversity and lower relative abundance of Parabacteroides. Alpha diversity is the diversity in a single sample site, while beta diversity is the difference in diversity in different regions of the gut.
For red wine, intake of 2.8 glasses (250 mL) per week was associated with 3.7 mm Hg lower systolic BP of which 15.2% could be explained by a combination of alpha diversity and higher relative abundance of unclassified Ruminococcaceae.
There were no associations with diastolic BP.
Comments
According to the researchers, the magnitude of the association between anthocyanin intake and systolic BP (−4.8 mm Hg) is similar to their previous study in a female cohort.
“A reduction in systolic BP of this scale is likely to have clinical benefits with previous studies showing that 5 mm Hg reduction in systolic BP reduces stroke risk by 13% over 295 652 patient-years”, the authors explain. Anthocyanins have previously been shown to have anti-inflammatory, antioxidant, and lipid-lowering effects.
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In the news: EPA/DHA Intake Linked to Early AMD Risk; Excess Sugar May Impact Mitochondria
Omega-3 Fatty Acids & Risk of AMD
Several established mechanisms may account for the impact of the intake of DHA and EPA on AMD risk. Omega-3 fatty acids have demonstrated beneficial effects on anti-inflammatory and anti-thrombotic processes. Omega-3 PUFAs have shown antioxidant effects on the retinal pigment epithelium and photoreceptors. Additionally, EPA and DHA can generate inflammation-resolving molecules.
It’s also thought that atherosclerosis of the vessels that supply the retina contributes to the risk of AMD in the same way this mechanism underlies coronary heart disease (CHD). According to this theory, dietary fats related to CHD may also be related to AMD. Increased intake of the omega-3 fatty acids EPA and DHA for example have been associated with a reduced risk of CHD and may have a similar association with AMD.
However, population studies on the relationship between dietary fatty acids and the risk of AMD have yielded inconclusive results. To gain further insight into this relationship, researchers recently conducted a dose-response meta-analysis of prospective cohort studies to evaluate the link between specific types of dietary and plasma fatty acid and early and advanced AMD risk.
Higher EPA/DHA Lowers Early AMD Risk
Eleven observational cohort studies with over 167,000 participants were included in the meta-analysis. For highest versus lowest comparison and dose-response analyses, the authors analyzed the relative risk estimates with a 95% confidence interval. During the follow-up periods, which ranged from 3 to 28 years,6,318 cases of AMD were recorded.
Dietary intake of EPA and DHA combined (per 1 gram per day increment) were found be associated with a 33% risk reduction of early AMD.
The dose–response analysis revealed that a 1 g/day increase in dietary DHA and EPA intake was significantly associated with a 50% and 60% decrease in the risk of early AMD, respectively.
Plasma DHA and EPA were significantly associated with reduced risk of advanced AMD. However, no clear associations were found between AMD risk and other types of fatty acids – monounsaturated, saturated, and polyunsaturated fatty acids, including alpha linolenic acid.
The authors conclude that the dose-response meta-analysis provides high quality evidence that a higher dietary intake of DHA and EPA was significantly associated with a decreased risk of early AMD. In terms of advanced AMD, insufficient evidence precluded definitive conclusions concerning dietary fatty acids and plasma fatty acids.
Excess Sugar & Mitochondrial Dysfunction
Mitochondria are intracellular organelles necessary for synthesizing cellular energy (ATP) and cell survival – including cells of the retinal pigment epithelium (RPE). Mitochondrial dysfunction induced by environmental toxicants may be an important risk factor in the etiology of dry AMD. Altered morph-ology and dysfunction of RPE mitochondria has been observed in eyes with AMD, and mitochondrial DNA from these eyes show more oxidative damage.
Using a new mouse model to study metabolic disease, researchers report that excess sugar may cause mitochondrial inefficiency. Too much glucose in cells, which is directly linked to sugar consumption, reduces PUFAs in mitochondrial membranes. The excess sugar is instead made into a less flexible fatty acid which changes the membrane composition and damages mitochondria. The investigators were able to reverse this effect in mice by feeding them a low-sugar ketogenic diet.
As Americans consume on average roughly 2-3 times the recommended amount of sugar daily, this novel pre-clinical finding might eventually lead to better eye health by cutting back on added sugar.
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In the news: Flavonoids Quercetin & Catechins Associated with Better Anti-VEGF Outcomes in Wet AMD
Intake of Certain Flavonoids Linked to Better anti-VEGF Treatment Outcomes Over Time
Flavonoids, a group of vasoactive phytochemicals found in fruits, vegetables, grains, tea, and wine, have been shown to display a range of antioxidant and anti-inflammatory activity in ocular tissues. But aside from a Blue Mountain Eye Study report linking higher total intake of flavonoids and several flavonoid classes with a lower risk of AMD, research on the relationship between these nutrients and AMD has been scarce.
Australian vision researchers from the Universities of Sydney and Perth sought to assess whether dietary intake of phytochemicals from the six major classes of bioflavonoids would be associated with treatment outcomes among patients with neovascular age-related macular degeneration (nAMD) receiving anti-vascular endothelial growth factor (anti-VEGF) therapy.
The recently published study found an association between three flavonoids – quercetin, epigallocatechin (EGC), and epigallocatechin 3-gallate (EGCG) – and better treatment outcomes.
Design & Methods
In this longitudinal study, 547 participants with a recent diagnosis of neovascular AMD (nAMD) were recruited and 494 were followed-up after receiving 12 months of anti-VEGF therapy. Dietary intake of total and specific flavonoids over the 12 months prior to the baseline data was obtained using a validated food frequency questionnaire. Intake of flavonoids was divided into three equal groups (tertiles).
At follow-up, presence of intra-retinal and sub-retinal fluid, retinal pigment epithelium detachment and central macular thickness were assessed by OCT scans. Visual acuity was documented using LogMAR charts.
Results
At follow-up, participants in the first or lowest tertile of quercetin, EG and EGCG intake had significantly worse vision than those in the highest or third tertile of intake. (Multivariable-adjusted LS mean of visual acuity: 14.68 vs. 19.53 [p = 0.04]; 14.06 vs. 18.89 [p = 0.0 4]; 13.86 vs. 18.86 [p = 0.03], respectively).
Those in the first vs. third tertile for the flavan-3-ol class of bioflavonoids, EG, and ECGC intake all had a two-fold higher risk of intra-retinal fluid. (Multi-variable-adjusted p trend of 0.03, 0.01, and 0.02, respectively).
The first vs. the third tertile of tea intake had significantly worse vision (LS mean visual acuity: 13.49 vs. 19.04, p = 0.02), increased risk of intra-retinal fluid (OR 2.13), and greater mean central macular thickness (279.59 μm vs. 256.52 μm, p = 0.04).
Tea is a common source of EGC and EGCG while quercetin is abundant in a variety of fruits and vegetables as well as tea.
Comments
This longitudinal cohort study found an independent association between higher intake of select bioflavonoids and treatment outcomes at 12 months.
There is evidence that quercetin (from the flavanol class of bioflavonoids and catechin (from the flavan-3-ol class) exert anti-angiogenic activity. So, in addition to acting as antioxidants and anti-inflam-matory nutrients they may also act in slowing the growth of abnormal new blood vessels from the choroid under the macula – a hallmark of wet AMD.
Intervention studies are warranted to confirm these associations and, perhaps, identify a promising new adjunct for standard neovascular AMD therapy.
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In the news: 50th Anniversary of Landmark Omega-3 Discoveries
50th Anniversary of Basic Omega-3 Discoveries
It has been fifty years since the Danish medical researchers Hans Olaf Bang and JØm Dyerberg published their first landmark paper on the traditional Inuit people of Greenland in 1971 – findings that led to omega-3’s evolving role in human health.
The prevailing mindset in the 1960’s was that all dietary fat was unhealthful and should be kept to a minimum for weight management and cardiovascular health. During this period Ancel Keys and others were just beginning to highlight the links between diet, serum cholesterol and risk of heart attack.
Against this backdrop, Bang and Dyerberg became fascinated with the Inuit who consumed a very high fat diet (primarily whale and seal blubber and fatty fish) yet had virtually no incidence of acute heart attack. They began to explore this apparent outlier population.
The investigative paths that led these Danes to establish one of the most impactful research areas in last half century is chronicled by noted omega-3 experts in the May issue of Nature Food .
As the authors point out, the level of scientific interest in the omega-3s is put into perspective by noting that of the most researched molecules in medical history, the omega-3s are essentially tied for 5th place with folic acid, after penicillin, aspirin, vitamin D and prednisone.
Bang and Dyerberg’s 1st paper focused on plasma lipids and lipoproteins. Why did they observe high levels of dietary animal fat but rather low levels of plasma cholesterol in the Inuit? They knew that the Inuit diet provided large amounts of polyunsaturated fatty acids (PUFA), and they theorized that total PUFA or perhaps specific fatty acids in the Inuit’s diet were reducing atherosclerotic risk.
Their 2nd paper (1975) focused on comparing plasma fatty acids in Greenland Inuit eating a traditional diet to Inuit living in Denmark and white Danes. They found low levels of linoleic acid (the major omega-6 poly-unsaturated fatty acid) in native Inuit – a finding that contradicted their initial idea that total PUFA was responsible for the observed low blood cholesteroland triglyceride levels in Inuit. However, Bang and Dyerberg’s seminal observation was that native Inuit had high blood levels of the omega-3 fatty acids EPA and DHA while the Inuit who had migrated and white Danes did not.
By the time that their 3rd paper was published in 1978, other investigators had identified potent molecules (e.g., thromboxane, prostacyclin) that regulate platelet aggregation, vessel constriction, and play important roles in coagulation and the vessel blocking clots of thrombosis.
The Danes proposed that EPA could reduce heart disease risk not just by affecting cholesterol levels, but by also by its anti-thrombotic actions when converted to the series 3 anti-aggregatory eicosinoids. The idea that fatty acids could affect cardiovascular pathways beyond cholesterol was eye opening and led to a surge of research into the anti-inflammatory, heart rate lowering, and pro-resolving properties of EPA/DHA.
Omega-3 Research Continues, Intake Lags
These unique nutrients have been found to play important roles in cardiovascular risk, the resolution of inflammation, and early life brain and eye development. The omega-3 may also contribute to other conditions: neurocognitive disorders including Alzheimer’s, depression, and ocular disorders.
Despite widespread public awareness of omega-3, many Americans apparently do not include sufficient amounts in their diet. In an analysis of National Health and Nutrition Examination Survey data, serum levels of long-chain omega-3 were compared with levels associated with consuming the recommended amount of EPA and DHA by the Dietary Guidelines for Americans and the Omega-3 Index (EPA+DHA). Low serum levels of EPA, DHA and sum of omega-3 were observed across all life stages, with particularly low EPA and/or DHA serum levels seen in children aged 2-5, adult males, and Mexican American /Hispanic and non-Hispanic Black individuals.
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In the news: Omega-3s Protect Corneal Nerve in Type 1s, Obesity Ups Risk of Some Eye Diseases, & NEI Follow-up Affirms AREDS2 Results
Omega-3s Neuroprotective in Type 1 Diabetes
Diabetic sensorimotor polyneuropathy (DSP), also called diabetic peripheral neuropathy, is the most common diabetic complication – about 50% of diabetics are affected. Early-stage DSP is associated with loss of small sensory corneal nerve fibers, and monitoring changes in the corneal nerve provides a non-invasive, sensitive, and reliable marker for DSP progression.
Since intensive blood glucose control is the only established method for slowing DSP in type 1 diabetes, more therapies are needed to reduce progressive peripheral nerve damage. Based on results from animal studies and an open label trial in type 1 diabetics, the omega-3 fatty acids may be one promising intervention. This prompted University of Melbourne researchers to conduct a randomized, controlled pilot trial to observe the effects of supplemental omega-3 fatty acids in type 1 diabetics.
They report that 6 months of supplemental omega-3 promotes corneal nerve regeneration.
In the study, type 1 diabetics received either 1800 mg of fish oil or a similar placebo of olive oil. The 1° end-point was change in corneal nerve fiber length (CNFL). After 180 days, the increase in CNFL for the omega-3 group compared to placebo was 2.70 mm/mm2 (p<0.001). No between-group differences in most small or large nerve fiber function was observed.
The findings are “consistent with a corneal neuro-regenerative effect”, according to the authors who call for trials to assess whether these fatty acids confer similar benefits in peripheral nerve structure / function.
Obesity as Risk Factor in Age-Related Eye Disease
The relationship between obesity and age-related ocular diseases including cataract, glaucoma, AMD, and diabetic retinopathy (DR) have remained somewhat elusive. Now a new systematic reviewreports that, overall, evidence supports associations between obesity and age-related eye diseases.
Researchers from London, Singapore and Germany teamed to conduct a systematic review of longitudinal population-based studies that described associations between measures of obesity including body mass index (BMI), waist-circumference (WC), and waist-to-hip ratio (WHR), and age-related eye diseases. WC and WHR are measures of abdominal obesity – a hallmark of insulin resistance. The search yielded 14, 10, 16 and 8 papers meeting eligibility criteria for cataract, glaucoma, AMD, and diabetic retinopathy (DR), respectively.
BMI-defined obesity was positively associated with incident cataract, AMD and DR in Western populations, but in Asian populations associations with incident AMD were not significant and associations for DR were inverse. WC-defined obesity was linked to incident glaucoma in non-Western populations, while WHR-defined obesity was linked to incidence or progression of AMD in Western populations. Studies are needed to answer the question: Does weight loss reduce eye disease risk in the obese?
10-Yr Follow-Up Study Affirms AREDS2 Findings
When the 5-year AREDS2 trial ended, a follow-up study was initiated with telephone calls every 6 months for 5 years to collect further information.
In brief, the AREDS2 trial was designed to test the effect of adding lutein/zeaxanthin (L/Z) and fish oil to the original AREDS formula. The results showed that fish oil offered no benefit beyond the AREDS supplements while L/Z reduced progress to vision-threatening AMD vs. beta carotene, which also doubled the chance of lung cancer.
The current follow-up study results prevented this month at ARVO showed a more favorable response for L/Z than beta carotene and that L/Z was safer, as beta carotene again doubled lung cancer risk. For more details see abstract: https://arvo2021.arvo.org/meetings/virtual/kbJm2RP9iWdhetrp9
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In the news: Low vitamins D & K Up Mortality Risk; High GI Diet Increases CVD & Death
Follow-up: Low Vitamins K & D Ups Mortality Risk
The last issue of EduFacts examined the relationship between vitamins D and K2 : While vitamin D promotes calcium absorption, vitamin K directs calcium to bone and reduces the deposition of calcium in blood vessel walls and soft tissue. The findings of a newly published study from medical researchers in the Netherlands lends weight to the importance of vitamins D and K status on clinical outcomes.
To explore the association of both plasma vitamin D and K concentrations with all-cause and cardio-vascular mortality in middle-aged individuals in the general population, the researchers studied 4,742 participants of the PREVEND Study. Vitamin D was measured by plasma 25-hydroxyvitamin D and vitamin K by uncarboxylated matrix GLA protein at baseline, and patients were categorized into adequate and insufficient levels of both vitamins and compared to reference values.
Combined low vitamin K and D status was present in 20% of participants and was associated with a greater risk (hazard ratio 1.46 ) of all-cause mortality over a 14+-year median follow-up. The combined association of low status for both vitamins was greater than the sum of low vitamin D and K status alone, indicating that poor status of both amplifies the risk of mortality.
For cardiovascular mortality and cardiovascular events, the researchers observed similar trends – hazard ratios of 1.42 and 1.28, respectively – though neither achieved statistical significance.
In related news, preliminary observations have shown a correlation between low vitamin K and more severe COVID-19, as have low levels of vitamin D. A randomized, double-blind, placebo-controlled trial is underway in the Netherlands with the objective of determining whether vitamin K2 status affects degradation of elastic fibers in the lung (Clinical Trials.gov Identifier NCT04770740). Vitamin K-dependent matrix GLA protein protects elastin from both calcification and breakdown.
Since vitamin K is important for regulating lung health and blood clotting, the researchers postulate that supplemental vitamin K2 might help reduce COVID-related thrombosis and lung damage.
High GI Diet Linked to Higher Risk of CVD, Death
Foods with a high glycemic index (GI) such as white bread and rice, and sugary drinks raise blood glucose levels more rapidly than lower GI foods such as whole grains, beans, green vegetables and most fruit. Glycemic load not only measures how quickly a food makes glucose enter the bloodstream but how much glucose per serving it can deliver.
Studies have associated diets with a high glycemic index (GI) and/or a high glycemic load with increased risk of cardiovascular disease (CVD), as well as age-related macular degeneration and cataract. Most data showing a link between the GI and CVD come from high-income Western populations, with little data from other countries with low or middle incomes. To fill this gap, researchers analyzed data from nearly 138,000 participants from 20 culturally and economically diverse countries across 5 continents who were followed for a median 9.5 years. The 1º endpoint was a composite of a major cardiovascular event (nonfatal heart attack, death, stroke, heart failure) or death from any cause. It was found that:
• the highest GI diets vs. the lowest were associated with increased risk of death and CVD in those with and without preexisting CVD (hazard ratios 1.51 and 1.21 respectively), and was most pronounced in the overweight / obese
• the results for glycemic load were similar to those of the GI findings among those with pre-existing CVD, but the association was not significant among those without CVD at baseline
The evidence suggests a simple take home message: eat quality carbohydrates for better heart health.
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In the news: Role of Vitamin K in Vascular Health
Low Awareness of Vitamin D & K Relationship
The importance of vitamin D in maintaining bone mineral density and in modulating the immune system is well known. However, fewer are aware of the role vitamin K2 plays in vitamin D and calcium metabolism.
Case in point, a recent study by dermatologists from the University of Kansas and Baylor College of Medicine found that of 50 patients counseled to take vitamin D supplements due to recommended sun protection, only 4 of the 50 surveyed understood the relationship of vitamins K2 and D – a finding of potential importance since most people consuming a typical Western diet do not obtain sufficient K2.
Vitamin K is the generic name for a family of structurally similar compounds that include phylloquinone (vitamin K1) and a series of menaquinones (vitamin K2), designated MK-4 through MK-13, based on the length of their side chain.
Evidence supports a synergistic effect of vitamin K2 on vitamin D, potentially explaining “the calcium paradox” – i.e., that supplemental calcium promotes bone mineral density and strength, but may also raise the risk for heart disease by accelerating the deposit of calcium in blood vessel walls and soft tissue. In short, vitamin D promotes calcium absorption, while vitamin K directs calcium to bone and reduces artery calcification.
Vitamin K functions as a coenzyme for a vitamin K-dependent enzyme that synthesizes the protein osteocalcin. Osteocalcin produced by bone cells (osteoblasts) helps take calcium from the circulation and bind it to the bone matrix for mineralization.
Vitamin K is also required for the synthesis of the protein matrix GLA which is produced by cells of vascular smooth muscles and helps regulate the accumulation of calcium in blood vessel walls.
Growing Importance of Vitamin K2
Both vitamin K1 and K2 forms are important and can activate osteocalcin and matrix GLA. However, K1 is considered much less efficient as it is transported to the liver first to activate coagulation proteins.
The results from population-based studies lend credence to the relationship of vitamin K2 and cardiovascular (CV) health. For example, a population-based study with 16,000 healthy women followed for 8 years reports that high intake of dietary vitamin K2 is linked to protection against CV events. For every 10 mcg of dietary K2 as MK-7, -8 and -9, CHD risk was reduced by 9%.
In long-term clinical trials, supplemental vitamin K2 as MK-7 has been found to improve both bone health and cardiovascular health as measured by ultrasound and pulse-wave velocity.
Role for vitamin K in Retinal Health?
Studies suggesting that active matrix GLA helps maintain the integrity of kidney and myocardial microcirculation have prompted researchers to ask whether vitamin K has a role to play in preserving the retinal microcirculation as well.
A recent study, for instance, found that a marker for poor vitamin K status (inactive matrix GLA) is a long-term predictor of smaller retinal arteriolar diameters in the general population5. And, interestingly, in an animal model of glaucoma, supplemental vitamin K1 has been reported to protect against damage of retinal ganglion cells6.
When trying to achieve adequate calcium and vitamin D intakes, it’s important not to overlook K. Vitamin K1 is found primarily in green leafy vegetables such as kale, spinach and collards. Fermented foods like natto and cheeses are the best source of vitamin K2, while meat, dairy, and eggs contain low K1 and modest K2 levels. Since both vitamins K1 and K2 can activate coagulation factors, those on warfarin should check with their prescribing physicians before increasing dietary or supplemental vitamin K.
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In the news: Egg Intake Tied to Healthy Vision New Studies on Vitamin D & COVID-19
Egg Consumption, Serum Lutein & MPOD
Observational studies have shown that dietary consumption of lutein and zeaxanthin are inversely associated with age-related macular degeneration (AMD) risk. Eggs are one of the richest sources of lutein and zeaxanthin, with one egg yolk providing approximately 200 mcg of lutein. Due to their fat content, eggs have greater lutein and zeaxanthin bioavailability relative to other carotenoid-rich foods, including vegetable sources such as spinach and kale.
To date, five clinical trials have been conducted to assess the influence of egg-rich diets with varying concentrations of lutein on serum lutein levels, and its effect on macular pigment optical density (MPOD). The results of these trials have been mixed, leading researchers to perform the first meta-analysis or systematic review of these studies. The aim of the study was to determine the effect of egg consumption on MPOD and serum lutein levels in those with AMD and in healthy subjects.
The authors used a random-effects model to obtain pooled weighted mean differences and standard deviations for each outcome. Using the Cochrane Collaboration’s tool to assess the quality of eligible studies, five trials (296 participants) were included.
Egg consumption was found to significantly increase MPOD (weighted mean difference +0.037, P = .027) and serum lutein (weighted mean difference +0.150 µmol , P = 0.009). A subgroup analysis revealed that egg consumption increased MPOD to a greater extent in a healthy population than in AMD patients.
The findings also indicate that daily egg consumption is associated with reduced AMD progression, according to the authors who also caution that further long-term trials are necessary to confirm their findings.
Eggs are a good source of protein (about 6 g/egg), vitamin D and choline. Years ago, the advice was to eat no more than 1-2 whole eggs per week. But that advice has changed, with the American Heart Association currently suggesting one egg per day for those who can eat them and as part of an overall healthy diet. Eggs, which contain about 200 mg cholesterol, have been found to consistently raise HDL cholesterol without increasing total or LDL cholesterol. However, since individual response to dietary cholesterol can vary, those with high blood cholesterol should check with their physician.
Vitamin D & COVID-19: New Findings
Two new studies addressing the influence of vitamin D status on COVID were recently published. The first, a systematic review and meta-analysis, reports that vitamin D insufficiency worsens COVID-19 infections.
The analysis, which included 27 epidemiological studies, found 64% more vitamin D deficiency present among severe cases compared with mild cases. In addition, insufficient blood levels of the vitamin significantly increased odds of hospitalization and mortality. No association between vitamin D deficiency and a higher chance of COVID-19 infection was seen.
In contrast to the lack of a link between vitamin D status and increased chance of infection in the meta-analysis, the results of another newly published study suggests that deficiency of the vitamin is associated with increased COVID risk.
Analyzing data from a University of Florida database, the investigators found that those deficient in vitamin D were 4.6 x more likely to be positive for COVID-19 than those with sufficient levels of the vitamin. The vitamin D-COVID association decreased after adjustment for race, diabetes, obesity and periodontal disease status, but still remained robust (P < 0.001). Importantly, the risk of developing COVID increased by a factor of 5 after adjusting for age, the authors wrote.
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In the news: Omega-3 Status in AMD offspring with ‘Foveal Dip’; Med Diet Linked to Lower Risk of Sjögren’s
Background: The Early Biomarkers of AMD Study
Macular pigment is composed of the dietary carotenoids lutein and zeaxanthin, and the lutein metabolite meso-zeaxanthin. Reduced central macular pigment optical density (MPOD) is a potential bio-marker for age-related macular degeneration (AMD), and poor intake of lutein, zeaxanthin as well as fish (a source of omega-3 fats) are reported AMD risk factors.
In addition, a central dip collectively termed the ‘foveal macular pigment dip” or FMPD is considered a further risk; high foveal MPOD is protective, while individuals with FMPD are at increased risk of AMD.
Children of parent(s) with AMD have a 45% lifetime risk of also developing the disease. Researchers from Scripps Institute and University of California at Irvine recently investigated the prevalence of FMPD among healthy but high-risk AMD offspring, and evaluated the association of FMPD with genetic risk and carotenoid and omega-3 fatty acid status.
Methods and Results
Macula pigment 3D topography was evaluated using specular reflectance in 130 Caucasian men and women, mean age 62.8 years. Buccal genetic cheek swab, circulating serum dietary carotenoids and long-term red blood cell (RBC) omega-3 fatty acid status, as well as common secondary clinical structural and vision function parameters were obtained.
Forty one percent (41%) of those with a parental history of AMD presented with FMPD. These offspring were about 4 years younger than those without FMPD (controls; P = 0.012) and had thinner foveas (P = 0.010). There were no differences in gender, BMI, % body fat, visual acuity or contrast sensitivity between those with and without FMPD.
The % of the omega-3 fatty acid DHA in RBC membranes was reduced in FMPD offspring vs. control offspring (P = 0.04). The Omega-3 Index--a measure of long-term EPA and DHA in blood--was significantly decreased in the FMPD group (P = 0.03).
Conclusions
According to the authors, the % of FMPD in AMD offspring is nearly twice that reported for the general population. Although offspring with FMPD had similar AMD genetic risk, they had significantly reduced % RBC membrane omega-3 fatty acids and thinner foveas compared with those without FMPD. “Our data support the importance of essential fatty acids as an independent AMD risk factor”, the authors stated.
Of clinical interest, all study participants were free of three of the major predisposing factors associated with the foveal dip phenomenon: advanced age, smoking and a clinical diagnosis of AMD.
Med Diet Lowers Risk of Sjögren’s
UK researchers report that higher adherence to the Mediterranean (Med) diet is associated with a lower likelihood of developing primary Sjögren’s syndrome (SS), the autoimmune disease characterized by oral and ocular dryness and fatigue.
Participants were classified into SS and non-SS (dry eye and mouth with no presence of autoimmune disease). A Med diet score (MDS) was calculated based on dietary intake data.
A higher total MDS was associated with 19% lower odds of SS per one unit of MDS, corrected for energy intake, BMI, sex, age, duration of symptoms and smoking status. Fish intake was Med diet component most strongly linked with lower likelihood of SS.
The authors hope these findings will stimulate further research, larger studies, and dietary intervention trials if warranted.
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In the news: Pro-inflammatory Diets May Increase Long-Term CVD Risk
Pro-inflammatory Diets Up CVD Risk Long-Term
Inflammation plays an important role in the develop-ment of cardiovascular disease (CVD). While research has shown that diet influences inflammation, whether dietary patterns that promote inflammation can increase the long-term risk of CVD is still unknown.
In a new study, Harvard researchers sought to shed light on this question. Their findings suggest that reducing the inflammatory potential of the diet may be an effective strategy for preventing CVD.
The researchers prospectively followed 74,578 women from the Nurses’ Health Study (1984–2016), 91,656 women from the Nurses’ Health Study II (1991–2015), and 43,911 men from the Health Professionals Follow-up Study (1986–2016) who were free of CVD at baseline.
Diet was assessed by food frequency questionnaires every 4 years. The inflammatory potential of diet was evaluated using a food-based empirical dietary inflammatory pattern (EDIP) score that was pre-defined based on levels of 3 systemic inflammatory biomarkers (CRP, IL-6 and TNF-alpha).
The 3 cohorts provided 5,291,518 person-years of follow-up. A pooled analysis of the cohorts adjusted for potential confounding variables, showed that the highest dietary inflammatory potential (highest EDIP score vs. the lowest score) was associated with:
These associations were consistent across the 3 cohorts and between sexes, and they remained significant after further adjustment for other dietary quality indices.
In a subset of 33,719 participants, a higher EDIP score was associated with a higher circulating profile of proinflammatory biomarkers, lower levels of adiponectin, and an unfavorable blood lipid profile (p < 0.001).
The study suggests that modulating chronic inflammation may be a mechanism linking dietary patterns with CVD, according to the authors.
For patients looking for an eating plan that closely follows the tenets of anti-inflammatory eating, consider the Mediterranean diet. It is high in anti-inflammatory foods including fruits, vegetables, nuts, whole grains, fish, olive oil and wine, while low in red meat, processed meat and sugar (among the more pro-inflammatory foods).
The Mediterranean diet has also been linked to lower risk of age-related macular degeneration and a reduced risk for cataract surgery.
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In the news: Mindfulness Meditation Lowers IOP & Impacts Ocular Tissue
Mindfulness Meditation Lowers IOP in Glaucoma
Many glaucoma patients have high levels of anxiety and depression with poor psychosocial functioning and stress due to anticipated vision loss. This stressful state may be a contributing factor to the worsening of the disease. Stress, for example, can cause a rise in endogenous cortisol level which can in turn lead to an increase in IOP.
A new prospective randomized controlled study from the All India Institute of Medical Sciences indicates that a short course of stress reduction through mindfulness meditation in glaucoma patients significantly reduces intraocular pressure (IOP) and appears to have a direct impact on ocular tissues.
Methods
The study included sixty POAG patients with IOP > 21 mmHg receiving maximal topical medication and scheduled for trabeculectomy. Thirty of the patients received 3 weeks of mindfulness meditation (45 minutes daily) in addition to their routine medical therapy, while the remaining 30 patients continued on medical therapy only.
The primary outcome was change in IOP after 3 weeks of mindfulness mediation. Secondary outcomes were probability of success, percentage reduction in IOP, effect on diurnal variation of IOP, change in quality of life and changes in gene expression pattern in the trabecular meshwork.
Results
At the end of 3 weeks, a significant decrease in IOP was seen in the meditation group (20.16 ± 3.3 to 15.05 ±2.4 mmHg, P = 0.001), compared to the non-meditation group (21.2 ± 5.6 to 20.0 ± 5.8 mmHg, P = 0.38).
The change in IOP was significantly higher in the meditators than non-meditators (5.0 ± 1.80 versus 0.20 ± 3.03 mmHg, P = 0.001).
Gene expression analysis of trabecular meshwork tissue samples revealed significant upregulation of nitric oxide synthetase (1 and 3) and neuro-protective genes with downregulation of pro-inflammatory genes in meditators vs. nonmeditators (P = 0.001).
A significant decrease in diurnal variation in IOP (4.07 ± 1.3 to 2.95 ±1.75 mmHg) was seen at 3 weeks in meditators (P = 0.006) compared to the nonmeditation group (4.5 ± 2.17 to 4.38 ± 2.3 mmHg, P = 0.83). There was a significant difference between the two groups at 3 weeks (P = 0.001).
There was also a significant improvement in the glaucoma-specific quality of life questionnaire score after 3 weeks of meditation (P = 0.0001).
Comments
Though the study was small and short in duration, the results are promising: mindful meditation was effective in significantly lowering IOP in POAG patients with a concomitant reduction in diurnal fluctuation of IOP. Eyes that underwent trabeculectomy after the mindful meditation course also had better outcomes in the early post-operative period as compared to the control group.
The changes in gene expression patterns in the trabecular meshwork reflect that the meditation practice positively affected cellular mechanisms involved in glaucoma pathogenesis through both IOP-dependent and independent mechanisms.
Mindfulness meditation is simply observing the breath by focusing attention on the natural relaxed flow of air going in and out of the body. In the study, it was directed by a certified yoga instructor. As glaucoma patients face anxiety – likely exacerbated by the current pandemic – online mindfulness mediation may be just what the doctor ordered.
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In the news:Meta-analysis Links Vitamin D & DED; Vitamin B3 for Fibrotic Eye Disease?
Potential Vitamin D Mechanisms in DED
Studies have begun to shed light on the potential role of Vitamin D in the development of dry eye disease. An underlying cause of DED is inflammation which appears as discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface. There is evidence that the immune and anti-inflammatory effects of vitamin D might influence DED by regulating the production of pro-inflammatory cytokine IL-17 and anti-inflammatory IL-6.
Vitamin D could also affect ocular pain or discomfort through modulating nociception. There are several theories about the mechanism linking vitamin D to pain. Serotonin, which can extend chronic pain response, has been shown to be high in subjects with DED. Vitamin D is known to affect serotonin synthesis. Additionally, vitamin D could modulate pain by decreasing nitric oxide, a nociceptive neurotransmitter.
Another mechanism proposed for a beneficial effect of vitamin D in DED is its ability to improve corneal epithelial barrier function. The epithelium of the ocular surface functions as a barrier to the penetration of harmful substances into the cornea and maintains ocular surface integrity.
Yet despite the progress made in understanding the mechanistic connections between this vitamin and DED, studies examining the relationship of vitamin D status to DED have not been consistent.
Systematic Review and Meta-Analysis Results
To address this issue, researchers conducted a systematic review and meta-analysis of observational studies evaluating the association between serum vitamin D and DED in patients as compared to healthy adult subjects
A total of 14 studies out of 252 met the inclusion criteria and were included in the review and analysis. Serum 25(OH) D3 was lower in dry eye disease subjects compared to healthy ones (p<0.001). Vitamin D was also associated with the results of the Ocular Surface Disease Index score (p=0.043). No association, however, was found between serum vitamin D and tear break-up time (TBUT) and Schirmer’s test results.
According to the authors, this finding was in line with previous observational studies, though a previous intervention study reported a beneficial impact of supplemental vitamin D on TBUT and Schirmer’s.
Vitamin B3 for Fibrotic Eye Diseases?
A study reporting that vitamin B3 (nicotinamide form) may improve inner retinal function in those with glaucoma was summarized in a recent EduFacts (see SBH.com). From researchers at Mt. Sinai Hospital comes a new study that suggests vitamin B3 can inhibit aggressive cell trans-formations during wound healing
According to a Mt. Sinai statement, the findings apply to a condition in which cells in the retinal pigment epithelium, a layer that supports the retina, transform and develop the characteristics of more aggressive cells known as mesenchymal cells. The condition can be triggered by aging, diabetes, or eye injury. This causes development of fibrous membranes that resemble damaging cells found in retinal scar tissue and leads to retinal detachment. (https:/www.mountsinai.org/about/newsroom/2020/researchers-find-that-nicotinamide-may-help-treat-fibrotic-eye-diseases-and-mitigate-vision-pr)
Testing the vitamin in human cells, the investigators found that vitamin B slowed down the aggressive cellular transformation. It could also promote the opposite transition, from mesenchymal to epithelial, helping to preserve the cell’s original identity.
The findings may be key to the development of therapies to treat fibrotic eye disease. Diseases such as AMD, diabetic retinopathy and neovascular glaucoma have in common the final pathological denominator of chronic wound healing leading to fibrosis.
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In the news: Array of Nutrients May Impact Risk of AMD Progression
Nutrient Association with Risk of AMD Progression
Age related macular degeneration (AMD) arises from a complex interplay between aging, genetics, and environmental factors, including dietary factors. The AREDS 1 and 2 trials showed that supplementation with specific combinations of antioxidants and minerals decreases progression from intermediate to late AMD, particularly neovascular AMD.
However, it is possible that other nutrients or bioactive components in food could provide additional protection against progression to late AMD. Recent analyses of the AREDS and AREDS2, for example, showed that closer adherence to a Mediterranean dietary pattern, and to its fish component, were highly associated with a slower progression to late AMD, geographic atrophy especially.
Against this backdrop, researchers from the National Eye Institute analyzed data from AREDS 1 and 2 to assess whether dietary intake of various vitamins, minerals and other nutrients are linked to progression to late AMD, progression to large drusen, and whether any nutrients interact with AMD genotypes.
Methods
This post hoc analysis included participants with no late AMD at baseline in AREDS (n=4,504) and in AREDS 2 (n=3,738), for a total of 14,135 eyes. Fundus photographs were collected at annual study visits and graded centrally for late AMD. Dietary intake of multiple nutrients was calculated for each participant from food frequency questionnaires.
Results
Over a median follow-up of about 10 years, one third of the eyes advanced to late AMD.
The highest vs. lowest intake of 9 nutrients were significantly (p< 0.0005) associated with decreased risk for late AMD: vitamins A, B6, and C, folate, β-carotene, lutein/zeaxanthin, magnesium, copper, and alcohol.
The highest intake of three nutrients were associated with increased risk: saturated fatty acid, monosaturated fatty acids, and the mono-unsaturated fatty acid oleic acid.
Similar results were seen for geographic atrophy.
For neovascular AMD, 9 nutrients were nominally associated with lower risk: vitamins A and B6, β- carotene, lutein/zeaxanthin, magnesium, copper, omega-3 fatty acid, DHA and alcohol, while the same three fatty acids linked to late AMD progression were also associated with increased risk of progression to neovascular AMD.
These associations were stronger for geographic atrophy than for neovascular AMD. In separate analyses, many of the same nutrients also tended to have protective associations against large drusen development.
The researchers also found that strong genetic interactions exist for some nutrient-genotype combinations, particularly omega 3 fatty acids and CFH (complement factor H) genotype.
Comments
The most consistent finding from over 300 previous prospective studies have included a decreased risk of late AMD associated with higher levels of DHA/EPA and lutein/zeaxanthin intake. The current study lends credence to the protective impact of these long chain fatty acids and carotenoids, but also broadens the array of nutrients linked to slower progression of AMD.
According to the authors, “these data may justify further research into underlying mechanism and randomized trials of supplementation.
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In the news: AHA Advocates Diet Screening, Counseling. Vitamin B3 Shows Promise in Glaucoma
AHA: Routine Checkups Should Include Dietary Screening
A new scientific statement from the American Heart Association (AHA), recommends that a rapid diet-screening tool be incorporated into routine checkups.
“It is critical that diet quality be assessed and discussed at the point of care with clinicians and other members of the healthcare team to reduce the incidence and improve the management of diet-related chronic disease, especially cardiovascular disease,” the authors of the statement wrote.
The statement can be read online, open access: https://www.ahajournals.org/doi/10.1161/HCQ.0000000000000094.
According to the authors, poor dietary quality has ‘surpassed all other mortality risk factors, accounting for 11 million deaths and about 50% of cardiovascular deaths globally.”
Dietary screening or counseling is not usually part of routine medical visits. But the widespread use of electronic health records offers an unmet opportunity to provide evidence-based clinician-delivered dietary guidance using rapid diet screener tools.
The paper reviewed 15 such tools, pointing out their strengths and weaknesses. Three of them met the most “theoretical and practice-based criteria” for an optimal diet screening tool: the Mediterranean Screener (and variations), Rapid Eating Assessment for Participants (modified and shortened version) and Starting the Conversation Tool (modified version).
Flexibility is key, with the authors suggesting that clinicians discuss which tool would work best in their unique clinical workplace, and how it should be administered and by whom. These rapid diet screener tools can be used not just in primary care settings, but in relevant specialty care prevention settings as well.
Vitamin B3
Nicotinamide (aka niacinamide) is one of four major precursors of nicotinamide adenine dinucleotide or NAD+, the active form of vitamin B3. NAD+ is a critical co-enzyme in multiple metabolic processes and is key for mitochondrial health. Recent work suggests that serum levels of NAD+ are low in glaucoma patients, and nicotinamide has been shown to prevent age-related declines in NAD+.
Retinal ganglion cells endure significant metabolic stress in glaucoma but maintain the capacity to recover function. In preclinical models, nicotinamide supplementation has been shown to protect retinal ganglion cells. However, the potential of nicotin-amide in human glaucoma is unknown.
Recently, a double-blind, crossover, RCT led by the Center for Eye Research Australia, examined the effects of supplemental nicotinamide in 57 glaucoma patients.
In addition to their regular IOP-lowering treatments, participants received 6 weeks of 1.5 g/day of nicotinamide, then 6 weeks of 3.0 g/day followed by crossover. Visual function was measured using electroretinography, and perimetry. Participants were seen at baseline and during 6 weekly visits, where visual acuity, IOP and blood pressure were also measured, and a slit lamp exam administered.
PhNR Vmax improved in 23% of participants following nicotinamide vs 9% on placebo. Overall, Vmax improved by 14.8% on nicotinamide and 5.2% on placebo. Vmax ratio improved by 12.6% (P = .002) following nicotinamide; 3.6% on placebo. A trend for improved visual field mean deviation was observed with 27% improving ≥1 dB on nicotinamide and fewer deteriorating (4%) vs. placebo (P = .02).
The authors conclude that nicotinamide improved inner retinal function in glaucoma and indicate that further studies will elucidate the effects of long‐term supplementation.
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In the news: Covid-19 Related Topics of Interest
Covid-19 (SARS-CoV-2) Information of Interest for Eye Care Professionals
As we move through the challenges of the coronavirus pandemic, SBH truly hopes that all of our EduFacts readers stay safe and well.
The following are topics that may be of interest to eye care professionals, with links to full papers and resources. Click on the links below:
• Study suggests that the risk of Covid-19 transmission in tears may be low
• Covid-19 can cause viral conjunctivitis undistinguishable from other viral causes
• Controversy: Use of ACEIs and ARBs in Covid19 patients, harmful or helpful? Some Perspectives:
o Renin–Angiotensin–Aldosterone System Inhibitors in Patients with Covid-19
o Coronavirus Disease 2019 (COVID-19) Infection and Renin Angiotensin System Blockers
• The CDC offers guidance on contact lens wear related to COVID-19.
• While it’s engendered debate, some Chinese and US physicians have employed IV ascorbic acid as a supportive treatment in Covid-19. There is also a clinical trial of IV vitamin C for severe Covid-19-induced pneumonia underway. What is the rationale?
o High-dose intravenous vitamin C treatment for COVID-19
o Vitamin C Can Shorten the Length of Stay in the ICU: A Meta-Analysis
o Assessment of Evidence for COVID-19-Related Treatments: Updated 4/10/2020
• Multiple vitamins and minerals with immune-supporting roles may modulate immune function and reduce the risk of infection, particularly vitamins C, D and zinc. Inadequate status of vitamin D, especially, is common. Healthful eating is important to maintain a well-functioning immune system:
o Vitamin D for Treatment and Prevention of Infectious Diseases: A Systematic Review of Randomized Controlled Trials
o A Review of Micronutrients and the Immune System–Working in Harmony to Reduce the Risk of Infection
• Finally, for a respite from Covid-19 related tension, try watching the ‘Jelly Cam’ at the Monterey Bay Aquarium!
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In the news: Role of Vitamin D in COVID-19? Nutrients & Diabetic Retinopathy
Update: Vitamin D Status and Coronavirus
Over the last few months, the role of vitamin D in relation to COVID-19 has been the subject of debate. Some experts say the evidence is not strong enough to support recommending supplemental vitamin D beyond the Daily Value to help potentially protect against coronavirus. Others say that the available evidence is sufficient to act upon, particularly because the pandemic has curtailed outdoor activities (and hence the sunlight exposure needed to synthesize one’s own vitamin D), and that vitamin D is considered safe at supplemental levels of 1,000-2,000 IU daily, with a Tolerable Upper Intake Level of 4,000 IU.
Past intervention studies provide evidence that vitamin D can lower the risk of upper respiratory tract infections such as colds and the flu in people with low blood levels of the vitamin. There is also evidence that adequate levels are needed for proper immune system function, and that vitamin D stimulates the release of antimicrobial proteins and helps reduce inflammation.
But when it comes to COVID-19 specifically, the idea that vitamin D could influence susceptibility to the disease or affect the severity of symptoms is based on observational studies suggesting that deficiencies of the vitamin are common among groups that have been hard hit by the virus. Risk factors for vitamin D inadequacy include obesity, diabetes, hypertension, ethnicity – factors also associated with increased risk of severe COVID-19 illness.
Recently, a rapid review by the UK government looked at five published observational studies on vitamin D status and COVID-19 symptoms and mortality . The report indicates that four of the studies found an association between poor vitamin D status and subsequent infection with COVID-19, but that the studies didn’t account for confounders which may have independent correlations with the disease or with vitamin D status.
Another group of international medical societies issued guidance as well . They state that while the role of vitamin D in COVID-19 remains unclear, older and younger adults can safely take 400-1,000 IU daily to keep vitamin D levels within the range recommended by the US Institute of Medicine when they can't get 15-30 minutes of sunlight daily.
To provide further clarity about the potential role of vitamin D in COVID-19, Harvard researchers at Bingham and Women’s Hospital will be conducting a randomized controlled trial of supplemental vitamin D among patients recently diagnosed with COVID-19, to see if it can reduce the risk for developing severe illness or the need for hospitalization. The study will also assess whether supplementation can reduce the risk of developing the infection for others in the patient’s household.
Review: Nutrients and Diabetic Retinopathy
Researchers from the University of Miami Miller School of Medicine, Departments of Neurology and Ophthalmology, have reviewed the role of various nutrients in relation to elevated homocysteine and oxidative stress, two biological targets in the development of diabetic retinopathy .
The paper discusses deficiencies of various vitamins, minerals and related compounds that may lead to elevation of homocysteine and insufficiencies of co-factors for the release of neuro-trophic and neuroprotection growth factors.
The authors conclude that nutritional interventions provide safe and simple strategies that may help protect the retina and choroid, and support, not conflict with, conventional therapies for diabetic retinopathy.
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In the news: Pro-Inflammatory Diet Ups Risk of Crohn’s; Call for Zinc & COVID-19 Research
Dietary Pattern a Risk Factor for Crohn’s
Crohn’s disease is a chronic inflammatory disorder in which the immune system attacks the GI tract. According to the National Institute of Diabetes and Digestive and Kidney Diseases, Crohn’s is becoming more common in the US and in other developed countries. The incidence is increasing in developing nations as well.
The exact cause of Crohn's disease is unknown, but studies suggest that it is a multifactorial condition attributable to a combination of environmental and immune factors, as well as alterations in the gut microbiome, in genetically susceptible individuals.
A newly published analysis of three large prospective cohorts provides evidence that a pro-inflammatory eating pattern may also be a factor in the development of Crohn’s, though not ulcerative colitis .
In the study, researchers from Massachusetts General Hospital and Harvard Medical School used dietary data collected at multiple time points from nearly 167,000 women and 42,000 men who participated in the Nurses’ Health Study I and II, and the Health Professionals Follow-up Study.
Self-reported Crohn’s and ulcerative colitis cases were confirmed by medical record review. Empirical dietary inflammatory pattern (EDIP) scores were calculated to evaluate dietary inflammatory potential and the risk of developing Crohn’s and ulcerative colitis. The EDIP score has been shown to reflect circulating inflammatory biomarkers.
Over 4,949,938 person-years of follow-up, 328 cases of Crohn’s and 428 cases of ulcerative colitis were documented. Compared with participants in the lowest quartile of cumulative mean EDIP scores, those in the highest quartile had a 51% higher risk of Crohn’s.
Compared to those who persistently consumed a low potentially inflammatory diet over time (measured at 2 time points 8 years apart), participants who continually consumed a pro- inflammatory diet – or who shifted from a low to high inflammatory diet – had a 2-fold greater risk of developing Crohn’s.
Comments
While specific foods have previously been linked to a higher risk of inflammatory bowel disease, this study is the first to underscore the importance of an overall anti-inflammatory dietary pattern on the risk of developing Crohn’s. The Mediterranean diet which has been linked to many general and ocular health benefits, has been shown to have a high anti-inflammatory potential.
Call to Study Zinc for COVID-19 Preventative
Writing in the American Journal of Ophthalmology, an international team from the Netherlands, UK and US, make a case for studying oral zinc as a potential prophylactic treatment for those at risk for COVID-19 .
The authors point out experimental data suggesting that zinc may inhibit the interaction of the corona-virus (SARS-CoV-2) S protein spike and the ACE2 receptor, which is critical for viral entry into host cells.
The anti-viral effects of zinc against rhinoviruses is briefly discussed, with the effects thought to be due to enhanced immune cell function and/or the ability of zinc to interfere with the binding of these viruses to cells.
Serum zinc levels can be low in the elderly – a group particularly vulnerable to COVD-19. Given that a vaccine is likely at least a year away, the authors call for more research into zinc, possibly assessing whether there is a difference in progression of respiratory disease between AREDS2 users and non-users in the AREDS2 trial.
The article can be accessed in full at: https://www.ajo.com/article/S0002-9394(20)30213-0/fulltext.
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In the news: “Med’ Diet & Lower Risk of Late AMD; Low Vitamin D a Factor in Covid-19 Severity?
Med Diet, Fish Intake Influence Late AMD
Closer adherence to the Mediterranean (Med) diet lowers the risk for late AMD, more so for geographic atrophy (GA) than wet AMD, according to the authors of a new analysis of AREDS and AREDS2 data .
The researchers aimed to determine whether more closely following the Med diet (and its individual food components) alters the risk of progression to late AMD and its sub-types. Additionally, they analyzed progression to large drusen and assessed interactions with AMD genotype.
Over a median follow-up of about 10 years, 34% of the total 13,204 eyes from both studies with no late AMD at baseline had progressed to late AMD.
Comparing the greatest adherence to Med diet vs. the lowest (tertile 3 vs. tertile 1) showed a 22% reduction in relative risk for late AMD, a 29% reduction for GA (p< 0.0001 for both), and a 16% reduction for neovascular AMD (p=0.005).
Consuming more fish contributed to the Med diet’s protective effect. Comparing the highest fish intake vs. the lowest (quartile 4 vs. quartile 1) indicated a 31% lower risk for late AMD in AREDS (p<0.0001) and an 8% risk reduction in AREDS2 (p=0.28).
The benefit of greater adherence to the Med diet and higher fish intake was more pronounced in participants with the CFH protective genotype. In separate analyses, closer diet adherence was also associated with a 21% lower risk of progression to large drusen.
These findings lend further support to the ocular benefits of the Mediterranean-type diet.
Vitamin D Status and Covid-19 Severity
Researchers in Dublin, Ireland propose that improving vitamin D status in the population could possibly reduce serious COVD-19 complications .
Synthesized in the body with sunlight exposure, vitamin D plays a role in regulating the immune system. At the cellular level, it modulates both the adaptive and innate immune system through cytokines and regulation of cell signaling pathways. It’s the impact of vitamin D deficiency on cytokine response that is potentially important in context of Covid-19 “cytokine storms” according to the authors.
Although there are currently no randomized controlled trials to prove that vitamin D supple-mentation beneficially influences COVID-19 outcomes, the researchers present data that higher vitamin D status is associated with better outcomes.
The team analyzed European studies, completed since 1999, that measured vitamin D status in older adults. Countries were selected by severity of Covid-19 infection (high and low) and mortality data was gathered from the WHO.
Counter-intuitively, lower latitude and typically ‘sunny’ countries such as Spain and Italy had low mean plasma vitamin D concentrations and high rates of vitamin D deficiency. These countries have experienced the highest infection and death rates in Europe.
Northern latitude countries (Norway, Finland, Sweden) which receive less UVB sunlight than southern Europe (but where supplementation is common), had much higher mean blood vitamin D, low levels of deficiency and for Norway and Finland, lower infection and death rates.
The vitamin D status-covid19 association has also been reported in a study from Northwestern University that has not yet been published. Analyzing patient data from 10 countries, a correlation was found between low vitamin D levels and hyperactive immune systems.
The notion that vitamin D strengths innate immunity and prevents overactive immune responses in Covid-19 deserves attention and further study.
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In the news: B Vitamins Needed for Cognitive Benefits of Omega-3 in Alzheimer’s? B Vitamins Needed for Cognitive Benefits of Omega-3 in Alzheimer’s?
B Vitamins Needed for Omega-3 Brain Benefits?
Population health studies have linked the intake of long-chain omega-3 fatty acids with a lower risk of Alzheimer’s disease (AD), while animal studies have shown that these fatty acids, DHA in particular, can reduce Alzheimer’s-like brain disease. However, intervention trials testing whether EPA/DHA can slow the cognitive decline in mild cognitive impairment (MCI) or early to moderate AD have yielded mixed results.
Recent work by a team of Swedish researchers from Uppsala University offers some insight into why these studies may have produced conflicting results. Their work indicates that the protective effect of omega-3 fatty acids is influenced by the status of B vitamins.
In an earlier study , the Swedish team conducted a post-hoc analysis of the 2-year long VITACOG study – a randomized, double-blind, placebo-controlled study
evaluating the effect of moderately-high dose B vitamins (folic acid, 0.8 mg; vitamin B6, 20 mg; vitamin B12, 0.5 mg) in elderly participants with MCI.
The analysis showed that the protective effect of the B vitamins on brain atrophy rates depended upon initial plasma levels of DHA and EPA.
In those with high plasma DHA + EPA at the study’s start, the B vitamin treatment slowed the rate of brain atrophy by 40% compared with placebo – notable since a faster rate of brain atrophy is characteristic of those with MCI who go on to develop AD.
In the present study , the researchers performed a post-hoc analysis of another trial in patients with mild to moderate AD, the OmegAD study. This trial, also randomized and controlled, evaluated the effect of omega-3 (2300 mg DHA + EPA daily) on cognitive out-comes: changes in the Mini-Mental State Examination and the Alzheimer’s Disease Assessment Scale.
While the supplemental fatty acids did not significantly delay cognitive decline overall in this 6-month study, a small patient group with mild AD did experience cognitive benefits.
The Swedish team sought to determine whether interactions between initial homocysteine levels (a measure of B vitamin status) and the supplemental omega-3s could have played a role in the observed cognitive and functional outcomes.
Compared to those with higher homocysteine levels (and lower B vitamin status), participants with levels below 11.7 mmol/L saw a 7.1% improvement in cognitive performance p = 0.03) and a 22.3% reduction on the rating scale of dementia vs. placebo (p = 0.009).
The authors conclude that the effect of omega-3 supple-mentation on measures of cognitive performance and clinical status could be dependent on having sufficient levels of B vitamins.
How do the Omega-3s and B Vitamins Interact?
Omega-3 fatty acids, particularly DHA, is concentrated in neuronal membranes in the brain, while folate and vitamins B6 and B12 are necessary for producing monoamine neurotransmitters, phospholipids and nucleotides. Importantly, these B vitamins are required to form phosphatidyl choline which is necessary to carry DHA and EPA across the blood brain barrier.
Interestingly, AD and age-related macular degeneration (AMD) share some epidemiological, genetic, molecular and clinical links. For instance, AD and AMD share the underlying factors of oxidative stress and neuro-inflammation. Beta-amyloid, the main component of senile plaques and a hallmark of AD, is also an important component of drusen, the hallmark of AMD. Perhaps future studies evaluating the effects of omega-3 fatty acids in AD, MCI and AMD should take into account the functional B-vitamin status of participants.
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Vision 2020
B Vitamins Needed for Omega-3 Brain Benefits?
We asked an optometrist, ophthalmologists and nutrition scientists what they envision as key areas of focus for nutrition and ocular health in 2020 and beyond. Here are their predictions.
Stephen Pflugfelder, MD. Cullen Eye Institute, Baylor College of Medicine.
Prediction: We’ll learn more about how dietary components help protect the ocular surface.
There is ever increasing evidence that nutrition is an important factor for maintaining ocular health, including preventing macular degeneration and dry eye. While the exact mechanisms for these protective effects are still being investigated, I believe 2020 and beyond will bring greater insight into how these dietary components are working and how they contribute to a healthier ocular surface.
It appears from research done by our group that dietary constituents, including vitamin A metabolites, DHA in fish oil, and vitamin D can decrease dry eye associated inflammation via signaling through the retinoid X receptor alpha (RXRa). Age and disease related disruptions in ligand metabolism, delivery or receptor expression may reduce the activity of these nutrition-associated pathways.
Interestingly, oleic acid, the predominant fatty acid in olive oil is also an RXRa ligand and this could explain the clinical improvement seen in the olive oil placebo group in the DREAM study.
Paul Bernstein, MD, PhD. Moran Eye Center, University of Utah School of Medicine.
Prediction: Prenatal supplements may routinely include lutein and zeaxanthin in the future.
Having worked in the field of ocular nutrition for over two decades, I am pleased that we now have excellent basic science understanding of many key nutrients for age-related macular degeneration (AMD) such as lutein, zeaxanthin, and omega-3 fatty acids, and large randomized clinical studies such as AREDS2 have made nutritional interventions against AMD standard-of-care in appropriate populations. What lies ahead for ocular nutrition in the upcoming years and decades?
While we have a good grasp on ocular nutrition in the senior years, my research group is now exploring the roles of carotenoids at the other end of the lifespan. The macular carotenoid pigment is present at birth, implying a fundamental importance in early life beyond protection against AMD that we do not fully understand yet. Perhaps the macular pigment is important for structural and functional development of the visual system. We have recently initiated a two-year clinical study funded by the National Eye Institute on lutein and zeaxanthin in pregnancy (the L-ZIP study).
Sixty women in their first trimester of pregnancy will be randomized to standard-of-care prenatal vitamins with and without 10 mg of lutein and 2 mg of zeaxanthin. Our main outcomes will be maternal and infant carotenoid status in the eye, skin and plasma at birth along with structural assessment of infant foveal maturity. Going forward, we hope to continue to follow these children as they grow and mature to see if early nutritional intervention with carotenoids enhances visual and/or cognitive performance. If we see positive results, I foresee widespread incorporation of lutein and zeaxanthin in prenatal supplements around the world.
Kelly Nichols, OD, MPH, PhD. Dean, School of Optometry, University of Alabama at Birmingham.
Prediction: The field of nutrition science has garnered a lot of accolades and news commentary in the last year, and I don’t expect that to change in 2020 and beyond.
What we eat is now only part of the equation; how often and when we eat have become the topic of magazines, internet and more importantly science. Recent research conducted by Assistant Professor Courtney Peterson, PhD, Assistant Professor in the Department of Nutrition Sciences and a scientist in UAB’s Nutrition Obesity Research Center (NORC), Diabetes Research Center (DRC), and the UAB Comprehensive Diabetes Center (UCDC), has shown that intermittent fasting, or limiting the hours when eating occurs, improves blood sugar control, blood pressure, inflammatory events, and oxidative stress, even when people don't change eating habits. Her work has yet to cross over to the eyecare arena, but her focus on diabetes, lifestyle intervention, caloric restriction and intermittent fasting have made her work a “must watch” and are not far removed from all of the important elements we are interested in related to macular and overall ocular health.
My clinical research interest is in the area of ocular surface disease, and it is understood that dry eye and contact lens discomfort involve inflammation. I am convinced that low-to-moderate grade systemic inflammation plays a significant role in maintaining the homeostasis of the tear film and ocular surface. Future understanding of the role of intermittent fasting on systemic inflammation will be knowledge that crosses over many fields of science.
Allen Taylor, PhD. Director, Laboratory for Nutrition and Vision Research, Tufts University
Prediction: Greater understanding about the relationship of unhealthy carbohydrates, other dietary components, the microbiome and AMD risk. I predict that consuming lower glycemia diets will be the recommended standard of care for AMD patients.
Clearly, it would be a tremendous boon to personal and public health if risk for age related AMD could be limited by dietary management. Our group has focused on understanding how AMD is connected to the quality of carbohydrates one consumes.
Using baseline AREDS data, we found that diets with higher intake of vegetables, legumes, fruit, whole grains, tomatoes, and seafood (aka “Oriental” diet) were protective against early and advanced AMD, relative to the “Western” pattern of higher red and processed meat, high-fat dairy, French fries, refined grains, and eggs. Importantly, we found that the more one adhered to the Western pattern, the greater the risk for early or advanced AMD. Similarly, the more one subscribed to the Oriental food pattern, the less the risk for early or later AMD.
Epidemiologic studies indicate that consuming lower glycemic index (GI) diets is protective against risk for and progress of AMD. Lower GI diets are those low in carbohydrates that cause a rapid rise in blood glucose, such as white bread and rice, sugars, and processed foods with no to low fiber. Importantly, the benefits gained by consuming low GI diets are in addition to the benefits of eating Oriental or “prudent” diets.
To corroborate the apparent benefit of consuming lower GI diets to diminish risk for AMD, we fed two types of mice (Wild type, and Nrf2-/- with a compromised ability to mount stress and oxidant responses) either low or high GI isocaloric diets beginning at 12 months of age (middle-age) through 24 months of age (old age). After 6 months, half of the mice receiving the high GI diet were switched to the low GI diet. Mice fed the high GI diet displayed many features of AMD, including retinal pigment epithelial hyper-pigmentation and atrophy, lipofuscin accumulation, and photoreceptor cell loss. Those in the low-GI diet group did not. The low GI diet also limited advanced glycation end products (AGEs) and peroxidized lipids. Crucially, the damage seen while on the high GI diets was halted or reversed when mature mice were switched from the high to the low GI diet.
The diets also affected the microbiome and the blood and urinary metabolome, all of which were related to retinal integrity and to each other. In the WT mice, for example, the microbiomes were dramatically altered due to diet and age. Changing from high to low GI diet returned the micro-biome from the high GI profile to that of the older low GI diet animal.
The results suggest that switching to a low GI diet, even late in life, is beneficial. This is remarkable because it’s achievable without major behavioral changes. Our findings of many altered proteins, particularly AGEs, also indicate that glycation is altering bulk proteins as well as the enzymes that might normally selectively recognize and remove them. Additionally, we identified new, potential biomarkers for AMD – important because none are currently available. These will allow us to design new drugs and predict when people will get AMD and when to exploit diets or new drugs to diminish the AMD burden.
Lisa Olmos de Koo, MD, MBA. Ophthalmology Dept., University of Washington
Prediction: We may find that some botanical extracts can help mitigate the damaging effects of macular disease.
There are several promising botanical extracts to watch for their use in macular disease. As we know, even those patients with early macular disease whose objective Snellen visual acuity is not affected often report subjective visual disturbances such as eye strain and poor contrast and flicker sensitivity, and it is exciting that supplementation with botanicals could possibly mitigate these effects, producing a better quality of vision for our patients.
Saffron (Crocus sativus) is a spice with a history of traditional use as an herbal medicine for a variety of conditions throughout Eurasia and Africa. The spice comes from the flower stigma, which contains crocin and crocetin, carotenoids that have been shown in animals to protect photoreceptor morphology and function and protect against cellular death. The most recent and largest human study to date on saffron included 96 subjects with mild to moderate AMD and was double-blind, randomized, and placebo controlled. After 3 months of supplementation with 20 mg of saffron extract, mean-pooled multifocal ERG latency was reduced in the saffron group vs. placebo, along with a modest (< 1 letter) but statistically significant gain in visual acuity. Other smaller studies by a group of Italian researchers demonstrated improvement in focal ERG sensitivity in participants taking saffron for a longer period of time. We await the results of larger and longer future trials.
Curcumin, a component of the spice turmeric, is another botanical extract of great interest. Turmeric is derived from the rhizome or root of Curcuma longa and is one of the main components of curry powder. In India and other parts of Asia, turmeric is used in traditional medicine to treat many health conditions. Pre-clinical and animal studies on curcumin have shown a protective effect on retinal pigment epithelial cells against oxidative stress. Low solubility and oral bioavailability have posed a challenge in the use of curcumin supplementation; however, recent small clinical trials on the effectiveness of curcumin formulated with a hydrophilic carrier in treating diabetic retinopathy have shown promising results.
Penelope Edwards, MPH, CNS. SBH Nutrition Scientist
Prediction: Nutrition education will become an integral component of medical curricula.
As a UCLA grad student in nutrition in the 1970’s, I participated in the ½ day seminars in nutrition fundamentals that our division provided to medical students annually. The seminars, though woefully brief, seemed to be well received. Much has evolved in the field of nutrition since then, with evidence overwhelmingly showing that diet is vital to good health, including ocular health. An 18 year-long study published this month, for example, found that those eating an unhealthy “Western” diet had a three-fold greater risk of developing late AMD.
Unfortunately, not much has changed over the years in terms of incorporating nutrition into medical education, even though many Americans cite medical doctors as their most reliable source of information on diet and dietary supplements. The Harvard Law School Food Law and Policy Clinic reported last year that the average medical student spent less than 1% of lecture hours on nutrition, even as they note that nutrition training improves outcomes for patients and mitigates the immense costs of preventable diseases.
But that educational lag may be about to change. A pilot program at Wayne State University School of Medicine teaching 1st year med students the science behind plant-based nutrition – and how to integrate that knowledge into clinical practice – is enjoying early success, with plans to expand nationally. I predict that programs like this will catch on in the medical community in the foreseeable future, closing the gap in nutrition science education within the medical curriculum and ultimately improving patients' health.
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In the news: Unhealthy Eating Pattern Associated with 3-Fold Higher Risk of Late AMD
Diet: One Way to Modify Risk of AMD Vision Loss?
According to the National Eye Institute, the estimated number of people with AMD is expected to more than double from 2.07 million to 5.44 million by 2050 – a projected increase that underscores an urgent need to identify risk factors for this common eye disease.
The results of a new, long-term study suggest that what we consume may be one important – and modifiable – factor influencing whether AMD-related vision loss occurs later in life.
Objective and Methods
Researchers from the State University of New York, Buffalo set out to determine the association between dietary patterns and the 18-year incidence of AMD. Subjects in the current investigation were participants in the Atherosclerosis Risk in Communities or ARIC Study (a large prospective, population-based study) who showed change in AMD lesions between retinal photographs taken at visit 3 and visit 5 in ARIC.
Retinal photographs taken at visits 3 and 5 were graded side by side to determine the number of those who developed AMD out of 1,256 without AMD and 22 with early AMD at visit 3. Over a mean 18 years of follow-up, 117 participants developed early AMD and 27 developed late AMD.
ARIC participants completed dietary surveys (food frequency questionnaires) twice, at visits 3 and 5. The researchers used that dietary data to identify 29 food groups and categorize dietary patterns into two types using average food group servings.
The first of the two dietary patterns, called “Western” (unhealthy), included large amounts of processed and red meats, fried food, dessert, eggs, refined grains, high fat dairy and sugar sweetened beverages.
The other pattern, called “prudent” (healthy) was high in all vegetables (particularly cruciferous, carotene-containing and dark leafy greens), legumes (e.g. beans, peas), poultry, fresh fruits, fish and seafoods
Logistic regression was used to estimate ORs and 95% CIs for incident AMD (any, early and late) after dividing the dietary pattern scores into three groups (tertiles) adjusted for age, race, education, total calories and smoking status.
Results
While no significant associations were observed between either dietary pattern and incident ‘any’ or incident early AMD, a threefold higher incidence of late AMD was seen among participants with a Western pattern score above, as compared with below, the median (OR=3.44 (95% CI 1.33 to 8.87), p-trend= 0.014).
The risk of developing late AMD was decreased, but not statistically significant, among participants with a Prudent pattern score above vs. below the median. (OR=0.51 (95% CI 0.22 to 1.18), p-trend= 0.054).
Comments
The results of this study suggest that consuming a Western pattern diet could well be a risk factor for developing late AMD. The findings complement those from two recent prospective studies which found a reduced risk of late AMD among people who ranked high vs. low on a Mediterranean (healthy) diet score.
Nutrients present in the ‘prudent’ and Mediterranean diet such as lutein, zeaxanthin and the omega-3 fatty acids EPA and DHA, are thought to promote a healthy immune system and reduce oxidative stress due to free radicals and inflammatory changes in the retina.
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In the news: Omega-3s & Colorectal Cancer Precursors; Dietary Zinc Important in Wet AMD Omega-3s & Colorectal Cancer Precursors; Dietary Zinc Important in Wet AMD
Omega-3 May Help Some Cut Colorectal Cancer Risk
Earlier this year, the primary findings of the large-scale placebo-controlled prevention trial, the Vitamin D and Omega-3 Trial (VITAL), were reported. With the notable exception for participants with low fish intake at baseline, VITAL found no reduction in the incidence of major cardiovascular events with omega-3 (ω-3) supplementation.
In addition, no overall benefit for omega-3 in lowering cancer risk was found, although the number of cases was too small for a well-powered analysis specifically on colorectal cancer risk.
Experimental data indicate that marine omega-3 fatty acids have potent anti-inflammatory effects and may protect against colorectal cancer (CRC), the fourth most common cancer in the US. Several prospective studies also indicate that these fatty acids may be chemo-protective in the early stage of CRC development.
These data provided the rationale for a prespecified ancillary study in VITAL examining the effect of omega-3 supplementation (460 mg EPA, 380 mg DHA) on conventional adenomas and serrated polyps, 2 major groups of CRC precursors. The study included 25,871 adults, who were treated a median 5.3 years.
The findings of the prespecified ancillary study showed that supplemental omega-3 did not reduce risk of conventional adenomas or serrated polyps in the cohort as a whole.
However, in secondary analyses a beneficial association was observed among participants with low plasma levels of omega-3 index at baseline. A 24% lower risk of conventional adenomas was seen in those with an index of 2.5% or less at baseline. (The omega-3 index is the percentage of EPA and DHA present among all fatty acids in red blood cell membranes).
The omega-3 treatment was also associated with a 41% lower risk of adenomas in African American persons, whereas no association was found in other racial/ ethnic groups. This difference can’t be explained by a variation in omega-3 status prior to randomization because baseline plasma levels of EPA and DHA and fish consumption did not show major differences across racial/ethnic groups.
In short, omega-3 daily supplementation with marine omega-3 fatty acids appears not to reduce the risk of colorectal premalignant lesions in the average-risk US population. However, African Americans and individuals with low plasma levels of omega-3 may benefit. The authors note that a similar beneficial interaction between omega-3 treatment and baseline omega-3 status (low fish intake) was found for cardiovascular events in VITAL.
Zinc for Those with Wet AMD on Anti-VEGF
Supplemental zinc along with antioxidants have been shown to slow AMD progression, but little is known about the impact of these nutrients in patients with late-stage disease undergoing anti-VEGF treatment.
To learn more, Australian researchers explored the relationship between dietary zinc consumption and clinical outcomes in 547 patients with neovascular AMD .
Participants whose daily zinc intake was below vs. above 8.1 mg had greater odds of having subretinal fluid – an association that was stronger in those with at least 6 months of anti-VEGF treatment.
Increased central macular thickness was also seen in patients with the lowest 25% of zinc intake compared to those in the upper 75% of intake. These findings suggest that higher zinc intake can favorably influence clinical outcomes in those with neovascular AMD receiving anti-VEGF treatment.
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In the news: Grape & Blueberry Target Cognitive Decline
Review: Systemic Drugs & Glaucoma Risk
Synergy of Grape, Blueberry in Memory Decline
According to United Nations projections, the world’s elderly population will reach an estimated 2 billion by the year 2050. Since aging is often accompanied by a decline in mental abilities, developing strategies to prevent, delay or slow down age-related cognitive decline is becoming critical.
Long term intake of berries and flavonoids have been linked to slower rates of cognitive decline and better cognitive function in the elderly. Preclinical and clinical studies have largely confirmed these observations.
In new research, French and Canadian investigators drew from previous studies and their own work to design a study testing whether an extract combining grape and blueberry polyphenols would affect cognition in older men and women . Previous animal research by the team showed a synergistic effect of the fruit, with grape extract enhancing the absorption of the polyphenols in the blueberry extract.
In the 6-month long trial, 215 healthy men and women aged 60-70, were randomly assigned to a polyphenol-rich grape-blueberry extract (providing 258 mg of flavonoids daily) or placebo.
The primary outcome was change from baseline in tests of visuospatial learning and episodic memory. Additional tests assessed changes in episodic verbal memory, recognition memory and working memory.
After 6 months, the investigators saw no difference between the groups in performance on the primary outcome testing, although the fruit extract improved verbal recall overall.
When the participants were divided into groups based on their initial test performances, significant improvement in episodic memory was seen in the fruit extract group with greatest memory decline at baseline. Episodic memory is the collection of past personal experiences that occurred at a particular time and place.
The authors concluded that the fruit extract improves age-related episodic memory decline in those with the highest cognitive impairment – a group they called “decliners”.
In the “decliners” group, cognitive age estimated from baseline tests improved by almost 14 years in the fruit extract group vs. about 5 ½ years in the placebo group. According to the authors, the nutritional intervention appears to rejuvenate the decliners’ memory to the normal cognitive age for their age group (60-70 years)
The authors state that their results emphasize the need to develop and define a recommended daily allowance for flavonoids. This is echoed by many in the nutrition field, as polyphenol-rich foods have been shown to have protective effects against risk of many chronic diseases.
Meds that May Affect Glaucoma Risk
A review published in the Nature journal Eye, provides a summary of reported associations between different systemic medications and the risk of developing glaucoma or experiencing disease progression .
Medication classes covered in the review that are known to or may modulate the risk of open-angle glaucoma include corticosteroids, beta blockers, calcium channel blockers, metformin, statins, selective serotonin reuptake inhibitors, bupropion, post-menopausal hormones, and cannabinoids.
Medication classes addressed in the review that may increase the risk of angle closure glaucoma include anticholinergics, adrenergic agonists, certain classes of antidepressants, sulfonamides, and topiramate.
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Turmeric May Benefit Endothelial Function
The vascular endothelium, or inner lining of vessels, regulates the passage of substances and cells from the blood to the tissues and is central to regulating the balance between blood vessel constriction and dilation. Endothelial dysfunction is characterized by a shift toward impaired vasodilation and a prothrombotic and proinflammatory state.
Impaired endothelial function is an important risk factor for cardiovascular disease (CVD), and a key factor linking older age to increased risk of clinical CVD. As the vascular endothelium is a major target for oxidative stress, the potentially protective effects of dietary factors with anti-inflammatory and antioxidant activity are of research interest. One such factor of interest is curcumin, a key polyphenol in the spice turmeric.
In the first meta-analysis to evaluate the effect of curcumin supplementation on endothelial function , researchers report that curcumin supplements were associated with significant increases in flow mediated dilation (FMD), a measure of a vessel’s ability to relax and dilate.
The investigators used Cochrane Collaboration risk of bias tool to assess the methodological quality of trials, and 10 studies meeting the criteria were included. Data were pooled using a random-effects model, and weighted mean differences (WMDs) were considered as the overall effect sizes. A significant increase in FMD following curcumin supplementation (WMD 1.49) was noted compared to control groups.
There was, however, no effect of curcumin supplement on pulse wave velocity or augmentation index (measures of arterial stiffness), endothelin-1 (vasoconstrictor) or soluble intercellular adhesion molecule-1 (marker of occlusive coronary events).
According to the authors, curcumin’s salutary effect on endothelial function may be by suppressing inflammation and/or oxidative damage via down-regulating tumor necrosis factor-alpha, a major inflammatory cytokine.
‘Glass 1/2-Full’ Outlook Lowers Cardiovascular Risk
Abundant evidence has shown that negative emotions are linked to adverse cardiac outcomes. However, a potential link between positive and negative mindsets and cardiac risk has been less well studied.
Researchers from the Dept. of Cardiology, Mount Sinai St. Luke’s Hospital joined with other investigators to conduct a meta-analysis of the association between optimism and risk for future cardiovascular events and all-cause mortality . The results were published last month in JAMA Network Open.
The meta-analysis of 15 studies included nearly 230,000 individuals, and the mean follow-up was 13.8 years.
On pooled analysis, optimism was significantly associated with a 35% lower risk of cardiovascular events and a 14% lower risk of all-cause mortality.
The findings suggest that optimism is associated with cardiovascular benefits and that pessimism is associated with cardiovascular risk, with a pooled association that was similar to that for well-established cardiac risk factors.
The authors point out that mindsets can, in part, be modified making them a relevant target for clinical intervention. Future studies should seek to understand how to better promote an optimistic mindset and reduce pessimism. since a positive outlook appears to be important for preventive health.
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In the news: Flavonoids Lower Mortality Risks; Air Pollution May Increase AMD Risk
Flavonoids May Lower Risk of Cancer & CVD Death
A study published in Nature Communications reports that a diet moderate and consistent in plant-based flavonoids may lower the risk of all cause, cancer and cardiovascular mortality .
Short-term clinical trials have shown that flavonoid compounds and flavonoid-rich foods improve markers of CVD risk, while results from preclinical studies suggest that flavonoids may also lessen the risk of cancer. Last year, an independent and protective association between higher flavonoid intake and the likelihood of having AMD was also reported.
In the present study, Danish and Australian researchers aimed to learn more about flavonoid intake and mortality – especially cancer mortality, where observational data is scarce.
The researchers assessed the diets of over 56,000 Danes and followed their health and diet prospectively for 23 years, during which 14,083 deaths occurred.
After controlling for relevant factors (smoking, high blood pressure, and numerous other potential dietary and lifestyle confounders), they found that those with the highest flavonoid intake (top 20% of intake) had a 17% lower risk for all-cause mortality and a 15% lower risk for death from CVD compared to those with the lowest intake. Cancer mortality risk was reduced by 20% in the highest vs. lowest flavonoid groups.
The inverse associations between total flavonoid intake and mortality outcomes were strong and plateaued at daily intakes of about 500 mg for non-smokers and low-moderate alcohol drinkers.
For smokers and heavy alcohol consumers, the associations were even stronger and more linear.
According to the authors, emerging evidence suggests that flavonoids may afford greater protection to those with these lifestyle habits. Flavonoids may be protective against some detrimental effects these lifestyle factors have on nitric oxide bio-availability, endothelial function, blood pressure, inflammation, blood lipids, platelet function, and/or thrombosis.
The authors point out that meeting the threshold level of 500 mg flavonoids/day is readily achievable. One cup of tea, 1 apple, 1 orange, about 3 ½ ounces each of blue-berries and broccoli would provide most of the 6 sub- classes of flavonoids and over 500 mg total flavonoids. Tea, chocolate, wine, apples, and pears were the main flavonoid sources in the present study population.
Air Pollution May Up the Risk of AMD
In the first study of its kind, Taiwanese researchers report in BMJ’s Journal of Investigative Medicine that long term exposure to vehicle exhaust-related air pollution is associated with a nearly two-fold increase in AMD risk . While the effects of air pollutants on the risk of respiratory and cardiovascular disease are well acknowledged, not much evidence has been generated suggesting that air pollution impacts ocular disorders.
Analyzing air-quality data (1998-2010) and health insurance data for nearly 40,000 AMD-free urban dwellers (aged 50+), the researchers explored whether long term exposure to the common pollutants nitrogen dioxide (NO2) and carbon monoxide (CO) is associated with AMD risk. Over the 11-year follow-up, 1442 participants developed AMD
Compared with the lowest exposures, those with the highest NO2 exposures were 91% more likely to develop the disease while the highest CO exposure increased the risk by 84%.
Interestingly, exposure to moderate levels of the pollutants did not significantly raise AMD risk, raising the possibility of a threshold effect. More research to confirm these findings remains to be done.
According to the lead author, these macula-harmful pollutants are more likely to be entering the blood stream after being inhaled rather than entering the eye directly. NO2 and CO damage cells by creating reactive molecules (free radicals), which underscores the importance of the eye’s antioxidant defense system.
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In the news: Vitamin D Improves Allergic Rhinitis; Vitamin D Linked to Uveitis Activity
Vitamin D Supplements in Allergic Rhinitis
Allergic rhinitis, commonly called hay fever, refers to a group of symptoms that occur in sensitized individuals such as sneezing and nasal itchiness, discharge, and congestion, and often accompanied by allergic ocular symptoms as well.
Studies suggest that vitamin D may play an important role in the prevention of various autoimmune as well as allergic diseases. Vitamin D affects both innate as well as adaptive immunity and almost all types of immunologic cells, including T, B, dendritic cells, monocytes and macrophages. In addition to its effects on immune cells by modulating a variety of cytokines, vitamin D may have a key role in the pathogenesis of many allergic disorders, including allergic rhinitis.
Against this backdrop, university endocrinology researchers aimed to determine whether short-term vitamin D supplementation could improve symptoms in allergic rhinitis (AR) patients with low vitamin D levels.
This randomized double-blind placebo-controlled clinical trial was performed on 80 AR patients with vitamin D deficiency. AR was diagnosed by the Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines and confirmed by skin prick testing. Half the group received vitamin D (50,000 IU weekly) plus routine antihistamine medication (cetirizine); the other half received cetirizine plus placebo. The clinical symptoms questionnaire was completed at baseline and after 4 and 8 weeks of treatment
Comparison of the mean scores of symptoms severity showed no significant difference between the groups at study initiation and 4 weeks, whereas a significant difference was seen between baseline and 8 weeks of treatment (p = 0.007). Many of the individual symptom scores improved in the vitamin D group vs. placebo, including rhinorrhea, nasal pruritus, and sneezing (all p = 0.001); eyelid edema reached borderline significance (p = 0.06). Vitamin D levels increased significantly in the supplemented group.
The authors conclude that supplemental vitamin D along with antihistamines can result in symptom improvement in AR patients with vitamin D deficiency.
Effects of Vitamin D Levels on Uveitis
Numerous studies have associated low serum levels of vitamin D with increased risk of ocular inflammation such as non-infectious uveitis and scleritis.
In the current prospective case-control study, Australian researchers compared vitamin D levels and patterns of UV and dietary exposure between patients with active and non-active non-infectious uveitis, and population controls2.
Vitamin-D levels were compared between patients with active (n = 74) and inactive uveitis (n = 77) and population-based estimates, stratified by geographic region and season. Vitamin D intakes and exposures based on questionnaire results, including vitamin D sup-plementation and sunlight exposures on weekdays and weekends, were compared between active and inactive uveitis groups.
The median serum vitamin D level in those with active uveitis was found to be significantly lower than the inactive control group (p<0.001). The active uveitis group also had lower median serum vitamin D levels than the local population median.
Vitamin D supplementation was also significantly associated with uveitis inactivity (Kendall’s tau test, p = 0.026). In a sub-analysis of vitamin D deficient participants, UV exposure was significantly associated with uveitis inactivity (p=0.014 for weekday and weekend analyses).
Additional prospective studies are warranted to evaluate whether low vitamin D increases uveitis risk, and the role of vitamin D supplementation in the prevention and treatment of uveitis.
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In the news: Genotype Doesn’t Modify Response to AREDS2 Supplements; Aspirin Use Not Linked to AMD Progression
AREDS2 Supplement Benefits Do Not Differ by Genotype
A new post hoc analysis of the Age-Related Eye Disease Study 2 (AREDS2) concludes that two major risk alleles for AMD, complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2), do not modify the response to AREDS2 supplements for the treatment of AMD . Genotype made no difference in the benefits derived from AREDS2 supplements.
Whether or not genotyping should be considered for AMD patients who meet the criteria for AREDS supplementation has been controversial. When there is an interaction between genotype and treatment, it means that the response to the treatment differs depending on an individual’s genotype.
Several post hoc analyses have suggested that there are genetic subgroups who may respond differently to nutrient components (e.g. zinc vs. antioxidants) in AREDS supplements, while other analyses haven’t found any significant interactions. Recently, independent groups from three different academic centers each evaluated the available evidence and concluded that genotyping of CFH and ARMS2 to guide supplement choice for slowing AMD progression is unwarranted.
Since all previous analyses have used data from the original AREDS1 trial, and no other intervention study as large as AREDS is available to independently replicate previous findings, investigators decided to evaluate AREDS2 for any interaction between these risk alleles and response to AREDS2 supplements.
AREDS2 evaluated the following additions to the original AREDS formula (vitamins C, E, beta-carotene, zinc and copper): lutein/zeaxanthin, EPA + DHA, both or placebo. A secondary randomization tested further modifications of the original formula: lower zinc dose, no beta-carotene, both or no modification. Most of the participants also received the original AREDS formula.
The current analyses used 2775 eyes without late AMD at baseline of participants with complete data who were followed for a median of 5 years.
Genotype did not significantly modify the response to any of the AREDS2 supplements in respect to the progression of late AMD, including geographic atrophy (GA) and wet AMD. Subgroups based on CFH or ARMS2 did not respond differently to supplements with either lutein/ zeaxanthin, EPA/DHA, beta-carotene or high or low zinc doses. This was also true for groupings based on both CFH and ARMS2 genotypes.
The ARMS2 risk allele was significantly associated with progression to late AMD and wet AMD, but not with GA. No association between the CFH risk allele and AMD progression was seen.
The results suggest that AREDS2 supplements can be recommended to those with at least intermediate AMD who carry risk alleles CFH or ARMS2.
Aspirin Use not Associated with AMD Progression
In addition to analyzing for genetic interactions with AREDS2 supplements, AREDS researchers have also looked at interactions between the risk of AMD progression and taking aspirin – one of the most widely used drugs worldwide. Some observational studies have reported a link between regular aspirin use and increased risk of wet AMD .
Matching by propensity score (propensity for aspirin use) showed that the characteristics of the users and non-users were similar in both AREDS and AREDS2, so both studies were analyzed. Participants were stratified by quintiles, with quintile 5 being the highest propensity for aspirin use and quintile 1 the reference.
No significant association with progression to late AMD, geographic atrophy or wet AMD was observed for any quintile 2-5. The authors conclude that “patients with AMD need not avoid aspirin for this reason, when its use is medically indicated.”
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In the news: Supplements Stabilize Intermediate AMD? Glucosamine May Lower CVD Risk
Can Supplements Stabilize Intermediate AMD?
The authors of a multi-center controlled trial report that supplementation of carotenoids, vitamins, minerals and omega-3 fatty acids over a 2-year period led to a meaningful stabilization of intermediate AMD.
The AREDS2 trial indicated that lutein and zeaxanthin are more appropriate than β-carotene in slowing progression of AMD. Despite experimental and epidemiologic evidence suggesting a protective role of the omega-3 fats, AREDS2 also found no additional benefit of these fatty acids when combined with an AREDS formula.
According to the new study’s authors, a consortium of Italian ophthalmologists, the role of supplemental omega-3 fats in dry AMD is still being debated and additional clinical data are needed.
In this prospective, randomized double-blind study, 80 patients with intermediate AMD (AREDS Research Group classification) received placebo or a nutritional supplement (90 mg. vitamin C, 10 mg lutein, 2 mg zeaxanthin, 4 mg astaxanthin, 30 mg vitamin E, 22.5 mg zinc, 1 mg copper and 500 mg fish oil containing EPA 185 mg and DHA 140 mg).
AMD progression, the 1° endpoint, was assessed by retinography (digital fundus photographs), and BCVA was evaluated. An independent reading center judged all photographs taken during the trial. Progression of AMD was evaluated by retinography, by visual acuity both distance and near, and by a combination of all three parameters.
Seventy-four participants completed the study, 48 in the supplement arm and 26 in the placebo arm. Only 5 out of 74 (6.8%) patients showed AMD progression according to retinography: Three had an increase in atrophy while two developed wet AMD. Four out of these 5 patients were in the placebo arm (15.4%) and only one was in the supplement arm (2.1%). BCVA data alone did not differ between groups. No patients worsened in the supplement group when BCVA distance, BCVA near, and retinography were analyzed together. In contrast, 3 patients in the placebo arm worsened in all three parameters (p = 0.04 for between group comparison). The relatively short follow-up and small number of patients are limitations of this study.
However, the findings may warrant further study to evaluate the long-term effects of antioxidants / omega-3s in intermediate AMD.
Glucosamine Linked to Lower Risk of CVD
Supplemental glucosamine is widely used to relieve joint pain in osteoarthritis, with about 20% of US adults using it daily. Emerging evidence from animal and cross-sectional studies suggests that glucosamine may have a role in preventing CVD and reducing mortality, but prospective data is lacking.
A team from Harvard and Tulane Universities conducted a prospective study to assess the association of glucosamine use with the risk of CVD events . The study enrolled over 466,000 participants free of CVD at baseline who were followed for about 7 years. After adjusting for numerous factors, chronic glucosamine use was linked to a 15% lower risk of total CVD events, and a 22%, 18% and 9% lower risk of CVD death, coronary heart disease and stroke, respectively. Whether this commonly used supplement could help prevent CVD is an avenue of research worth exploring in clinical trials.
One caution about glucosamine use is worth noting. Several studies have raised the possibility that glucosamine use might increase IOP in those with glaucoma or ocular hypertension. One small retro-spective analysis in 17 people with these conditions reported that IOP was about 18% higher while taking glucosamine compared to pre-use levels and returned to pre-use levels after glucosamine was discontinued. The results of two subsequent studies suggest that for people without these conditions, and particularly younger people without these conditions, glucosamine appears to have little to no ocular effect.
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In the news:Vitamins, Carotenoids & Age-related Cataract; B-vitamin Levels Clue to Omega-3 Brain Effects
Vitamins, Carotenoids May Lower Risk of ARC
Numerous studies suggest that dietary vitamins and carotenoids may be associated with a reduced risk of age-related cataract (ARC), but a quantitative summary of these associations has been lacking. That led university researchers in Xi’an China to conduct a meta-analysis of 8 randomized controlled trials (RCTs) and 12 cohort studies of vitamin and carotenoid intake and ARC risk .
Most of the nutrients evaluated in the cohort studies were significantly associated with a reduced relative risk for ARC including: Vitamin A (19%), Vitamin C (20%), Lutein or zeaxanthin (19%), and Vitamin E and beta-carotene (each 10%). In the RCTs, neither vitamin E nor beta-carotene reduced risk vs. placebo.
Further dose-response analysis indicated that in cohort studies the risk of ARC significantly decreased by 26% for every 10-mg/day increase in lutein or zeaxanthin intake and decreased by 18% for each 500-mg/day increase in vitamin C intake (P < 0.001, respectively).
The dose-response was more modest for beta-carotene at 8% risk decrease per 5-mg/day, and for vitamin A with a 6% risk decrease per 5-mg/day (P < 0.001, respectively).
“If we could delay the onset of ARC by 10 years, it could halve the number of people requiring surgery," stated one of the study’s co-authors.
Understanding Omega-3 Effects in Alzheimer’s
The OmegAD trial was a 6-month double-blind trial in 204 mild to moderate Alzheimer’s patients randomized to 1.7 g DHA and 0.6 g EPA daily or placebo. The 1 outcome was cognitive change (measured by Mini-Mental State Examination or MMSE); the 2 outcome was clinical status (Clinical Dementia Rating Scale). The results showed positive effects only in a sub-group of patients with mild AD.
Significant interactions between omega-3 supple-mentation and baseline homocysteine levels on cognition and clinical stage were observed in the current analysis of OmegAD. In patients with elevated homo-cysteine (which reflects poor B-vitamin levels), supple-mental omega-3 significantly improved both measures of cognitive performance and clinical status.
B-vitamins (folic acid, vitamins B6 and B12) are necessary to form phosphatidyl choline, an important carrier of DHA and EPA in blood and across the blood brain barrier. So adequate B-vitamins could be important in delivering omega-3s to the brain.
An earlier RCT, VITACOG , evaluated high dose B-vitamins in mild cognitive impairment. Analysis found that a protective effect of the B vitamin intervention on brain atrophy rates was dependent on the plasma concentrations of DHA and EPA at the study’s start. Only those participants with high baseline plasma DHA and EPA showed lower rates (40%) of brain atrophy with the B-vitamin treatment vs. placebo.
Taken together, these findings suggest that both omega-3 and B-vitamin status are important in those with cognitive decline. The functional status of B-vitamins appears to be a relevant factor to consider when evaluating the effect of supplemental omega-3.
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In the news: New Study Emphasizes CVD Benefits of a Plant-Based Diet
Changing to a High-Quality Plant-Based Diet Reduces Risk of Total & CVD Mortality
The reported findings of a new study add compelling evidence for the heart benefits of a plant-based diet. The investigation, from the Harvard School of Public Health, was recently presented at the American Heart Association Epidemiology, Prevention, Lifestyle and Cardiometabolic Health Scientific Session in Houston.
The results suggest that it’s never too late to increase longevity and reduce the risk of death from cardio-vascular disease (CVD) by adding high-quality plant-based foods, even for those who start out with poor-quality diets.
While previous studies have shown that eating a high-quality plant-based diet can reduce heart disease risk, this is the first to examine how dietary changes – both positive and negative – may impact the risk of total and CVD mortality.
The study included 47,983 participants in the Nurses’ Health Study and 25,737 participants in the Health Professionals Follow-Up Study – none of whom had a history of heart disease or cancer at the start of those studies.
The researchers used three diet scales for plant-based diets to examine dietary changes: an index for overall consumption of plant-based foods, an index for healthful plant-based foods (e.g. whole grains, fruits, veggies, beans and nuts), and an index for lower quality plant-based foods (e.g. fruit juices, refined grains, potatoes and sweets). Changes in the participants’ diets were assessed over a 12-year follow-up (1998-2014).
Compared with participants whose diets were stable during the follow-up period, those with the largest increase in an overall plant-based diet showed an 8% lower risk in all-cause mortality. Those with the greatest increase in a healthy plant-based diet had a 10% all-cause mortality risk.
In contrast, an 11% increase in mortality risk was seen in those with the biggest increase in an ‘unhealthy’ plant-based diet.
For death from CVD, a 10-point increase on the healthy plant-based diet scale was linked to a 10% lower risk, while a 10-point increase on the unhealthy plant-based diet scale was associated with a 6% higher risk.
Comments
Adopting a healthy plant-based diet doesn’t mean eating plant foods exclusively, but rather consuming less animal derived foods (e.g. red meat, processed meats) and swapping healthier plant derived foods for less healthy ones such as fried potatoes, sugary beverages, deserts and refined grains. This study emphasizes the link between a healthful plant-based diet and total and CVD mortality.
There are a number of ways that plants may be cardioprotective: They are sources of phytonutrients like carotenoids and polyphenols, generally lower in saturated fats and cholesterol, and tend to be less inflammatory. A study published last year, for instance, found that adherence to the plant-based Mediterranean diet was associated with fewer CVD events, and reduced markers of inflammation, glucose metabolism and insulin resistance .
For patients who want to transition to a heart healthier way of eating, the Harvard website ‘The Right Plant-Based Diet for You’ offers practical suggestions. (https://www.health.harvard.edu/staying-healthy/the-right-plant-based-diet-for-you).
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In the news: NEI Study: No Evidence Calcium Raises Risk of AMD Progression
The Role of calcium in AMD Progression?
Two previous studies exploring the role of dietary and supplementary calcium in AMD produced mixed results, leaving eye care professionals and their patients wondering whether extra calcium is safe or harmful for the aging eye.
In 2015, a cross-sectional analysis of the National Health and Nutrition Examination Survey observed an increased prevalence of AMD among participants with supplemental calcium intake of more than 800 mg. daily.
In contrast, a 2014 analysis of the Blue Mountains Eye Study involving more than 2000 participants with a 15- year follow-up, reported a link between low dietary calcium intake and the development of late AMD .
Could it be that supplemental calcium as well as too little dietary calcium are both detrimental? To shed further light on this question, National Eye Institute researchers conducted a secondary analysis of 4751 participants in the AREDS trial to evaluate the association of baseline dietary and supplementary calcium intake with AMD progression .
Measures and Methods
Main outcomes and measures were development of late AMD, geographic atrophy (GA, central or non-central), or neovascular AMD detected on centrally graded baseline and annual fundus photographs.
Men and women with varying severity of AMD were categorized into quintiles of baseline dietary calcium intake determined by food frequency questionnaire, and energy adjusted. Baseline calcium supplement use was determined via an additional questionnaire.
Results
The analysis found that participants with the highest intake of dietary calcium compared with those in the lowest quintile had a 27% lower risk of developing late AMD, a 36% lower risk of central GA, and a 20% lower risk of developing any GA.
Participants in the highest intake of supplementary calcium had a 30% lower risk of developing neovascular or wet AMD compared with those who did not supplement.
Conclusion and Commentary
“Despite these protective associations of dietary and supplementary calcium, the results may be considered hypothesis generating, requiring validation with further investigations”, the study’s authors concluded.
An accompanying editorial points out that higher intake of calcium was also associated with higher intake of lutein in this study, suggesting that the outcome might be attributed to concomitant higher lutein intake, rather than a direct effect of calcium. How calcium might beneficially affect the macula is not known.
Another interesting finding is that the size of drusen and other sub-retinal pigment epithelium deposits, which are known to contain calcium, were not associated with higher intake of this mineral.
According to the editorial, the evidence suggests that higher calcium intake is not harmful to the macula, and people taking calcium supplements can be reassured that higher calcium intake is unlikely to affect their AMD. Some 50% of men and 65% of women in the US are estimated to regularly use calcium supplements.
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In the news: Nutrition Support May Work Synergistically with Anti-VEGF for Wet AMD
Anti-VEGF Plus Nutrition Support May Be Beneficial in Wet AMD
Although evidence has clearly shown that monthly or bi-monthly intravitreal injection of anti-vascular endothelial growth factor (VEGF) can prevent vision loss and may even improve visual acuity in wet AMD, about 5-10% of patients continue to lose visual acuity. Further, monthly injections are an economic burden. Against this backdrop, university researchers in Italy conducted a pilot study to see whether complementary therapies could improve treatment success of anti-VEGF injections.
Methods
This prospective, randomized, 12 month-long pilot study included 60 patients with new-onset neovascular AMD and no prior intravitreal treatment. Patients were randomized to one of three groups: 1) aflibercept (IVA) therapy alone, 2) aflibercept combined with the non-steroidal anti-inflammatory 0.1% pranoprofen eye drops 3 times daily, or 3) aflibercept plus an AREDS2 formula (modified) with 325 mg EPA + DHA daily. All participants received an initial injection of 2 mg IVA followed by two additional monthly injections. A blinded examiner prescribed further IVA injections as per designated retreatment criteria. Primary outcomes were the changes in best-corrected visual acuity (BCVA in the enrolled eye and in central retinal thickness (CRT). The secondary outcome was a comparison of the required IVA retreatments over the 12-month period among the treatment arms.
Results
At 12 months, all groups showed significant improvement in BCVA, with no between group differences.
The mean CRT change from baseline to 12 months was -76.9 ± 10.9 μm, -129 ± 19.9 μm, and -105 ± 11.6 μm in groups 1, 2 and 3, respectively. A small but significant difference in central retinal thickness was observed with pranoprofen co-treatment (Group 2) vs. anti-VEGF treatment alone (p = 0.001).
Co-therapy with nutritional support (Group 3) yielded a significant difference of one less aflibercept injection in the 12-month period compared with anti-VEGF treatment alone (p < 0.001).
Comments
These findings suggest that nutritional support and topical anti-inflammatory drops may complement anti-VEGF therapy, the first line of treatment in exudative AMD. The results of this pilot study, however, need to be validated in larger and longer trials,
Previous clinical trials found that topical NSAIDS augmented the activity of intravitreal anti-VEGF in reducing central retinal thickness – findings that agree with those for co-treatment with pranoprofen in the current study.
A previous study also reported that omega-3 supplementation combined with anti-VEGF treatment was associated with decreased vitreal VEGF-A levels in wet AMD patients – a finding that might explain the reduced need for aflibercept injection seen in the present study.
Although inflammation is not central to AMD as it is in uveitis for example, it has been reported to play a role in AMD development and progression. Nutritional support or NSAIDS could contribute by influencing the inflammatory cascades and angiogenesis involved in AMD pathogenesis.
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In the news: Vitamin K and Retinal Health
The results of a new observational study from Belgium and the Netherlands, highlight a possible role for vitamin K in promoting retinal health.
Matrix Gla Protein and Vitamin K
Matrix Gla protein is a small, vitamin K-dependent protein that binds to calcium ions. It is expressed in vascular smooth muscle and endothelial cells, where it acts as an inhibitor of vascular mineralization.
Once activated by vitamin K (referred to as active matrix Gla protein or MGP), it becomes a potent, locally acting inhibitor of calcification in large arteries and protects against macrovascular complications and arterial stiffening. MGP is also found in the kidneys and micro-vessels of the heart, where it contributes to maintaining organ function.
In addition, MGP is abundantly produced in the eye. In ocular tissues it helps protect the structural integrity of the trabecular meshwork, the sclera, and retinal ganglion cells. Animal studies have demonstrated that MGP is expressed in retinal vessels as well.
Inactive matrix Gla is a biomarker for poor vitamin K status. It is also a risk factor for cardio-vascular disease. A number of studies have shown that the diameters of micro-vessels in the retina can offer valuable information. Narrower retinal arteriolar caliber and smaller arteriovenous ratio, for instance, predict the incidence of diabetes and coronary heart disease.
Against this backdrop, researchers from the University of Leuven in Belgium assessed whether levels of circulating inactive matrix Gla might predict retinal microvascular diameters in a longitudinal cohort study .
Study Highlights
The study included 935 randomly recruited men and women who were participants of the large Flemish Study on Environment, Genes and Heath Outcomes. The researchers measured plasma levels of inactive matrix Gla protein, a marker of inadequate vitamin K, at baseline (1996-2010) using an ELISA-based assay.
Retinal microvascular diameters, which included central retinal arteriolar and venular equivalent (CRAE and CRVE), and arteriole-to-venule ratio (AVR), were measured at follow-up (2008-2015) employing retinal photography and IVAN software.
CRAE (p= 0.005) and AVR (p= 0.08) at follow-up decreased across tertiles of inactive matrix Gla protein. The key finding is that, even with multiple adjustments, smaller microvascular diameters were associated with higher circulating baseline levels of inactive matrix Gla protein.
According to the authors, these findings are in line with studies showing expression of MGP in capillaries and small arterioles, and in particular in the glaucoma-relevant tissues of the eye and the retina’s large network of arterioles, capillaries, and venules.
Comments
This is the first longitudinal population-health study to assess the association of retinal microvascular diameters and circulating levels of inactive Gla. The researchers call for further studies to clarify underlying molecular pathways and to substantiate their theory that vitamin K supplementation might promote ocular health and prevent glaucoma-induced optic nerve damage.
In the meantime, consuming adequate vitamin K is important for bone and cardiovascular health, as well as proper blood clotting. (Avoiding fluctuations in vitamin K intake is necessary for those taking coumadin, who should follow the advice of their physician). The best food sources of vitamin K are leafy green vegetables, followed by cruciferous vegetables. Fish, meat, egg and cereals contain small amounts.
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In the news: Sleep Apnea & Ophthalmology; Metabolic Syndrome & Cataracts
Obstructive Sleep Apnea & Ocular Disorders
Obstructive Sleep Apnea (OSA) is a sleep disorder characterized by pharyngeal collapse and partial obstruction of the upper airway, resulting in intermittent hypoxia. The hypoxia caused by repeated lapses in breathing during the night increases the risk and progression of coronary artery disease, heart failure, stroke, and diabetes.
OSA can also affect the eyes, which are particularly susceptible to both vascular and mechanical consequences of the condition. OSA is associated with floppy eye lid syndrome, anterior ischemic optic neuropathy, glaucoma, and diabetic retinopathy as well as other ocular conditions.
It’s estimated that 12% of adults suffer from OSA in the United States and that 80% of the patient population is undiagnosed. Obesity and particularly central adiposity (accumulation of fat in the lower torso and abdomen) are potential risk factors for sleep apnea. Thus, it’s no surprise that the prevalence of OSA is on the rise along with the epidemic of obesity here in the US.
There is growing recognition that eye care professionals have a role to play in OSA, not only in detecting and monitoring pathology associated with the condition but in referring patients to appropriate health care providers for OSA treatment. Several recent review articles on OSA and eye disorders are highlighted below, along with links to the abstract or full paper in the reference section.
Several articles(1,2) worth reading discuss the possible mechanisms for how OSA might affect the eye, and review the literature with respect to diabetic retinopathy, central serous retinopathy, retinal vein occlusion, glaucoma, floppy eye syndrome, non-arteritic ischaemic optic neuropathy, keratoconus and AMD. The authors also highlight gaps that remain in the evidence and in our knowledge.
Another potentially useful article(3) discusses newer home-based sleep apnea testing which can be implemented via physician clinics, with oversight by certified sleep physician. While CPAP is the gold-standard, the author also emphasizes that OSA management should also include diet and exercise. Patients with OSA and ocular disorders would benefit by the sharing of information by eye care professionals, primary health care providers, nutritionists and those that are treating OSA.
Metabolic Syndrome and Cataract Extraction
The metabolic syndrome (METS) is a cluster of metabolic risk factors for cardiovascular disease and type 2 diabetes, which include obesity (particularly abdominal fat), elevated blood glucose, high blood pressure and dyslipidemia.
A previous prospective study found that having METS or some of its components raised the risk of cataract extraction in women, especially those 65 years or less. To see if these findings might apply to men as well, Swedish researchers(4) examined the relationship of the individual METS components of abdominal adiposity, diabetes and hypertension to cataract extraction in a prospective cohort of over 45,000 men.
Over the 15‐year follow‐up, 7573 incident cases of cataract extraction were identified. After controlling for potential confounders, all three individual METS components raised the risk of cataract removal. The risk of cataract extraction increased with increasing numbers of metabolic syndrome components (p < 0.0001), and men who were 65 or younger at baseline with all three METS components had a 2.43-fold higher risk for cataract extraction.
These findings underscore the importance of weight control and a healthy lifestyle in cataract prevention.
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In the news: Dietary Nitrates & AMD; Overview of Vital Study
Green Leafy Vegetables & Early AMD Risk
Australian medical researchers report a link between intake of dietary nitrate, a precursor of nitric oxide, and risk of AMD . While a previous Harvard study found that greater nitrate intake was associated with risk reduction of POAG, this is the first time that the effects of dietary nitrate on AMD risk has been measured. [See also EduFacts archives at SBH.com: Vol. 18, Intake of Dietary Nitrate Associated with Lower POAG Risk].
The researchers analyzed data from 2,037 participants of the longitudinal population-based The Blue Mountains Eye Study for which complete dietary data and AMD information was available. The participants were re-examined 15 years later and included in the analysis.
Incidence of AMD (the main outcome measure) was determined by color retinal photographs of the macula which were graded for the presence of early and late AMD. Dietary data were collected using a food frequency questionnaire, and nitrate intake calculated based on a comprehensive nitrate database of foods.
After adjusting for age, sex, smoking, energy intake, fish consumption, and AMD risk alleles (CFH and ARMS-2 polymorphisms), those who consumed 100-142 mg of vegetable-sourced nitrates each day had a 35% risk reduction of developing early AMD vs. those eating less than 69 mg vegetable nitrates daily.
No additional risk reduction was seen at the highest vegetable nitrate intake level (>142 mg per day), suggesting a non-linear association or possible threshold effect. In this study, the largest benefit was seen with moderate nitrate intake. This observation is consistent with the results of a previous study which also showed a non-linear association between dietary nitrate and, in that case, vascular disease mortality.
If these findings are confirmed, dietary nitrates may be another good reason to eat leafy vegetables in addition to the lutein and antioxidants they contain. Beet root too, is a rich source of nitrates.
Overview of the VITAL Trial
Results from The Vitamin D and Omega-3 Trial (VITAL) were published in the Nov. 10th issue of the New England Journal of Medicine , . Neither vitamin D nor omega-3 supplementation lowered the incidence of major cardiovascular events (a composite of heart attack, stroke or death from CVD causes) or invasive cancer of any type, the primary endpoints evaluated in the trial.
However a number of secondary findings appear to be encouraging: a lower incidence of heart attack (nominal 28% reduction in risk) and death from heart attack (nominal 50% reduction in risk) with fish oil vs. placebo, and a lower mortality from cancer with vitamin D (nominal 17% reduction in risk) vs. placebo. These secondary findings must be interpreted with caution, but raise the possibility that supplements might be of benefit in preventing CHD or cancer death for some.
It’s worth noting that subgroup analyses showed a lower incidence of the primary cardiovascular endpoint with fish oil supplementation vs. placebo for those with low fish intake. Baseline dietary fish intake modified the fish oil intervention’s effect on major cardiovascular events (nominally significant reduction in risk of 19%) in participants consuming < 1 ½ servings weekly, while no risk reduction was observed for those with higher intake. These apparent findings could shape the designs of future trials, as poor fish intake was common in VITAL and is common in the US.
VITAL is a randomized, double-blind, placebo-controlled trial (with a two-by-two factorial design) assessing the effects of vitamin D (2,000 IU daily) and fish oil (1,000 mg daily, 460 mg EPA/380 mg DHA, Lovaza) on the primary prevention of CVD and cancer in 25,871 men (> 50 yrs) and women (> 55 yrs). The participants, with no history of cancer or CVD at baseline, were assigned to one of four regimens: both vitamin D and fish oil, vitamin D and placebo, fish oil and placebo, or two placebos daily. Participants were followed for about 5.3 years.
The strengths of the trial include the large number of people enrolled and the applicability of the findings to many in the population as African Americans, men and women, and those with normal as well as low blood levels of vitamin D were included. Importantly, no adverse effects were seen for vitamin D or omega-3 supplementation in VITAL, including no excess bleeding or high blood levels of calcium.
An accompanying editorial emphasized that the positive secondary results should be interpreted cautiously because there was no statistical correction for the multiple comparisons conducted (partly due to the number of secondary end points evaluated). Also for fish oil, the secondary effects (less heart attacks or fatal heart attacks) have not been consistently seen in all large, well-controlled trials.
For vitamin D and cancer, however, experimental studies consistently demonstrate an anti-cancer mechanism, and a recent meta-analysis reported a significant benefit with vitamin D and cancer mortality5.
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In the news: Overview of VITAL: Vitamin D & Omega-3 in Primary Prevention of CVD, Cancer
Overview of the VITAL Trial
Results from The Vitamin D and Omega-3 Trial (VITAL) were published in the Nov. 10th issue of the New England Journal of Medicine(1,2). Neither vitamin D nor omega-3 supplementation lowered the incidence of major cardiovascular events (a composite of heart attack, stroke or death from CVD causes) nor invasive cancer of any type, the primary endpoints evaluated in the trial.
Secondary Findings
A number of secondary findings could be viewed as encouraging, particularly the lower mortality from cancer (17% reduction in risk) seen for vitamin D vs. placebo. While omega-3 supplements didn’t lower all major cardio events as a group, a 28% reduction in risk was seen for heart attack when analyzed separately. In addition, analyses found a 50% reduced incidence of death from heart attack and 17% reduction in risk for total coronary heart disease or CHD with fish oil vs. placebo.
These secondary findings must be interpreted with caution, but do raise the question of whether supplements might be of some benefit in preventing CHD or cancer death. The study was large, and the secondary measures were built into the study design.
Low Fish Consumption
It’s worth noting that subgroup analyses showed a lower incidence of the primary cardiovascular endpoint with fish oil supplementation vs. placebo for those with low fish intake. Baseline dietary fish intake modified the fish oil’s effect on major cardiovascular events (nominally significant reduction in risk of 19%) in participants consuming less than 1½ servings weekly, while no risk reduction was observed for those with higher intake. These apparent findings could shape the design of future trials, as poor fish intake was common in VITAL and is common in the US.
Trial Design, Strengths and Safety
VITAL is a randomized, double-blind, placebo-controlled trial assessing the effects of vitamin D (2,000 IU daily) and fish oil (1,000 mg daily, 460 mg EPA/380 mg DHA, Lovaza) on the primary prevention of CVD and cancer in 25,871 men (> 50 yrs) and women (> 55 yrs). The participants, with no history of cancer or CVD at baseline, were assigned to one of four regimens: both vitamin D and fish oil, vitamin D and placebo, fish oil and placebo, or two placebos daily. Participants were followed for about 5.3 years.
The strengths of the trial include the large number of people enrolled and the applicability of the findings to many in the population as African Americans, men and women, and those with normal as well as low blood levels of vitamin D were included. Importantly, no adverse effects were seen for vitamin D or omega-3 supplementation in VITAL, including no excess bleeding or high blood levels of calcium.
Cautionary Considerations
An accompanying editorial(3) emphasized that the positive secondary results should be interpreted cautiously because there was no statistical correction for the multiple comparisons conducted (partly due to the number of secondary end points evaluated). Also for fish oil, the secondary effects (e.g. less heart attacks or fatal heart attacks) have not been consistently seen in all large, well-controlled trials.
For vitamin D and cancer, however, experimental studies consistently demonstrate an anti-cancer mechanism, and a recent meta-analysis reported a significant benefit with vitamin D and cancer mortality(4), Further, in one VITAL analysis, the rate of death from cancer was 25% lower with vitamin D vs. placebo when the first two years of the five-year study were excluded. Although this was not a “pre-planned” analysis, the apparent lower rate of cancer death with vitamin D is in line with the meta-analysis findings.
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In the news: Med Diet Lowers AMD Risk; RCT: Meditation Helpful in Glaucoma
Mediterranean Diet May Lower Risk for AMD
Adherence to the Mediterranean diet may contribute to the prevention of age-related macular degeneration (AMD), according to research conducted by a consortium of Spanish, German, Dutch and French researchers. Study participants with better adherence had a 41% reduction in risk of incident advanced AMD versus those with poor adherence .
The researchers examined the associations of adhering to the Mediterranean eating pattern with the incidence of advanced AMD in two population-based prospective cohorts, the Rotterdam Study 1 (RS-1) and the Alienor Study. Included in the analysis were 4,446 Dutch participants aged 55 years or older from RS-1 and 550 French subjects aged > 73 years from the Alienor Study with complete ophthalmologic and dietary data available.
Exams were performed every 5 yrs. over a 21-yr. period in RS-1, and every 2 yrs. over a 4-yr. span in the Alienor cohort. Adherence was assessed using a 9-component Med Diet score based on intake of fruits, vegetables, cereals, fish, meat, legumes, dairy, alcohol and a mono-unsaturated (e.g. olive oil) to saturated fat ratio. The main outcome was incidence of advanced AMD evaluated by fundus photographs.
Among the participants, 155 total developed advanced AMD. Pooling data for both cohorts, those with high Med Diet scores (6-9) had a significantly reduced risk for advanced AMD compared to those with low scores (0-3), HR 0.59 and p for trend = 0.04.
These findings, according to the authors, support the role of a diet rich in healthful nutrient-rich foods in preventing AMD. The abundant polyphenols and antioxidant nutrients provided by the Med Diet are thought to target inflammation and oxidative stress – significant drivers of AMD pathobiology.
AMD is a complex disease involving aging and genetics – factors that can’t be modified. However, stopping smoking and adopting a Med style of eating are positive risk-reducing steps that can be taken.
Meditation Complements Glaucoma Treatments
Glaucoma sufferers and their clinicians should take heed of a study just published in Journal of Glaucoma. The study found that 60 minutes of meditation each morning resulted in intraocular pressure (IOP) lowering similar to that typically seen with prostaglandin analogues like latanoprost or β-blockers such as timolol. The best part about these findings is that the meditation techniques are easy to learn and incorporate for most glaucoma patients.
Stress is a key risk factor affecting mechanisms at play in glaucoma including ischemia, oxidative stress, glutamate excitotoxicity, inflammation/glial activation, neurotrophin loss and vascular dysregulation. Knowing that sight-threatening glaucoma causes stress and anxiety in patients, and that stress often leads to elevated blood pressure, the investigators set out to assess the impact of stress reduction on IOP.
In the randomized trial , 90 POAG patients (180 eyes; age >45) treated with eye drops were assigned to a waitlist control or a mindfulness meditation group led by a yoga instructor and practiced daily for 3 weeks. IOP (the primary endpoint), quality of life (QOL), stress-related serum biomarkers (cortisol, β-endorphins, IL6, TNF-α, BDNF, ROS, TAC) and whole genome expression were measured.
Between group comparisons showed that this short course of meditation therapy lowered IOP by nearly 5 points on average (OD: 18.8 to 12.7, OS 19.0 to 13.1 mm Hg). The mean IOP reduction correlated with a normalization of all the stress biomarkers evaluated (all P values < 0.001). The meditators improved in QQL (p < 0.05). These changes also correlated well with gene-expression profiling. Whether stress reduction will lead to improvements in visual fields is still to be studied. However the findings to date are important and impressive.
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In the news: Plant-Sourced Mono-unsaturated Fats, Sleep & Risk of CVD
Plant MUFAs May Curtail CVD, All-Cause Mortality
A preliminary report of a large-scale observational study adds to the evidence that a diet higher in plant-sourced mono-unsaturated fatty acids (MUFAs) is protective against heart disease.
Study results, presented earlier this year at the AHA’s Epidemiology and Prevention Session in New Orleans, suggest that we should be consuming more MUFAs from olive oil, nuts, seeds and avocados, while moderating MUFA intake from full-fat dairy, eggs, red meat and poultry. Further benefits may accrue from replacing saturated fats, trans-fats or refined carbo-hydrates with plant MUFAs .
Harvard-based researchers used data from over 63,000 women (Nurses’ Health Study) and » 30,000 men (Health Professionals Follow-Up Study) to assess the impact of MUFAs on death from CVD and other causes. Detailed food frequency questionnaires were administered every 4 years to evaluate dietary composition; Participant follow-up was a mean 22 yrs.
Findings, adjusted for potential confounders, include:
Connecting Olive Oil, Sleep & Heart Attack
Impaired sleep and short sleep duration are risk factors for the development of CVD. When it comes to heart attack and stroke, what might unsaturated fats and sleep patterns have in common? According to recent work from Keenan Research Centre for Biomedical Science of St. Michael’s Hospital in Toronto, the connection between them may be a plasma protein known as ApoA-IV, which the researchers determined to be an inhibitory factor for platelets . Platelet aggregation can block blood flow and lead to thrombosis, a common cause of heart attack and ischemic stroke.
Using both experimental models and humans, the research team found that ApoA-IV can both decrease platelet aggregation and slow plaque build-up in vessels.
In a previous randomized controlled study , it was found that circulating ApoA-IV increased after participants consumed meals containing unsaturated fats, including MUFA-rich olive oil. Platelets are stimulated after eating, and increasing ApoA-IV via consumption of unsaturated fat mitigates platelet hyperactivity and bonding. This could reduce inflammation after meals, and thus the risk of heart attack and stroke.
ApoA-IV was also observed in the present investigation, to exhibit a circadian rhythm in healthy volunteers. Greater ApoA-IV activity occurred overnight and diminished in the morning. It’s known that heart attacks occur more frequently in the early morning hours, which is due, in part, to increased platelet adhesiveness and an increase in stress hormones. According to the researchers, the low levels of apoA-IV in the morning likely contribute to enhanced platelet aggregation, and may lead to more adverse cardiovascular and cerebro-vascular events.
While these intriguing findings are preliminary, they raise the possibility that foods high in unsaturated fats like MUFAs, along with good sleep patterns may be cardioprotective.
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In the news: Flavonoid-Rich Diets & an Orange a Day May Help Keep AMD at Bay
Dietary Flavonoids and Risk of AMD
The majority of research to date has focused on the effects of antioxidants such as vitamins C, E, and A and the carotenoids lutein and zeaxanthin on AMD risk and progression. Increasingly, researchers are also exploring the potential role of phytochemicals with antioxidant and anti-inflammatory properties, including flavonoids – the bioactive compounds found in foods such as tea, chocolate, red wine, fruit, and vegetables.
There are 6 main classes of flavonoids: flavonols, flavan-3-ols, flavones, flavanones, anthocyanins, and isoflavones. In addition to the antioxidant and anti-inflammatory activities of flavonoids, there is strong evidence that they positively affect vascular health through improved endothelial function.
While flavonoids could act against AMD by minimizing oxidative stress and inflammation-associated damage and by improving vascular function, it is important to first establish whether intake of these phytochemicals is, indeed, beneficially associated with the risk of AMD.
To that end, a team of investigators from Australia conducted a population-based cohort study with a 15 year follow up to examine the relationship between dietary flavonoid intake and flavonoid classes, and the prevalence and 15-year incidence of AMD .
Notably, the researchers observed significant and protective associations between the intake of total flavonoids, as well as total flavonol and total flavanone intakes with AMD prevalence. They also observed more modest associations with several flavonoid classes, a key flavonoid and risk of incident late AMD.
Methods
Two thousand eight hundred fifty-six adults from the Blue Mountains Eye Study aged ≥49 years at baseline and 2037 participants followed up 15 years later, were included in prevalence and incidence analyses, respectively. Dietary intake was assessed by using a semiquantitative food-frequency questionnaire (FFQ). Estimates of the flavonoid content of foods in the FFQ
were assessed by using USDA Flavonoid databases. AMD was assessed by retinal photographs.
Results
Each 1 standard deviation increase in total overall flavonoid intake was associated with a 24% reduced likelihood of any AMD. (Multivariable-adjusted OR: 0.76; 95% CI: 0.58, 0.99).
Each 1 standard deviation increase in dietary intake of total flavonols and total flavanones was associated with 25% and 23% reduced odds, respectively, of the prevalence of any AMD. [Multivariable-adjusted OR (95% CI): 0.75 (0.58, 0.97) and 0.77 (0.60, 0.99), respectively].
A 61% reduced risk of late AMD after 15 years was observed in participants who reported consuming one or more servings of oranges per day compared with those who never consumed oranges at baseline. (Multivariable-adjusted OR: 0.39; 95% CI: 0.18, 0.85).
A marginally significant trend (P = 0.05) was observed between increasing the intake of total flavanone and the individual flavanone hesperidin (from the first to the fourth quartile), and reduced likelihood of incident late AMD, after multivariable adjustment.
Comments
These findings are plausible based on the biological activities of flavonoids reported in the published literature, and in line with existing evidence that adequate consumption of fruit and vegetables (abundant in flavonoids) is protective against AMD .
Consuming oranges and orange juice in particular (key contributors of flavanones in this cohort) was inversely and independently associated with both the prevalence and incidence of late AMD. Since there is a striking gap between the total flavonoid intake in this cohort (median 875 mg/day) and the total flavonoid intake in the US (median 117 mg/day), taking in more flavonoids daily should be a priority for those concerned about macular health. An orange a day may be a good way to start.
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In the news: Emerging Evidence For a Gut-Retina Axis
High Glycemic Index Diets Linked to AMD
Analyses of large-scale studies such as the Nurses Study, Blue Mountains Eye Study and AREDS, suggest that high glycemic index diets are a risk factor for AMD onset or progression in nondiabetics . High glycemic index (GI) diets are characterized by consumption of carbohydrates that cause a rapid rise in blood glucose, such as white bread and rice, sugars, and processed foods with no to low fiber.
Scientists Allen Taylor and Sheldon Rowan of Tufts Human Nutrition Research Center, Nutrition and Vision Research Lab, have embarked on a project to explore the underlying mechanisms connecting the consumption of refined carbohydrates and AMD.
Low GI Diets Protective Against AMD Features
In a recently published experiment , Taylor, Sheldon and colleagues uncovered an interaction between carbohydrate quality and the gut microbiota in mice.
The Tufts team fed wild-type mice either low or high GI isocaloric diets beginning at 12 months of age (middle-age) through 24 months of age (old age). After 6 months, half of the mice receiving the high GI diet were switched to the low GI diet. Despite lacking a macula, this wild-type aged mouse model has been previously shown to be useful in exhibiting retinal damage characteristic of dry AMD.
Mice fed the high GI diet displayed many features of AMD, including retinal pigment epithelial hyper-pigmentation and atrophy, lipofuscin accumulation, and photoreceptor cell loss, while those in low-GI diet group did not. The low GI diet also limited advanced glycation end products (AGEs) and peroxidized lipids, as well as increased C3-carnitine in retina, plasma or urine. (We refer to AGEs in later text).
Critically, the damage seen while on the high GI diets washalted or reversedwhen mature mice were switched from the high to the low GI diet.
Gut Microbiota and Bacterial Metabolites
The team also looked at the animals’ gut microbiota and found a difference in response to the diets. They identified microbiota in Clostridales order as being associated with the high GI diet.
With the low GI diet, protection from the features of AMD, was associated with Bacteroidales order.
Untargeted metabolic analysis revealed that microbial co-metabolites, particularly higher blood levels of serotonin, were protective against AMD features. Serotonin is synthesized in the intestine in response to signals produced by gut microbes.
In addition to serotonin, increased blood levels of C-3 carnitine (propionylcarnitine) were associated with less AMD features. C3-carnitine plays a role in cellular fatty acid metabolism, and is found in many low GI foods including whole wheat and legumes (beans and peas).
Currently there is a lack of early biomarkers for AMD, and this work identifies potential markers for future testing: AGEs, peroxidized fats, C-3 carnitine, and serotonin.
Identifying metabolites associated with changes in gut microbiota and protection against AMD features, has led the researchers to propose the existence of a gut-retina axis. In a more recent paper , the Tufts team explored additional gut microbiota-AMD interactions that point toward possible pathogenic roles for some microbiota families (e.g. Ruminococcaceae, Lachnospiraceae, and some members of Clostridiaceae and others).
Nutrition research has traditionally focused on direct interactions between nutrients and physiological organ systems to learn how diet influences health and disease. Now, it’s increasingly important to consider nutrient effects on the microbiome as well for a more complete picture. Diet impacts the risk for and pro-gression of AMD. Could a gut-retina axis be part of that picture?
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In the news: Anti-Inflammatory Dietary Pattern May Lower Risk of Depression
Inflammation and Depression
According to the World Health Organization, depression is the leading cause of disability world-wide, and it affects more than 15 million American adults in a given year.
Greater attention is being paid to its role as a major independent risk factor in many chronic illnesses such as heart disease and certain cancers, and it has been associated with ocular conditions as well. Depression and anxiety are reported to be more prevalent in dry eye disease (DED) patients than in controls, for example . A recent study also reported that symptoms rather than clinical signs of DED were more predictive of depression in a cohort of female DED patients .
There is also increasing recognition that ongoing, chronic inflammation may have a part to play in depression. One investigation, for example, found that people with depression had higher blood levels of the inflammatory marker C-reactive protein (CRP). Brain scans of depressed individuals have also indicated increased neuroinflammation compared to those without depressive symptoms.
Further, dietary factors consistently have been shown to affect inflammation through both pro- and anti-inflammatory mechanisms. The Western-type diet (high in sugar, fried foods, high-fat dairy products, and refined grains) is associated with higher levels of CRP and interleukin-6. In contrast, the Mediterranean diet (high in whole grains, green leafy vegetables, and fish, low in red meat and butter, with moderate alcohol
and moderate to high olive oil intake) is associated with down-regulation of those inflammatory markers.
Pro-inflammatory Diet & Depression Risk
In 2014, a collaborative team from the University of South Carolina and Harvard developed a dietary inflammatory index (DII) as a tool to assess an individual’s diet on a continuum from maximally anti-inflammatory to maximally pro-inflammatory. To test the assessment tool, the team first used the DII to compare three different dietary patterns already linked to pro- or anti-inflammatory effects: fast food diet, Mediterranean diet, and macrobiotic diet which is a modified traditional Japanese diet (high whole grains, vegetables, beans, with lower fish, fruit, and sweets).
As expected, the macrobiotic and Mediterranean diets produced strong anti-inflammatory DII scores vs. the DII score for the fast food diet, which had strong pro-inflammatory potential. Using the DII tool, the researchers have gone on to explore the relationship of inflammatory eating patterns and many chronic diseases such as heart disease and osteoporosis.
In the newest investigation , the team looked at a pro-inflammatory diet and the presence of depressive symptoms in a group of over 3,600 participants (mean @ 60 years) with or at risk for osteoarthritis of the knee. The relationship between baseline DII score and incident depression was assessed through Cox's regression analysis, adjusted for potential con-founders, and reported as hazard ratios.
Over an 8-year follow-up, 837 participants developed symptoms of depression. Those consuming the most pro-inflammatory diet were found to have a 24% increased risk of developing depression compared with those eating the most anti-inflammatory diet (HR: 1.24; 95% CI: 1.01-1.53; p = 0.04).
This study adds to the growing body of evidence that at least some forms of depression may be affected by diet. And though interventional studies are needed, the authors suggest that transitioning to a more anti-inflammatory diet may reduce depression risk. For a simple list of foods that promote or counter inflammation, see the Harvard Medical school site: https://www.health.harvard.edu/staying-healthy/foods-that-fight-inflammation.
References
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In the news: Low vitamin D status Increases Uveitis Risk; Dry Eye Symptoms Linked to Depression in Women
Low Vitamin D Increases Risk of Uveitis
Uveitis, or inflammation of the eye’s uvea, is one of the leading causes of blindness worldwide among the working age population. It is postulated that noninfectious uveitis is caused by immune dysfunction.
Vitamin D plays an important role in both the innate and adaptive immune systems. It has been shown to contribute to the etiology of T-cell–mediated auto-immune diseases for example, via upregulating type 2 anti-inflammatory T helper cells and suppressing type 1 T helper cells. Low levels of vitamin D are reported to be common in the US, and the 2015-2020 Dietary Guidelines for Americans indicate that vitamin D is a nutrient of concern.
To better understand the relationship of vitamin D status and noninfectious uveitis, researchers from Harvard Medical School and the University of Pennsylvania Departments of Ophthalmology, conducted a retrospective case-control study using data from a large health care claims database .
The researchers identified 558 adults who received a diagnosis of noninfectious uveitis from an eye care clinician (with receipt of a confirmatory diagnosis within 120 days of the initial diagnosis) and who had a vitamin D level measured within 1 year before the first diagnosis. Each case patient was matched with 5 controls on the basis of age, sex, race/ethnicity, and index date of diagnosis (2790 controls). Low levels of vitamin D (hypovitaminosis D) was defined as a vitamin D level ≤20 ng/mL.
Patients with normal vitamin D levels were found to have a 21% lower odds of having noninfectious uveitis than patients with low levels (P = .04). African American patients had 51% increased odds for developing uveitis. P = .004).
This is not the first report to link low vitamin D status with increased risk of uveitis. Most recently, another retrospective study reported that the odds of having uveitis were 1.92 times higher for patients with hypovitaminosis D compared to patients with normal Vitamin D levels .
Though investigations to date do not establish a causal effect, prospective studies are warranted to evaluate whether low vitamin D does in fact cause increased risk of uveitis, and the role of vitamin D supplementation in the prevention and treatment of this condition.
Dry Eye Symptoms Linked to Depression
In a cross sectional study of women participating in the Sjögren's International Collaborative Clinical Alliance at 9 international sites, researchers sought to better understand the relationship of patient-reported symptoms and depression in those with and without Sjögren's syndrome . Notably, the researchers found that symptoms rather than clinical signs were better predictors of depression.
Dry eye complaints produced a1.82-fold higher odds of having depression compared to being symptom-free (p < 0.001). In both women with or without Sjögren's, the presence of symptoms of dry eyes and/or dry mouth rather than Sjögren's itself resulted in higher odds of depression.
Additionally, complaints of specific ocular sensations were associated with a 2.25 higher odds of depression including burning sensation compared to those without complaints (p < 0.001).
One particular ocular feature of Sjögren's, a positive ocular staining score, was inversely correlated with depression.
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In the news: Omega-3 as Adjunct in Diabetic Macular Edema Treatment; Vitamin A & Retinitis Pigmentosa in Children
Omega-3 Fatty Acids & Diabetic Eye Disease
Previously, an analysis of the PREDIMED trial found that participants with type 2 diabetes consuming at least 500 mg daily of EPA and DHA and followed for 6 years, had a 48% decreased risk of sight-threatening diabetic retinopathy . That study, published in JAMA Ophthalmology in 2016, increased awareness of the potential role of these long-chain omega-3 fatty acids in diabetic eye disease.
Long chain omega-3s may also favorably impact the treatment of diabetic macular edema, according to the 3-year results of a single blind, randomized controlled trial published last month in the journal Retina .
In this study, the effects of the anti-VEGF drug ranibizumab alone, or combined with a daily dose of DHA (1,050 mg), EPA (147 mg) and antioxidants were evaluated in patients with diabetic macular edema. Twenty-six patients (31 eyes) received the drug plus the nutritional supplement, while the drug alone was administered to 29 patients (38 eyes). In both groups, intravitreal ranibizumab (0.5 mg) was given monthly for the first 4 months, followed by a pro re nata (as needed) regimen throughout the trial. The treatment evaluator was masked to the patients’ assigned treatment.
At 36 months, there was a greater mean decrease of central subfield macular thickness (CSMT) in the supplemented group than in controls (275 vs. 310 micrometer). Between group differences in CSMT measures were significant at 25 months (p = 0.024), months 30 (p = 0.05), 33 months (p = 0.011), and 34 months (p = 0.039).
Between group differences in serum HbA1c, plasma total antioxidant capacity values, erythrocyte DHA content, and serum IL-6 levels were all significant in favor of the supplemented group at 36 months.
In short, patients receiving omega-3s and antioxidants achieved better-sustained improvement in CSMT outcome than ranibizumab alone. These results are promising, and augmenting anti-VEGF treatment with omega-3 and antioxidants deserves further study using a larger sample size and a double-blind design.
Vitamin A Associated with Slower Progression of Retinitis Pigmentosa in Children
In 1993, the results of a randomized clinical trial of 601 adults (18-46 years) with the common forms of retinitis pigmentosa treated with vitamin A and/or vitamin E for 4 to 6 years were reported . Vitamin A palmitate, 15,000 IU/d, on average, slowed the course of retinal degeneration, while oral vitamin E (400 IU/day, on average), appeared to hasten the course of retinal degeneration as monitored by full-field cone ERG to 30-Hz flashes.
The authors of that earlier investigation conducted a case-control study of children with common forms of retinitis pigmentosa to assess whether the mean course of the disease monitored by ERG in 55 children receiving vitamin A differed from a control cohort of 25 unsupplemented children.
The age-adjusted doses were 5,000 IU/day for ages 6 up to10 years, 10,000 IU/day for ages 10 to 15 years, and 15,000 IU/day for those 15 and older. All children taking vitamin A had normal serum liver function test results prior to supplementation.
Vitamin A supplementation was associated with a nearly 50% slower loss of cone ERG amplitude. The mean rates of decline were estimated to be 13.2% per year in the unsupplemented control cohort and 6.9% per year in the cohort taking vitamin A. The authors report finding no safety concerns linked to supplemental vitamin A.
While the findings are not definitive because of the relatively small sample and retrospective, non-randomized study design, they suggest that vitamin A is beneficial in children with retinitis pigmentosa.
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In the news: Omega-3s & Cognitive Decline; Diet and Diabetic Retinopathy
n-3s Improve Measures of Cognitive Function
Cognitive impairment is prevalent among the elderly, and the omega-3 (n-3) fatty acids EPA and DHA may have a protective role in age-related cognitive decline.
The results of previous clinical trials investigating supplemental EPA/DHA in healthy older adults, in mild cognitive impairment (MCI), and in Alzheimer’s, suggest that those with MCI are more likely to respond. MCI, which is associated with a 10-fold increased risk of developing dementia, has become an important stage for early intervention.
Against this backdrop, university researchers in China conducted a 6-month, randomized controlled trial in 86 older patients (mean age 71 years) with MCI to examine the effects of fish oil on cognitive function assessed by Basic Cognitive Aptitude Tests (BCAT). Participants received fish oil (daily dose of 720 mg EPA, 480 mg DHA) or placebo (olive oil).
Compared to controls, changes from baseline were significantly improved for the primary outcome measures of total BCAT scores, perceptual speed, space imagery efficiency, and working memory in the fish oil-supplemented group (all p < 0.01). Working memory, the ability to access information required for ongoing cognitive processes, is thought to underpin learning. There was no difference between groups for mental arithmetic efficiency or recognition memory. Subgroup analysis by sex showed that the cognitive improvements were more pronounced in men than women.
Since inflammation is a characteristic of many neuro-degenerative diseases, including Alzheimer’s, it’s hypothesized that early management of inflammation could prevent the cognitive decline of MCI.
Many studies have shown that n-3 supplementation can reduce plasma levels of cytokines IL-6, IL-10, TNF-α, and secretory phospholipase A2 (sPLA2) in humans, to achieve anti-inflammatory effects.
The researchers also measured these inflammatory markers as part of this study, finding a significant decrease in IL-6, TNF-α, and sPLA2 in the group receiving supplemental fish oil. No significant changes in these markers were noted in the placebo group.While the sample size was relatively small in this study, the results suggest that n-3 fatty acids may improve some aspects of cognitive function in MCI, and they add to the overall body of evidence evaluating n-3 fats in this condition. Larger studies of longer duration are needed.
Diet & Diabetic Retinopathy: Systematic Review
Evidence linking dietary intake with diabetic retinopathy (DR) is growing, but still unclear. Australian researchers conducted a systematic review of the literature, with 31 studies (3 interventional, 28 observational) meeting the criteria for inclusion.
Higher intakes of dietary fiber, oily fish, and greater adherence to a Mediterranean diet were found to be protective of DR. Higher total caloric intake was associated with a higher risk of DR. They found no association with DR for carbohydrate, vitamin D, and sodium intake, while associations with antioxidants, fatty acids, proteins and alcohol with DR were equivocal.
Comments: Several caveats apply when interpreting the results of this study. First, the included studies addressed intake from foods and dietary patterns, and did not include intake from supplementation.
Secondly, while total ’carb’ intake was not linked with DR risk, the studies reviewed did not take ‘carb’ quality (i.e. high vs. low glycemic index) into account. DR is a complication of diabetes, and abundant evidence associates lower glycemic index diets GI with a decreased risk for type 2 diabetes.
Finally, while the review found that oily fish intake was protective of DR, no link specifically between omega-3 intake and DR was found. However, the quality of the included studies varied, and a large study published in JAMA (2017) found that dietary intake of at least 500 mg/day of n-3 fatty acids was associated with a nearly 50% relative risk reduction for vision-threatening DR.
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Review: Potential Role of Ginkgo Biloba in Glaucoma
Ginkgo Biloba Review: Potential Role in Glaucoma
Treatment of glaucoma largely focuses on lowering intraocular pressure (IOP), a major risk factor for progressive glaucomatous optic nerve damage. However, it is clear that IOP is just one of many factors contributing to the pathophysiology of glaucoma. In addition to elevated IOP, vascular dysfunction, mitochondrial dysfunction and oxidative stress have been posited as mechanisms of glaucomatous damage.
According to the authors of a new review on the effect of Ginkgo biloba extract in glaucoma patients , physicians, researchers and patients have explored complementary approaches to traditional glaucoma treatment, including the use of antioxidants and botanicals. Since as many as 5-10% of glaucoma patients report use of such strategies, it is important for clinicians to be knowledgeable about the research and literature on complementary and alternative medicine (CAM) therapies, wrote the authors from the University of California, San Francisco (UCSF), Department of Ophthalmology and the UCSF Koret Vision Center.
Results. The paper, which includes a summary of standardized Ginkgo biloba (GBE) pharmacology, indicates that published clinical studies to date evaluating the effect of GBE in ocular vasculature support the ability of GBE to increase ocular blood flow. The authors describe the most recently published investigation, a controlled cross-over trial of 45 patients with OAG which examined the effects of GBE and antioxidants on ocular blood flow .
Data from animal models suggest that GBE may have a neuro-protective effect on retinal ganglion cells. However, the clinical effect of GBE on glaucoma outcomes such as visual field performance remains inconclusive.
Safety. In terms of safety, the authors conclude that GE is well tolerated with a low side effect profile. Several systematic reviews report no difference in side effects with GBE compared with placebo at doses ranging from 80-600 mg daily for at least 22 weeks. There have been some concerns regarding the bleeding risk while on ginkgo supplementation, particularly when used with aspirin. A systematic review of case reports of bleeding associated with ginkgo showed that out of 15 cases, 13 had other risk factors for bleeding and three cases reported increased bleeding times. Other studies looking at the concurrent use of GBE and aspirin found no difference in bleeding time, platelet function or coagulation parameters, compared with aspirin alone.
A recently published randomized controlled trial (6-month duration, 348 patients), lends credence to those findings . GBE (400 mg daily) combined with aspirin (100 mg daily) alleviated cognitive and neurological deficits after acute ischemic stroke more effectively than did aspirin alone, without increasing the incidence of vascular or adverse events.
Future Directions. The authors of this review point out that studies published on GBE and ocular blood flow have utilized color Doppler imaging (CDI), or confocal scanning laser Doppler flowmetry (CSLDF) imaging techniques, or both. Although CDI is a useful method to evaluate larger retrobulbar ocular blood vessels, it cannot provide information on retinal vasculature. CSLDF does provide information on retinal vasculature, but this technique may be sensitive to changes in illumination and eye movement. A future direction in studying the effects of GBE in glaucoma is to employ imaging techniques such as optical coherence tomography angiography (OCT-A).
Conclusion. Larger clinical studies are necessary to establish the clinical benefit of GBE with or without antioxidants in normal and high-tension glaucoma patients. For clinicians whose patients do use GBE-containing supplements, current evidence supports the safety of GBE and its apparent ability to increase ocular blood flow. The important caveat is that patients understand that GBE cannot displace or replace the use of other interventions known to preserve the visual field.
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Research Roundup: Recent Omega-3 Findings in Cardiovascular & Eye Health
Ω-3s Further Reduce Lipids with Statin Treatment
Over all, statins lower high triglycerides by 10-20% (or more if baseline levels are greatly elevated). EPA and DHA are also known to lower elevated triglycerides by inhibiting their release from the liver, and by increasing their rate of clearance from plasma. Is there value in combining statins with omega-3 supplements?
High dose omega-3 supplementation does appear to benefit patients, at least when triglyceride levels remain elevated despite statin use, according to results of a multicenter controlled trial of patients with hypercholesterolemia and at high risk for CVD .
After a 4-week run in treatment period with 20 mg daily of rosuvastatin, 201 patients with residual elevated triglycerides (mean 263 mg/dL) remained on the statin and were randomized to receive omega-3 (1,520 mg DHA + 1,840 mg EPA) or placebo for 8 weeks.
Average triglyceride levels decreased by 26% in the omega-3 group vs. 2% reduction in placebo takers. A greater reduction in non-HDL cholesterol of 11% was also seen in those taking the statin with omega-3s compared to 2% in those taking stain alone.
Higher Fish Intake Linked to Less Severe DR
Recent studies have shown favorable associations between fish consumption and diabetic retinopathy (DR). A relative decrease in risk for sight-threatening DR of 48%, for example, was seen in a Spanish population of type 2s consuming at least 500 mg/day of omega-3 and followed for 6 yrs. A newly published paper lends some credence to this observation.
The study evaluated the association of dietary fish intake with varying severity of DR and retinal vascular caliber (RVC) in 357 Asians with type 2. RVC provides information about microcirculation in the eye and the risk of DR. Increasing frequency of fish consumption was significantly associated with lower odds of having severe DR. The likelihood of severe DR was reduced by almost 10% per a one serving increase of fish weekly. In addition, the highest level of fish intake was also associated with wider RVC among diabetics with no signs of diabetic retinopathy.
Meta-analysis: Ω-3s May Reduce Resting Heart Rate
Elevated resting heart rate (HR) has emerged as a risk factor for all-cause and cardiovascular mortality. It’s been suggested that marine omega-3s may influence sudden cardiac death by reducing HR. In a recently conducted meta-analysis of 51 randomized controlled trials that included about 3000 people, researchers found that EPA and DHA supplementation mildly but significantly reduced HR (mean − 2.23 beats per minute) compared to controls . In the few trials where DHA and EPA were administered alone, DHA rather than EPA slowed HR.
The authors note that “the HR of the majority of participants included in this meta-analysis was within normal range – the state where reducing HR is conventionally not a medical indication. At the population level, however, such HR reduction may have significant public health implications, as a reduction of 3.2 beats per minute would roughly correspond to a 7.5% lower risk of sudden cardiac death.”
Dietary Fatty Acid Intake Linked to Glaucoma
It is important to know whether polyunsaturated fatty acid (PUFA) intake influences the development of glaucoma, as it could offer a modifiable risk factor for the disease. An analysis of data from 3,865 participants in the National Health and Nutrition Examination Survey offers some insight into the relationship of PUFA consumption and glaucoma .
The study found that increased daily levels of EPA and DHA were linked to significantly lower risks of glaucoma (OR, 0.06 for EPA and for DHA). Higher levels of total PUFAs (omega 6 + omega 3), however, significantly raised glaucoma risk (OR, 2.84 and 2.97 for 2nd and 3rd quartiles respectively). The authors hypothesize that increasing the ratio of omega-3 to -6 while watching overall PUFA intake, could be glaucoma-protective.
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In the news: Role of DHA in Future Survival of Retinal Cells; Progress in Eye Scans For Alzheimer's
DHA Preconditions Future Survival of Retinal Cells
A team of researchers from the Neuroscience Center at Louisiana State University Health New Orleans, reports that the omega-3 fatty acid DHA not only protects photoreceptor and retinal pigment epithelial (RPE) cells from potentially lethal initial insults, but also from future insults. The study, through in vitro and in vivo experiments, showed that the omega-3 fatty acid, DHA, and its derivatives “precondition” these cells to survive future injury .
The study’s authors define preconditioning as an acquired protection or resilience by a cell, tissue, or organ to a lethal stimulus enabled by previous sub- lethal stressors or stimuli . Preconditioning takes place, for example, when the blood supply to an organ is interrupted for a short time and then reestablished. The protective response from that first injury would carry over to a subsequent blood supply shortage, much like the immunity a vaccine confers against future exposures to disease.
According to the researchers, “This [preconditioning] happens in the heart, brain and retina, as well as other organs. To harness the therapeutic potential of preconditioning, it is very important to identify the molecules directly involved.”
DHA is the precursor of docosanoids, mediators that are made ‘on demand’ when factors threaten to disrupt cellular homeostasis. Docosanoids include molecules such as resolvins and neuroprotectin D1, regulators of neuroprotective, anti-inflammatory, and anti-angiogenic activity. In contrast, eicosanoid derivatives of omega-6 arachidonic acid have pro-inflammatory actions.
The research team showed that the protective actions of oxidative stress preconditioning require DHA and docosanoid synthesis, while also showing that DHA and docosanoids are involved in both ischemic preconditioning and light exposure preconditioning protection. They found that the free pool size of DHA is increased to form docosanoids, which play a critical role in survival signaling.
Although they are released concomitantly from phospholipids in cellular membranes, DHA can alter the action of arachidonic acid. When DHA was supplemented prior to the oxidative stress insult, the synthesis of protective DHA derivatives increased while arachidonic acid synthesis decreased over time. “Our findings demonstrate that DHA and the induction of docosanoid synthesis is necessary for preconditioning protection, and thus daily survival, of photoreceptor and RPE cells,” the authors conclude
Curcumin & Eye Scans for Alzheimer's
According to Cedars-Sinai Medical Center neuro-scientists, Alzheimer's disease (AD) essentially starts about 20 years prior to patients developing symptoms. And by the time one becomes symptomatic, significant loss of brain weight, brain cells and connectivity has already occurred. It’s therefore important to develop means of early detection so that the disease can be treated early through drugs and lifestyle interventions.
While PET scans are used to detect amyloid plaques, they are expensive and require injecting tracers into patients’ brains. However, it was discovered that curcumin - the dark yellow component of turmeric spice - floresces when it binds to the amyloid-beta plaques of AD. Additionally, animal studies have shown that the amount of plaques present in the retina correlates with levels in brain tissue. This has led to the development of curcumin-florescence eye scans for AD detection, though further testing is needed before it is approved for clinical use.
A new study by Cedar-Sinai investigators is a promising step in this direction. The researchers examined the brains and eyes from human cadavers with and without AD, finding that plaques tend to congregate in the superior quadrant of the retina. They next fed enhanced bioavailable curcumin to AD patients and healthy volunteers. Using a modified ophthalmoscope to detect fluorescence, they found that AD patients had about twice the level of amyloid-beta plaques as the controls.
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In the news: Higher Magnesium Intake Lowers Type 2 Risk in Those with High GI Diet
Magnesium, Glycemic Index & Disease Risk
As the global prevalence of type 2 diabetes increases, so will the number of people with diabetic retinopathy and other micro-vascular complications of the disease. Prevention of diabetes by addressing modifiable risk factors such as obesity, poor diet, and physical inactivity is paramount, although achieving sustainable behavior change is often difficult.
Based on the newly published findings of Tufts and Harvard researchers, one fairly simple step toward type 2 risk reduction may be to ensure adequate intake of magnesium. Recognized as a shortfall nutrient in the Scientific Report of the 2015 Dietary Guidelines Advisory Committee, nearly 50% of the US population has inadequate magnesium intake.
Hypomagnesemia tends to be more pronounced in pre-diabetes, insulin resistance or diabetes. Low serum levels have been associated with increased risk of prediabetes and diabetes via insulin resistance pathways. Magnesium is integral to insulin secretion and sensitivity. It’s been shown that low levels of magnesium impair insulin function, while the compensatory overproduction of insulin that occurs with insulin resistance depletes magnesium levels.
The new research, which combined cohorts from three large studies followed for 28 years, found that higher magnesium intake is associated with lower risk of type 2, especially in those consuming high glycemic index (GI) diets- diets low in fiber and high in processed carbohydrates such as white flour and sugar. The high GI diet is a common dietary pattern in the US, and one that has been associated not only with the risk of diabetes, but with cataract and early AMD as well.
Design and Methods
This analysis used data from the Nurses’ Health Study (n= 69,176), the Nurses’ Health Study 2 (n= 91,471) Health Professionals’ Follow-Up Study (n= 42,096). In these studies, dietary intake was assessed from food frequency questionnaires every 4 years. Magnesium intake was from food and supplements. Type 2 diabetes was ascertained by biennial and supplementary questionnaires.
Multivariate hazard ratios of magnesium intake and incident diabetes were calculated and adjusted for multiple factors including age, BMI, family history of diabetes, physical activity, smoking, hypertension, hypercholesterolemia, energy intake, trans fatty acids, and other factors. The joint associations of magnesium and carbohydrate quality on diabetes risk were also considered.
Results
Over 28 years of follow-up, 17,130 incident cases of type 2 diabetes were documented.
In pooled analyses across the three cohorts1, those with the highest magnesium intake had 15% lower risk of type 2 diabetes compared with those with the lowest
intake (pooled multivariate HR in quintile 5 vs. 1:0.85 [95% CI 0.80-0.91], P < 0.0001).
Higher magnesium intake was more strongly associated with lower risk of type 2 diabetes among participants with high GI or low cereal fiber than among those with
low GI or high cereal fiber (both P interaction <0.001).
Conclusion
Higher magnesium intake is associated with lower risk of type 2 diabetes, especially in the context of lower carbohydrate-quality diets.
Comments
These results are consistent with a large body of observational literature on the beneficial role of magnesium on type 2 diabetes risk. A recent meta-analysis of 25 prospective cohort studies, for example,
indicated a linear dose-response relationship between magnesium intake and type 2 diabetes, with an 8-13% lower risk per 100 mg/day increase in intake. The recommended daily magnesium intake for adults is 420 mg (men) and 320 mg (women). Good food sources include green leafy vegetables such as spinach, legumes, nuts, seeds, and whole grains.
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In the news: Genetic Tests Don't Predict Response to Supplementation in AMD
Results from independent analyses of the Age-related Eye Disease Study (AREDS) indicate that no genetic testing is needed before offering zinc and antioxidants to AMD patients who meet the criteria for AREDS supplementation . These results appeared online Oct 9th, ahead of print in the journal Ophthalmology.
Genetics & AREDS Supplements: The Controversy
Whether or not genotyping should be considered for AMD patients who are eligible for AREDS supplementation has been controversial. In brief, Awh et al. have reported an adverse interaction between CFH risk alleles and high dose zinc in analyses of AREDS data, concluding that patients with certain genotypes should receive antioxidants alone.
In contrast, reanalysis by the original AREDS authors Chew et al, failed to find that genotype predicts treatment effect, and concluded that combined zinc and antioxidants reduced the rate of AMD progression across all genotype groups.
To help resolve this debate, the Office of Intramural
Research at the NIH asked three separate bio-statistical groups to reexamine the data used by Awh et al. and Chew et al. to determine whether genotype predicts response to supplements in AMD. Data from both groups were provided to biostatisticians at Duke University, MD Anderson Cancer Center, and Memorial Sloan Kettering Cancer Center, all of whom remained anonymous to Awh, Chew, and their colleagues.
Participants and Methods
The population of interest was genotyped AREDS participants with AMD worse than category 1. Though the data provided by the Awh and Chew groups did not overlap perfectly, the same CFH and ARMS2 single nucleotide polymorphisms were measured by both groups in a dataset involving 879 participants.
Each statistical group took a separate but complementary approach. The MD Anderson Cancer Center group focused on checking data and evaluating the concordance between different data sets.
The Duke University group’s role was to replicate the key findings of Awh et al concerning interactions between genotype and outcome. The Sloan Kettering group took a blank slate approach, using all baseline data, including both clinical variables and genotype data, to determine whether benefit from treatment could be predicted.
Results
Conclusion
All three statistical groups concluded that genotyping of CFH and ARMS2 to guide AREDS supplement choice for the prevention of AMD progression is unwarranted.
Comments
One issue raised by the authors of this paper is the lack of adjustment for multiple testing by Awh et al - a fundamental and uncontroversial aspect of statistical methodology, especially when analyzing genetic data.
Notably, the authors also remind us of a well-accepted principle: conclusions based upon retrospective analysis of a single study require validation in a prospective study. Those who advocate genetic testing would do well to collect and analyze new data because currently “we do not have good reason to believe that genotyping will do more good than harm,” according to this study’s authors.
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In the news: Vitamin B3 Prevents Disease In Mouse Model of Glaucoma
RGCs More Vulnerable to Damage with Age
Glaucoma is characterized by the progressive dysfunction and loss of retinal ganglion cells (RGCs). High intraocular pressure (IOP) and increasing age are important risk factors for glaucoma. However, specific mechanisms that render retinal ganglion cells (RGCs) more vulnerable to damage with age are unknown.
A research team led by Simon W.M. John of the Jackson Laboratory set out to identify key age-related susceptibility factors that change with age and increase vulnerability to neuronal disease. The team used DBA/2J (D2) mice, a widely used model of chronic age-related inherited glaucoma, and age, sex, and strain-matched D2-Gpnmb+ mice (which do not develop high IOP or glaucoma) as controls to address how increasing age and high IOP interact to drive neurodegeneration.
The findings, published in the journal Science , could lead to vitamin B3 therapy in glaucoma and potentially other age-related neuronal diseases.
NAD+ & Mitochondrial Function in Aging RGCs
Conducting a variety of elegantly designed genomic, metabolic, neurobiological, and other experiments, the researchers found that mitochondrial disturbances are among the very first changes occurring within RGCs during glaucoma.
They next assessed metabolites in retinas of the D2 and control mice as they aged and as the disease developed. They detected early decreases in the levels of a molecule central to cellular energy metabolism, niacinamide adenine dinucleotide (NAD+), as well as antioxidant enzyme glutathione.
According to the researchers, the data supported a model of age-dependent declines of total NAD and glutathione in the retina, making RGCs vulnerable to damage from elevated IOP. Theorizing that increasing NAD+ levels would allow the RGCs to better resist IOP-induced stress, the team administered oral vitamin B3 (niacinamide, a precursor of NAD+) to D2 mice.
Vitamin B3 Increases NAD, Prevents Disease
Oral administration of vitamin B3 prevented the decline of NAD+ levels up to 12 months of age (a standard end stage for assessing neurodegeneration in this model of glaucoma). Electron microscopy revealed that vitamin B3 administration inhibited the formation of dysfunctional mitochondria. Vitamin B3 also limited the synapse loss that occurs in this model; less perturbed cellular metabolism was also seen (decreased PARP activation, decreased levels of DNA damage, and transcriptional induction of HIF 1-alpha).
Administration of a 3.6 fold higher dose of vitamin B was observed to be extremely protective: 93% of treated eyes did not develop glaucoma and had no optic nerve damage. “The degree of protection afforded by administering this single molecule is unprecedented and unanticipated,” the authors stated.
In further experiments, it was also determined that single gene therapy (driving expression of Nmnat1, a key NAD+-producing enzyme) was protective both prophylactically and as a treatment in the D2 model.
Future, Current Research with Vitamin B3
The authors indicate that they plan to evaluate the effect of vitamin B3 in glaucoma patients, which would likely entail testing high doses. There are two forms of vitamin B3: niacinamide (nicotinamide), and nicotinic acid (niacin). While nicotinic acid causes vasodilatory side effects such as headache, flushing and hypo-tension, niacinamide lacks these adverse effects.
A recent phase III study found that a high daily dose of vitamin B3 safely reduced the risk for recurrence of non-melanoma skin cancers. Niacinamide (NAD precursor) replenishes ATP levels in human keratinocytes after UV exposure, an effect thought to be a key mechanism by which the vitamin enhances DNA repair and reduces skin cancer risk.
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In the news: AREDS Supplements Cost-Effective; Vitamin D Reduces Pain in Chronic Widespread Pain
UK Study Finds AREDS Supplements Cost Effective in Category 4 AMD Patients
A UK multi-center study team concluded “AREDS supplements are a dominant cost-effective intervention for category 4 (advanced) AREDS patients, as they are both less expensive than standard care and more effective, and therefore should be considered for public funding.”
Savings could also be made in patients with Category 3 (intermediate) AMD in both eyes, according to the study authors, though the case for public funding was not as compelling and “would depend on the healthcare system willingness to pay.”
To estimate cost savings, the researchers used data from the AREDS study as well as real world outcomes, drawing upon a prospective neovascular AMD (nAMD) database (the National Health Service Electronic Medical Record) containing 92,976 ranibizumab (anti-VEGF) treatment episodes.
Two treatment approaches were compared: immediate intervention with AREDS supplements or no supplements (AREDS1 and AREDS2 supplements were considered equivalent). Main outcome measures: quality-adjusted life years (QALYs) and healthcare costs were accrued for each strategy, and incremental costs and QALYs were calculated for the lifetime of the patient.
The statistical model used to predict outcomes between supplemented and non-supplemented patients incorporated five different states of visual acuity and modeled AMD progression while assessing the probability of requiring anti-VEGF injections.
Category 4 patients with nAMD in one eye, showed a cost-savings of € 3,225 ($3,829) per patient over the lifetime of treatment vs. those not supplemented. Supplementation also increased QALYs by 0.16. The cost savings derived from requiring fewer anti-VEGF injections: over the lifetime of the patient, patients received an average 7.67 less intravitreal injections which are expensive.
In a UK survey 11% of patients with AMD who did not take AREDS supplements cited cost as a main factor. One public health strategy might be to actively provide AREDS supplements to Category 3 and 4 AMD patients. In the US, neither Medicare nor Medicaid cover patients’ cost of AREDS supplements to date.
Meta-Analysis: Vitamin D Reduces Pain Scores in Chronic Widespread Pain
Chronic non-specific widespread pain (CWP) including
fibromyalgia is characterized by widespread pain, reduced pain threshold, and multiple tender points on examination. Vitamin D has been proposed as an associated factor in CWP, and a recent meta-analysis of four randomized trials evaluated the effectiveness of vitamin D supplementation in managing CWP . Study outcome was assessed using visual analog scale of pain intensity.
Compared with those taking placebo, CWP patients receiving vitamin D treatment reported significantly lower VAS scores. Despite the fact that vitamin D decreased pain scores and improved pain, there was no association observed between changes in serum levels of the vitamin and VAS scores.
Possible mechanisms by which vitamin D may modulate pain pathways include decreasing inflammation and decreasing nitric oxide production, which affects neuro-transmission and vasodilation.
Comment: Marginal status or deficiency of vitamin D has been associated with a higher risk of dry eye in population health studies. Presence of ocular discomfort, dryness and grittiness is also one of the more common complaints in fibromyalgia. In addition, neuropathic ocular pain is associated with other chronic pain syndromes. It would be interesting to explore whether vitamin D has a role in reducing dry eye in fibromyalgia and/or neuropathic ocular pain.
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In the news: Lutein & Artery Inflammation in CAD; CVD & Risk of Rapid Glaucoma Progression
Lutein and Artery Inflammation in CAD
Persistent, low-grade inflammation is widely recognized in patients with coronary artery disease (CAD), despite drug treatment, arterial by-pass surgery, or lifestyle modifications.
Inflammation plays a prominent role in CAD, from the development of plaque to plaque destabilization. Elevated levels of inflammatory biomarkers like C-reactive protein and interleukin-6 (IL-6) have also been consistently shown to predict the risk of CAD.
Low plasma levels as well as low dietary intake of carotenoids have been associated with high cardiovascular disease risk, including CAD. Further, inverse associations between circulating levels of carotenoids and inflammatory markers have been demonstrated in multiple studies. This has led some to hypothesize that carotenoids exert anti-inflammatory effects.
To learn more about the anti-inflammatory potential of carotenoids, researchers assessed the relationship between IL-6 and individual carotenoids in CAD patients, then conducted ex-vivo experiments . The results suggest that lutein could potentially reduce chronic inflammation in CAD.
Plasma lutein, zeaxanthin, beta-cryptoxanthin, lycopene, alpha- and beta-carotene and IL-6 were measured in 134 patients with stable angina and 59 patients with acute coronary syndrome. Long term, low-level inflammation is predominant in stable angina, while acute inflammation is characteristic of acute coronary syndrome.
Only lutein + zeaxanthin were inversely correlated with IL-6 at baseline (r = -0.366, p < 0.001) and follow-up (r= -0.546, p < 0.001), and only in the patients with stable angina.
Peripheral blood mononuclear cells from the patients with angina were then pre-treated with lutein and incubated with lipopolysaccharide to induce secretion of IL-6 and other cytokines.
Pre-treatment with lutein dose-dependently lowered secretion of IL-6, IL-1b (p < 0.01) and TNF (p < 0.05), and also reduced IL-6, IL-1b and TNF mRNA expression (p < 0.05).
In short, the team showed that immune cells absorb and store lutein, and that greater content of lutein in these cells suppress production of inflammatory molecules.
“Future dietary intervention studies are warranted to confirm whether increasing the consumption of lutein has beneficial effects on clinical outcomes in patients with CAD,” the authors wrote. The authors also note that population-based studies have consistently associated higher plasma lutein levels with decreased carotid artery intima-media thickness, raising the hypothesis that lutein plays a role in early protection against atherosclerosis.
CVD: Risk Factor for Rapid Glaucoma Progression
In this retrospective case-control study , university researchers in Australia set out to determine how intraocular and systemic risk factors differ between a cohort of patients with rapidly progressing glaucoma disease and those with non-rapid disease progression.
Those with rapid progression were older, had significantly lower central corneal thickness and baseline intraocular pressures (IOPs), and were more likely to have pseudoexfoliation, disc hemorrhages, changes in ocular medication, and IOP-lowering surgery.
The authors also found a correlation between cardiovascular disease (CVD) and rapid progression. Those with CVD were 2.33 times more likely to develop rapidly progressive glaucoma disease, despite lower mean and baseline IOPs.
“Cardiovascular disease is an important risk factor for rapid glaucoma disease progression irrespective of IOP control”, the study concluded. The authors suggest that clinicians pay careful attention to CVD risk factors in their glaucoma patients.
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In the news: Switching to a Low-Glycemic Diet May Help Arrest AMD Development
Low Glycemic Diet May Help Deter AMD
Several analyses of participants in the AREDS trial and the Nurses Health Study have reported an association between a high glycemic index diet (dGI) and early signs of AMD, or that consumption of a low dGI is associated with decreased AMD risk . Among non-diabetic AREDS participants, a positive association was observed between high dGI and large drusen in early AMD, and a 49% increased risk of advanced AMD (geographic atrophy plus neo-vascularization) was associated with a dGI higher than the median for men and for women . These findings suggest that dGI may influence the risk of both early and late AMD.
The glycemic index (GI) is a scale that ranks carbohydrate-rich foods by how much they raise blood glucose levels compared to a standard food, usually glucose or white bread. High GI foods include sweets, white rice and bread, processed cereals and French fries, while lower GI foods are generally fiber-rich such as beans, whole grain bread, brown rice and oatmeal.
Switching to a Low Glycemic Diet Arrests AMD
To learn more about transitioning from a high to a low dGI, researchers from Tufts University’s Human Nutrition Research Center performed a study using an aged mouse model. Fifty-nine mice were randomized to either a low dGI or high dGI. The only difference between the diets was the carbohydrate source. After 6 months, the mice fed the high dGI either remained on that diet or were switched to the low dGI.
High dGI promoted the onset of several AMD features: retinal pigmented epithelial atrophy, photoreceptor dysfunction and lipofuscin accumulation. These AMD precursors were not seen in the mice fed a low dGI.
Critically, mice that were moved from the high to the low dGI midway through the study had retinas that were indistinguishable from those of the mice fed a low dGI for the entirety of the study. This dietary alteration appeared to effectively repair the damage that had accumulated while on the high dGI.
Potential AMD Biomarkers
The researchers also identified potential biomarkers of AMD features. Low dGI diets limited the accumulation of advanced glycation end products (AGEs), long-chain polyunsaturated lipids and their peroxidation end-products, and increased C3-carnitine in retina, plasma, or urine.
AGEs are known to be a factor in aging and in the development of many degenerative diseases, including AMD. Lipid peroxidation results in the degradation of cellular membrane lipids. C3-carnitine (propionylcarnitine) plays a role in cellular fatty acid metabolism, and it is found in many low-glycemic foods, such as whole wheat and legumes.
Higher levels of serum serotonin were also related to consuming the low dGI and less manifestation of AMD features. Serotonin is produced in the intestine in response to signals from gut microbes.
The researchers found that gut microbiota were responsive to diet, identifying microbiota in the Clostridiales order as being associated with AMD features and the high dGI, while protection against AMD features was associated with the Bacteroidales order and the low dGI. These observations led the authors to postulate that there may be a gut-retina axis to protect against diet- and age-induced AMD.
These findings add to a growing body of research on the relation between the quality of the dietary carbo-hydrates we consume and the development of AMD. While long-term prospective trials are needed to confirm the salutary effects suggested by this and previous investigations, a high dGI has already been implicated in the development of diabetes, CVD and some cancers.
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In the news: Inflammatory marker HLA-DR In Dry Eye Disease: New Findings
Background: HLA-DR, an Inflammatory Marker
It’s widely recognized that inflammation plays a prominent role in the development and progression of dry eye disease (DED). Tear film instability and hyperosmolarity can induce ocular surface damage and initiate an inflammatory cascade that generates innate and adaptive immune responses. These immuno-inflammatory responses lead to further ocular surface damage and a self-perpetuating inflammmatory cycle.
Human leukocyte antigen-DR (HLA-DR) is a biomarker of inflammation, which is normally expressed on most immune-competent cells. HLA-DR molecules are upregulated in response to signaling, reflecting immune activation. HLA-DR, for example, serves as a dendritic cell activation (maturation) marker that increases when exposed to inflammatory cytokines.
The expression of HLA-DR has been associated with many immune disorders, inflammatory processes, and ocular surface diseases such as DED. The results of several new clinical investigations suggest that HLA-DR is a useful tool in evaluating DED.
HLA-DR & DED Signs, Symptoms
In the first report , researchers from the Institute of Vision, Sorbonne Universities collected baseline data from three large, phase III randomized clinical trials conducted on moderate to severe DED patients. Measures of DED, at baseline and after treatment with cyclosporine (1 mg/mL) and placebo (in two of the three studies), were analyzed and correlations performed in 311 patients. HLA-DR was quantified by flow cytometry in impression cytology specimens.
The investigators found that HLA-DR significantly increased with the diagnosis of Sjögren's syndrome and meibomian gland disease (p<0.0001, p=0.02 respectively). The strongest significant correlation was seen with HLA-DR and corneal fluorescein staining (r =0.30, p<0.0001), to a lesser extent with Schirmer’s test, and weakly with TBUT and symptom reporting questionnaires. Importantly, HLA-DR was significantly reduced after cyclosporine treatment compared to placebo (p=0.02 in both studies).
Dry eye signs and symptoms are often inconsistent. The expression of HLA-DR in conjunctival cells has the potential to bridge the gap between signs and symptoms, according to the paper’s authors.
HLA-DR & DED Severity, Goblet Cell Loss
The second report comes from Baylor College of Medicine, where researchers examined whether clinical severity and goblet cell loss is correlated with dendritic cell maturation markers HLA-DR and CD86 in the conjunctiva of aqueous tear deficient patients .
Compared to the control group, the percentages of dendritic cell activation markers (HLA-DR+, CD86+ and others) were found to be higher in the conjunctiva of the aqueous tear deficient group. Clinical severity negatively correlated with goblet cell density (r = -0.54, P<0.05) and positively correlated with percentage of CD45+HLA-DR+ cells (r = 0.71, P<0.05). Goblet cell density negatively correlated with percentage of CD45+HLA-DR+ cells (r = -0.61, P<0.05).
In short, a greater percentage of activated (mature) dendritic cells were found in the conjunctiva of aqueous tear deficient patients, and that increased presence of mature dendritic cells was consistent with greater clinical severity and the loss of goblet cells.
Evaluating HLA-DR expression by impression cytology is emerging as an effective and reliable way to assess conjunctival inflammation in DED patients and as a useful means to monitor the effectiveness of anti-inflammatory treatments in DED. In a long-term, controlled trial of postmenopausal women with DED, for example, supplementation with the fatty acids GLA, EPA and DHA, prevented the increase in HLA-DR seen in placebo-treated patients .
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In the news: Restoring B12 Sufficiency Eases Neuropathic Pain in Dry Eye
Vitamin B12 & Neuropathic Ocular Pain
Dry eye disease (DED) associated ocular pain is considered chronic when it persists for more than 6 months. In chronic ocular pain, changes can occur in the ocular sensory apparatus and eventually in the central nervous system. Chronic inflammation and nerve damage can lead to abnormal activation of the eye’s sensory fibers and result in neuropathic pain.
Ocular pain may result from various diseases that lead to progressive corneal nerve damage. Deficiency of vitamin B12, essential for normal neurosensory functioning, may be a contributing factor. It has been associated with pain disorders such as myofascial pain, and it’s experimentally shown to improve corneal reinnervation.
University researchers in Turkey observed that some dry eye patients in their clinical practice continued to suffer from chronic ocular pain after local anesthetic instillation and treatment with cyclosporine and artificial tears. It was determined that a subset of patients were B12 deficient, leading the researchers to investigate the effect of vitamin B12 deficiency and therapy on ocular pain and symptoms in DED .
Design and Methods
Ninety patients with severe DED were enrolled and followed for 12 weeks. Those with overt B12 deficiency (n= 45) received parental vitamin B12 (1000 mcg/ml intramuscular injection) along with topical treatment (artificial tears and cyclosporine); those with normal B12 serum levels received only topical treatment. OSDI score, OSDI 3rd question score (to determine pain and pain frequency), TBUT, and Schirmer’s test were evaluated at baseline and at 12 weeks.
Results
All four evaluation measures improved in both groups (p<0.001 for each measure, all groups). Mean vitamin B12 levels improved in the vitamin deficient group from 144 pg/ml at baseline to 450 pg/ml at study’s end, similar to the baseline values in the B12 sufficient group (417.5 pg/ml). While mean score changes between groups was not statistically significant, the OSDI score and 3rd OSDI question score decreased markedly in the B12 deficient group (-30.8 and -2.82 respectively, both p<0.001). TBUT and Schirmer’s values rose significantly in the B12 deficient group (+7.98 and +12.16 mm, respectively), as well as in the B12 sufficient group (+6.18 and +6.71, respectively). The improvement in both evaluation measures was better in the group with poor B12 status. Conclusion Neuropathic pain is more likely to be chronic, difficult to treat, and thus important to distinguish in dry eye patients. “Serum vitamin B12 levels should be measured and taken into account for managing symptoms and neuropathic pain in DED patients who continue to have dry eye symptoms while on current therapies,” according to the authors.
Comments
While vitamin B12 deficiency alone does not cause ocular surface disease, it may aggravate pathologic changes and neurosensory damage to corneal nerves, resulting in neuropathic pain.
Marginal to deficient status of this vitamin may be more widespread than previously thought, particularly in older individuals, vegans, some vegetarians, and during pregnancy. While the overall prevalence of vitamin B12 deficiency is unknown, the Framingham Offspring Study found up to 39% of US adults at risk for vitamin B12 deficiency (defined as serum vitamin B12 <258 picomols/L; <350 picograms/mL).
It’s important to note that, though vitamin B12 was given parenterally in this study, high dose oral B12 supplements are proven to work as well as injections in correcting deficiency and at a lower cost .
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In the news: Multicenter Study of Lutein & Antioxidants in Chronic CSC
Subheader
Central serous chorioretinopathy (CSC), the fourth most common nonsurgical retinal disease, is characterized by fluid build-up under the retina and distorted vision. The fluid is believed to come from the choroid, due to isolated or diffuse leaks in the retinal pigment epithelium (RPE). As a result, a small detachment forms under the retina, known as serous retinal detachment (SRD).
Far more common in men than women, the incidence of CSC in men is about 10 cases per 100,000 population. According to a review published just last month , type A behavior, high blood pressure, H. pylori infection, steroid or psycho-pharmacologic medication use, sleep disturbances, and autoimmune disease are likely risk factors.
Acute CSC generally affects individuals 30-50 years of age and tends to resolve spontaneously or with focal laser photocoagulation targeting the leaking spots, while SRD often relapses or persists at advanced ages. In these chronic cases, photo-receptors are impaired with RPE atrophy. This can result in distorted vision and/or gradual vision loss.
RCT of Lutein & Antioxidants in Chronic CSC
Based on preliminary studies of antioxidant and lutein supplementation in CSC, a team of Japanese researchers from 5 university hospitals conducted a multicenter controlled trial of these nutrients in chronic CSC .
One hundred chronic CSC patients (100 eyes) randomly received a supplement containing 15 mg lutein, 288 mg vitamin C, 150 mg vitamin E, 9 mg zinc, and 1.2 mg copper (total daily dose) or placebo for 6 months. “Chronic” CSC was defined as an eye with a symptomatic history of at least 6 months, visual acuity loss without other causal diseases, or hyper-autofluorescence reflecting long-standing SRD. Best-corrected visual acuity (BCVA) and subfoveal fluid height (via optical coherence tomography) were measured at baselines 1, 3 and 6 months.
Seventy-nine patients completed the study, and there were no differences between the groups at baseline. At 6 months, mean BCVA was significantly improved in the supplement group (p = 0.003), while no significant change was seen in the placebo group (p = 0.589). A 28.6% reduction in subfoveal fluid height was observed with supplementation (p = 0.028). In contrast, subfoveal fluid height was insignificantly reduced by 3.3% in the placebo group (p = 0.898). See Fig. 4.
The researchers theorize that antioxidants may protect the RPE from oxidative stress, improving the viability of RPE cells, and facilitating reconstruction of the blood-retinal barrier - thus helping to reduce subretinal fluid.
One limitation of this study is the small number of subjects and rate of drop out. The authors indicate that some patients dropped out to request an alternative medical treatment due to the lack of a reduction in SRD. While no statistically significant differences in remission rates between groups was seen, differences might have been apparent had a larger number of eyes been enrolled. Also, 6 months may not have been long enough to adequately assess visual outcomes.
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In the news: Gut Microflora & AMD Risk; Ginkgo biloba & Oxidative Stress in Glaucoma
Can Gut Microflora Affect AMD Development?
One of the most rapidly expanding scientific fields of inquiry is that of the human microbiome and its potential influence on many aspects of human health. According to a series of intriguing experiments conducted by University of Montreal researchers, bacterial communities in the gut may even affect the evolution of AMD.
Epidemiological data suggests that the second most important environmental risk factor for men’s progression to neo-vascular AMD (the first being smoking) is abdominal obesity . However, the mechanisms underlying this observation remain poorly defined.
Since it is known that high-fat diets can impact intestinal flora, the researchers used mouse models of neo-vascular AMD, microbiotal transplants, and other gut flora-altering methods to uncouple weight gain from confounding factors. This allowed them to determine whether high fat diets worsen choroidal neovascularization (CNV) by altering gut microbiota. They found that fat-rich diets alter the gut micro-biome and in turn elevate choroidal and systemic inflammation and heighten pathological CNV.
In one of the experiments, fecal transplants were used to transfer the microbiota of mice fed regular-fat diets to mice receiving high-fat diets. The fecal transfer restored microbial proportions found in the normal fat diet group to the high-fat fed animals. While mice in the high-fat group showed about a two-fold increase in CNV compared to the regular-fat group, the fecal transfer diminished CNV by ~35% and lessened intestinal permeability. The researchers speculate that altered gut permeability caused by microbial imbalance allows entry of pro-inflammatory signaling molecules. These molecules are produced by intestinal bacteria and induce low-grade systemic inflammation.
“Our study suggests that gut microbiota influences development of neovascular lesions associated with AMD, particularly when obesity is a predisposing factor” , wrote the authors. Can modifying microbiota in humans through diet and/or pre- and probiotics reduce systemic and local choroidal inflammation, reduce neovascularization, and help prevent or stall exudative AMD?
Ginkgo May Reduce DNA Breaks in Glaucoma
While elevated IOP is a major risk factor for glaucoma, increasing evidence suggests that disease development is also linked to other factors, such as disturbed ocular blood flow and oxidative stress . Unstable ocular blood flow is thought to enhance oxidative stress. Oxidative stress may be an important cause of increased IOP by triggering trabecular meshwork degeneration, as well as causing retinal ganglion cell damage. One measure of oxidative stress is the quantification of DNA breaks by comet assay. Increased DNA breaks in trabecular meshwork and circulating leukocytes have been reported in glaucoma.
Researchers from the Dept. of Ophthalmology at Bern University conducted a retrospective clinical study to quantify single-stranded DNA breaks in circulating leukocytes of bilateral open-angle glaucoma patients (n= 60). These patients were treated for at least 6 months with a) 5 mg of Nifedipine daily; b) 120 mg of Ginkgo biloba daily; or c) no systemic treatment. The study’s aim was to assess whether systemic oxidative stress could be lowered by treatment with Ginkgo (shown to be reduced in vitro), or with a low-dose calcium channel-blocker (Nifedipine), which improves blood flow regulation by inhibiting effects of endothelin-1.
Patients treated with Ginkgo biloba and Nifedipine had a significantly lower amount of comet tails indicative of DNA damage compared with control leukocytes of untreated patients (p < 0.001). Ginkgo biloba exhibited a trend toward having a stronger effect in lowering DNA breaks compared with Nifedipine (p = 0.052). While retrospective studies have inherent limitations, these findings merit prospective investigation.
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In the news: Pediatric Dry Eye & Smartphone Use; Omega-3s Reduce Inflammatory Markers in Obese
Smartphones Linked to Pediatric Dry Eye
While it’s known that more children are getting cell phones at a younger age, the results of a recent study by the American Academy of Pediatrics are still startling. In this study, researchers found that 75% of 4 year-olds in an urban, low-income community had their own smartphone.
Smartphone users often stare at their devices for long periods of time, blink less frequently, and read at a closer focusing distance. Therefore, many speculate that more frequent use of smartphones and other devices can cause dry eye in children. The findings from a new study of school-aged Koreans offer some evidence that may confirm such speculation. The researchers found that the rate of pediatric dry eye disease strongly correlates with daily hours of smartphone as well as computer use.
Over 900 children (1st - 6th grade) were enrolled in the case-control study, which evaluated whether smartphone or computer use is related to dry eye incidence. Dry eye was defined based on the International Dry Eye Workshop guidelines (ocular exam, OSDI score). The participants and their families completed a detailed questionnaire to determine device use and outdoor activity.
The incidence of dry eye overall was 6.3%, with a lower incidence seen in participants living in rural (2.8%) compared to urban (8.3%) areas (p=0.03). A Similarly, city dwellers used smartphones more than their rural counterparts (p=0.04). Older kids used smartphones more than younger ones, and they also had a greater chance of having dry eye (p<0.001 and p=0.03, respectively).
Compared to controls, those with dry eye disease used smartphones longer each day (p<0.001, OR=13.07) and spent less time doing outdoor activities (p<0.01, OR=0.33). Importantly, those in the dry eye group improved both in subjective and objective symptoms after stopping smartphone use for 4 weeks. Together, these findings support the notion that curtailing smart-phone use and encouraging more outdoor activities may help prevent dry eye in children.
Beyond ocular health, some concerns exist for cell phone use in general. Cell phones emit radio-frequency energy (a form of non-ionizing radiation) from their antennas, which can be absorbed by tissues nearest to the antenna. The three largest epidemiologic studies to date do not support an association between cell phone use and risk for certain cancers; nor do the available data support such an association in children. However, children have the potential of accumulating more years of cell phone exposure than adults, and studies are underway to further explore this issue.
Omega-3s May Dampen Inflammation in Obese Women
According to researchers from the UK and Poland , supplemental EPA + DHA may reduce the chronic low-grade inflammation associated with obesity. The team concluded that the omega-3s help combat chronic inflammation via increasing DHA-derived pro-resolving mediators and decreasing pro-inflammatory proteins.Â
Fifty-nine obese women were placed on a calorie-controlled diet and randomly assigned to receive 1.8 EPA + DHA or placebo daily for a three-month period. Plasma levels of lipoxins, resolvins, protectin X, and inflammatory markers were measured. Microarray was used to assay whole blood transcriptome, the full range of messenger RNA, expressed by genes.
Both groups had significant reductions in body mass, fat mass, and BMI. Only the omega-3 group, however, had significantly decreased concentrations of several inflammatory markers including hsCRP, fasting triglycerides and insulin, and increased levels of pro-resolving DHA derivatives in plasma. The microarray data showed effects of the omega-3s on various target genes, including up-regulation of the resolvin receptor.
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In the news: Myopia: Too Much Near Work, Too Little Time Outdoors? Meta-analysis: Fish Consumption & AMD Risk
Myopia: Role of Close Work, Time Outdoors?
According to an article published last year in the journal Nature, there has been a dramatic increase in myopia worldwide. Myopia now affects about 50% of young adults in the US and Europe – double the prevalence of a half-century ago . The predominate theories as to why this ‘epidemic’ is occurring center around the possibility of too much sustained near work or insufficient outdoor bright light exposure.
A recent systematic review evaluated myopia in East Asian and Southeast Asian young adults. The authors conclude that increased myopia is now largely associated with environmental factors rather than genetic background and that recent trials suggest the onset of myopia may be reduced by increasing time children spend outdoors.
How outdoor time might be protective isn’t well understood. One theory is that sunlight exposure triggers the release of dopamine in the retina, which blocks elongation of the eye during development. Another potential explanation involves sunlight stimulating vitamin D production. It’s thought that vitamin D influences ocular growth through interactions with vitamin A. Finally, others postulate that more time outside might simply mean less time engaged in sustained near tasks.
Results from the just published 3-year follow-up of The Beijing Myopia Progression Study challenge the idea that outdoor time is protective. This cohort study, which analyzed the refractive error and daily activity data of 222 urban students, reports no significant association between outdoor activity and myopic refractive change.
After stratifying the students’ activity hours (assessed via a daily questionnaire) into quartiles, students with a greater near workload at baseline exhibited a greater myopic refractive change and had a higher risk of developing myopia. While this finding suggests that greater near work activity is a myopic trigger, more research is needed to learn whether sunlight and outdoor time are also contributing factors.
Fish Intake Linked to Lower AMD Risk
Because the association between fish consumption and risk of AMD is still unclear, a research team from the Ophthalmology Departments of several university-affiliated Chinese hospitals collaborated to conduct a meta-analysis of select observational studies.
The authors report finding a linear (dose response) association between the amount of fish consumed (0-5 servings weekly) and AMD risk (p = 0.001). As little as one serving weekly was linked to an 11% risk reduction (RR = 0.89, 95% CI, 0.83–0.96).
The analysis identified prospective cohort studies that reported relative risks (RRs) and 95% confidence intervals (CIs) for the link between fish consumption and risk of AMD. A total of 8 cohort studies of high methodological quality were included, involving nearly 129,000 participants and 4202 cases of AMD.
The main finding was a risk reduction of 24% when any AMD was considered (RR = 0.76, 95% CI, 0.65-0.90). Subgroup analyses by AMD stage showed that fish consumption reduced the risk of both early and late AMD by 17% and 24% respectively. (For early AMD, RR = 0.83, 95% CI, 0.72–0.96; for late AMD, RR = 0.76, 95% CI, 0.60–0.97).
Stratified analyses by the type of fish consumed indicated that dark meat fish intake was associated with a reduction in risk of 32% (RR = 0.68, 95% CI, 0.46-0.99). Tuna fish consumption, in particular, was associated with a 42% risk reduction (RR = 0.58, 95% CI, 0.47-0.71). Darker fleshed fish generally have higher omega-3 fatty acid content than leaner fish species with lighter colored flesh.
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In the news: Long-term Multi Use Lowers CVD Risk; Retinal Vessel Caliber Marks CVD Risk
Long-term Daily Multi Use Lowers CVD Risk
Few prospective studies have investigated the association of daily multivitamin and mineral (multi) supplements with the long- and short-term risks of cardiovascular disease (CVD). The findings from two studies that have examined this relationship are instructive.
The first, a Harvard study published in 2012, found no benefit of daily multi use among US male physicians followed for about a decade . Now, the same researchers report that among those initially healthy physicians, multi use for 20 years or more is associated with a significant reduction in major CVD events : A 44% reduced risk of heart attacks or strokes, and a 14% lower risk of needing cardiac revascularization (stents and/or cardiac surgery).
In the new research, the Harvard team studied 18,530 male physicians aged 40 years and older from the Physicians' Health Study I cohort who were free of CVD and cancer at baseline. All men provided a wide range of self-reported lifestyle and clinical factors plus intake of selected foods and dietary supplements. Cox proportional hazards models were used to calculate multivariable-adjusted hazard ratios (95% confidence intervals).
As with the earlier investigation, no risk reduction was observed in the first 10 years of following these men, who were on average under 50 years of age at baseline. Cardiovascular benefits did not become apparent until daily multi use reached the duration of 20 or more years.
According to Michael Roizen, MD Chair of the Cleveland Clinic Wellness Institute and Chief Wellness Officer of the Cleveland Clinic, these two differing study results make sense since most heart attacks and strokes occur after age 60; it takes cardiovascular events happening to assess prevention of those events .“ Today, there is substantial evidence of benefits for long-term multvitamin use for supporting overall wellness and reducing the risk of various illnesses, including cardiovascular disease,” Dr. Roizen opined.
Retinal Vessel Caliber is a Marker for CVD Risk
Wider retinal venules (very small veins that collect blood from capillaries), and narrower retinal arterioles (branches of an artery that lead into capillaries), have been associated with negative cardiovascular (CV) outcomes in the past.
In a new study, Harvard researchers looked at whether retinal vessel calibers (determined by retinal photography) are linked with cardiovascular outcomes over the long-term, and compared these measures against the American Heart Association’s pooled cohort equation (PCE) in predicting CV events .
After following 10,470 participants of the Atherosclerosis Risk in Communities Study for a mean 16 years, a significant association was found between wider retinal vessels or narrower retinal arterioles and rate of ischemic stroke (p<0.0001 for both venules and arterioles) and death (p<0.001 for venules and p=0.02 for arterioles).
One intriguing finding was that in women, but not men, these retinal vessel features were associated with higher rates of coronary heart disease (p=0.02). In fact, 21% of the women who were considered low risk by the PCE risk calculator would have been moved up to the intermediate risk category based on the retinal measures.
The retinal vasculature provides a unique window to assess vascular health noninvasively and directly, and this study validates the benefit of retinal vessel caliber measures for predicting the risk for ischemic stroke and mortality in the general population.
References
1. Sesso HD, et al. Multivitamins in the prevention of cardiovascular disease in men: the Physicians Health Study II randomized controlled trial. JAMA 308:1751-60, 2012.
2. Rautiainen S, et al. Multivitamin use and the risk of cardiovascular disease in men. J Nutr 146:1235-40, 2016.
3. www.nutri-facts.org. Expert Opinion: Using Science to Make Sense of Contradictory Multi-Vitamin Headlines. Michael Roizen, MD. Sept. 12, 2016.
4. Seidelmann SB, et al. Retinal vessel calibers in predicting long-term cardiovascular outcomes: The Atherosclerosis Risk in Communities Study. Circulation [EPub, Sept. 28, 12016].
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Omega-3 Intake Associated with a Lower Risk of Incident Diabetic Retinopathy
Omega-3s & the Risk of Diabetic Retinopathy
Although treatment of diabetic retinopathy may slow the progression of vision loss, it usually won’t cure the condition or restore normal vision. Thus, the best treatment for diabetic retinopathy is prevention. Strict control of blood glucose is one means of significantly reducing the long-term risk of vision loss. Also of interest is the relationship between intake of long-chain omega-3 polyunsaturated fatty acid (LCω3PUFAs) and risk of diabetic retinopathy.
The retina is rich in LCω3PUFAs, which are substrates for the formation of oxylipins – compounds with anti-inflammatory and anti-angiogenic activity. Inflammation and angiogenesis are important molecular factors in the development and progression of this ocular complication of diabetes.
Although experimental models support a protective role for dietary LCω3PUFAs, clinical data are lacking. This led Spanish investigators of the largescale PREDIMED trial to examine whether LCω3 PUFA intake is associated with a decreased incidence of sight-threatening diabetic retinopathy .
Design & Methods
The PREDIMED trial tested Mediterranean diets supplemented with olive oil or nuts vs. a control diet for primary cardiovascular prevention. For this prospective trial, researchers recruited 3,614 participants (aged 55-80) in the PREDIMED trial with a previous diagnosis of type 2 diabetes. Full data was available for 3,482 participants.
The frequency of consuming eight types of seafood was determined using a validated questionnaire at baseline, and habitual seafood consumption was tracked over time. Participants were assessed as meeting or not meeting the dietary LCω3PUFA recommendation of at least 500 mg daily for primary cardiovascular prevention. The main outcome measure was incident sight-threatening diabetic retinopathy – i.e. requiring laser photocoagulation, vitrectomy, and/or anti-angiogenic therapy.
Results
A total of 2,611 participants (75%) met the target LCω3PUFA recommendation. During a median follow-up of 6 years, 69 new events were documented. After adjusting for age, gender, intervention group, as well as lifestyle and clinical variables, those who consumed at least 500 mg LCω3PUFAs at baseline were 48% less likely to develop incident sight-threatening diabetic retinopathy compared to those consuming less (HR 0.52, p = 0.001). The association was slightly stronger for yearly updated LCω3PUFA intake.
Conclusion
In middle-aged and older type 2 diabetics, intake of 500 mg or more of LCω3PUFAs daily is associated with a decreased risk of vision-threatening diabetic retinopathy. The results are consistent with findings from experimental models and the current model of diabetic retinopathy pathogenesis. The target intake is achievable by eating at least 2 servings of oily fish weekly.
Comments
Since the Mediterranean diet incorporates fish and chicken at the expense of red meat, it is not surprising that 75% of participants met the marine omega-3 goal. In the U.S., however, a recent analysis of the National Health and Nutrition Examination Survey shows that a large percentage of our population is not meeting recommendations for omega-3 fatty acid consumption. Median intakes of EPA and DHA were found to be 18 mg/day and 50 mg/day, respectively.
References
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Do Genes Alter Response to AREDS Supplements? New Study Fuels Debate; Routine Testing Still Premature
Do Genetic Factors Alter the Response to AREDS Supplements?
The impact of the AREDS nutritional supplements on the rate of progression to advanced AMD for patients within specific genotype groups has been the subject of debate. Studies evaluating whether the effects of AREDS treatments (zinc alone, antioxidants alone, or both combined) differ according to genotype have produced conflicting results. A new analysis from Tufts University continues the debate, but does not clarify this complex issue.
The new retrospective study by Johanna Seddon and colleagues differs from previous studies in that the analytical method selected, survival analysis, evaluated individual eyes instead of the participant as the unit of analysis.
Among 4124 eyes (2317 participants with available genetic samples), 882 progressed to overall advanced disease (both neovascular and geo-graphic atrophy). The investigators assessed the effect of supplementation on AMD outcomes, and interaction effects between supplement treatment groups and two AMD-related genotypes: Complement factor H (CFH) Y402H, and age-related maculopathy susceptibility 2 (ARMS2) A69S.
Looking at the genotyped cohort as a whole, the zinc alone treatment had a beneficial effect on progression to neovascular AMD (HR: 0.65, p = 0.004), as did the combined antioxidant and zinc treatment (HR: 0.71, p = 0.024). There was no significant effect on geographic atrophy. A protective effect of the antioxidant treatment for progression to overall advanced disease was also noted (HR: 0.79, p = 0.025).
Among those taking the combined zinc and antioxidants treatment, a lower risk of progression to overall advanced disease was seen in those with a non-risk genotype for CFH (TT) vs. placebo (HR: 0.55, p = 0.033), and progression to neovascular disease (HR: 0.34, p = 0.004).
No significant treatment effect was apparent for those who were homozygous for the CFH risk allele (CC).
A protective effect of the combined treatment on progression to advanced disease was also observed among high-risk ARMS2 (TT) carriers (HR: 0.52, p = 0.005), and for progression to neovascular AMD (HR: 0.38, p = 0.003).
Four genetic groups that combined the number of risk alleles for CFH Y402H and ARMS2 were also evaluated for interaction with AREDS supplements. Low risk was defined as having no risk alleles; high risk as having 1-2 risk alleles:
| # CFH Alleles | # ARMS2 Alleles | Combined Group |
|---|---|---|
| 0 | 0 | Low, Low |
| 0 | 1-2 | Low, High |
| 1-2 | 0 | High, Low |
| 1-2 | 1-2 | High, High |
Only the low / high genetic risk group received a statistically significant benefit from the combined zinc and antioxidant treatment for progression to overall advanced AMD compared to the placebo (HR: 0.52, p = 0.039). Most of the benefit in the low / high group was derived from lowering the risk of progression to neovascular disease.
The authors conclude that the effectiveness of antioxidant and zinc supplementation may differ by genotype. No harmful effects of combined supplementation were apparent in these analyses.
It seems fairly clear that genetic susceptibility can modify the risk of progressing to advanced AMD. However, it is still not clear whether an individual’s genotype can alter the effectiveness of zinc plus antioxidant treatment. In contrast to the findings of the present analysis, no significant interaction between supplement treatment and genetics was seen in an AREDS analysis by Chew, et al .
Genetic Testing in the Clinical Setting Premature
Do the findings by Seddon, et al. support the use of genetic information for patients at risk of AMD in the clinical setting? And should genetic information be used to guide the choice of supplemental therapy? Not according to the Academy of Ophthalmology Task Force on Genetic Testing, who currently advise against routine testing, and not in the view of a comprehensive new review of AMD genetics for the clinician . [To access full article: https://www.dovepress.com/genetics-and-age-related-macular-degeneration-a-practical-review-for-t-peer-reviewed-fulltext-article-OPTH].
The new review underscores the complex nature of AMD, which has both genetic and environmental risk factors that interact in unknown ways. AMD genetic complexities are discussed and current research findings are put into perspective. The authors conclude that the bulk of the available peer-reviewed evidence suggests that genetic testing is more useful as a research tool than for clinical management of patients.
The article emphasizes that a randomized clinical trial (AREDS) designed to answer a specific question offers a higher level of evidence than do retrospective analyses from the same trial that attempt to answer a separate question.
Additionally, genetic association studies can often be misleading. For example, there are many patients with risk variants at both loci (CFH or ARMS2) that do not develop AMD, just as there are many patients who carry no risk variants at either loci who do develop the disease. Thus analyzing risk variants at only two loci (CFH and ARMS2) yields limited information, when 52 gene variants within 34 loci have been associated with AMD.
References
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In the news: Omega-3s Decrease Arterial Stiffness; May Reduce Hospital Stay Post Cardiac Surgery
Arterial Elasticity: Predictor of CV Mortality
Large arteries moderate increases in systolic pressure and maintain sufficient diastolic pressure to perfuse the heart. With age and disease, these arteries lose their natural elasticity leading to high systolic and low diastolic blood pressure levels.
That loss of elasticity, or arterial stiffness, is now considered an increasingly important, independent predictor of cardiovascular mortality in the elderly, hypertensives, diabetics, and renal failure patients as well as in the general population.
Arterial Stiffness’ Role in Ocular Conditions?
Arterial stiffness may also play a role in some ocular diseases. It’s been reported that patients with AMD have increased systemic arterial stiffness compared with age-matched controls, for example. Arterial stiffness indices have also been found to be abnormal in patients with branched retinal vein occlusion vs. healthy and hypertensive controls. And in a recent study , greater arterial stiffness was associated with both glaucoma and normotensive glaucoma in diabetics vs. age matched controls.
PWV for Evaluating Arterial Stiffness
Among the different methods of evaluating arterial stiffness, the most widely used in the literature is pulse wave velocity (PWV). PWV measures the rate of pressure waves moving down a vessel, specifically in the area running from the common carotid artery to the common femoral artery.
In stiffer arteries the speed at which the pressure wave moves increases, as does the speed at which reflected pressure waves move back toward the heart. When these pressure waves travel faster, the cardiovascular system has to work harder.
Supplemental Omega-3s Improve Artery Elasticity
Researchers from the University of Pennsylvania
College of Medicine evaluated the effect of omega-3 supplements on arterial stiffness in both younger (aged 21 – 35, mean 25 yrs) and older (aged 60 –
80, mean 66 yrs) healthy men and women . The participants received two 1 gram capsules of omega-3 fatty acids (465 mg EPA and 375 mg DHA) twice daily for 12 weeks. Central arterial stiffness was measured by carotid-femoral PWV, and arterial wave reflection by central augmentation index.
Carotid-femoral PWV and central augmentation index were greater in the older group (988 + 65 cm/sec and 33 + 2%) than in young adults (656 + 16 cm/sec and 3 + 4%; both P < 0.05) before the intervention.
Omega-3 supplementation significantly decreased PWV by 9% in older, but not younger subjects. Central augmentation index and arterial blood pressure were unchanged. The mechanism underlying reduced central arterial stiffness with omega-3 supplementation is not known, but may be independent of effects on arterial blood pressure or arterial wave reflections. Previous research found improved arterial stiffness and a parallel anti-inflammatory effect with omega-3 supplementation in adults with metabolic syndrome. Larger and longer controlled trials are warranted.
Pre-Surgical omega-3s May Reduce Hospital Stay
A new meta-analysis and systematic review which included 11 RCTs and 1,038 patients, found no effect of pre-operative omega-3son the primary outcome of length of stay in the intensive care unit.
However, the analysis did find changes in pre-defined secondary outcomes: omega-3 supplements reduced overall length of hospital stay by up to 2.4 days (P = 0.010). A 22% odds reduction in the occurrence of post-operative atrial fibrillation was also noted (P = 0.004). The results are in agreement with a 2013 meta-analysis , which found pre-operative omega-3 dosing significantly prevented post-operative atrial fibrillation in patients undergoing cardiac surgery, especially coronary artery bypass surgery.
References:
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In the news: Meta-Analyses on Vitamin D in AMD; Brain Involvement in Glaucoma? Alpha Lipoic Protects RGCs in Glaucoma Model
Circulating Vitamin D & AMD Risk: 2 Reviews
A relationship between serum vitamin D [25(OH)D] levels and AMD occurrence was first reported in 2007. Other epidemiologic studies followed, the majority of which found inverse associations between circulating levels of this vitamin and AMD. Recently, two systematic reviews and meta-analyses examining this association have been published.
The first meta-analysis , performed by university researchers in China, included 10 studies. The researchers found a non-significant association per 10 ng/mL increase of serum D in this meta-analysis, with no inverse associations seen between serum D levels and stages (early, late, advanced) or subtypes (dry vs. wet) of AMD risk. The authors, however, indicate that opposite results from US and Korean studies accounted for the non-significance, with US studies showing decreasing risk – and Korean studies increasing risk – with higher serum D levels.
In contrast, French researchers found evidence that high serum D concentrations may be protective against AMD, and that concentrations below 50 nmol/L (≈ 20 ng/mL) are associated with late AMD . Twenty-one studies met the selection criteria for this meta-analysis and systematic review. AMD was shown to be inversely associated with the highest serum D quintile compared to the lowest quintile (OR=0.83). Notably, those with the highest serum D levels were 53% less likely to develop late AMD.
The observed connection between vitamin D and AMD is biologically plausible: inflammation and angiogenesis are part of the disease process, and vitamin D has both anti-inflammatory and anti-neovascular activity. Well-designed longitudinal studies are needed to better understand the role of vitamin D in different stages and types of AMD.
Glaucoma: Disease of the Eye or Brain Too?
One outstanding issue in glaucoma research is whether glaucoma should be considered an eye disease exclusively, or also a brain disease. Alzheimer’s and glaucoma, for example, share many biological and mechanistic features, and some research suggests an overlap of these neurodegenerative diseases. To further examine this issue, a Dutch and Japanese team used Diffusion Tensor Imaging to study the brain’s white matter integrity in 30 Japanese with normal-tension glaucoma, and age-matched controls .
Evidence of neurodegeneration was found in the brain’s occipital lobes (the main centers for visual processing), the forceps major and corpus callosum. In particular, according to the authors, degeneration of the corpus callosum suggests that neurodegeneration is not limited to the primary visual pathways. The findings raise provocative questions: Does a brain component, independent from eye damage, play a role in glaucoma development? Are different mechanisms involved in normal and high pressure glaucoma? Click to view the paper.
α-Lipoic Acid Protects RGCs in Model of Glaucoma
Evidence suggests that oxidative stress worsens neurodegenerative diseases, including glaucoma. In a mouse model of glaucoma (DBA/2), researchers tested the contribution of oxidative stress in glaucoma development . They found lipid peroxidation and up-regulation of oxidative stress-related mRNA and protein in the retinas of these animals.
Mice were then fed α-lipoic acid (ALA) starting at age 6 months, to test the role of ALA as an intervention in disease progression. Separately, mice were raised on an ALA-supplemented diet to test its effect on prevention. Both ALA treatment paradigms showed increased antioxidant gene and protein expression and increased protection of retinal ganglion cells (RGCs) compared to controls. Decreased measures of oxidative stress in the retina were seen in both treatments. The authors conclude that ALA reduces oxidative damage and improves RGC survival.
References:
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In the news: Vitamin D & Multiple Sclerosis; Recent Findings
Multiple Sclerosis: Background
Multiple sclerosis (MS) is a progressive disease of the CNS that affects more than 2.3 million people worldwide, according to the National MS Society. In MS, the immune system attacks the protective lipid-protein myelin sheath that insulates nerve fibers, which interrupts or distorts nerve impulses traveling to and from the brain and spinal cord.
Symptoms, which vary among individuals, are commonly fatigue, weakness, poor balance, lack of muscle control, and vision problems, including optic neuritis, double vision, and nystagmus, or uncontrolled eye movements. Vision problems, in fact, are often the first symptom of MS.
It’s believed that MS is triggered in genetically susceptible individuals by a combination of one or more environmental factors. Vitamin D deficiency was theorized to be one of those factors in the early 1970’s. Since then, many publications have linked vitamin D insufficiency with MS development, and some research has suggested that adequate status of the vitamin may be protective.
Several recent studies provide insight into the effects of vitamin D on MS progression, immune regulation, and on the risk of deficiency during pregnancy.
Vitamin D May Predict Progression in Early MS
Does vitamin D status predict disease activity and prognosis in early MS? To shed light on this question, Harvard researchers looked at serum levels of vitamin D in 465 participants of a randomized trial originally designed to evaluate the impact of early vs. delayed interferon beta-1b treatment in MS . The patients were followed clinically and by MRI for 5 years.
Higher serum levels of vitamin D (25-hydroxyvitamin D, a marker of vitamin D status) predicted a reduction in MS activity and a slower rate of progression. Higher serum levels within the first 12 months predicted a 57% lower rate of new active lesions, a 57% lower relapse rate, a 25% lower yearly increase in inflammatory lesion volume, and a 0.41% lower yearly loss in brain volume. Similar associations were seen in MS activity or progression from 24 to 60 months, and higher serum vitamin D (> 20 ng/mL) at up to 12 months predicted lower disability during the next 4 years.
Maternal Vitamin D & MS Risk in Offspring
Using serum samples from the Finnish National Cohort biobank, Harvard researchers compared the maternal vitamin D levels during pregnancy of 176 of their offspring diagnosed with MS, with the maternal vitamin D levels of 326 unaffected children (all 18-27 yrs.) .
The children of mothers with vitamin D deficiency during their pregnancy had a 2-fold greater risk of developing MS than those whose mothers were not deficient (< 12.02 ng/mL vs. 12.02 to < 20.03 ng/mL).
In an accompanying editorial , Dr. B.M. Greenberg explained that one mechanism that might explain the link of vitamin D insufficiency with MS is the vitamin’s co-factor role in myelin formation. Deficiency of vitamin D during critical growth periods may create “weak myelin” prone to damage in MS.
Vitamin D Helps Regulate T-Cells in MS
Another connection between vitamin D and MS focuses on the effect of vitamin D receptor activation on the immune system . Vitamin D receptor activation can suppress IL-17, leading to pro-inflammatory T-cells.
A Johns Hopkins team randomized 40 MS patients to receive 10,400 IU or 800 IU vitamin D daily for 6 months, People in the high-dose group had a reduction in the percentage of inflammatory T-cells related to MS severity. These changes weren’t seen with the low-dose. The researchers concluded that high dose vitamin D is safe for those with MS and may help regulate the body’s hyperactive immune response. Whether the changes in inflammatory T-cells translate to less severe MS is the subject of clinical trials currently underway.
References
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Ocular Blood Flow in Glaucoma: The Leuven Eye Study
Impaired Ocular Blood Flow in Glaucoma
Current glaucoma treatment strategies aim to delay disease progression by reducing one the main risk factors for this disease, intra-ocular pressure (IOP). However, in a significant number of patients, IOP-reduction alone is not enough to halt or adequately slow disease progression, suggesting that other factors may be involved in the disease process.
One possibility is that underlying vascular dysfunction in patients with glaucoma may further aggravate ganglion cell damage. In fact, extensive literature provides support that patients with glaucoma have signs of ocular and systemic vascular abnormalities.
However, a large ocular blood flow oriented trial to integrate these findings in the clinical setting is lacking. To address this gap, Belgian researchers from the Department of Ophthalmology at University Hospitals Leuven, undertook a prospective study to help identify vascular data that might be used as a clinical tool for screening and disease stratification .
Design and Methods
Patients with primary open-angle glaucoma (POAG), normal-tension glaucoma (NTG), ocular hypertension (OHT), glaucoma suspects and healthy volunteers were recruited for this prospective, cross-sectional, case-control, hospital-based study.
In addition to a comprehensive ophthalmological examination, a vascular-oriented questionnaire was completed and ocular blood flow assessment was performed using: color Doppler imaging of retrobulbar vessels, retinal oximetry, dynamic contour tonometry, and optical coherent tomography enhanced-depth imaging of the choroid.
Results
A total of 614 subjects (291 males) were recruited between March and December 2013 (POAG: 214, NTG: 192; OHT: 27; glaucoma suspect: 41; healthy controls: 140). Glaucoma groups (NTG and POAG) were age and gender matched with the control group (p > 0.05). Glaucoma groups were paired In terms of functional and structural parameters (p > 0.08).
Mean ocular perfusion pressure was higher in the glaucoma groups than in controls (p < 0.001). Glaucoma groups had lower retrobulbar velocities (see table 3), higher retinal venous saturation and choroidal thickness asymmetries compared to the healthy group, in line with the current literature.
Comments
The Leuven Eye Study stands as one of the largest clinical trials on ocular blood flow and appears to be adequately powered. The study team created a database of 600+ patients over a 9-month period, and spanning over five groups (healthy controls, POAG, NTG, ocular hypertension and glaucoma suspects).
Encompassing over 100 variables, the database may help integrate the vascular aspects of glaucoma into the clinical practice of glaucoma according to the study authors.
References
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Intake of Dietary Nitrate Associated with Lower POAG Risk
Nitric Oxide and Open Angle Glaucoma
Nitric oxide (NO), an important cell signaling molecule and vessel dilator, is formed in the body by the constitutive enzymes endothelial nitric oxide synthase (eNOS) and neuronal NOS (nNOS) from the amino acid L-arginine and oxygen. The inducible form of NOS (iNOS), is involved in the immune response, producing NO as a defense mechanism.
NO derived from the endothelium and nerve cells helps regulate ocular blood flow dynamics. Elevated intraocular pressure (IOP) and impaired auto-regulation of optic nerve blood flow are implicated in primary open-angle glaucoma (POAG). Endothelial dysfunction, a key contributor to vascular regulatory impairment, is involved in both processes. Endothelium dysfunction impairs ocular blood flow by reducing the bioavailability of NO and increasing the production of reactive oxygen species.
Dietary Nitric Oxide Precursors and POAG
An alternative to the L-arginine–NO pathway is the nitrate-nitrite-nitric oxide pathway. This pathway comes into play under conditions of hypoxia or when NOS may be dysfunctional, which may occur in POAG. In this pathway, dietary nitrate can be reduced to nitrite and converted to NO in tissues.
Evidence supports a role for NO in the development of POAG. Animal studies suggest, for example, that NO may induce IOP lowering. There is also evidence that dietary nitrate or nitrite, precursors for NO, is beneficial for blood circulation.
Although plasma nitrite levels or intake of specific vegetables have been associated with POAG, nitrate intake as a specific nutrient had not been assessed.
This led Harvard researchers to evaluate dietary nitrate and incident POAG in a more than 25-year prospective study of nearly 64,000 women in the Nurses’ Health Study (NHS) and over 41,000 men in the Health Professionals Follow-up Study (HPFS) .
Study Design and Methods: Participants in the prospective cohorts of the NHS and HPFS were followed for over 25 years and checked at 2-year risk periods. Eligible participants were 40 years or older, free of POAG, and reported eye examinations. Information on diet and potential confounders was updated with validated questionnaires.
The main outcome was POAG incidence and POAG subtypes; 1483 cases were confirmed with medical records and classified into subtypes defined by IOP (>22 or <22 mmHg), or by visual field loss pattern at diagnosis – peripheral loss only, or early paracentral location loss. Cohort-specific and pooled multivariable rate ratios and 95%CIs were estimated.
Results: 1483 incident cases of POAG were identified. The lowest 20% of dietary nitrate intake (about 80 mg/day) was compared with the highest 20% of intake (about 240 mg/day). Greater intake of dietary nitrate and green leafy vegetables (a source of nitrates) was associated with a 20-30% lower POAG risk.
The association was particularly strong (40%-50% lower risk) for POAG with early paracentral visual field loss at diagnosis, for which difficulty in regulating ocular blood flow has been implicated.
Comments: These findings could have important implications for POAG if the association of higher dietary nitrate and green leafy vegetable intake with a lower POAG risk is confirmed in observational or intervention studies.
NO is emerging as a potential target for the treatment of glaucoma . Dietary sources of nitrate may be an important alternative source of NO in POAG. One lettuce serving, for example, can yield more NO than that generated daily via the L-arginine–NO pathway.
Overall, the literature on the role of NO in optic neuropathy is suggestive of a dual action, with low levels exhibiting neuro-protective effects and high levels (from induction of iNOS and/or up-regulation of nNOS) bringing about neuro-degenerative effects.
References
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In the news: Telomere Length & AMD: ‘Multi’ Use Linked to Longer Telomeres in Women
Telomeres as a Marker of Biological Aging
Telomeres are the regions of repetitive DNA located at the end of chromosomes. They protect the end of the chromosome from deterioration, preventing chromosomes from fusing together or rearranging, which can lead to cancer.
Interest in telomeres arose from the observation that human cells can undergo only a limited number of divisions to produce new cells, and that telomere length may determine that limit.
In somatic (non-reproductive) cells, telomeres shorten with each cell division, eventually leading to cells that are no longer capable of dividing or to cellular self-destruction (apoptosis). Therefore, telomere length has been proposed as a marker of biological aging.
Consistent with this hypothesis, epidemiologic studies have related shorter telomeres to higher mortality, accelerated aging, and greater risk of some age-related chronic diseases including cognitive decline, dementia and recently, AMD .
Telomere Length Linked to GA type of AMD
Researchers in China looked at the relationship of leukocyte telomere length and AMD in 197 AMD patients and 259 healthy controls using the established quantitative polymerase chain reaction (PCR) technique. Logistic regression was performed to evaluate the association of leukocyte telomere length and AMD.
After adjusting for age and sex, a significant association between AMD and telomere length was seen (OR=2.24; 95% CI=1.68-3.07; P=0.0001).
Notably, the results showed a strongly significant association between the geographic atrophy (dry AMD) subtype and telomere length (OR=4.81; 95% CI=3.15-7.82; P=0.0001), but no association was found in the wet AMD subgroup. The observed 2-fold risk of AMD and nearly 5-fold risk for dry AMD suggest that telomere shortening could play a role in the development of AMD.
‘Multi’ Use Linked to Longer Telomeres
Experimental evidence suggests that oxidative stress and chronic inflammation contribute to the gradual loss of telomeres, and that some vitamin and minerals may affect telomere length by influencing these processes. Based on these findings, researchers from the NIH examined whether multivitamin use is associated with longer telomeres in women .
The research team performed a cross-sectional analysis of data from 586 early participants (age 35–74 years) in the Sister Study, a prospective cohort study of healthy sisters of breast cancer patients. Multivitamin use and nutrient intakes were assessed with a 146-item food-frequency questionnaire, and relative telomere length of leukocyte DNA was determined using quantitative PCR, confirmed by duplicate assays.
After adjusting for age and other potential confounders, multivitamin use was associated with longer telomeres.
Compared with nonusers, the relative telomere length of leukocyte DNA was significantly longer among daily multivitamin users (P for trend 0.002).
Higher intakes of vitamins C and E from foods were each associated with longer telomeres, even after adjustment for multivitamin use. Further, intakes of both vitamins C and E were associated with telomere length among women who did not take multivitamins.
The associations of telomere length with AMD and of longer telomeres with multi use in women should be further evaluated. In the meantime, taking a daily multi-nutrient supplement is a prudent idea since recommendations for anti-oxidant and nutrient-rich fruit and vegetable intakes are met by fewer than 17% and 14% of US adults, respectively .
References:
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In the news: Modified Med Diet Reduces Retinopathy Risk: Carotenoids Linked to Lower AMD
Modified Med Diet Reduces Retinopathy Risk
To date, no clinical trials have specifically evaluated the role of dietary patterns in the incidence of microvascular diabetes complications, according to the investigators of the PREvención con DIeta MEDiterránea or PREDIMED Study. These researchers hypothesized that a nutritional intervention based on the Mediterranean diet (MedDiet) would have a protective effect on diabetic retinopathy and nephropathy. The PREDIMED Study was a multicenter, randomized nutritional intervention trial conducted in a population at high risk for CVD.
This post hoc analysis looked at a cohort of over 3,600 PREDIMED participants with type 2 diabetes who were free of microvascular complications at enrollment. Participants were randomly assigned to one of three dietary interventions: MedDiet supplemented with extra virgin olive oil, MedDiet with mixed nuts, or a low-fat control diet.
During a median follow-up of 6 years, 74 new cases of retinopathy and 168 of nephropathy were identified. The results showed that a MedDiet enhanced with extra virgin olive oil significantly decreased incident diabetic retinopathy by 44% compared to the low-fat control diet (adjusted Hazard Ratio = 0.56, 95% CI, 0.32–0.97).
A relative risk reduction, though non-significant, was also seen for the MedDiet plus nuts vs. the control diet. Unlike the results from some observational studies that found favorable effects of the MedDiet on kidney function, no effects on nephropathy were seen in this analysis.
Carotenoids and Advanced AMD Risk
While the primary analyses of the AREDS2 trial failed to prove a protective effect of lutein/zeaxanthin, a 26% reduction in risk was seen for participants at the bottom 20% of dietary intake of these carotenoids. Given the unlikely occurrence of another large-scale, randomized trial like AREDS2, data from large and long-running prospective cohort studies may be the best evidence we’ll have to evaluate the potentially protective role of lutein/zeaxanthin.
Harvard researchers recently examined associations between carotenoid intakes and AMD in two large, prospective cohorts with repeated dietary assessments who were followed for over two decades (24-26 years) . Data was analyzed from more than 63,000 females in the Nurses’ Health Study and 38,600 males in the Health Professionals Follow-Up Study.
The researchers computed predicted plasma carotenoid scores directly from food intake, assessed by repeated food frequency questionnaires.
Associations between predicted plasma carotenoid scores and AMD were determined.
About 2.5% of the participants developed either intermediate or advanced AMD (mostly wet AMD) during the follow-up. Comparing highest vs. lowest quintiles of predicted plasma lutein/zeaxanthin scores showed a risk reduction for advanced AMD of about 40% in both women and men (pooled relative risk comparing extreme quintiles = 0.59; 95%CI, 0.48-0.73; P for trend < .001).
Predicted plasma carotenoid scores for other carotenoids, including β-cryptoxanthin, α- and β-carotene, were associated with a 25% to 35% lower risk of advanced AMD when comparing top and bottom quintiles. No link between carotenoids and intermediate AMD was seen.
The authors point out that α-carotene and β-carotene are found in human RPE and choroid where they could protect against light-induced oxidative damage and locally produced free radicals. While very high dose supplemental β-carotene competitively reduced absorption of lutein/zeaxanthin in AREDS2, consuming a wide variety of fruits and vegetables – i.e. a carotenoid-rich diet – may be a sound public health strategy for reducing the risk of advanced AMD.
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In the news: Vitamin D Linked to AMD by Genetic Risk: Vitamin D Status & Glaucoma
Low Vitamin D Status & Ocular Conditions
The findings of two newly published studies suggest that inadequate blood levels of vitamin D may be a risk factor in ocular diseases.
Vitamin D Insufficiency & AMD Genetic Risk
Vitamin D, with its anti-inflammatory and immune modulating activities, is theorized to play a protective role in the development of age-related macular degeneration (AMD). Several studies have noted a relationship between low blood levels of the vitamin and greater likelihood of AMD. In the Carotenoids in Age-Related Eye Disease Study (CAREDS), for example, the odds for AMD were increased in postmenopausal women who had low vs. high vitamin D status assessed by intake and blood levels.
These findings led University of Buffalo investigators to examine whether that observed association was stronger in women with established AMD risk genotypes. They also determined whether AMD is associated with single nucleotide polymorphisms (SNPs) involved in the transport, metabolism and genomic functions of vitamin D .
Nine hundred and thirteen CAREDS participants were included in the analysis. Of these, 550 had adequate vitamin D levels (> 20 ng/mL), 275 had inadequate or suboptimal levels (> 12 to < 20 ng/mL), and 88 were deficient (< 12 ng/mL).
When looking at vitamin D status and AMD risk alone, deficiency was associated with a 2.6-fold increased odds of AMD compared with adequate status. Suboptimal levels increased the odds of AMD 1.5 fold vs. adequate levels.
When assessing the joint effects of vitamin D status and genetic risk, a 6.7-fold increased odds of AMD was seen in vitamin D deficient women who had 2 risk alleles for CFH (Y202H). For deficient women with 2 high-risk CFI alleles (rs10033900), the odds were 6.3- fold higher. None of the vitamin D genes assessed affected the odds of AMD.This is the first study to explore the interaction between genetic risk of AMD and vitamin D status. While the study had limitations – notably the small number of cases in the joint effects analyses, the results suggest synergy between vitamin D and high-risk genotypes of the complement cascade. It’s possible that maintaining sufficient vitamin D levels could help prevent AMD, especially in people at high genetic risk.
Vitamin D Status & Presence of Glaucoma
In non-human primates, vitamin D drops have been reported to lower intraocular pressure by 20%, raising the possibility of a link between vitamin D and primary open-angle glaucoma (POAG). Spurred by this report and others related to vitamin D and AMD, university medical researchers from Singapore and France teamed to determine whether vitamin D insufficiency is associated with the presence and severity of POAG . This case control study of older adults included 150 cases of moderate-to-severe POAG and 164 age-matched healthy controls.
Compared to controls, the POAG group had lower vitamin D blood levels – about 15% lower than controls, and a greater prevalence of vitamin D inadequacy. Higher mean vitamin D concentrations were associated with lower POAG frequency, even after adjustment for potential confounders. Similarly, low vitamin D status was associated with a 2-fold increase in POAG. No significant difference in vitamin D blood levels between moderate and severe POAG was seen.
This study found low vitamin D levels to be directly associated with the presence, though not severity, of POAG. The authors call for prospective observational studies and clinical interventions to determine whether vitamin D plays a role in POAG development.
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Glaucoma Associated With Vascular Dementia
POAG, Alzheimer’s and Dementia
Primary open angle glaucoma (POAG) and Alzheimer’s are both neurodegenerative diseases that have some features in common and other features that are distinct. Retinal ganglion cells are lost in both conditions, for example. The modified tau proteins that make up the tangles or twisted fibers in Alzheimer’s are also found in the retina of those with POAG. In addition, abnormal retinal deposits of amyloid-beta have been seen in animal models of glaucoma as well as the amyloid plaque found in the brains of Alzheimer’s patients.
On the other hand, the two conditions differ in some of their risk factors; cigarette smoking is thought to increase risk of Alzheimer’s for instance, but not of POAG. The genetic risk factors for the two conditions also appear distinct. The major genetic variant for Alzheimer’s is at apolipoprotein E, with carriers of the E4 allele having a higher Alzheimer’s risk. But in most studies E4 allele does not influence POAG risk.
Is there a connection between these two diseases? Previous epidemiologic studies looking at their potential relationship have had inconsistent results, leading a team of UK researchers to further study whether individuals diagnosed with POAG are at greater risk of subsequently developing Alzheimer’s .
The investigators also examined whether the risk of developing vascular dementia in subsequent years was linked to POAG, as there has been ongoing interest in potential associations between POAG and vascular disease.
Study Design
In this record linkage study, A POAG cohort of 87,658 people was constructed from English National Health Service-linked hospital statistics from 1999 to 2011. An Alzheimer’s cohort (251,703 people), a vascular dementia cohort (217,302 people) and a reference cohort (>2.5 million people) were similarly constructed. Risk of dementia following POAG was determined; rate ratios were calculated based on standardized rates of dementia in the POAG cohort.
Results
The researchers found no elevated risk of developing Alzheimer’s following a diagnosis of POAG. The rate ratio was 1.01 (95% CI 0.96 to 1.06).
However, a modest but significant positive association was seen between POAG and vascular dementia, with a rate ratio of 1.10 (95% CI 1.05 to 1.16). They also found that the likelihood of a hospital record of POAG following Alzheimer’s or dementia diagnosis was very low, with rate ratios of 0.28 (0.24 to 0.31) and 0.32 (0.28 to 0.37), respectively.
Comments
The potential relationship between POAG and vascular dementia is interesting, and further study is warranted. If this observed association is confirmed, it could have important implications for understanding disease pathophysiology in the two conditions, and provide insights into whether treatment strategies for one disease might be effective against the other.
Also, the finding that Alzheimer’s and dementia patients do not commonly have a record of developing POAG could represent a genuine deficit in ophthalmic care for people with a loss of mental ability.
Possible explanations for the observed link may include risk factors that are shared between POAG and vascular dementia. For example, diabetes and hypertension are strong risk factors for vascular dementia, and also increase the risk of POAG. In addition, previous research has shown that patients with POAG have reduced cerebrovascular blood flow and vaso-reactivity compared with controls.
As some glaucoma experts are now asking, could damage from glaucoma be the ocular manifestation of more widespread vascular problems involving the brain, rather than a separate process isolated only to the eye ?
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Vitamin D Deficiency Associated With Dry Eye Signs, Symptoms
Vitamin D Deficiency and Dry Eye
In addition to its well-known effects on bone and muscle, vitamin D plays a prominent role in gene regulation and is a potent immune modulator. It promotes innate immunity, indirectly regulates cytokine and immunoglobulin synthesis, and reduces inflammation.
Vitamin D deficiency (<20 ng/mL) and/or insufficiency (20-29 ng/mL) have been associated with a variety of health problems, from heart disease to ocular disorders such as optic neuropathy, myopia and AMD.
It has been shown that the cornea contains mRNA for vitamin D receptors and the enzyme that activates vitamin D (1 alpha-hydroxylase), as well as significant vitamin D concentrations. Experimentally, vitamin D is reported to enhance corneal epithelial barrier function.
These findings led researchers to examine whether vitamin D deficiency is related to dry eye and impaired tear function. The research team also asked whether dry eye is associated with the main symptoms of vitamin D deficiency: pain, fatigue and functional impairment such as muscle weakness .
Design & Methods
Fifty premenopausal women deficient in vitamin D (serum levels < 20 ng/mL) and 48 controls with serum vitamin D in the normal range (> 20 ng/mL) were included in this comparative study. Among the exclusion criteria was postmenopausal status, as hormonal changes may be associated with dry eye. Participants were assessed by Schirmer’s test, tear break-up time test (TBUT), ocular surface disease index (OSDI), Stanford Health Assessment Questionnaire (HAQ,) disability scale, fatigue severity scale (FSS), and visual analogue scale-pain (VAS-pain).
Results
Mean age did not differ between women with vitamin D deficiency and controls. Vitamin D level, Schirmer’s test and TBUT scores were lower, while OSDI, VAS-pain, HAQ and FSS scores were higher in the vitamin D deficient group than in the control group (all p< 0.001). In the vitamin deficient women, vitamin D level was negatively correlated with OSDI (p< 0.001), and positively correlated with Schirmer’s test and TBUT scores (p< 0.001 and p=0.001, respectively).
FSS (fatigue) was negatively correlated with both Schirmer’s test and TBUT scores (p= 0.038 and p= 0.002, respectively). VAS-pain was negatively correlated with TBUT scores (p= 0.023).
Of the vitamin deficient women, 52%, 74%, and 70% had dry eye according to the results of Schirmer’s test, TBUT, and OSDI respectively. The frequency of dry eye differed significantly between groups (see Table 3).
Comments
The finding of dry eye and impaired tear function in vitamin D deficient women could indicate a protective role for vitamin D in the development of dry eye, probably by enhancing tear film stability and reducing ocular surface inflammation, according to the authors. This could be of public health importance since the overall prevalence rate of vitamin D deficiency in US adults is estimated to be about 42%.
In the study, two of three major vitamin D deficiency symptoms correlated with dry eye parameters: fatigue with the amount of tears and the stability of the tear film layer, and pain with tear film layer stability.
Yildirim P., et al. Dry eye in vitamin D deficiency: more than an incidental association. Int J Rheum Dis, Epub Aug 13, 2015.
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In the news: Carbohydrate Quality, Quantity Linked to Risk of Cataract
Meta-analysis: Carbohydrate Quantity & Quality Linked to Cataract Risk
Various risk factors including age, diabetes, smoking, UV-B light exposure and dietary intake of the B-vitamins have been reported to play important roles in cataract development. A number of studies have also investigated the possible association between carbohydrate nutrition and age-related cataract.
To evaluate this association, Zhejiang University researchers conducted a meta-analysis with results published in 2014 . The analysis, which included 7 studies (11,944 participants) of good methodological quality, used the random-effect model to calculate pooled ratios. The researchers also performed dose-response analyses, analyses based on cataract subtypes and assessed publication bias.
The authors looked at both the dietary glycemic index (GI) and the glycemic load (GL). The GI compares the potential of foods containing the same amount of carbohydrate to raise blood glucose, but it doesn’t take into account the amount of carbohydrate in the actual serving of a food. The GL incorporates both the quality and quantity of carbohydrates in the diet, and is a more accurate indicator of how a carbohydrate food will affect blood glucose.
Higher ‘carb’ intake (GL) and GI were significantly associated with an18% and 15% increased risk of age-related cataract, respectively, vs. lower intake. Sub-group analyses revealed a marginally significant association between higher carb intake and cortical cataract risk, and a significant association between greater GI and risk of nuclear cataract.
Additionally, a significant dose-response association was observed between intake of carbs and cortical cataract risk. No significant publication bias was detected.
The results indicate that higher quantity and lower quality (higher GI) of carbs may raise the risk of cortical and nuclear cataract, respectively. The authors call for more studies to further clarify these associations.
Positive Link: GL & Cataract Extraction Risk
The findings of a recently published study, not included in the meta-analysis, are consistent with the idea that a higher glycemic load is associated with developing age-related cataract. In this case-control study conducted in a Mediterranean population, Italian epidemiologists analyzed data from 761 cases of cataract extraction and 1,522 age and gender matched hospital controls . Multivariate odds ratios for GL and GI were obtained from logistic regression models, taking into account confounding factors including non-carbohydrate energy intake, smoking and diabetes.
A 57% higher odds of cataract extraction was seen when the top 1/3 and lowest 1/3 of GL were compared. A 20% non-significant trend was observed for GI in the same tertile comparison. Excluding those with diabetes from the analysis did not materially change the results. The cases and controls did not differ significantly across the categories of age, gender, education, smoking habits and body mass index.
Comments
The observed association between carbohydrate nutrition and lens opacities is biologically plausible. Metabolic studies have shown that a high intake of high GI carbs can cause a rapid glucose response after eating. Compared with many cells and tissues with a rapid uptake of glucose, the uptake of glucose from plasma into the aqueous humor and lens is relatively slow and the glucose is slowly turned over. This can lead to prolonged exposure of lens proteins to elevated glucose levels which could disrupt the polyol pathway, and lead to lipid peroxidation, cross-linking, and glycation – i.e. more oxidative stress.
View more information on low GL and GI foods
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In the news: Omega-3s Not Linked to Prostate Cancer & May Benefit Mental Function
Omega-3s not Linked to Prostate Cancer
In 2013, a widely publicized meta-analysis conducted by Brasky, et al reported an association between omega-3 fatty acid intake (EPA / DHA) and the risk of developing prostate cancer. However, a comprehensive new meta-analysis by Alexander, et al does not support those earlier findings.
The results of the Brasky paper were met with some degree of skepticism by lipid researchers for several reasons. First, the omega-3s are known to have anti-inflammatory, pro-apoptotic and anti-proliferative effects on prostate cancer cells – effects suggesting that these long chain fats might inhibit prostate cancer development. In addition, no plausible mechanism by which omega-3s could contribute to prostate carcinogenesis has been identified.
The meta-analysis also found trans-fatty acids to be protective, contrary to the widely held position that consuming trans-fats increases the risk of heart disease and stroke.
Using a fixed-effects meta-analysis model to examine prospective nested case-control and case-cohort studies, Brasky, et al found significantly positive associations between EPA / DHA intake and prostate cancer incidence. At the time this meta-analysis was published, some experts suggested that using a random-effects statistical model might have delivered different results, as it accounts for variation both between studies and within individual studies.
The new paper by Alexander et al utilized a random-effects meta-analysis. It included prospective studies: 12 self-reported dietary intake studies (446,243 participants) and 9 biomarker studies (14,897 participants).
Employing the random-effects model – and even when using the same statistical model as Brasky, et al – no link between omega-3 fatty acids intake and prostate cancer risk was found. In fact, some trends observed by Alexander and colleagues suggest a potentially protective effect, though they did not achieve significance.Omega-3s & Mental Flexibility in At-Risk Adults
Higher intake of the omega-3s might benefit cognitive function in healthy older adults at risk of Alzheimer’s, according to a cross-sectional study conducted by researchers at the University of Illinois .
The study examined the neural mechanisms that mediate the relationship between omega-3 fatty acids (EPA / DHA) and executive functions in 40 at-risk (APOE e4 carriers), cognitively healthy older adults aged 65-75. Carrying the e4 version of the APOE (apolipoprotein E) gene increases an individual's risk for developing late-onset Alzheimer disease.
The researchers hypothesized that higher blood levels of omega-3s are associated with better performance in a particular component of the executive functions, namely cognitive flexibility. Cognitive flexibility has been described as the mental ability to switch between thinking about two different concepts, and to think about multiple concepts simultaneously. It’s the ability to change what one is thinking about, how one thinks about it, and even what one thinks about it.
Participants with higher blood levels of the omega-3s fared better on tests assessing cognitive flexibility. Measured by MRI, these participants also had a greater volume of gray matter within regions of the prefrontal cortex called the anterior cingulate cortex – a region thought to be important for cognitive flexibility.
The findings suggest that consuming DHA and EPA might support mental flexibility by bolstering the size of the anterior cingulate cortex. According to the authors, the anterior cingulate cortex appears to mediate the relationship between the omega-3s and cognitive flexibility in cognitively intact adults at risk for cognitive decline.
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In the news: Vitamin D & Diabetic Neuropathy: AMD Genetic Testing Premature
Vitamin D & Diabetic Neuropathy Symptoms
Vitamin D (25-hydroxyvitamin D) deficiency is common in diabetic patients, and low concentrations are associated with the presence and the severity of various diabetic complications including retinopathy, nephropathy and sensory neuropathy. Vitamin D deficiency has been shown to be an independent risk factor for diabetic peripheral neuropathy (DPN). Two previous studies report that topical and oral vitamin D reduce the symptoms and pain of DPN, leading a research team to prospectively evaluate the effect of vitamin D in DPN.
This randomized, double blind, placebo controlled trial included 112 type 2 diabetic patients with DPN and vitamin D deficiency . DPN was assessed using a neuropathy symptom score, a neuropathy disability score, and a nerve conduction study. The primary outcomes were changes in symptoms and disability scores from baseline. Patients received either oral vitamin D capsules (50,000 IU) or placebo once weekly for 8 weeks.
Serum vitamin D levels significantly improved in the vitamin D treatment group compared to the placebo group (p < 0.0001). Similarly, the improvement in neuropathy symptom values was significantly greater in the treatment group than in placebos (p < 0.001). The main symptom improvement observed was in the sensation of neuropathic pain, especially burning and increased sensitivity to stimuli (hyperesthesia). No improvement was seen for the other outcomes.
According to the authors, these findings establish that oral vitamin D corrects vitamin D deficiency, which leads to a reduction in the symptoms of neuropathy. It’s not clear whether the symptom improvements were due to an increase in the pain threshold or to an improvement in the function of the affected nerves, or both. Vitamin D is a potent inducer of neurotrophins and neurotransmitters, and experimentally, it has been shown to increase the action of nerve growth factor – a protein required for developing and maintaining neurons in the peripheral nervous system. While the present trial utilized very large, less frequent doses of vitamin D to correct the deficiency state, such high doses are not necessarily required. In an earlier study in type 2s with neuropathic pain and vitamin D deficiency, a daily mean dose of 2059 IU vitamin D for 3 months significantly reduced pain scores.Genetic Testing Not Recommended for AMD
Writing in the journal JAMA Ophthalmology, Edwin M. Stone, MD, PhD, an ophthalmologist who specializes in genetic eye diseases at The University of Iowa Carver College of Medicine, presents a reasoned perspective on why genetic testing for AMD is currently unjustified .
The author describes the various risks associated with routine genetic testing, and is of the opinion that a comprehensive eye exam with up to date imaging is superior to any current genetic test in predicting the clinical course of AMD. The primary issue with routine genetic testing is that there is no evidence from prospective, randomized clinical trials that genotype testing leads to improved outcomes, according to Dr. Stone.
He points to studies from two different groups (Awh, et al and Chew, et al) that have both used clinical data from AREDS and have come to opposite conclusions. Awh, et al contend that specific ARMS2 and CFH genotypes are associated with different responses to supplemental antioxidants and zinc – a hypothesis based on a retrospective analysis. The author emphasized that the burden of proof of this hypothesis lies with Awh and colleagues. In contrast, Chew et al advise the full complement of AREDS nutrients for AMD patients regardless of genotype, as does Dr. Stone.
The author notes that routine genetic testing for AMD is not recommended by the AAO task force on genetic testing, nor is there consensus on how genetic testing would be integrated into clinical practice. He concludes that routine genetic testing may someday play a role in achieving better outcomes for AREDS patients, but today the risks of such testing outweigh any benefits.
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In the news: Environmental Factors in Exfoliation Syndrome
Exfoliation Syndrome: Background
Exfoliation syndrome (XFS) is the most common cause of secondary open angle glaucoma. Patients with this syndrome are also predisposed to develop angle-closure glaucoma, and XFS can lead to retinal vein occlusion and increased cataract formation. XFS is also suspected to be a systemic disorder and has been preliminarily associated with transient ischemic attacks, stroke, hypertension, and heart attack.
The underlying mechanism of XFS is believed to involve abnormal extracellular matrix metabolism, which produces elastic fiber components that clump and accumulate in many ocular tissues. Deposits of white material on the anterior lens surface are the most consistent, important diagnostic feature of XFS.
Genetics play a role in XFS. The enzyme lysyl oxidase-like 1 (LOXL1) is pivotal in bolstering the tensile strength of collagen and elastin in extracellular matrices. Common gene variants in LOXL1 have been found in approximately 99% of XFS cases in Scandinavian populations. However, about 80% of controls also had disease-associated LOXL1 gene variants. Similar findings were seen in cases and controls from Australia. These observations suggest that other factors in addition to genetics contribute to XFS. Harvard researchers recently reviewed findings on factors that may influence the development of XFS .
Environmental Factors: Recent Findings
The review identified and discussed non-genetic factors associated with increased risk of XFS, including:
Diet
Low serum folate levels are linked with increased risk of XFS. Low levels of serum folate can lead to elevated homocysteine, and homocysteine levels are higher in the serum, aqueous humor and tear samples of XFS patients compared with controls. Elevated homocysteine may increase exfoliation material formation by contributing to vascular damage, oxidative stress, and changes in the extracellular matrix.Coffee consumption may be another factor that alters XFS, as heavy consumption is associated with increased risk. It may be that drinking too much coffee causes homocysteine levels to rise. The exact mechanism by which homocysteine enhances the formation of exfoliation material remains unclear, but it may involve extracellular matrix metalloproteinase regulation.
Climate
Colder temperatures in the summer and winter months appear to be independent risk factors for XFS. In fact, many countries with cold mean temperatures such as Iceland, Norway and Sweden have a high prevalence of the syndrome. One possible explanation for this observation is that extracellular deposits of XFS are the result of a precipitation reaction that develops at colder temperatures.
Sun Exposure
Cold can’t be the only factor involved in XFS, however, since the Arctic-dwelling Inuit people are relatively immune to developing the syndrome. A number of studies have linked outdoor occupations or time spent outdoors during summer months with greater XFS risk. UV-light exposure has been found to up-regulate the expression of LOXL1 and major elastic fiber proteins found in the exfoliation extracellular deposits.
Additionally, longer exposure to reflective surfaces such as water or snow increases the odds of developing XFS. Snow reflects as much as 80% of UV-B during midday, suggesting that ocular exposure to light from reflective surfaces may be an important UV source in the pathogenesis of XFS.
The authors conclude that a better understanding of the environmental components associated with XFS could lead to lifestyle changes that help prevent the syndrome and its consequences.
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In the news: Lutein & Functional Vision: Carotenoids in Early AMD
Carotenoids, Functional Vision and AMD
AREDS 2 showed that lutein and zeaxanthin reduces the risk of developing advanced AMD, at least in those with low dietary intake. While it’s not yet known how these carotenoids might impact the disease process in early AMD, there is growing evidence that they may benefit visual performance.
Several past studies have reported that higher macular pigment optical density (MPOD) and lutein/zeaxanthin supplementation are related to improvements in glare disability, photo stress recovery, and chromatic contrast both in patients with early AMD and in healthy individuals .
Two studies related to these areas of investigation have recently been published. One study examines the effect of supplemental lutein on inflammation in early stage AMD. The other assesses the link between lutein/ zeaxanthin, MPOD, and measures of visual function in young adults via a randomized trial.
Lutein & Complement System in Early AMD
The complement system is an important player in the inflammatory process, and evidence suggests its activation contributes to AMD. Susceptibility genes encoding for complement factor H have been identified, and complement proteins have been found in drusen.
The present study , conducted by researchers from the Netherlands and the UK, is the first to explore whether lutein might affect complement activation.
Seventy patients with signs of early AMD randomly received a 10 mg daily dose of lutein or placebo for 1-year. Participants’ plasma levels of sC5b-9 (soluble complement membrane attack complex) were determined by ELISA at various time points. A marker of systemic inflammation, sC5b-9 is the final product of the 3 different complement activation pathways.
A significant monthly decrease of 1.1 ng/ml in plasma sC5b-9 was seen for the lutein group, resulting in an annual decline from an initial 60.3 ng/ml to 46.3 ng/ml at 1 year. In placebos, sC5b-9 went up 0.6 ng/ml monthly, with a yearly increase of 51.6 to 58.4 ng/ml.The relative contribution of the 3 different complement pathways is not yet known in AMD patients, nor could the researchers pin down which of the pathways lutein affected. However the study provides evidence that lutein inhibits complement activation, and the authors conclude that lutein “can be considered as a potential prevention and treatment for AMD”.
Lutein & Zeaxanthin Improve Visual Function
Carotenoids can influence the optical characteristics of the eye, but can they impact vision in a meaningful way? University of Georgia researchers explored this question, measuring functional vision parameters in 115 healthy young adults randomized to receive 10 mg lutein and 2 mg zeaxanthin or placebo in a 1-year trial .
Results: Intent to treat analysis showed that MPOD increased significantly in the carotenoid group vs. placebo at all measured eccentricities (distances from the center of the macula). Chromatic contrast and photo stress recovery time improved significantly versus placebo. Glare disability was correlated with MPOD throughout the study period, but did not increase significantly in the treated group.
One limitation of the study was a high drop out rate, with 34 subjects withdrawing over the course of the year (largely students leaving the university). However, the findings are generally consistent with other randomized controlled trials, most of which report that increasing MPOD leads to better visual performance.
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Recent Flavonoid Findings: From Healthy Aging to Potential Heart Protection
Flavonoids in Health and Disease Prevention
Observational studies suggest that flavonoid-rich diets may lower the risk for a variety of chronic diseases, particularly cardiovascular disease. Abundant in fruits and vegetables, tea, and wine, these polyphenolic nutrients may contribute to risk reduction by decreasing oxidative stress and inflammation – two pathways underlying many age-related health problems, including AMD.
This issue of EduFacts highlights recent research exploring the role of flavonoids in health and disease prevention. One study takes a holistic approach in evaluating the potential of flavonoids, while the others provide insight into how these nutrients might confer protection.
Flavonoids & Healthy Aging in Women
There are several subclasses of flavonoids, and food databases are now available to quantify the different types of flavonoids in the diet. Using these expanded databases, Harvard researchers investigated the relationship of flavonoid intake at midlife to overall health and wellbeing in women as they age .
Analyzing data from 13,800 participants in the Nurses Health Study who were initially free of chronic diseases and in their mid-fifties, the researchers identified 1,500 women who met their “healthy aging” criteria after a 15 year follow-up.
Healthy aging was defined in relation to usual aging at 70, and based on reaching 70 or older without a major chronic disease or having impaired physical or mental function.
Women with the highest intake of several flavonoid subclasses had greater odds of healthy aging. Specifically, flavones, flavonones, anthocyanins and flavonols bolstered the odds by 32%, 28%, 25% and 18%, respectively (all p-trend ≤ 0.02).
Consistently, consuming more of the major sources of these flavonoids – oranges, berries, onions, and apples – increased the likelihood of health and wellbeing in this population.Berries, Blood Pressure & Arterial Stiffness
Florida State University investigators found that blueberries, a concentrated source of anthocyanins, produce clinically significant reductions in both diastolic and systolic blood pressure of 5.1% and 6.3% respectively, while improving the health of arteries in women with pre- and Stage 1 (mild) hypertension .
Of the 48 women randomly assigned to get 22 g of blueberry powder (equivalent to 1 cup of fresh berries) or placebo powder daily, those in the berry group had meaningful drops in blood pressure (p<0.05), increased levels of artery-relaxing nitric oxide (p<0.01), and a reduction in arterial stiffness at the end of 8 weeks (p<0.01). No changes in these parameters were seen in the placebo group.
The researchers conclude that consuming blueberries regularly can potentially delay the progression of high blood pressure and reduce CVD risk in post-menopausal women. Several additional small trials testing the effects of blueberries in pre-hypertension have reported similar results.
Flavonoids May Cut Smog-Related Heart Risks
Heart rate variability, the beat-to beat changes in heart rate, allows the cardiovascular system to respond to changes in the need for blood flow and oxygen. Low heart rate variability is a predictor of heart-related death, and air pollution can reduce the heart’s ability to vary its rhythm.
Researchers from Harvard’s School of Public Health report that higher flavonoid intake cushioned the effects of air pollution on heart function in 573 elderly men participating in the Normative Aging Study . Comparing clinical measures with air quality data collected over 11-years, the investigators saw heart rate variability decline when smog levels rose for 48 hours.
They also evaluated whether over methylation of Toll-like receptor 2 (TLR2), a protein fundamental to the immune response, impacts the smog-associated effect on the heart. It did. Greater methylation of TLR2, a reversible epigenetic process, worsened heart rate variability during smoggy periods. However, the association between heart rate variability and pollution levels was far weaker among men consuming the most flavonoids.
While these findings are preliminary, it’s quite possible that flavonoids trigger epigenetic changes that help counter the heart’s susceptibility to the hazardous effect of pollution. There’s a growing body of evidence, for instance, that certain polyphenols can reduce over methylation of DNA in critical genes associated with cancer.
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In the news: Zinc May Be Protective in AMD by Blocking Complement Activation
The Complement System and AMD
The complement system has important protective functions in both the innate and the adaptive immune systems. It helps defend against invading microorganisms and clears away cellular debris. But the complement system can also, when inappropriately activated, cause inflammation and tissue damage.
Three lines of evidence support the involvement of complement in AMD. First, it’s been found that drusen contain proteins of the alternative complement pathway (one of three pathways of complement activation). This has led to the hypothesis that drusen could be involved in local complement-mediated inflammation.
Second, there is a strong association between AMD and genetic variants in complement factor H (CFH) gene, which is a major inhibitor of the alternative complement pathway. This also suggests that complement-mediated inflammation at the level of the retina plays a pivotal role in AMD. A third line of evidence comes from studies showing that AMD patients have higher levels of complement activation products in their blood.
Exploratory Study of Zinc & Complement
The findings of the AREDS trial established the importance of zinc in AMD: zinc alone significantly slowed disease progression, and its effectiveness was amplified when combined with antioxidants. However, the mechanism by which zinc exerts its beneficial effect has not yet been identified.
To better understand zinc’s protective mechanism, researchers examined the effect of zinc on the activity of the alternative complement pathway in AMD patients. They also asked whether the response to zinc supplements correlates with the CFH and Age-Related Maculopathy Susceptibility 2 (ARMS2) genotypes. Lastly, they evaluated whether zinc directly affects complement activation in vitro.Study Details and Results
In this open-label study , 72 randomly selected AMD patients in various stages of AMD received 50 mg zinc/1 mg copper daily for 3 months. Serum complement catabolism – a measure of complement activation and defined as the C3d/C3 ratio – was assessed at baseline and over the 3 month period.
Results
AMD patients with high levels of complement catabolism at baseline exhibited a steeper decline in serum complement activation (p <0.001) during the 3 months of supplementation compared to those with low baseline complement catabolism levels.
In vitro, zinc showed direct and dose-dependent inhibition of complement activation in hemolytic assays. Zinc was also shown to dose-dependently inhibit the deposit of membrane attack complex (MAC) on retinal pigment epithelial cells in response to oxidative stress (with activation of the alternative complement pathway, MAC disrupts membranes and destroys cells).
Lastly, no association between the change in complement activation and CFH and ARMS2 genotypes was observed. Genotype did not have an effect on either baseline or change of complement activation levels.Comments
Though relatively small and exploratory, this study offers one possible explanation of how zinc slows AMD progression. The results suggest that zinc benefits AMD patients with high complement activation levels, independent of genotype.
In contrast, a recent subgroup analysis using AREDS data reports that the response to zinc and antioxidants may be influenced by CFH and ARMS2 genotypes . The authors recommend that those with CFH genotype avoid zinc, though the methods employed in that analysis raise concerns about the validity of the findings.
A new analysis from the NEI used a different subset of AREDS participants to test the validity of the purported detrimental effect of zinc on CFH genotype. In this analysis, the combination of antioxidants and zinc was found to be beneficial and the treatment of choice for both people with CFH and ARMS2 genotypes .
For more information on these and related studies, go to: www.sbh.com/genetic
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In the news: Meta-analysis of Lutein & AMD, Glucose Metabolism & Glaucoma
Role for Lutein in Managing AMD
Researchers from the Dept. of Ophthalmology at one of the largest teaching and research hospitals in Beijing, China conducted a meta-analysis to assess the effectiveness of lutein supplementation in managing age-related macular degeneration (AMD) .
Parameters of interest were macular pigment optical density (MPOD) and visual acuity. Heterogeneity of the data was determined and publication bias assessed. Five randomized controlled trials involving 445 participants met the inclusion/exclusion criteria.
Supplemental lutein treatment was associated with highly significant improvement in MPOD, with a mean difference between lutein and placebo groups in the change from baseline of 0.09 (p < 0.00001).
Visual acuity also improved, though less significantly, with a mean difference between groups in the change from baseline of -0.04 (p < 0.05).
The authors conclude that lutein alone is capable of improving MPOD and visual acuity. Though zeaxanthin is also an indispensible component of macular pigment, they point out that lutein is the dominant carotenoid of the two in the diet (provided in ratio of about 5:1 lutein to zeaxanthin). The researchers also note that a lutein dose of 10 mg/day appears to be more efficient as it leads to similar improvements as 20 mg/day.
Glucose Metabolism and Glaucoma Risk
The association between diabetes and glaucoma has been evaluated in many studies. However, few have examined the relationship between metabolic syndrome or glucose metabolism biomarkers and glaucoma, and the results have been conflicting. Two recent studies shed further light on this subject. In the first, a cross-sectional study , researchers examined the relationship between diabetes, pre-diabetes, metabolic syndrome, and markers of glucose metabolism with the prevalence of glaucoma in the general US population. They used data from 3,300 participants in the 2005-2008 National Health and Nutrition Examination Survey (NHANES).
A higher prevalence of glaucoma in people with diabetes was seen, even after controlling for multiple potential confounders. Those with diabetes had just over twice the risk of having glaucoma.
Pre-diabetes and metabolic syndrome were not consistently associated with the prevalence of glaucoma. However, markers of glucose metabolism showed significant non-linear associations with glaucoma, including a J-shaped association for fasting glucose, and hockey-stick shaped associations for fasting insulin, HbA1c and HOMA-IR (a measure of insulin resistance). These non-linear relationships suggest that once glucose metabolism markers reach a threshold, the risk for glaucoma increases.
The authors recommend regular eye exams for patients with diabetes, as well as those with elevated levels of glucose metabolism parameters, to monitor for the onset or progression of glaucoma.
In the second study , researchers conducted a systematic review and meta-analysis of 47 studies involving more than 2.9 million people from 16 countries to examine the association between diabetes and blood glucose levels with glaucoma, intraocular pressure (IOP), and ocular hypertension.
They found that diabetes, longer duration of having the disease, and elevated blood glucose levels significantly raised the risk for glaucoma. Diabetes and fasting blood glucose levels were associated with slightly higher IOP.
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In the news: Carotenoids & Visual Processing, Carotenoids in Early AMD
Carotenoids and Neural Processing Speed
Aging is often accompanied by a decline in central nervous system efficiency that tends to manifest as deficits in such functions as short-term memory and decision-making ability, as well as more basic functions such as reaction time. A slowing of processing speed appears to be central to these declines, is an important marker of optimal brain function, and may predict future cognitive decline.
One potential approach to improving neural processing and influencing brain function is to provide dietary components that reflect neural tissue composition. Over half the brain is fat, for example, and the brain tends to preferentially accumulate fluid fats like DHA over more rigid saturated fats.
Lutein and zeaxanthin are also components of the nervous system. It has been hypothesized that these carotenoids influence the processing of visual signals within and beyond the retina, and that increasing lutein and zeaxanthin levels in the visual system will lead to improved processing speeds.
To test that hypothesis, University of Georgia researchers measured macular pigment optical density (MPOD), visual motor reaction time, and critical flicker fusion (CFF) in 64 young healthy adults randomly assigned to receive a combination of lutein, zeaxanthin and omega-3 fatty acids, or zeaxanthin alone, or placebo for 4 months .
At baseline, significant correlations were found between MPOD and CFF thresholds and visual motor performance. The supplement groups (combined to increase statistical power) showed significant increases of about 12% in CFF thresholds and about 10% in visual motor reaction time compared to placebo. Average MPOD increased (about 0.09 log units) with supplementation.
This line of research is relatively new, and more and larger studies are needed to determine whether modifying neural levels of these carotenoids actually improves processing speeds and cognitive function. So far, one small placebo-controlled trial has found
that supplemental DHA, lutein and zeaxanthin improves cognitive function in elderly women. In studies with monkeys, measuring MPOD has been shown to be a good proxy for the amount of lutein and zeaxanthin in the brain. Further, CFF has been associated with cognitive performance. Taken together, this suggests that lutein and zeaxanthin may influence neural processing speed in both the brain and the eye.Carotenoids & Neural Sensitivity in Early AMD
Some AMD intervention studies report that supple-mentation with macular carotenoids increases MPOD and improves visual function, while others have found no significant improvements in visual function despite increases in MPOD. That may be because structural changes do not affect retinal function in earlier stages of the disease, or because visual measurements have not been sensitive enough to detect visual benefits.
To shed light on this question, researchers randomly assigned 112 patients with early AMD to receive 10 mg lutein, 20 mg lutein, lutein and zeaxanthin (10 mg each) or placebo for 2 years . Retinal sensitivities were measured by multifocal electroretinogram (N1P1) and in terms of micro-perimeter-determined mean retinal sensitivity (MRS).
Carotenoid supplementation in all active treatment groups significantly increased MPOD. N1P1 response densities increased in rings 1 and 2 (though not rings 3-6) in all active treatment groups. Increases in MRS were seen with either 10 mg or 20 mg lutein, while no increases were seen in the placebo arm.
This study shows that MPOD can be augmented and visual function enhanced with supplemental macular carotenoids. The fact that gains in MPOD were similar between 10 and 20 mg lutein doses at 2 years reinforces the idea that incorporation of macular carotenoids in the retina is a saturable process.
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In the news: Vitamin D Levels in AMD, Omega-3s & Anti-VEGF in AMD
Vitamin D Levels in ‘Wet’ vs. ‘Dry’ AMD
Over the past several years, a number of studies have found an association between serum vitamin D levels and both early and late stage AMD. Researchers from the Department of Ophthalmology, Duke University Medical Center now report results of the largest study to compare vitamin D levels in patients with different clinical forms of AMD .
The researchers found that mean serum vitamin D [25(OH)D] levels were significantly lower in 146 patients with neovascular AMD compared to 216 patients with the non-neovascular form and to 100 controls without AMD.
The prevalence of vitamin D insufficiency (< 30 ng/mL), deficiency (< 20 ng/mL), and severe deficiency (< 10 ng/mL) were highest in the neo-vascular group.
The highest 20% or quintile of serum vitamin D levels (> 40 ng/mL) was associated with 65% lower odds for neovascular AMD versus the lowest quintile, adjusted for age and BMI.
As a retrospective review, this study has limitations. The results are compelling, though, because of the biologic plausibility of the association. In addition to its anti-inflammatory properties, active vitamin D has demonstrated anti-neovascular activity in rodent models of diabetic retinopathy, for example, and to interrupt key signaling pathways in angiogenesis.
The authors call for further study to examine whether improving vitamin D status may lower the risk for developing ‘wet’ AMD.
Currently, the recommended daily intake of vitamin D set by the Institute of Medicine is 600 IU daily for adults and 800 IU per day for those 70 and older, based largely on the impact of vitamin D on skeletal outcomes. In contrast, the US Endocrine Society indicates that 1500–2000 IU per day may be needed for adults and those over 70 to raise serum [25(OH)D] consistently above 30 ng/mL which is considered to be the optimal level by the guideline Task Force.Omega-3 Fats and Anti-VEGF in Wet AMD
Inhibitors of vascular endothelial growth factor (VEGF) have proven to be effective treatments against wet AMD. However, as with any medication, anti-VEGF may have some associated risks such as a higher incidence of geographic atrophy in patients receiving more frequent anti-VEGF injections. This prompted researchers from the University of Montreal, Canada to explore an adjunct therapy in anti-VEGF treatment.
The study, an open label pilot trial, included 3 cohorts with wet AMD and a control group with epiretinal membrane or macular hole . Wet AMD patients already being treated with anti-VEGF (bevacizumab) were randomly assigned to daily supplements of antioxidants, zinc, and carotenoids with (Group 1, n=10) or without (Group 2, n=10) omega-3 fatty acids (200 mg of DHA and 400 mg of EPA). A third group (n=10) consisted of wet AMD patients who were just beginning anti-VEGF treatment. Group 4 was the control group (n=10). Groups 3 and 4 were not supplemented.
Patients receiving omega-3s (Group 1) had significantly lower levels of vitreal VEGF-A compared to Group 2 and Group 3, but similar levels to the control group. All groups showed similar values for plasma VEGF-A and measurements of central foveal thickness.
This pilot trial reports a significant decrease of VEGF-A in the vitreous of wet AMD patients on anti-VEGF therapy taking EPA and DHA – omega-3s thought to influence processes implicated in retinal angiogenesis. The results suggest that omega-3s selectively lower pathological levels of VEGF-A in the retina, but not in the general circulation where the normal function of VEGF is to create new blood vessels after injury, muscle following exercise, and new vessels to bypass blocked vessels. Long-term studies will be required to determine whether the omega-3s plus anti-VEGF therapy translates into slower progression of new vessel formation in the choroid.
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In the news: Coffee & Type 2 Diabetes Risk, Ocular Blood Flow in Glaucoma Patients with Diabetes
Ocular Blood Flow in Diabetics with OAG
Some research suggests that people with diabetes are more likely to develop glaucoma than are non-diabetics, and that the likelihood of developing diabetes is higher in those with open angle glaucoma (OAG). Other studies have not observed these associations. While the relationship between glaucoma and diabetes remains unclear, vascular complications are common to both.
Autoregulation is the ability of vascular beds to maintain relatively constant blood flow despite changes in pressure, while meeting the metabolic needs of the tissue. Numerous studies suggest that glaucoma patients have impaired autoregulation in vascular systems of the eye. Likewise, diabetic patients have been shown to exhibit impaired vascular regulation. These defects can lead to ischemic damage of the optic nerve head (ONH).
Researchers at Indiana University recently evaluated the impact of retinal blood flow on ONH structure (morphology) in 66 OAG patients with and without diabetes . Changes in retinal capillary blood flow, assessed at baseline and at 3 years, were more strongly correlated with detrimental changes in ONH morphology in diabetic patients – results suggesting that OAG patients with coexisting diabetes may be more sensitive to abnormal retinal blood flow.
Coffee May Lower Risk of Type 2 Diabetes
According to the American Diabetes Association (ADA), 25.8 million Americans have diabetes (mostly type 2), while 79 million aged 20 and older have prediabetes. Increased physical activity and healthy weight maintenance are considered cornerstones of type 2 prevention. It may be that drinking coffee confers some protective benefit as well.
The results of prospective cohort studies suggest that long-term caffeinated coffee consumption is associated with type 2 diabetes risk reduction. To further test this association, researchers from the Harvard School of Public health examined the associations between 4-year changes in coffee consumption and risk of type 2 in the following 4 years.2 The researchers prospectively followed over 123,700 men and women. At the end of follow-up, 7,269 cases of incident type 2 diabetes were documented.
People who increased their consumption of caffeinated coffee by more than a cup per day had an 11% lower risk of type 2 diabetes compared with those whose consumption held steady, while decreasing coffee intake by more than a cup a day was linked to a 17% increased risk. These changes in risk were independent of initial coffee intake and 4-year changes in other dietary and lifestyle factors.
‘Decaf or Regular’? How Much Coffee Daily?
No changes in risk were seen for decaffeinated coffee drinkers in this study. However consumption was low and only a small portion of ‘decaf’ drinkers made substantial changes in their intake. Many other studies have linked higher intake of both caffeinated and decaf with a lower risk for type .
How much coffee may be of benefit? Previous studies suggest that up to 6 cups daily may lower risk, and that coffee is associated with risk reduction in a dose response manner. A recent review of prospective studies found 9% and 6% risk reductions for each additional daily cup of caffeinated and decaf coffee, respectively .
Older people with high blood pressure should check with their physician about caffeine consumption. However, a review and meta-analysis found no association between long-term coffee consumption and increased blood pressure or between habitual coffee intake and an increased risk of CVD in hypertensives .
References
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In the news: Blood Pressure, Medications, & Ocular Health
Hypertension, Medications & Ocular Health
Four recently published papers report associations between blood pressure – or commonly used drugs – and intraocular pressure (IOP), ocular disease, or ocular function. In the context of these studies, the DASH diet (Dietary Approach to Stop Hypertension) merits renewed attention. View instructions for implementing this AHA and NHLBI recommended diet.
Blood Pressure Associated with IOP, Glaucoma
The 1st investigation , a systematic review and meta-analysis that included 60 observational studies, found a consistent association between hypertension and increased IOP.
A significant link between elevated blood pressure and primary open angle glaucoma (POAG) was also observed when patients with hypertension were compared to those without it. The authors point out that additional studies are needed to clarify the role of blood pressure in POAG development.
Link Between Systemic Medications and IOP
Lower IOP was associated with oral use of β-blockers or nitrates (vasodilators) in the 2nd investigation, a population-based study of 7000+ older British men and women. Use of these drugs was independently linked to lower IOP: roughly 1 mmHg and 0.6 mmHg lower for β-blockers and nitrates, respectively.
The findings of this study may have implications for managing glaucoma patients who are taking nitrates, to treat or prevent angina, or those using β-blockers for cardiovascular disorders including hypertension.
Beta-blockers, Nitrates and AMD Risk
While β-blockers and nitrates could potentially have salutary effects on IOP, the results of the 3rd study raise questions about their impact in AMD. The researchers report that in the long-term Beaver Dam Eye Study, use of any vasodilator, particularly oral nitroglycerin, was associated with a 72% greater risk of developing early AMD. Patients using oral β-blockers faced a 71% increased risk of neovascular AMD. As significant as these results may appear to be, these findings need to be replicated before changing patients’ medication regimens.
Blood Pressure & Acquired Impaired Color Vision
Is blood pressure related to acquired color vision impairment (ACVI) in middle-aged men? To shed light on this question, authors of the well designed and conducted Japanese Okubo Color Study compared the highest vs. the lowest blood pressure categories in men diagnosed with ACVI (using 15 hue and 100 hue tests).
The study excluded those with congenital color vision defects, previous cerebrovascular or ocular diseases, and the use of certain medications that can affect vision, and the analyses adjusted for these and other risk factors. The authors report that hypertension significantly raised the odds of having ACVI in both “15 hue and 100 hue” tested patients.
The positive correlation of high blood pressure with the prevalence of ACVI suggests that hypertension negatively impacts vision-associated neuronal function. Deterioration of the ability to discriminate between colors has long been recognized as one of the earliest indicators of neurological degeneration, and may be related to cognitive impairment and Alzheimer’s disease later in life. The authors of this cross-sectional study call for large prospective studies to confirm their results.
References
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In the news: Vitamin D & Blood Pressure: Omega-3 & Periodontal Disease
Vitamin D Found to Reduce Blood Pressure
The previous issue of EduFacts discussed research related to hypertension and ocular health. Germane to that research topic are two new studies that suggest a role for vitamin D in maintaining normal blood pressure.
Low vitamin D status has been linked to elevated blood pressure in a number of population health studies, spurring researchers from China to evaluate the effects of vitamin D in patients with essential hypertension.
In this randomized controlled trial , 126 patients with grades I-II essential hypertension received either 2,000 IU vitamin D or a placebo daily in addition to an anti-hypertensive drug (nifedipine, a calcium-channel blocker, 30 mg/day).
At the end of 6 months, the vitamin D group had a 24-hour mean blood pressure -6.2 (systolic) and -4.2 mm/Hg (diastolic) lower than the placebo group for intention-to-treat analysis. For patients whose vitamin D levels were low (<30 ng/ml) at baseline, the drop in systolic and diastolic pressures was greater: -7.1 and -5.7, respectively. The authors conclude that vitamin D may be an effective adjuvant therapy in this patient population.
Causal Link Between Vitamin D & Blood Pressure?
Results from a new genetic investigation provide evidence that poor vitamin D status may play a causal role in the development of hypertension.
An international team of researchers evaluated genetic data from the D-CarDia collaboration and other consortia, involving more than 140,000 individuals . Using a mendelian randomization approach to reduce confounding and bias, they generated an allele score based on two common variants of genes that affect circulating vitamin D [25(OH)D] levels.
The team observed changes in diastolic pressure of -0.29 mm Hg and in systolic pressure of -0.37 mm Hg, for each 10% increase in vitamin D [25(OH)D] concentration. An 8% decrease in the odds of developing hypertension was also seen.
The authors conclude that increased plasma concentrations of 25(OH)D may reduce the risk of hypertension, and indicate that the findings warrant further investigation in an independent, similarly powered study. Since vitamin D insufficiency appears to be fairly common globally, replication of these findings could potentially lead to a cost-effective way to help prevent hypertension.
Omega-3 Fatty Acids & Periodontal Disease
Omega-3 fatty acids are associated with a number of health benefits, including reduction in the risk of CVD and AMD. Harvard researchers now provide evidence for another potential benefit, that of improving periodontal outcomes.
In a randomized controlled trial , participants with moderate periodontitis received low dose aspirin (81 mg) and either 2,000 mg of DHA or placebo daily for 3 months. Significantly decreased pocket depth and improvements in the gingival index were seen in the DHA group. The inflammatory biomarkers IL-1B and hsCRP were lower in gingival crevicular fluid of the DHA group compared to placebo.
The same research group had previously reported that higher dietary intakes of DHA and, to a lesser degree, EPA, were associated with lower prevalence of periodontitis among participants of the National Health and Nutrition Examination Survey .
References:
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A Conversation with Harvard’s Dr. William Christen, Noted Eye Disease Researcher
William G. Christen Jr, ScD, PhD, OD, is Associate Professor (Medicine) in the Division of Preventive Medicine, Brigham and Women’s Hospital, Harvard Medical School, in Boston. Dr. Christen has studied the epidemiology of eye disease in randomized trials and large cohort studies for over 25 years. Here he talks with ScienceBased Health about his research. This is an edited, condensed version of the full interview, available at sciencebasedhealth.com
ScienceBased Health (SBH): Dr. Christen, you and your collaborators conducted a large intervention trial of B-vitamins in women free of AMD at the outset. Can you briefly describe this trial and its findings?
William Christen (WC): In the Women’s Antioxidant and Folic Acid Cardiovascular Study (WAFACS), comprised of women at high risk for CVD, we found that among the more than 5,000 women who had no reported AMD at study entry, those randomly assigned to a daily combination of folic acid (2.5 mg), vitamin B6 (50 mg), and vitamin B12 (1 mg), compared to those given placebo, had a 35% to 40% lower risk of AMD after 7.3 years of treatment and follow-up.
SBH: You’ve also investigated the relationship between low dose aspirin use and AMD in women, finding no harm or benefit over 10 years. Some recent studies have reported a link between aspirin use and AMD risk. Can you comment?
WC: Several recent observational studies have reported that long-term users of aspirin have an increased risk of AMD, specifically neovascular AMD. As you might expect, these reports have raised concern in the vision community and beyond, particularly given the widespread use of aspirin for cardioprotection. But before concluding causality, we need to consider the inherent limitations of observation studies, most notably uncontrolled confounding.
In all three studies, persons who reported being regular aspirin users differed from non-regular users in a number of ways including being much more likely to report a personal history of CVD. Aspirin therapy is commonly recommended for persons with CVD, so this isn’t surprising. But AMD and CVD are thought to share similar underlying mechanisms and risk factors, so the potential for confounding, particularly confounding by indication, is great in these studies.
SBH: Your group recently reported results for the multivitamin component of the large-scale Physician Health Study II. What did you find?
WC: We examined whether a daily multivitamin taken for an average of 11 years affected the incidence of
cataract or AMD in a large cohort of male physicians. Our results showed that men in the multivitamin group, compared to those in the placebo group, had a statistically significant 9% lower risk of cataract over the course of treatment.
Although the risk reduction is modest, cataract is so common that if the findings are real, even a modest reduction in risk would have a large public health impact. There was no significant benefit or harm of multivitamin supplementation on visually significant AMD (i.e. AMD of sufficient severity to reduce best-corrected visual acuity to 20/30 or worse).
SBH: Several studies have associated low vitamin D status with increased risk of AMD or higher serum levels with protection against early AMD in women. Do you think it’s time for an intervention trial?
WC: It’s interesting you should ask. In fact, we are collecting data for AMD in the ongoing VITamin D and OmegA-3 TriaL (VITAL). VITAL is a large 2×2 factorial trial designed to test whether vitamin D (cholecalciferol, 2000 IU/day) and marine omega-3 fatty acid (EPA +DHA, 1 g/day) can prevent cancer and CVD. The trial is enrolling a multi-ethnic population of more than 25,000 US men aged ≥50 and women aged ≥55.
AMD is one of several secondary endpoints, in addition to the primary endpoints of cancer and CVD that will be examined in VITAL ancillary studies. Current plans are for an average treatment and follow-up of about 5 years. So we anticipate that in the near future, we should be able to provide reliable data to evaluate whether vitamin D (and EPA + DHA) can prevent AMD.
SBH: What projects are you currently working on?
CW: In addition to examining AMD occurrence in the VITAL trial, we are also collecting data to examine the effects of the VITAL interventions on dry eye. We’re also trying to better understand the apparent beneficial effect of B vitamin supplements on AMD that we observed in WAFACS; is it due to homocysteine-lowering or some other mechanism? Finally, we’re collaborating with other groups to examine the genetic epidemiology of glaucoma.
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In the News: Omega-3s & Blood Pressure; AREDS2 CVD Study Results
Hypertension Common in U.S.
According to the National Heart, Lung and Blood Institute (NHLBI), about 1 in 3 adults in the U.S. have hypertension. While the condition usually has no outward signs or symptoms, cardiac, vessel and renal damage can occur over time if left untreated. There is also increasing evidence to suggest that patients with systemic risk factors such as hyper-tension are at higher risk of AMD .
Meta-analysis: Omega-3 Fats & Blood Pressure
A meta-analysis published online ahead of print in the American Journal of Hypertension suggests that consuming omega-3 supplements or omega-3 rich foods may be as effective as some lifestyle changes for reducing elevated blood pressure.
The meta-analysis, which included data from 70 randomized controlled trials (RCTs) that were greater than 3 weeks in duration, reports advantages for both normo- and hypertensives, with the greatest benefits seen in those with untreated high blood pressure.
The strongest effects of eicosapentaenoic and docosahexaenoic acids (EPA+DHA) were observed among untreated hypertensive subjects. The average reductions in systolic and diastolic pressures were 4.51 mm Hg and 3.05 mm Hg, respectively. For perspective, studies in untreated hypertension show that reducing sodium decreases systolic pressure by 2-8 mm Hg, alcohol by 2-4 mm Hg, and that physical activity reduces systolic values by 4-9 mm Hg.
Blood pressure was also lowered among normo-tensive subjects (systolic pressure = - 1.25mm Hg; diastolic pressure = - 0.62mm Hg). Noting that blood pressure tends to rise with age, the NHLBI states that a healthy lifestyle can help some people delay or prevent this rise. The results of this meta-analysis suggest that consumption of omega-3 fats might help pre-hypertensives from becoming hypertensives.
The study’s authors conclude that, overall, available evidence from RCTs indicates that ≥2 g of EPA+ DHA per day reduces systolic and diastolic pressures. Lower doses (between 1-2 g daily) may reduce systolic, though not diastolic pressure.
AREDS2 Cardiovascular Outcome Study
Results from the Cardiovascular Outcome Study (COS), an ancillary study of the Age-Related Eye Disease Study 2 (AREDS2), were published online ahead of print this month . The purpose of COS was to determine whether supplemental omega-3 fatty acids (EPA+ DHA) or lutein+ zeaxanthin taken along with AREDS nutrients reduce the rate of cardiovascular disease (CVD) in elderly participants with AMD.
Neither supplementation of omega-3 fatty acids nor lutein+ zeaxanthin reduced the risk of CVD events or CVD mortality. (Although a 25% reduction in CVD events was required to achieve statistical significance, an accompanying editorial opined that a reduction of 10-15% would have been “more prudent and realistic.”)
Despite the overall null results, pre-specified subgroup analyses suggest potential benefits for certain healthy people – specifically, those with no history of CVD or at low risk of developing the disease.
A significant 34% reduction in CVD risk was observed in those with no baseline history of hypertension. Similar, though non-significant, trends of 19% and 18% reductions in risk were seen for participants with no history of CVD and no history of elevated cholesterol, respectively. The omega-3 supplements were also well tolerated with no adverse effects noted.
These observed protective effects support the notion that regular intake of omega-3 fatty acids may help reduce the risk of CVD among healthy populations.
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In the News: Diabetes, Dementia and Dietary Flavonoids
Higher Blood Glucose Raises Dementia Risk
Findings recently published in the NEJM echo previous reports connecting higher blood glucose levels with an increased risk of dementia in diabetes. However in this prospective, community-based cohort study , greater risk was observed not only in diabetics, but among non-diabetics as well.
The researchers looked at data from over 2000 patients (average age 76) who were initially free of overall dementia. Among diabetics, a 40% greater risk of dementia was seen for those with higher average blood glucose levels (190 mg/dl) vs. those with lower average levels (160 mg/dl). A nearly 20% greater risk was seen for non-diabetics with higher levels (average of 115 mg/dl vs. 100 mg/dl).
The study was noteworthy for the extensive clinical data available (including 35,264 clinical measures of glucose levels), for the long-term follow-up of patients (median 6.8 years), and for the large number of dementia cases (524) sthat developed during the study period.
Higher blood glucose level may contribute to an increased risk of dementia through several potential mechanisms, including acute and chronic hyper-glycemia and insulin resistance, and increased small vessel disease of the brain .
Flavonoids May Lower risk of Type 2
A flurry of recent investigations is raising interest in the potential role of flavonoids both in diabetics and those without the disease. While flavonoids have antioxidant properties, their mechanisms of action are complex, broad, and go well beyond direct radical scavenging. There are a number of flavonoid subclasses, and even within the same subclass, individual flavonoids can differ considerably in bioavailability and bioactivity.
Substantial experimental evidence suggests that several flavonoid subclasses are involved in glucose metabolism, and three new observational studies provide evidence of this relationship in humans. The largest, a case-cohort study conducted in 8 European countries with over 340,000 participants and 12,400 incident cases of type-2, reports that higher intake of certain flavanols and flavonols (both mostly from tea and/or fruit) lowered type 2 diabetes risk .In the 2nd study , a Tufts and Harvard team followed 2900 plus members of the Framingham Offspring cohort who were free of type 2, for a mean 11.9 years. They found that each 2.5 fold increase in flavonol intake was associated with a 26% lower incidence of type 2.
A 3rd paper5 which evaluated data from nearly 2,000 participants in the TwinsUK Study, found that higher consumption of flavones (herbs, vegetables) and anthocyanins (berries) was associated with lower insulin resistance and lower levels of the inflammatory biomarker C-reactive protein.
Results of RCTs Support Flavonoid Promise
The results of a handful of small controlled trials suggest that the observed relationship between certain flavonoid subclasses and diabetes is real. In one year- long study for example, 93 postmenopausal women with type 2 receiving flavanols (tea, chocolate) and isoflavones (soy) showed significant improvements in insulin resistance and sensitivity compared to placebo .
Additionally, a pair of randomized cross-over studies from UK and European collaborators report that anthocyanins (blueberries) improved blood vessel elasticity (measured by flow-mediated dilation) compared to a control in 21 healthy men.
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In the news: Genetics & AREDS Supplements; Antioxidants & Cataract Risk; Predicting Future Memory Deficits
To Test or Not to Test? That is the Question
Two genes consistently shown to have the strongest associations with AMD risk are the complement factor H (CFH) gene and the Age-Related Maculopathy Susceptibility 2 gene (ARMS2). Both genes have been evaluated in studies asking whether genotype in high-risk AREDS participants influences the response to treatment with zinc and/or antioxidants. The results and conclusions of these studies differ greatly.
In brief, one paper (Klein et al) reports that all CFH genotypes (both high and low risk) benefited from zinc and antioxidants, and found no association between AREDS treatment assignment and having ARMS2 risk alleles. The authors concluded that their results did not justify routine genetic screening.
The second (Awh et al) reports an increased risk of disease progression associated with zinc treatment in CFH risk genotypes, and a deleterious response associated with antioxidant supplements in those with ARMS2 risk genotypes. The study authors recommend routine genetic testing in AMD, and customizing AREDS supplements based on genotype.
At the 2013 American Academy of Opthalmology annual meeting, Dr. Emily Chew of the National Eye Institute indicated that analysis of the Awh et al study reveals that it was insufficiently powered to show statistical significance . She added that the AREDS Research Group recently explored interactions between genotype and treatment assignments in AREDS category 3 and categories 3 and 4 patients. No significant differences were seen.
Dr. Chew also pointed out that The American Academy of Ophthalmology Task Force on Genetic Testing recommends avoiding routine genetic testing for genetically complex disorders like AMD until specific treatment or surveillance strategies have been shown in published trials to benefit individuals with specific genotypes.So, to test or not to test? The answer seems clear for the moment: Until more research is conducted, it’s premature to do routine genetic testing of AMD patients and to customize AREDS supplements based on the results.
Antioxidants Linked to Lower Cataract Risk
A prospective, population-based study from Sweden is the first of its kind to investigate the association between all antioxidants in the diet and age-related cataract . Previous studies have focused on individual dietary or supplemental antioxidants. The Swedish researchers instead examined total antioxidant capacity (TAC), which measures the capacity from all antioxidants in the diet and takes into account their synergistic effects.
Looking at the diets of more than 30,000 women (aged 49-83) followed for over 7 years, they found that those consuming the most antioxidants (mainly through fruits, vegetables, whole grains and coffee) had a 13% lower risk of developing age-related cataract. Though women who ate more antioxidants tended to be more educated and less likely to smoke, the association of high TAC and cataract incidence was consistent across subgroups based on potential risk factors and sources of oxidative stress.
A new, comprehensive review on nutrition and cataracts lends support to the ‘TAC’ approach taken by the Swedish team. The review points out that with observational data “it’s been difficult to tease apart the effects of single – or even groups of a few – nutrients, suggesting there may be synergistic effects of multiple nutrients with regard to lens health”.
Early Warning for Future Memory Problems?
When memory starts to slip in older adults, is it more likely due to normal aging or a harbinger of conditions such as mild cognitive impairment (MCI) or Alzheimer’s (AD)?
Cornell University scientists have published a study assessing a method to distinguish memory loss associated with healthy aging from more serious memory problems, years before symptoms emerge.
Employing advanced dual-retrieval models of recall that use clinical data for testing hypotheses about MCI and AD, the investigators looked at two types of memory processes – reconstructive and recollective – in healthy subjects and those with cognitive impairment.
Reconstructive memory is recalling an event by piecing together clues about its meaning, while recollective memory is recalling a word or event exactly.
The researchers found that declines in recollective memory were a feature of normal aging. Declines in reconstructive memory, however, were associated with MCI and AD, and not with healthy aging. They found no evidence of further reconstructive memory decline after age 69 in samples of nationally representative older adults.
The authors conclude that over periods of 1½ - 6 years, declines in reconstructive memory processes are accurate predictors of future conversion to MCI and AD – even better predictors than the best genetic marker of these conditions.
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Multivitamin Use Lowers Cataract Risk in Male Physicians
Nutrients and Risk of Cataract
A recent meta-analysis of 6 high quality prospective studies involving 42,000 participants reported that higher consumption of lutein and zeaxanthin was associated with a 25% reduced risk of nuclear cataract . The study’s authors also observed a dose-response relationship: For every 300 mcg (0.3 mg) of additional lutein intake daily, the risk of nuclear cataract declined by 3%. These findings echo the results of AREDS2 , where participants with the poorest intake of dietary lutein and zeaxanthin were 32% less likely to progress to a level of cataract requiring surgery. The average US intake of lutein and zeaxanthin at 2 mg daily is considerably below the 6 mg daily that has been linked to cataract risk reduction.
Thus it appears that adequate intake of these carotenoids may be protective of developing cataract, particularly nuclear cataract the most common type and the most common type associated with aging.
In addition to lutein and zeaxanthin, a relationship between daily multivitamin supplementation and cataract formation has also been observed. Now, the final results for cataract and AMD from the multivitamin component of the Physicians’ Health Study II (PHS II) have been reported. They indicate that long-term daily ‘multi’ use (with only trace levels of lutein and zeaxanthin) modestly and significantly reduces the risk of cataract.
Study Design
The PHS II was a randomized, double blind, placebo controlled, factorial trial evaluating a daily multivitamin, alternate day vitamin E, and daily vitamin C in the prevention of cancer and CVD among 14, 461 male physicians aged 50 and older. Cataract and AMD were pre-specified secondary end points of PHS II.
A total of 11,497 participants did not report cataract at baseline and were included in this analysis. Of these, 5,736 men were in multi group and 5761 were in the placebo group. A total of 14,233 men did not report AMD at baseline, with 7,111 assigned to the multi group and 7,122 to placebo.
The main outcome measures were incident cataract and visually significant AMD with BCVA 20/30 or worse.
Results
During an average 11.2 years of treatment and follow-up, a total of 1,817 cataract cases and 281 cases of visually significant AMD were confirmed.
Overall, there was a significant 9% lower risk of cataract in the multi group compared with placebo. The risk of nuclear cataract was 13% lower in the multi group. Multi- vitamin use had no significant effect on visually significant AMD.
Figure courtesy of Ophthalmology Journal
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In the News: Vitamin D Trials in Progress: Prevention of Diabetes, CVD, Cancer, AMD?
Can Vitamin D & Omega-3s Prevent AMD: VITAL
When the Institute of Medicine released its report recommending an increase in the RDA for vitamin D in 2010, the IOM panel concluded that the evidence is clear that vitamin D has bone benefits but that current research is inconclusive as to whether higher vitamin D intake can cut the risk for cancer, heart disease, stroke, or other chronic diseases.
In response to this uncertainty, the ongoing VITAL (VITamin D3 and OmegA-3 TriaL)1 was initiated by researchers at Brigham and Women’s Hospital, an affiliate of Harvard Medical School, and Harvard’s School of Public Health.
This large-scale 2×2 factorial trial is designed to test whether vitamin D3 (cholecalciferol, 2000 IU/day) and marine omega-3 fatty acids (EPA +DHA, 1 g/day) can prevent cancer and cardiovascular disease in people without a prior history of these illnesses.
VITAL is enrolling a multi-ethnic population of more than 25,000 U.S. men aged ≥50 and women aged ≥55. More than 24,000 participants have been enrolled to date.
In addition to the primary endpoints, over a dozen sub-studies are testing the effect of vitamin D and fish oil on other health outcomes such as cognitive function, diabetes-related kidney disease, and age-related macular degeneration (AMD).
Several studies have found a relationship between vitamin D and AMD. The most recent of these reports an association of higher serum levels of vitamin D with a reduced risk of developing early AMD among women under 75 years of age.
Current plans are for an average treatment and follow-up of approximately 5 years for VITAL participants. Thus, in the near future, we should have reliable data to evaluate whether vitamin D (and EPA + DHA) have a role in the primary prevention of AMD as well as other chronic diseases.
Can Vitamin D Protect Against Diabetes: D2d Trial
Tufts Medical Center researchers have received a large NIH grant to examine whether vitamin D supplements can help to prevent or delay the onset of Type 2 diabetes in adults with pre-diabetes – blood glucose levels that are higher than normal but not yet high enough to be diagnosed as diabetes. Approximately 79 million Americans have pre-diabetes.
Called the D2d Trial (Vitamin D and Type 2 Diabetes)2, it will be the first study to definitively answer whether vitamin D3 (4,000 IU daily) can reduce the risk of developing diabetes.
The trial aims to recruit about 2.500 people over 30 years of age, and will be conducted at approximately 20 medical centers countrywide. D2d has been launched and recruitment is underway.
Past observational studies suggest that higher vitamin D levels may be protective against Type 2. Based on these studies, it’s estimated that vitamin D could reduce diabetes risk by about 25%. Preliminary research by Tufts investigators has also found that vitamin D can improve blood glucose levels in those at increased risk for the disease.
A positive outcome of the D2d study would mean an affordable and accessible way to help reduce the health care burdens of this disease, including complications such as diabetic retinopathy. Up to 21% of patients with type 2 have retinopathy at the time of first diagnosis of diabetes, and most develop some degree of retinopathy over time.
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In the News: Drug-Disease Interaction; Omega-3s & Depression; Anthocyanins & Endothelial Function
Statins Linked to Increased Cataract Risk
Following a Canadian analysis published last year, a second, large-scale retrospective study has also implicated statin use as increasing cataract risk .
The study matched nearly 7,000 statin users with non-users in a propensity score-matched analysis of roughly 45,000 people in a military healthcare system. Statin users in the propensity matched meta-analysis showed a risk increase of 9%. The risk of developing cataracts was 29% higher in statin users when the researchers looked at all patients with no comorbidities at baseline. The results were consistent regardless of the duration of statin use – 2, 4, or 6 years.
Propensity score analysis is a statistical matching technique used to balance two non-equivalent groups and reduce bias due to confounding variables. Observational studies of statins and cataracts have been conflicting, with some reporting increased risk and others a beneficial effect. The use of propensity matching to try to eliminate baseline confounding is seen as an important tool to help resolve divergent findings about this potential drug-disease interaction.
EPA / DHA & Symptoms of Depression
Higher intake of omega-3 fatty acids is associated with a significant 49% reduction in risk of elevated depressive symptoms in women, according to a new study led by a National Institutes of Aging Aresearcher. A similar pattern was seen for the lowest ratio of highly unsaturated omega-3 (EPA & DHA) to highly unsaturated omega-6.
The investigators assessed whether there was a relationship between omega-3 consumption and elevated depressive symptoms (a score of ≥16 on the Center for Epidemiologic Studies Depression Scale) in over 1700 adults aged 30-65 residing in Baltimore City, MD. Elevated symptoms of depression were seen in 26% of women and 18% of men. Evidence that depressive symptoms are inversely related to omega-3 fatty acids is growing among US adults, and the results of this study support a protective effect of the omega-3s against these symptoms, at least in women.Three mechanisms were proposed by the researchers to explain the findings. The first involves the serotonergic neurotransmitter system, which is regulated by the omega-3s. The second, called the “macrophage theory of depression”, involves inflammatory responses. EPA, which can form of anti-inflammatory compounds, is proposed as a prophylaxis against depression and omega-6 fat as a promoter. The third mechanism involves impaired phospholipid metabolism and fatty acid-related signal transduction.
Anthocyanins Support Endothelial Function
Epidemiologic studies suggest that increased consumption of anthocyanins (a type of flavonoid found in blueberries, bilberries and grapes) lowers the risk of cardiovascular disease, the most common cause of mortality among men and women. The results of a new randomized, controlled, crossover trial suggest that anthocyanins may improve circulatory function in healthy men . German and British collaborators investigated the effect of blueberry flavonoids on endothelial function. They assessed the effects of various doses of anthocyanins on flow-mediated dilation, a measure of vessel elasticity.
The effective doses of anthocyanins identified are equivalent to those found in 3 ½ to 8 ½ oz. of blueberries. Flow mediated dilation increased significantly after an hour, and again at 6 hours. The results suggest that regular consumption of anthocyanins supports cardiovascular health by promoting endothelial function.
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Anthocyanins May Benefit Open Angle Glaucoma by Normalizing ET-1
Anthocyanins Improve Ocular Blood Flow, Slow Visual Field Decline in Glaucoma
Anthocyanins are a type of dietary flavonoid found in bilberries, black currants, and other red and purple berries and grapes. These flavonoids possess direct antioxidant activity, decrease inflammation, effect cell-signaling pathways, and promote vasodilation. Orally administered anthocyanins have been shown to accumulate in ocular tissues, including the retina, choroid and ciliary body.
Previously, researchers at Sapporo Medical University in Japan evaluated the effects of anthocyanins on disease progression of open angle glaucoma (OAG) in a randomized, placebo-controlled, 2-year trial.
The study subjects had been treated for more than 2 years by anti-glaucoma drops, had IOP measured every 1-2 months, and had undergone visual field testing (Humphrey visual field 30-2 test) every 3-6 months prior to entering the study.
The results, published in 2012 , showed that anthocyanins slow down visual field deterioration and improve ocular blood flow.
The deterioration of the Humphrey visual field mean deviation at 24 months was significantly less in patients receiving anthocyanins (50 mg daily from black currant extract) compared to placebo-treated patients. Additionally, ocular blood flow (at the optic nerve head, its rims and surrounding retina) significantly increased relative to the placebo group.
Based on these findings, the same research team initiated the present study to clarify the mechanisms by which anthocyanins induced these effects .
Study Design
During the original 2-year trial, serum samples were obtained from participants every 6 months. These samples were separated into those from the anthocyanin and placebo groups. Serum samples were also acquired from age and gender matched healthy volunteers, who served as a control.
Concentration of serum endothelin-1 (ET-1), nitrite (NO2-) and NO2- + nitrate (NO3-) levels, advanced protein oxidation products, and antioxidant activities were measured using commercially available kits.
Results
At baseline in the original trial, serum ET-1 concentrations were significantly lower in patients with OAG compared to healthy controls.
During the 24-month treatment period, ET-1 in the active group increased to levels seen in healthy volunteers. In contrast, ET-1 in the placebo group remained at levels lower than in controls over the study period.
All other serum measurements in OAG patients were comparable to those seen in controls, and no significant changes in these measures were seen over time in either the anthocyanin or placebo groups.
Comments
The authors conclude that one action of anthocyanins in this population of glaucoma patients is to normalize abnormal levels of ET-1.
ET-1 is a potent vasoconstrictor believed to play a role in local auto-regulation of blood flow. One receptor for ET-1, ETA, is mainly present on vascular smooth cells and is responsible for the vaso-constriction caused by ET-1. Another receptor, ETB, is found primarily on the vascular endothelium and is believed to produce transient vasodilatation through release of nitric oxide.
The authors believe that anthocyanins normalize serum ET-1 levels by stimulating the ETB receptors. In turn, this may cause an increase in ocular blood flow and slow down glaucoma progression.
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Supplement Shown to Benefit Dry Eye Patients
Dry eye is a Public Health Problem
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Study investigators John D. Sheppard, MD, MMSc and Stephen C. Pflugfelder, MD discuss key HydroEye study findings.
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Dry eye is one of the most prevalent eye diseases and reasons for seeking eye care. Dry eye prevalence is expected to rise as the population ages, along with increased costs in care. The current economic burden of dry eye is estimated to be $3.84 billion in direct annual health care costs .
While a wide variety of treatments are available, many have disadvantages: some provide only transient relief, or have cost or compliance issues. Others have been associated with GI, ocular or systemic side effects. Thus, clinicians continue to seek additional treatment options.
Dietary Supplement Reported to Benefit Dry Eye
One promising option is dietary supplementation with polyunsaturated fatty acids (PUFAs). Ocular surface inflammation contributes to the irritation symptoms and ocular surface disease that can develop in dry eye, while PUFAs such as GLA, EPA and DHA are known to help counteract inflammation.
Investigators from Baylor College of Medicine and Virginia Eye Consultants recently evaluated a dietary supplement (HydroEye®, ScienceBased Health) – containing black currant seed and fish oils (sources of GLA / ALA and EPA / DHA, respectively), antioxidants and nutrient co-factors – for its effects on moderate-to-severe dry eye in older women .
The researchers report that women taking the supplement had significant improvement in dry eye symptoms over time, and vs. placebo. A smoother corneal surface and lower levels of inflammation were also noted in the supplemented group.
Study Design
The purpose of this randomized, double-blind trial was to evaluate the effect of a PUFA formulation on:
Thirty-eight eligible post-menopausal women were randomly assigned to receive two softgels twice daily of a PUFA supplement (HydroEye®, ScienceBased Health) or an identical placebo for 24 weeks.
Ocular Surface Disease Index (OSDI), Schirmer test, tear breakup time, conjunctival fluorescein and lissamine green staining, topographic corneal smoothness indexes, and other parameters were assessed at baseline and at 4, 12, and 24 weeks.
Results
Mean OSDI scores in the supplement group were significantly improved by 12 weeks and at 24 weeks (P = 0.004), and were significantly lower than placebo (21 ± 4 vs. 34 ± 5) after 24 weeks (P = 0.05). [See Fig. 2].
SAI is a marker of corneal smoothness that has been found to increase in dry eye and to correlate with quality of vision. SAI was significantly lower in supplement-treated subjects (0.37 ± 0.03) than placebo (0.51 ± 0.03) at 24 weeks (P = 0.005).
HLA-DR is a dendritic cell activation marker that increases when exposed to inflammatory cytokines, and increased HLA-DR expression in the conjunctiva has been observed in dry eye. CD11c is a molecule on certain dendritic cells that regulates their migration.
HLA-DR intensity significantly increased from baseline to 24 weeks in the placebo group (P=0.03). CD11c intensity was also significantly increased at 12 and 24 weeks in placebo (P= 0.004). Compared to the supplemented group, the placebo group had significantly increased intensity for both biomarkers – by 36% ± 9% for HLA-DR, and by 34% ± 7% for CD11c – at the study’s conclusion (P= 0.001). [See Fig. 3 and 4].
Neither treatment had any effect on tear production, tear breakup time, or corneal or conjunctival staining.
Comments
The PUFA, antioxidant and nutrient combination clearly had a positive impact in this patient population.
The OSDI score began to improve early on, reaching significance within 3 months. No progression of ocular surface inflammation was seen with supplementation, while inflammation worsened in placebo-takers. Participants taking the supplement also maintained corneal smoothness while surface irregularity progressed in placebo takers.No difference in corneal fluorescein staining between the treatment groups was observed in this trial. The authors suggest that this may be due to visit-to-visit variability in dye staining in certain patients, and that the HLA-DR biomarker may be a more relevant measure than ocular surface dye staining with regard to irritation symptoms.
The effects of individual nutrients in the test supplement were not separately evaluated. The supplement, for example, contains a much higher level of vitamin C than is typically consumed from the diet. Although the beneficial effects of vitamin C have been reported in cases of dry eye and moderate Sjögren’s syndrome, the trial only examined the effects of the supplement as a whole.
This trial studied post-menopausal women, the largest group of dry eye sufferers. However, the salutary effects of the PUFA formulation may well apply to other populations suffering from dry eye since inflammation is believed to be a common thread in this condition.
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AREDS 2: Primary Results & Beyond
For those who have read about the primary findings in the abstract of the AREDS2 paper, the trial’s instructive secondary and sub-group findings may have gone unnoticed. Those findings are highlighted here, and help explain the current recommendation of the National Eye Institute:
| Patients with at least moderate AMD should consider taking – or continue to take – the original AREDS formula, with beta-carotene replaced by 10 mg of lutein and 2 mg of zeaxanthin. |
Synopsis: AREDS2 Study Design & Methods
AREDS2 enrolled 4203 patients with bilateral moderate AMD (large drusen with or without pigment changes) or advanced AMD in one eye.
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The primary objective was to determine whether the addition of lutein/zeaxanthin (L+Z) or omega-3 fatty acids (omega-3s ) to the AREDS formula would be more effective in reducing the 5-year risk of advanced AMD or cataract (results of the cataract portion of the trial were published separately) .
Another goal was to assess whether eliminating beta-carotene or changing zinc levels in the original AREDS formula would affect risk of progression.
To accomplish these goals, all participants were randomly assigned to receive daily: L+Z (10 mg, 2 mg), omega-3s (1,000 mg), both, or placebo. The placebo group served as controls.
Patients also received either the original AREDS formula or a modified AREDS formula with no beta-carotene and/or lower zinc.
Results
A description of participants’ baseline characteristics can be found in EduFacts Vol. 13, No. 9. Fifty-nine percent (59%) had bilateral large drusen, and 32% had advanced AMD in one eye and mean visual acuity of 20/32 in non-advanced eyes.
About 50% of AREDS2 participants were former smokers, and another 7% were current smokers. Those who smoked and those who had stopped less than a year prior to enrolment were excluded from receiving beta-carotene.
Serum Levels of Lutein & Zeaxanthin:
After 5 years, serum levels of lutein and zeaxanthin in those receiving L+Z and getting a beta carotene-containing AREDS formula were significantly lower than those getting L+Z and no beta-carotene. The three carotenoids compete with each other for absorption, and this finding indicates that high dose beta-carotene interferes with the absorption of lutein and zeaxanthin.
Primary analyses:
Compared to taking only the AREDS formula (controls), neither L+Z nor omega-3s co-supplemented with an AREDS formula met the 25% additional decrease in risk required to show effectiveness.
Main Effects Analyses:
Comparing participants who received L+Z to those who did not, showed a 9% reduction in risk of progression for the L+Z group.
Secondary Randomization Analyses:
Participants in the secondary randomization who were assigned to formulas with no beta-carotene were compared to those receiving formulas that contained beta-carotene.
Eliminating this carotenoid did not curb the protective effect of the AREDS formula against developing advanced AMD, as the removal of beta-carotene had no significant effect on risk of progression.
Similarly, comparing formulas modified with low dose zinc (25 mg) vs. the original zinc dose (80 mg) showed no statistical difference for risk of progression. However a trend favoring better protection was observed for the higher dose of zinc.
When participants were stratified by dietary intake of lutein and zeaxanthin, those with the lowest intake of these carotenoids at baseline who received L+Z had a 26% reduction in risk for progression compared to those who did not get L+Z.Further Sub-group Analysis:
To investigate relative treatment effects, those taking L+Z and modified AREDS formulas without beta-carotene were compared to those taking no L+Z, plus an AREDS formula with beta-carotene.
An 18% lower risk of advanced AMD was seen for participants taking no beta-carotene plus L+Z. Essentially, this analysis addressed the question ‘what would happen if you replaced beta-carotene with L+Z in the original AREDS formula?
Safety
Lung cancers were observed in 2% of participants who took AREDS containing beta-carotene compared to 0.9% who received no beta-carotene, and about 91% of those who developed lung cancer were former smokers. Lutein/zeaxanthin was not associated with lung cancer risk. Thus, lutein and zeaxanthin appears to be a safer choice for former smokers.
No clinically or statistically significant differences in adverse events were seen when comparing the low versus high dose zinc groups.
Comments
The preponderance of evidence from AREDS2 suggests that lutein and zeaxanthin offer some protection against AMD advancement. Though subgroup analyses are rigorously interpreted with a measure of caution, many of the secondary and sub group analyses were pre-specified to be evaluated in the study’s design.
The apparent competitive absorption between high dose beta-carotene and lutein/zeaxanthin may have reduced the ability of the study to detect a significant impact of L+Z on progression to advanced AMD compared to controls.
Importantly, L+Z appeared to benefit those with inadequate intake of these carotenoids. While AREDS2 patients were generally well nourished, their intake of lutein and zeaxanthin is not representative of the general US population, where low consumption is common. The authors suggest that a greater reduction in risk may have been seen if the subjects’ diets had more closely resembled that of the overall population.
Though not discussed above, results from the age-related cataract portion of AREDS2 indicate that those consuming insufficient levels of lutein and zeaxanthin also gained some protection.
While L+Z plus an AREDS formula did not help reduce the risk of progression to cataract surgery, there was a 32% reduction in the subsequent need for surgery for those consuming the least dietary lutein and zeaxanthin. A 30% lower risk of developing any cataract – and a 36% reduction in risk of developing any severe cataract – was also noted in this group.
Omega-3 fatty acids demonstrated no benefit above and beyond that conferred by the AREDS formula to those with at least moderate AMD. Whether or not the omega-3s have a role in the primary prevention of AMD awaits further investigation.
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Omega-3s May Modify Genetic Susceptibility to Dry AMD
Omega-3 Fats & Advanced AMD Development
The omega-3 long-chain polyunsaturated fatty acids have anti-inflammatory and anti-oxidative properties, and increased dietary intake of these fats has been shown to slow or reduce development of advanced stages of age-related macular degeneration (AMD) in a number of studies.
AMD has a strong genetic component, and several genes are associated with advanced AMD including CFH, ARMS2/HTRA1, C3, C2, CFB, CFI and LIPC. The exact mechanisms by which some people never progress beyond the early or intermediate stages and others go on to develop geographic (GA) or neo-vascular (NV) AMD are not completely understood.
Together, these factors led a team from Tufts Medical Center and New England Eye Center to investigate the impact of specific types of fat on GA and, controlling for genetic susceptibility, whether their intake could affect progression to GA.
Study Design and Methods
This study was an observational analysis of a prospective cohort: 2531 participants from the Age-related Eye Disease Study (AREDS). Among these participants, 525 eyes progressed to GA while 4,165 did not.
Eyes without advanced AMD at baseline were evaluated for progression to GA. Behavioral data were collected at baseline using questionnaires.
Food frequency questionnaires were used to calculate omega-3 (EPA and DHA), omega-6 fatty acids, monounsaturated, saturated, polyunsaturated and total fat, which were adjusted for sex and calories and divided into quintiles.
Eight single nucleotide polymorphisms in 7 genes (listed previously) were genotyped.
Cox proportional hazards models were used to test for associations between incident GA and intake ofdietary lipids, and interaction between dietary fat and genetic variation on GA risk.
Two models were used: Model A was adjusted for baseline grade, as well as demographic and environmental characteristics (age, sex, education, smoking, whether or not they were assigned to the antioxidants group in AREDS, and body mass index or BMI). Model B was adjusted for all the covariates in Model A plus all genes.
Results
Higher DHA intake was significantly associated with a lower risk of progression to GA in model A that controlled for behavioral risk factors and Model B that controlled for behavioral and genetic risk factors (P trend = 0.01 and 0.03 respectively).
EPA + DHA was significantly associated with reduced risk of GA progression in the model controlling for both genetic and behavioral factors (P trend = 0.02).
Total fat and saturated fat did not affect risk of progression, while there was a trend toward higher monounsaturated intake and risk in Model A.
Most notably, DHA had a protective effect among people with the ARMS2/HTRA1 homozygous risk genotype (P = 0.002).
Comments
Based on this study, the authors conclude that eating at least one or more 3 oz. portion of omega-3 rich fish weekly may reduce the risk of developing the GA form of AMD, even among those with genetic vulnerability to progression.
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Nutrition Research Findings & Your Patients
As March is National Nutrition Month, this issue of EduFacts highlights recent findings of interest.Evidence for Mediterranean Diet Compelling
Though diet is not often talked about in medicine, findings from the largest randomized trial to date on the Mediterranean (‘Med’) diet, make this way of eating worth mentioning to patients.
In this trial of more than 7,400 men and women at risk of cardiovascular disease (CVD), individuals were randomly assigned to 3 different diets: two were Med-diets enriched with either nuts or extra-virgin olive oil, and the third was a low-fat diet. In the two Med-diet groups, there was a significant reduction in the primary endpoints of major cardiovascular events, namely death, heart attack or stroke. Particularly notable was the risk reduction seen in stroke – a significant 49%.
Why is the trial noteworthy? It was well conducted and demonstrates that the Med-diet has a role in primary prevention of CVD (benefit in secondary prevention of CVD was shown in a previous trial). In addition, the results were dramatic. Investigators halted the study early when an interim analysis revealed that the low-fat control group was at a clear-cut disadvantage.
Study participants did not have to restrict their calorie intake, and compliance with the Med-diets during the median 4.8 years of follow-up was good. This suggests that the Med-diet is user-friendly to adopt.
The Med-diet is rich in fresh fruits and vegetables, seafood, whole-grains and mono-unsaturated fats (the type found in olive oil). All groups in this study were able to cut back on meats, sweets, dairy and alcohol. However, the main difference between interventions was that the Med-diet group ate fewer carbohydrates (especially sugar and processed carbs) and more fats (mostly from olive oil), fruit, beans, and nuts.
Relevant to ocular health, the diet is rich in vegetables (leafy green) and fish, sources of lutein, zeaxanthin, and the long-chain fatty acids EPA and DHA. These nutrients have been linked to a lower risk of AMD development or progression.
Berries Reduce Heart Attack Risk in Women
If the Med-diet encourages consumption of fruit, the findings of a study from Harvard suggest that blueberries and strawberries are one of the fruits to choose on a regular basis.
Data was analyzed from 93,600 women participating in the Nurses’ Health Study II, where dietary data was collected every four years. During the study, 405 heart attacks were documented.
The highest consumption of the two berries – 3 or more servings weekly – was associated with a one-third reduction in risk of heart attack. This risk reduction was seen even in women who otherwise ate a diet abundant in other fruits and vegetables.
The researchers attribute the apparent benefits to the berries’ anthocyanin content. In another recent study , 320 mg of purified anthocyanins daily for 6 months was reported to significantly reduce the inflammatory bio-marker C-reactive protein and soluble vascular cell adhesion molecule-1 compared to placebo in 150 subjects with elevated cholesterol levels.
Beware of Grapefruit-Drug Interactions
A review of grapefruit – drug interactions, concludes that the number of oral drugs that react adversely with this fruit is higher than previously thought, nearly half of those drugs may be associated with potentially serious adverse effects, and interactions occur at lower levels than formerly suspected (as little as 7-8 oz. of juice).
Of the more than 85 common medications known or predicted to interact, many were anti-infective, anti-lipidemic (e.g. statins), and GI agents. The culprits in grapefruit are the furanocoumarins, which irreversibly inhibit the cytochrome P450 enzyme CYP3A4 in the GI tract. These compounds are also found in Seville oranges (but not navel or Valencia), limes and pomelos. Read more
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Zinc and Ocular Health: From Antiquity to Modern Times
Wide-Ranging Cellular Functions of Zinc
Although zinc was found to be essential to living organisms in 1869, the idea that zinc deficiency can occur in humans wasn’t established until much later. Pioneering work by Annada Prasad, and co-workers in 1961-63, identified zinc deficiency as the cause of dwarfism and hypogonism prevalent in Iranian men at the time. It was later found that phytate, a compound naturally occurring in the high cereal grain-diets of these men, greatly impaired the absorption of zinc, leading to deficiency and retarded growth.
Since then, zinc has gained considerable recognition of its role in human health, and extensive research has elucidated its structural, regulatory and catalytic functions. Zinc plays an important role in stabilizing the structure of proteins and cell membranes; is involved in regulating gene expression and cell signaling; and over 100 different depend on zinc to help catalyze chemical reactions.
Zinc is required for proper growth and development, reproduction, and neurological function. Zinc also acts as an intracellular signal molecule for immune cells, and is involved in many immunological processes. Evidence suggests that even marginal deficiencies of zinc contribute to the decline in immune function associated with aging.
The Role of Zinc in Ocular Health and AMD
Zinc serves important functions in the eye as well. It is needed to mobilize vitamin A from the liver to the eye, and several key enzymes in the chorioretinal complex require zinc. In the retina and retinal pigment epithelium, zinc is believed to interact with taurine and vitamin A, modify photoreceptor plasma membranes, regulate the light-rhodopsin reaction, and modulate the passage of a neural impulse across synapses.
Zinc is thought to play a part in the development of age-related macular degeneration (AMD) for several reasons. First, zinc is highly concentrated in the retinal pigment epithelium, a key area of the retina that is affected by AMD. Secondly, the retinal content of zinc has been shown to decrease with age, as have the activities of some zinc-dependent retinal enzymes.
Ophthalmic Use of Zinc Dates to Ancient Times
While the benefits of supplemental zinc came to the forefront with publication of the AREDS trial in 2001, it appears that a role for this mineral in ocular health is rooted in history.
Italian researchers recently analyzed disc-shaped tablets that were uncovered in a 2000 year-old shipwreck off the coast of Tuscany, and reported their findings in the Proceedings of the National Academy of Sciences. The zinc-containing supplements were found in the Pozzino, a ship that sank in the 2nd century B.C., and were preserved underwater in oxygen-free metal tins called pyxis. According to the researchers, the composition and form of the tablets are consistent with an ophthalmic use of zinc as described in several ancient texts – some dating back as far as 300 B.C.
AREDS 2 and Future Research Directions
In 1988, David Newsome and colleagues reported that zinc-treated patients with drusen or AMD had significantly less vision loss than those receiving a placebo – findings that led to the AREDS trial. AREDS then demonstrated that treatment with zinc alone slowed the progression to advanced stages in patients with intermediate stage AMD, and when combined with antioxidants not only slowed disease progression but also reduced vision loss. The results of AREDS 2, expected later this year, may reveal whether a lower dose of zinc (25 mg) is as effective as that assessed in the first trial (80 mg).
There remains much to learn about zinc’s role in AMD. The exact mechanism(s) by which zinc slows this disease is still unclear, for instance. How does zinc interact with genetic risk factors for AMD such as different variants of complement Factor H? These questions and more await further investigation.
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Carotenoids, Antioxidants Benefit Visual Acuity & Slow Progression in Early AMD
Carotenoids and Antioxidants in Early AMD
There is scientific support for the hypotheses that oxidative stress is involved in the pathogenesis of early age-related macular degeneration (AMD), and that a lack of lutein and zeaxanthin play a role in the development of AMD.
Based on the available evidence, a research team from Ireland undertook a randomized, controlled trial of supplementation with lutein, zeaxanthin and antioxidant vitamins and minerals in persons judged to be at highest risk of progression to advanced AMD.
Called the CARMA study, this trial enrolled participants who were followed for a minimum of 1 year. No difference was found between placebo and treatment groups for the primary endpoint of best-corrected visual acuity (BCVA) at the end of 12 months (data in press). However, a number of secondary outcomes were collected, including BCVA, for participants who had a longer than 12 month follow-up.
This paper reports on those secondary outcomes, and the results suggest that long-term supplementation of carotenoids and antioxidant nutrients have functional and structural benefits in people with early AMD.
Methods
Participants included 433 adults, 55 years or older who were classified into two groups. Group 1 included those with early AMD in one eye and late-stage disease in the fellow eye. Group 2 consisted of those with early AMD in both eyes.
Participants received supplemental lutein and zeaxanthin (12.6 mg combined carotenoids), vitamins C (150 mg), E (15 mg), copper (.4 mg) and zinc (20 mg), or placebo daily.
Participants recruited in the early phases of the study were followed for up to 36 months (3 years). The main outcome measures included differences in BCVA at 24 and 36 months, contrast sensitivity, Raman spectroscopy (counts), serum antioxidant levels, and progression along the AMD severity scale at 12, 24 and 36 months.
Results
By 24 months, a steadily increasing difference was observed between groups in BCVA that favored the active group by 1.4 letters (p=0.04). Average BCVA in the active group was approximately 4.8 letters better compared to the placebo group for those who had 36 months of follow-up (p=0.04). (See Figure below).
Figure courtesy of Ophthalmology Journal
In the longitudinal analysis, an increase in serum lutein levels correlated with improvements in BCVA. For a 1-log-unit increase in serum lutein, visual acuity was better by 1.4 letters (p=0.01; 95% CI, 0.03-2.5).
An increase in serum lutein was also associated with a slower progression on the AMD severity scale in the eyes of participants in the active group compared to the placebo group (p=0.014).
Macular pigment, as measured by Raman spectroscopy (Raman counts), demonstrated a small increase with time, while that of the placebo group showed a steady decline. Raman counts were recorded at 6-month intervals from baseline to 36 months. The difference in Raman counts over time between active and placebo groups was highly significant at all time points.
Changes in contrast sensitivity marginally favored the active group, but no statistically significant differences were seen.
Comments
One weakness of the CARMA study was a loss of follow-up of some 20% of participants in the first year of the trial. A number of the withdrawals were due to death or the development of late stage disease (neovascular or geographic atrophy) in the sole study eye, which was a pre-specified participant withdrawal requirement.
However, in this controlled, dual-site trial, supplementation with lutein, zeaxanthin and co-antioxidants benefited visual acuity at 2 years and beyond, and higher serum lutein values were associated with a slowing of AMD progression.
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Physicians’ Health Study II: Multivitamins, Cancer & CVD
Background: Physicians’ Health Studies I & II
The landmark Physician’s Health Study I began in 1982 to test the benefits and risks of aspirin and beta-carotene in the primary prevention of cardiovascular disease (CVD) and cancer. This trial ended in 1995, and found that low-dose aspirin decreased the risk of a first myocardial infarction (MI) by 44%. It also didn’t find any benefit or harm from beta-carotene.
A second randomized trial, the Physicians’ Health Study II (PHS II), was started in 1997 to test the benefits and risks of vitamin C, vitamin E and a multi-vitamin/mineral supplement for the primary prevention of CVD, cancer, age-related eye disease, and cognitive decline. PHS II randomized 14,642 men, 50 years and older who had not taken part in PHS I. Each participant was assigned to daily intake of one of 16 possible combinations of vitamin C, vitamin E, beta-carotene, a multivitamin, or their placebos.
The vitamin C and vitamin E components of PHS II, which ended in 2007, found that these antioxidant vitamins did not prevent major cardiovascular events, cancer, or eye disease in this healthy population of male physicians.
The multivitamin component ended in mid-2011, and the results for cancer and those for CVD were published in the October and November issues of the Journal of the American Medical Association.Multivitamins and Cancer
The physicians who took part in the trial were quite healthy, with good dietary and lifestyle habits. Over 2/3 of them exercised regularly and only 4% smoked (though 40% were former smokers). They were also fairly diligent about taking the supplements over time, as compliance was 76.8% (vitamin) and 77.1% (placebo) at 4 years, and remained high at the end of the follow-up period at 67.5% and 67.1%, respectively. The men were followed 11.2 years on average.
The PHS II investigators report a significant 8% decrease in total cancer occurrence. The reduction in total cancer rate was found to be 12% when prostate cancer was removed from the analysis (no effect was seen for prostate cancer). Regular multivitamin use also lessened the risk of dying from cancer, with a 12% reduction in cancer mortality. Though not quite statistically significant, this was a consistent finding.The study’s findings are important both from a public health and an individual perspective. An 8% decrease in cancer risk may seem modest. But with more than 1.6 million new cancer cases diagnosed yearly in the US, this risk reduction would translate into about 130,000 cancers prevented every year.
The study also confirms that multivitamins are generally safe, as no major differences in adverse effects were seen between groups.
Multivitamins and CVD
In contrast to the findings on cancer, PHS II reports no significant reductions for major cardiovascular events, heart attack, stroke or death from CVD with multivitamin use. There were fewer total deaths among those in the multivitamin group; however the difference was not statistically significant.
Analysis showed that the small number of multivitamin users with CVD at the study’s start were significantly less likely to die from a heart attack, with a 44% reduction in risk. However, statistical power was limited, with only 9 cases of MI death occurring during the trial.
PHS II investigators acknowledge that multivitamins may play a role in populations with nutritional deficiencies, and that their study results don’t extend to the large number of population sub-groups with marginal intakes of various vitamins and minerals.
Multivitamins and Cataract, AMD, & Cognition
Publication of the main findings for the study’s multivitamin on eye disease component (cataract and macular degeneration), as well as early cognitive decline, is expected in the very near future.
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In the News: Vitamin B6 & Inflammation, Coffee & Exfoliation Glaucoma, Dietary Lycopene & Stroke
Low Vitamin B6 Levels Linked to Inflammation
Previously, studies have identified low vitamin B6 status in patients with inflammatory diseases, including cardiovascular disease, rheumatoid arthritis, inflammatory bowel disease, and diabetes.
Based on those findings, researchers from Tufts, Boston University, and Safra Children’s Hospital conducted the first large-scale study evaluating B6 status and inflammation . They report an association between low plasma levels of vitamin B6 and a wide range of inflammatory markers.
The researchers measured 13 individual markers of inflammation and plasma B6 concentrations in a cohort of over 2,200 (55% women, mean age 61 yrs). Plasma B6 levels correlated with a summary score of the inflammatory markers. Those with lower B6 levels were significantly more likely to show signs of inflammation. At the same time, markers of inflammation tended to decrease as vitamin B6 levels rose (p-trend <0.0001). The same associations were not observed with other B-vitamins.
Intervention studies are needed to determine whether improving B6 levels can help curb inflammation. However, it’s worth noting that inadequate plasma B6 is much more common than previously believed in pre-menopausal women, men who smoke, Afro-American men, and people over 65. These 4 groups have the highest rates of low plasma B6 levels according to the results of a recent large-scale study .
Lycopene-Rich Diet May Cut Stroke Risk
The results from a prospective Finnish study suggest that high serum levels of lycopene reduce the risk of stroke in men. Lycopene, a carotenoid nutrient, is concentrated in tomatoes and tomato-based foods.
The research team followed over 1,000 men (aged 46-65) for an average of 12 years. Of those with lowest blood levels of lycopene, 25 experienced a stroke, while stroke occurred in 11 of the men with the highest lycopene levels. This amounts to a 55% reduction in stroke risk (p = 0.036), and a 59% risk reduction (p = 0.042), looking at ischemic stroke alone. Blood concentrations of alpha-carotene, beta-carotene, and vitamins A and E were not related to stroke risk.
These results add to the large body of evidence linking high fruit and vegetable intake with a lower risk of stroke, and suggest that consumption of lycopene-rich tomatoes could be especially important.
Can Caffeinated Coffee Raise Glaucoma Risk?
Drinking 3 or more cups of caffeinated coffee a day may increase the odds of developing exfoliation glaucoma by 34% (p-trend = 0.06), compared to abstaining from the beverage . The odds may also rise considerably for women with a family history of glaucoma who drink > 3 cups daily (p-trend = 0.06).
Those are the main findings of Harvard and Brigham and Women’s Hospital researchers who followed women in the Nurses’ Health Study (about 79,000) and men from the Health Professionals Follow Up Study (approx. 41,200) who were at least 40 years of age and glaucoma-free.
The participants were followed for 12 years, during which their intake of caffeine-containing beverages was regularly updated. Caffeinated sodas, tea, chocolate, and decaffeinated coffee did not affect risk.
There may be a plausible mechanism to explain the link between heavier caffeinated coffee intake and exfoliate glaucoma. Coffee’s chlorogenic acid has been shown to raise levels of homocysteine, as has caffeine. Elevated homocysteine, in turn, can damage vascular tissue and contribute to dysfunctional extracellular matrix re-modeling. In addition, several studies have found elevated homocysteine in the blood, aqueous humor and tears of people with exfoliation glaucoma.
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In the News: Produce & Glaucoma Risk; Vitamin D & Inflammation; Oxidative Stress in CRVO
Fruits & Veggies Linked to Glaucoma Risk
Greater intake of certain fruits and vegetables rich in vitamins A and C and carotenoids is associated with a lower risk of glaucoma in older African-American women according to research from the Jules Stein Eye Institute, UCLA .
Five hundred and eighty four African-American participants in the Study of Osteoporotic Fractures were included in this evaluation of diet and the presence of glaucoma. Glaucoma was diagnosed in at least 1 eye in 77 subjects using disc photographs and supra-threshold visual field tests.
Women who ate at least 3 daily servings of fruits/fruit juices were 79% less likely to have glaucoma than those consuming one or no servings per day. Fresh oranges and peaches in particular, were protective.
For vegetables, more than 1 weekly serving of green leafy vegetables (collard greens/kale) decreased the odds of glaucoma by 57% compared to those eating about 1 serving monthly.
Protective trends were found for individual nutrient intakes of vitamins A, C and alpha carotene. Close to significant trends were seen for beta-carotene, folate, and lutein/zeaxanthin.
It’s biologically plausible for antioxidant nutrients found in fruits and vegetables to modify the risk of glaucoma, as some evidence suggests that oxidative stress contributes to the etiology of this disease. These dietary nutrients may help protect the trabecular meshwork, retinal ganglion cells, and/or the vascular system that nourishes the optic nerve.
Vitamin D May Reduce Retinal Inflammation
Vitamin D3 plays a key role in immune regulation, and has recently been linked epidemiologically to protection against age-related macular degeneration.
To explore the effects of this vitamin in the retina, researchers at University College London’s Institute of Ophthalmology supplemented the diets of aged mice with vitamin D3 for 6 weeks . Compared to controls, the supplemented mice showed significant reductions in retinal inflammation and levels of amyloid beta accumulation, which is a hallmark of aging.
According to the investigators, the outer retina has the highest metabolic demand in the body. With age, the depositing of amyloid beta makes the interface between the outer retina and its blood supply less permeable.
The researchers also found significant reductions in retinal macrophage numbers, a marker of chronic inflammation, and marked shifts in macrophage morphology in treated mice. These changes were reflected in a significant improvement in visual function.
Homocysteine & Oxidative Stress in CRVO
Elevated homocysteine can damage the vascular endothelium, and is considered to be a risk factor for central retinal vein occlusion (CRVO) in young adults.
Investigators from the Department of Biochemistry and Cell Biology, Vision and Medical Research Foundation in India wanted to determine whether oxidative stress is an independent risk factor for CRVO, or whether it’s dependent on high homocysteine levels . Twenty-three young adult CRVO patients and 54 age and sex-matched controls were included in their study.
Plasma TBARS (a marker of oxidative damage) were significantly higher, while superoxide dismutase and total antioxidant capacity (markers of oxidative stress) were significantly lower in CRVO cases compared with controls. They found that total antioxidant capacity and homocysteine both influence TBARS significantly.
In cultured retinal endothelial cells, they observed that homocysteine increased TBARS in a dose and time dependent manner. Since oxidative stress (TBARS) can be influenced by both elevated homocysteine and poor antioxidant status, it is possible that homocysteine-lowering folic acid, as well as increased intake of antioxidants, could be helpful in some cases of CRVO.
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GLA & EPA / DHA Blend Reduces Inflammatory Marker in Dry Eye
Dry Eye Syndrome (DES) and Fatty Acids
A wide range of anti-inflammatory therapies have been investigated to reduce DES, including the use of supplements containing the omega-6 fatty acid gamma linolenic acid (GLA), and the omega-3 fatty acids eicosapentaenoic and docosahexaenoic (EPA and DHA).
Supplements providing GLA have been shown to increase the concentration of anti-inflammatory prostaglandin E1 in tears, and to reduce inflammation of the ocular surface as shown by a significant decrease in the inflammatory marker human leukocyte antigen-DR (HLA-DR) in conjunctival epithelial cells. HLA-DR class II antigen is usually expressed by antigen-presenting cells with major histocompatibility complex (MHC) on their surfaces such as dendritic cells and macrophages.
The fatty acids EPA and DHA also have anti-inflammatory action believed to result from the synthesis of prostaglandin E3 and leukotriene B5. Leukotriene B5 inhibits the conversion of arachidonic acid to potentially harmful inflammatory mediators, prostaglandin E2 and leukotriene B4.
Combining GLA and EPA/DHA in DES
The efficacy of combining GLA and EPA/DHA has been reported in an animal model of DES, where only the combined fatty acids (versus GLA or EPA/DHA alone) reduced the expression of MHC II and inhibited the production of inflammatory cytokines . In a pilot trial, 3-months of treatment with the fatty acid combination suggested a beneficial effect on the clinical signs of ocular dryness .
The objectives of the present controlled trial were to investigate the effect of omega-6 and omega-3 supplementation on HLA-DR inflammatory marker in conjunctival cells, and to determine the impact on signs and symptoms in patients with DES.
Study Design
138 eligible adult patients with mild to moderate DES were randomized to receive placebo or treatment supplement containing omega-3 and omega-6 fatty acids, vitamins and zinc 3 times daily for 3 months. Impression cytology was performed at baseline and 3 months to assess the percentage of cells expressing
HLA-DR and to evaluate fluorescence intensity, an alternate measure of HLA-DR. Signs of dry eye (Schirmer, TBUT, fluorescein and lissamine staining) were evaluated; Symptoms were evaluated via a quality of life questionnaire. Statistical analyses were performed on the full analysis set, and on those patients who completed the trial (per-protocol set or PPS).
Results
Of the patients randomized, 121 with available impression cytology were included in the full analysis set. Of those 121 patients, 106 with no major protocol deviations comprised the PPS.
In the PPS, there was a significant reduction the % of HLA-DR positive cells in the fatty acids group compared to placebo (p = 0.021). Expression of HLA-DR as measured by fluorescence intensity was also reduced in the fatty acids group of the full analysis set (p = 0.041) and in the PPS compared to placebo (p = 0.017). No significant difference between groups was found in signs and symptoms, though there was a tendency toward improvement in the fatty acids group.
Comments
The authors conclude that this supplemental fatty acid combination can reduce expression of conjunctival inflammatory markers.
A discrepancy between signs and symptoms and a biological marker is very common in ocular surface disease, and highlights the need for objective endpoints like inflammatory marker assessment for an earlier and reliable evaluation of ocular surface inflammation.
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Cataracts & Fractures, AREDS2 Update
Cataract Removal Lowers Risk of Hip Fracture
The results of a study published in the August 1st issue of JAMA suggest that individuals shouldn’t necessarily be regarded as ‘too old’ or ‘too ill’ to have cataract extraction.
The study , conducted by researchers from the Dept. of Ophthalmology, Warren Alpert Medical School of Brown University, and the Jules Stein Institute at UCLA, found that elderly patients who undergo cataract surgery had a 16% lower risk of hip fracture [adjusted odds ratio of 0.84] within one year after the procedure compared to those with cataract who don’t have the surgery.
Included in the study were over 1.1 million patients 65 years and older with a diagnosis of cataract who represented a 5% random sample of US Medicare Part B beneficiaries. Between 2002 and 2009, about 37% of these patients underwent cataract surgery. The authors adjusted for age, gender, ethnicity, residency, cataract severity, physically limiting conditions and other ocular and systemic diseases, including the Charlson Co-morbidity Index (CCI).
The largest reduction in hip fracture risk was seen among people 80-84 years of age with scores in the highest categories for CCI. Risk reduction was 28% [adjusted OR of 0.72] – the lowest odds of hip fracture among all the age groups.
Study limitations include its retrospective and observational design. The large number of patients included was the study’s greatest strength, providing the statistical power to accurately see differences between the 2 groups.
AREDS2 Reports Baseline Characteristics
The primary purpose of the second AREDS trial, begun in 2006, is to evaluate the efficacy and safety of supplemental lutein plus zeaxanthin and/or the omega-3 fatty acids EPA and DHA in reducing the risk of developing advanced AMD. The study also assesses a reduction in zinc and removing beta-carotene from the original AREDS formulation.
In a first report published in the journal Ophthalmology, AREDS2 investigators inform readers of the baseline characteristics of 4203 participants enrolled at 82 U.S. clinical centers.
The mean age of participants is 74 years, and the majority of them are women (57%) and Caucasian (97%).
Seven percent are current smokers. Participants who were current smokers – or those who had stopped smoking within the year before enrollment – were randomly assigned to study arms that omitted supplemental beta-carotene.
Nineteen percent had cardiovascular disease prior to entering the study, and 44% and 50% are taking cholesterol-lowering statin drugs and aspirin, respectively. The rate of diabetes is more than double among AREDS2 participants (13%) than it was in the AREDS population (6%).
Ocular characteristics include 59% with bilateral large drusen, and 32% with advanced AMD in one eye and mean visual acuity of 20/32 in eyes without advanced AMD.
The AREDS authors also state that AREDS2 study visits are scheduled for completion by December 2012, and that results of the study are likely to be published by the end of 2013.
In a related paper , Paul Bernstein MD and colleagues at the Moran Eye Institute of the University of Utah report that the baseline macular pigment optical density in a relatively small group of AREDS2-enrolled subjects was unusually high compared to age-matched controls that did not regularly use lutein/zeaxanthin supplements.
According to the authors, this finding is consistent with the high rate of carotenoid consumption for Utah AREDS2 subjects prior to their enrollment. MPOD is being measured only in this ancillary Utah study, not in all AREDS2 subjects.
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Ginkgo May Slow Visual Field Loss in Normal Tension Glaucoma
Glaucoma and Altered Ocular Blood Flow
There are two leading theories to explain the mechanisms underlying glaucoma. The first, a mechanical theory, postulates that increased intraocular pressure (IOP) stretches the lamina cribrosa and damages retinal ganglion cell axons. The second theory suggests that an inadequate vascular supply, such as reduced blood flow to the optic nerve, results in ganglion cell damage.
Although there’s agreement that IOP reduction is a beneficial treatment in both high and normal tension glaucoma (NTG), the vascular theory may be more relevant in explaining NTG pathogenesis. In support of this idea is the observation that glaucoma continues to progress in many patients despite IOP reductions, and the fact that a reduction in blood flow often precedes optic nerve damage. Additionally, risk factors for NTG – such as low blood pressure, orthostatic hypotension, nighttime hypotension, migraine and sleep apnea – result in reduced blood flow to the brain.
Ginkgo biloba: Mechanisms & Research Findings
Ginkgo biloba leaf extracts have been used in Chinese traditional medicine for 5000 years. In recent times, Ginkgo has been reported to be neuroprotective for retinal ganglion cells in animal models of chronic glaucoma, and clinically shown to increase ocular blood flow and reduce visual field damage in NTG patients in the short term. Ginkgo has demonstrated antioxidant activity, and may increase blood flow by changes in blood viscosity and inhibition of platelet activating factor.
The current study was conducted to evaluate the long-term effects of G. biloba extract on progression of visual field defects in patients with NTG.
Study Design
In this retrospective study, 42 eyes of 42 NTG patients were evaluated for more than a 4-year period before and 4 years after receiving 80 mg of Gingko biloba extract twice daily (total of 160 mg per day). Patients had at least 5 visual field (VF) tests in the 4 years prior to and after supplementation. The VF tests were routinely preformed at diagnosis, 3 months later, and every 6-12 months thereafter with the Humphrey VF Analyzer. The change of progression rate was evaluated using mean deviation, pattern standard deviation, and visual field index. The time course of mean total deviation in 10 zones corresponding to the glaucoma hemifield test was analyzed using a linear mixed effects model with unequal random effects variance.
Results
The mean follow-up period was 12.3 years. After Ginkgo treatment, the regression coefficients of the mean deviation (MD), pattern standard deviation (PSD) and visual field index (VFI) change improved significantly (p<0.001). Before and after treatment regression coefficient values were as follows:
In zone 1, after Ginkgo biloba administration, visual field damage was significantly slowed (rate of the regression coefficient of mean total deviation change significantly increased; p<0.05).
Comment
The authors conclude that Ginkgo biloba extract slowed the progression of visual field damage in patients with NTG, especially in zone 1 which corresponds to the superior central field. A number of studies have shown that the superior central field is the main location of visual field defects in NTG, whereas high tension glaucoma defects tend to be more diffuse .
No ocular or systemic adverse effects were reported among patients during follow-up in this retrospective study cohort. This appears to be the first study to compare visual field progression in the same patients after Ginkgo supplementation, and the results suggest that Ginkgo biloba may be useful as a complementary treatment for glaucoma.
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Antioxidants, Zinc & Omega-3s Reduce Genetic Risk of Early AMD
Introduction: Genes, Nutrients and AMD Risk
AMD is clearly a complex disease with multiple environmental and genetic risk factors. In terms of genetics, two of the more prominent AMD susceptibility genes identified to date are Complement Factor H (CFH) and LOC387715 / HTRA1.
There are several different forms (variants) of these genes that significantly raise the risk of AMD. Carrying the CFH Y402H variant increases risk of AMD up to 11 times. For carriers of the variant LOC387715 A69S, the risk is up to 15 times greater.
Together, these variants may contribute to late AMD in more than 80% of cases. Thus finding ways to counter these major gene effects is of public health importance.
The only protective factors for AMD known to date are nutrients. Zinc and antioxidants were shown in the AREDS trial to reduce the risk of progression from intermediate to advanced AMD. Population based studies have also found a reduction in AMD risk progression with higher intakes of lutein/zeaxanthin, or with higher intakes of the omega-3 fatty acids EPA and DHA.
Is the protection afforded by these nutrients sufficient to reduce AMD risk in carriers of well-known risk variants? To address this question, authors of The Rotterdam Study have explored the relationship between a healthy diet, genetic risk and early AMD in a nested, case-control study .
Study Design
Dietary intake was assessed at baseline using a food frequency questionnaire for 2167 participants (> 55 years) at risk of AMD from the population-based Rotterdam Study. Genetic variants were determined using TaqMan assay. Incident early AMD was determined by fundus photography at 3 follow-up visits.
The synergy index was used to evaluate biological interaction between risk factors; Hazard ratios were calculated to estimate risk of early AMD in strata of nutrient intake (stratified by tertiles) and genotypes.
Results
During a median follow-up of 8.6 years, 517 participants developed early AMD. Significant synergy indices supported a biological interaction between:
Homozygotes of CFH Y402H with zinc intake in the highest tertile reduced their hazard ratio of early AMD from 2.25 to 1.27. For intakes of beta carotene, lutein / zeaxanthin, and EPA / DHA, these risk reductions were from 2.54 to 1.47, 2.63 to 1.72, and 1.97 to 1.30, respectively. (See table).
Graphic courtesy of Archives of Ophthalmology
Carriers of LOC387715 A69S with the highest intake of zinc and EPA / DHA reduced their risk from 1.70 to 1.17 and 1.59 to 0.95, respectively (all p trends < .05).
Comments
These results suggest that higher dietary intake of zinc, carotenoids and EPA/DHA can attenuate the incidence of early AMD in those carrying important genetic variants. The authors conclude that “clinicians should provide dietary advice to young, susceptible individuals to postpone or prevent the vision-disabling consequences of AMD”.
It’s well established that complement activation and inflammation play an important role in development of AMD. The CFH gene is a key regulator of complement, and the Y420H variant impairs its regulatory function. As for LOC387715, evidence suggests that the A69S variant may jeopardize mitochondrial function and lead to free radical formation and apoptosis.
There are plausible mechanisms that could explain the effect of these nutrients in carriers of both variants. For example, antioxidant nutrients can counter oxidative damage, an activator of the complement cascade, while omega-3s act as anti-inflammatory agents in the retina. Dysfunctional mitochondria may increase complement activation which, evidence suggests, zinc may counter.
Ho L, et al. Reducing the genetic risk of age-related macular degeneration with dietary antioxidants, zinc, and ω-3 fatty acids. The Rotterdam Study. Arch Ophthalmol 129:758-66, 2011.
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In the News: Recent Omega-3 Research Findings
Omega-3 Reduces Risk of Irregular Heartbeat In Older Individuals
Atrial fibrillation (AF) is the most common type of chronic arrhythmia in adults, and the risk for AF increases considerably with age.
Animal studies and short-term clinical trials suggest that increased intake of omega-3 fatty acids might improve cardiac function by influencing blood pressure, systemic vascular resistance, and myocardial efficiency, and/or via anti-inflammatory and anti-fibrotic effects. Omega-3 may also increase electrical stability by modulating ion channels.
Although some studies have assessed the association of omega-3s with incident AF, nearly all have estimated dietary intake via dietary questionnaires – with inconsistent results. Also, prior studies have focused on predominantly middle-aged populations rather than older adults, who are most at risk.
Now, findings from the Harvard School of Public Health provide evidence that omega-3 fatty acids may also protect against onset of atrial fibrillation (AF) later in life . The researchers looked at circulating levels of omega-3 – a more objective and accurate measure of omega-3 intake – among 3326 participants over 65 and free of AF or heart failure at baseline.
The highest average levels of total omega-3 fatty acids as well as DHA were associated with a reduction in AF risk of about 25%. Additionally, when evaluated as percent of all fatty acids, each 1% higher level of total omega-3s was linked to a 9% lower risk of AF.
Omega-3 May Reduce Key Inflammatory Biomarker Linked to Cardiovascular Disease & Cancer Risks
Two new studies published in the American Journal of Nutrition suggest that higher intakes of omega-3s may confer both cardiac and anti-cancer benefits through decreasing levels of an inflammatory biomarker, soluble intercellular adhesion molecule-1 or sICAM-1. Accumulating evidence suggests that low circulating levels of sICAM-1 contribute to a decrease in atherosclerosis risk.
The first study , a meta-analysis, analyzed 18 randomized trials that involved omega-3 supplementation and provided data on sICAM-1 concentrations. Results showed that supplemental omega-3 was associated with sICAM-1 reductions in both healthy individuals and people with abnormal levels of blood lipids.
According to the researchers, the findings suggest that omega-3s reduce inflammation by selectively inhibiting monocyte activation rather than endothelial activation. Since the protective effects were observed in both healthy subjects and those with dyslipidemia, it’s possible that supplemental omega-3 may help prevent the development of atherosclerosis as well as slow its progression.
In the second study , a team from the National Institute of Health and Medical Research in Paris investigated whether omega-3 intakes might alter sICAM-1 concentrations and cancer risk by comparing 408 cancer cases with 760 healthy people with similar characteristics.
Levels of sICAM-1 were indeed related to omega-3 levels, and this association was seen for different types of cancer, including prostate and breast cancer. In addition, sICAM-1 was positively linked with cancer risk in people who had below average omega-3 intakes.
Two mechanisms may explain the observations. First, the omega-3s may be decreasing the expression of adhesion molecules like sICAM-1. Secondly, the omega-3s may act by intervening in the pro-cancer pathway stimulated by sICAM-1.
While more research is needed, the two studies taken together support the idea that supplemental omega-3 can reduce the biomarker sICAM-1, resulting in potential cardiovascular and anti-cancer benefits.
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Plasma Lutein & Zeaxanthin Tied to Cataract Risk
Oxidative Stress, Carotenoids and Cataract
Cataracts can be defined as clouding of the lens in the eye due to clumping of lens protein and coloration of the lens because of age, smoking, sunlight exposure, use of oral corticosteroids, estrogen replacement therapy, and diabetes. Nuclear cataract is the most common type of cataract among older individuals, especially women.
The inability to sufficiently defend against or repair accumulated damage from a variety of environmental stressors, including photochemical formation of free radicals, can lead to cataract development. Reactive oxygen species, for example, can damage lens proteins and fiber cell membranes.
Lutein and zeaxanthin are the most abundant carotenoids that accumulate in the lens of the eye, where they appear to filter phototoxic blue light and neutralize reactive oxygen species. Many, though not all, longitudinal studies that have looked at dietary intake or plasma levels of lutein and zeaxanthin and cataract incidence have reported a relationship between these carotenoids and cataract.
In the present investigation, Finnish researchers examined whether plasma concentrations of lutein and zeaxanthin are related to age-related nuclear cataract in elderly participants of the Kuopio Ischaemic Heart Disease Risk Factor (KIHD) Study.
Study Design
The KIHD Study is an ongoing population-based, cohort study designed to investigate risk factors for CVD and other degenerative disease in a sample of middle-aged men and women. Plasma concentrations of carotenoids were determined in 1689 participants (1557 men and 783 women), aged 61-80 years. Nuclear cataract diagnoses were determined by an ophthalmologist using lens photography and grading.
Nuclear cataracts diagnosed were classified into tertiles according to plasma concentrations of lutein and zeaxanthin. The association of plasma lutein and zeaxanthin concentrations with age-related nuclear cataract was assessed using the Cox proportional hazards model.
Results
A total of 113 cases of incident age-related cataracts were confirmed, of which 108 cases were nuclear cataracts.
Subjects in the highest tertiles of plasma concentrations of lutein and zeaxanthin had 42% and 41% lower risks of nuclear cataract, respectively, compared with those in the lowest tertiles. (Relative risk (RR) 0.58, 95% CI 0.35, 0.98; p = 0.041 for lutein. For zeaxanthin, RR 0.59, 95% CI 0.35, 0.99; p= .0.046).
These associations were observed after adjustment for age, examination year, sex, BMI, smoking, alcohol consumption, serum LDL-cholesterol, serum HDL-cholesterol, years of education, use of oral corticosteroids, history of diabetes and history of hypertension with current use of antihypertensive medication.
Comment
These results suggest that higher plasma levels of the carotenoids lutein and zeaxanthin are associated with risk reduction for nuclear cataract in the elderly. According to the authors, “there may be other protective factors of the diet (e.g. synergism of carotenoids with vitamin C or other antioxidants) that may partly explain the observed results”.
The researchers also note that both compounds appear to provide similar levels of protection from cataracts, an observation that challenges the hypothesis that dietary zeaxanthin intake is more important for lens health.
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In the News
Folic acid, B12 & Vision in Astronauts
| Omega-3s & Brain Volume
Visual Changes Post-Space Flight May be Due to Altered Folic Acid & B12 Metabolism
About 20% of astronauts who’ve been on International Space Station (ISS) missions have developed ophthalmic changes after flight, including optic disc edema, globe flattening, choroidal folds, hyperopic shifts, and cotton wool spots. But why are some but not other astronauts affected? NASA researchers in collaboration with several universities have conducted experiments on ISS since 2006 to answer this question.
The investigative team found biochemical differences in crewmembers with vision issues, which strongly suggest that their folate and vitamin B12 dependent 1-carbon transfer metabolism was affected before, during, and after flight. One-carbon metabolites, including homocysteine, were 25-45% higher (P, 0.001) in those with ophthalmic changes than in those without them, and crewmembers with vision issues had consistently lower serum folate during flight. Pre-flight levels of homocysteine and cystathionine, and in-flight levels of folate, correlated with changes in refraction observed after flight .
The researchers believe that common polymorphisms in enzymes of this pathway (e.g. MTHFR 677C/T) interact with the shift in cranial fluids encountered at “zero” gravity in space to cause these ophthalmic changes.
While it’s not likely that you’ll encounter an astronaut in your waiting room anytime soon, these findings may have clinical import to those on Earth as well.
One of the most studied polymorphisms in this pathway is MTHFR 677C/T, which has an allele frequency of 30% in many ethnic groups. Heterozygotes (C/T) have a 30% decrease in the activity of the enzyme MTHFR and homozygotes (T/T) a 60% decrease in this critical enzyme. Evidence suggests that individuals with these polymorphisms may require more folic acid to maintain their status of this B-vitamin.
While Americans are getting more dietary folic acid than ever due to food fortification, getting some extra folic acid via a multi-vitamin supplement may be a good idea considering the high frequency of the polymorphisms, and that elevated homocysteine is a risk factor for ischemic stroke, inter-cranial aneurysms, migraine headaches, and possibly occlusive retinal vascular disease and some types of glaucoma. Many could also benefit from supplemental B12 due to the difficultly of its absorption in older people.
Brain Volume Tied to Omega-3 Intake
According to new findings, low blood concentrations of the omega-3s are associated with smaller brain volume and poorer performance on mental acuity tests .
Researchers from UCLA looked at the fatty acid content of red blood cells from over 1,500 men and women who were free of dementia and averaged 67 years of age. MRI scans were used to measure brain volume and white matter hyperintensities, a radiological finding that indicates vascular damage.
Study participants in the lowest quartile of omega-3 blood levels were observed to have significantly smaller total cerebral brain volume compared to those in the top quartile – a finding that held even after adjusting for age, smoking, body mass index and other variables.
Those with low omega-3 also fared poorer on tests of visual memory, abstract memory and executive function, defined as the control and management of other cognitive processes.
The investigators believe that the omega-3’s reduce vascular pathology and thus slow down the rate of brain aging. Too little omega-3 could promote accelerated brain aging.
Few people in the study used fish oil supplements, so the benefits were due to consuming more oily, cold-water fish. It may be that omega-3 supplementation could benefit brainpower – as well as cardiovascular health and perhaps vision maintenance – for those getting insufficient omega-3s from diet alone.
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Omega-3s & Vitamin A Help Preserve Vision in Retinitis Pigmentosa
Omega-3s, Vitamin A & Retinitis Pigmentosa
Retinitis pigmentosa is a group of inherited disorders affecting about 2 million people worldwide. Research suggests that the course of this condition may respond to nutrient intervention.
Three clinical trials conducted by a Harvard research team between 1984 and 2008, provided evidence that vitamin A supplementation (15,000 IU daily) alone or combined with an omega-3 rich diet could slow rate of decline in retinal function. In these trials, each lasting 4-6 years, a slower rate of decline was observed for electroretinograms (ERGs) or visual field. No significant slowing in decline of distance or retinal acuity was reported. However, Visual acuity usually declines very slowly in retinitis pigmentosa patients.
Eligibility criteria for the three trials were comparable, and test methods were the same for measuring acuity and estimating omega-3 intake. This enabled the team to combine data from all three trials to increase the statistical power and clarify whether dietary omega-3 had any effect on acuity over a 4-6 year period.
Methods
Dietary intake was calculated from questionnaires completed annually by 357 adult retinitis pigmentosa patients from the three randomized trials who were all receiving 15,000 IU vitamin A daily for 4 to 6 years. Rates of visual acuity decline were compared between those with high (> 200 mg omega-3 fatty acids/day) versus low (> 200 mg daily) intake of omega-3. The analyses took age of the participants into account.
Some patients were excluded from the ERG analyses primarily because their initial values were too low. Thus, the annual rate of decline of 163 patients with high omega-3 intake was compared with the rate of decline of 103 patients with low intake.
Results
Mean annual rates of acuity decline were slower among those with higher omega-3 intake. Mean rates of change in distance acuity (ETDRS) were -0.59 letter per year amongst the high intake group compared with -1.00 letter in the low intake group (p = .001). For retinal acuity (Snellen), a 1.5% decline per year versus a 2% yearly decline was seen with high vs. low consumers, respectively (p = .03). There was no effect of age on either distance or retinal acuity decline.
Comment
This appears to be the first report of omega-3 intake slowing, though modestly, the yearly rate of visual acuity decline in retinitis pigmentosa.
DHA / vitamin A interactions may account for the observed benefits of this combination. It’s thought rods give cones vitamin A via Muller cells, and DHA is required for releasing vitamin A from the protein (IRBP) that transports it between Muller cells. Further, rod degeneration can lead to shortages of both nutrients.
No significant difference in annual rates of decline for full-field cone ERGs was detected. Since this measure is generated predominately by mid- and far peripheral cones, this observation suggests that omega-3 benefit is limited to acuity and central field preservation.
Based on their findings, the authors estimate that the combined vitamin A and omega-3 rich diet would result in an additional 18 years of vision if the nutritional intervention begins at age 37, the average age of the participants in the combined trials.
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Omega-3s Influence Macular Pigment
Investigating the role of omega-3s in macular pigment formation
High dietary intake of lutein and zeaxanthin, or their oral supplementation, is known to increase their accumulation within the macula to form protective macular pigment (there is evidence that this accumulation relies on specific carotenoid binding proteins).
Omega-3 fatty acids and particularly DHA, are abundant in the human retina where they play structural, functional and neuroprotective roles. A number of epidemiological studies have observed decreased AMD risk with higher intake of the omega-3s EPA and DHA.
Since lutein and zeaxanthin are fat soluble, their metabolism is strongly interlinked with lipids. It has been suggested, in fact, that dietary omega-3 intake enhances retinal accumulation of lutein and zeaxanthin.
To better understand the factors influencing macular pigment accumulation, French investigators recently looked at the relationship between MPOD and plasma levels of lutein, zeaxanthin and omega-3s in a homogeneous population of healthy volunteers. The researchers report a significant correlation between MPOD and all of these dietary nutrients.
The results of this study suggest that omega-3 fatty acids may act synergistically with lutein and zeaxanthin in constituting the macular pigment, and could be an added reason for concurrent supplementation of these nutrients. Such supplementation is currently being tested in the ongoing AREDS 2 clinical trial.
Results
MPOD within 6° correlated with plasma levels of lutein and zeaxanthin (r=0.35, p<0.001 and r=0.30, p<0.005, respectively).
MPOD also significantly correlated with total plasma omega-3 polyunsaturated fatty acids (PUFAs) (r=0.22, p<0.05).
Among the different omega-3 PUFAs, docosapentaenoic acid (DPA) had the highest correlation with MPOD (r=0.31, p<0.001), while correlation with EPA was moderate (r=0.21, p<0.05), and did not reach significance for DHA.
Comments
In this study, MPOD correlated not only with plasma lutein/zeaxanthin, but also with the omega-3 long chain fatty acids – particularly EPA and DPA. DPA, a metabolic intermediate between EPA and DHA, is the second most abundant long chain omega-3 found within the retina.
While the mechanisms by which the omega-3 may influence MPOD remain to be determined, it is possible that they: 1) modulate the gastro-intestinal uptake of lutein and zeaxanthin; 2) enhance transport of these carotenoids to the eye by lipoproteins; or 3) affect the concentration or utilization of lutein and zeaxanthin in the macular area.
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Lutein & Zeaxanthin Protect Lens Cells from Oxidative Damage
Background: Lutein, Zeaxanthin & Cataract
Epidemiologic studies indicate that high dietary intake or blood levels of lutein or zeaxanthin may decrease the risk of cataract. The most recent study reports that subjects with the highest plasma concentrations of lutein and zeaxanthin had 42% and 41% lower risk of nuclear cataract, respectively (see EduFacts Vol 13, No 5).
Lutein and zeaxanthin are the only carotenoids detected in the lens. While their role in the lens and the mechanism by which they may reduce the risk for cataract aren’t fully understood, it has been proposed that the benefit of these two carotenoids is related, at least in part, to their antioxidant properties.
Oxidative stress is, in fact, a major risk factor for age-related cataract, particularly nuclear cataract. One of the major oxidants in the lens and aqueous humor is H202 (hydrogen peroxide), and levels of H202 in the aqueous humor of those with cataracts have been shown to be higher than in the aqueous humor of normal individuals.
In a recently published study, researchers from Tufts University and Sun Yat-sen University in China used cultured lens epithelial cells exposed to H202 as a model system to study the effects of supplemental lutein or zeaxanthin on oxidative damage, and their interaction with intracellular glutathione – an antioxidant enzyme that prevents damage by peroxides.
Study Design
Human lens epithelial cells were pre-incubated with or without 5 μM lutein, zeaxanthin, or α-tocopherol for 48 hours, and then exposed to 100 μM H202 for 1 hour. Alpha tocopherol ( vitamin E) was used as a positive control because the same researchers previously demonstrated that adding α-tocopherol to cultured rabbit lens epithelial cells can improve cellular redox status and restore the resistance of glutathione-depleted cells to H202. Markers of damage to proteins (protein carbonyls), lipids (maldonaldehyde) and DNA (damaged nuclei), were assessed by western-blotting analysis, HPLC, and comet assay, respectively. Glutathione (reduced and oxidized) were measured by HPLC.
Results
Exposure of the lens cells to H202 significantly increased levels of oxidized proteins, lipid peroxidation, and DNA damage. Pre-incubation with lutein, zeaxanthin, or α-tocopherol dramatically reduced the levels of H202 -induced protein carbonyl, MDA, and DNA damage.
The addition of lutein, zeaxanthin, or α-tocopherol increased glutathione levels and the ratio of reduced to oxidized glutathione, particularly in response to oxidative stress. Alpha tocopherol, but not lutein or zeaxanthin, partially restored the resistance of glutathione-depleted cells to H202.
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| Figure courtesy of Molecular Vision |
Figure 5. Supplementation with lutein, zeaxanthin or α-tocopherol suppressed H2O2-induced DNA damage in human lens epithelial cells (HLEC). Subconfluent HLEC were incubated with or without 5 μM of lutein, zeaxanthin or α-tocopherol for 48 h and then exposed to 100 μM H2O2 for 1 h. A: Fluorescence micrograph of nuclei of normal HLEC. B: Fluorescence micrograph of nuclei of oxidative insulted HLEC. |
Comment
These findings imply that sufficient intake of lutein and zeaxanthin may reduce the risk for senile cataract via protecting the lens from oxidative damage. They also suggest that vitamin E is important in protecting lens cells when glutathione levels are depleted.
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Low Antioxidant Status Seen in Glaucoma
Oxidative Stress & Development of Glaucoma
Primary open-angle glaucoma (POAG) is a chronic, slowly-progressing optic neuropathy characterized by a distinctive pattern of visual field defects. Psuedoexfoliation syndrome (PEX) is distinguished by abnormal extracellular fibrillar material that accumulates in the anterior segment of the eye and in other organs. PEX is the most common identifiable cause of open-angle glaucoma worldwide.
Oxidative stress – the presence of increased levels of reactive oxygen species relative to antioxidant defenses – may contribute to the development of both POAG and psuedoexfoliation glaucoma (PEG). Greater oxidative damage to trabecular meshwork cells has been reported in POAG and PEG vs. non-glaucoma patients , for example, and oxidative stress has been implicated as an underlying mechanism of retinal ganglion cell death .
In the present study, researchers examined the antioxidant status and established the presence of oxidative stress in patients with POAG and PEG3 .
Study Design
The study enrolled 23 POAG patients, 24 PEG patients, and 19 healthy control subjects; all 3 groups included men and women within the same age range.
As indicators of antioxidant status, the total antioxidant capacity of serum and total activity of superoxide dismutase were determined by spectrophotometry. Total antioxidant status represents the cumulative action of all antioxidants present in serum.
Total oxidant status, nitric oxide, protein carbonyl levels, and maldonaldehyde were also measured from blood sample by spectrophotometry as indicators of oxidative stress. Maldonaldehyde and protein carbonyl reflect the level of lipid peroxidation and protein oxidation, respectively.
Results
Antioxidant Status Indicators: Mean total antioxidant capacity in the POAG and PEG groups was about half that of controls (p = 0.001).
Mean superoxide dismutase levels were significantly higher in both glaucoma groups compared to the control group (p = 0.001). Concentrations of superoxide dismutase are known to rise as a consequence of oxidative stress, and in accordance with the degree of stress conditions.
Oxidative Stress Indicators: Mean total oxidant status was significantly higher in both glaucoma groups compared to controls (p = 0.001), as was maldonaldehyde (p = 0.001). The POAG group showed higher serum nitric oxide levels than controls (p = 0.005), although the PEG group did not.
Those with PEG had higher serum protein carbonyl levels than both the POAG and control groups (p = 0.001), while protein oxidation in the POAG group was no different from controls.
Comments
These results add to the growing body of evidence supporting a role for oxidative stress in POAG and PEG. The finding of lower antioxidant defense systems in the glaucoma patients are also consistent with reports from other researcher groups .
The relatively small number of subjects assessed can be considered a study limitation. However, the breadth of biomarkers measured is certainly one of the study’s strengths, since no one biomarker of antioxidant or oxidant status gives a full picture of the oxidative state. The consistency of results observed between the various biomarkers that were measured lends credence to the findings overall.
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Meta-Analysis: Antioxidants Lower HbA1c In Type 2 Diabetes
Role of Oxidative Stress in Type 2 Diabetes
For almost 25 years, oxidative stress has been considered to play a central part in the type 2 disease process, with over 6,000 related articles published over that time.
Some articles reflect growing evidence that cellular oxidative stress triggers cascades (p38 MAPK) that, in turn, interfere with signaling from the insulin receptor. Other findings suggest that diabetic complications arise from oxidative stress, which is defined as an imbalance of oxidants and antioxidants in the favor of oxidants. Hyperglycemia underlies the development of diabetic complications, most likely due to a greater production of free radicals, more specifically reactive oxygen and nitrogen species.
Combating Oxidative Stress
To combat oxidative stress, a number of trials have investigated administering vitamins C and/or E, since plasma levels of these nutrients are often reduced in those with type 2. In addition, epidemiological studies have found that type 2 individuals with reduced plasma status of vitamins C and E are at increased risk for cardiovascular events.
Antioxidant intervention trials in diabetic patients have not been uniform, however, and this has hindered their interpretation. Recently, researchers conducted a meta-analysis to clarify whether a defective antioxidant network contributes to insulin resistance in diabetes, or to its complications .
Study Design
Databases were searched for randomized, placebo-controlled trials examining the effect of supplemental vitamins E and/or C on glycemic control markers in non-pregnant adults with type 2 diabetes.
The analysis focused upon the effects of these nutrients on 1) plasma glucose and insulin concentrations as an indicator of the ability of the antioxidant to interfere with disease process, and 2) on glycated hemoglobin A1c (HbA1c) as a measure of antioxidant effects on protein modification implicated in disease complications.
Results
Fourteen vitamin E or C intervention studies were identified that met the study inclusion criteria. Collectively, these studies included 572 participants and ranged from 4 weeks to 12 months in duration.
Vitamin C supplementation was from 100 mg to 2 grams daily, while vitamin E supplementation ranged from 200 IU to 1800 IU per day.
Combined analysis revealed that antioxidant supplementation did not affect plasma glucose or insulin levels. However, HbA1c levels (reported in 13 of the 14 studies) were significantly reduced by the supplemental nutrients, suggesting that antioxidants have benefit in protecting against complications of the disease.
Key: Random effects model of meta- analysis of weighted mean difference of HbA1C compared to control group, showing the mean difference for each study and 95% confidence intervals, with the pooled meta-statistic shown as a diamond.
DL pooled effect size = -0.571078 (95% CI = -0.934883 to -0.207273)
Comments
HbA1c is the gold standard marker of long term glucose control, and a surrogate for risk of diabetic complications. This analysis found an overall improvement in HbA1c in patients receiving antioxidants (see figure), with the most pronounced effects seen in those getting higher dose vitamin E for at least 2 months.
While some concerns about high dose vitamin E safety have been previously reported, the most recent analysis (Cochrane review) does not support any negative or positive effects on mortality .
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In the News:
Vitamin C & Retinal Cell Function,
Metformin & Vitamin B12 Depletion,
Meta-analysis: lutein & AMD
Background: Role of GABA in Retina
GABA (gamma-aminobutyric acid) is the main inhibitory neurotransmitter in the central nervous system (CNS). GABA receptors modulate the rapid communication between brain cells by acting as an inhibitory ‘brake’ on excitatory nerve cells.
There are different types of GABA receptors: The ‘a’ type, for example mediates fast inhibition, while the ‘c’ receptor mediates slow and sustained responses. GABAc receptors are expressed in many regions of the brain, with prominent distribution on retinal neurons. These receptors are thought to play important roles in retinal signal processing.
Vitamin C Needed for Retinal Neuron Function
Researchers at Oregon Health and Science University report this month that the function of both retinal GABAa and c receptors is regulated by vitamin C .
According to the authors, “the cells need to be bathed in relatively high doses of vitamin C inside and out” for proper receptor function. Conversely, the receptors failed to function in the absence of the vitamin.
Vitamin C appears not only to play an indispensible role in retinal nerve cells, it may also be important for brain function. “Because the retina is part of the CNS, this suggests there’s likely an important role for vitamin C throughout our brains, to a degree we had not realized before”, explained the lead investigator. Vitamin C stores in the brain are known to be the last to be depleted during times of vitamin C deprivation.
The findings may also have implications for other conditions involving malfunctioning nerve cells in the retina and brain, such as glaucoma and epilepsy, the investigators theorize, and it “may be that a vitamin C-rich diet could be neuroprotective for the retina”.
Metformin and Vitamin B12 Depletion
There’s been increasing concern over the risk of vitamin B12 deficiency in type 2 diabetics taking the common diabetes medication metformin (e.g. Glucophage®). According to some studies, 10-30% of people taking this drug show evidence of decreased B12 absorption. Since people over 50 are generally less efficient at absorbing B12, this drug-nutrient interaction could exacerbate levels that are already low. Vitamin B12 depletion is more common in people who’ve been taking metformin the longest, and/or at high doses.
Clinicians suggest that patients who’ve used the medication for several years or who take a high dose, should have their B12 levels tested. Checking blood levels of B12 should always be done with signs of deficiency, especially those related to nerve problems such as numbness, pain or tingling in the hands or feet.
Lutein Reduces Risk of Late Stage AMD
Lutein and zeaxanthin are thought to decrease the incidence of AMD; however, findings have not always been consistent. A team of Chinese researchers from Peking University recently conducted a systematic literature review and meta-analysis to evaluate the relationship between dietary intake of lutein and zeaxanthin and AMD risk .
Six longitudinal cohort studies met the strict inclusion criteria, and their results were pooled for analysis. The researchers excluded studies that examined the use of supplemental carotenoids.
Comparing the highest with lowest category of intake showed that higher intakes of these carotenoids were associated with a 26% reduction in the risk of late-stage AMD, and a risk reduction of 32% for neovascular AMD. Little effect of lutein and zeaxanthin in the early stages of this disease was found.
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Meta-Analysis: Omega-3 Fatty Acids Reduce Artery Stiffness
Arterial Stiffness and Cardiovascular Events
Arteries stiffen and become less flexible as a consequence of aging and arteriosclerosis. Age-related stiffness occurs when the elastic fibers within the arterial wall (elastin) begin to fray due to mechanical stress. Stiffer arteries require a greater amount of force in order to expand and take up the blood ejected from the heart. This, in turn, causes the heart to contract harder to accommodate the artery.
Arterial stiffness, in fact, has recently emerged as a significant predictor of cardiovascular disease. For example, a recent meta-analysis of 17 longitudinal studies confirmed that aortic stiffness is a significant predictor of future cardiovascular events and all-cause mortality . Thus, evidence-based approaches to reducing arterial stiffness are of significant clinical importance.
Omega-3 Fatty Acids and Arterial Flexibility
One candidate for helping to alleviate arterial stiffness is the omega-3 fatty acids found in fish oil – EPA and DHA. Fish oils have long been known to mildly reduce elevated blood pressure, and evidence suggests that they may lower heart rate and prevent arrhythmia. They are also known to benefit those with coronary heart disease by reducing mortality. But do they have an effect on arterial stiffness?
Although current evidence from randomized and controlled human clinical trials suggests that fish oils may be beneficial in reducing arterial stiffness, no quantitative synthesis of this data has been conducted. This gap in knowledge led a team of researchers from Melbourne, Australia to conduct the first systematic review and meta-analysis of controlled trials to assess whether fish oils are of benefit in arterial stiffness .
Study Design
Multiple databases and clinical trial registries were systematically searched up until September 2010 for randomized and controlled adult human clinical trials to investigate the effects of long-chain n-3 fatty acids on arterial stiffness. No limits were set on dosage sizes or sample characteristics.
A total of 10 omega-3 trials met the final inclusion criteria; 4 using pulse wave velocity and 6 using arterial compliance, measured as capacitive compliance or systemic arterial compliance, as respective outcome measures.
Results
Meta-analysis revealed that omega-3 was statistically significant in effectively improving both pulse wave velocity (P<0.01) and arterial compliance (P<0.001). There was no evidence of heterogeneity or publication bias. Results were not influenced by changes in blood pressure, heart rate or BMI.
Comments
The findings of the present analysis suggest that high dose supplementation with EPA and DHA offers a scientifically supported means of reducing arterial stiffness, and may account for some of the cardio-protective effects of these omega-3 fatty acids, according to the authors.
One possible limitation of this analysis is that none of the studies included used carotid-femoral pulse wave velocity, which is regarded as the ‘gold standard’ in the measurement of arterial stiffness. However, the measures used in the present meta-analysis such as brachial-ankle pulse wave velocity and systemic arterial compliance are also valid and predictive of CVD and or mortality.
In terms of any potential impact on ocular health, associations between arterial stiffness and AMD and arterial stiffness and glaucoma have been reported in some epidemiologic investigations, though not others.
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Research Briefs: Vitamin D, AREDS Antioxidants & Citrus Flavonoids
Introducing EduFacts Research Briefs
While EduFacts will continue to highlight a newly published study or review article on nutrition and ocular health, it will now occasionally present Research Briefs: short summaries of several studies from various journals.
Vitamin D Again Linked to Reduced AMD Risk
Researchers from the University of Wisconsin and elsewhere examined the relationship between serum vitamin D and the prevalence of early AMD among 3000+ postmenopausal women . Higher serum vitamin D concentrations (> 38 nmol/L) were found to be significantly associated with a 48% decreased odds of early AMD and a 57% decreased risk of pigmentary abnormalities in women under 75 yrs. For those over 75, the association was of borderline significance.
In terms of vitamin D intake from supplements and foods, those consuming the highest amount (on average about 600 IU) daily, had a 59% lower risk of AMD compared to those obtaining the least (about 300 IU on average). This is the 2nd study to report a relationship between vitamin D and AMD. Because vitamin D has known anti-inflammatory and immune modulating actions, the authors speculate this nutrient may suppress destructive inflammation that occurs at the RPE-choroid interface in early stage disease.
AREDS, Ocular Blood Flow & Endothelial Function
Oxidative stress is a contributor to ocular diseases such as diabetic retinopathy, cataract, AMD, uveitis, and possibly glaucoma. The presence of increased oxygen radicals in vascular tissue is believed to cause endothelial dysfunction, leading to decreased dilation, more inflammatory cell and platelet adhesion, and increased coagulation activity. The retina is especially vulnerable to oxidative stress because of its high oxygen consumption, its high concentration of poly-unsaturated fatty acids, and its direct exposure to light.
Using an experimental protocol, clinicians from the Medical University of Vienna showed that systemic inflammation diminishes the retinal vascular response to hyperoxia. (The protocol uses an endotoxin to reduce the response of retinal blood flow under conditions of excess oxygen). The reduced response is due to endothelial dysfunction caused by oxidative stress. In a double-blind, placebo-controlled parallel study , 21 healthy volunteers were given the AREDS formula or a placebo for two week periods. At the beginning and end of each period, retinal blood flow and retinal blood flow reactivity to hyperoxia was assessed.
The investigators found that the AREDS antioxidants restored retinal vascular reactivity. According to the authors, this was likely due to oxygen radical scavenging by the antioxidants. The results suggest that this model might be a good approach to screening antioxidants for their relative beneficial effects in the retina.
Flavonoids, Inflammation and Blood Pressure
Researchers studied the effects of orange juice (OJ) and its major flavonoid, hesperidin, on blood pressure and blood vessel function in overweight but otherwise healthy men . About 1/3 of the men had elevated blood pressure but were taking no anti-hypertensive medications. During 3 month-long periods, the men drank either 17 oz of OJ daily, a control drink with 300 mg hesperidin capsules (the same amount as the OJ contained), or a control drink plus a placebo capsule. At the end of both the OJ and hesperidin test periods, diastolic pressure was significantly lower than after the placebo period. Studies suggest that even a decrease of just 3-4 points in diastolic pressure could result in a 20% reduction in the incidence of coronary heart disease. Hypertension also appears to raise the risk of retinopathy in non-diabetics .
The researchers also tested a variety of measures of blood vessel activity, including the ability to dilate. Both OJ and hesperidin showed positive effects compared to placebo. This finding is consistent with recent data linking higher intake of citrus flavonoids with lower markers of inflammation and endothelial dysfunction in participants of the Nurses Health Study .
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Role for Omega-3s in Prevention of AMD?
Omega-3s May Reduce Risk of AMD in Women
While an AREDS-tested antioxidant supplement has been shown to slow progression in people with intermediate AMD, there is no recognized means of prevention for those currently free of the disease or the estimated 7.3 million Americans with early AMD.
Evidence from observational studies suggests that regular dietary intake of fish, DHA and EPA may reduce AMD risk. In fact, the randomized trial, AREDS-2, is currently evaluating whether supplemental DHA and EPA can lower the risk of progression to advanced AMD. However, the available data for early AMD are limited and inconsistent.
To increase that evidence base, a team of Harvard University researchers has examined the relationship between omega-3, fish consumption and AMD in a large cohort of women health professionals who were free of the disease at the study’s start.
The researchers now report that regular consumption of EPA, DHA and fish is associated with a 34-42% risk reduction of visually significant AMD incidence. They conclude that consistent omega-3 consumption may be of benefit in the primary prevention of AMD.
Design
In this prospective study, dietary information was obtained by food-frequency questionnaire at baseline for 39,876 health professionals who participated in the Women’s Health Study. A total of 38,022 women, 54 years of age on average and free of a diagnosis of AMD, completed the questionnaire and were followed for an average of 10 years.
The main outcome measure was incident AMD responsible for a reduction in best corrected visual acuity to 20/30 or worse, based on self-report confirmed by medical record review.
Results
A total of 235 cases of AMD, most characterized by some combination of drusen and retinal pigment epithelial changes, were confirmed during an average 10 years of follow-up.
Women in the highest 1/3 of intake for DHA, compared with those in the lowest, had a multivariate-adjusted 38% lower risk of AMD (RR 0.62, 95% confidence interval 0.44-0.87).
For EPA, women in the highest tertile had a 34% reduced risk (RR 0.66, 95% confidence interval 0.48-0.92).
Consistent with the findings for DHA and EPA, a 42% lower risk was observed in women who consumed 1 or more servings of fish weekly compared to those consuming less than 1 serving monthly (RR 0.58 95% confidence interval, 0.38-0.87).
Comments
There are many mechanisms by which omega-3s could affect AMD occurrence. For example, they have been shown to protect against the damaging effects of blue light in the parafovea.
DHA and EPA may also contribute to macular protection by modulating inflammatory and immune processes thought to play a role in AMD pathogenesis. They enhance production of resolvins and neuroprotectins—compounds thought to dampen and resolve inflammatory responses. EPA and DHA also affect the expression of signal transduction genes and genes for pro-inflammatory cytokines.
These findings by WG Christen and his colleagues are broadly consistent with previously published findings, and appear to be the strongest observational evidence to date in support of a role for omega-3 and fish intake in the primary prevention of AMD.
Because early AMD is associated with an increased risk of developing advanced AMD, these data also suggest that regular omega-3 intake could ultimately reduce the number of persons who have advanced AMD.
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Selenium Found to Improve Mild Graves’ Orbitopathy
Treating Milder Forms of Graves’ Orbitopathy
The most common form of hyperthyroidism is Graves’ disease, and about 1/2 of patients with this disease have ocular involvement in the form of Graves’ orbitopathy (GO). An autoimmune inflammatory disorder affecting the orbit around the eye, GO is characterized by upper eyelid retraction, swelling, redness, conjunctivitis, and bulging eyes. Moderately severe and active forms of this disease can be effectively treated with glucocorticoids and/or orbital irradiation.
Since milder forms may improve spontaneously, the usual treatment is use of artificial tears, ointments, and prisms simply to control symptoms. However, a ‘wait-and-see’ strategy in which patients are monitored until symptoms worsen, can be challenged.
First, many patients with even mild forms of GO have a substantial decrease in their quality of life, as assessed by a Graves’ orbitopathy-specific quality-of-life questionnaire. Second, a natural history study of mild GO, found that spontaneous improvement occurred in about 20% of patients, while the disease remained static in 65% and progressed in 15%. Thus, some believe that therapy would be justified.
Oxidative Stress, Selenium and Graves’
A number of in vitro studies have suggested that increased generation of oxygen free radicals and cytokines play a role in GO. Because the trace mineral selenium is a co-factor for antioxidant enzymes and has an important effect on the immune system, researchers representing the European Group on Graves’ Orbitopathy investigated whether selenium or the anti-inflammatory agent pentoxifylline might be beneficial in patients with mild GO. Their findings, published in the May 19th issue of NEJM, indicate that selenium is clinically useful in this condition.
Design
This randomized, double-blind, placebo-controlled trial was carried out in 159 patients with mild Graves’ orbitopathy. The patients received 2x daily: selenium (100 μg), pentoxifylline (600 mg), or placebo for 6 months and were then followed for 6 months after treatment was withdrawn. Primary outcomes at 6 months were evaluated by means of an overall ophthalmic assessment, conducted by an ophthalmologist who was unaware of the treatment assignments, & a GO–specific quality-of-life questionnaire, completed by the patient.
Results
At the 6-month evaluation, treatment with selenium, but not with pentoxifylline, was associated with an improved quality of life (p<0.001), less eye involvement (p = 0.01), and slower disease progression (p = 0.01), compared with placebo. The Clinical Activity Score decreased in all groups, but the change was significantly greater in the selenium-treated patients. Exploratory evaluations at 12 months confirmed the results seen at 6 months.
Two patients assigned to placebo and 1 assigned to pentoxifylline required immunosuppressive therapy for deterioration in their condition. No adverse events were evident with selenium, whereas pentoxifylline was associated with frequent gastrointestinal problems.
Comments
In this study, supplemental selenium significantly improved quality of life, reduced ocular involvement, and slowed progression of the disease, suggesting clinical utility of this mineral in treating milder forms of GO.
Marcocci C, et al. Selenium and the course of mild Graves’ Orbitopathy. NEJM 364:1920-31, 2011.
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Lutein, Zeaxanthin and AMD Risk
The low values of macular pigment density seen in some people, coupled with the age-related decline of natural defenses in the retina and RPE can increase oxidative stress, a risk factor for AMD. AMD risk is thought to be further increased by exposure to blue (short-wavelength) light, although the results of observational studies have been conflicting.
One of the observational studies reports that estimated lifetime blue light exposure increased the risk of neovascular AMD specifically in individuals with low plasma levels of antioxidants, including zeaxanthin. However, experiments to evaluate the relationship of the macular pigment xanthophylls (lutein and zeaxanthin) to light damage and macular disease have been few, due to a lack of appropriate animal models. Only higher primates have a macula lutea, with its high foveal concentration of macular pigment.
Working with a unique set of rhesus monkeys raised on lutein and zeaxanthin-free diets, a research team has now looked at the effects of macular pigment absence – followed by xanthophyll supplementation – on blue light damage. The researchers also examined whether a deficiency of omega-3 fatty acids affects sensitivity to blue light as well.
Study Design and Methods
The study included 8 rhesus monkeys with no lifelong intake of xanthophylls and no detectable macular pigment. Four of the monkeys had low omega-3 intake and 4 had adequate dietary intake.
Retinas received 150 μm-diameter exposures of low-power 476 nm laser light either at 0.5 mm [~2(o)] eccentricity, adjacent to the macular pigment peak, or parafoveally at 1.5 mm [~6(o)]. Exposures of xanthophyll-free animals were repeated after supplementation with pure lutein or zeaxanthin for 22-28 weeks.
Visible lesion areas were plotted as a function of exposure energy, with greater slopes of the regression lines indicating greater sensitivity to damage. The results were compared to data from control animals with typical levels of xanthophylls and omega-3 in their diets and retinas.
Results
For control animals with normal macular pigment, the fovea was less sensitive to blue light damage than the parafovea. However in the monkeys lacking macular pigment, fovea and parafovea were equally vulnerable.
After supplementation, foveal protection in xanthophyll-free animals did not differ from controls. And, like controls, the fovea was now less sensitive to damage than the parafovea.
In the parafovea (but not the fovea), animals low in omega-3 fatty acids showed greater sensitivity to damage compared to those with adequate omega-3.
Comments
These findings confirm the photo-protective effect of lutein and zeaxanthin in the fovea where their con-centration is greatest, and indicate that omega-3 fatty acids lessen damage in the parafovea. Although the study showed protection against acute blue light damage, it seems probable that these nutrients would also protect the macula against chronic blue light exposure.
The omega-3 fatty acid DHA is present at exceptionally high levels in the retina, particularly in photoreceptor outer segment membranes. There are a number of ways by which DHA could act to lessen blue light damage: it serves as the precursor for neuroprotective factors and helps counter inflammation. In addition DHA helps block abnormal vessel growth (see EduFacts Vol. 12 No. 1).
“Our results”, conclude the study authors, “offer hope that good nutrition, augmented by supplementation when appropriate, can contribute to reduction of risk for AMD, especially for persons with reduced macular xanthophyll levels due to retinal disease, poor diet, or genetic predisposition”.
Barker FM, et al. Nutritional Manipulation of Primate Retinas. V: Effects of Lutein, Zeaxanthin and n–3 Fatty Acids on Retinal Sensitivity to Blue Light Damage. IOVS Papers in Press. Published on January 18, 2011 as Manuscript iovs.10-5898
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Revealing How Omega-3s Work against Retinopathy
Deciphering Pathways Could Pay Dividends
The omega-3 fatty acids EPA and DHA appear to play an important role in thwarting the new growth of irregular blood vessels in the retina. For example, the omega-3s have been shown to protect against retinal angiogenesis in an animal model of retinopathy and higher omega-3 intake has also been found to correlate with decreased neovascularization in AREDS participants. However, we still don’t know exactly which lipid pathways and which molecules govern specific protective effects.
Deciphering the pathways by which omega-3s block abnormal vessel growth in the eye could lead to the development of new targeted treatments to augment the currently used anti-VEGF approaches to treating retinopathy. It could also tell us whether common inhibitors of omega-3 related enzymes such as aspirin and NSAIDs can be used without losing the beneficial effect of these dietary fatty acids.
Background: Meet the COX and LOX Families
The principal enzymatic pathways that convert the omega-3 and omega-6 fatty acids into bioactive metabolites are the cyclooxygenases (COXs) and the lipoxygenases (LOXs).
The COXs play a primary role in producing prostaglandins (which mediate inflammatory and anaphylactic reactions), thromboxanes (mediators of vessel constriction), and prostacyclins (which are involved in the resolution phase of inflammation).
The LOXs, on the other hand, generate biologically active products such as the leukotrienes, lipoxins, and the recently identified omega 3–derived resolvins and protectins. Resolvins and (neuro)protectins, which can be formed from both EPA and DHA, have very potent anti-inflammatory and immune-regulating actions.
Bottom line is that the beneficial effects of the omega-3s are mostly mediated by these hormone-like compounds derived via the COX and LOX enzymes.
Study Details
Montreal, UC Berkeley, the NEI and elsewhere, sought to clarify the overall contribution of COX and LOX enzymes in blocking destructive neovascularization.
In brief, omega-3 diets were fed to 4 lines of mice, each of which were deficient in one of the 4 main enzymes that convert omega-3s to active metabolites (COX 1 or 2, or LOX 5 or 12/15). Retinopathy was then induced by oxygen exposure.
Results
The research team found that protection against retinopathy required the 5-LOX enzyme. Specifically, the protective effect was due to 5-LOX oxidation of DHA to the metabolite 4-HDHA (4-hydroxy-DHA).
4-HDHA directly inhibited endothelial cell proliferation and sprouting angiogenesis.
This action was independent of 4-HDHA’s anti-inflammatory effects. Instead, 4-HDHA worked by activating PPAR gamma, a transcription factor that regulates the expression of genes.
In addition, the investigators found significant concentrations of 4-HDHA in healthy human subjects, suggesting that their findings may apply to the way omega-3s block angiogenesis in humans.
The fact that COX 1 and 2 were not involved in inhibiting angiogenesis suggests that COX inhibitors such as aspirin and ibuprofen can be used without negating the beneficial effect of dietary omega-3s.
In contrast, clinical use of 5-LOX inhibitors (e.g. the drug zileuton) in patients at risk of ocular neovascular disease warrants closer investigation in light of these findings.
This new information about omega-3s could make them a promising new treatment option considering that the monthly cost of omega-3 supplementation is a fraction of the up to $4,000 cost per month of anti-VEGF therapy.
Sapieha P,et al. 5-Lipoxygenase metabolite 4-HDHA is a mediator of the antiangiogenic effect of w-3 polyunsaturated fatty acids. Sci Transl Med 3, 69ra12 (2011).
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Positive News on the AMD Front: Prevalence Down
Prevalence of AMD May be Declining
In 2004, the Eye Diseases Prevalence Group, using a meta-analysis of regional population-based studies, estimated that late AMD was present in more than 1.75 million people in the US. They also projected that the number with AMD would increase to almost 3 million by 2020, since Americans are living longer.
Those projections didn’t take into account the effects of changes in treating people at high risk for late AMD, such as more frequent recommendations for the use of zinc and antioxidant vitamins following publication of results from the AREDS trial in 2001. The predictions also assumed that AMD risk factor rates would remain unchanged.
More recently, another study forecast that the number of people with early AMD would jump from 9.1 million to 17.8 million, and that late AMD would go from 620 000 to 1.6 million over the next 40 years, owing to the aging of our population.
Now, an updated estimate based on the 2005-2008 National Health and Nutrition Examination Survey (NHANES) tells us that AMD prevalence has actually declined since the last report (1988-1994 NHANES).
Study Design
Retinal photographs (45° digital images) from both eyes of more than 5,500 people 40 and older from the 2005-2008 NHANES were graded for severity using a standard protocol, with AMD as the main outcome.
Results
Overall, the prevalence of any AMD was 6.5%, which is considerably lower than the 9.4% prevalence reported in the 1988-1994 NHANES. The prevalence of large and soft drusen, RPE de-pigmentation, increased retinal pigment, exudative macular degeneration, geographic atrophy, and early / late AMD are shown in Table 2 below.
Comments
This study estimates that about 1 in 15 people over 40 – 7.2 million Americans in all – have AMD. In addition to a greater number of at risk people taking AREDS supplements, the authors speculate that reductions in smoking and cholesterol levels, and/or improvements in diet, exercise and blood pressure may have contributed to the decrease in prevalence.
Currently, however, adults and children are more overweight than ever, and a large portion of Americans fail to meet dietary recommendations. 2011 is also the year that the first wave of baby boomers will turn 65 – at the rate of 7000 per day. So it’s important to delve deeper and try to understand why the drop in AMD prevalence occurred. If we can better understand what’s behind the decline, it might provide insights to help prevent future generations from developing this disease.
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Polyphenols Bolster Drug Effects in Ocular Hypertension
Ocular Hypertension and Risk of Glaucoma
Ocular hypertension is a leading risk factor for the development of primary open angle glaucoma (POAG), and is the only modifiable risk factor acknowledged at present.
It’s estimated that 4 to 7% of Americans over 40 years of age have ocular hypertension. The Ocular Hyper-tension Treatment Study (OHTS) clearly showed that lowering IOP is effective in delaying or preventing the onset of POAG in individuals with ocular hypertension. Recent results from a long-term study by the OHTS group indicates that those at high risk of POAG can benefit from early preventive treatment .
Spurred by previous findings that a combination of polyphenols (anthocyanins and procyanidins) could improve IOP and blood flow in ocular hypertension, the same researchers recently compared the effects of those polyphenols alone and with latanoprost in ocular hypertensive patients with no signs of POAG .
Study Design
The study recruited 79 men and women, mean age 49 yrs, with diagnosed elevated IOP (> 35 and < 40 mmHg). All subjects had complete eye exams, showing no signs of POAG. Patients were randomly divided into 3 groups to receive latanoprost (Xalatan, one drop per eye daily), one tablet of the polyphenol combination, or both.
The supplement tablet contained a daily dose of about 28 mg anthocyanins (Bilberry extract) and 28 mg procyanidins (French Maritime Pine Bark Extract). IOP was consistently measured at the same time in the a.m. by the same investigator, and in triplicate. High resolution color Doppler imaging was used to measure the peak systolic flow velocity, and the end diastolic flow velocity of the central retinal artery.
Results
Comments
The polyphenol and drug combination was more effective for lowering IOP, and the combination yielded better retinal blood flow. Evidence suggests that bilberry anthocyanins may act by countering increased permeability of blood capillaries, while the procyanidins may improve endothelial function. These promising results warrant further research with a larger patient group, according to the authors.
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Healthy Eating Lowers Cataract Risk in Women
Dietary Components and Cataract Risk
Individual components of the diet have been associated with cataract risk over the past few decades. Antioxidants, for example, may lower risk for nuclear cataract by lowering oxidative stress or systemic inflammation (which can lead to oxidative stress). Having high intakes or blood levels of lutein and zeaxanthin and the use of multivitamin supplements have been most consistently related to lower risk for cataract. Less consistently, high dietary intake or blood levels of vitamins C and/or E have been associated with reduced risk.
A few studies have also associated other dietary components with lower risk for nuclear cataract or cataract extraction, including high intake of long-chain omega-3 fatty acids or low intake of refined carbohydrates (as indicated by a low glycemic index score). Only one previous study has directly evaluated the overall impact of a healthy diet on the occurrence of cataract. In that study, adherence to a Healthy Eating Index over a 10-year period was linked to a lower risk for early nuclear lens opacities .
The Carotenoids in Age-Related Eye Disease Study (CAREDS), part of the Women’s Health Initiative (WHI), previously found that high intake and blood levels of lutein and zeaxanthin lowered the risk for nuclear cataract in this cohort. CAREDS researchers now report that an overall healthy dietary pattern is related to a low prevalence of nuclear cataract .
Study Design
Presence of nuclear cataract was determined from slit-lamp photographs and self-reports of cataract extractions were assessed in 1,808 CAREDS participants. Scores on the 1995 Healthy Eating Index, which reflect adherence to 1990 guidelines, were assigned from responses to food frequency questionnaires at the WHI baseline.
Results
Having a high Healthy Eating Index score was the strongest predictor of low prevalence of nuclear cataract among numerous risk factors examined. The multivariate-adjusted odds ratio for high vs. low quintile for diet score was 0.63 (95% confidence interval, 0.43-0.91).
Higher prevalence of nuclear cataract was also associated with other modifiable factors (smoking and marked obesity) and non-modifiable factors (having brown eyes, myopia, and high pulse pressure).
Comments
Healthy Eating Index scores in the highest quintile were associated with a 37% lower risk for nuclear cataract after adjusting for non-dietary risk factors. These women ate diets that were lower in fat, saturated fat and sodium, and higher in lutein and zeaxanthin, vitamins C and E, and all other vitamins and minerals compared with women whose overall scores were in the lowest quintile. The authors conclude that “eating foods rich in a variety of vitamins and minerals may contribute to postponing the occurrence of the most common type of cataract in the U.S”.
While there is a large body of observational studies linking multivitamin use with lower risk of nuclear cataract, no association was found in the present study. The lack of a protective association could have resulted from the relatively healthy diets of the women sampled, according to the authors. It is also possible that multi-vitamins may protect against nuclear cataract only in people who have poor diets.
If that is the case, many Americans could potentially benefit from a multi-vitamin supplement to ensure adequate micronutrient intake. A newly published study which examined the dietary habits of over 16,000 individuals found that more than 80% of those 70 and older, and more than 90% of all other groups of both sexes, consumed too many calories from fats, added sugars and alcohol. Nearly everyone failed to meet recommendations for dark green and orange vegetables, and whole grains.
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Green Tea Polyphenols Reduce Oxidative Damage in Ocular Tissues
Green Tea and its Catechin Components
Daily consumption of green tea has been linked to a number of potential health benefits. The results of several well-designed epidemiologic studies, for example, indicate that green tea consumption may be of modest benefit in preventing myocardial infarction or stroke.
The four primary polyphenols found in fresh green tea leaves are epigallocatechin gallate (EGCG), epigallocatechin, epicatechin gallate, and epicatechin. These tea catechins have been shown to have antioxidant activities in many biological systems, and have been shown to be protective against oxidative challenge in retinal photoreceptors in vitro. However, whether orally ingested catechins accumulate in eye tissues and actually exert a protective effect in vivo had not been examined until recently.
Researchers from the Chinese University of Hong Kong have now published the first paper to show distribution of individual catechins after ingestion of green tea extract and to evaluate their in vivo antioxidant effects in various compartments of the mammalian eye.
Study Design
Eleven groups of Sprague-Dawley rats of equal weight and age were fasted and fed 550 mg/kg of powdered green tea extract (GTE) suspended in water and administered via feeding tube. One group received water with no GTE, and served as controls.
The rats were sacrificed at various time points after GTE administration, and the aqueous and vitreous humors, cornea, lens, retina, and choroid-sclera were dissected out immediately and assayed for catechin content. 8-epi-isoprostane, a unique bioactive product of lipid peroxidation, was assayed in ocular tissues and fluids.
Results
Catechins were differentially distributed in eye tissues. Gallocatechin was present at the highest concentration in the retina, and epigallocatechin in aqueous humor. No catechin was detected in any of the tissues and fluids in the control group.
The time of maximum concentration of the catechins varied from 0.5 to 12.2 hours. Some catechins remained at high levels even after 20 hours of administration, for example gallocatechin in vitreous humor and in choroid-sclera.
Significant reductions in 8-epi-isoprostane levels were found in all compartments except the choroid-sclera or plasma, indicating antioxidant activities of catechins in these tissues (see graphs below).
Comments
The researchers concluded that green tea consumption can benefit the eye against oxidative stress. “Many studies on the antioxidative effect of green tea have focused on EGCG,” report the researchers. “However, in this study, we found its tissue level was not high. Gallocatechin, epigallocatechin, catechin, and epicatechin, on the other hand, sustained high levels in many ocular compartments. Although these compounds have a reducing power similar to or lower than that of EGCG, use of a mixture, such as green tea extract, was better than use of a single catechin because of synergistic antioxidant effects and bioavailability,” they added.
Chu KO, et al. Green tea catechins and their oxidative protection in the rat eye. J of Agricultural and Food Chemistry 58:1523-34, 2010.
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Vitamin Deficiencies After Bariatric Surgery & Ocular Consequences
Bariatric Surgery? Nutritional Vigilance Wise
More than 60% of U.S. adults now meet the criteria for being overweight or obese, and bariatric surgery has become a popular way to combat this problem. Despite complications such as nutrient deficiencies that are associated with weight loss surgery, it’s estimated that the number of obesity surgery patients in the U.S. will exceed 1 million in the next few years.
Most bariatric surgery centers offer guidelines for how to eat and drink to avoid complications post-op, as well as how to consume nutrient-dense foods for the long haul. Surgeons also emphasize the need for multi-nutrient supplementation, which should begin prior to surgery, and continue for life. But the problem is that many patients don’t follow up with their surgeons as advised. Thus, nutritional vigilance by all health care professionals is increasingly important.
What Are Common ‘Problem’ Nutrients?
According to the most recent reviews, bariatric surgery patients are commonly at risk for deficiencies of water-soluble vitamins B12, B1, folate and C; fat-soluble vitamins A, D, E and K; and the minerals iron, zinc, selenium, calcium, magnesium and copper. Deficiencies of vitamin B12 and iron are perhaps the most commonly observed, but shortfalls of the fat-soluble vitamins can also occur. Keep in mind, too, that these patients are more likely to have marginal levels or deficits of multiple nutrients rather than a single deficiency.
The risk for micronutrient depletion is highest after surgeries that affect digestion and absorption, such as the Roux-en Y gastric by-pass (RYGB), the most frequently preformed type of weight-loss surgery. RYGB greatly increases the risk for vitamin B12 deficiency. But other B vitamins – especially B1 – as well as minerals can also be affected.
Biliopancreatic surgeries (BPD), the second most frequently conducted, increase the risk for a number of nutrient shortfalls. The risk for fat-soluble vitamins A, D and K appears to be higher, as fat malabsorption is induced with this procedure.
In the past it was thought that nutrient deficiencies wouldn’t be a problem in patients undergoing “restrictive” types of surgery such as the adjustable gastric band or “lap banding”. However, poor food choices, food intolerances and the limited size of food portions can all contribute to the risk of vitamin and mineral shortfalls. Deficits of thiamine (B1), folate and others have been reported – especially in “banding” patients experiencing vomiting, inadequate food intake or rapid weight loss.
Signs & Symptoms: Vitamins B1 and A Deficiencies
Deficiencies of vitamins B1 and A can sometimes include ocular signs. One early symptom of low vitamin B1 levels is fatigue since this vitamin is required for the energy-yielding metabolism of carbohydrates. Overt deficiency can lead to dry beriberi and even Wernicke encephalopathy which affects the nervous system. A patient with “bariatric beriberi” may have weakness, dizziness, blurred vision, peripheral neuropathies (often beginning with a tingling in the toes and hands), and difficulty walking.
One central neurologic complication of B1 deficiency is Wernicke encephalopathy which classically presents as mental confusion, memory loss, rapid or abnormal eye movements (nystagmus), and an unstable gait. Many of these symptoms can be mistaken for stroke, so it’s important to know a patient’s surgical history. Treatment is considered a medical emergency, entailing rehydration as well as IV administration of thiamine to avoid long-term mental impairment.
Vitamin A is another example. Night blindness, drying of the conjunctiva with Bitot’s spots, dry skin and poor wound healing can be early symptoms of deficiency. More advanced deficiency symptoms include corneal damage, softening and degeneration of the cornea (keratomalacia), inflammation of the ocular cavities and adjacent structures (endophthalmitis), rough dry skin (xerosis) and hyperkeratinization of the skin. Some treatment guidelines call for 10,000-25,000 IU of vitamin A orally for several weeks when there are no corneal changes. When corneal changes are present, higher levels (50,000-100,000 IU) are sometimes given intramuscularly for several weeks.
Shortfalls of Lutein and Zeaxanthin?
Eye care professionals are in a unique position to monitor the status of lutein and zeaxanthin – two non-vitamin, but important fat-soluble nutrients. This might be accomplished by assessing a patient’s macular pigment density, and recommending supplemental lutein and zeaxanthin where warranted or even as a cautionary measure.
Concentrations of these macular pigments decline naturally with age, which is thought to increase the risk for AMD. It’s possible that post-bariatric malabsorption of lutein and zeaxanthin could exacerbate that risk over time. Since only the status of traditional vitamins and minerals are routinely monitored, there’s scant information about the impact of weight-loss surgery on the status of nutrient such as lutein and zeaxanthin. Nor are many primary care physicians or bariatric surgeons aware of this potential issue.
How Can Eye Professionals Help?
In addition to watching for nutrient deficiency signs and symptoms, here are several tips for helping weight-loss surgery patients keep on track:
Non-compliance with taking recommended supplements is often what gets patients who’ve undergone bariatric surgery in trouble. Supplementation must be continued for life, and the supplemental level required to prevent deficiencies for many nutrient far exceeds what any healthy diet can supply.
Even those already taking supplements should be closely monitored for vitamin deficiencies.
Some deficiencies, such as vitamin B1, can occur rapidly, while deficiencies of fat-soluble vitamins can take much longer to develop. Many patients also require extra supplements of specific nutrients in addition to a daily multi-vitamin and mineral. For example, current recommendations for gastric by-pass patients include: 10,000 IU vitamin A, 50-100 mg B1, 300-500 mcg of B12 (some may also require B12 injections), 300 mcg daily of vitamin K, 800-1200 IU vitamin D and 1200-1800 mg of calcium.
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GLA Acts Synergistically in Treatment of Meibomian Gland Dysfunction
Meibomian Gland Dysfunction & Treatment
Meibomian gland dysfunction (MGD) is a common, yet often overlooked, chronic disease of the posterior eyelids. MGD is most often caused by an obstruction of the meibomian glands secondary to hyper-keratinization of the duct epithelium and plugging with a solidified secretion. These changes lead to alterations in the tear film lipid layer. Evaporation and tear osmolarity increase, resulting in dry eye signs and symptoms.
For patients with significant inflammation, systemic antibiotics and topical antibiotic/steroid combinations are used in the short term. Long-term treatment is aimed at controlling symptoms through eyelid hygiene.
Oral GLA May Enhance Hygiene Therapy
Supplementation with the omega-6 fatty acids linoleic acid and gamma-linolenic acid (GLA) has been reported to be of benefit in treating chronic inflammatory disorders such as rheumatoid arthritis. These fatty acids have also been found to reduce ocular surface inflammation and improve dry eye symptoms in patients with Sjögren’s syndrome and keratoconjunctivitis sicca.
In the present study, researchers assessed the effect of modest supplemental amounts of linoleic acid and GLA on MGD. The results suggest that oral fatty acids enhance eyelid hygiene in improving symptoms and reducing eyelid margin inflammation.
Study Design
Fifty-seven patients with MGD (27 men and 30 women) were randomly divided into 3 groups of 19. Group A received linoleic acid (28.5 mg) and GLA (15 mg) daily, while group B performed eyelid hygiene each day. Group C received both treatments.
Initially and after 60 and 180 days of therapy, all patients completed a self-evaluation questionnaire on ocular surface disorders and underwent slit-lamp examination. The following signs were evaluated: eyelid edema, eyelid margin hyperemia, meibomian secretion appearance, meibomian gland obstruction, conjunctival hyperemia, conjunctival papillae, corneal staining, and foam collection in the tear meniscus. The appearance of foam in the tear margin is indicative of meibomian gland malfunction.
Results
In total, 49 (86%) of the 57 patients completed the study; 2 patients dropped out at day 60, and 6 were lost at follow-up on day 180.
Significant improvement in symptoms occurred in all groups.
After 180-days, group A (oral fatty acids) showed reductions in meibomian gland obstruction (P = 0.0001) and secretion turbidity (P = 0.02), while group B (eyelid hygiene) had reductions in eyelid edema (P = 0.02), corneal staining (P = 0.01), secretion turbidity (P = 0.01), and meibomian gland obstruction (P = 0.0001).
In group C (combined therapy), the researchers noted reductions in eyelid edema (P = 0.003), corneal staining (P = 0.02), secretion turbidity (P = 0.0001), meibomian gland obstruction (P = 0.0001), and foam collection in the tear meniscus (P = 0.02).
Comments
The authors conclude that the combined omega-6 fatty acids and eyelid hygiene regimen improves symptoms and reduces eyelid margin inflammation in MGD more than either therapy alone.
The results suggest that the omega-6 fatty acids could play a dual role. They may have an anti-inflammatory effect and contribute to reducing eyelid edema, and the congestion of blood (hyperemia) in the eyelid margin and conjunctiva. In addition, the fatty acids may modify the lipid composition of meibomian secretion, which appears less turbid and dense after treatment. These changes may increase the effectiveness of eyelid hygiene.
The improvement in symptoms and clinical signs suggest that the fatty acids are a viable adjuvant therapy for standard treatment of MGD, and warrant further large-scale studies.
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EPA & DHA Linked to Lower AMD Risk in AREDS 2 Baseline Data
AREDS 2 Basics
AREDS 2 is a nationwide study to determine whether high dose carotenoids (lutein and zeaxanthin) and omega-3 fatty acids (DHA and EPA) can slow vision loss in people at moderate to high risk for the progression of AMD. The study began in the fall of 2006, and is expected to be completed in 2013.
The 3 interventions arms for the carotenoids and omega-3s are: 1) 10 mg of lutein and 2 mg of zeaxanthin plus placebo; 2) 350 mg of DHA and 650 mg of EPA plus placebo; and 3) a combination of the DHA/EPA and lutein/ zeazanthin. In addition, all participants are offered the original AREDS formula (now considered standard of care) or 3 variations of this formula: (1) no beta-carotene; (2) lower amounts of zinc; and (3) no beta-carotene and lower zinc.
At the Association for Research in Vision and Ophthalmology's meeting in May, researchers presented the baseline demographic and dietary characteristics of AREDS 2 participants, and their associations with AMD . They report that people consuming the most DHA or EPA had the lowest rating of AMD severity.
Study Design
Baseline fundus photographs were centrally graded with a standardized protocol using drusen size and pigment characteristics to assign the AREDS 5 level simple scale score of severity. Participants completed a dietary assessment at baseline, and nutrient density values were classified into quintiles. Data were adjusted for age, gender and
Results
Demographic characteristics are shown in Table 1. Dietary DHA and EPA were inversely related to AMD severity score in energy-adjusted comparisons of highest versus lowest quintile intake (p<0.05 for both nutrients, see Table 2). Trend tests on quintile median nutrient values yielded a p-value of <0.01 for both EPA and DHA. The association of lutein and zeaxanthin intake with severity score was in the direction of benefit, but did not achieve statistical significance.
Comments
At baseline, AREDS 2 participants had good visual function in their study eye(s). The majority had large drusen and/or pigmentary changes in the retinal pigment epithelium, risk factors for progression to advanced AMD. The authors conclude that those with the highest intake of DHA or EPA were significantly less likely than their peers to have higher AMD severity scores.
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Lutein & Vitamin A May Slow Mid-Peripheral Vision Loss in Retinitis Pigmentosa
Lutein and Vitamin A in Retinitis Pigmentosa
Retinitis pigmentosa (RP) causes progressive vision loss to about 1 in 4000 people worldwide. Patients typically report deficient night vision in adolescence, and loss of mid-peripheral and then far peripheral field in adulthood with development of tunnel vision. Central vision is usually lost after age 60.
The previous EduFacts (Vol. 11, No. 1) summarized an investigation that found macular pigment optical density (MPOD) to be independently related to serum lutein in patients with retinitis pigmentosa . Provocative results from a new clinical trial suggest daily supplementation with lutein and vitamin A may help preserve mid-peripheral vision in RP .
Study Design
The objective of this randomized, controlled, double-masked trial was to determine whether lutein supplementation slows visual function decline in patients with RP also receiving vitamin A at a level previously reported by the same investigators to slow the rate of RP progression.
225 non-smoking patients, aged 18 to 60 years, were evaluated over a 4-year interval. Patients received 12 mg of lutein or placebo daily in addition to 15,000 IU/day of vitamin A palmitate. Randomization took into account genetic type and baseline serum lutein level.
The primary outcome was the total point score for the Humphrey Field Analyzer (HFA) 30-2 program. Secondary outcomes were the total point scores for the 60-4 program and for the 30-2 and 60-4 programs combined, 30-Hz electroretinogram (ERG) amplitude, and Early Treatment Diabetic Retinopathy Study acuity.
Results
There was no difference between groups in the rate of loss for the primary outcome measure, or in the secondary outcome measures between groups for rates of loss of the HFA 30-2 plus 60-4 total point score, ERG amplitude, or visual acuity. However, a significant effect of treatment on the rate of loss for the HFA 60-4 total point score (p=.05) was observed. Mean decline with the 60-4 program was slower among those with the highest serum lutein level or with the highest increase in MPOD at follow up (p=.01 and p=.006, respectively). Those with the highest increase in MPOD also had the slowest decline in HFA 30-2 and 60-4 combined field sensitivity (p=.005).
Comments
The researchers conclude that their data support the use of 12 mg / day of lutein to slow visual field loss among nonsmoking adults with RP taking vitamin A. They estimate that, based on the randomized comparison, the benefit in preserving mid-peripheral field sensitivity would be 3 additional years. Based on MPOD observational results, they estimate that the benefit would be 10 additional years. In the latter case, a patient taking vitamin A who begins supplemental lutein at age 40 could expect to lose mid-peripheral field by age 61 compared to age 51 for those not taking lutein according to the authors. Patient follow-up would be needed to confirm these estimates.
In an accompanying editorial , Massof and Fishman point out that this study, as well as 2 previous trials conducted by the same researchers produced no clear-cut results. One trial tested vitamin A, while the other evaluated vitamin A with 1,200 of DHA daily. According to the editorial, while all 3 trials were well designed and executed, they raise 2 issues: 1) the risk of misinterpreting outcomes because of assumptions built into the data analysis, and 2) the question of how much weight should be placed on clinical recommendations that are based on secondary analyses.
Although some might argue that there is no other viable treatment for RP and the conclusions drawn by the investigators are reasonable, the editorial concludes that neither vitamin A with lutein nor with a diet high in omega-3 have been convincingly shown to slow the rate of progression of RP.
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Serum Lutein and Macular Pigment Density in Retinitis Pigmentosa
Lutein Studied in Retinitis Pigmentosa
It has been suggested that increasing macular pigment optical density (MPOD) with lutein supplementation might shield cone photoreceptors from UV-related oxidative damage and possibly slow the rate of cone degeneration over the long term. Previous studies have raised the possibility that lutein may be a potential treatment for retinitis pigmentosa, with one trial showing that supplemental lutein helped preserve visual function .
However it has also been reported that macular pigment optical density (MPOD) is not directly related to serum lutein in patients with retinitis pigmentosa, as it is in healthy individuals. This report led researchers from Harvard Medical School and the USDA Human Nutrition Research Center on Aging at Tufts University to further investigate the relationship between MPOD and serum lutein in retinitis pigmentosa patients . Their findings shed light on what factors influence MPOD in people with this disease.
Study Design
The authors measured MPOD with heterochromatic flicker photometry, serum lutein and serum zeaxanthin by high performance liquid chromatography and central foveal retinal thickness by optical coherence tomography in 176 patients aged 18–68 years with typical forms of retinitis pigmentosa. Thirty seven (21%) of these patients had cystoid macular edema (CME).
The researchers adjusted for potentially confounding variables such as age, sex, iris color, central foveal thickness and, in some analyses, serum total cholesterol.
Results
MPOD increased with increasing serum lutein (P = 0.0017, see figure 4) and decreased with increasing serum total cholesterol (P = 0.0025) but was unrelated to serum zeaxanthin.
MPOD was higher in patients with brown rather than lighter irises (P = 0.014). MPOD was also related to central foveal retinal thickness (P < 0.0001), being lower in eyes with more photoreceptor cell loss and in eyes with moderate to marked CME.
The relationship between MPOD and serum lutein tended to be stronger in men than in women, which is compatible with some previous results in healthy subjects based on measurements of serum lutein.
In summary, this study found MPOD to be independently related to serum lutein, serum total cholesterol, iris color, and central foveal retinal thickness in patients with retinitis pigmentosa.
Comments
The authors offer some possible explanations for a number of their observations. The lack of an association between MPOD and serum zeaxanthin, for example, may be explained by the observations that lutein is more abundant in the diet, and that about half of the zeaxanthin in the center of the fovea is derived from lutein. This raises the possibility that it may be easier to increase macular pigment in the axons of cone photoreceptor in patients with retinitis pigmentosa by focusing on supplemental lutein rather than zeaxanthin.
The inverse relationship between MPOD and serum cholesterol suggests that higher serum cholesterol levels impede transport of lutein into the retina.
Finally, the linear relationship observed between MPOD and central foveal thickness when data from patients with CME were excluded, could mean that moderate to marked edema hinders the uptake of lutein into the macula or distorts the radial arrangement of the foveolar cone axons.
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Serum Levels of Vitamin C & Uric Acid in Normal Tension Glaucoma
Oxidative Stress & Normal Tension Glaucoma
The occurrence of normal-tension glaucoma (NTG) varies worldwide. In the US, up to 15-25% of people with primary open-angle glaucoma (POAG) experience NTG. It is considerably more prevalent in Japan, with NTG comprising more than 70% of glaucoma cases.
In NTG, progressive damage can occur even with intraocular pressure (IOP)-lowering intervention. The cause of optic nerve damage in NTG is not fully understood, but oxidative stress is believed to be one contributing factor. Current evidence, for example, points to the association between oxidative stress and ganglion cell death without elevated IOP. In addition, there are some reports of lower levels of circulating antioxidants such as the major cellular antioxidant glutathione, in POAG patients.
These and other findings led Japanese researchers to examine serum levels of antioxidant vitamins A (beta-carotene), C and E, as well as folic acid and endogenous uric acid in NTG patients.
Beta-carotene and vitamin A are fat soluble antioxidants, while water soluble ascorbic acid and uric acid are strong reducing agents and potent antioxidants. In humans, over half the antioxidant capacity of plasma comes from uric acid, and vitamin C is highly concentrated in the aqueous humor. While not an antioxidant, folic acid insufficiency results in microvascular-damaging levels of homocysteine.
Study Design
Sixty patients with newly diagnosed POAG were consecutively screened for inclusion in this study. After diagnosis of POAG, patients underwent 24-hr IOP measurements, and 47 newly diagnosed consecutive NTG patients (18 males, 29 females; mean age 59.5 years) were enrolled. The control subjects were recruited from subjects who came to the clinic for annual refractive check-up. The 44 consecutive control subjects (16 males, 28 females; mean age 62.7 years) had no ocular diseases.
Serum levels of vitamins A, folic acid, C, E, and uric
acid were measured, and the values compared between the NTG and control groups by the Mann-Whitney U test.
Results
Serum levels of vitamin C were significantly lower in NTG patients than in normal healthy controls (P=0.04; NTG 4.6±4.0 μg/ml, and control 6.3±3.9 μg/ml).
Uric acid concentrations were significantly higher in NTG patients compared to controls (P=0.01; NTG 5.8±1.5 mg/dl, and control 4.9±1.4 mg/dl).
No statistically significant differences were observed in the other vitamins measured.
Comments
The results of this study indicate that uric acid levels were increased and vitamin C levels were decreased in NTG patients. The authors speculate that higher serum uric acid and lower serum vitamin C may change the trabecular meshwork physiology. In turn, this may decrease the outflow facility of aqueous humor, causing eventual IOP elevation and glaucomatous optic neuropathy.
The diurnal IOP of the NTG patients in this study was under 21 mmHg, yet significantly higher than that of the normal controls (P=0.001). According to the authors, low vitamin C levels may cause modest IOP elevation and optic neuropathy even in NTG patients.
Vitamin C is thought to play an important role in reducing reactive oxygen species in the trabecular meshwork. Recent studies suggest that oxidative stress accelerates trabecular meshwork cell death. Further, in vitro studies indicate that interactions between uric acid and vitamin C can change the viscosity of some glycosaminoglycans, which are found in the trabecular meshwork.
The authors call for placebo-controlled trials to investigate the effects of vitamin C on IOP and visual field change in patients with NTG.
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Procyanidins Benefit Microcirculation in Early Retinopathy
Diabetic Retinopathy Expected to Increase
In the next 25 years, the number of Americans living with diabetes will nearly double, increasing from 23.7 million in 2009 to 44.1 million in 2034. Over the same period, spending on diabetes will almost triple, rising from $113 billion to $336 billion, even with no increase in the prevalence of obesity, researchers at the University of Chicago reported in the December, 2009 issue of Diabetes Care.
Those projections portend an increase in the prevalence of diabetic complications as well, including retinopathy. In addition, between 40 and 50% of Americans diagnosed with diabetes already have some stage of diabetic retinopathy, according to the National Institutes of Health.
Procyanidins Studied in Retinopathy
Pine bark extract, a source of dietary procyanidins, has previously been shown to improve objective parameters such as vascular permeability in patients with retinopathies associated with diabetes. [See: Review in EduFacts Vol. 9 No 6]. A new study now reports that pine bark extract may extend vision-saving benefits to diabetics with early stage retinopathy by improving retinal blood flow and inducing regression of edema .
Study Design
Men and women with well-controlled type 2 diabetes for at least four years were recruited into this double-blind, randomized trial. The patients, who had early stages of retinopathy, characterized by mild to moderate retinal edema without hemorrhages or hard exudates in the macula center, received 150 mg of pine bark extract (Pycnogenol®) or placebo daily for three months.
Patients’ visual acuity was assessed using the standard Snellen Chart. Evaluation of diabetic retinopathy was carried out by ophthalmoscopy following pupil dilation, and retinal blood flow was quantitatively evaluated by color duplex scanning. Retinal thickness was determined using high resolution ultra-sound.
Results
Retinal edema score and retinal thickness showed statistically significant improvement as compared to placebo, which showed negligible changes from baseline. Laser Doppler flow velocity measurements at the central retinal artery showed a statistically significant increase from 34 to 44 cm/s in the treatment group as compared to marginal effects in controls. Testing of visual acuity showed significant improvement from baseline (14/20 to 17/20), whereas no change was found in the control group.
Comments
The major finding of this study is the reported visual improvement, which was subjectively perceived in 75% of treated patients. According to the lead researcher, the findings suggest that pine bark extract taken in the early stages of retinopathy may enhance retinal blood circulation accompanied by a regression of edema to favorably affect vision.
Steigerwalt R, et al. Pycnogenol® improves microcirculation, retinal edema, and visual acuity in early diabetic retinopathy. J Ocular Pharmacol Therap 25:537-40, 2009.
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Review: Lutein & Zeaxanthin Metabolism
Metabolism is Key to Lutein’s Protective Role
Growing evidence suggests lutein and zeaxanthin play an important role in protection against AMD by filtering out blue light or quenching free radicals. While much remains to be learned, researchers from Waterford Institute and Regional Hospital in Ireland and the University of Utah’s Moran Eye Center have reviewed mechanisms involved in absorption and transport of these carotenoids, their uptake by the retina and how they are stabilized . Below are highlights of these findings, along with editorial comment on implications for diet, lifestyle and supplement use.
Absorption of Lutein and Zeaxanthin
Dietary fat is important for the absorption of xanthophyll carotenoids like lutein and zeaxanthin. Fat stimulates bile flow from the gall bladder to emulsify fat-soluble vitamins into lipid micelles – microscopic fat droplets – so they can be absorbed in the small intestine. Inadequate fat intake can result in reduced absorption of carotenoids, even if the diet is carotenoid-rich. Experimental data suggest absorption of lutein is mediated by a non-specific transporter protein (this protein, scavenger receptor class B type I, appears to play a primary role in intestinal absorption, but other proteins or passive diffusion may also be involved). Of note, some competition for absorption is seen when similarly structured carotenoids like beta-carotene and lutein are consumed together.
Comments: Though different carotenoids compete for absorption, some evidence suggests that balanced amounts of various carotenoids consumed together over time don’t interfere with each other in terms of bioavailability . Importantly, doses of lutein (10 mg) and zeaxanthin (2 mg) now being used in the AREDS 2 trial, did not reduce serum levels of other important carotenoids in a dosing study .
Transport of Lutein and Zeaxanthin
Dietary lutein and zeaxanthin are delivered to the retina via plasma lipoproteins, chiefly LDL and HDL cholesterol. While LDL is the primary carrier for most carotenoids, LDL and HDL carry about equal amounts of lutein and zeaxanthin. Several studies suggest relatively low HDL levels could hinder transport and capture of these carotenoids. Lower HDL levels have been found in overweight and obese individuals, for example, and higher body fat percentage is linked to risk of AMD progression as well as to lower macular pigment density. Lipoproteins also include protein components known as apolipoproteins. Researchers are investigating whether a person’s apolipoprotein profile might influence transport and delivery of these carotenoids to the retina. Of many apolipoproteins types, ApoE has the strongest link with AMD.
Comments: Lower levels of HDL have been found in overweight individuals, consistent with the possibility that a relative lack of HDL may impair transport and/or retinal capture of the carotenoids. Obesity has been identified as a risk factor for AMD. Take home message? Aerobic exercise, which aids weight loss and increases HDL, may prove useful in lowering AMD risk.
Retinal Uptake of the Xanthophyll Carotenoids
The mechanisms governing retinal capture and accumulation of lutein and zeaxanthin to the exclusion of other carotenoids are still poorly understood. However, retinal capture of xanthophyll carotenoids is performed by xanthophyll-binding proteins (XBP). XBPs may also be involved in: a) stabilizing xanthophylls in cell membranes, the cytosol or the cytoskeleton, b) mediating inter-conversion of lutein, zeaxanthin and various metabolites within the retina, and c) facilitating antioxidant activity of macular carotenoids. Importantly, it has been found that XBPs can become saturated, with implications for xanthophyll carotenoid supplementation.
Comments: Macular pigment density often increases dramatically in the first 4 weeks of supplementation, and then levels off. In a number of studies testing 10-12 mg of lutein, macular pigment density reached a plateau after the first month. This may be due to saturation of binding proteins, and suggests higher doses may not further enhance macular pigment over time.
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Strategies to Prevent AMD Urgently Needed
Age-related macular degeneration (AMD) is a major cause of irreversible vision loss among people of Western European ancestry. It’s estimated that 3.35 million Europeans and 1.75 million Americans are living with sight-threatening AMD. Over the next 20 years these numbers are expected to increase by 50% if preventive interventions aren’t identified. Finding low cost ways to prevent progression to advanced AMD is particularly important since treatments for wet AMD are limited in scope, invasive, costly and may result in complications as severe as end-stage disease.
National Eye Institute researchers have examined whether omega-3 intake is associated with a reduced likelihood of developing central geographic atrophy and neovascular AMD in a cohort within AREDS – a multicenter clinical trial, which ran from 1992 to 2005. The investigators report that participants with the highest omega-3 intake were 30% less likely than their peers to develop dry or wet AMD.
Study Design
The research team looked at a sub-group of 1,837 AREDS participants considered to be at moderate-to-high risk of advanced AMD. Baseline data of omega-3 intake was obtained using a validated food-frequency questionnaire. Trained fundus graders ascertained AMD status from annual stereoscopic color photos by using standardized methods at a single reading center across a 12-year period.
Results
Nearly 20% of participants progressed to dry AMD, and about 32% progressed to wet AMD over the 12-year period. Those in the highest quintile of combined EPA and DHA intake were 30% less likely to develop dry and wet AMD than their peers in the lowest intake quintile. Median intake in the highest quintile was 11% of total calories, based on 2000 kcal daily.
Comments
“If these results are generalizable, they may guide the development of low-cost and easily implemented preventive interventions for progression to advanced AMD”, according to the researchers led by John Paul SanGiovanni. A 4000-person, 5-year randomized clinical trial designed to test the efficacy of omega-3 for this purpose is now underway (www.areds2.org). The omega-3 fatty acids may work by multiple mechanisms. For example, AMD appears to have an inflammatory etiology, and the omega-3s have the capacity to affect pathologic inflammatory processes in the retina.
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GLA and EPA Have Complementary Actions
The fatty acids gamma-linolenic acid (GLA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) affect cellular processes involved in inflammation, including the production of eicosanoids. Prostaglandins are the major eicosanoids that are produced from specific fatty acids during inflammation:
It’s well known that inflammation plays a role in ocular surface dryness. Most dietary supplements investigated in dry eye have tested GLA or EPA and DHA. However, combining these fatty acids may optimize their ability to modulate inflammation.
Human studies, for example, have demonstrated that the addition of EPA and DHA in a balanced ratio to GLA prevents elevations in serum arachidonic acid , thus leading to decreased levels of pro-inflammatory prostaglandin. A combination of omega-3 and omega-6 fatty acids also results in lower arachidonic acid in the retinas and exorbital lacrimal glands in animals . A recently published study lends credence to the idea that a GLA, EPA and DHA combination may provide advantages to supplementation with fatty acids from either the omega-3 or omega-6 family alone.
Study Design and Methods
Female Lewis rats were fed diets containing 1) GLA; 2) EPA and DHA; or 3) a combination of GLA, EPA and DHA for 2 months before the induction of dry eye using a continuous delivery of scopolamine, and during scopolamine treatment. Two, 10 and 28 days after dry eye-induction, clinical signs of corneal dryness were evaluated in vivo using fluorescein staining. Major histocompatibility complex Class II (MHC-II) expression and mucin (rMuc5AC) production in the conjunctival epithelium were evaluated by immuno-staining. Lipids and prostaglandins were analyzed from the exorbital lacrimal gland.
Results
Dietary supplementation of omega-6 (GLA) and/or omega-3 fatty acids (EPA and DHA) improved the clinical signs of dry eye, although at a moderate level. All three of the fatty acid enriched diets minimized the occurrence of corneal keratitis after 28 days of treatments, and all the diets partially prevented a decrease in mucin.
The combined omega-6 and omega-3 diet, however, led to a lower arachidonic acid content in phospholipids (where fatty acids are stored), and a higher dGLA content when compared to the GLA-only enriched diet. Further, the over-expression of MHC II in the conjunctival epithelium caused by dry eye induction was significantly reduced only with the GLA + EPA + DHA diet after 28 days of treatment.
Comments
According to the study authors, these results point out the efficacy of combining omega-3 with omega-6 GLA. GLA, dGLA, EPA and DHA have all been described as decreasing inflammation by reducing the expression of MHC II and inhibiting the production of inflammatory cytokines such as TNF-α and IL-1β. In this study, only the combined fatty acids reduced MHC II expression.
These findings are in agreement with those from a pilot clinical trial conducted by the same researchers . In this trial, 3-month treatment with combined GLA, EPA and DHA demonstrated improved symptoms, and suggested a beneficial effect on the clinical signs of ocular dryness. The authors state that GLA with EPA and DHA may be useful in a dry eye therapy strategy along with classical therapy such as artificial tears.
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Is CVD a Major Risk Factor for AMD?
That very question was addressed in an editorial appearing in the September issue of the American Journal of Ophthalmology, and the evidence to date suggests that CVD is an important risk factor for AMD. Epidemiologic studies conducted over the past two decades indicate (with the possible exception of diabetes) that all of the traditional cardiovascular risk factors such as smoking, hypertension, elevated cholesterol levels, and higher body mass index (BMI) are associated with AMD risk.
So far, the link between smoking, hypertension and AMD is stronger than that between cholesterol, BMI and AMD, while newer studies suggest that less traditional markers of CVD such as inflammation and endothelial dysfunction are also involved in AMD pathogenesis. Overall, there is good evidence that AMD and CVD share similar risk factors and mechanisms that underlie disease development, according to the editorial.
Are AMD Patients at Greater Risk for CVD?
Conversely, emerging data indicates that the presence of AMD also signals an increased risk of CVD, independent of the effects of age and shared risk factors. “Taken in totality, these newer data suggest that patients with signs of AMD, particularly younger patients, may be at increased risk of CVD”, the editorial concludes.
Newly published findings from The Cardiovascular Health Study provide further support that AMD is associated with underlying systemic vascular disease.
Study Design and Methods
The Cardiovascular Health Study is a population-based prospective cohort study of CVD in adults 65 years of age and older. To examine the associations of AMD with incident coronary heart disease (CHD), AMD was evaluated by fundus photographs in 1,786 white and Afro-American participants free of CHD or 2,228 participants free of stroke, aged 69-97 years.
Early AMD was defined as the presence of soft drusen alone, retinal pigment epithelium (RPE) depigmentation alone, or a combination of soft drusen with increased retinal pigment or RPE depigmentation in the absence of late AMD. Late AMD was defined as the presence of signs of exudative AMD or pure geographic atrophy.Incident CHD and stroke were ascertained using standardized methods. Participants underwent a
standardized assessment of cardiovascular risk factors, including examiner-administered questionnaires,
Results
Of the 1786 persons free of CHD, 303 developed incident CHD over 7 years. The 277 participants with early AMD had a higher cumulative incidence of CHD than participants without early AMD (25.8% vs. 18.9%,
P = 0.001).
The presence of early AMD was associated with a 57% increased risk of CHD, after adjusting for age, gender, race, systolic and diastolic blood pressure, hypertension status, fasting glucose, triglyceride, low-density lipoprotein cholesterol, cigarette smoking, pack years of smoking, and C-reactive protein. Late AMD (n= 25) was not associated with incident CHD. Among 2228 persons at risk, 198 developed incident stroke; neither early nor late AMD was associated with incident stroke.
Comments
The findings suggest that early AMD raises the risk of CHD, though not stroke. According to the authors, the association may be explained by broad underlying pathogenic mechanisms shared with both conditions. For example, atherosclerosis may represent a pathogenic process in AMD development, based on its effects upon the choroid capillaries and extracellular drusen (lipid) deposits. Inflammatory mechanisms seem to be another plausible biological basis that may involve both coronary and retinal circulation.
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Omega-3s Slow AMD in Animal Model
It is known that omega-3 fatty acids, particularly DHA, play an important role in the layer of nerve cells in the retina, and studies have already reported that omega-3 may protect against the onset of AMD. A meta-analysis, for example, reported in the June, 2008 issue of the Archives of Ophthalmology found that a high intake of omega-3s and fish may reduce the risk of AMD by up to 38%. The Australian authors of this review noted that the benefits of omega-3 were most pronounced against more advanced AMD, while twice weekly fish consumption was associated with a lower risk of both early and late AMD .
In line with the epidemiologic data, are the results of a new National Eye Institute study which found that omega-3 fatty acids could retard the progression of lesions in a murine mouse model of AMD . Even more intriguing are the findings that mice in the high omega-3 group displayed some reversion of the lesions.
Study Design and Methods
The study evaluated the effects of a high omega-3 diet on the retinas of Cc12 - / - / Cx3cr1- / - mice - a model that develops AMD-like retinal lesions that include focal deep retinal lesions, abnormal retinal pigment epithelium, photoreceptor degeneration, and accumulation of A2E, a component of human retinal lipofuscin (an aging pigment and likely product of lipid peroxidation).
The mice were raised on low or high omega-3 diets, and clinical endpoints were measured using fundus photography, histopathology, transmission electron microscopy, A2E extraction and enzyme-linked immunoabsorbant assay to evaluate serum prostaglandin levels.
Results
Mice that were fed the high omega-3
diet showed a slower progression of lesions compared to the low
omega-3
fed mice. Some mice ingesting the high omega-3
diet exhibited regression of lesions. No retinal lesions were
noted in the normal wild mice used as controls and fed a regular
diet.
Compared to the low omega-3 group, mice consuming the omega-3 enriched diet had lower levels of inflammatory molecules such as prostaglandin E2 and leukotriene B4, and higher levels of anti-inflammatory mediators such as prostaglandin D2. Higher omega-3 also resulted in lower IL-6 transcript levels and concentrations of ocular TNF-alpha, an inflammatory cytokine.
Comments
In summary, a diet enriched in EPA and DHA ameliorated the progression of retinal lesions in this useful animal model of AMD. These results are supportive of the findings from population health studies, and await further confirmation in humans by the AREDS 2 trial in progress.
EPA and DHA are concentrated in the retina and retinal vascular endothelium, and DHA accounts for about 50% of the lipids in photoreceptor rod outer segments. Vital retinal functions, including damage repair, depend on the existence of adequate levels of DHA.
In the eye, the omega-3 fatty acids and their derivatives play an extensive role in many biologic processes such as the inflammatory cascade, apoptosis and neuroprotection. In this study, the researchers focused on the function of the omega-3s in inflammation, since the role of inflammation in the pathogenesis of AMD is evident. Arachidonic acid, an omega-6 fatty acid, is the starting material for the synthesis of pro-inflammatory mediators such as various cytokines. When fish oil is provided, EPA and DHA are incorporated into cellular membranes at the expense of arachidonic acid.
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Prioritizing Preventable Causes of US Deaths
Modifiable risk factors responsible for many premature or preventable deaths fall into three main categories: Lifestyle factors such as smoking and physical inactivity; Dietary risk factors such as a high salt intake and a low intake of fruits and vegetables; And "metabolic" risk factors, such as obesity and hypertension, which shorten life expectancy by increasing the odds of developing CVD and diabetes.
With health care costs skyrocketing, it's important to know how many deaths are caused by each risk factor before developing policies and programs to improve the nation's health. Although previous studies have provided some information, they have not used consistent and comparable methods to estimate the number of deaths attributable to different risk factors. In addition, previous studies have rarely considered dietary and metabolic risk factors.
In a new study, jointly funded by the CDC and the Association of Schools of Public Health, Harvard researchers estimated the number of deaths due to 12 different modifiable risk factors.
Study Methods and Findings
The researchers used a method called "comparative risk assessment." They retrieved data on exposures to the 12 selected risk factors from US national health surveys, and obtained information on deaths from different diseases from the US National Health Center for Health Statistics. They also used previously published studies to estimate how much each risk factor increased the risk from a disease, and applied a mathematical model to estimate the number of deaths related to each factor.
Smoking and high blood pressure, which both have effective interventions, are responsible for the largest number of preventable deaths, followed by obesity, physical inactivity and high salt intake. Notably, 84,000 deaths were attributable to insufficient omega-3 intake, slightly higher than high trans fatty acid intake (82,000).
  |
Comment
Though the study focused upon the most common
causes of death such as cancer, heart disease and respiratory
diseases, the findings that inadequate consumption of omega-3,
and fruits and vegetables are important risk factors may be notable
for visual health as well. EPA
and DHA
(from fish), as well as lutein
and zeaxanthin
(from produce), have been strongly linked to the risk of AMD and,
possibly, other ocular conditions. The typical intake of EPA
and DHA
for example is 100-200 mg daily, while the AREDS-2 trial is testing
1,000 mg. In addition, 10 mg of lutein
and 2 mg of zeaxanthin
are being employed in AREDS-2, while the average daily consumption
of these carotenoids is 2 mg.
Danaei G, et al. The Preventable Causes of Death in the United States: Comparative Risk Assessment of Dietary, Lifestyle, and Metabolic Risk Factors. PLoS Med 6(4): e1000058.
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Can Too Many Steaks Shorten Life, Hasten AMD?
A preponderance of observational data indicates that too much red meat is a risk factor for heart disease and cancer. The results of two new prospective studies support that idea, and suggest that excessive intake might impact visual health as well.
The first study, published in the Archives of Internal Medicine, reports that eating red and processed meat is associated with modest increases in total mortality, cancer mortality, and cardiovascular mortality rates . Red meat consumption was also positively linked with early AMD in another paper appearing in the American Journal of Epidemiology .
First Study Summary
The National Institutes of Health's AARP Diet and Health Study enrolled about half a million people aged 51-71, estimated their intake of meat using a food frequency questionnaire, and used Cox regression models to determine hazard ratios and confidence intervals within quintiles of meat intake. Red meat included all types of beef and pork, the white meat category included poultry and fish, and processed meat category contained both red and white meat in the form of cold cuts, hot dogs, bacon and sausage.
After 10 years of follow-up, red and processed meat raised the risk of CVD, cancer and total mortality in both men and women in the highest quintile of intake. In contrast, those with the highest white meat intake (and a lower red and processed meat diet) had a decreased risk in both total and cancer mortality.
Second Study Summary
To help clarify the role of red meat intake in AMD, approximately 5600 subjects aged 58-69 took part in the Melbourne Collaborative Cohort Study. The presence of AMD was determined by non-mydriatic retinal photography. There were 1680 cases of AMD, defined as the presence of drusen 63 µm or larger, with or without the presence of hyper / hypo-pigmentation. Cases of late AMD, indicated by the presence of choroidal neovascularization or geographic atrophy, numbered 77. Compared with eating red meat less than 4.5 times weekly, downing it 10 or more times a week raised the odds of having early AMD by 47%. Intake of chicken was not related to early AMD, but eating it at least 3.5 times weekly lowered the risk of late AMD.
While confirmatory data are needed, a high level of red meat consumption may be a novel risk factor for early AMD, according to the study's authors. They point out that high meat intake is associated with higher levels of N-nitroso compounds, heme iron, and advanced glycation end products, which could result in oxidative damage and ultimately be toxic to the retina.
The Clinician's Role as Public Health Advocate
An editorial accompanying the first study notes that too few clinicians speak out about the importance of dietary moderation. One useful tool to engage patients in healthful eating is the 2009 Mediterranean Diet Pyramid. Endorsed by the WHO and the Harvard School of Public Health, the Mediterranean style of eating is also a lower glycemic diet - a factor that may also be protective of retinal health .
Note: A colorful, 2009 updated poster of the Mediterranean Pyramid for display in medical practices is available from www.oldwayspt.org
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Preventive Steps May Lower AMD Costs
Preventing Age-Related Macular Degeneration (AMD) and delaying its progression would best preserve people's quality of life while containing health care system costs. The results from two new analyses suggest that adopting dietary habits or using supplements that slow progression from early to late stages, could ease the future burden of this disease.
Combined Dietary Factors Reduce AMD Risk
Foods provide many nutrients that may interact to modify the risk for AMD. Therefore, instead of looking at isolated nutrients, researchers from Tufts University developed a composite scoring system to examine the combined effect of dietary nutrients on AMD risk.
Study Design and Results
Data was analyzed for 4,003 Age-Related Eye Disease Study (AREDS) participants, involving 7,934 eyes. Levels of AMD-protective nutrients, including vitamins C and E, zinc, lutein, zeaxanthin, omega-3 fatty acids (DHA and EPA), as well as low-GI (Glycemic Index) foods, were assessed using participants' food intake reports. Each dietary factor was assigned a percentile score, and factor scores were added up to find each participant's compound score. Compound scores were related to participants' AMD risk, based on stereoscopic fundus photographs of the macula taken when they joined AREDS.
Participants whose diets included higher levels of these protective nutrients and of low-GI foods were at substantially lower risk for early and advanced AMD. Validation analyses showed the relationships to be robust.
Conclusion and Comments
The results suggest that the compound score summarizing the overall effect of diets rich in the AREDS trial nutrients (vitamin C, vitamin E, and zinc), the AREDS 2 trial nutrients (DHA, EPA, lutein and zeaxanthin), and low-GI foods are independently associated with lower risk for prevalent drusen and advanced AMD. Beta-carotene did not affect risk levels. The findings are in accord with earlier research linking low GI-diets with reduced risk of AMD and cataract, and further research is warranted.
New Therapies May Mitigate Rise in AMD
The Vision Health Cost-Effectiveness Study Group - encompassing investigators from the CDC, the National Center for Chronic Disease and Prevention and other institutions - report that while the prevalence of AMD will increase substantially by 2050, the use of new therapies can mitigate its effects.
Study Design and Results
The study simulated cases of early AMD, choroidal neovascularization (CNV), geographic atrophy (GA), and AMD-attributable visual impairment and blindness with five possible scenarios:
 | (1) No treatment; (2) Focal laser and photodynamic therapy (PDT) for CNV; (3) Vitamin prophylaxis at early-AMD incidence with focal laser/PDT for CNV; (4) No vitamin prophylaxis followed by focal laser treatment for extra and juxtafoveal CNV and anti-vascular endothelial growth factor treatment; (5) Vitamin prophylaxis at early-AMD incidence followed by CNV treatment, as in scenario. |
Cases of early AMD nearly doubled, increasing from 9.1 million in 2010 to 17.8 million in 2050 across all scenarios. In non-vitamin-receiving scenarios, cases of CNV and GA increased from 1.7 million in 2010 to 3.8 million in 2050 (25% lower in vitamin-receiving scenarios). Cases of visual impairment and blindness increased from 620,000 in 2010 to 1.6 million in 2050 when given no treatment and were 2%, 22%, 17%, and 35% lower in scenarios 2, 3, 4, and 5, respectively (see Figure 2E).
Figure 2E
Number of Americans with pre-vision-threatening age-related macular degeneration (AMD) and blindness, with 5 alternative treatment scenarios from 2010 to 2050. Scenario 1 indicates no treatment (baseline); scenario 2, focal laser or photodynamic therapy (PDT) for CNV; scenario 3, universal vitamin prophylaxis at early AMD incidence with focal laser or PDT for CNV treatment; scenario 4, no vitamin prophylaxis followed by focal laser treatment for extrafoveal and juxtafoveal CNV and anti-vascular endothelial growth factor (anti-VEGF) treatments for subfoveal CNV for 2 years followed by PDT; scenario 5, universal vitamin prophylaxis followed by focal laser and anti-VEGF treatments for subfoveal CNV for 2 years followed by PDT.
Conclusion and Comments
The authors found that use of vitamins and existing therapies could reduce AMD by as much as 35%, translating to 565,000 fewer cases of visual impairment and blindness in 2050.
A 23% reduction in cases of visual impairment and blindness could be achieved using only vitamin prophylaxis in conjunction with focal laser and PDT therapies for patients who develop CNV - which amounts to a reduction of 375,000 cases of visual impairment and blindness five decades from now.
According to the authors, additional efforts to expand the use of AREDS level dietary supplements Is a cost-effective method of delaying AMD progression and cost-effective use of health care resources. However, research indicates it is not widely used among patients with early-stage disease and the correct dosage is seldom used. For example, though 68% of patients with early AMD who visited a retinal specialty practice in Edmonton, Canada, took some form of AREDS-recommended antioxidant supplement, no patients were taking the correct dosage of all 4 recommended vitamins. Public prevention efforts should focus on expanding the use of antioxidant vitamins in people with early AMD, and ensuring that these patients use the correct dosage.
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Dry Eye Common in Contact Lens Wearers
Contact lens wearers commonly report a sensation of 'dryness' - a symptom that often results in reduced wear time or discontinued use. In most cases of contact lens-induced dry eye, objective signs are lacking and a diagnosis is based on symptoms alone. However, it has been demonstrated that intolerant contact lens wearers show significantly reduced tear stability and volume compared to successful wearers.
A variety of conventional strategies have been employed to alleviate contact lens-induced dry eye including use of artificial tears, changing lens parameters, or preserving tears with punctal plugs. However, novel treatment strategies using anti-inflammatory or immune modulating agents may also be effective. A recent pilot study, for example, offers evidence that cyclosporine may be beneficial in contact lens intolerant patients .
Oral GLA of Benefit in Inflammatory Dry Eye
Another more 'natural' approach involves the use of supplemental gamma-linolenic acid (GLA), an omega-6 fatty acid with anti-inflammatory properties found in oils derived from black currant seeds and the evening primrose plant. Several small trials testing GLA and linoleic (LA) oil in dry eye syndrome with an inflammatory component report reduced ocular surface inflammation and symptom improvement . These beneficial findings led researchers to examine the effects of GLA in contact-related dry eye patients .
Study Design and Methods
In this randomized, double-blind controlled trial, 76 female soft contact lens wearers with documented dry eye or borderline dry eye (McMonnies score =10), were treated for 6 months with GLA (300 mg daily) from evening primrose oil (EPO) or placebo (olive oil).
Participants were examined at 3 time points: baseline and at 3 and 6 months. At each exam, subjects answered a questionnaire relating to lens comfort and dry eye symptoms, and underwent a series of tests of tear film characteristics (tear meniscus height, break-up time), meibomian gland function (lipid layer thickness and quality), and ocular surface parameters (hyperaemia and staining).
Results
The GLA group showed a significant improvement in the specific symptom of 'dryness' at 3 and 6 months (p <0.01) as well as significant improvement in overall lens comfort at 6 months (p<0.01). Tear meniscus height was increased in the GLA group at 6 months relative to baseline (p<0.01), although all other objective signs were unchanged (See figures 2 and 4).
Comments
This study provides evidence for a beneficial effect of oral GLA in alleviating symptoms and improving overall lens comfort in patients suffering from contact lens associated dry eye. According to the authors, this may be via a reduction in ocular surface inflammation that has been previously documented in contact lens wearers. An effect on tear secretion could also be a contributing factor. The authors indicate that "future studies will investigate the efficacy of a combined preparation (GLA, EPA and DHA), since it is likely that omega-3 fatty acids could act synergistically with omega-6 to enhance the therapeutic effect of each fatty acid".
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Alcohol, Omega-3 Fats, and Heart Health
The heart benefits of the traditional Mediterranean diet high in fish, fresh produce and red wine, have been well documented. A new study, part of the European IMMIDIET project, has shed new light on one of red wine's positive cardiovascular benefits.
The aim of the IMMIDIET project, funded by the European Union's initiative on food nutrition and health, is to examine the role of genetic and lifestyle factors in CVD prevention in Italians living at home, as wells as Italian immigrants to other countries.
High dietary and plasma concentrations of the marine fatty acids EPA and DHA are known to be protective against coronary heart disease (CHD) and sudden cardiac death. Alcohol, too, lowers the risk of ischemic stroke and CHD via a number of proposed pathways: increasing HDL, decreasing platelet aggregation and coagulation factors and exerting beneficial effects on endothelial function and inflammation.
Evidence also suggests that alcohol influences fatty acid metabolism. Low alcohol intake appears to increase long-chain fatty acid concentrations, while high alcohol decreases their concentration. Alcohol-induced increases in marine fatty acids might be a unique cardio-protective mechanism of alcohol.
In IMMIDIET, the researchers examined whether the heart benefits of alcohol extend to healthy men and women as well as male patients with cardiovascular disease as was shown in a previous study, the Lyon Diet Heart Study. They also examined whether various alcoholic beverages might affect marine lipid concentrations differently.
Study Design and Methods
In the framework of IMMIDIET, 1,604 men and women aged 26-65 years were enrolled in Italy, Belgium and England. A food frequency questionnaire was used to evaluate dietary and beverage intake. Blood samples were obtained, and plasma and red blood cell omega-3 fatty acids were assessed by gas chromatography.
Results
In fully adjusted multivariate analyses, alcohol intake In fully adjusted multivariate analyses, alcohol intake was positively associated with plasma EPA, DHA and EPA + DHA concentrations (p < 0.0001, p < 0.036 and p < 0.002 respectively) in women. EPA and EPA + DHA index in red blood cells were also positively associated with alcohol intake in females (p < 0.0001 and p < 0.037 respectively). In men, only plasma and red blood cell EPA concentrations were linked with intake of alcohol (p < 0.003 and p < 0.004 respectively).
In wine drinkers, stratified analyses revealed a statistically significant positive association between alcohol intake and both plasma and red cell EPA, DHA and the EPA + DHA index. In contrast, no association was found in those who drink beer and spirits.
Comments
This study examined three different populations with different dietary habits who consumed different types of alcoholic beverages. Analyses carried out on different beverages showed that the link between alcohol and omega-3 fatty acids was present in both wine drinkers and beer or spirits drinkers. However, adjusting for alcohol content of alcoholic beverages abolished the association with omega-3s in beer or spirits drinkers, while the associations with EPA and DHA were maintained or strengthened in wine drinkers.
These findings suggest that components in wine other than alcohol may be responsible for the higher omega-3 concentrations observed. The study authors propose that the polyphenol antioxidant components of wine may stimulate the synthesis of EPA and DHA from the precursor alpha-linolenic acid. Polyphenols may also be involved in that process by preventing alcohol-induced oxidation of long chain fatty acids, thus delaying their breakdown.
de Giuseppe R, et al. Alcohol consumption and n-3 polyunsaturated fatty acids in healthy men and women from 3 European populations. Am J Clin Nutr 89:354-62, 2009.
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Diabetes Prevalence is Increasing
Twenty four million Americans - or 8% of the population and nearly 25% of those 60 and older - currently suffer from diabetes according to 2007 prevalence data from the Centers for Disease Control (CDC). The 2007 figure is 3 million higher than 2005 prevalence data. The CDC reported that an additional 57 million had pre-diabetes, a condition that most often precedes a diagnosis of diabetes.
Diabetes can lead to damage of several different tissues, particularly those that are insulin insensitive such as the retina, kidney and nerves. Type 2 diabetes is most common, accounting for 90-95% of all diabetic patients. Both forms cause long-term complications such as neuropathy, nephropathy, cataract and retinopathy. Up to 21% of patients with type 2 diabetes have some signs of retinopathy at time of first diagnosis, and most will develop some degree of retinopathy over time.
The potential role of Pycnogenol (pine bark extract) in the treatment of type 2 diabetes is discussed in a 2008 systematic review from the Ophthalmic Research Group at Aston University in Birmingham England.
Mechanism of Action of Pine Bark Extract
Pycnogenol is the brand name for a standardized extract of bark of the French maritime pine (Pinus pinaster). It contains bioactive procyanidins as does generic standardized pine bark extract. Pine bark extract (hereafter referred to as "Pycnogenol") has been shown to protect endothelial cells against oxidant-induced injury. Pycnogenol promotes a protective antioxidant state by up-regulating important enzymatic and non-enzymatic oxidant scavenging systems. It is a potent natural antioxidant and also has an affinity for proteins such as collagen, which may be responsible for the reduction of pathologically increased capillary permeability observed.
Pycnogenol significantly decreases nitrogen monoxide generation and it is thought that this function may result from a combination of several biological activities including its radical oxygen species and nitrogen monoxide scavenging activity, inhibition of the enzyme nitric oxide syntase (iNOS), and inhibition of iNOS-mRNA expression. Pycnogenol can readily cross the blood-brain barrier to provide antioxidant protection to central nervous system tissue. It is also reported to possess anti-inflammatory action.
Highlighted Clinical Studies
Supplementation of conventional diabetes treatment with 100 mg day) Pycnogenol for 12 weeks has been shown to lower glucose levels, and improve endothelial function (Liu et al., 2004). Glycosylated hemoglobin levels were significantly reduced after 1 month of supplementation. Plasma concentrations of the prostacyclin metabolite, 6-ketoprostaglandin F1, were elevated in both treatment groups, and considerably more pronounced in the Pycnogenol group (p < 0.001).
Pycnogenol is licensed in France for the treatment of diabetic retinopathy. In one investigation, a 6-month double-masked trial of Pycnogenol versus Dexium 500 (calcium dobesilate) was carried out with type 1 and 2 diabetic participants. The pharmacology of Dexium is similar to that of Pycnogenol except that it does not have such a high binding affinity for collagen. Pycnogenol was found to reduce exudates in the eyes of significantly more participants than Dexium. The authors concluded that Pycnogenol might also be beneficial for improvement of visual field loss (Leydhecker, 1986).
Another double-masked, placebo-controlled trial investigated the effect of 150 mg day of Pycnogenol on objective parameters in patients with retinopathies associated with diabetes, atherosclerosis and hypertension (Spadea, 2001). Examination of the ocular fundus showed a significant improvement in those treated with Pycnogenol, as well as improvements in electrophysiology and fluoroangiography measures. The group taking Pycnogenol also experienced a significant reduction in vascular permeability and an improvement in the blood-retinal barrier.
Finally, in a very recent double-blind study of hypertensive type 2 diabetics taking ACE inhibitors, 125 mg of Pycnogenol for 12 weeks was reported to decrease use of ACE inhibitors by 50%. Fifty eight percent achieved blood pressure control, and LDL levels and fasting blood glucose levels were improved vs. placebo.
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Retina is Vulnerable to Effects of Blue Light
While wavelengths in the UV radiation range are largely absorbed by the cornea and lens, the retina is exposed to visible light, including blue light. Animal and laboratory studies have shown that blue light damages the retinal pigment epithelium and choriocapillaris through generation of reactive oxygen species and may be a factor in the pathogenesis of age related macular degeneration (AMD).
Protection against the harmful effects of blue light is provided by the retinal antioxidant defense system, which includes antioxidant enzymes supported by vitamins C and E, lutein and zeaxanthin, and zinc. Lutein and zeaxanthin are highly concentrated in the macula, where they act as scavengers of reactive oxygen species and filter blue light.
Only a few studies have investigated associations of sunlight exposure with AMD in human populations, and the results have been inconsistent. Up to now, however, studies have paid little attention to possible interactions between antioxidant levels and light exposure, though the adverse effects of sunlight may be attenuated by the protective effects of antioxidants.
Now, the European Eye (EUREYE) Study has examined the association of sunlight exposure and antioxidant levels with AMD. The study was designed to maximize a diversity of sunlight exposure and antioxidant levels by selecting study centers throughout Europe.
Study Design and Methods
Four thousand seven hundred fifty-three participants 65 years or older in the EUREYE Study underwent fundus photography, were interviewed for adult lifetime sunlight exposure, and gave blood for antioxidant analysis. Blue light exposure was estimated by combining meteorological and questionnaire data.
Results
Data on sunlight exposure and antioxidants were available in 101 individuals with neovascular AMD, 2182 with early AMD, and 2117 controls. No link was found between blue light exposure and neovascular or early AMD. However significant associations were found between blue light exposure and wet AMD in participants in the lowest quartile of individual antioxidant levels - vitamin C, zeaxanthin, vitamin E, and dietary zinc - with an odds ratio (OR) of about 1.4, or a 40% higher risk, for 1 standard deviation unit increase in blue light exposure.
Low blood levels of certain antioxidant combinations showed higher ORs of blue light exposure compared with single antioxidants. Higher odds ratios for blue light were observed with low levels of vitamin C, zeaxanthin and vitamin E, especially (odds ratio, 3.7; 95% CI 1.6-8.9), which were also associated with early AMD stages.
Comments
These results suggest that higher UV exposure may contribute to AMD in those with sub-optimal levels of select antioxidants. The authors conclude that … " people in the general population should use ocular protection and follow dietary recommendations for the key antioxidant nutrients."
Fletcher AE, et al. Sunlight exposure, antioxidants, and age-related macular degeneration. Archives Ophthalmology 126:1396-1403, 2008.
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EPA and DHA Again Linked with AMD Risk
According to a meta-analysis published in the June issue of Archives of Ophthalmology, a higher intake of the omega-3 fatty acids EPA and DHA reduced the risk of age-related macular degeneration (AMD). In analyzing 9 studies that included roughly 88,900 participants, the Australian authors report that higher intakes of EPA and DHA cut the risk of early AMD substantially and yielded a 38% risk reduction for advanced AMD.
Most recently, a study published in the August issue of the American Journal of Clinical Nutrition is the first in Europeans to show a beneficial association between neovascular AMD and the consumption of oily fish (e.g. mackerel, tuna, salmon, sardines, and herring). The study, funded in part by the European Commission and the Macular Disease Society UK, is consistent with results from studies in the US and Australia.
Study Design and Methods
The EUREYE study is a cross-sectional population-based study in persons aged 65 years or older in 7 centers located from north to south Europe. Participants in the cross-sectional population-based EUREYE study underwent fundus photography and were interviewed by using a food-frequency questionnaire. Fundus images were graded by the International Classification System for Age Related Maculopathy.
Questionnaire data were converted to nutrient intakes with the use of food-composition tables. Survey logistic regression was used to calculate odds ratios (ORs) and 95% CIs of energy-adjusted quartiles of EPA or DHA with neovascular AMD, taking into account potential confounders.
Results
Dietary intake data and fundus images were available for 105 cases with neovascular AMD and for 2170 controls without any features of early or late AMD.
Eating oily fish at least once per week compared with less than once per week was associated with a halving of the odds of neovascular AMD (OR = 0.47; 95% CI: 0.33, 0.68; P = 0.002). Compared with the lowest quartile, there was a significant trend for decreased odds with increasing quartiles of either DHA or EPA. Odds ratios in the highest quartiles were 0.32 (95% CI: 0.12, 0.87; P = 0.03) for DHA and 0.29 (95% CI: 0.11, 0.73; P = 0.02) for EPA.
In short, habitual consumption of oily fish at least once a week was linked to a 50% reduction in the risk of developing wet AMD. Further, people who consumed at least 300 mg per day of DHA and EPA were 69% less likely to have wet AMD then those consuming less.
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Inflammation and Chronic Diseases
Inflammation is a complex series of reactions designed to prevent ongoing tissue damage and activate repair processes and defense mechanisms against infectious diseases. Prolonged inflammation, however, contributes to the pathogenesis of chronic such as Alzheimer's, diabetes, cancers, and CVD. Chronic inflammation is also believed to contribute to such eye diseases as AMD, dry eye, diabetic retinopathy and glaucoma.
Dampening inflammation may help retard the development of such diseases. Inflammatory injury may be mediated by reactive oxygen species (ROS) or their reaction products, and antioxidant therapy has been shown to prevent in vivo tissue injury during inflammation.
Role of NF-kB in the Inflammatory Response
The transcription factor nuclear factor-kB (NF-kB) controls expression of genes involved in the inflammatory response and is activated by oxidative stress and other pro-inflammatory stimuli. Activation of NF-kB results in coordinated expression of inflam-matory genes and secretion of pro-inflammatory chemokines and cytokines, which are associated with increased risk of disease and poor outcome of chronic inflammatory diseases. Thus, dampening NF-kB activation has been suggested as a strategy to prevent chronic inflammatory diseases.
Anthocyanins Dampen Inflammation
Anthocyanins are water-soluble red and blue flavonoid pigments responsible for the dark color of grapes, plums, black currants, blueberries and bilberries. The anthocyanins are effective antioxidant compounds in vitro, and have also been shown to suppress cancer, cataract, and neurodegeneration in animal models.
These data led researchers from the University of Oslo to examine whether bilberry and blackcurrant anthocyanins could inhibit NF-kB activation in vitro and in humans. The results of this study suggest that anthocyanin supplementation may have a role in pre-venting or treating chronic inflammatory diseases by inhibiting NF-kB trans-activation and deceasing plasma concentrations of pro-inflammatory chemokines, cytokines, and inflammatory mediators.
Study Design and Methods
The researchers studied whether anthocyanins inhibit LPS-induced NF-kB activation in cultured monocytes. Monocytes were pre-incubated with a combination of black currant and bilberry anthocyanins or placebo (dimethylsulfoxide). NF-kB activity was induced by LPS.
In the parallel-designed, placebo-controlled clinical study, 120 participants were randomly assigned to receive 300 mg of anthocyanins or placebo for 3 weeks. The amount of anthocyanins provided corresponded to 100 g of fresh bilberries. The subjects maintained their regular diet during the intervention period.
Blood samples from fasting at baseline and after the intervention period were collected and analyzed for cytokines [IL-1b, IL-1 receptor antagonist (IL-1Ra), IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-13, IL-17, TNFa, IFNa, IFNg, granolyte/macrophage colony-stimulating factor (GMCSF), and others were measured in plasma by a sandwich immunoassay-based protein array system.
Results
In the cultured cells incubated with anthocyanins, NF-kB activation was suppressed by 28% compared with cells incubated with vehicle only (p = 0.003). Anthocyanins also decreased the LPS-induced p65 DNA binding, another assay for NF-kB-activation, by 18% (p =.041).
In the clinical trial, differences were observed in several NF-kB related inflammatory mediators in the anthocyanin group compared to placebo.
Decreases from baseline in the NF-kB controlled pro-inflammatory chemokines IL-8, ''regulated upon activation, normal T cell expressed and secreted,'' and IFNa (an inducer of NF-kB activation) in the anthocyanin group differed significantly from those in placebos.
Similarly, decreases from baseline in IL-4 (60%) and IL-13 (38%) in the active group differed significantly from the slight decreases seen in placebos. Both of these cytokines mediate pro-inflammatory responses and activate NF-kB.
Karlsen A , et al. Anthocyanins Inhibit Nuclear Factor-kB Activation in Monocytes and Reduce Plasma Concentrations of Pro-Inflammatory Mediators in Healthy Adults. Journal of Nutriton. 137: 1951-1954, 2007.
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Italian-American Trial of Multi Use & Cataract
A recent prospective cohort analysis of the National Eye Institute (NEI)-supported Age-Related Eye Disease Study (AREDS) reported that consistent use of a multi-vitamin and mineral supplement may delay the progression of lens opacities [See EduFacts Vol. 8 No. 4]. That analysis found a 25% reduction in risk of nuclear cataract, a similar - though non-significant - risk reduction for cortical cataract, and no beneficial effect for posterior subcapsular opacity.
The NEI has also supported The Italian-American Clinical Trial of Nutritional Supplements and Age-Related Cataract (CTNS), a 13-year, single-center clinical trial designed to evaluate whether multi use can affect the development or progression of lens opacities in a well-nourished Western population.
Results from the CTNS trial, published in the April issue of the journal Ophthalmology, support multivitamin supplementation for preventing or delaying the more common nuclear, and perhaps cortical opacities as well.
Study Design and Methods
In this double-blind, placebo-controlled trial, a total of 1,020 subjects aged 55-70 with early or no cataract were randomized to receive a multivitamin/mineral supplement or placebo daily, and were followed for an average of 9 years. Baseline and annual lens photographs were graded for severity of lens opacities according to a modification of the Age-Related Eye Disease Study system for classifying cataracts.
The primary outcome was a pre-specified increase from baseline in nuclear, cortical, or posterior subcapsular cataract (PSC) opacity grades or cataract surgery. Secondary outcomes included an increase in type-specific opacity grades, cataract surgery, and visual acuity loss from baseline > or = to 15 letters. The statistical analyses yield estimates of hazard ratios (HRs) that can be interpreted as relative risks.
Results
There was an overall benefit and a decrease in total lens events in participants assigned to the multivitamin and mineral formulation compared with those assigned to the placebo (hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.68 - 0.98; P= 0.03). Participants assigned to the multi were 34% less likely to experience a nuclear opacity event than participants assigned to a placebo (HR, 0.66; 95% CI, 0.50-0.88; P= 0.004). Multi users were also 22% less likely to experience a cortical event, although the difference did not reach statistical significance (HR, 0.78; 95% CI, 0.60 -1.02; P= 0.07).
Comments
First, there was no significant decrease in cataract removal or benefit for visual acuity. Is a larger or longer trial necessary for an adequate evaluation of the effects of multivitamins on visual acuity and/or cataract surgery rates? It should also be noted, however, that the multi tested in the CTNS trial did not contain lutein or zeaxanthin. These carotenoids are being examined in AREDS 2, and have been consistently linked to lower cataract risk, particularly nuclear opacity, and reduced risk for cataract surgery in observational studies.
Secondly, the benefits seen for the most common types of cataract, nuclear and cortical, are consistent with the findings from a number of observational trials, and the Linxian, China randomized trial, which reported a 36% reduction in the risk of nuclear cataract with multivitamin supplements. This implies that supplementation could help delay cataract and result in public health savings.
Lastly, the increased risk for PSC is puzzling, as most studies to date have shown no benefit but also no higher risk for PSC from supplemental antioxidants or multis. PSCs are less common than cortical or nuclear, and are often associated with eye trauma and steroid use. It is possible that the mechanisms involved in nuclear or cortical cataract formation are more susceptible to the level of oxidative stress than are PSC. Further research is needed.
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Nuclear Cataract, Lutein and Zeaxanthin
Nuclear cataract is the most common type of cataract among older Americans, and the most common type for which cataract surgery is performed. It occurs more often in women than men and among Caucasian individuals.
The pathogenesis of nuclear cataract is known to involve the inability to sufficiently defend against or repair the damage due to a variety of environmental stressors, including photochemical formation of free radicals. Lutein and zeaxanthin are the most abundant lens carotenoids. They scavenge superoxide and hydroxyl radicals, protect against UV B-induced lipid peroxidation, and may play a role in membrane stability. Diets high in lutein plus zeaxanthin have also been inversely associated with nuclear cataract or cataract extraction in several previous observational studies.
The Carotenoids in Age-Related Eye Disease Study (CAREDS) is an ancillary study of the Women's Health Initiative (WHI). The authors of CAREDS previously found that a stable intake of lutein and zeaxanthin over time could reduce the risk of AMD by about 43% in healthy women under 75 [see EduFacts Vol. 6 No. 9]. The CAREDS investigators now report that diets high in lutein and zeaxanthin are also linked to a lower prevalence of nuclear cataract.
Study Design and Methods
A total of 1802 women aged 50 to 79 years with intakes of lutein and zeaxanthin above the 78th (high) and below the 28th (low) percentiles in the WHI were recruited 4 to 7 years later into CAREDS. The primary outcome was nuclear cataract, defined as a nuclear sclerosis severity score of 4 or greater in the worst eye and/or a history of cataract extraction in either eye.
Nuclear cataract was determined from slit lamp photographs. Dietary estimates were made from responses to a validated, semi-quantitative food frequency questionnaire. Serum levels of lutein, zeaxanthin, and tocopherols were determined at Tufts University by a reverse-phase HPLC analysis.
Results
Women in the group with high dietary levels of lutein and zeaxanthin had a 23% lower prevalence of nuclear cataract (age-adjusted odds ratio, 0.77; 95% CI, 0.62-0.96) compared with the low level group. (Table 2)
Women in the highest quintile category of diet or serum levels of lutein and zeaxanthin as compared with those in the lowest quintile category were 32% less likely to have nuclear cataract (multivariable adjusted odds ratio, 0.68; 95% CI, 0.48-0.97; P for trend=.04; and multi-variable-adjusted odds ratio, 0.68; 95% CI, 0.47-0.98; P for trend=.01, respectively). The associations were similarly strong for serum concentrations of the combined carotenoids.
Comments
The observed association between these carotenoids and nuclear opacity was stronger when examining intake of lutein plus zeaxanthin across all of the levels of intake in this sample (by quintile categories) than when comparing the 2 groups of women sampled who had lutein and zeaxanthin intakes above the 78th and below the 28th quintiles. The results from CAREDS are consistent with a body of evidence that supports a protective relationship between lutein and zeaxanthin and nuclear cataract.
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Antioxidants, Omega-3 and Dry AMD
Dry, atrophic, or non-exudative, age-related macular degeneration (AMD) is the most common form of the disease, and is characterized by progressive devitalization of retinal pigment epithelium (RPE) and the formation of fatty deposits under the RPE known as soft drusen. Patients not receiving treatment have demonstrated a loss of visual acuity at 6 months of at least 0.8 lines and up to 1.5 lines.
Studies have suggested that nutritional factors can play a significant role in slowing the onset or limiting the effects of AMD. In 2004, the Lutein Antioxidant Supplementation Trial (LAST) demonstrated that nutritional supplementation with lutein or lutein together with antioxidants, vitamins and minerals improved visual function and symptoms in male patients with atrophic AMD. Currently, the 2nd Age-Related Eye Disease Study (AREDS II) is examining the effects of carotenoids and omega-3 fats on AMD.
The Taurine, Omega-3 Fatty Acids, Zinc, Antioxidant, Lutein (TOZAL) study was conducted to investigate the impact of combined omega-3, antioxidants, and other nutrients on visual function in those with atrophic AMD. The results suggest that such a nutritional approach may help maintain visual acuity.
Study Design and Methods
The primary objective of this prospective, open case-controlled study was to measure the change from baseline in visual function - Best-Corrected Visual Acuity (BCVA) via the ETDRS chart, contrast sensitivity, central 10 degree visual fields and retinal imaging (angiograms and photographs) at 6 months in subjects with atrophic (dry) AMD treated with a targeted nutritional supplement.
Thirty seven mixed gender patients with a mean age of 76.3 +/- 7.8 years were enrolled at 5 independent study sites and received standard of care along with a nutritional supplement containing lutein; zeaxanthin; vitamins A, C and E; beta-carotene; taurine; zinc, copper; EPA and DHA. Results were compared to a placebo cohort constructed from the literature that was matched for inclusion and exclusion criteria. A paired t-test was used to test a null hypothesis and a two-sided alpha level of 0.05 was used to determine statistical significance.
Results
Seventy-six percent of subjects receiving the nutritional supplement demonstrated stabilization or improvement of BCVA at 6 months. Subjects gained an average of 0.0541 logMAR or one-half of a line of visual acuity (VA) over the 6-month period. There was a statistically significant improvement in VA from baseline (p = .045).
Comments
"The results provide strong evidence that the treatment being studied produces an improvement in VA" according to the authors. Supplementation increased VA above the expected baseline decrease in the majority of patients in this population. The results of the TOZAL study agree with the LAST and CARMIS studies and are predictive for positive visual acuity outcomes in the AREDS II trial. However, supplementation for longer than 6 months is likely required to effect changes in additional visual parameters.
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Omega-3 Fatty Acids and Risk of AMD
According to AMD Alliance International, AMD affects approximately 25-30 million people worldwide, and the incidence of this disease is projected to triple by 2025. New treatments for AMD are limited to patients with exudative AMD and are not without risks. Thus, primary prevention of AMD by modifying risk factors remains an important public health strategy.
Insufficient intake of certain dietary components may be one of those risk factors. There is growing interest in the long - chain omega-3 fatty acids EPA and DHA since they play an important role in the layer of nerve cells in the retina and may be involved in the prevention or progression of AMD.
Epidemiological studies have generally shown inverse associations between intake of these fatty acids from fish and AMD. Now, a systematic review and meta-analysis from the University of Melbourne reports that higher intakes of EPA and DHA significantly decrease the risk of both early and late AMD.
Study Design and Methods
Seven databases were systematically searched using standardized criteria, with no limits on publication year or language. Randomized controlled trials and prospective cohort, case-control, and cross-sectional studies were included. Of 2,754 abstracts identified, 3 prospective cohort, 3 case-control, and 3 cross-sectional studies met the criteria. Measures of associations were pooled quantitatively using meta-analytic methods.
Results
Nine studies provided data on a total sample of 88,974 people including 3,203 AMD cases.
A high dietary intake of omega-3 fatty acids was associated with a 38% reduction in the risk of late AMD, when the highest intake was compared with the lowest (pooled odds ratio [OR], 0.62; 95% confidence interval [CI], 0.48-0.82).
Fish intake at least twice weekly was associated with a 24% and 33% reduced risk of early and late AMD respectively (pooled OR, 0.76; 95% CI, 0.64-0.90; and pooled OR, 0.67; 95% CI, 0.53-0.85).
Combining the results from all 9 studies also showed that a high dietary intake of EPA was linked to a 23% lower risk of early AMD, while DHA was associated with a 30% reduction.
In contrast, a high intake of the omega-3 alpha linolenic acid was associated with a 49% increase in risk.
Comments
In this study the definition of 'early AMD' included vision loss, and hence might be more indicative of an intermediate stage of AMD. However, the findings suggest that a greater intake of EPA and DHA can slow AMD progression. In addition, results from the current analysis are consistent with another systematic review in which the authors critically reviewed 6 observational studies for evidence that omega-3 fatty acids prevent AMD.
While the benefits of EPA and DHA require confirmation in long-term intervention trials such as AREDS-2, the authors underscore the strong underlying biological rationale of these fatty acids.
DHA plays an essential structural role in the membrane of the retina and is found in high concentrations. Further, the outer photoreceptor cell segments of the retina are constantly shed in the normal visual cycle and deficiency of DHA could initiate AMD.
According to the authors: "There is also evidence that such long-chain fatty acids protect against oxygenic, inflammatory, and age-associated pathology of the vascular and neural retina, which are possible pathogenic factors for AMD development."
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Mitochondrial Dysfunction & Antioxidants
Primary open angle glaucoma (POAG) is generally associated with elevations in intraocular pressure (IOP) caused by abnormal resistance of aqueous outflow through the trabecular meshwork, a specialized tissue lining the eye's outflow pathway.
A key suspect in the progression of POAG is local oxidative stress. Oxidative free radicals and reactive oxygen species (ROS) are reported to trigger degeneration in the trabecular meshwork, subsequently leading to increases in IOP and glaucoma. There is mounting evidence that ROS play a fundamental role in reducing local antioxidant activities in the region of the trabecular meshwork. The mitochondria are the main source of cellular ROS and adenosine triphosphate (ATP), and are key regulators of mechanisms controlling cell survival and death. A spectrum of mitochondrial abnormalities in patients with POAG has recently been reported.
The authors of a newly published paper, now provide evidence that mitochondrial dysfunction is a possible mechanism for the loss of trabecular meshwork cells in POAG. They also report that the antioxidants vitamin E and n-acetyl cysteine (NAC), as well as mitochondrial permeability transition (MPT) inhibitors, can reduce the progression of this condition.
Study Design and Methods
Trabecular meshwork from patients with POAG and age-matched subjects without disease were obtained by standard surgical trabeculectomy. Primary cultures of trabecular meshwork were treated with 3 different respiratory chain inhibitors specific for Complex I, II and III. The protective effect of vitamin E, NAC and cyclosporine A was examined by adding these antioxidants or the MPT inhibitor to the cells 30 minutes before treatment with the respiratory chain inhibitors. Mitochondrial function was determined by changes in mitochondrial membrane potential and ATP production with fluorescent probes and a luciferin/luciferase-based ATP assay, respectively. ROS levels were determined by H2-DCF-DA, and cell death was measured by lactate dehydrogenase activity.
Results
The trabecular meshwork cells of patients with POAG exhibited senescence and degeneration compared with those of controls. There was spontaneous generation of ROS, decreased mitochondrial membrane potential, decreased ATP production, and loss of cell viability in primary cell cultures of patients with POAG compared with those of control subjects. ROS generation was associated with dysfunction at the level of mitochondrial complex I.
It was also determined that vitamin E, NAC (fig. A below), and the MPT inhibitor cyclosporine A protected POAG trabecular meshwork cells from cytotoxicity by attenuating ROS production and cytochrome c release from the mitochondria and by inhibiting the mitochondrial permeability transition opening.
Comments
Taken together, the results support the hypothesis that a defect in mitochondrial complex I contributes to progressive loss of tabecular meshwork cells in patients with POAG by promoting excessive mitochondrial ROS production. The finding of a protective effect of vitamin E and NAC (a key component of glutathione) adds to the growing evidence that antioxidants are beneficial in POAG and are worthy of further investigation.
(A) Reduction of ROS production in GTM cells by antioxidants Vit E and NAC. Treatment with antioxidants vitamin E (Vit E; 200 µM) or N-acetylcysteine (NAC; 10 mM) induced a decrease in ROS production in GTM cells. Pretreatment with Vit E or NAC for 30 minutes also significantly reduced ROT-induced ROS production in GTM cells. Data are expressed as a fold change in fluorescence levels of GTM to NTM. Results are expressed as the mean SE of six separate experiments performed in triplicate. *Significant differences from untreated control at P = 0.05.
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Oxidative Stress and AMD
Oxidative stress is one of the pathogenic mechanisms in AMD. The retina is thought to be highly susceptible to oxidative stress given its high oxygen consumption, high concentration of polyunsaturated fatty acids and photosensitizers, and exposure to light. Phagocytosis by the retinal pigment epithelium also leads to oxidative stress.
AREDS provided evidence that high dose zinc and antioxidant vitamin supplementation can slow AMD progression in relatively advanced early AMD cases. Additionally, the Rotterdam Study reported that above-median dietary intake of all 4 of the nutrients studied in the AREDS trial was associated with a statistically significant 35% reduction in incident AMD risk.
The Blue Mountains Eye Study is a population-based cohort study of vision, common eye diseases, and other health outcomes in an urban Australian population. A new analysis from this study confirmed the AREDS result that zinc is protective against AMD, and found that higher intake of lutein and zeaxanthin reduced the risk of long-term incident AMD.
Study Design and Methods
Of the 3,654 participants in the study at baseline, 2,454 were re-examined after 5 years, 10 years, or both. The Wisconsin Grading System was used to evaluate stereoscopic retinal photographs. Risk ratios and 95% confidence intervals were calculated after adjusting for age, gender, smoking and other factors. Energy-adjusted intakes of vitamins A, C, and E; alpha-carotene; beta-carotene; beta-cryptoxanthin; lutein and zeaxanthin; lycopene; iron and zinc were assessed via food frequency questionnaires.
Results
Those in the highest decile of total zinc intake (> or = 15.8 mg/day) were found to be significantly less likely to develop early or any AMD compared with the remaining population (RR 0.54; CI 0.30-0.97 and RR 0.56; CI 0.32-0.97 respectively).
Similarly, for dietary lutein and zeaxanthin intake, those in the top tertile (> or = 972 mcg/day) had a 65% reduced risk of incident neovascular AMD (RR 0.35; CI 0.13-0.92). For those with above-median intakes, 34% reduction in risk of incident indistinct soft or reticular drusen was noted (RR 0.66; CI 0.48-0.92).
In contrast, the highest vs. the lowest tertile of total beta-carotene intake from diet predicted incident neovascular AMD in both smokers and non-smokers (RR 2.68; CI 1.03-6.96).
Comments
These results suggest a possible threshold effect of total zinc intake on risk of early or any AMD. A protective effect from high intakes of zinc is biologically plausible. Zinc is concentrated in the retina and is a cofactor for many enzymes, including the antioxidant enzymes present in human retinal pigment epithelium. Zinc is also a cofactor for vitamin A metabolism and is essential for the synthesis of retinol binding protein. In AREDS, the protective effect shown with combined zinc and antioxidants seemed driven largely by zinc. The recently reported findings from the Rotterdam Study also seemed to be driven by zinc, and perhaps vitamin E.
These results also suggest a possible threshold protective effect of dietary lutein and zeaxanthin intake on the risk of neovascular AMD or indistinct soft drusen. Lutein and zeaxanthin are the only carotenoids that concentrate in the macula, where they are the main components of macular pigment.
The finding of a link between higher intake of beta-carotene and increased risk of AMD are inconsistent with other reports. In addition to the previously mentioned findings of AREDS and the Rotterdam Study, the Eye Disease Case-Control Study Group also reported a reduced risk for AMD with higher dietary intakes of carotenoids, particularly beta-carotene, lutein and zeaxanthin.
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Oxidative Theory of Cataract Formation
The oxidative hypothesis of cataract formation holds that reactive oxygen species can damage lens proteins and fiber cell membranes, and that nutrients with antioxidant actions can protect against these changes. Results of laboratory and animal studies generally support this theory, though findings from epidemiologic studies have varied.
Results of a new prospective study from Brigham and Women's Hospital and Harvard Medical School add to the body of evidence suggesting that lutein, zeaxanthin and vitamin E may help delay cataract formation. The study was published in the January issue of Archives of Ophthalmology.
Study Design and Methods
Dietary intake was assessed at baseline in 39,876 female health professionals by using a detailed food frequency questionnaire. Information on antioxidant nutrient intake from food and supplements was obtained from a total of 35,551 women who were free of a diagnosis of cataract.
The main outcome measure was cataract, defined as incident, age-related lens opacity responsible for a reduction in best-corrected visual acuity in the worse eye to 20/30 or worse based on self-report, and confirmed by medical record review.
Results
A total of 2031 cases of incident cataract were confirmed during a mean 10 years of follow-up.
Women with the highest daily intake of lutein and zeaxanthin, averaging about 6.7 mg, had an 18% lower risk of developing cataract compared to women consuming the least, or a mean of 1.2 mg a day. The multivariate relative risk of cataract was 0.82 (95% confidence interval, 0.71-0.95; test for trend, P =.04) for combined intake of lutein and zeaxanthin.
Comparing women in the extreme quintiles for vitamin E from food and supplements combined, a 14% risk reduction was noted. Those in the highest quintile consumed a mean of 262 mg vitamin E daily, while those in the lowest quintile consumed an average 4.4 mg. The multivariate relative risk of cataract was 0.86 (95% confidence interval, 0.74-1.00; test for trend, P =.03).
No relationship was observed between cataract risk and intakes of other carotenoids and antioxidants, including beta-carotene, beta-cryptoxanthin, lycopene and alpha-carotene.
Comments
lutein and zeaxanthin are the only carotenoids detected in the human lens, where they filter harmful short-wave blue light. The presence of oxidation products of lutein and zeaxanthin in the lens further supports a functional role for these carotenoids in maintaining lens clarity. Findings from observational epidemiologic studies also generally support a possible beneficial effect of lutein and zeaxanthin.
The association of vitamin E with lower cataract risk in this study comes in the wake of an intervention trial that reported no benefit of 600 IU vitamin E (every other day) on cataract in women.
Though speculative, it is possible that moderate amounts of antioxidants such as vitamins C and E and lutein along with B-vitamins, might have beneficial effects beyond that of a single nutrient administered at high levels. This notion is consistent with the findings from several prospective epidemiologic studies reporting a lower occurrence of cataract in regular users of multi-vitamin and mineral supplements (see EduFacts Volume 8, Number 4). A recent analysis of AREDS for example, linked consistent use of a multi-nutrient supplement with a lower risk of cataract even though the high dose antioxidants studied in that trial showed no benefit.
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Multi-Nutrient Supplements and Cataract
A number of prospective epidemiologic studies have reported a lower occurrence of cataract in regular users of multi-vitamin and mineral supplements (1-3).
The Physicians' Health Study noted significantly fewer self-reported cataracts or confirmed cataract surgery in multi users during 5 years of follow-up. The Longitudinal Study of Cataract found that regular multi users reduced their risk of nuclear opacification by one-third. Finally, taking a multi for 10 years or more was reported to lower the risk of nuclear and cortical cataracts in the Beaver Dam Eye Study. In contrast, the Nurses' Health Study found no association between multi-supplement use and incidence of cataract extraction.
The cataract portion of the AREDS trial also failed to show an effect of high dose antioxidants on the risk of development or progression of lens opacities. However, a recent prospective cohort analysis of AREDS has found that consistent use of a multi-vitamin and mineral supplement may delay the progression of lens opacities.
Study Design and Methods
There were 4596 participants enrolled in the AREDS cataract trial, half of whom were assigned to high-dose antioxidants and half to no antioxidants. Two-thirds of the subjects elected to take a multi vitamin and mineral supplement containing RDA-level potencies that was offered to all participants.
Lens photographs at baseline and at 5 to 6 years follow-up were compared. An "any" lens opacity event was defined as the occurrence of change from baseline of specified amounts of nuclear, cortical, or posterior subcapsular opacity, or the performance of cataract surgery.
The AREDS researchers used a propensity score approach to provide a means of adjusting for selection bias that may have occurred with the elective use of the multi supplement and for confounding. The use of propensity scores tends to produce unbiased estimates of treatment effects. It balances the covariates between treatment groups, much as trials use randomization to achieve balance. Risk of progression to a lens event was assessed by odds ratios (OR) with 95% confidence intervals (CI).
Results
With adjustment for propensity score and baseline covariates, the risk of development of or progression to any cataract was reduced by 16% in regular multi takers (OR = 0.82, CI = 0.71-0.95, p = 0.025). For nuclear cataract, a 25% risk reduction was observed in the multi-supplement users (OR = 0.75, CI = 0.61-0.91, p = 0.004). (See Table)
There was a similar reduction in risk of cortical lens events, although significance was not reached. No beneficial effect was seen for posterior subcapsular opacities.
Comments
Individual nutrients have been linked to a lower risk of various cataract types including vitamins C and E, lutein, and the B-vitamins riboflavin and thiamin. Rather than supplementing with only a few, high-dose antioxidants, it may be that supplementation with a broad-spectrum of nutrients is a more effective strategy. The NEI in fact, is currently supporting a controlled trial of more than 1000 subjects in Italy to assess the effect of multi use on development and progression of cataracts. Median follow-up is 7 years, with completion likely this year.
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Vitamin E: More Than an Antioxidant
Vitamin E is best known as the body's major fat-soluble antioxidant. Its main function is to intercept free radicals and prevent chain reactions of lipid destruction. However the discovery of complex molecules that control vitamin E metabolism such as tocopherol transfer protein, alpha tocopherol membrane receptors, and intracellular transfer proteins, triggered the idea that the activity of vitamin E extends beyond its antioxidant capacity.
Vitamin E is now known to affect the expression and activity of immune and inflammatory cells, to enhance vasodilation, and to inhibit the activity of the important cell signaling molecule protein kinase C (PKC).
Modulating the PKC pathway may be relevant in glaucoma. For instance, PKC inhibitors have been shown to relax the trabecular meshwork, and to affect matrix metalloproteinase and PGF2 alpha.
Vitamin E and PKC could also have a vaso-regulatory effect in the retina. In different experimental models, retinal vascular dysfunction due to hyperglycemia was reportedly prevented by vitamin E via the diacylglycerol-PKC pathway (1,2).
These findings prompted researchers at Istanbul University to evaluate the clinical potential of vitamin E in glaucoma patients. They report prevention of visual field loss in this preliminary study, and conclude that vitamin E deserves further attention in preventing glaucomatous damage .
Study Design and Methods
Thirty glaucomatous patients (60 eyes) with controlled IOP, were randomly divided into three groups. Group (A) received no vitamin E, while groups (B) and (C) were given a daily dose of 300 and 600 mg of vitamin E respectively, as d-alpha tocopheryl acetate for 12 months. Blood levels of vitamin E were measured via HPLC.
Disease progression for each subject was monitored via visual field measurements and color Doppler imaging of ophthalmic and posterior ciliary arteries at baseline, and at 6 and 12 months. Retinal blood flow of ophthalmic and posterior ciliary arteries was evaluated, and resistivity and pulsatility indexes were obtained. Mean deviation values for Fastpac visual fields were recorded at all time points, and the difference in mean deviation values calculated. The change in mean deviations of Groups (B) and (C) were compared with Group (A), and the Mann-Whitney U-test was employed for statistical analysis.
Results
There were no significant differences between the groups in mean ages, IOP, best corrected visual acuities of 10/10 ratios and disease etiologies. The average differences between the pulsatility indexes (PI) and resistivity indexes (RI) of both ophthalmic arteries and posterior ciliary arteries of both supplemented groups were significantly lower than those of the non-supplemented groups at 6 months and 1 year. RI decreases observed in posterior ciliary arteries at both time points, and PI decreases observed in ophthalmic arteries at the 6th month were statistically significant.
Compared with those receiving vitamin E, non-treated subjects showed a statistically significant reduction in visual field (change in mean deviation) at 6 and 12 months (Tables, below).
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Figure courtesy Eur J Ophthalmol
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Women's Antioxidant & Folic Acid Study
Results from the vision component of the Women's Antioxidant and Folic Acid Cardiovascular Study, also known as WACS, were presented at the ARVO 2007 Annual Meeting. Researchers from the Brigham and Women's Hospital and the National Eye Institute concluded that the data from this randomized trial indicate that supplementation with folic acid, vitamins B6 and B12 reduced the risk of AMD in women with cardiovascular disease (CVD) .
These three B-vitamins, particularly folic acid, have been shown to reduce high levels of the naturally occurring compound, homocysteine. Research has implicated elevated plasma levels of homocysteine in the development of vascular diseases including choroidal neovascularization in exudative AMD.
Study Design and Methods
A total of 8,171 female health professionals, 40 years or older with pre-existing CVD or having at least three risk factors for the disease were enrolled in the trial. The women were randomized to receive vitamin C (500 mg daily), vitamin E (600 IU every other day), beta-carotene (50 mg every other day) or placebo in the WACS secondary prevention trial.
Of this group, 5,422 women were subsequently randomized to also receive a placebo or folic acid (2.5 mg), vitamin B6 (50 mg) and vitamin B12 (1 mg) daily. Of these women, 5,205 did not have a diagnosis of AMD, and were included in this analysis. There were two primary outcome measures: a) confirmed AMD (self reported and supported by medical record evidence of an AMD diagnosis after randomization) and b) confirmed AMD with vision loss - defined as vision to 20/30 or worse which was attributable to this condition.
Results
A total of 137 cases of AMD were documented, including 69 cases of AMD with vision loss, during an average of 7.3 years of treatment and follow-up. Fifty-five cases occurred in the treatment group, while the placebo group had 82 documented cases. Relative risk was 0.66 (95% confidence interval, p = 0.02). For AMD with vision loss, there were 26 cases in the B-vitamin group compared to 43 among placebo takers. Relative risk was 0.60 (95% confidence interval, p = 0.04). In summary, women taking supplemental B vitamins were 34% less likely to develop AMD and 40% less likely to have AMD-related vision loss than women in the control group.
Commentary
While very high doses of the 3 B vitamins were tested in this group of women with CVD, lower doses may well have been effective. For example, a placebo-controlled, randomized dose response study in people with a history of CVD found that the decrease in homocysteine was proportionate to the folate dose up to - and not beyond - 800 mcg daily. This dose achieved an average 23% drop in plasma homocysteine compared to placebo - a drop of about the same magnitude found in trials using up to 5,000 mcg folate daily. Additionally, excessive amounts of folic acid have recently been implicated in colorectal tumor growth (4,5).
Antioxidant - CVD Outcomes in WACS
The WACS authors report that vitamins C, E or beta-carotene had no overall effects on CVD events in these high-risk women , pointing out that antioxidants are no magic bullets for the secondary prevention of this disease. However, the study did confirm the safety of high potency antioxidants, and women who received both vitamins C and E experienced fewer strokes. The same research group is following up to determine whether the combination of vitamins C and E affect the biomarkers in blood that strongly predict stroke. That work will use blood samples from 300 participants taken at the beginning and end of the WACS study.
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AREDS Reports Numbers 20 and 22
Dietary data was collected from participants when they enrolled in the AREDS trial so that investigators could later examine the relationship of AMD case groups with intake levels of individual nutrients.
To explore these relationships, AREDS subjects were divided into four groups based on increasing severity of drusen or type of AMD. The dietary information from those four groups was then compared with that from AREDS participants categorized as being 'free' of AMD. AMD-free was defined as having no drusen or less than 15 small drusen. Nutrient intake values were adjusted for energy intake then stratified into quintiles.
Results of the analyses were published in the May and September issues of the journal Archives of Ophthalmology. The first of these case-control studies reports on the relationship of dietary lipids and AMD, while the second study assessed whether nutrients such as carotenoids, vitamins A, C and E and others, were related to AMD risk.
Omega-3 and Fish Intake Lower AMD Risk
The researchers found that only higher intake of total long chain omega-3 and fish (the primary dietary source of EPA and DHA), were linked to a decreased likelihood of having neovascular AMD. Benefit was not seen for the other AMD groups.
Arachidonic acid was the only dietary lipid directly associated with neovascular AMD prevalence. Participants getting the most arachidonic acid in their diets were 54% more likely to have late AMD. Arachidonic acid, an omega-6 fat abundant in meat and dairy, is a precursor for inflammatory eicosinoids.
No statistically significant relationships were seen for other dietary lipids such as the monounsaturates, found in olive oil for example, or saturated fats.
It's interesting to note that the omega-3 fat alpha-linolenic acid, found in flaxseed oil for example, was associated with decreased AMD risk only when it was included along with EPA and DHA as part of the total intake of long chain polyunsaturated fats. Assessed alone, alpha-linolenic was not related to AMD. Alpha-linolenic acid must first be metabolized to EPA to provide anti-inflammatory activity, and this conversion is only 10-20% effective.
Comparing the highest to lowest quintiles, those consuming the most total omega-3 fats were about 39% less likely to have neovascular AMD. Risk reduction for greater fish intake was the same. A 46% lower chance of having late AMD was linked with the highest consumption of DHA.
EPA, DHA and arachidonic acid are major fatty acids in the diet. Both arachidonic acid and DHA (which can be formed from EPA), are key components of retinal photoreceptor outer segments and vascular tissue. While all three of these lipids are essential, a better balance of EPA and DHA to arachidonic acid is recommended for cardiovascular health. This study strongly suggests that improving that balance can favorably influence retinal health as well.
Only Lutein / Zeaxanthin Independently Linked to AMD
Higher dietary intake of lutein and zeaxanthin was independently associated with a reduced likelihood of having neovascular AMD, geographic atrophy, and large or extensive intermediate drusen. No other nutrients were independently related to AMD.
After adjusting for total energy intake and other non-nutritional risk factors, subjects consuming the highest amount of lutein and zeaxanthin were 35% less likely to have neovascular AMD and 55% less likely to have geographic atrophy than those eating the least. Those whose diets provided the most of these two carotenoids also had a 26% reduced likelihood of having large or extensive drusen.
The findings from both of these AREDS case-control studies are, in part, the basis for testing 10 mg of lutein, 2 mg of zeaxanthin, 650 mg EPA and 350 mg of DHA in the AREDS 2 trial currently underway.
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Dietary Glycemic Index (GI) and Early AMD
A previous EduFacts reported results from the first study ever to evaluate the relationship between the quality of carbohydrate intake and AMD. That study, which examined 526 women enrolled in the Nurses' Health Study, found that consuming a high Glycemic Index diet (dGI) was significantly associated with early signs of AMD. The glycemic index is a measure of how quickly carbo-hydrates are metabolized - the faster they are broken down into glucose, the higher the GI.
The same research group from Tuft's Research Center on Aging has now evaluated the dGI and AMD relationship among AREDS participants. Compared with the earlier investigation, the present study had older subjects, was much larger, offered a far greater number of AMD cases, and reflected a more complete spectrum of lesions that define AMD.
Lower GI Reduces Early and Late AMD Risk
The new findings are generally consistent with those of the previous study, finding a positive association between dGI and large drusen. They also report a 49% increased risk of advanced AMD (geographic atrophy plus neo-vascularization) for those with a dGI higher than the median for men and for women. According to the authors, 20% of prevalent AMD cases would have been eliminated if participants had consumed diets below those median values.
Study Design and Methods
Dietary information was obtained from 4099 non-diabetic participants aged 55-80 (56% women) in the ARED Study. A total of 8125 eligible eyes at baseline were classified into 1 of 5 AMD groups according to the size and extent of drusen, the presence of geographic atrophy, and neovascular changes. A generalized estimating approach was used to evaluate relationships between dGI and risk as well as severity of AMD, with eyes as the unit of analysis.
Higher the GI, the Greater the AMD Severity
When participants were split into 5 groups based on dGI, eyes in the 4th and 5th quintiles had a significantly or suggestively higher risk of large drusen, geographic atrophy and neo-vascularization compared to eyes in the 1st quintile. A significant positive relation between dGI and severity of AMD was also noted (P for trend 0.001). There was a 49% increase in the risk of advanced AMD for persons with a dGI higher than the sex median (women: >77.9; men: >79.3). The data show that the higher the dGI, the greater the severity of AMD (see Figure 1 below).
FIGURE 1. Multivariate-adjusted mean dietary glycemic index (dGI) by age-related macular degeneration (AMD) groups. Error bars represent 95% confidence levels.
Importance of Limiting Simple Sugars
According to senior author Dr. Allen Taylor, simple sugars can modify proteins (creating advanced glycation end-products), cause oxidative stress that increases inflammation, and may damage vessels due to the sharp rise in blood lipids that can follow their consumption. This is important because there's been a trend of increasing carbohydrate intake (simple sugars found in cakes, cookies, sodas, white bread, etc) over the past 30 years. While long-term prospective trials are needed to confirm the adverse effects suggested by this study, a high dGI has already been implicated in the development of diabetes, CVD and some cancers.
Chiu CJ et al. Association between dietary glycemic index and ARMD in non-diabetic participants in the Age-Related Eye Disease Study. Am J Clin Nutr 86:180-8, 2007.
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Retinopathy and Omega-3 Fatty Acids
Retinopathy affects an estimated 4 million diabetic patients and about 40,000 premature infants in the US. Retinopathy has two critical phases: loss of vessels in the retina which leads to hypoxia, followed by new vessel growth spurred by the lack of oxygen. The new vessels grow abnormally, are malformed, leaky and over-abundant. In the later stages of the disease, the abnormal vessels pull the retina away from its supporting layer, and the detachment ultimately results in blindness.
The role of omega-3 lipids in angiogenesis is beginning to be defined, and it appears that EPA and DHA are involved in regulating vessel loss and neo-vascularization.
In a study published in the July issue of Nature Medicine, omega-3 fatty acids protected against the development and progression of retinopathy in mice. It was found that increasing tissue levels of EPA and DHA decreases the area of vascular loss in the retina by increasing normal vessel regrowth after injury, and by reducing the hypoxic stimulus for growth of abnormal vessels.
The study was a collaborative effort by researchers at Children's Hospital Boston, Brigham and Women's Hospital, Massachusetts General Hospital, the University of Göteborg in Sweden, and the National Eye Institute. The authors concluded that "supplementing omega-3 polyunsaturated fatty acid intake may be of benefit in preventing retinopathy".
Study Summary
Mice subjected to oxygen-induced retinopathy were fed isocaloric diets enriched with 2% fatty acids - either omega-3 (EPA and DHA) or omega-6 (arachidonic acid). Additionally, the researchers also examined retinopathy in the Fat-1 model. Fat-1 mice are genetically altered to convert omega-6 to omega-3 - a conversion that humans and other mammals cannot do.
Mice receiving the omega-3 rich diet were observed to have 40-50% less initial retinal vessel loss compared to omega-6 fed mice. As a result, the omega-3 group had a similar 40-50% reduction in pathological vessel growth. The results were virtually identical in the Fat-1 mice, confirming that increased retinal omega-3 levels inhibited neo-vascularization.
Omega-3 Protective Mechanism
The investigators demonstrated that the omega-3 diet suppressed production of the cytokine called TNF-alpha, reducing the inflammatory response in the retina. In contrast, the arachidonic enriched diet increased TNF-alpha production. The retinas of the omega-3 group also had higher levels of neuroprotectin D1 and resolvin D1 (both derived from DHA), and resolvin E1, which is derived from EPA. These compounds also potently protected against pathological vessel growth, and were not detected in retinas of the omega-6 fed mice.
Commentary
"It is remarkable that with only a 2% change in dietary omega-3 intake, we observed an approximate 40-50% decrease in retinopathy severity", commented one of the study's lead authors Dr. Kim Connor. "Our studies suggest that after initial loss, vessels re-grew more quickly and efficiently in the omega-3 fed mice", said Connor. "This increased the oxygen supply to retinal tissue, resulting in a dampening of the inflammatory alarm signals that lead to pathological vessel growth".
According to the other lead author, Dr. John Paul SanGiovanni, "this is a major conceptual advance in the effort to identify modifiable factors that may influence inflammatory processes implicated in the development of common sight-threatening retinal disease".
The American Diabetic Association currently advises people with diabetes to consume more omega-3 to lower their risk of heart disease. If the findings of this study are confirmed in humans, fish oil may also lessen the risk for one of the long-term complications of diabetes, retinopathy. A clinical trial at Children's Hospital Boston is set to test the effects of omega-3 supplementation in premature infants at risk of retinopathy.
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Vitamin D: Beyond Bone Health
Most people think of vitamin D simply as a regulator of calcium homeostasis and bone mineralization. Over the past decade, however, it has become clear that the active or hormonal form of this vitamin also plays a significant role in xenobiotic metabolism, in the immune system, and in cellular proliferation and differentiation. As a result, adequate vitamin D status is viewed as important for reducing the risk of many malignancies and autoimmune diseases. Now, a recent study suggests that vitamin D is also involved in protecting macular health.
Study Design and Methods
The objective of the study was to evaluate the association between levels of vitamin D (25-hydroxyvitamin D) in serum and prevalence of both early and advanced age-related macular degeneration (AMD) among participants of the 3rd National Health and Nutrition Examination Survey (NHANES III). NHANES III, which is conducted by the Centers for Disease Control, is a representative sampling of the general population. Of 7,752 people (> 40 years) analyzed from this survey, 11% had AMD as determined by non-mydriatic fundus photographs. Questionnaires assessed dietary and supplemental intake, and blood samples were taken to determine vitamin D serum levels.
Protective Effect Seen for Higher Serum D
When participants were split into five groups based on serum vitamin D levels, those in the highest quintile had a 40% lower risk for early AMD compared to those in the lowest quintile (see table). An inverse association between AMD and greater vitamin D-fortified milk consumption was observed. The researchers also found a significantly reduced prevalence of AMD among consistent vitamin D supplement users who did not consume milk daily.
Anti-Inflammatory Role is Likely Connection
A growing body of epidemiologic evidence suggests that inflammation underlies AMD pathology, and the authors of this study speculate that vitamin D may reduce AMD risk by its anti-inflammatory actions. Studies report that vitamin D decreases proliferation of T helper cells, T cytotoxic cells, and natural killer cells, while enhancing T suppressor cell activity. Vitamin D also decreases the production of pro-inflammatory interleukins such as IL-6 and 8. In addition, a recent study has shown that vitamin D intake reduces C-reactive protein, a marker of systemic inflammation.
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There is growing evidence for the benefits of supplementing zinc and lutein in those with signs of AMD. This issue of EduFacts explores the benefit of these nutrients beyond macular health.
Supplemental Zinc and Immunity
Many eye care professionals advise their patients with at least moderate AMD to take the high dose zinc and antioxidant combination found to slow vision loss and disease progression. In subsequent analyses, AREDS authors reported that subjects receiving zinc (alone or with antioxidants) had improved survival time from all causes. The positive association of zinc with increased longevity did not appear to be due to a reduction in deaths from circulatory disease or cancer. Instead, a possible protective effect for respiratory causes of death was observed. The authors noted that zinc's effect on mortality could be related to an improved immune response, which declines with aging. Results from a recent study lend credence to that postulation.
Fewer Infections, Less Oxidative Stress
Investigators from the University of Michigan and Wayne State University Medical School examined whether zinc supplements could improve immunity in fifty healthy seniors aged 55 to 87. Zinc is essential to optimal immune function, and low plasma zinc is common in older individuals. At baseline, subjects had lower serum zinc and higher levels of oxidative stress compared to younger adults. Study participants received 45 mg of zinc or placebo daily for 1 year. The zinc group had significantly fewer infections (Table 3), lower oxidative stress markers, and reduced ex-vivo generation of pro-inflammatory cytokines (TNF-alpha) than placebo.
Lutein and Skin Health
In the controlled, year-long LAST trial, lutein was found to increase macular pigment density and improve measures of visual function such as glare recovery and near visual acuity in men with atrophic AMD. Since lutein filters potentially damaging UV light in the macula, scientists have theorized that lutein plays a similar protective role in the skin. Now, results of a double-blind trial from the University of Naples suggest that those taking supplemental lutein for ocular concerns might also derive a skin-protective effect .
Reduction in UV-Induced Skin Damage
One hundred twenty women with different skin types, but each exhibiting signs of premature aging, were followed for 12 weeks after assignment to one of four groups: A) oral placebo and topical placebo; B) oral placebo plus topical treatment with lutein and zeaxanthin; C) 10 mg of oral lutein with .06 mg zeaxanthin and topical placebo; or D) the oral supplement combined with topical lutein and zeaxanthin.
Photo-protection was calculated from skin surface redness after a 2 minute exposure to UV radiation on forearms and from susceptibility to sunburn, defined as the minimum erythematous dose. Photo-protection was increased in all the lutein and zeaxanthin treated groups (Fig). Oral supplements provided a 4-fold increase in protection, while the combined topical and oral intervention provided a 6-fold increase in photo-protection compared to controls. Surface lipids and skin hydration were significantly improved in all lutein-treated groups, while peroxidation of skin lipids decreased. Skin elasticity improved only in those topically treated.
Effect of Lutein and Zeaxanthin Upon Photoprotective Activity by Treatment Group Over the Study Period
# p < 0.05 vs. the week 2 treatment value within the same treatment group.
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Relationship of AMD and CVD
Various studies have found that cardiovascular disease (CVD) (hypertension, coronary artery disease), CVD risk factors (total serum cholesterol, body mass index), and CVD treatment with statins or anti-hypertensive medications can influence the risk of age-related macular degeneration (AMD). However, the link between CVD, its risk factors or treatment and AMD has not been consistent across different studies.
The association of these factors with AMD was examined in the Women's Health Initiative Sight Examination (WHISE). The recently published findings from WHISE suggest that smoking, use of calcium channel blockers, diabetes and obesity are risk factors for late AMD in women. However, the association of late AMD with systolic blood pressure and the effects of other CVD risk factors on early AMD need to be further explored, according to the study authors.
Design and Methods
The WHISE is an ancillary study to the Women's Health Initiative's (WHI) large scale clinical trial of hormone replacement therapy. Twenty-one of the 39 WHI clinical centers participated in WHISE, enrolling a total of 4,288 women age 63 years and older for whom AMD status could be established for at least one eye by standardized grading of fundus photographs.
Information on CVD and its risk factors were obtained from a standardized questionnaire and examination. The form included questions about diabetes status, lipid-lowering medications, anti-hypertensive medications and medications taken for diabetes. Information on history of myocardial infarction, stroke and anti-hypertensive medication use were collected at the first screening visit of WHI as were measurements of blood pressure and those needed to calculate BMI.
Results
Prevalence of any AMD was 21.4% (919 women). Of those with AMD, only 5.8% had signs of exudative AMD or pure geographic atrophy, which limited the power to examine associations. However, significant and independent associations between late AMD and CVD risk factors were found to be older age, more pack years smoked, increased systolic blood pressure, taking calcium channel blockers, history of diabetes and greater body mass index.
History of myocardial infarction, stroke, use of statins and white blood cell count were not associated with AMD.
Comments
The primary purpose of the WHISE was to examine the effects of hormone replacement therapy on AMD. The results, published in 2006, showed that treatment with conjugated estrogens alone or combined with progestin do not affect early or late-stage AMD, although the combined hormones may reduce the risk of soft drusen or neovascular AMD.
In this analysis, there appear to be limited consistent associations of the factors studied and the observed endpoints in women. This is possibly due to differences in the pathogenesis of early AMD and its characteristic lesions (soft drusen and pigmentary abnormalities), and late AMD with its characteristic lesions (exudative AMD and geographic atrophy).
The authors report that higher systolic blood pressure was also found to be associated with soft drusen and inversely associated with RPE de-pigmentation, lesions defining the presence of early AMD. It has been hypothesized that increased blood pressure damages the choroidal circulation affecting the RPE.
Though epidemiologic data regarding this relationship have been inconsistent, people with hypertension in the AREDS trial and in the Beaver Dam Eye Study were more likely to develop neovascular AMD than those with normal blood pressure. It may be time for a randomized clinical trial to test whether lowering blood pressure can slow AMD progression.
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Zinc and the AMD Disease Process
Zinc is concentrated in the choriocapillaries, retinal pigment epithelium (RPE) and retina. Long term supplementation with zinc, either alone or combined with antioxidants, was shown to slow AMD progression in the AREDS trial. Not much is known, however, about the effects elicited by this mineral.
Recent results from an ancillary study to AREDS suggest one way that zinc may help protect against AMD. Zinc appears to improve the transport and use of cysteine - a sulfur containing amino acid and rate limiting factor in the manufacture of glutathione, the major antioxidant within cells.
Glutathione helps inactivate the reactive oxygen species hydrogen peroxide by reducing it to water. In this process, the reduced form of glutathione (GSH) is oxidized to produce GSSG. Like glutathione, cysteine also contains a thiol or sulphhydryl group. Thiol groups can undergo oxidation/reduction (redox) reactions; when cysteine (Cys) is oxidized it forms cystine (CySS). Due to its ability to undergo redox reactions, cysteine has antioxidant properties.
Studies have shown that plasma levels of cysteine and glutathione become more oxidized with age, age-related diseases, and oxidative stress. Plasma levels of the reduced and oxidized forms of these metabolites are thought to be a reliable marker for oxidative stress and antioxidant defenses.
Methods
Plasma samples were obtained from AREDS participants at the Emory and Wilmer Eye Centers sites. At both study sites, blood specimens were obtained at two time points, an average of 1.7 and 6.7 years after enrollment. For this study, the four AREDS treatment groups were combined into two groups: zinc supplementation and no zinc. Plasma was analyzed for the reduced and oxidized forms of glutathione and cysteine (GSH / GSSG and cysteine / cystine), and their redox status.
Results
To control for factors that may have an effect on the plasma levels of these metabolites, demographic characteristics were compared. There were no significant differences in these characteristics between subjects receiving zinc or no zinc at either blood draw.
At the first blood draw (20 months), most subjects had already entered the study and were receiving zinc or placebo. No differences were seen in any of the thiols, disulfides or redox states between the two groups.
At the second blood draw (80 months), a significant decrease in plasma levels of oxidized cysteine (cystine, CySS) was found in the group receiving zinc compared to the non-zinc group (Fig. 1 below).
FIGURE 1. Long-term zinc supplementation resulted in lower plasma cystine (CySS) in the AREDS patients. Plasma CySS was measured in AMD patients before and after five years of zinc supplementation. Subjects who had received zinc had significantly lower CySS than their baseline values (P= .05). Additionally, at draw 2, plasma CySS was significantly higher in the no zinc group compared to the zinc group (P = .02).
Discussion
How might the lower plasma levels of oxidized cysteine (CySS) affect retinal cells? Whether the magnitude of change found in this study affects RPE function remains to be determined. However, earlier studies found that exposing cultured human RPE cells to a more oxidized "cystine environment" makes them more susceptible to apoptosis or programmed death.
Moriarty-Craige BS, et al. Effects of long-term zinc supplementation on plasma thiol metabolites and redox status in patients with age-related macular degeneration. Am J Ophthalmol 143:206-11, 2007.
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Inflammation: Friend and Foe
The acute inflammatory response defends against invading microorganisms and damaged cells, and is essential for wound healing & tissue repair. Chronic inflammation, however, damages tissues and can lead to or worsen chronic diseases such as arthritis, heart disease & dry eye syndrome.
GLA as an Anti-Inflammatory Nutrient
A recent review underscores the role of the fatty acid gamma linolenic acid (GLA) in modulating the inflammatory response. GLA has gained recognition over the last few decades for its anti-inflammatory and anti-cancer actions. Some key findings from controlled clinical trials include:
Sources & Rationale for Supplementation
Dietary intake of GLA is typically negligible as GLA is present only in trace amounts in some green leafy vegetables and nuts. Supplemental sources include the oils of: borage (Borage officinalis), 20-26% GLA; black currant (Ribes nigrum), 15-18%; and evening primrose (Oenoethera biennis), 8-12%. According to Tufts researchers, black currant seed oil is a preferred source because it contains 13-16% of the omega-3 fatty acid alpha-linolenic as well as GLA. Examining the effects of black currant seed oil (vs. placebo) in healthy elderly subjects, researchers from Tufts found that GLA reduced levels of PGE2 and improved immune function.
GLA is produced in the body as an intermediate in the metabolism of linoleic acid (LA). However this reaction is very slow and further restricted by alcohol use, stress, smoking, saturated and trans-fatty acid intake, and deficiencies of magnesium, vitamin B6 and zinc. These factors - as well as hypertension, arthritis, psoriasis and diabetes - impair the activity of delta-6-desaturase, the enzyme that converts linoleic acid to GLA. Administering oral GLA is a means to bypass this often inefficient and rate-limiting step in the metabolism of LA to GLA.
Anti-Inflammatory Mechanism of Action
GLA is rapidly converted to dihomo GLA (DGLA) which is incorporated into cell membrane phospholipids. When released by the action of the enzyme phospholipase A2, DGLA competes with arachidonic acid for the enzymes COX and LOX. Arachidonic acid is the omega-6 found abundantly in meat and dairy, and the precursor to pro-inflammatory eicosinoids like PGE2.
The COX products of DGLA include prostaglandins of series 1 (PGE1) and thromboxane A1. These products exert anti-inflammatory, anti-aggregation and vaso-dilatory actions.
A key LOX product of DGLA, 15-HETrE, inhibits production of leukotriene B4 from inflammatory cells including neutrophils. Some research suggests that DGLA may act directly on T-cells to modulate immune response in diseases such as rheumatoid arthritis.
Anti-Cancer Mechanisms of Action
Pre-clinical research indicates that the anti-cancer properties of GLA include: direct cytotoxic action on cancer cells, anti-angiogenic action in tumor cells, stimulation of apoptosis, gene activation, and the effects of DGLA eicosinoids. Preliminary clinical studies suggest that GLA may have benefit in some cancers. GLA injected directly into tumor cells of patients with advanced glioma significantly reduced tumor mass.
Safety of Supplemental GLA
Supplemental GLA has been safely administered in clinical trials at oral doses of 2.8 grams per day or less, for up to a year (3-5). GLA-rich oils have also been commonly used in the U.S. for over 20 years, with no reports of serious adverse events or effects.
Americans, who generally obtain an excess of omega-6 fats through over-consumption of meat, dairy, vegetable cooking oils and shortenings, are advised to consume more omega-3s from fatty fish and nuts. The amount of omega-6 fatty acids present in common doses of GLA-rich oil do not make a significant contribution to overall fat intake - typically about 67 grams daily for a 2000 kcal diet with 30% of calories from fats. Further, black currant seed oil contains a recommended ratio of omega-6 to omega-3 fats.
GLA & EPA: Complementary Actions
One concern related to DGLA, is that it could be further metabolized to arachidonic acid with subsequent pro-inflammatory effects. This is not relevant in inflammatory cells such as neutrophils, since these cells lack enzyme (delta-5-desaturase) activity needed to convert DGLA to arachidonic acid. Importantly, inflammatory cells from subjects supplemented with GLA produce significantly less pro-inflammatory leukotriene B4 (8,9) .
In contrast to inflammatory cells, high levels of supplemental GLA have been shown in some but not other studies to elevate serum arachidonic acid levels. Human studies, however, have demonstrated that the addition of fish-derived omega-3 EPA in a balanced ratio to GLA, blocks the activity of delta-5-desaturase and prevents elevations in serum arachidonic acid (10,11).
Co-ingesting similar levels of EPA and GLA increases cellular membrane content of both DGLA and EPA (precursor to anti-inflammatory eicosinoids). In short, this supplementation strategy successfully maintains the anti-inflammatory capacity of GLA and increases serum EPA, without causing accumulation of arachidonic acid.
Flaxseed oil is a concentrated source of omega-3 alpha linolenic acid. However, conversion of this fatty acid to EPA is limited, and further metabolism to DHA is very low or negligible (12). Typically, only 15-40% of alpha linoleic is converted to EPA This may, in part, explain why omega-3 fatty acids from fish or fish-oil supplements, but not alpha-linolenic acid, have been found to benefit cardiovascular disease outcomes in primary- and secondary-prevention studies (13). Thus GLA-enriched oils are more effectively paired with fish oil rather than flaxseed oil to promote the complementary actions of GLA and EPA.
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Nutrient Supplementation for RP
Retinitis pigmentosa (RP) refers to a group of inherited progressive retinal dystrophies characterized by photoreceptor degeneration. The rods are affected initially, followed by gradual death of the cones. It's estimated that 1 in 4,000-5,000 people have RP worldwide. Since no generally accepted medical or surgical treatment can stop the course of the disease, researchers have undertaken studies with various nutritional supplements in hopes of improving visual function or slowing disease progression. Along with vitamin A , DHA and an omega-3 rich diet, lutein has recently been reported to be of potential benefit in RP.
Lutein May Benefit Visual Field and Acuity
Spurred by previous studies suggesting lutein as a potential treatment with positive effects on macular pigment density, researchers from the Wilmer Eye Institute conducted a double-blind, randomized placebo-controlled trial with a cross-over design. Thirty-four adult RP patients were randomized to 2 groups and followed for 48 weeks. One group received lutein supplements (10 mg/day for 12 weeks followed by 30 mg/day) for the first 24 weeks, then placebo for the following 24 weeks. The second group received placebo prior to lutein. Both groups were given a multi-vitamin and mineral supplement.
Lutein supplementation had a significant effect on central visual field. Visual acuity also improved slightly, though no effect on contrast sensitivity was observed. Comparing the development of vision measures against the natural loss expected to occur over 48 weeks, most measures showed reduced decline. These reductions were significant for normal illumination visual acuity and contrast sensitivity. The results, according to the authors, suggest that lutein supplementation improves visual field and may also modestly improve visual acuity.
Vitamin A Helps Preserve Visual Function
In 1993, Harvard investigators reported that 15,000 IU of vitamin A palmitate slowed the rate of decline of retinal function over 5 years as measured by ERG. In this study of 600 RP patients, high dose vitamin A helped preserve retinal function, while those getting high dose vitamin E (400 IU) were more likely to show a functional decline. A later study following adult RP patients taking high dose vitamin A for about 12 years concluded that prolonged intake is considered safe in this age group, although routine monitoring of liver function and fasting serum vitamin A levels are advised. Women of childbearing age should not take high dose vitamin A, which may raise the risk of birth defects.
Antioxidants Protect Cones in Animal Model
Why the negative affect of high dose vitamin E on RP function? It is possible that high dose vitamin E might have inhibited the absorption or transport of vitamin A, since patients receiving high doses had slight but significant decreases in serum A levels compared with those receiving lower doses in the 1993 Harvard study.
However, further exploratory studies of combined antioxidants in RP patients may be warranted. A recent study in an animal model of RP found that high dose antioxidants (vitamins E, C, alpha lipoic acid others) significantly reduced oxidative damage in cones, increased cone cell density and preserved cone function. These results, according to the Johns Hopkins authors, suggest that the gradual cone death that occurs after rod cells die is due to oxidative damage, and that antioxidants could provide benefit .
Omega-3 Fatty Acids Support Visual Field
While a 4 year long study published in 2004 reported that 1,200 mg of supplemental DHA along with high dose vitamin A did not slow the course of RP overall, further subgroup analysis showed benefit for those starting vitamin A supplementation for the first time (5,6). In addition, those study participants taking vitamin A (but not DHA) who also had a higher dietary omega-3 intake experienced substantial benefit. The rate of visual field decline was retarded by 40-50% yearly in those whose omega-3 intakes were equivalent to 1-2 servings of fatty fish weekly.
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Omega-3s: From Inuit to Implementation
While the relationship between the omega-3 fatty acids and age related cognition and retinal function have only recently begun to emerge, the cardio-vascular effects of EPA and DHA have been studied for nearly three decades. Interest in these fatty acids from cold water fish began in the late 1970's when studies revealed that Greenland's indigenous Inuits had a significantly lower rate of heart attack compared with Western control subjects. These observations generated an estimated 5000 studies to explore this and other effects of omega-3 fats, and ultimately led to the American Heart Association's recommendations for regular omega-3 consumption in 2002. Research continues to support the cardio-protective role of these fatty acids as evidenced by the findings of several newly published studies.
Fish Fatty Acids More Effective Than Defibrillators
Omega-3 fatty acids may prevent more sudden deaths than automated external defibrillators (AED) in homes and public places or implanted defibrillators according to results of a study supported by the Centers for Disease Control. Researchers compared these preventive strategies in a computer-simulated community of 100,000 people that resembled the population of Olmsted County, Minnesota.
Raising the omega-3 fatty acid levels among the cyber-Olmsted citizens resulted in lowering overall mortality rates by 6.4%. In contrast, AEDs reduced death rates by 0.8% and implanted defibrillators (ICDs) lowered the rates by 3.3%. Three-quarters of the reduction in deaths from increased omega-3 levels would come from raising them among the healthy portion of the population.
Raising blood levels of the omega-3 in people after a heart attack could save 58 lives yearly according to the simulation's predictions, while only 7 lives were saved by AEDs and implanted defibrillators prevented 30 deaths yearly. While heart attack survivors are routinely given omega-3 supplements in some European countries, this is generally not the case in the U.S., though the evidence supports it. According to a study published in the September issue of the Journal of the American Board of Family Medicine, only 17% of family doctors were likely to advise patients - including those who had suffered a heart attack - to take omega-3 supplements. There is a great need, the authors concluded, to "improve awareness of this important advice."
Heart Benefits Confirmed In Systematic Review
A recently published systematic review of randomized controlled trials, prospective cohort and case-control studies, concludes that the evidence suggests that fish or fish oil supplements reduces the rates of all cause mortality, cardiac and sudden death, and possibly stroke(3). The evidence was stronger for secondary than primary prevention.
Commissioned by the NIH, the review found that increased consumption of EPA and DHA - but not the omega-3 fatty acid alpha linolenic (ALA) - reduces the rates of these CVD outcomes. Data on the effects of ALA, found in flaxseed and other vegetable oils, were reportedly limited and typically of poor quality.
Future Directions: An Omega-3 Index
A second review published online in August ahead of print in the journal Cardiovascular Research, also concludes that the majority of the evidence supports the benefits of omega-3 intake for heart health. The authors, from Saint Luke's Hospital, University of Missouri-Kansas City School of Medicine, have proposed an omega-3 index as a modifiable risk factor for CVD. The Index measures the sum of EPA+DHA in the membrane of erythrocytes as the percent of all fatty acids in the red blood cell membrane. The authors also determined that membrane EPA+DHA index equal to or exceeding 8% is associated with the greatest cardio-protection. In the future, this measure of EPA/DHA status could help physicians tailor advice to their patients to help them achieve levels of omega-3 scientifically reported to provide CVD benefits.
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Lutein/Zeaxanthin and AMD Risk
Lutein and zeaxanthin are the only carotenoids that concentrate in the macula. There is evidence of three mechanisms by which lutein and zeaxanthin may afford protection against AMD: by absorbing blue light, by quenching free radicals and by increasing membrane stability.
Many previously published studies which have examined the relationship between AMD and these carotenoids have reported an inverse association between the disease and intake of lutein plus zeaxanthin. These carotenoids are commonly obtained from leafy green vegetables, corn, egg yolks, broccoli, peas, squash - as well as from supplements.
The authors of the Carotenoids in Age-Related Eye Disease Study (CAREDS) now report that a stable intake of these carotenoids over time could reduce the risk of AMD by about 43% in healthy women under 75.
Design and Methods
CAREDS is an ancillary study of the Women's Health Initiative (WHI), a prospective cohort study. CAREDS was designed, in part, to evaluate the relationship between lutein/zeaxanthin and the prevalence of intermediate AMD. Over 1780 women aged 50-79 who had high or low intake of lutein plus zeaxanthin at WHI enrollment were recruited into CAREDS 4-7 years later, when the presence of AMD was determined by fundus photographs.
To maximize extremes in intake of these carotenoids in the study sample, women with intakes of lutein plus zeaxanthin above the 78th (high) and below the 28th (low) percentiles at baseline in the WHI were recruited. Dietary assessments were performed by means of food frequency questionnaires administered at the study's start and over the previous 15 years. Logistic regression analyses examined the prevalence of AMD, after accounting for potential covariates.
Results
While an association between dietary intake of these carotenoids and AMD was not observed in the overall study population, secondary analyses disclosed a statistically significant protective effect in women younger than 75 with stable intakes of lutein and zeaxanthin.
Higher intakes of lutein/zeaxanthin (2,868 mcg or more daily) compared to lower consumption (792 mcg daily) in women with stable intakes resulted in a substantial 43% lower risk of intermediate AMD (odds ratios [0.57; 95% confidence interval, 0.34-0.95]). The younger women (< 75 years) did not have a history of chronic diseases such as cardiovascular disease and diabetes that are often associated with diet changes and instable intakes of lutein/zeaxanthin rich foods.
Similar protective associations were observed for large drusen. While not statistically significant, associations in this sub-sample were in the protective direction for the more advanced lesions of pigmentary abnormalities, as well as for the exploratory outcome, advanced AMD.
The researchers observed the strongest inverse associations between intermediate AMD and high intake of vegetables in general, as well as of green vegetables. Blood levels of the carotenoids were not associated with risk of AMD.
Comments
According to lead author Dr. Suzen Moeller of the University of Wisconsin, the findings are consistent with a broad body of evidence from observational and experimental studies suggesting that these carotenoids may protect against AMD. There was evidence that diet instability may have biased the associations and, together with the possibility of selective mortality bias, may explain our inability to detect the hypothesized association in the full study population, wrote Dr Moeller.
Moeller SM et al. Age-Related Macular Degeneration and Lutein and Zeaxanthin in the Carotenoids in Age-Related Eye Disease Study (CAREDS). Archives of Ophthalmology 124:1151-1162, 2006.
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Inflammation and Sjögren's Syndrome
Affecting more than 1.4 million Americans, Sjögren's syndrome is an autoimmune disorder in which immune cells attack and destroy the glands that produce tears and saliva. The hallmark symptoms of the disorder are dry mouth and dry eyes. Sjögren's syndrome is also frequently associated with rheumatic disorders such as rheumatoid arthritis.
T-cell infiltration and markers of immune activation have been noted in both the conjunctiva and lacrimal glands of these patients. Topical anti-inflammatory treatment of patients with dry eye reportedly produces a significant reduction of activated lymphocyte in the conjunctiva, thus demonstrating the potential for anti-inflammatory treatment of dry eyes.
Anti-inflammatory Activity of GLA
Gamma-linolenic acid (GLA) and its precursor linoleic acid (LA) are essential fatty acids found in certain plant seed oils such as black currant seed oil. Oral administration of GLA and LA has been shown to have beneficial effects in the treatment of chronic inflammatory disorders such as rheumatoid arthritis, and several pilot studies conducted in the 1980's suggest that these fatty acids may also benefit the ocular status of patients with Sjögren's.
GLA is metabolized to dihomo-linolenic acid (DGLA), the immediate precursor of PGE1, an eicosanoid with known anti-inflammatory action. In addition, both GLA and DGLA modulate the immune responses by acting directly on T lymphocytes. Researchers from the University of Messina in Italy now report that modest amounts of supplemental GLA and LA raise PGE1 tear content in Sjögren's, and improve signs and symptoms of ocular discomfort in these patients.
Design and Methods
This randomized, double-blind, controlled trial involved 40 patients with primary Sjögren's Syndrome divided into 2 groups. One group received GLA (15 mg) and LA (112 mg) twice daily for 1 month (GLA group), while the other group received placebos. Subjects underwent 3 examinations: baseline (T0), after 1 month (T1), and 15 days after treatment was suspended (T2). At each exam, the following tests were performed: tear sampling from the inferior meniscus, TBUT, fluorescein stain of the ocular surface, and tear basal secretion. A symptom score was also obtained each time. PGE1 was evaluated by enzyme immunoassay, and PGE1 content of tears was the primary endpoint.
Results
Tear PGE1 levels were significantly increased in the GLA group after 1 month of treatment. Fifteen days after treatment was halted, a significant reduction of the PGE1 levels toward baseline was observed. The symptom score was significantly lower in the GLA group after 1 month, with several symptoms (burning, foreign body sensation and dryness) remaining improved after treatment was stopped. The corneal fluorescein stain in this group also showed a significant improvement after the first month, which was sustained 15 days after treatment cessation.
No statistically significant differences were found for the other tests. In contrast to the GLA group, no statistically significant changes were noted in the placebo group at all examination time points. These results are summarized in the table below (group 1 = supplemented; group 2 = placebo).
Conclusions
According to the authors, these results indicate that supplemental GLA and LA effectively increases PGE1, an indicator of anti-inflammatory activity, improves ocular surface status and reduces dry eye symptoms.
Aragona P, et al. Systemic omega-6 essential fatty acid treatment and PGE1 tear content in Sjogren's syndrome patients. Invest Ophthalmol Vis Sci 46:4474-9, 2005.
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Dietary Flavonoids Afford Cellular Protection
It is increasingly clear that new approaches to treating AMD should focus on both preventing the initial insults that lead to disease progression, and rescuing the retinal pigment epithelium (RPE) and photoreceptor cells that have been damaged. Mounting evidence suggests that chronic oxidative stress may damage the retinal-RPE and predispose it to developing age-related macular degeneration (AMD).
Flavonoids are a large class of polyphenolic compounds found in fruits, vegetables, teas and wine that have evolved to protect plants from the oxidative damage caused by chronic UV exposure. Flavonoids are potent antioxidants that can also influence many cellular enzyme functions. They directly neutralize reactive oxygen species (ROS), and they modulate cell-signaling pathways. In particular they can induce expression of phase-2 proteins that enhance the cell's natural defenses against oxidative stress.
Large-scale observational studies have linked greater dietary intake of certain flavonoids with a lower risk of cardiovascular disease and some cancers. In addition, many of the foods associated with a reduced risk of AMD in epidemiologic studies contain high concentrations of flavonoids, and at least one flavonoid has been identified in the mammalian retina. Earlier experiments report that specific flavonoids can protect retinal ganglion cells from oxidative stress.
Taken together, these observations led investigators from the Scripps Research Institute to determine whether specific flavonoids found in common fruits and vegetables can protect human RPE cells from oxidative stress-induced death.
Research Questions and Methods
A series of experiments were conducted utilizing cultured adult human RPE cells to address the following questions: 1) Can specific dietary flavonoids protect RPE cells from oxidative stress induced cell death? 2) Can these flavonoids prevent cell death after the exposure has occurred? 3) Can these flavonoids act through an intracellular route to reduce the accumulation of ROS? 4) Do flavonoids activate Nrf2 in human RPE cells and induce the expression of phase-2 genes? The techniques employed to answer these questions included cytotoxicity assays, microscopy, isolated RNA analysis, delayed response cyto-protection assay, determination of ROS production and Western blot analysis of HO-1 and Nrf2 expression.
Results
All six flavonoid classes were tested, and the most effective were the flavones and flavonols. Specific members of these two classes which protected against oxidative-stress induced death with good efficacy and low toxicity include quercetin, fisetin, luteolin and EGCG.
These same flavonoids and several others induced the expression of phase-2 detoxification enzymes in the cultured RPE cells. Compared with control cells, quercetin was more protective of RPE cells than vitamin C or various vitamin E compounds (see figure below), although both of these vitamins are known to be better absorbed in vivo than quercetin.
Comments
These findings raise the possibility that flavonoids may be among the natural compounds that contribute to the ocular benefits associated with foods identified in epidemiologic studies. Spinach, for example, is not only a source of the more familiar lutein and zeaxanthin, but is a rich source of quercetin and luteolin which were two of the most effective flavonoids in this study. Quercetin is also found red wine, and is highly concentrated in foods such as onions, peppers, currants and black tea, which is also a rich source of EGCG.
Hanneken A, et al. Flavonoids protect human retinal pigment epithelial cells from oxidative stress-induced dealth. Inv Ophthalmol Vis Sci. 47:3164-77, 2006.
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Support for Macular Benefits of Omega-3
Reviewers from the National Eye Institute recently summarized the functions of the omega-3 fatty acids eicosapentenoic acid (EPA) and docosapentaenoic acids (DHA) in retinal tissues. [See EduFacts, Vol. 5 No 7]. According to the reviewers, studies looking at the relationship of the omega-3 fats to the prevalence of advanced AMD have generally observed a protective effect. A new study by Australian researchers adds to this growing body of evidence, and suggests that regularly consuming omega-3 fat, especially from fish, protects against early and late AMD in older individuals.
Design and Methods
To assess longitudinal associations between dietary fat and incident AMD, dietary intakes were measured by food frequency questionnaires at baseline in 2895 participants of the Blue Mountains Eye Study (BMES). Since the questionnaires can under- or over-report food consumption, dietary data were verified in a sub- group of participants who completed 4-day weighed food records 3 times over the course of a year. The results were generally in good agreement with the questionnaire data. Seventy five percent of the BMSE cohort (2335 persons) was re-examined after 5 years. Presence of AMD was graded from retinal photographs (Wisconsin ARM Grading System). Logistic regression adjusted for age, sex, vitamin C intake and smoking.
Results
The researchers examined the risk of incident AMD participants in the lowest and highest quintiles of dietary fat intakes with respect to the 60% of the population who represent a moderate, normal intake, or those in the middle 3 quintiles. Participants in the highest vs. the lowest quintiles of omega-3 fat intake had a lower risk of incident early AMD (odds ratio 0.41 [0.22-0.75])
A 40% reduction of incident early ARM was associated with fish consumption at least once a week (odds ratio 0.58 [0.37-0.90]). Consuming fish at least 3 times weekly resulted in about a 70% reduction in the incidence of late AMD (odds ratio 0.25 [0.06-1.00]). (See Table)
When the intake of specific types of fats was calculated, a trend toward increased risk of developing early AMD was noted for people with the lowest intake of monounsaturated fats and omega-3 including alpha-linolenic acid.
Comments
Though several population health studies have linked high dietary fat intake from any source to increased AMD risk, this study found no evidence that dietary fat of any kind raised that risk. The findings are largely in agreement with other studies showing that diets high in omega-3 fatty acids, particularly DHA derived largely from fish, may protect against retinal oxidation and degeneration, according to the authors. They propose that insufficient omega-3 intake could cause abnormal metabolism in the retina and affect cell renewal.
ORs and CIs of Early and Late ARM with Increasing Frequency of Certain Food Types in BMES Participants*  | |||
5-y Incidence, OR (95% CI) | |||
 | |||
Early ARM (n = 130) | Late ARM (n = 22) | ||
| |||
Margarine | |||
<1/wk | 1.00 (Reference) | 1.00 (Reference) | |
1-6/wk | .89 (0.57-1.38) | 1.55 (0.44-5.40) | |
Daily | 0.87 (0.58-1.29 | 0.85 (0.33-2.22) | |
Butter | |||
<1/wk | 1.00 (Reference) | 1.00 (Reference) | |
1-6/wk | 0.48 (0.22-1.02) | 0.82 (0.18-3.76) | |
Daily | 0.77 (0.48-1.24) | 0.85 (0.27-2.66) | |
Total Fish † | |||
< 1/mo | 1.00 (Reference) | 1.00 (Reference) | |
≥1/wk | 0.48 (0.37-0.90) | 0.44 (0.16-1.21) | |
≥3/wk | 0.62 (0.38-1.03) | 0.25 (0.06-1.00) | |
Nuts | |||
| Never | 1.00 (Reference) | 1.00 (Reference) | |
≥ 1/wk | 0.80 (0.52-1.25) | 0.82 (0.29-2.34) | |
≥ 1/wk | 0.79 (0.46-1.34) | 0.55 (0.14-2.16) | |
| |||
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Dietary Links to AMD and Cataract
Within the next 2 decades, it's anticipated that the number of AMD and cataract cases will each increase by 50%. Prevention remains the best approach for addressing these public health issues, and dietary changes may represent one of the most cost-effective strategies.
Several dietary factors have been linked to AMD, including antioxidant vitamins and minerals, carotenoids such as lutein and beta-carotene, and long chain omega-3 fatty acids. Similarly, certain carotenoids and antioxidants like vitamin C have been associated with some types of cataract. Two new reports suggest that the type of carbohydrates consumed is also related to both visual conditions.
The glycemic index (GI) is a scale that ranks carbohydrate-rich foods by how much they raise blood glucose levels compared to a standard food, usually glucose or white bread. High GI foods include sweets, white rice and bread, processed cereals and French fries, while lower GI foods are generally fiber-rich such as beans, whole grain bread, brown rice and oatmeal.
Glycemic Index and Early AMD
The first study included 1036 eyes from 526 participants in the Nurses' Healthy study without a previous diagnosis of AMD. The presence and degree of AMD were classified by the AREDS system, while dietary information was based on data from an average of 4 food-frequency questionnaires collected over a 10-year period before AMD was assessed. Odds ratios for AMD were estimated in a manner that accounted for the lack of independence between 2 eyes from the same subject.
After multivariate adjustment, GI was related to AMD, specifically to retinal pigment abnormalities. The total amount of carbohydrates consumed showed no relationship. The odds ratio for those in the highest third of GI values compared to the lowest third was 2.71. Neither GI nor total carbohydrate intake was related to drusen.
Commentary
This was the first study to evaluate the relationship between the quality or quantity of carbohydrate intake and AMD. The results showed that retinal pigment abnormalities characteristic of AMD are positively associated with long-term dietary GI, and independent of total carbohydrates and other known or suspected risk factors. The link between GI and AMD could be explained by several hyperglycemia-mediated pathways: glycation, oxidative stress, activation of protein kinase C, direct toxic effects of glucose on the retinal pigment epithelium and capillary endothelium, and associated inflammatory and angiogenic responses. Most notably, a high-GI diet has been proposed to play a role in exacerbating the pro-inflammatory process.
Glycemic Index and Cataract
In the second study, dietary information was obtained by food frequency questionnaire from 3,377 participants in the AREDS trial. Lens status was evaluated by using the AREDS System for Classifying Cataracts. Associations were examined for eyes with only a single, or pure, type of lens opacity by using the generalized estimating approach to logistic regression.
For those in the highest fourth of GI values, GI was associated with a higher prevalence of pure nuclear opacities (grade > 2 and odds ratio of 1.29), and moderate nuclear opacities (grade > 4 and odds ratio of 1.43). When comparing the highest vs. the lowest total intake of carbohydrates, the odds ratio was 1.27 for cortical opacities of any severity. In short, GI - or carbohydrate quality - was linked to nuclear cataract, while carbohydrate quantity was related to cortical type.
Commentary
How might higher dietary GI raise the risk of nuclear cataract? After consuming the same amount of high compared to low GI foods, it takes longer for blood glucose levels to return to baseline concentrations. It's possible that higher GI foods may damage the metabolically limited lens nuclear tissue by exposing the tissue to glucose for longer periods. The link between total carbohydrate intake and cortical cataract seen in this study has also been reported in the Blue Mountains Eye Study and the Nutrition and Vision Project.
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Lutein and Ischemic Injury
Lutein and its isomer, zeaxanthin, are carotenoids with antioxidant properties that are concentrated in ocular tissues, especially the retina. Observational studies have linked higher dietary intake levels of lutein and zeaxanthin to a decreased risk of AMD. Because these carotenoids absorb blue light, it's believed that they reduce photochemical damage that would otherwise occur in the retina when exposed to light of these wavelengths. However this may not be their only biochemical action, as new findings shed light on lutein's anti-inflammatory effects.
Retinal ischemia, or reduced blood flow to the retina, leads to neuronal cell death, which is seen in such conditions as retinal ischemic diseases, optic and diabetic neuropathies. Ischemic injury kills neurons by excitotoxicity (excessive glutamate), and also increases free radicals. Under ischemic conditions, excessive neuronal nitric oxide and the pro-inflammatory protein cyclo-oxygenase 2 (COX-2) are contributors to ischemia-mediated retinal cell death.
Study Design and Results
Investigators examined the effects of lutein on retinal ischemia, reported to be a good model for retinal neuronal cell death. High intraocular pressure was used to induce retinal ischemia in 8 week old Sprague-Dawley rats. The rats received an intravitreal injection of lutein (20% in corn oil) ½ hour before retinal ischemia was induced, while control animals were injected with corn oil only. Expression of COX-2 and neuronal nitric oxide synthetase (nNOS) was measured.
While the control group had an increased expression of these two proteins, lutein inhibited their expression in a dose-dependent manner. In addition, lutein was injected intraperitoneally 1 hour before and 1 hour after ischemia in another group. Compared to controls, survival of retinal neurons increased significantly to 85% in the ganglion cell layer and 88% in the inner cell layer. No difference in the protective effect of lutein was seen between the peritoneal and the vitreal routes of lutein administration (see figure 2).
Conclusions & Comments
"We have confirmed that nNOS and COX-2 expression are inhibited by lutein. These results suggest that lutein acts via two mechanisms: 1) an antioxidant effect and 2) direct inhibition of nNOS and COX-2 expression", wrote the lead investigators.
This study suggests a role for lutein in reducing damage caused by retinal ischemia and diabetic retinopathy - two diseases associated with oxidative stress caused by high intraocular pressure and high blood glucose levels, respectively. According to the lead author, "these results suggest that a lutein supplement may help protect against ischemia-mediated cell death in the retina".
Choi JS, et al. Inhibition of nNOS and COX-2 expression by lutein in acute retinal ischemia. Nutrition 22:608-71, 2006.
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DHA and Cell Survival
A paper E-published in March, 2006 reports on the role that the omega-3 fatty acid docosahexaenoic acid (DHA) in fish oil plays in protecting cells in the retina from degenerative diseases like age-related macular degeneration and retinitis pigmentosa .
In both of these blinding eye diseases, photoreceptors (rods and cones) degenerate and die. Although this process can be triggered by many different things, one of the most significant protective factors may be the close association of retinal pigment epithelial cells (RPE) and the amount of DHA they contain.
The main role of RPE cells is photoreceptor maintenance. RPE cells conduct the daily shedding, internalization and degradation of the tips of photo-receptor outer segments. Now it appears that RPE cells are also crucial to the survival of photoreceptor cells.
Closer to Solving a Complex Riddle
Both RPE and photoreceptor cells are exposed to potentially damaging factors such as sunlight and high oxygen tension on a daily basis. It's known that antioxidants such as lutein afford some protection, but exactly how these cells avoid harm from these and other factors, has been somewhat of a mystery up to now. However, Nicolas Bazan, MD, PhD, Director of the Neuroscience Center of Excellence at LSU Health Sciences Center in New Orleans, working in col-
laboration with Harvard researchers, has made several important discoveries that are beginning to provide answers to this complex question.
One of the answers is the importance of DHA. RPE cells cope with UV and oxidative stress, as well as trauma, by using antioxidants like vitamin E present in cellular membranes. Part of the RPE cells' response to these insults is to activate the synthesis of a major neuroprotective compound called neuroprotectin D1 or NPD1. Oxidative stress and other triggers turn on genes that lead to inflammation and cell death. NPD1 inhibits these genes. RPE cells contain DHA, which has been found to be the precursor to NPD1.
The DHA - NPD1 Connection
RPE cells regulate the uptake, conservation and delivery of DHA to photoreceptor cells. In addition to stimulating the production of NDP1, DHA promotes protective cell signaling by facilitating the expression of helpful rather than destructive proteins. DHA and NPD1 also decrease the production of damaging free radicals.
DHA is known to be in short supply in patients with retinitis pigmentosa and Usher's syndromes, and an oral supply of DHA has been shown to improve the condition of retinitis pigmentosa patients with chronic progressive neurodegeneration. Additionally, studies have found that higher dietary intake of DHA is associated with AMD risk reduction. DHA has been shown to promote the survival and inhibit cell death not only of photoreceptor cells, but also of neurons in an experimental model of Alzheimer's disease.
Other important questions remain, including the identification of another receptor believed to be an important pathway for NPD1, and more information is needed about the signals that control NPD1 formation. It's important to define these initial events, notes Dr. Bazan, since early clinical manifestations of retinal degeneration precedes massive photoreceptor cell death.
Physiological and pathological features of DHA in photoreceptors
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CVD & AMD Share Common Risks, Processes
A Harvard research team led by Dr. Johanna Seddon notes that age-related macular degeneration (AMD) and cardiovascular disease (CVD) share common risk factors, such as smoking and higher body mass index (BMI). They propose that mechanisms involved in developing AMD could be better understood by evaluating biomarkers of CVD. A number of analyses, in fact, have shown that systemic biomarkers for inflammation and artery damage, including C-reactive protein (CRP) and homocysteine (HCY), are related to AMD. Basic research also demonstrates that inflammatory, immune and atherosclerotic processes are related to AMD development.
To further explore mechanisms related to AMD pathogenesis, these researchers evaluated the relationships between CRP, HCY and other known risk or protective factors for AMD in subjects from the original AREDS trial. According to Dr. Seddon, the findings indicate that "sick eyes may occur in sick bodies related to smoking, overweight, inadequate nutrient intake, and other unhealthy behaviors".
Study Design
After randomization for AREDS, 934 subjects from two clinical sites underwent blood draws, measurements, photographs of the macula and answered questionnaires. Dietary, behavioral and medical risk, and protective factors for AMD were evaluated for their associations with blood values of CRP and HCY. This original data provided information on intake of fish as well as antioxidants such as vitamins C and E, alpha- and beta-carotene and lutein/zeaxanthin. In addition, serum nutrient values obtained from participants at one of the sites were also evaluated for their association with CRP and HCY. Multivariable regression analyses were performed after adjusting for age, gender and AREDS treatment.
Results
Higher levels of serum antioxidants vitamin C and lutein/zeaxanthin and higher fish intake (a source of omega-3 fats) were associated with lower serum CRP levels. CRP levels decreased 2 milligrams per litre for every 1000 microgram per decilitre increase in blood levels of lutein/zeaxanthin. A 0.2 milligram per litre decrease in CRP was also associated with more than 2 servings of fish weekly.
Increased BMI and smoking were associated with increased CRP, while serum alpha-carotene, dietary intake of antioxidants and vitamin B6 were associated with lower levels of plasma HCY. Levels of HCY were observed to be higher in those with hypertension. While serum vitamin E was linked to lower concentrations of HCY, it was unexpectedly linked to higher levels of CRP.
Comments
Factors reported to be related to AMD, namely antioxidants, smoking, BMI, HCY and fish intake, are also associated with inflammatory, immune, or other CVD mechanisms. These results are consistent with previous findings associating smoking, BMI, and the biomarkers CRP and interleukin-6 with AMD in a different study cohort of AMD patients.
The relationship between fish intake, BMI, and levels of inflammatory markers have been previously reported in other "non-ocular" study populations. These data support and expand on these associations. The positive link between higher vitamin E and CRP deserves further study, according to the authors. This finding disagrees with the recent Rotterdam study, which found that vitamin E significantly lowered AMD risk [EduFacts Vol.6 No.1].
Overall, the Harvard study adds to a growing body of data showing a protective effect of antioxidants such as lutein/zeaxanthin, and omega-3 fats against AMD.
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The Rotterdam Study Findings
The Rotterdam Study is an ongoing population-based, prospective cohort study of the factors influencing cardiovascular, neurologic and ophthalmologic diseases. Unlike AREDS, which focused on antioxidant supplementation for people who already had signs of AMD, the current investigation examined whether regular dietary intake of antioxidants could impact the risk of developing AMD in an older Dutch population free of clinical signs of the disease at baseline.
The results, reported in the December 28, 2005 issue of JAMA, strongly suggest that regular intake of antioxidants can markedly lower the risk of developing AMD, in this case by approximately one third.
Study Design
Dietary intake was assessed at baseline for 4,170 people who were at risk of AMD and who completed the follow-up. This at risk population was 55 or older and had no AMD in either eye. Participants had no drusen or pigment irregularities, hard drusen only, or soft drusen without pigment changes.
Incident AMD until final follow-up in 2004 was determined by grading fundus color transparencies. Potential for bias was minimized by grading the photographs in a blinded manner. The main outcome measure was incident AMD, defined as soft distinct drusen with pigment changes, indistinct or reticular drusen, geographic atrophy, or choroidal neo-vascularization.
Results
After a mean follow-up of 8 years (0.3-13.9 years), AMD occurred in 560 participants. After adjusting for known confounders such as atherosclerosis and smoking, dietary intake of vitamin E and zinc were found to be inversely associated with incident AMD. A dose-response relationship between both vitamin E and zinc intake and a reduced risk of AMD was noted.
The researchers also analyzed the combined intake of all 4 antioxidants studied in the AREDS trial: vitamins E and C, zinc and beta-carotene. An intake above the median for all 4 nutrients reduced AMD risk by 35%.
While no relationship between lutein consumption and risk of AMD risk was seen, the difference in intake levels among the lowest and highest quartiles of dietary intake (1.4 vs. 3.6 mg) was small.
Commentary
These findings may have important public health implications, for they strongly suggest that long-term consumption of antioxidants could prevent or delay the development of early AMD. Recent data, in fact, suggests that oxidative modification of retinal proteins play a critical role in the formation of drusen, implying that antioxidants may have their strongest effect at the initiation of AMD.
Risk reduction was observed for dietary intake above the RDA for all 4 antioxidant nutrients compared to each one alone. This indicates that the combination acted synergistically in exerting a protective effect, and underscores the need to maintain a regular, above-RDA intake of all of 4 nutrients over time.
The majority of people in this Dutch cohort appeared to consume a healthy diet. Additionally, the independent relationship between antioxidant supplements and AMD could not be examined in this study since the number of antioxidant supplement users was relatively small, and the necessary data on dose and duration of use was lacking. However supplementation may be helpful in US populations where subgroups fail to consistently consume adequate amounts of antioxidant nutrients.
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Progress in Understanding AMD Genetics
While a number of environmental and dietary risk factors have been linked with AMD, progress in identifying genetic components associated with the disease has been somewhat slower. However significant progress has been made over the last few years: up to six regions of the genome have been identified as potentially harboring AMD genes.
One region repeatedly linked to AMD in family based studies is located on chromosome 1. This year, several independent research teams reported a strong association of AMD with a chromosomal 1 gene that encodes the protein, complement factor H (CFH). A single base change in the CFH gene introduces a single amino acid change into the sequence of the variant CFH protein it produces, replacing the amino acid tyrosine with histidine. Understanding this simple genetic alteration - a change in a single unit of DNA out of the 3 billion or so units that make up our genetic blueprint - could hold future promise for those at risk for AMD. For now, the research findings are clarifying how AMD develops and how the disease is related to the immune system.
What is the Role of CHF?
The CHF protein helps regulate inflammation in part of the immune system that attacks diseased and damaged cells. CHF helps regulate complement - an arm of the immune system that provides rapid defense against microbes and clears out immune complexes & debris. When immune complexes, clusters of interlocking antigens and antibodies, aren't rapidly removed and continue to circulate they can be trapped in tissues or blood vessels where they can set off reactions that lead to inflammation. Phagocytic inflammatory cells such as macrophages can generate damaging reactive oxygen species. It appears that the abnormal CHF protein is less able to keep the complement system - and inflammation - under control.
AMD: Partly an "Immunogenetic" Disease?
The biological role of CFH as a modulator of inflammation through its regulation of complement makes it an attractive candidate gene for AMD susceptibility. Inflammation has repeatedly been implicated in the AMD disease process. For example, researchers have detected elevated levels of the inflammatory marker c-reactive protein in advanced AMD. They've also observed macrophages localized near neovascular lesions, and complement-related proteins contained in drusen deposits. In fact, some cell biologists believe that inflammation and difficulty in regulating the immune system play a causal role in forming drusen, a hallmark of AMD.
What Might the Future Hold?
The new gene findings could apply to many people. Two of the studies published earlier this year indicate that the CFH gene variant likely explains 43-50% of the overall risk of developing AMD in older adults. In another study the likelihood of having AMD was reportedly increased by a factor of 7.4 in people with the variant.
These findings may eventually lead to screening for the gene to assess a person's risk well before any symptoms develop. It also opens the door to developing new drug or gene therapies that might slow progress of the disease. The identification of CFH may also spur researchers to examine whether antioxidants, such as those used in the AREDS trial, or anti-inflammatory dietary strategies are helpful for those genetically susceptible to AMD.
Although the CHF gene has generated much excitement, we probably don't yet know the whole story. Genetic interactions are complex, many genes are involved, and environmental influences must be factored in as well. Yet 2005 will likely be remembered as a watershed year of progress toward understanding the basic causes of AMD.
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Identifying modifiable risk factors for cataract is a public health priority. The number of Americans affected by cataracts is expected to rise dramatically in the next 20 years, and cataract surgery is one of the costliest outpatient surgeries in the U.S. Body Mass Index (BMI) appears to be one modifiable - and independent - risk factor. BMI, calculated by dividing weight in kilograms by height in meters squared, generally indicates whether weight falls within a healthy range. A BMI below 18.5 indicates underweight, 18.5-24.9 is normal, 25-30 is overweight, and > 30 signifies obesity.
While a number of studies report that variations in BMI influence cataract risk, a lack of consensus as to the direction and nature of the risk has hampered application of the findings for risk intervention. A study using data from the large U.S. Nurses' Healthy and Health Professionals Follow-up Studies, for example, found that being overweight or obese raises the risk for all cataract types, while the Salisbury Eye Evaluation Project (SEE Study) reported that being underweight or overweight affects the risk for certain types of cataract.
Many factors likely contribute to the differences in findings including the use of different criteria for defining cataract or relying on self-reported anthropometric data rather than measurements conducted by trained personnel. The results of a newly published and well-conducted study support the assertion that BMI is an independent risk factor for cataract and - similar to the findings from the SEE Study - suggest that there is some trade-off between nuclear and cortical opacities.
The Shihpai Eye Study
The new study included 1360 men and women 65 years and older, with 806 of the participants diagnosed as having age-related cataract of any type. LOC System III was used to grade cataracts, and weight and height were measured by intensively trained interviewers. Potentially confounding factors such as smoking, age, sex, socio-economic status, history of hypertension and presence of diabetes were evaluated. A U-shaped relationship between BMI and nuclear opacity was observed, indicating that risk was lower in those with normal weight, but higher in the overweight and obese (fig. 1). In contrast, a reverse U shape association was seen for cortical opacity (fig. 2). Women were found to have a higher BMI and greater prevalence of cataract.
While the exact mechanism by which BMI influences cataractogenesis is not clear, some theorize that glucose intolerance and insulin resistance - even in the absence of clinical diabetes - play a role for those who are overweight. The increased risk in thinner subjects has been interpreted by some as an indicator of under-nutrition or poorer quality of diet.
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Introduction
The omega-3 fats EPA and DHA are mainly obtained from coldwater fish, while the more commonly consumed omega-6 fats primarily come from vegetable oils, meats and dairy products. Evidence suggests that the high ratio of omega-6 fats to low levels of omega-3 fats currently consumed in the U.S. promotes a number of chronic diseases. For example, the cardio-protective benefits of consuming more omega-3 are well established. Studies looking at the relationship of omega-3 to the prevalence of advanced AMD have also observed a protective effect [see table below].
Omega-3 & Major Retinal Diseases
A newly published review of omega-3 functions in the retina from the NEI Division of Epidemiology and Clinical Research supports those observations. According to the reviewers, consistent evidence suggests that the omega-3 play a pivotal role in protecting the vascular and neural retina.
The authors discuss omega-3 related bioactive compounds in relation to three retinal diseases of major public health significance: ARMD, diabetic retinopathy and retinopathy of prematurity EPA and DHA may protect against factors and processes involved in the pathology of the retina's vasculature and nerve cells such as ischemia, damage from light exposure, reactive oxygen species and free radicals, inflammation and age-related retinal changes.
General Function of the Omega-3
Lipids found in cellular membranes reflect the type of dietary fats we consume. Tissue status of long-chain omega-3 can be modified by - and is dependent on - our dietary intake of these fatty acids. In nerve cell membranes omega-3 serve structural and function roles. They maintain membrane fluidity and flexibility, and modulate ion channels, receptors and ATPases. They also serve as precursors for the formation of eicosanoids, a family of hormone-like agents that act locally in the cells that make them or in adjacent cells. Eicosanoids influence processes such as inflammation, vessel dilation and constriction, clotting, the movement of calcium in and out of cells, and cell division and growth.
Omega-3 Role in the Retina
DHA is a major structural component of retinal photoreceptor outer segment membranes, and it affects the permeability, fluidity and thickness of these membranes. The omega-3 can influence such key processes as retinal cell signaling, gene expression, differentiation and retinal cell survival.
Omega-3 also affect the production and activation of angiogenic growth factors, vasoregulatory eicosinoids, and other factors implicated in abnormal retinal neovascularization, vascular permeability and inflammation. The formation of new and abnormal blood vessels, or angiogenesis, is common to 'wet' AMD, proliferative diabetic retinopathy and retinopathy of prematurity. Clarifying the role of omega-3 in retinal health and disease is important since tissue stores can be increased by consuming a better balance of omega-3 to omega-6.
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The Nutrition and Vision Project
The Nutrition and Vision Project (NVP) is an ongoing collaboration between the Nutritional Epidemiology Program at the USDA Center at Tufts, the Center for Ophthalmic Research at Brigham and Women's Hospital at Harvard, and the Nurses' Health Study at Harvard.
Findings from the NVP research team over the years strongly suggest that antioxidants provide protection against nuclear and cortical opacity. They have observed, for example, that:
In a new study, the NVP reports that long-term vitamin E supplementation and higher intake of several B-vitamins may reduce cataract progression.
Study Design
The present study examines the change in nuclear lens opacity during a 5-year follow-up period in women aged 52 to 74. Nutrient intake was determined from multiple food frequency and supplement use questionnaires. The degree of nuclear density (opacification) was assessed using computer-assisted analysis of digital lens images.
Results
The median 5-year change in nuclear density of 18 was positively correlated with amount of opacity at baseline (p< .001). Geometric mean 5-year change in nuclear density was inversely associated with the intake of riboflavin (p trend = .03) and thiamin (p trend = .04). However, the strongest inverse correlation was between change in nuclear density and length of vitamin E supplement use (p trend = .006). The increase in nuclear density among women who never used vitamin E supplements was 42% higher than for those who used vitamin E supplements for 10 or more years (Table 1).
Summary
The authors conclude: "Our observation that vitamin E intake is associated with a reduction in nuclear opacification is consistent with other longitudinal studies and strengthens the hypothesized role for this specific nutrient in nuclear cataract formation".
Discussion
The authors offer several possible explanations as to why the inverse association between vitamin C intake and cataract seen previously was not observed in this study. First, women who did not use vitamin C supplements and had a greater risk of increased nuclear density were, unfortunately, excluded from the analyses. Secondly, different nutrients may influence the process of lens opacification at different stages. Previous studies examined very early opacities, while the current study largely examined their progression. Vitamin C may help protect lens crystallins from initial insults, while vitamin E and other nutrients seem to act at a later stage, perhaps protecting lens membranes against damage.
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Systematic reviews and recent studies indicate that Ginkgo biloba is a promising herbal supplement for improving cognition and function in people with age-related dementia . Preliminary research also points to a role for Ginkgo in some eye conditions. Small controlled trials report that Ginkgo improves pre-existing visual field damage in patients with normal tension glaucoma, and long distance visual acuity in AMD patients.
The beneficial effects of Ginkgo are attributed to its antioxidant properties and ability to enhance cerebral blood flow. There have been reports linking Ginkgo use with spontaneous bleeding or increased bleeding post-surgically. However, it is not always clear from these observations whether ginkgo is contributory or simply associated with these occurrences. According to the conclusions of a recent independent and systematic review of the world's medical literature, the probability of Ginkgo causing such bleeding is "unlikely" . However the use of Ginkgo at effective levels (120 mg. or higher) along with anti-coagulation or anti-platelet medications could raise the risk of increased bleeding and likely should be monitored with occasional bleeding time tests. Some experts also believe that Ginkgo, like aspirin, should be discontinued between 36 hours and 14 days before surgery.
Medical experts at the University of Exeter, England searched 5 medical databases for cases reports in which bleeding had been observed in patients who had been using some type of preparation containing Ginkgo. The review was initiated in recognition that numerous published articles and reviews on Ginkgo have acknowledged the theoretical possibility that use of Ginkgo extract as a medicine or dietary supplement may result in bleeding due to Ginkgo's well-documented mechanism of inhibiting platelet aggregation.
Twelve case reports met the authors' inclusion criteria. They examined each of these published reports and scored them according to a previously published scoring scale that rates the reliability of each report based on the amount of evidence. This scale classifies each study into one of 3 categories: "not able to evaluate" - the report contains inadequate information to assess the likelihood of a causal relationship; "possible" - the report provides some evidence for a causal relationship but there may be other causes of the event (e.g., the use of anti-coagulant drugs); and "likely" - the report is well documented and appears to provide reliable evidence for a causal relationship.
The authors concluded that the evidence in the reports was "far from compelling." In all but one of the cases the evidence for causality did not rate higher than "possible". They noted that with such widespread use of Ginkgo - 5 million unit doses are sold each year in Germany alone - the number of case reports of bleeding was "extremely low."
The authors discuss the apparent contradiction in the case reports and the results from controlled clinical trials. The researchers concluded that since there have been no cases of bleeding observed in 9772 subjects in 44 controlled clinical trials that they reviewed, that the probability of such cases happening with Ginkgo users was "unlikely."
"Case reports can rarely be conclusive," they write, "and under-reporting can significantly distort the picture. While the case reports suggest that [Ginkgo] does affect blood coagulation, the controlled clinical trials do not support such a hypothesis. Weighing the conclusiveness of this evidence, it seems likely that the case reports are 'false positives' and that the controlled trials depict the true situation: Ginkgo biloba does not cause bleeding abnormalities."
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According to a report released in May, an estimated 18 million Americans now have diabetes and another 20 million have impaired glucose tolerance that can lead to the full-blown disease. The prevalence of type 2, in fact, has tripled in the last 30 years along with the steady upsurge in obesity. In addition to facing higher rates of heart disease and potential complications such as neuropathy and retinopathy, diabetics are also more likely to suffer from dry eye according to findings from a recent prospective study.
Researchers followed the medical records of nearly 160,000 patients, 22,382 of them diabetics, in one of Israel's largest HMOs for 1 year. All filled prescriptions for ocular lubricants were documented, and the proportion of ocular lubrication consumers among diabetic and non-diabetic patients aged 50 and older was compared. HbA1c was also measured to examine the relationship between glycemic control and lubricant use.
A significantly higher percentage of diabetics (21%) were shown to receive the medications compared with non-diabetics (14%) in all age groups and for both sexes (Fig 1). Significantly more diabetics were frequent users of the medication (> 12 filled prescriptions yearly) than were KCS patients without diabetes. A clear trend between higher lubricant use and poorer glycemic control, regardless of age, was also observed.
The findings suggest that blood sugar control is important in preventing or reducing KCS in diabetics. According to the authors, small vessel damage and autonomic neuropathy may reduce lacrimal gland function. Decreased corneal sensitivity, which interrupts tearing reflex, could also play a role.
Commentary
Results from several small controlled trials report that supplemental gamma-linolenic acid (GLA) improves symptoms of dry eye in KCS and post PRK (2,3). While this fatty acid has not been evaluated specifically in diabetic patients, there is evidence that GLA metabolism is impaired in diabetes. Additionally, GLA (480 mg daily) has been shown in a placebo-controlled trial to improve diabetic neuropathy.
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There's a growing interest in nutrigenomics - the study of how different foods may interact with specific genes to modify the risk of chronic diseases. The underlying premise is that the influence of diet on health is related to individuals' genetic or phenotypic make-up. The aim is to identify the bioactive molecules in the diet that affect health by altering gene expression. As with any emerging field, there are knowledge gaps to close and questions about whether testing and targeted nutrition therapy will be cost effective public health strategies. However knowledge is increasing.
For example, researchers are identifying genotypes that appear to put meat consumers more at risk for colorectal cancer, and finding genetic variations that may increase susceptibility to osteoporosis and require early intervention with calcium and other nutrients. We've also learned that a common polymorphism of one gene is linked to elevated homocysteine levels and increased risk of heart disease when folic acid intake is low (3,4).
Predicting Who Can Benefit from Vitamin E
Researchers from Israel's Institute of Technology are pursuing another line of inquiry. It's known that people vary in their phenotype of haptoglobin (Hp), a blood protein that attaches to free hemoglobin and is used clinically to assess the rate of red blood cells destruction. Hp is also an antioxidant protein that prevents hemoglobin-induced tissue oxidation. The Hp gene locus is polymorphic, and people can inherit one of 3 different haptoglobin types referred to as Hp 1:1, Hp 2:1 and Hp 2:2. These inherited variations appear to influence response to antioxidant therapy.
The Israeli team tested this hypothesis in the Women's Angiographic Vitamin and Estrogen Trial (WAVE), a prospective study that evaluated the effects of vitamins C and E with or without hormone replacement therapy in treating atherosclerosis in post-menopausal women - a study that failed to find any benefit in taking antioxidants. In analyzing data from this trial, the Israeli researchers found significant benefit of the vitamins in slowing coronary artery stenoses, but only in women with a certain haptoglobin type.
Vitamin E May Benefit Haptoglobin 2:2 Diabetics
Hp 2:2 is a very poor antioxidant compared to other Hp types, and Hp 2:2 appears to be predictive of heart disease in diabetics who tend to generate more free radicals. About 40% of diabetics are estimated to have the Hp 2:2 form. In the newest study, the team analyzed serum samples from the Heart Outcomes Prevention Evaluation (HOPE) trial, another trial that showed no benefit for 400 IU vitamin E supplementation on cardiovascular risk in all patients. When analyzed by Hp type, those diabetics with Hp 2:2 who took vitamin E had an apparent 43% reduction in risk of heart attack.
Large Scale Trial Underway
According to the researchers at Technion, a large-scale, 5-year study of some 2000 diabetics with Hp 2:2 is being conducted. If this larger study confirms the results seen so far, vitamin E might represent a way to reduce the risk of CVD and heart attack in a significant proportion of diabetics. It may also help explain the disparity in results from antioxidant trials in recent years.
Other research teams have reported links between Hp 2:2 and refractory hypertension, risk of gestational diabetes and other disorders. If further research corroborates the predictive value of haptoglobin type, it may be a useful tool to identifying those who can benefit from targeted nutrition strategies.
References
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Dr. EJ Johnson of the USDA Human Research Center on Aging offers an intriguing evaluation of the mechanisms by which obesity increases the risk of Age-related Macular Degeneration (AMD). The number of Americans with AMD is expected to triple within the next 30-40 years. Obesity is also on the rise. Currently, more than 44 million are obese, a figure that has grown by 74% since 1991. Interestingly, a number of studies have reported a higher risk for AMD in people with a greater body mass index or BMI (see table 2). Obesity is defined as having a BMI greater than 30.
According to Dr. Johnson, the connection between obesity and AMD may be due to changes in lutein metabolism. The pigment lutein functions as an antioxidant and blue-light filter, and is believed to protect the macula and retinal structures from light-initiated oxidative damage. Population and case-control studies suggest that AMD risk is inversely related to dietary intake of lutein, and recent studies also report that supplemental lutein improves visual function in AMD patients (2,3).
Obesity, Oxidative Stress & Inflammation
Obesity increases oxidative stress when the activity of "free radicals" exceeds the ability of antioxidants to neutralize them. Antioxidant defense mechanisms have also been reported to be lower in obesity. Oxidative stress is believed to be involved in the etiology of AMD, just as systemic oxidative stress contributes to atherosclerosis in the obese.
Obesity and inflammation also go hand in hand. C-reactive protein, a marker of inflammation, has been found to be higher in people with a greater body mass index (BMI) and to drop when weight is lost. Analysis of the National Health and Nutrition Examination Survey suggests that chronic inflammation elevates levels of C-reactive protein and - importantly - reduces serum carotenoids such as lutein and zeaxanthin.
How Does Obesity Affect Lutein Metabolism?
The changes that occur in obesity - more oxidative stress, inflammation and changes in lipid profiles - could also increase destruction of lutein and decrease the amount being delivered to the macula. Four mechanisms may be involved:
The author concludes that efforts to prevent obesity and to improve lutein/ zeaxanthin status may be important in AMD prevention.
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Introduction
About 20 million Americans have vision-obstructing cataracts, with 500,000 new cases diagnosed annually. The estimated current cost of $3.4 billion annually to surgically extract cataracts is expected to increase along with the growing number of people over the age of 65. Among the risk factors associated with age-related cataracts, UV exposure and oxidative stress appear to be the most relevant. The lens is equipped with antioxidant mechanisms - such as glutathione peroxidase, vitamins C and E and carotenoids - to defend against the harmful effects of UV radiation and reactive oxygen species (ROS). Indeed, some epidemiologic studies suggest a reduced risk of developing various types of cataract with higher intake of vitamin C, E or lutein and zeaxanthin, the only carotenoids present in the lens and macula.
Although considerable efforts are being made to define the potential role of the xanthophylls lutein and zeaxanthin in the macula, information about their uptake and function in the lens is extremely limited. Epithelial cells, the outermost cellular layer of the lens, are exposed to UV irradiation not filtered by the cornea. UV-induced damage is mediated via production of ROS, and characterized by alterations in cell growth, morphology, changes in membrane potential, and oxidation of lipids, proteins and DNA. The present study examined the ability of xanthophylls to protect cultures of immortalized human lens epithelial cells (HLE) against UVB insult.
Results:
Cultured HLE cells accumulated xanthophylls and alpha tocopherol in a dose and time-dependent manner, with uptake of lutein exceeding that of zeaxanthin. Cultures were pretreated with either xanthophylls (2 µmol/L) or alpha tocopherol (10 µmol/L) for 4 hours, then exposed to 300 J/m2 UVB radiation - a dose roughly equivalent to that a person receives when they get a mild tan. Lipid peroxidation was observed to decrease by 47-57% compared with UVB-treated control cells.
The ability of xanthophylls and vitamin E to inhibit UVB-induced stress signaling was also assessed. Pretreatment with xanthophylls and alpha tocopherol inhibited UVB-induced activation of c-JUN NH2 terminal kinase and p38 activation by 50-60% and 25-32%, respectively. The concentration of Vitamin E required to significantly inhibit these stress signaling markers was roughly 10-fold higher than that of the xanthophylls, suggesting that xanthophylls are more potent for protecting HLE cells against UVB insult in this model.
Conclusions
According to the researchers from Ohio State University, their results are the first to provide physical evidence suggesting that lutein and zeaxanthin decrease damage caused by UV radiation. "In addition to protective enzymes and compounds like vitamins C and E, we think that low concentrations of lutein and zeaxanthin in the eye's lens help shield the eye from the harmful effects of UVB radiation", they stated in a post-publication interview.
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Published in 2001, the AREDS clinical trial reported that zinc (80 mg), copper (2 mg) and the antioxidants vitamin E (400 IU), vitamin C (500 mg) and beta-carotene (15 mg), reduced the risk of AMD progression by 25%. Because ocular disorders such as cataract, AMD and diabetic retinopathy have been reported to be significant predictors of decreased life span, AREDS investigators examined the relationship between AMD, cataract and mortality among AREDS participants. They also analyzed the relationship between mortality and the high-dose supplements used in AREDS.
Cataract and AMD Increase Mortality
At baseline, the median age of the 4757 AREDS participants was 69 years. During a median follow-up of 6.5 years, 11% of the 4753 AREDS participants died. In fully adjusted models, participants with advanced AMD had increased mortality compared with those with few if any drusen (RR 1.41), and advanced AMD was associated with cardiovascular death. Nuclear opacity (RR 1.40) and cataract surgery (RR 1.55) were also associated with higher all-cause mortality and with cancer deaths.
Supplemental Zinc Improves Survival
Participants randomly assigned to receive zinc, whether alone (RR 0.73) or combined with antioxidants (RR 0.88), had lower mortality than those not taking zinc. That represents a 27% reduced risk of mortality for zinc alone, and a 12% lower risk for those who took zinc combined with beta-carotene, vitamin C and vitamin E. This finding contrasts with that of a recent meta-analysis which linked high dose vitamin E with increased mortality.
The positive association of zinc with improved survival did not seem to be due to a reduction in deaths from circulatory disease or cancer. Further analysis suggested a possible protective effect for respiratory causes of death. The beneficial effects of zinc on mortality in this study may be related to an improved immune response, which is known to decline with aging.
Lower Survival May Reflect System-Wide Processes
These findings are generally consistent with other large population-based studies that have reported associations between impaired vision and increased mortality. Ocular disorders, particularly cataract, may be markers of systemic processes associated with accelerated physiologic aging and earlier death, and not just local processes. For example, generalized oxidative damage might play a role in the development of cataract as well as aging. The association noted between AMD, all-cause mortality and death from circulatory diseases may be explained by an underlying vascular basis for AMD, a hypothesis suggested by some epidemiologic studies.
This is the first large randomized trial to report a benefit of high doses of zinc on survival, though other researchers have reported that moderate zinc and selenium doses improved immunity and resistance to infections in the elderly. More randomized trials of supplemental zinc and mortality are needed to confirm these findings.
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Introduction:
Observational as well as in vitro and intervention studies suggest that lutein may play a preventive role in age-related macular degeneration (AMD) (1-5). In the Lutein Antioxidant Supplement Trial or LAST, the effects of lutein on macular pigment optical density (MPOD) and objective visual outcomes were evaluated in patients with established atrophic AMD. First reported at an annual meeting of ARVO, the findings were published in the April, 2004 issue of Optometry.
Methods:
This study enrolled 90 veterans with atrophic AMD in a prospective, placebo-controlled, double-blind trial that involved repeated visual measures over a 12 month period. Volunteers were randomly assigned to receive 10 mg of lutein alone, 10 mg of lutein along with antioxidants* or a placebo. The investigators used a clinical evaluation protocol that was previously validated in a pilot case series. Several tests were used to detect and follow the disease in a serial manner. One, the contrast sensitivity function (CSF) assessment measures the least amount of contrast needed to detect a visual stimulus. CSF assessment enables the detection of changes in visual processing earlier than visual acuity. The investigators also employed the SKILL Card clinical test to assess visual acuity at low levels of light and contrast, and monocular visual acuity was measured by Snellen letter equivalent. Additional tests included the Amsler grid, the Activities of Daily Vision Scale and Glare Recovery, a test of macular function where the dark adaptation of the eye is measured after a flash of light centered on the macula. MPOD was measured by heterochromic flicker photometer.
Results:
Subjects in the lutein, and lutein/antioxidant groups showed a significant increase in average MOPD (repeated measures ANOVA; p<.05) over 12 months, compared to a slight decline in the placebo group. The increased MPOD was seen across all stages of AMD (II-IV). While the placebo group had no significant changes in any of the measured outcomes, both the lutein and the lutein/antioxidant treatments improved some measures of visual function, including glare recovery, quality of vision reflected by CSF and near visual acuity. For the lutein group, near visual acuity increased by about 1 line, while it decreased for the placebo-takers.
Conclusion:
According to the authors, this modest prospective clinical trial agrees with studies suggesting AMD to be, in part, a nutrition responsive disorder. LAST demonstrated improvements in symptoms of clinical concern to patients, and indicates the need for larger and longer-term trials to confirm these salutary findings.
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Introduction:
Glaucoma is the second leading cause of blindness in the world after cataracts. While research has identified non-pressure dependent risk factors for glaucoma, elevated intraocular pressure due to reduction in aqueous outflow remains a major causal factor. Several lines of evidence suggest that chronic oxidative stress is important in glaucoma pathogenesis: age-dependent clinical onset, constant exposure of the trabecular meshwork to H2O2 in the aqueous humor, and altered cellular and molecular responses to H2O2 exposure in vitro. Results of a recent investigation provide convincing evidence that oxidative damage to the trabecular meshwork is involved in glaucoma.
Study Design and Results:
Specimens of trabecular meshwork collected from 45 glaucoma patients and 45 controls of similar age and gender, were analyzed for levels of 8-hydroxy-2'-deoxyguanosine (8-OH-dG). Levels of 8-OH-dG, an indicator of oxidative DNA damage, were measured using a 32P post-labeling procedure. The researchers observed a more than three-fold increase in the amount of 8-OH-dG in the meshwork tissue of glaucoma patients. This increased DNA damage was found to correlate significantly (p= .0001) with clinical parameters such as intraocular pressure indexes and visual field losses (see Figure 1).
Because several metabolic pathways affect the cellular response to oxidative DNA damage, the investigators also evaluated the status of genes involved in detoxifying oxidative radicals - in particular GSTM1 and GSTT1. The enzymes encoded by these two genes catalyze the deactivation of reactive oxygen species by glutathione. The absence of GSTM1 was associated with primary-angle glaucoma.
Discussion:
Trabecular meshwork cells and the aqueous humor rely on antioxidant mechanisms for protection. In the meshwork for example, reduced glutathione protects against H2O2-induced oxidative damage, and it becomes depleted when the aqueous humor is under oxidative stress.
"Our results may have implications for the prevention and treatment of glaucoma", the researchers stated. "Use of antioxidants may be worth studying for the prevention of primary open-angle glaucoma and psuedoexfoliative syndrome, and for treating overt cases". According to an accompanying article in the same journal, these findings shed new and important light on the molecular mechanisms involved in glaucoma, and also suggest a possible genetic predisposition to the disease.
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Introduction:
The botanical Ginkgo biloba has been extensively examined for its cognitive effects in patients with dementia. Recently, a six-month double blind trial conducted at UCLA found significant improvement in verbal recall among subjects with age-associated memory impairment. Using positron-emission tomography, the researchers reported that improved recall correlated with better function in key brain memory centers of those taking ginkgo supplements. The effects of ginkgo are attributed to its ability to enhance cerebral blood flow and provide antioxidant activity.
Over the past decade, research has identified non-pressure dependent risk factors for glaucoma, including cerebral and ocular ischemia. There is increasing awareness that the prevalence of normal-tension glaucoma (NTG) is greater than previously realized, and that progressive damage can occur even with IOP-lowering intervention. Since Ginkgo has been shown to increase ocular blood flow, the effects of a ginkgo extract on pre-existing visual field damage in normal tension glaucoma was evaluated in a prospective, randomized, double-blind crossover trial.
Trial Results:
Twenty seven patients with bilateral visual field damage resulting from NTG received 120 mg of ginkgo extract (40 mg, 3x daily) for 4 weeks, followed by a wash-out period of 8 weeks, then 4 weeks of placebo treatment. Other patients underwent the same regimen, but took the placebo first and ginkgo last. Visual field tests, performed at baseline and at the end of each phase of the study, were evaluated for changes in visual field and any ocular or systemic complications.
After ginkgo treatment, a significant improvement in visual field indices was observed.
No significant changes were found in intraocular pressure, blood pressure, or heart rate after placebo or ginkgo treatment. The investigators concluded that Ginkgo biloba is a useful therapy for some patients with NTG. An accompanying editorial in Ophthalmology points out that the mechanisms of ginkgo are plausible, and that the beneficial effects were not maintained in this study after discontinuation of ginkgo treatment. Both of these observations lend credence to the findings.
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Introduction
Transitory dry eye is a common complication after PRK and LASIK, lasting longer in patients with pre-operative dry eye. The anti-inflammatory properties of the fatty acid gamma linolenic acid (GLA) have long been known, and recent studies report that supplemental GLA increases tear concentrations of anti-inflammatory prostaglandin E1 (2,3), and increases tear production while reducing dry eye symptoms in post-PRK patients.
Consistent with these findings, are the results from several preliminary investigations of HydroEye®*, reported by Frank A. Bucci Jr, MD at the 2002 and 2003 ASCRS meetings. In the first study, administration of HydroEye daily to 13 normal patients was found to increase mean tear lactoferrin levels by 60% at the end of 8 weeks. Additionally, 12 pre-LASIK patients given HydroEye daily 1-4 weeks prior to LASIK, experienced a 40% increase in lactoferrin when measured the day before the procedure.
Follow-Up Trial
In a follow-up study reported at ASCRS earlier this year, Dr. Bucci evaluated the effects of pre-treatment with HydroEye in 40 patients undergoing bilateral LASIK. Twenty patients with a history of evaporative or aqueous-deficient dry eye were assigned to take the daily recommended dose of HydroEye for one month before surgery, continuing for a month post-operatively.The remaining 20 patients, age-matched but with no prior history of dry eye, served as untreated controls.
Tear lactoferrin levels were measured (Tear Profile Analyzer) at baseline, on the day of the procedure, and at one day and one month after surgery. At the beginning of the study, the treated group had a higher incidence of ocular surface disease and a lower lactoferrin level than the control group (.95 vs. 1.1 ng/ml, respectively).
In the treated patients, mean lactoferrin increased a significant 32% during the pre-treatment period, becoming significantly higher (mean 24%) than the control group by the day of surgery. Lactoferrin levels dropped one day post-op in both groups. However the post-surgery decrease was less marked in the treated compared to untreated patients (.88 v .77 ng/ml respectively), with lactoferrin levels still 12% higher in those taking HydroEye. Lactoferrin rose in both groups during the month following surgery, with levels remaining slightly above baseline measurements in the treated group. No difference in lactoferrin was noted between the two groups at the end of this period.
Levels of tear lactoferrin, an indicator of ocular surface health, have been shown to be decreased in those with tear-deficient dry eye, according to the study's author. "Against that background, the results of this study support the pre-operative, prophylactic use of oral omega fatty acids in patients with mild to moderate risk for dry eye after LASIK," Dr. Bucci concluded.
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Introduction:
PRK is known to cause a temporary reduction in corneal sensitivity, leading to tear film changes, lowered reflex tearing, and production of inflammatory cytokines and free radicals. Transitory dry eye is a common complication after PRK and LASIK, lasting longer in patients with preoperative dry eye.
The anti-inflammatory properties of the fatty acid GLA have long been known. Recent studies report that oral administration of GLA and LA leads to a significant increase in tear concentrations of anti-inflammatory prostaglandin E1 (2,3), and reduces the symptoms of dry eye. The aim of this study was to evaluate the effects of GLA and LA on tear production, tear fluorescein clearance, dry eye symptoms, and the ocular surface after PRK.
Methods:
In this randomized, controlled trial, 31 patients received modest amounts of oral GLA and LA 3 days prior to 30 days after undergoing PRK. Another 29 patients underwent PRK without the supplement, serving as controls. The following measurements were made at baseline and at the end of the study period: symptom questionnaire, Schirmer 1 test, fluorescein clearance test using standardized visual scale and corneal fluorescein staining.
Results:
All 60 patients completed the study. Statistical analysis showed a significant mean difference between the groups for dry eye symptoms, fluorscein clearance, and Schirmer's results. Compared to controls, the treated group had lower symptom scores, greater Schirmer test values, and more favorable fluorescein clearance scores [See Figures 1-3]. Both groups showed no signs of corneal staining at baseline. While more areas stained in controls than treated patients at 1 month post-surgery (0.09 ± 0.10 vs. 0.25 ± 0.21 respectively), the difference was not significant. The researchers concluded that oral precursors of prostaglandin E1, GLA and LA, could be helpful in increasing tear production and clearance after PRK.
Figure 1. Results of symptoms questionnaire (mean score) before starting study (T0) and 1 month after PRK (T1). (*P<0.05)
Figure 2. Results of Schirmer 1 test (mm/5 min) before starting study (T0) and 1 month after PRK (T1). (*P<0.0001)
Figure 3. Results of fluorescein clearance test by means of visual scale (mean score) before starting study (T0) and 1 month after PRK (T1). (*P<0.0001)
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Introduction
Cataract incidence increases with age, reduces visual performance, and is responsible for about 30-50 million cases of blindness worldwide, according to the authors of a study published this month. Since oxidative damage is thought to play a role in initiating and promoting cataract, antioxidant nutrients may be of benefit by reducing oxidative stress in the lens. Observational studies have linked higher intake of vitamin E and lutein, as well as long-term vitamin C supplementation, with lower risk of cataracts (2-4).
Intervention trials with high-dose beta-carotene, along with vitamins C and E have produced mixed results (5,6). In contrast to beta-carotene, lutein and its isomer, zeaxanthin, are the only carotenoids detected in lens and macula. Therefore, an association between these carotenoids and cataract is biologically plausible. The aim of this study was to assess the effect of high-dose vitamin E and lutein in senile cataract.
Methods:
In this double-blind trial, seventeen volunteers with mostly posterior subcapsular and nuclear opacities, were randomized to receive one of three treatments: a) 15 mg lutein capsule (as esters, equivalent to about 7 mg free lutein); b) 100 IU vitamin E capsule OR c) placebo capsule (corn oil). The supplements were taken three times weekly. Average supplementation time was 26 months (range of 12-36 months). Visual function, tested every three months, was measured with routine static (visual acuity) and several dynamic (glare sensitivity) clinical diagnostic tests. Visual acuity at baseline was within the same range for all groups, but placebo-treated subjects showed lower levels compared to subjects in the lutein group.
Results:
Compliance was greater than 80%. Some subjects dropped out during the 3-year study, mainly in the placebo group, to undergo cataract surgery. Therefore only data from the first 24 months were used for statistical analysis. Both visual acuity and glare sensitivity improved in the lutein group, with visual acuity significantly improved over baseline (p<.005). A trend toward maintenance of visual acuity was seen in the vitamin E group, while it tended to decrease in placebo takers. Clinical examination showed that cataracts did not progress in four of five patients in the lutein group, three of five in the vitamin E group, and one of five among placebo subjects.
Figure 1. Changes in visual acuity of patients with cataracts during the supplementation study (eyes were assessed individually). Lutein group (n = 9), a-tocopherol group (n = 10), and placebo group (n = 7). CI = confidence interval.
Comments
According to the researchers, this pilot study suggests that increasing lutein intake though lutein-rich foods or supplements improves the visual performance of patients with age-related cataract. Interesting, the serum levels of lutein achieved in this study were very close to those associated with substantial increases in macular pigment density seen in other trials. These results call for larger studies to confirm the benefits of lutein in patients with cataract.
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Related Information: View / Listen to an Interview with Paul Bernstein, MD, PhD on the Role of Lutein & zeaxanthin in Macular Health
The results from a new NEI-sponsored study suggest that low ocular levels of antioxidants lutein and zeaxanthin - carotenoids found in dark green, leafy vegetables such as spinach and kale - could contribute to age-related macular degeneration (AMD). The research team also reports that AMD patients who had begun taking high-dose lutein supplements after initially diagnosed with AMD were able return those levels back to normal.
The investigators' primary objective was to quantify and compare macular pigment levels in AMD and normal subjects. Macular carotenoid levels were measured in 93 eyes from 63 patients with AMD and in 220 normal eyes from 138 volunteers using resonance Raman spectroscopy - a method which measures the signal intensity generated by the carbon-carbon double bond vibrations of lutein and zeaxanthin. Because this method provides a non-invasive, objective and sensitive means to determine carotenoid levels and optical density in the eyes of living people, it is particularly useful in large-scale clinical studies.Macular carotenoid levels declined with age, reaching a stable low level after age 60, when AMD incidence begins to rise dramatically (Fig 1). They also found that macular pigment levels in the eyes of AMD patients not consuming high-dose lutein supplements were 32 percent lower than elderly normal eyes (p = 0.001) (Fig 2). Patients who began taking high dose lutein supplements (ranging from 4 - 20 mg) after their initial AMD diagnosis had significantly higher macular pigment levels compared to those who did not (p = 0.038). In fact, macular content of the AMD patients using high-dose supplements was also similar to that of normals.
Figure 1.
"These results taken together lead us to believe that low macular levels of lutein and zeaxanthin represent a pathogenic risk factor for the development of AMD," (2,3) said lead investigator Paul Bernstein. "As a safeguard, patients at risk for visual loss from AMD should consider supplementing their diets with at least 4 mg of lutein each day along with other antioxidant nutrients."
Figure 2.
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Due to contact lens intolerance, dry eye is a major reason for patients to consider LASIK. Dry eye is also a common post-LASIK complication, with compromised tear function and ocular surface typically lasting for at least one-month after surgery. Recovery time after surgery is also increased when dry eye develops. These factors led a group of researchers to investigate whether preoperative dry eye affects the visual outcome and incidence of complications after LASIK, and whether it is a risk factor for severe dry eye after surgery.
Methods:
The investigators divided 543 eyes (290 patients) into three groups: those without dry eye (NDE), those with probable dry eye (PDE), and subjects with definite dry eye (DE). Subjects were diagnosed for DE or PDE and categorized into one of the three groups according to the modified criteria of the Japanese Dry Eye Association, which included the Schirmer test with anesthesia, tear Break-Up Time (BUT), fluorescein and rose bengal staining of the ocular surface, and symptom assessment. Follow-up tests were performed at 3, 6, and 12 months after the procedure. To evaluate the effectiveness of LASIK correction, uncorrected (UCVA), best-corrected visual acuity (BCVA), and manifest refraction in the spherical equivalent were examined at 1, 3, 6, and 12 months.
Results:
No significant differences were found among the groups in UCVA and BCVA, except at 1 month, when UCVA was better in the NDE than in the DE group (p>.03). In the DE group, manifest refractive deviation was slightly larger than in the NDE group only at 3 months (p>.01).
The mean results of the Schirmer test were lower in both the DE and PDE subjects compared with the NDE group at all follow-ups after LASIK. Tear BUT was shorter in the DE compared to the NDE group before and at post-LASIK follow-ups. For ocular surface abnormality, fluorescein scores were higher in the DE than the NDE group before and after LASIK up through the one-year mark. Similar results were found with the rose bengal scores.
Dryness was significantly more severe for the DE group compared to the NDE group before LASIK and at 3, 6, and 12 months. This also held true for the PDE vs. the NDE patients at 6 months and 1 year (See figure 1).
Conclusions:
The results indicate that the safety and efficacy of LASIK are not affected by preexisting dry eye status. However, preoperative dry eye is a risk factor for severe postoperative dry eye with lower tear function, more vital staining of the ocular surface, and more severe symptoms. Bottom line: those that start out with dry eye suffer more discomfort over a longer period. This is a significant problem, as more than 75% of the patients who undergo LASIK at their clinic have dry eye at the outset according to these investigators.
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Introduction:
Epidemiological observations (1,2), as well as in vitro and interventional studies (3-5) suggest that lutein may play a role in AMD. A recent study, the Lutein Antioxidant Supplement Trial or LAST, evaluated the effects of lutein and lutein combined with antioxidants on atrophic AMD. Results from the trial were reported at the meeting of the Association for Research in Vision and Ophthalmology (ARVO) in May, 2002.
Methods:
This study enrolled 90 veterans with atrophic AMD in a prospective, placebo-controlled, double-blind trial that involved repeated visual measures over a 12 month period. Volunteers received 10 mg of lutein alone, 10 mg of lutein along with antioxidants*, or a placebo.
The LAST study used a clinical evaluation protocol that was previously validated in a pilot case series. Several tests were used to detect and follow the disease in a serial manner. One, the contrast sensitivity function (CSF) assessment measures the least amount of contrast needed to detect a visual stimulus. CSF assessment enables the detection of changes in visual processing earlier than visual acuity. The investigators also employed the SKILL Card clinical test to assess visual acuity at low levels of light and contrast.
Additional tests included the Amsler grid, the Activities of Daily Vision Scale, and Glare Recovery, a test of macular function where the dark adaptation of the eye is measured after a flash of light centered on the macula. Macular pigment optical density using a heterochromic flicker photometer and lens opacification rating was also assessed.
Results:
Subjects who were given lutein, and lutein plus antioxidants showed a 50% increase in average macular pigment optical density (repeated factors ANOVA; p<0.05) over 12 months, compared to the placebo group. Both the lutein and the lutein/antioxidant treatments significantly improved some measures of visual function, including glare recovery, contrast sensitivity, and visual acuity.
Conclusion:
According to the authors, this modest prospective clinical trial agrees with studies suggesting AMD to be, in part, a nutrition responsive disorder. Larger and longer-term trials must be conducted to confirm these findings.
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A number of studies over the past decade have suggested that antioxidant vitamins C & E and carotenoids reduce the risk of age-related cataract. REACT was a multi-centered, prospective, double-blind and placebo controlled trial conducted in the U.K. and U.S. to examine whether an antioxidant mixture could slow the progression of early age-related cortical, nuclear, or posterior subcapsular cataract.
After a three-month placebo run-in period, 297 patients were randomized to one of three clinical centers in Boston, Bradford and Oxford England. The subjects were stratified by cataract type and randomly chosen to receive placebo or antioxidants (750 mg C, 600 IU E, and 18 mg beta-carotene). Clinic visits occurred about every four months and patients were followed, on average, for three years.
Cataract severity was documented by serial digital retro-illumination imagery of the lens. Cataract progression, the primary outcome, was measured by image analysis of the increase in area of opacity. This change in area was assessed by "increase in percent pixels opaque" called IPO.
When the combined treatment groups in both countries were compared to all placebo takers after three years, a statistically significant reduction in opacification was found in the group getting vitamins (1.66% IPO vitamin vs. 3.27% IPO placebo). The beneficial effect was more pronounced when looking only at the US participants, particularly in sub-groups with early or no cataract. However in their British counterparts, in whom cataracts were more mature at baseline, treatment and placebo groups were not significantly different. The observed reductions in opacity were not specific to one type of cataract.
While the slowing in cataract progression among the antioxidant takers was modest, it could be very important in the long term, according to the authors. The extent of lens opacification was 1.61% less in the antioxidant treated group over the three-year period. The investigators point out that if antioxidants were supplemented for ten to twenty years, the observed reduction in progression would translate into a clinically important 5-10% reduction-a slowing that could have a sizable impact on the burden of providing cataract surgery.
This projected benefit is strengthened by the findings of the Vision and Nutrition Project where long-term use-ten years or more-of antioxidants like vitamin C, reduced cataract risk markedly. Other longitudinal studies have noted risk reduction in those with higher plasma levels of vitamin E. Recent studies have also linked lutein, rather than beta-carotene, to reduced risk. Since early cataract probably begins at about age 45, people in their 30's and 40's might potentially delay the onset or progression of lens opacity by improving their antioxidant status.
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Findings from this multicenter, NEI and NIH sponsored study were reported in the October 2001 issue of Archives of Ophthalmology. The study followed 3,640 participants, aged 55-80, for an average of 6.3 years. Patients were initially enrolled in four AMD categories based on the size and extent of retinal drusen and level of visual acuity decline (Table 1), and were randomly assigned to one of four treatment arms:
While the investigators acknowledged the importance of lutein and zeaxanthin for macular health, these carotenoids were not available for use in supplements when the study began. Instead, the investigators chose beta-carotene, which was then being studied for heart disease and cancer.
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Although the antioxidant and zinc supplements each appeared to offer some protection, the benefits of supplementation were greatest for those patients who received the antioxidant and zinc combination, and who were in the highest-risk category groups.
Supplementation with combined antioxidants and zinc significantly reduced the risk of progression to advanced AMD in these groups by 25%. A significant risk reduction in vision loss was also seen in the higher-risk groups taking both zinc and antioxidants, with an odds reduction of 27% (Table 2).
Very few patients with less severe AMD went on to develop advanced cases. Therefore the study was unable to detect whether the zinc and antioxidant combination might delay or prevent progression in subjects at an earlier stage. However, when the researchers included the less severe category (category 2) with the more advanced categories (3 and 4), the combined supplements showed an odds reduction in the visual acuity outcome that approached statistical significance (Table 2).
Most of the participants experienced few side effects. People in the zinc groups had more frequent urinary-tract related problems than placebo-takers (7.5% vs. 5%), although it's not clear whether zinc played a role in their occurrence. Another caveat is that high dose beta-carotene is contra-indicated for smokers and recent ex-smokers. The AREDS trial confirmed the general safety and benefit of these high-potency nutrients in preserving vision among well-nourished, older people with intermediate to more advanced AMD.
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Age-Related Eye Disease Study Research Group. A Randomized, Placebo-Controlled, Clinical Trial of High-Dose Supplementation with Vitamins C and E, Beta Carotene, and Zinc for Age-Related Macular Degeneration and Vision Loss. Arch Ophthalmol 119:1417-36, 2001.
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Studies have shown that dry eye patients experience a chronic inflammatory cycle, causing symptoms and impacting tear production. A Phase III FDA study of cyclosporine, an immunomodulatory drug, demonstrated that in moderate and severe cases of Sjögren's syndrome and keratoconjunctivitis sicca (KCS), markers of inflammation were significantly reduced from baseline following treatment with this drug. However, this potent immunomodulatory drug is not a first-line defense.
A more effective and preventive approach may be to address the biochemical basis of a healthy and intact tear film. Studies have shown that nutritional supplementation with omega-3 and omega-6 fatty acids and nutrient cofactors involved in the biosynthesis of the prostaglandin PGE1 result in reduced symptoms in dry-eye and KCS patients (1,2). PGE1 is necessary for tear secretion and also regulates inflammation. Essentially, in the event of reduction of PGE1 synthesis (due to a deficiency of omega-3 and omega-6 fatty acids), there is overproduction of series 2 prostaglandins (PGE2). Increased PGE1 production is anti-inflammatory because it down-regulates PGE2 production, and thus reduces over-reactive B-cell activity and may be a regulator of the arachidonic acid cascade. Wu and colleagues carried out a placebo-controlled study of the effect of dietary supplementation with black current seed oil (BCSO) on immune response in healthy subjects 65 years or older.
Methods:
This was a randomized double-blind study. Forty patients were randomized to receive either 750 mg BCSO or 750 mg soybean oil. BCSO contains linoleic acid and 15% gamma-linolenic acid (GLA) - both omega-6 fatty acids, as well as the omega-3 fatty acids alpha-linolenic acid and stearidonic acid. The ratio of omega-3 to omega-6 fatty acids in BCSO is about 1 to 4. The level of vitamin E intake in both groups was controlled equally. Supplementation continued for 2 months.
Results:
BSCO supplementation, significantly increased plasma concentrations of gamma-linolenic acid (omega-6), alpha-linolenic acid (omega-3), and dihomo-gamma-linolenic acid compared with baseline. These increases were not evident in the control group. The BCSO group exhibited enhanced response to tetanus toxoid. In the BCSO group, stimulated PGE2 production was significantly reduced from baseline (488 ng/L to 258 ng/L). This was significantly (p<0.05) different from the control (soybean oil) group, which did not exhibit this reduction (Figure). The authors concluded that BCSO has a moderate immune enhancing effect attributable to reduction of PGE2 production.
Comment:
This study and previous research suggests that the combination of omega-3 and omega-6 fatty acids in black current seed oil both results in increased PGE1, which both stimulates aqueous tear secretion and reduces the production of PGE2.
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In the previous EduFacts (Volume 4, Number 6) we summarized preliminary work by Horrobin and colleagues which indicated that an effective approach to the treatment of dry eye disorders may be to address the biochemical basis of an intact tear film. In this preliminary study the authors had evaluated the use of supplemental intake of the essential fatty acids (EFA); linoleic and gamma linolenic acids; vitamin B6 ; and vitamin C to treat dry eye. These nutrients are necessary components of the pathway for biosynthesis of prostaglandin E1 (PGE1), which is necessary for aqueous tear secretion by the lacrimal glands. The rationale for their study was based on earlier research showing that gamma linolenic acid (GLA), an upstream metabolite of the EFA linoleic acid, was lower among patients with Sjögren's Syndrome. This suggested a breakdown in the biochemical pathway which might be remedied by supplying both GLA, linoleic acid and the vitamin cofactors involved.
Another controlled study of treatment with precursor EFAs was performed by Oxholm and colleagues on patients with primary Sjögren's Syndrome.
Methods:
28 patients with primary Sjögren's Syndrome were studied in a "cross-over" clinical study. Each patient received either Efamol (73% cis-linoleic acid, 9% gamma linolenic acid) or placebo for 8 weeks. Dosing was 6 3g capsules daily. Then each patient was "crossed-over" and received the opposite treatment for 8 more weeks. The initial treatment assignment was randomly chosen for each patient and the study was double masked - neither patients nor clinicians knew the treatment given to the patient. Clinical tests for keratoconjunctivitis sicca (KCS) included Schirmer test, tear-break-up-time, and Bijstervald score. These tests were evaluated before and after treatment. A combined ocular score was also computed. In addition the levels of DGLA (a metabolite of linoleic acid produced during biosynthesis of PGE1) were measured in serum and in erythrocytes before and after treatment.
Results:
Statistically significant baseline-to-post-treatment improvement in the overall ocular score was found in the Efamol group (p<0.05). Fewer patients in the control group experienced improvement (baseline-to-post-treatment) in ocular score. Furthermore, levels of the metabolite Di-hommo-gamma linolenic acid (DGLA) were increased significantly in both plasma (25% increase, p<0.001), and erythrocytes (10% increase, p<0.05) during Efamol treatment but not placebo treatment.
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Treatment of Keroconjunctivitis Sicca and other surface disorders is generally palliative, with the administration of lubricating drops. Current topical products are formulated to both lubricate the eye and enhance certain characteristics of the tear film. For example, hypotonic solutions reduce osmolarity and mucolytic agents can decrease the symptoms of excess mucin strands. Other additives may help lower tension at the water-oil interfaces and mimic some actions of the mucin network. However these palliative measures are temporary and do not address the underlying causes. For example, reduced osmolarity upon instillation may last only about 10 minutes.
A more effective approach may be to address the biochemical basis of an intact tear film. D.F. Horrobin and colleagues have carried out some preliminary studies of the use supplemental intake of essential fatty acids, vitamin B6, and vitamin C to treat dry eye. The rationale for this treatment was based on the biosynthesis of prostaglandin E1 (PGE1), which is necessary for aqueous tear secretion by the lacrimal glands.
Methods:
In this pilot study, 17 patients were selected based on failure of tear secretion, objectively demonstrated (Schirmer Test), clinical exam, and the chronic need/use of lubricant drops. Patients received 2 X 500 mg capsules of evening Primrose oil (Efamol- 73% linoleic acid and 10% gamma linolenic acid), 50 mg vitamin B6 (pyridoxine) and 1 g vitamin C three times daily
Results:
Ten of the 17 patients showed substantial improvement of both symptoms and Schirmer test in 2-6 weeks. 3 additional patients reported improved symptoms though without demonstrating improved Schirmer. The authors conclude that this treatment approach is effective in many cases. They continue to work on dose optimization and plan further testing.
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The Scottish Heart Health Study is an ongoing prospective cohort study of men and women carried out to evaluate risk factors for various coronary heart disease (CHD) events. Patient accrual took place between 1984 and 1987. Reports quantifying various risk factors for prevalent CHD at baseline have been published. Furthermore, preliminary evaluation of risk factors for incident coronary events during long-term follow-up and all-causes mortality have been published. The authors of the present article point out that in the preliminary evaluation, intake levels of antioxidant vitamins were evaluated as risk factors unadjusted for total energy intake and that low intake of antioxidants did not rank as high as the "classic" risk factors for coronary heart events with respect to level of risk. In the present evaluation, the authors re-examined intake of antioxidant vitamins adjusted for total energy intake, age, and other CHD risk factors.
Methods:
11,629 participants were recruited through general practitioners from 25 Scottish districts. These were men and women aged 40-59 at baseline. Along with sociodemographic data, "classic" risk factor baseline data included Rose Chest Pain Question responses, medical record evaluation, ECG, BP, and serum total cholesterol. A semi-quantitative food frequency questionnaire was used and specifically validated for antioxidant levels against plasma levels. Nutrient intakes were calculated using standard tables. Dietary carotenoids were calculated as beta-carotene equivalents. Participants were flagged on the Scottish National Health Service Register and followed through hospital discharge data for coronary events and all-causes mortality, including through death certificate data. Mean current follow-up was 7.7 years.
Results:
The total energy-adjusted consumption of vitamins C and E, beta-carotene, and fiber were higher among women than men.
Among men, energy adjusted intake levels of vitamin C, beta-carotene and fiber in the upper quartile were associated with decreased risks of incident CHD (shown in graph). For fiber and vitamin C, intake level in the 3rd quartile was also associated with decreased risk of CHD. There were similar decreases in risk of all-causes mortality. Higher vitamin E intake was mildly associated with decreased risk of all-causes mortality (38% decrease, 95% CI=8,58) and, the authors concluded, with decreased risk of CHD (note: This reviewer noted that the tables reported in the article indicated weaker associations for vitamin E and CHD than found for vitamin C). Among women, whose overall intake of fiber and antioxidant vitamins was higher, only increased fiber intake was associated with decreased risk of CHD or all-causes mortality.
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The two most common reasons given for noncompliance with hormone replacement therapy (HRT) are fear of breast cancer and resumption of unwanted bleeding. A recent study sought to shed additional light on why women tend to reject the menopause treatment their doctors are most likely to recommend. A second study sought to verify the percentage of new users who discontinue use within one year.
Methods:
In the first study, a 17-item extensively validated survey was conducted by phone and mail from a suburban Chicago community teaching hospital. Women surveyed ranged in age from 50-80. The women had a higher income and educational level than the national average-two factors associated with higher use of HRT. In the other study, information was derived from computer databases of a large prescription benefit management company whose extensive data would result in a nationwide picture of hormone compliance. The data focused on women chiefly in the 45-60 age range.
Results:
Survey
28% of the surveyed group reported being on HRT, of whom 76% had been taking it for more than two years. Of those who were not on hormones, almost half, 49%, reported they were not on HRT. Specific reasons given included: 45% said they do not want to take it, 28% were afraid to take it, and 27% declared they were no longer menopausal. Of the women surveyed, it was determined that 27% did not recognize the common signs and risks of lower estrogen levels that occur as a result of menopause. These women had determined they were not menopausal although their survey answers indicated otherwise.
Prescription Database Study
Noncompliance within one year of receiving a prescription from a doctor is associated with a younger age and living in the South. Significantly more noncompliance occurred when women received their prescriptions from other than OB/GYNs. In the general population, 54.4% of women were no longer filling their prescriptions by the end of the first year (see figure).
Discussion:
Several observations can be made. Women are not likely to take HRT long enough to derive long term health benefits such as lowered heart disease and osteoporosis. More than one-half of the women seemed unaware that a lack of menopausal symptoms does not relate to the continuing decline of estrogen production and increased associated medical risks. Women focused on symptoms as bellwethers of whether or not they were "menopausal." The simple message "symptoms are annoying, risks kill" is a statement that needs to be heard.
Since compliance with HRT is so low, patient education on lifestyle and nutritional medicine is imperative. These patient-perceived "user-friendly" alternatives for diseases of the aging female are important and valid considerations for long-term health.
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In the September 1999 issue of The Lancet researchers from The Fetal Health Research Group, at Guy's, King's and St Thomas' School of Medicine reported the results of a randomized clinical trial of the effects of antioxidant supplements on the occurrence of preeclampsia in women identified as having an increased risk of preeclampsia. The rationale for the study was based on the hypothesis that free radicals, particularly superoxide anions, may promote maternal vascular malfunction. The authors briefly summarized published studies suggesting that in preeclampsia the placenta is in a state of oxidative stress. Articles cited in the Lancet report included evidence of elevated levels of markers of lipid peroxidation (malondialdehyde and 8-epiprostaglandin-F2α) in the plasma of women with preeclampsia and low concentrations of antioxidant in the plasma and placenta. The authors hypothesized that early supplementation with antioxidants could be beneficial.
Methods:
The study was a randomized double-blind controlled trial of early supplementation with vitamins C and E in women at increased risk of preeclampsia. Study endpoints included the diagnosis of preeclampsia (development of proteinuric hypertension) and markers of endothelial and placental function explained below:
a) plasminogen-activator inhibitor-1 (PAI-1) - the level should increase during normal pregnancy but the level is higher in preeclampsia than in normal pregnancy.
b) plasminogen-activator inhibitor-2 (PAI-2) - the level also increases with normal pregnancy but instead is decreased with reduced placental function during preeclampsia. The ratio of PAI-1 to PAI-2 should decrease in normal pregnancy as the placental mass increases. However it is high in preeclampsia due to endothelial cell activation and placental insufficiency. The ratio (adjusted for the baseline measure) was used as an index of disease process. Eligible participants were classified as at risk of preeclampsia based on: an abnormal Doppler waveform in either uterine artery at 18-22 weeks gestation, or a history in a preceding pregnancy of: preeclampsia requiring delivery before 37 weeks, or HELLP Syndrome. After screening 283 women were randomized to receive both vitamin C (1000 mg) and vitamin E (400 mg) or to receive placebo tablets starting at 16-22 weeks gestation.
Results:
Analyses were carried out on the 141 vitamin users and 142 placebo users. 13 placebo and 14 vitamin group patients dropped out before the end of the pregnancy but were included in the evaluation. Odd's ratios were adjusted for DBP, smoking, ethnic origin and chronic hypertension.
The PAI-1/PAI-2 ratio was reduced among the vitamin group by 21% (95% CI 4-35%) during gestation, indicating better placental function. The frequency of preeclampsia was reduced from 17% in the placebo group to 8% in the vitamin group - the adjusted odd's ratio was 0.39, representing a decreased risk of 61% (95% CI of 10-83%, p=0.02). The beneficial effect was even stronger in the group of women completing the study. The authors concluded that vitamin supplementation may prove beneficial in high risk pregnancies.
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Currently there are strong recommendations and advisories for adequate intake of the B-vitamin, folic acid, among women of childbearing age to prevent neural tube defects. Government mandated folate fortification of cereal grain products has been in place since 1998. Many current studies continue to evaluate use of nutritional supplements to reduce the risk of birth defects. A recent case-control study carried out by researchers at Harvard and Boston Universities evaluated the effect of periconceptual multivitamin supplementation on risk of specific birth defects.
Methods:
This evaluation was part of a large case-control birth defects study carried out in the Boston area. Births of infants with major malformations detected prior to 5 months (cases) were ascertained in birth and tertiary care hospitals. Cases also included pregnancies terminated due to malformations. There were 8 case groups (with N's ranging from 31 to 186): cleft lip with or without cleft palate, cleft palate only, conotruncal defects, ventricular septal defects, urinary tract defects, limb reduction defects, congenital hydrocephaly, and pyloric stenosis. Control groups were infants totally without birth defects (N=521) and those with birth defects other than those in the case groups (N=442). Mothers were interviewed in their homes regarding factors under study. Daily multivitamin supplementation was evaluated according to gestational timing categories including periconceptual. A multivitamin was defined as a supplement that contained at least 2 water soluble and 2 fat soluble vitamins. 90% of non-prenatal and 100% of prenatal vitamins contained folic acid.
Subjects were divided into groups based on quintile level of the lipid-standardized plasma vitamin E levels. Adjusted Odd's Ratios were computed, (adjusting for age, sex education, BMI, diabetes, smoking, and various cardiovascular parameters), using the lowest quintile as the reference group. After multivariate adjustment, lipid-standardized vitamin E was inversely associated with risk.
Results:
When Cases with limb reduction and urinary tract defects were compared with non-malformation controls, use of multivitamins during the periconceptual period (28 days before through 28 days after last menstruation) was higher among controls. The percent decrease in risk for each of these 2 defects is shown in the figure. Results were similar when cases were compared with malformed controls (defects other than the ones under study - a method of protecting against recall-bias in the interview).
The investigators also found a substantial decreased risk of cleft palate alone (no cleft lip) and of urinary tract defects when multivitamins were initiated in the second lunar month of pregnancy. The authors concluded that periconceptual vitamin supplementation may extend benefits beyond a reduction in neural tube defect risk. In this study, specific nutrient or nutrient combinations of benefit could not be discerned.
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In a previous EduFacts, (Volume 3, number 4) some results from the Nurses' Health Study were reported, which indicated an inverse relationship between lutein/zeaxanthin intake and risk of cataract extraction. The authors had presented this data at the 1998 annual meeting of the Society for Epidemiologic Research. The meeting abstract indicated a 22% decrease in risk of cataract extraction with higher intake of lutein/zeaxanthin. The full results were recently published and clarified that the 22% decreased risk was among those in the upper decile (10th percentile) intake level (energy-adjusted) of lutein/zeaxanthin compared with the lower quintile (20th percentile) intake level. Furthermore, there was a significant linear trend (p=0.04) of decreasing risk of cataract extraction with increasing intake level. In a separate publication , the same authors have evaluated the relationship between vitamin supplement intake and risk of cataract extraction in the same study cohort.
Methods:
The incidence of cataract extraction was determined during 720,082 person-years of follow-up in a total cohort of 73,956 women nurses aged 45 or older and free of cancer. Over half were followed for 12 years. Vitamin Supplement intake (multivitamins and, A, C and E) was determined at baseline (1980) and every 2 years afterward. Use was categorized as 'never', 'past use', and 4 categories of current use (<2, 2-4, 5-9, and ≥10).
Results:
There were 1377 cataract extractions. Age-adjusted relative risk (RR) associated with <2 years duration of use of vitamin A was elevated and risk of cataract decreased with increasing duration of current vitamin use. However these relative risks were attenuated with control for cigarette smoking.
Among 'never-smokers', duration of use of vitamins C and E of at least 10 years was associated with decreased risk of cataract extraction (relative risks of 0.71 and 0.79 respectively). Risk among 'never-smokers' using vitamin A could not be evaluated due to small numbers.
Despite the decreased risks of cataract extraction demonstrated among non-smokers taking vitamins C and E long-term, the authors concluded that their findings suggested little overall benefit of supplement use. However another interpretation of this study suggests that when eliminating the strong smoking risk factor for cataract, the use of certain supplements may in fact provide additional decreased risk of cataract.
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In a previous EduFacts (Volume 3, number 7) we summarized results from the prospective Pathologies Oculaires Liées á l'Age (POLA) Study, which demonstrated a high level of antioxidant enzymes in patients with AMD and cataract. The authors suggested that elevated levels of antioxidant levels may be a marker of oxidative stress in AMD patients. These same investigators recently published an evaluation of the relationship between prevalence of AMD and plasma levels of vitamin E, retinol and vitamin C to determine if a lower plasma level of these antioxidants was associated with higher risk of AMD.
Methods:
During 1995 through 1997, participants were recruited in the French city of Séte on the Mediterranean. At the baseline evaluation, presence of AMD was determined by fundus-photograph grading using the Wisconsin system in 2584 patients. Classification was collapsed for analysis into: none, early or late (neovascular) AMD.
Statistical Evaluation:
Subjects were divided into groups based on quintile level of the lipid-standardized plasma vitamin E levels. Adjusted Odd's Ratios were computed ( adjusting for age ,sex education, BMI, diabetes, smoking, and various cardiovascular parameters), using the lowest quintile as the reference group. After multivariate adjustment, lipid-standardized vitamin E was inversely associated with risk of late AMD (exudative/ atrophy). The relative risk of late AMD in the highest quintile level was 0.18 (p=0.004). This suggests a decreased risk of late AMD of over 80%. Lipid standardized plasma vitamin E level was also inversely associated with early signs of AMD ( any kind of soft drusen, hyperpigmentation). The Odd's Ratio was 0.72 (28% decreased risk) in the highest vs lowest quintile level.
The authors stated that these results suggest that vitamin E may provide protection against AMD but that randomized interventional studies were necessary to establish such an effect.
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Ophthalmologists continue to debate the best method of optimizing anti-oxidative processes in the eye. Some question the value of optimizing intake of these important nutrients through supplementation, and believe that dietary intake alone is adequate. In a recent EduFacts (volume 3, number 8) we reviewed a report from NHANES III, which showed that about a quarter of the population has a vitamin E plasma level of <20 µmol/L. It was also shown that vitamin supplementation was inversely associated with having a low plasma level of vitamin E. In the following EduFacts (volume 3, number 9) we reviewed a prospective study demonstrating that patients at or below this level were at increased risk of progression of early cortical cataract. An earlier case-control study (summarized in EduFacts volume 2, number 5) showed a decreased risk of cataract associated with vitamin supplement use. In this EduFacts we review some results, published in 1994, of the prospective Physicians Health Study, which suggested that use of multivitamin supplements is associated with decreased risk of cataract.
Methods:
The Physician's Health Study is a randomized double masked intervention trial, which evaluated the efficacy of low-dose aspirin therapy and beta-carotene for prevention of cardiovascular disease. The evaluation considered here was carried out as a sub-study. Study physician participants with no cataract at baseline (N=17,744) were followed an average of 5 years. At baseline, regular multiple vitamin supplement use was determined (never, past only, current) as well as single vitamin supplement use of vitamins C or E (never, past only, current). Vitamin A users were excluded because beta-carotene was an assigned treatment. Participants reported number of years of use. Other dietary covariables were collected. Follow-up was performed at 6-month intervals. Cataract diagnosis and/or extraction was determined by self-report among the physicians, verified, and detailed by the diagnosing ophthalmologists.
Results:
At baseline, 20% reported multivitamin use (12.5% multivitamin only; 7.5% multivitamin + vitamins C and/or E). During the average 5-year follow-up there were 370 incident cataracts and 109 cataract extractions with 10,983 person-years of observation. The main finding was that reported use of multivitamins was inversely associated with risk of incident cataract. The relative risk (RR), adjusted for possible confounding covariables, was 0.73 with a 95% CI of 0.0.54 to 0.99. This suggests a 27% decrease in risk. The RRs decreased with increasing durations of reported use (test for trend=0.06).
The authors considered these results as compatible with a hypothesis of decreased risk with supplement use, but pointed out the need for a long-term intervention trial.
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In an earlier EduFacts (volume 2, number 5) we reviewed data from 2 case control studies published in 1991, which demonstrated a decreased risk of cataract associated with increased intake of vitamin E - α-tocopherol - through diet or use of supplements. A more recent prospective study (published in 1996) was carried out in Finland, evaluating the effect of plasma vitamin E level on the progression of early cortical lens opacities.
Methods:
This prospective study was carried out as a sub-study of a population-based prospective clinical trial evaluating pravastatin in middle-aged men with elevated LDL. Of the 447 study participants, 410 completed ophthalmologic exams at baseline and at 18 months and 36 months after baseline. Plasma α-tocopherol concentration was measured at baseline using high performance liquid chromatographic methods. Lens opacity status was determined using the LOCS II system. Progression of lens opacity was defined as an increase in a particular LOCS grade from baseline to 18 months which was verified at the 36 month visit. 742 eyes were evaluated. Both plasma concentration of vitamin E in цmol/L and lipid-standardized plasma vitamin E concentration were evaluated and related to a progression in LOCS score(s). Statistical adjustments for the correlation between the 2 eyes of a single patient were employed. Plasma linoleic acid, certain carbohydrates, vitamin C, and cholesterol were found to be significantly associated with plasma vitamin E. These variables and pravastatin treatment were included in the statistical models as covariates.
Results:
The mean age in this middle-aged male sample was 57.3 years. Mean baseline plasma vitamin E concentration was 28.09 цmol/L (this is slightly higher than the U.S. population mean - see EduFacts volume 3, number 8). Baseline LOCII score distributions in this relatively young age group indicated that 20.2% of eyes had cortical opacity grades of 1 or more; 7.4% had cortical opacity grades of 2 or more. After 3 years of follow-up, baseline plasma vitamin E concentration and lipid-standardized vitamin E were found to be inversely associated with progression of cortical cataract grade.
Relative Risk of Cortical Cataract Progression (1)
(Lowest vs highest quartile level)
| Relative | 95% CI |
Plasma vitamin E | 3.68 | 1.15-11.76, p=0.028 |
Lipid-standardized vitamin E | 3.67 | 1.22-11.09, p=0.021 |
Plasma vitamin E and lipid standardized vitamin E were not associated with progression of nuclear opacity. The authors point out that in this middle-aged population, the majority of lens opacities at baseline were mild. Thus this study was useful in evaluating the effect of vitamin E levels in the early stages of lens opacity formation and progression. They concluded that in this population low plasma vitamin E concentration was a risk factor for progression of early cortical opacity.
ScienceBased Health's OcularProtect® contains vitamin E and other antioxidants to help protect ocular health.
References
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Increased dietary intake and serum levels of vitamin E – α-tocopherol – have been associated with decreased risk of cataract and AMD (See references listed below). Generally publications from these studies have reported odd's ratios - a kind of relative risk of having the disease - among those in the lowest quintile level (dietary intake or serum) compared to the highest quintile level. Obviously, the absolute average levels could conceivably differ among studies. The range or variation of vitamin E levels in a given study could also impact the ability to determine it's relationship with the disease. From a public health standpoint, knowing the status of the general population with respect to vitamin E levels would enhance interpretation of various studies. A recent publication from the Third National Health and Nutrition Survey (NHANES III) documents the epidemiology of vitamin E in the general population.
Methods:
The NHANES III survey used a complex multistage stratified sampling design with oversampling of certain demographic groups, resulting in a representative sample of the non-institutionalized U.S. population. Serum concentration of α-tocopherol was measured in participants using high performance liquid chromatography at CDC laboratories. The study was designed to measure possible correlates of vitamin E levels. These included age, sex, race, educational status, smoking status, systolic blood pressure, cholesterol levels, body mass index, physical activity, vitamin/supplement use, alcohol consumption, diabetes status, vitamin E dietary intake (single 24-hour recall), fruit and vegetable consumption and serum concentrations of other vitamins and nutrients.
Results:
16,295 participants 18-90 years of age had α-tocopherol levels measured. Mean concentration of α-tocopherol was 26.8 цmol/L. The 25th percentile was 19.6цmol/L and the 75th percentile was 30.4 цmol/L.
After age-adjustment, women had a mean concentration of serum α-tocopherol similar to that of men within each racial or ethnic group. However whites had significantly higher levels than did African Americans or Mexican Americans. Forty-one percent of African Americans vs 26% of white Americans had α-tocopherol levels below 20 цmol/L - i.e. about the 25th percentile for the population as a whole. Use of vitamin and mineral supplements was inversely associated with odds of a low ( Below 20 цmol/L) serum α-tocopherol level (odd's ratio=0.27 [95% CI=0.19, 0.39])
References
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It is generally believed that oxidative mechanisms play a major etiologic role in the development of age-related macular degeneration (AMD) and cataract. The etiology is a decrease in efficiency of the body's natural antioxidative mechanisms, including enzymatic, and non-enzymatic (antioxidant micronutrients). However, ophthalmologists continue to debate both the value of, and the best method for, optimizing anti-oxidative processes in the eye. For example, critics of recommending use of supplemental antioxidants sometimes suggest, even insist, that the epidemiologically studied associations between level of intake (both dietary, supplemental, or both) of antioxidant micronutrients and risk of cataract or AMD may not be causal - that decreased risk may be due to other factors in the food. One way of evaluating the role of oxidative stress in the disease process is to measure and evaluate the serum level of antioxidant enzymes in healthy patients and those with ocular disease. High systemic levels could be indicative of an increased level of oxidative stress. Investigators from the prospective Pathologies Oculaires Liées á l'Age (POLA) Study evaluated the association of age-related ocular pathologies with two antioxidant enzymes.
Methods:
During 1995 through 1997, participants were recruited in the French city of Séte on the Mediterranean. At the baseline evaluation, presence of AMD was determined by fundus-photograph grading using the Wisconsin system in 2,196 patients. Classification was collapsed for analysis into: none, early, or late (neovascular) AMD. LOCSII was used to determine presence of cataract (none, mild, moderate, severe). Erythrocyte superoxide dismutase (SOD) activity and plasma level of glutathione peroxidase (GPx) were measured using accepted laboratory technique. Percentiles of SOD and GPx were determined. Logistic regression was used to obtain adjusted Odd's ratios (high vs. low percentile of antioxidant enzyme) for presence of disease. Age, sex, and potential confounders were included in the statistical models.
Results:
Cataracts: A strong association was found between plasma GPx and prevalence of severe cataract. Subjects in the highest quintile of GPx had over a 6-fold higher prevalence of cortical cataract, and about a 2-fold higher prevalence of nuclear or mixed cataract. The Odd's ratios were all significant. AMD: Subjects in the highest 4 quintiles of GPx had a 10-fold greater prevalence of late AMD compared with the lowest quintile level. Excess risk was not found for early AMD. Highest quintile level of erythrocyte SOD activity was associated with about a 2-fold increased prevalence of nuclear cataract but not other cataract types or AMD.
Adjusted Odd's Ratios (Highest vs lowest quintile level)
| GPx Odd's Ratio* | SOD Odd's Ratio* | ||
Cortical Cataract | 6.3 | P<0.001 | 1.8 | NS |
Nuclear Cataract | 2.3 | P=0.004 | 2.2 | P=0.02 |
Mixed | 2.5 | P=0.003 | 1.4 | NS |
Late AMD | 10.0 | P=0.04** | 0.9 | NS |
The authors concluded that age-related eye diseases are linked to high levels of antioxidant enzymes, particularly GPx - which reduces mainly hydrogen peroxide and organic hydroperoxides. They suggested that a high concentration of antioxidant enzymes might be a marker that oxidative stress is present.
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In earlier EduFacts communiqués we have summarized reports in the literature evaluating the relationships between dietary intake levels/serum levels of dietary carotenoids and risk of age-related macular degeneration (volume 2, numbers 1, 4, 8, 9, 10, 11, and 14) and cataract (volume 2, number 13; volume 3, numbers 3 and 4). A recent evaluation of the Third National Health and Nutrition Examination Survey (NHANES III) data explored the relationship between diabetes mellitus and serum carotenoid levels.
The article points out that diabetes is a condition characterized by oxidative stress. This etiology is hypothesized based on demonstrated increased reactive oxygen species and, lipid peroxidation and increased free radical activity. The authors hypothesize that oxidative stress may result in a lowering of antioxidant concentrations in glucose-intolerant patients.
Methods:
Phase I of NHANES III was conducted between 1988 and 1991. This was a cross sectional survey using a sophisticated design enabling generalization of results to the non-institutionalized U.S. civilian population. Of the phase I subjects, 1665 had oral glucose tolerance tests yielding valid glucose tolerance status. Patients were classified as: 1) normal, 2) impaired glucose tolerance, and 3) newly diagnosed diabetes according to World Health Organization criteria. Five carotenoids were assayed at the CDC laboratory: alpha-carotene, beta-carotene, cryptoxanthin, lutein /zeaxanthin and lycopene. Covariate-adjusted geometric means of these carotenoids were computed for the 3 groups. The covariates included socio-demographic variables, physical activity, alcohol consumption, dietary intake (single 24-hour recall), vitamin use, serum cholesterol, HDL, BP, body mass index and activity levels.
Results:
Beta-carotene levels and lycopene levels (adjusted geometric means) decreased linearly with glucose tolerance status.
The authors concluded that the NHANES III data suggest that serum carotenoid concentrations are associated with insulin-resistance and glucose tolerance status. The ordinal status from normal to impaired to new diabetes showed a linear trend with respect to the levels of beta-carotene and lycopene.
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The Blue Mountains Eye Study is a cross-sectional population based study of common eye diseases carried out among urban residents in a specific area of Australia in the early 1990's. As part of this study retinal photos were obtained on at least one eye in 2900 subjects who had completed usable Food Frequency Questionnaires (FFQ). The Wisconsin grading system (Dr. Ronald Klein, Univ. of Wisconsin) was used to stage AMD lesions. In general the study compared diet factors comparing those with late AMD (classified as neovascular or geographic atrophy), early AMD or no AMD. In this sample, 47 subjects were graded as having late AMD; 181 were graded as having early AMD. The antioxidants evaluated were beta-carotene, zinc, vitamin C and vitamin A.
Odd's ratios (highest quintile vs lowest quintile intake)
Antioxidant | Odd's ratio* | 95% CL | P (trend) |
Beta-Carotene | 0.66 | 0.39 - 1.1 | 0.10 |
zinc | 0.79 | 0.47 - 1.33 | 0.18 |
Vitamin C | 0.86 | 0.52 - 1.41 | 0.55 |
Vitamin A | 1.19 | 0.72 - 1.96 | 0.46 |
* Relative risk of AMD
The authors reported that no significant associations were found between current intake level of any antioxidant evaluated and presence of early or late AMD. The risk of early AMD among subjects in the highest quintile intake-level of beta-carotene relative to that among subjects in the lowest quintile intake level (odd's ratio) was 0.66 (95 % CI 0.39 - 1.1) which numerically suggests a 30-35% decrease in risk. However this odd's ratio was not statistically significant.
Comments:
The authors did evaluate statistical power and determined that the odd's ratio computed for any evaluation would have to indicate an increased risk of 70% (odd's ratio=1.7, low intake relative to high intake) to be detected with 80% power. The small numbers of subjects with late AMD generally resulted in only about 8-10 cases in the highest and lowest intake quintiles of the nutrients evaluated. It really doesn't seem surprising that no statistical significance was achieved.
It is believed that AMD may develop due to cumulative oxidative damage in the aging eye. This etiology is consistent with epidemiological findings identifying some of the risk factors for AMD: age, smoking, increased sunlight exposure, low ocular melanin, and light-colored iris. There is evidence that increased serum levels of and dietary intake of specific carotenoids and other antioxidants are inversely related to risk of AMD .
Investigators in the NEI-funded Eye Disease Case-Control Study reported in 1993 that among the 1000-plus participants, those with high serum levels (upper quintile) of the antioxidant dietary carotenoids lutein/zeaxanthin, and beta-carotene, had a 70% decreased risk of neovascular AMD compared with those in the lowest quintile. High serum levels of cryptoxanthin and lycopene were associated with 40-50% decreases in risk. The Blue Mountain Study did not evaluate these carotenoids.
Vitamin C and vitamin E had numeric decreases in risk in the case-control study (30% and 40% respectively) but the odd's ratios did not reach statistical significance. Seddon and colleagues studied over 300 patients and reported a 57% decrease in risk of AMD in patients with increased dietary intake of lutein and zeaxanthin.
In a smaller case control study within the Beaver Dam Cohort, Mares-Perlman and colleagues found significant decreases in risk of AMD with higher serum levels of alpha-tocopherol and lycopene. On the whole the case-control design studies have provided better statistical power for detection of associations between nutrient intake and risk of AMD - especially late AMD .
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In the last EduFacts (volume 3, number 3) we summarized a recent study, demonstrating an inverse relationship between high lutein intake and risk of cataract among men and women in the Beaver Dam Eye Study. Another study summarized in a previous EduFacts (volume 2, number 13) demonstrated a similar relationship among male professionals. This month investigators from the Nurses' Health Study (NHS) are scheduled to present data on lutein and cataracts from the Nurses' Health Study Cohort at the 32nd annual meeting of the Society for Epidemiologic Research in Baltimore. This cohort of women constitutes an on-going long-term prospective health study of nurses (NHS). The NHS cohort of women has been interviewed every 2 years since 1977 to determine health status. Detailed prospective information on nutritional intake, including the use of various vitamin supplements has been collected. The Food Frequency Questionnaire (FFQ) was administered in 1980, 1984, 1986, and 1990.
Results:
Follow-up has been over 12 years. There were 1471 cases of cataract extraction during 761,762 person years of follow-up. After controlling for age, smoking, and other potential confounders, those with the highest intake of lutein/zeaxanthin (highest quintile) had a 22% decreased risk of cataract extraction compared to those in the lowest quintile. The relative risk was 0.78 (95% confidence interval=0.63 to 0.95, p for trend=0.04). Lutein is the only carotenoid found in the crystalline lens and could play a strong anti-oxidative role in protecting lens health.
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The benefits of optimal levels of dietary lutein are usually associated with decreased risk of AMD. However, in a previous EduFacts (volume 2, number 13), we summarized recent work by Harvard researchers Brown, Hankinson, Seddon and colleagues,(1) which demonstrated an 18% deceased risk of cataract extraction in male professionals who were at the highest quintile intake of dietary lutein. Their study was a prospective study with over 36,000 participants.
In the May 1999 issue of the American Journal of Epidemiology, Lyle, Mares-Perlman, Klein, et al reported some recent results of the Beaver Dam Eye Study, which also provide support for the positive role of dietary lutein in preventing cataract.
The Beaver Dam cohort consisted of 4926 people aged 43-84 residing in Beaver Dam, Wisconsin, who were enrolled into this prospective study in 1988-90. A random sample of 2429 subjects participated in a dietary study. Cataract status at baseline was determined using a 5-point photo grading system - subjects were classified as being free of severe opacity (grade£3 in both eyes) or having opacity (grade ³4) in at least one eye. Dietary intake of lutein and other nutrients was assessed and quantified rigorously. Diet both at baseline and in the distant past (10 years earlier than baseline) was quantified. Patients free of cataract at baseline were followed for 5 years. Incident cataract during the 5-year follow-up was determined. The risk of incident cataract among subjects in the highest quintile of intake, relative to that among those in the lowest quintile was determined (odds ratios) for each nutrient. The main finding in this study was that high lutein intake in the distant past significantly reduced the risk of incident cataract by 50% (odds ratio=0.5, p= 0.002.) High intake of lutein at baseline reduced risk of incident cataract by 60% (odds ratio=0.4, p =0.06) among subjects under 65 years at baseline. High intake of spinach/greens (with high lutein content) was also found to reduce risk of incident cataract. The authors concluded that nutrient intake in middle age may influence development of cataracts far into older age.
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In the previous EduFacts (Volume 3, Number 1) we summarized preliminary work by Horrobin and colleagues which indicated that an effective approach to the treatment of dry eye disorders may be to address the biochemical basis of an intact tear film. In this preliminary study the authors had evaluated the use of supplemental intake of the essential fatty acids (EFA), linoleic and gammalinolenic acids, vitamin B6 and vitamin C to treat dry eye. These nutrients are necessary components of the pathway for biosynthesis of prostaglandin E1 (PGE1), which is necessary for aqueous tear secretion by the lacrimal glands. The rationale for their study was based on earlier research showing that gamma linolenic acid (GLA), an upstream metabolite of the EFA linoleic acid, was lower among patients with Sjögren's syndrome. This suggested a breakdown in the biochemical pathway which might be remedied by supplying both GLA, linoleic acid and the vitamin cofactors involved.
Another controlled study of treatment with precursor EFAs was performed by Oxholm and colleagues on patients with primary Sjögren's syndrome.
Methods:
28 patients with primary Sjögren's syndrome were studied in a "cross-over" clinical study. Each patient received either Efamol (73% cis-linoleic acid, 9% gammalinolenic acid) or placebo for 8 weeks. Dosing was 6 3-g capsules daily. Then each patient was "crossed-over" and received the opposite treatment for 8 more weeks. The initial treatment assignment was randomly chosen for each patient and the study was double masked - neither patients nor clinicians knew the treatment given to the patient. Clinical tests for keratoconjunctivitis sicca (KCS) included Schirmer test, tear-break-up-time, and Bijstervald score. These tests were evaluated before and after treatment. A combined ocular score was also computed. In addition the levels of DGLA (a metabolite of linoleic acid during biosynthesis of PGE1) were measured in serum and in erythrocytes before and after treatment.
Results:
Statistically significant baseline-to-post-treatment improvement in the overall ocular score was found in the Efamol group (p<0.05). Fewer patients in the control group experienced improvement (baseline-to-post-treatment) in ocular score. Furthermore, levels of the metabolite Di-homo-gamma linolenic acid (DGLA) were increased significantly in both plasma (25% increase, p<0.001), and erythrocytes (10% increase, p<0.05) during Efamol treatment but not placebo treatment.
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Treatment of Keroconjunctivitis Sicca and other surface disorders is generally palliative, with the administration of lubricating drops. Current topical products are formulated to both lubricate the eye and enhance certain characteristics of the tear film. For example, hypotonic solutions reduce osmolarity and mucolytic agents can decrease the symptoms of excess mucin strands. Other additives may help lower tension at the water-oil interfaces and mimic some actions of the mucin network. However these palliative measures are temporary and do not address the underlying causes. For example, reduced osmolarity upon instillation may last only about 10 minutes.
A more effective approach may be to address the biochemical basis of an intact tear film. D.F. Horrobin and colleagues have carried out some preliminary studies of the use supplemental intake of essential fatty acids, vitamin B6, and vitamin C to treat dry eye. The rationale for this treatment was based on the biosynthesis of prostaglandin E1 (PGE1), which is necessary for aqueous tear secretion by the lacrimal glands.
Methods:
In this pilot study, 17 patients were selected based on failure of tear secretion, objectively demonstrated (Schirmer Test), clinical exam, and the chronic need/use of lubricant drops. Patients received 2 X 500 mg capsules of evening Primrose oil (Efamol- 73% linoleic acid and 10% gamma-linolenic acid), 50 mg vitamin B6 (pyridoxine) and 1 g vitamin C three times daily
Results:
Ten of the 17 patients showed substantial improvement of both symptoms and Schirmer test in 2-6 weeks. 3 additional patients reported improved symptoms though without demonstrating improved Schirmer. The authors conclude that this treatment approach is effective in many cases. They continue to work on dose optimization and plan further testing.
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The Third National Health and Nutrition Examination Survey (NHANES-III) provides a wealth of information on the Health Status of Americans. As one part of this cross-sectional survey study, researchers evaluated the relationship between serum levels of various antioxidant micronutrients and the prevalence of AMD. Data were presented at the 1998 annual meeting of the Society for Epidemiologic Research in Chicago.
Methods:
Cross-sectional relationships of serum levels of vitamins C, E and various carotenoids to the following: late AMD, presence of pigment abnormalities, and the presence of soft drusen (the latter 2 factors considered as early predictors of late AMD). Fundus photos and serum samples were obtained on 7935 participants age 40 and older. Age adjusted and multivariate logistic models were used. Factors adjusted for in the analyses included age, sex, race, smoking, alcohol, body mass index, hypertension, diabetes and eye color.
Results:
Prevalence of late AMD was 0.7%, while prevalence of overall AMD (not defined in Abstract) was 10.8%. In this cross sectional study, serum levels of vitamin C or vitamin E were not related to overall prevalence of AMD. However there were suggestive relationships found for pre-AMD conditions such as pigment abnormalities and soft drusen. In non-Hispanic whites, serum lutein level was weakly related to some pigment abnormalities. High vs. low levels of serum vitamin E was associated with a 30% decreased prevalence of soft drusen (vitamin supplement use was excluded as a confounding factor presumably because usage subsequent to diagnosis could not be determined). The authors stated that the data did not support a strong cross-sectional association between serum antioxidants and presence of AMD but recommended further study of the effect of lutein and vitamin E on AMD.
References
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Investigators from the Beaver Dam Eye Study presented an evaluation of the role of vitamin intake in diabetic retinopathy at the 1998 annual meeting of the Society for Epidemiologic Research in Chicago. Past evaluations of The Nutritional Factors in Eye Disease Study (as part of the Beaver Dam eye Study), have provided some evidence of decreased risk of lens opacities associated with increased antioxidant intake (see earlier EduFacts: "Vitamin A and Cataracts: Reviewing the Data").
Methods:
In the recent report, the relationship of vitamins C and E (through diet and supplements) and the incidence and progression of diabetic retinopathy was explored. Beaver Dam Eye Study Participants with diabetes at baseline were asked to provide retrospective information on diet and supplements using a modified Block Food Frequency Questionnaire. Of 230 patients with diabetes at baseline, 166 patients provided this information and were followed for 5 years. Incidence and progression of retinopathy were determined by grading of fundus photos.
Results:
Incidence of retinopathy was 28% (47 of 166 participants). Odd's Ratios (relative risks) were computed for risk of retinopathy among those at the highest quintile level of each micronutrient vs. those at the lowest quintile level.
Multivariate analysis was performed to control for factors such as gender, insulin use, diastolic BP etc. Relative risk for highest quintile vitamin C intake level vs. lowest quintile was 0.6 - indicating a 40% decrease in risk (p=0.06 for trend). Overall citrus food intake at the highest quintile level had a relative risk of 0.2 compared with lowest quintile intake. This was an 80% reduction in risk (p=0.03). Vitamin E was not associated with lowered risk of retinopathy in this study. The authors suggested further research in this area.
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The retinal carotenoids, lutein and zeaxanthin are replenished through dietary intake. In previous EduFacts issues we have summarized several published studies demonstrating an inverse relationship between high dietary intake of these retinal pigments and the risk of Age Related Macular Degeneration (AMD). The effect of dietary carotenoids on the density of the protective macular pigment has also been studied. One study demonstrated a significant increase in macular pigment (MP) density in subjects fed a diet vigorously enriched with spinach and corn - good source of both carotenoids. Another study demonstrated increases in MP density during lutein supplementation.
A recent study in the British Journal of Ophthalmology undertook to document relative levels of lutein and zeaxanthin in various food sources. Homogenates of 33 food items were analyzed to measure the mole% amounts of these nutrients using high performance liquid chromatography.
Foods rich in both Lutein and Zeaxanthin*
Food source |
Lutein - mole% |
Zeaxanthin - mole% |
Egg Yolk |
54 |
35 |
Corn |
60 |
25 |
Orange Juice |
15 |
20 |
Honeydew |
17 |
18 |
*adapted from Sommerburg, et al.
The Table lists those food sources rich in both nutrients. Eighteen other fruits and vegetables studied had levels of lutein in the 15-55 mole% range. However, only orange peppers, oranges, and mangos supplied a serious level of zeaxanthin.
The question of whether to optimize intake of these important nutrients through diet alone or through supplementation remains unanswered. Certainly a restricted diet - without eggs, for example, would eliminate an important source of zeaxanthin. Orange peppers, honeydews and mangos may be unavailable to many elderly, depending on the season.
Clearly, patients at risk for macular degeneration should be thoroughly evaluated nutritionally. They may have reduced their dietary intake of important nutrients for ocular health.
References
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The retinal carotenoid, lutein, is replenished through dietary intake along with zeaxanthin. Published studies have shown an inverse relationship between high dietary intake of these retinal pigments and the risk of age-related macular degeneration (AMD). A Recent report by researchers from Harvard University suggests that lutein may also play a protective role in the prevention of cataracts. The authors presented their work at the 1998 annual meeting of the Society for Epidemiologic Research in Chicago.
One etiology of cataract formation is the oxidation of lens proteins. Studies have shown that the antioxidant vitamins A, C and E are protective (see earlier EduFacts issues). Lutein is the only carotenoid found in the human lens. Since lutein does have antioxidant activity in the retina, the Harvard researchers hypothesized a similar role in the natural crystalline lens.
The authors evaluated 36,646 U.S. male professionals without previous diagnosis of cataract at the time of study intake in 1986. The cohort members were 45-75 years of age at that time. Dietary nutrient intake was assessed through a detailed questionnaire. Patients were followed 8 years. During 8 years 844 men had cataract extractions. After statistical adjustment for age, smoking, body mass index, alcohol consumption and other relevant covariants, the relative risk (RR) of cataract extraction for high lutein intake (highest quintile) versus the lowest intake (lowest quintile) was 0.82 (95% confidence interval of 0.66 - 1.03, p=0.03). This represents an 18% decrease in risk.
The authors concluded that lutein may help decrease the risk of cataracts requiring extraction.
References
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Age-related macular degeneration and senile cataract often dominate discussion of ophthalmic use of vitamin supplements. However research has also been carried out regarding other possible ophthalmic-related benefits of nutritional supplementation. An interesting study by Matthew Paul M.D. and colleagues was presented at the 1995 Annual ASCRS meeting. The presentation: One year follow-up of no-stitch cataract wound healing using vitamin supplementation was published in the 1995 "Best Papers of Sessions" issue of the journal.
The study was carried out in 1993-94. 50 cataract/IOL surgical cases were randomly assigned to a control group or a vitamin supplement group. The patients and examiners were both masked as to treatment. Depending on treatment assignment patients received either placebo tablets or 500 mg vitamin C tablets. Tablets were taken each day during the week before and the week after surgery.
There were 2 subgroups of wound types:
Unsutured (U) | Single horizontal suture (S) |
5.2 mm | 5.5 mm |
2-3 mm scleral tunnel | 2-3 mm scleral tunnel |
2 mm from limbus | 1 mm from limbus |
Phaco -Viscoat | Phaco -Viscoat |
Self sealing | Self sealing |
5 X 6 oval optic | 5.5 mm round optic |
Preoperative and postoperative keratometry was measured and vector analysis used to compute the amount of surgically induced astigmatism at one month and at one year after surgery. At one month there was significantly less against-the-rule astigmatism in the vitamin supplement group compared with placebo, regardless of suturing status (S vs U). This result was statistically significant and continued at one year after surgery.
Reference
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In one of our earliest EduFacts briefings ("Macular Pigment Density, Dietary Carotenoids and Age-Related Macular Degeneration") we reviewed a study which documented a near-twenty percent increase in macular pigment (MP) density in subjects fed a diet vigorously enriched with spinach and corn. The high levels of dietary spinach and corn effectively boosted lutein intake approximately 4-fold and zeaxanthin intake 3-fold. In the same article we reviewed 2 other studies relating increased serum and dietary intake of these dietary carotenoids with reduced risk of age related macular degeneration (AMD). While the value of adequate dietary levels of lutein and zeaxanthin is generally recognized, the value of using lutein/zeaxanthin supplements is disputed.
However, a recent (1997) experimental study demonstrates that the use of a lutein supplement can directly generate an increase in the density of the protective macular pigment. Landrum, Bone, and colleagues serially measured macular pigment optical density for a year in 2 test subjects who were given lutein supplements daily for 140 days. The subjects consumed lutein esters equivalent to 30-mg free lutein per day. MP optical density was measured before, during, and after the supplementation period using heterochromatic flicker photometry. The basic finding was that in all 4 test eyes, MP increased steadily during lutein supplementation (140 days) and continued at the same rate for another 40-50 days before leveling off. MP density then remained steady throughout the remainder of the observation period (through 350-400 days). Rate of increase ranged from 1.14 to 1.21 mAU per day. Supplementation caused a 10-fold increase in serum levels of lutein in both subjects within 10-20 days of treatment. After discontinuation of the supplement, serum levels fell to baseline levels after about 60 days.
References
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In an earlier EduFacts ("Vitamin E and Cataracts: Reviewing the Data") we reviewed two reports of case-control studies documenting decreased risk of cataract / opacity with increased dietary intake of vitamin E. The Lens Opacity Case Control Study evaluated total dietary intake of vitamin E. Another case-control study of cataract in Canada evaluated vitamin E supplements. These studies each suggested about a 40-45% decreased risk of cataract or opacity with higher vitamin E intake through diet or supplement use.
Although evidence from these retrospective case control studies is compelling, causality is best documented using prospective study designs. Leske and Chylack and co-authors have recently reported the results of an ongoing prospective study of lens opacity risk factors. Briefly, the study utilized data collected on the control patients in the earlier case-control study but used a highly detailed grading scale - the LOCS III - to regrade lens photos at the current study baseline, then to grade lenses again every year over a four year period. This system provided precise measurements of opacity grade to determine new opacities and to precisely grade changes in existing opacities. 744 patients were evaluated. The main nutritional findings in this study are summarized in the 2 figures. During follow-up 24% of patients had increases in nuclear opacities in at least one eye. The risk of an increase in nuclear opacity was 0.43 among users of vitamin E supplements relative to non-users - a decrease in risk of 57%. Those with high (vs low) plasma levels of vitamin E had a 42% decreased risk. The authors also reported a "dose" response relationship between vitamin E supplement use and risk of increased opacity in that decrease in risk was greater with longer use of vitamin E.
References
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In the previous EduFacts ("Dietary Carotenoids, Smoking, & Age-Related Macular Degeneration") data from the Eye Disease Case Control Study were presented, which suggested that high intake of the carotenoids lutein and zeaxanthin may modulate some of the risk of age-related macular degeneration AMD associated with smoking. While smoking has been identified as a risk factor for AMD since the early 1980's, the etiology of this risk factor has remained unclear even among recent studies. Generally the clinical studies suggest that smoking causes atherosclerotic and hypoxic damage to the choroidal vasculature resulting in maculopathy, or that smoking directly causes oxidative damage to retinal cells. In a 1996 report by Hammond and colleagues, 34 smokers were compared with 34 non-smokers matched for the following variables: age, weight, sex, degree of pigmentation (of eyes, skin and hair), dietary intake of carotenoids, fat, and iron. Macular pigment (retinal carotenoid) density was measured with a psychophysical method described in the paper. The main result of the study was that non-smokers had over twice the macular pigment density as smokers (p<0.0001). Almost 2/3 of the smokers had extremely low macular pigment densities. Since the investigators matched smokers and non-smokers on dietary carotenoid intake, smoking seems to be associated independently with substantially reduced retinal carotenoid density.
However the few smokers in the study who did have higher macular pigment densities, also had very high (> 2 std deviations above the mean) dietary carotenoid intake. This supports the suggestion by Seddon and colleagues that increasing the macular pigment density through increased intake of lutein/zeaxanthin could ameliorate some of the risk of AMD associated with smoking.
References
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In an earlier EduFacts ("Multivitamin Use and Cataracts: Reviewing the Data") some data from the Nutrition and Eye Disease Study was reported which suggested that regular multivitamin use could provide some modulation of the smoking risk factor for cataract development. Presumably this is caused by antioxidants in the multivitamin formula which provide added defense against the oxidative damage to the lens caused by smoking. Interestingly, data from Eye Disease Case Control Study suggest that high intake of the carotenoids lutein and zeaxanthin may modulate some of the risk of AMD associated with smoking. Seddon, Adjani and co-authors reported on 356 cases diagnosed with advanced AMD and 520 age and sex-matched controls.
Methods:
Dietary intake of specific food items was determined through use of a semi-quantitative diet questionnaire (including the use of supplements). The quantity of specific nutrients contained in food items was determined using U.S. Department of Agriculture sources. As one part of their analysis, patients in the lowest quintile of dietary intake of lutein/zeaxanthin (L/Z) and who had never smoked were used as the "reference" group (Odd's Ratio = 1).
Results:
Past smoking doubled the risk of AMD and current smoking tripled the risk among patients with low intake of lutein/zeaxanthin. Among patients in the upper fifth percentile of lutein/zeaxanthin intake, risk of AMD was reduced by 43% among those who had never smoked. However, past smokers and even current smokers with high L/Z intake continued to show reduced risk of AMD (16% reduction among past smokers and 38% reduction among current smokers) relative to non-smokers with low L/Z intake.
References
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Earlier EduFacts issues have reviewed evidence of the inverse relationship between decreased rates of lens opacities and/or cataract extraction and higher overall intake (supplements and/or food intake) of the anti-oxidative vitamins E and C. In this report, data supporting the value of vitamin A in cataract prevention are presented.
Vitamin A, or retinol, is part of the visual pigment in the human eye, protecting the retinal epithelium. The importance of vitamin A with respect to retinal health is well known; severe vitamin A deficiency is a leading cause of blindness among under-nourished populations. However, it is sometimes overlooked that vitamin A, as an anti-oxidant, is also of value in preventing lens opacities. The Lens Opacities Case-Control Study, the Nutritional Factors in Eye Disease Study (part of the Beaver Dam eye Study), and the Nurses' Health Study, provide evidence of decreased risk of lens opacities associated with increased vitamin A intake.
In the Case-Control study patients with opacities were compared with controls with respect to level of vitamin A obtained through supplements on a regular basis (at least once a week for at least a year). Increased vitamin A intake was associated with a 55% decrease in cortical opacities and a 40% decrease in mixed opacities (adjusted for age and sex).
In the Nutrition and Eye Disease Study moderate levels of vitamin A intake were associated overall with a 40% decreased risk of nuclear sclerotic opacity (p=0.002). This risk was adjusted for age, sex, smoking, and heavy drinking. Among smokers, risk of cataract was reduced 50%.
In the Nurses' Health Study, a large cohort of nurses has been followed for almost 20 years. In this longitudinal study increased dietary intake of vitamin A was associated with a 39% reduction in risk of cataract extraction.
References
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Over the past few years published reports have provided evidence of decreased rates of lens opacities and/or cataract extraction associated with higher overall intake of antioxidant vitamins. Nevertheless, some ophthalmologists question the added efficacy of using vitamin supplements in addition to healthy eating patterns. The Lens Opacities Case-Control Study and the Nutritional Factors in Eye Disease Study, (both reviewed in earlier EduFacts issues) both evaluated the use of multivitamins in addition to overall intake of specific vitamins.
In the Case-control study (See earlier EduFacts: "Vitamin E and Cataracts: Reviewing the Data") cases (any lens opacity in at least one eye explaining a decrease in vision) were compared with controls (no lens opacities, and 20/20 or better in both eyes) with respect to use of multivitamin supplements on a regular basis (at least once a week for at least a year). Regular use of multivitamins was associated with decreased risk of posterior subcapsular, cortical, and nuclear opacities and with decreased risk of mixed opacities.
In the Nutrition and Eye Disease Study 2376 participants in the Beaver Dam Eye Study were evaluated for past multivitamin use then followed forward to determine the current prevalence of lens opacities. Type and severity of lens opacities was determined by comparing (in masked fashion) photos taken under a uniform protocol with a set of photo standards. Among non-diabetic patients (N=1980) past use of multi-vitamins was reported in 21% of people and was associated with a 40% decreased risk of nuclear sclerotic opacities (adjusted for age, sex, smoking and heavy alcohol use). Among smokers risk of nuclear sclerotic opacities was reduced 50%. The protective effect of regular multivitamin use on risk for nuclear sclerotic opacity was significantly stronger in smokers (p<0.05) than in non-smokers. The authors cited reports documenting a higher risk for nuclear cataracts among smokers (who experience more oxidant stress) and suggest that smokers may thus be more susceptible to nutritional modulation of risk.
References
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Vitamin E (alpha-tocopherol) is taken as a supplement by many people because of its anti-oxidant activity. It if often used to protect against heart disease. Vitamin E is found in normal healthy cell membranes and prevents formation of lipid peroxides.
Reports published over the last decade have generally documented decreased risk of opacities and/or cataract extraction associated with intake of various antioxidant vitamins or with computed "antioxidant intake scores". Study designs and specific conclusions were varied. This EduFacts will focus on two case-control studies, which support the protective role of vitamin E supplements against cataract formation formation.
In the case-control study by Robertson, Donner and Trevithick, 175 cataract patients were individually matched with 175 cataract-free controls. Cataract was defined as a lenticular opacity impairing vision. All cases had just undergone or were scheduled for cataract surgery. Controls were matched on age (within 5 years) and sex. All participants were interviewed in their homes. Detailed information on the use of nutritional supplements within the previous 5 years was obtained through interview. Paired multiple logistic regression analysis was used to determine relative risks while controlling for confounding variables. The major finding in the study was that there was a 44% decrease in risk of cataract (p=0.004) associated with reported use of vitamin E supplements compared with non-use during the prior 5 years.
Also in 1991, Leske, Chylack and co-authors reported the results of another case-control study of cataract risk factors. This study evaluated 1380 ophthalmology outpatients at 2 sites. They were aged 40-79 and were evaluated for opacity grade using a standardized system. Cases (N=945) were defined as having a nuclear, cortical or PSC opacity in at least one eye explaining a decrease in vision. Controls (N=435) had no lens opacities and were 20/20 or better in both eyes. Cases were similar to controls with respect to demographics, and possible confounders. Nutritional data were obtained using a questionnaire devised for a large government survey of nutrition and health that provided estimates of dietary intake of various vitamins over long periods. Use of supplements was ascertained by questionnaire. With respect to vitamin E, it was found that there was a 42% (p<0.05) decreased risk of mixed cataract associated with high dietary intake of vitamin E compared with low intake.
Use of multivitamins was also evaluated in this study. Reported intake of these supplements was associated with a 30-48% decrease in risk of cataract depending on the opacity type.
These studies, with similar design and methodology, both reported consistent levels of decreased risk of cataract associated with vitamin E intake through supplement use or relatively higher dietary intake.
References
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In an earlier issue the relationship between macular pigment density, dietary carotenoids, and age-related macular degeneration (AMD) was explored. The studies summarized in that issue demonstrated the following relationships: 1) increased pigment density with increased dietary intake of lutein and zeaxanthin; 2) reduced risk of AMD with higher serum levels of the retinal carotenoids lutein and zeaxanthin; and 3) reduced risk of AMD with increased dietary intake of these carotenoids. There is evidence that increasing macular pigment MP density may help prevent AMD. There is wide inter-patient variation in macular pigment density. However, not much research has been carried out describing the variation among different groups.
In a study by Hammond and colleagues, results indicated a higher macular pigment density among males compared with females (38% higher density) despite similar plasma levels and dietary intake of carotenoids. This is consistent with epidemiological findings that women may be at greater risk of exudative AMD (at least at older ages). Furthermore the authors noted that in this study the relationship between dietary intake of fat and the effect on MP density differed between men and women; among women the relationship was negative (higher dietary fat = lower MP density) but among men it was positive. The relationship between individual genetics, gender, dietary patterns, and MP density is murky. The relationship between dietary and plasma levels of carotenoids is clearly moderated by individual and probably gender-related genetic factors. These factors, along with dietary practices would impact on the variation in MP density and would be consistent with the familial history risk factor for AMD. Hammond, Fuld and Curran-Celentano published an interesting twin study in 1995 to evaluate the importance of genetic factors in MP density.
|
Variable |
Twin with Higher MP: Mean |
Twin with lower MP: Mean |
|
Macular pigment |
0.45 |
0.15 |
|
Dietary fiber - g/day |
23.5 |
17.5 |
|
Oleic acid - g/day |
59.6 |
37.8 |
|
Linoleic acid -g/day |
29.2 |
19.9 |
|
Iron - g/day |
23.2 |
17.8 |
|
Total fat - g/day |
157.3 |
99.6 |
They enrolled 10 pairs of younger (19-22 years) monozygotic twins into the study. There were 6 male pairs and 4 female pairs. The method of measuring MP density is described in the paper. Dietary intake of various nutrients was determined using a 100-item food intake questionnaire, which gathers data on frequency, and serving size. A computer program from the National Cancer Institute was used to determine the nutrient composition of the food items ingested. Serum carotenoid levels were measured 7 times over a 3-month period.
Results:
The main finding was that half (5/10) of the monozygotic twin pairs had statistically significant differences in MP density despite the identical genetics. The twins showing differences in MP density had certain systematic differences in their diets. In each of the 5 pairs, the twin with higher MP density had higher dietary intake of fat, iron, linoleic and oleic acids, fiber and total calories. A composite score for these variables showed a statistically significant positive relationship with MP density. The authors cited studies supporting a possible hypothesis that these nutrients influence carotenoid metabolism and thus macular pigment levels. The authors concluded from this twin-study controlling genetic make-up, that a good deal of the variation in MP density is caused by external factors. They concluded that dietary factors contributed, although the relationships between dietary levels, uptake, plasma levels and the ultimate effect on MP density are complex.
Conclusion:
Dietary and supplement intake of specific nutrients probably affects MP density, which, in turn, affects the risk of AMD.
References
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A recently published article in the Journal of the American Geriatrics Society reported an inverse association between consumption of wine and risk of age-related macular degeneration (AMD) . The authors evaluated a sub-sample of people participating in the first National Health and Nutrition Examination Survey (NHANES-1) which was conducted on a large population-based representative sample during 1971-1975. The sub-sample consisted of people aged 45-74 who were given detailed eye examinations (1971-72) in addition to the general survey and medical history questionnaire. Of the NHANES-1 participants, 3072 were within the 45-74 age range, had been given detailed fundus exams and had responded to the group of alcohol consumption questions. They were divided into cases (having AMD) and controls (no evidence of AMD). Ophthalmologists from the National Eye Institute verified ocular diagnoses and supervised quality control.
Results:
Alcohol consumption was categorized by usage during the year (Y/N), frequency of use, most frequent alcohol type and usage during 24 hours. It was found that 4% of wine drinkers had AMD compared with 9% of people who drank no alcohol at all. Bivariate logistic regression was used to determine the relative risk of AMD between alcohol users and non-users. Drinking wine was associated with decreased risk of AMD as shown below. The risk was decreased by 34% among those drinking wine, by 34% for those drinking beer and wine, and by 26% for those drinking wine and liquor (p<0.001 for all 3 comparisons). Multiple logistic regression was also used to control for other confounding factors such as age , sex, income, history of congestive heart failure, and hypertension. Age is strongly associated with AMD and the other factors are associated with alcohol consumption. When these adjustments were included only wine drinking remained significantly associated with decreased risk of AMD (19% lowered risk, p=0.028). Obisesan and coauthors discussed their findings cautiously. They pointed out that the study had some limitations in design; it was cross sectional rather than prospective and it excluded people over 74. Alcohol use was determined very loosely based on any uses within the previous year. Furthermore most studies of this type will underestimate alcohol use (alcohol recall bias). The NEI issued a statement regarding the interpretation of the study. The statement reiterated these cautionary comments with respect to any inference of a causal relationship.
Clearly there is limited information regarding the relationship between alcohol consumption and AMD. In a study of the Beaver Dam Eye population, Ritter, et al found no statistically significant associations but presented data suggesting a weak positive association between exudative AMD and beer consumption. The Eye Disease Case Control Study found no association between AMD and alcohol consumption. Both these studies also have the methodologic problems inherent in alcohol consumption studies. Obisesan points out that the statistically significant inverse relationship between AMD and wine consumption in the NHANES-1 study is consistent with the known anti-oxidative role of red wine polyphenols in protecting against heart disease. They also point out that epidemiological reviews suggest that AMD and heart disease may both be associated in some fashion with certain common factors and that it would be worthwhile to further study a possible protective role for moderate wine consumption.
While data on this subject is very limited, it should be recognized that some patients in this age range do consume modest levels of wine to help protect against heart attack and that some take the antioxidant red wine polyphenol supplements to avoid the alcoholic content. While information is limited, it is possible that this practice could add some protective effect for AMD.
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Diet is believed to impact on the development and course of age-related macular degeneration (AMD) mainly by influencing the strength of the body's antioxidant defenses. zinc is found in high concentrations in the retinal pigment epithelium and plays a role in the metabolic function of several important enzymes in the chorioretinal complex. It may be a cofactor for the activity of enzymes providing oxidant defense. Severe zinc deficiencies have been associated with retinal pathology in animal models and in humans.
Treatment Effect of Zinc Supplements:
In a 1988 study, Newsome and coauthors documented the treatment value of zinc supplements in lessening both visual loss and maculopathy. In this prospective study, 150 patients with drusen or varying degrees of macular degeneration were randomized to receive zinc sulfate tablets (200 mg) or placebo tablets. Patients were followed 2 years. Visual acuity loss was significantly less (p<0.001) among zinc-treated patients than among placebo patients (mean letters lost was 2.5 vs 6.4 at 1 year). The amount of visual loss was also related to treatment compliance. Furthermore, there was a lessened increase of drusen and macular atrophy among zinc-treated cases over the 2-year period.
Protection of Macular Health:
Mares-Perlman and colleagues conducted an epidemiological study of patients from the Beaver Dam Eye Study to evaluate the effect of zinc and antioxidant nutrients as preventive of AMD. This was a retrospective longitudinal cohort study. Patients were examined to determine the AMD status (none, early or late AMD). They were interviewed regarding known risk factors and were given dietary interviews to determine intake of various nutrients of interest through the diet and of dietary supplements during a one-year period 10 years prior to the eye exam. Their methods of analyzing nutrient intake were rigorous, following validated systems used by the National Cancer Institute. Following logistic regression analysis to control for other confounding risk factors, the authors reported that patients with reported dietary intake of zinc in the upper 5th quintile had a 40% lower risk (p<0.05) of having early AMD 10 years later compared with those in the lowest quintile. The group in the highest quintile of zinc intake through food plus supplements had a measured 30% decreased risk which was not statistically significant. Patients in the upper quintile of zinc intake through food plus supplements showed a significant 40% decrease in risk of early AMD lesion in the form of increased retinal pigment. The authors considered the data to be weakly supportive of a protective effect of zinc. The authors point out that the fact that the decrease in risk was not more strongly documented may very likely be due to the retrospective nature of the study: patients were interviewed regarding food and supplement intake 10 years earlier and may not have continued at the same levels over the next 10 years. Furthermore, only 5% of study participants reported taking supplements containing zinc during the period making it difficult to detect a stronger association.
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Macular pigment is principally comprised of the retinal carotenoids zeaxanthin (Z) and lutein (L) which are derived through dietary intake (1,2). Macular pigment is believed to protect the retina from ultraviolet light. The protective effect is due to anti-oxidative activity. While there is a great deal of inter-patient variability in macular pigment density, it has been found that the pattern of retinal distribution of macular pigment correlates with the spatial profile of retinal pathology in patients with AMD; i.e. retinal changes are greatest where pigment is least dense. It is believed that AMD may develop due to cumulative oxidative damage in the aging eye. This etiology is consistent with epidemiological findings identifying the risk factors for AMD: age, smoking, increased sunlight exposure, low ocular melanin, light colored iris, family history, and female sex. Family history and gender, as risk factors, may be related in part to their effect on the macular pigment density. While the etiology of AMD is complex, there is evidence that increasing macular pigment density (through increased intake of lutein and zeaxanthin) may decrease the risk of AMD.
Dietary intake of Lutein and Zeaxanthin: Effect on macular pigment density
Researchers Hammond, Johnson, Russell and colleagues performed a study in which they measured macular pigment in 13 patients who received dietary modification for a period of up to 15 weeks. Subjects were given daily servings of spinach and corn, which added 11.2-mg lutein and 0.6 mg zeaxanthin. Relative to an average diet, this increased L intake 4-fold and Z intake 3-fold. Eight of 10 patients compliant on the spinach/corn supplement diet exhibited an average increase in macular pigment density of 19% (minimum of 13%).
Lutein and Zeaxanthin: Effect of dietary intake and serum levels on Risk of AMD
Investigators in the large NEI-funded Eye Disease Case-Control Study reported in 1993 that among the 1000-plus participants, those with serum levels of lutein and zeaxanthin at the 80th percentile had a 70% decreased risk of AMD. Those at the 20-80th percentile in serum levels experienced a 50-60% decrease in risk relative to those below the 20th percentile. Furthermore, increasing serum levels correlated linearly with a progressive decrease in risk of AMD. Seddon and colleagues studied over 300 patients and reported a 57% decrease in risk of AMD in patients with increased dietary intake of lutein and zeaxanthin.
These studies, which will be summarized in greater detail in future EduFacts, provide strong presumptive evidence of the value of increased dietary intake of lutein and zeaxanthin to maintain the macular pigment density and to protect macular health.
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