David A. Mark, PhD

July 1, 2009

12 Min Read
Natural brain boosters

You've experienced it: A customer comes to your store looking for a supplement to make her sharper. Good thing a few star ingredients are making news in cognitive health. David A. Mark, Ph.D., talks about the ones that should be on your radar. Mark is a Boston-based consultant for the functional-food and dietary-supplements industries and former manager of health and nutrition research and development for Welch Foods Inc.

If there were a magic pill that would prevent your memory, focus and acuity from blurring around the edges as you age, would you take it? New ingredients on the scene promise to do just that, slowing or preventing the onset of dementia—an umbrella term for symptoms of a variety of illnesses that cause cognitive deterioration. Alzheimer's disease, vascular dementia and Lewy Body dementia are the most commonly diagnosed conditions. Alzheimer's is the most familiar in North America and Europe, but vascular dementia plus mixed Alzheimer's/vascular dementia are dominant in some East Asian countries. Barring effective prevention or treatment, experts expect the prevalence of dementia in the U.S. to at least double by 2030, due to the baby-boom effect and rising obesity and diabetes rates, which elevate vascular-dementia risk. More than 40 supplements ingredients and foods have been identified as tentatively having beneficial effects on cognitive function. Some even specifically target dementia prevention or treatment.

Resveratrol, a polyphenol in red wine, gets hyped for playing a role in the "French Paradox"—the fact that the French, as a population, eat rich foods, smoke cigarettes, don't exercise and, yet, do not develop heart disease. Population studies in France and Italy have reported 25 percent to 80 percent reductions in dementia or Alzheimer's risk for people who consume moderate amounts of red wine compared to those who don't drink alcohol.

Is resveratrol responsible for the heart and brain benefits attributed to red wine? Probably not, says Roger Corder, a professor at William Harvey Research Institute in London, in his book The Red Wine Diet (Avery, 2007). Red wines contain about 1,500-3,500 mg polyphenols per liter. Of this, resveratrol makes up just 1-5 mg, or less than 1 percent.

Red wine's heart and brain benefits are consequences of drinking one to three glasses of wine a day (at higher intakes, the alcohol damage outweighs any polyphenol benefit). The prime suspect for the red-wine effect is a class of flavonoid polyphenols known as proanthocyanidins. Foods rich in flavonoids include red wine, dark-colored fruits and berries, cocoa-rich foods, hazelnuts, pecans, green tea, certain types of beans and some spices.

Although there are no published human resveratrol-efficacy trials, resveratrol research holds tremendous promise. There are nine resveratrol clinical trials listed at clinicaltrials.gov. Two studies, at the Medical College of Wisconsin in Milwaukee and Mount Sinai School of Medicine in New York, are investigating resveratrol for Alzheimer's disease. Medical College of Wisconsin is using the Longevinex brand resveratrol-containing product to deliver 215 mg per day of the polyphenol. Mount Sinai does not specify product or dose. Results from both trials are expected in late 2010.

Preclinical studies are supportive. In various cell lines known to produce amyloid-beta peptides (Abeta, which leads to Alzheimer's), incubation with resveratrol—but not quercetin or catechin—reduces Abeta concentrations in a dose-dependent relationship. The mechanism appeared to be via increased Abeta degradation. Mouse models of Alzheimer's disease also demonstrate improvements with resveratrol. Resveratrol and resveratrol-like drugs in development activate sirtuins, a class of regulating enzymes implicated in prolonging lifespan and various age-related functions in in vitro and animal models. The drug company to watch is Sitris Pharmaceuticals (sitrispharma.com), which has several resveratrol-like drugs in clinical trials. Resveratrol extracted from Japanese knotweed (Polygonum cuspidatum) is available in the U.S. as a dietary-supplement ingredient.

L-theanine is a non-nutrient amino acid found in tea leaves. Most reviews describe it as a component of green tea and estimate intake at 25-40 mg per cup of tea. However, a recent analytical report confirmed L-theanine in oolong and black teas, as well. Across all types of tea, the L-theanine content ranged from 40-300 mg per 100 grams dried tea leaf, which would result in an estimated intake range of 1-9 mg per cup. Hence, a person drinking four to five cups of tea a day could be getting 30-40 mg per day.

Synthesized L-theanine has been evaluated in several clinical trials. Doses of 50-200 mg have been shown to increase brain alpha waves and result in a relaxed state. Healthy subjects performing a stressful mental task reported less stress and had a lower heart rate during the test if they ingested 200 mg L-theanine before the test.

Nonhuman research links L-theanine much more directly to brain health and function. One proposed mechanism is that L-theanine either inhibits production or blocks receptors for the neurotransmitter glutamate, akin to mementine, a receptor-blocker drug approved by the Food and Drug Administration for Alzheimer's disease. There is also in vitro and animal evidence that L-theanine reduces the risk of cell death as a result of temporary oxygen deprivation. In one rat experiment, L-theanine significantly prevented memory impairment. This mechanism would apply to protection from vascular dementia.

Selenium is the favored antioxidant nutrient of the moment. In theory, cumulative free-radical damage, possibly preventable by antioxidant nutrients such as selenium, vitamins A and E and beta-carotene, is involved in neuron death in Alzheimer's disease and other neurodegenerative disorders. In autopsies, brains of Alzheimer's-afflicted people are characterized by increased lipid peroxidation, protein oxidation and DNA oxidation. Molecules concomitant with oxidative inflammation are also present.

A three-year vitamin E trial (2000 IU per day) assessed the progression from mild cognitive impairment to Alzheimer's disease. There was no reported benefit. But an epidemiological selenium study of 2,000 mainland Chinese subjects older than age 65 showed a strong correlation between selenium status as measured by nail and blood content and diet analysis against six of seven tests for cognitive function. One weakness of this study is that even the highest one-fifth of the subjects had dietary intakes even close to (but still below) the Dietary Reference Intake, or DRI, of 55 mcg per day for selenium. Actual intakes in the U.S. are higher. NHANES 2001-02 pegged median intakes for adult females at 89 mcg per day and males at 125 mcg per day. Results from a large human prospective study will not be available for several years.

SELECT is the acronym for a seven- to 12-year, 35,000-subject selenium trial (200 mcg), vitamin E (400 IU) or both as a means of preventing prostate cancer. A subset of 10,400 men who were older than age 60 at the onset of the study is also being tracked for development of dementia. The trial, known as PREADVISE, is described at clinicaltrials.gov. Results are not expected until 2013. In October, however, the SELECT trial was stopped after five years because researchers were finding no benefit and an insignificant trend toward risk of cancer and diabetes.

Lignans are a class of phyto-oestrogens found in flaxseeds and in lesser amounts in whole grains and other foods. Flax and spruce-tree lignans are available as ingredients in dietary supplements.

Although most of the literature is focused on helping maintain breast or prostate health, an interesting Netherlands study published in 2005 assessed cognitive function. Just fewer than 400 healthy women, average age 66 years, completed a dietary intake survey and a Mini-Mental State Examination, known as MMSE. Intact cognitive function (MMSE ≥ 26 on a 0 to 30 scale) was reported for 77 percent of the women. Higher intake of dietary lignans, but not isoflavones, was associated with a higher probability of intact cognitive function. The correlation remained after adjusting for diet and lifestyle variables known or suspected to have an impact on cognition (eg, education level, alcohol, tobacco, fatty-fish intake). The median lignan intake in this study was 0.62 mg per day, with only the top 25 percent exceeding 0.86 mg per day. Other studies have reported similar or slightly higher dietary intakes.

Flaxseed and lignan products used in clinical trials for other indications typically deliver 50-100 mg per day to have an impact. This begs the question about how differences in the comparatively low intakes of dietary lignan could affect development of dementia, unless by an entirely different mechanism than proposed for breast and prostate diseases.

Blueberries improve memory, strength, balance and coordination—in old rats. Which is fine, if you are an old rat. In several studies conducted by James Joseph, Ph.D., Barbara Shukitt-Hale and their coworkers at the U.S. Department of Agriculture-Agriculture Research Service Research Center on Aging at Tufts University in Boston, 19-month-old rats fed blueberries for two months showed improvements in memory, strength, balance and coordination in tests such as the Morris Water Maze, rod walking, wire suspension and plank walking (think of a testing lab set up as a miniature Cirque du Soleil, but without the music and costumes).

The memory gains have been confirmed by a different research group, and similar results have been demonstrated with aged rats fed Concord grape juice, and with mice fed grapeseed extract. Blueberries, dark grapes and grape seeds contain a wide range of polyphenolic molecules, including proanthocyanidins.

Although the mechanisms involved in the behavioral deficits of aging remain to be determined, researchers suggest that cumulative oxidative stress, chronic inflammation and changes in the production of neuroprotective proteins all contribute to the loss. Helen Kim and her coworkers at the University of Alabama in Tuscaloosa reported that in the brains of rats fed grapeseed extract, the direction of change of protein expression, either increased or decreased, was opposite to the direction associated with Alzheimer's disease.

Enough about rats and mice—what about humans? We should have a hint soon. Robert Krikorian, of the University of Cincinnati, recently completed but has not yet published a small 12-week study that compared placebo, blueberry juice and Concord grape juice on memory performance in subjects older than age 64, who have mild cognitive impairment. Earlier research has shown that a blueberry meal resulted in significant increases in plasma antioxidant capacity. It appears that blueberry polyphenols enter and are active in the blood circulation.

Omega-3 fatty acids, according to a growing body of scientific evidence from biological, observational and epidemiological studies, have a protective effect against dementia. The long-chain omega-3 fatty acids eicosapentanoic acid, or EPA, and docosahexanoic acid, or DHA, are well-known constituents of marine fish oil. These omega-3 fatty acids have been shown to be essential to infants' and children's brain development and now are appearing to be essential to maintaining brain health as we age. Greg Cole and his colleagues at the University of California at Los Angeles have used animal models to show that DHA reduces Abeta accumulation. Researchers with the Framingham Heart Study in Massachusetts used nine years of subject tracking to estimate that people in the top 25 percent of plasma DHA levels had a 47 percent reduction in the risk of developing dementia. To be in this top 25 percent, the people in the study were consuming an average of 180 mg per day of DHA via 2.9 fish servings per week. The bottom 25 percent were at 90 mg per day and 1.3 servings per week.

As a bonus to the dementia results, reviews suggest that omega-3 fatty acids also have an antidepressant effect. A meta-analysis of 10 placebo-controlled trials with a combined ‘n' of 329 patients reported a significant antidepressant effect of omega-3 fatty acids. A recent population study linked the dementia and depression effects: For 1,214 nondemented study participants, about age 75 and followed for four years, a higher plasma EPA concentration was associated with a 31 percent lower risk of developing dementia; the reduction of risk was even greater in the subset of patients with diagnosed depression.

Vitamin D & calcium in combination received massive negative press coverage in May 2007, as a result of a conference presentation by Martha Payne and coinvestigators from Duke University and the University of North Carolina. Elderly subjects were examined by brain MRI. Higher calcium and vitamin D intakes, as determined by food-intake questionnaires, were associated with increased brain-lesion volume. Brain lesions are associated with cognitive dysfunction, dementia, stroke and depression. The authors hypothesized that the nutrients could be promoting dietary-calcium absorption and subsequently calcification of blood vessels.

In this study the highest vitamin D intake from diet plus supplements was 1,014 IU per day. The average for subjects with a high brain-lesions load was 355 IU, and 326 IU for subjects with low-lesion load. The difference between the groups was statistically significant but numerically only a modest 8 percent difference. The authors acknowledge that there was no attempt to quantify sun exposure—which causes vitamin D synthesis in the skin—or measure serum vitamin D.

The results were unexpected and do not appear to jibe with the main body of scientific literature on vitamin D. Recommended vitamin D intake for people over age 70 is 600 IU. If anything, there is a growing consensus that the RDA should be increased to 1,000 IU. Two recent reviews defined serum vitamin D levels greater than 75 nmol/L as desirable, and estimated that intakes greater than 1,000 IU per day are needed to move the majority of Americans to this range.

According to the DRIs, abnormally elevated serum calcium—and thus the risk of calcification of blood vessels—was seen after three months at 3,800 IU per day but not at 2,400 IU per day. Thus the tolerable upper intake level of 2,000 IU was set to be below the lowest known effect.

In opposition to the negative effect reported by Payne, Wilkins reported in 2006 that in 80 elderly subjects, either healthy or with mild Alzheimer's disease, vitamin D deficiency as determined by blood levels was associated with low mood and impairment on two of four measures of cognitive performance. A larger study (n=225) of Alzheimer's patients found vitamin D-sufficient patients to score better on the Mini-Mental State Examination compared to vitamin-insufficient patients.

Prospective studies are needed. Alzheimer's patients often have very low serum vitamin D, but that is more likely to be a result of low vitamin D intake and no sunlight exposure rather than evidence that the deficiency is contributing to the disease. It is clear that consequences of vitamin D insufficiency include muscle wasting (sarcopenia), loss of strength, weight loss and increased risk of injury from falls. Johnson notes that accelerated weight loss precedes diagnosis of Alzheimer's disease. Theories implicate a direct effect via vitamin D receptors in muscle cells and an indirect effect via preventing elevated parathyroid hormone levels, but direct neurological and neuromotor consequences of vitamin D insufficiency warrant investigation.

Population studies in France and Italy have reported 25 percent to 80 percent reductions in dementia or Alzheimer's risk for people who consume moderate amounts of red wine compared to those who don't drink alcohol.


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