If I only had a brain (enhancer)

Joel Bernard/MasterfileUnlike the Scarecrow in The Wizard of Oz, we have brains. And, unlike the 'One-Hoss Shay' of Oliver Wendell Holmes' poem, our brains can break down or slow down before the rest of our parts do the same. David A Mark, PhD, investigates the leading natural bioactives in supplements and foods that beneficially influence cognitive health

Dementia is the umbrella term used to describe symptoms of a large group of illnesses that causes a progressive decline of mental function. The most common diagnosed conditions are Alzheimer's disease (AD), vascular dementia (VaD), combined Alzheimer's disease and vascular dementia, and Lewy Body dementia. AD is the most common cause in North America and Europe, but vascular dementia plus mixed AD/VaD are dominant in some eastern Asian countries.1,2,3,4,5

Given the combination of the baby-boom effect and the increased risk of vascular dementia due to consequences of obesity and diabetes, the prevalence of dementia in the US is projected to at least double by 2030, barring effective prevention and/or treatment.

Supplements and functional foods
More than 40 supplements ingredients and foods have been identified as tentatively having beneficial effects on cognitive functions, with some of them specifically targeting the prevention or treatment of dementia. Here's a sampling:

Resveratrol gets hyped for being the polyphenol in red wine responsible for the 'French Paradox' of how the French as a population eat rich foods, smoke cigarettes, don't exercise and, yet, do not develop heart disease. Less well known is the correlation between red wine and reduced risk for dementia and Alzheimer's disease. Population studies in France and Italy reported 25-80 per cent reductions in risk for dementia or Alzheimer's disease for moderate consumption of red wine, compared to those who did not drink alcohol.6,7,8

Is resveratrol, then, responsible for both heart and brain benefits attributed to red wine? In his book, The Red Wine Diet, Roger Corder, professor at William Harvey Research Institute in London, thinks probably not.9 The polyphenol content of red wines is in the range of 1,500-3,500mg/litre. Of this, resveratrol makes up 1-5mg/litre, or less than one per cent. Red-wine health benefits for heart and brain are a consequence 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 effects is a class of flavonoid polyphenols known as proanthocyanidins (PACs). Foods rich in PACs include red wine, dark-coloured fruits and berries, cocoa-containing foods, hazelnuts, pecans, green tea, certain types of beans, and some spices.10,11

Whither resveratrol? Although not the wine effects' molecule, resveratrol research holds tremendous promise.8 Resveratrol extracted from Japanese knotweed (Polygonum cuspidatum) is available in the US as a dietary-supplement ingredient. As of publication of this article there are no human resveratrol efficacy trials for any health effect in the published scientific literature. There are, however, nine resveratrol clinical trials listed at www.clinicaltrials.gov. Two studies, at Medical College of Wisconsin (MCW) and Mount Sinai School of Medicine (MSSM), are investigating resveratrol for Alzheimer's disease. MCW is using the Longevinex brand resveratrol-containing product to deliver 215mg/day resveratrol. MSSM does not specify product or dose. Results from both trials are expected in late 2010.

Pre-clinical 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.12 Mouse models of Alzheimer's disease also demonstrate improvements with resveratrol.13 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 (www.sitrispharma.com), with several resveratrol-like drugs in clinical trials.

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 25-40mg/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 40-300mg/100g dried tea leaf, which would result in an estimated intake range of 1-9mg/cup.14 A person drinking four to five cups of tea a day could be getting 30-40mg/day.

Synthesised L-theanine has been evaluated in several clinical trials. Doses of 50-200mg have been shown to increase brain alpha waves and result in a relaxed state.15,16,17,18 Healthy subjects performing a stressful mental task reported less stress and had a lower heart rate during the test if they ingested 200mg L-theanine before the test.19

There is little overlap in claimed mechanism of action between the dietary supplements and drugs targeting dementia
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, 20,21 akin to mementine, an FDA-approved receptor-blocker drug for Alzheimer's disease. There is also in vitro and animal evidence that L-theanine reduces the risk of cell death subsequent to temporary oxygen deprivation. 22,23 In one rat experiment, L-theanine significantly prevented the impairment of memory. 23 This mechanism would apply to protection from vascular dementia.

Selenium is the favoured antioxidant nutrient of the moment. In theory, cumulative free-radical damage, possibly preventable by antioxidant nutrients such as selenium, vitamin C, vitamin E and beta-carotene, is involved in neuron death in Alzheimer's disease and other neurodegenerative disorders. On autopsy, brains of people who had AD are characterised by increased lipid peroxidation, protein oxidation and DNA oxidation. Molecules concomitant with oxidative inflammation are also present.24

A three-year vitamin E trial (2000IU/day) assessed the progression from mild cognitive impairment to Alzheimer's disease. There was no reported benefit.25 But, a selenium epidemiological study of 2,000 mainland Chinese subjects older than 65 years reported a strong correlation between selenium status as measured by nail content, blood content and diet analysis, against six of seven tests for cognitive function.26 One weakness of this study is that even the highest fifth of the subjects had dietary intakes even close to (but still below) the US RDA of 55mcg/day for selenium. Actual intakes in the US are higher. NHANES 2001-02 pegged median intakes for adult females at 89mcg/day and males at 125mcg/day.27

Results from a very sizeable human prospective study will not be available for several years. SELECT is the acronym for a seven to 12 year, 35,000-subject trial of selenium (200mcg), vitamin E (400IU), or both as a means of preventing prostate cancer. A subset of 10,400 men who were older than 60 years at the onset of the study is also being tracked for development of dementia. The trial, known as PREADVISE, is described at www.clinicaltrials.gov. Results are not expected until 2013. [NOTE: In October, the SELECT trial was stopped, after five years, because researchers were finding no benefit and a non-significant 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.

While most of the literature is focused on helping maintain breast or prostate health, there is an interesting Netherlands study published in 2005 that assessed cognitive function. Just less than 400 healthy women, average age 66 years, completed a dietary intake survey and a Mini-Mental State Examination (MMSE). Intact cognitive function (MMSE >/= 26 on a 0 to 30 scale) was reported for 77 per cent 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).28

The median lignan intake in this study was 0.62mg/day, with only the top 25 per cent exceeding 0.86mg/day.28 Other studies have reported similar or slightly higher dietary intakes. Flaxseed and lignan products used in clinical trials for other indications typically deliver 50-100mg/day to have an impact. This begs the question as to 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 co-ordination — in old rats. Which is fine, if you are an old rat. In several studies conducted by James Joseph, PhD; Barbara Shukitt-Hale; and their coworkers at the USDA-ARS Research Center on Aging at Tufts University, 19-month-old rats fed blueberries for two months showed improvements in memory, strength, balance and co-ordination 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).29,30,31

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 grape-seed extract.32,33,34 Blueberries, dark grapes and grape seeds contain a wide range of polyphenolic molecules, including proanthocyanidins.

Although the mechanisms involved in the behavioural deficits of ageing 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.31,35 Helen Kim and her co-workers at the University of Alabama reported that in the brains of rats fed grape-seed extract, the direction of change of protein expression (either increased or decreased) was opposite to the direction associated with Alzheimer's disease.35

Enough about rats and mice — what about humans? We should have a hint soon. Robert Krikorian, University of Cincinnati, recently completed but has not yet published a small, 12-week study comparing placebo, blueberry juice and Concord grape juice on memory performance in >64-year-old subjects who have mild cognitive impairment.36 Earlier research has shown that a blueberry meal resulted in significant increases in plasma antioxidant capacity, so it appears that blueberry polyphenols enter and are active in the blood circulation.37

Omega-3 fatty acids, according to a growing body of scientific evidence from biological, observational and epidemiological studies, have a protective effect against dementia.38,39 The long-chain omega-3 fatty acids eicosapentanoic acid (EPA) and docosahexanoic acid (DHA) are well-known constituents of marine fish oil. These omega-3 fatty acids have been shown to be essential to the developing brains in infants and children, and now are appearing to be essential to maintaining brain health as we age. Greg Cole and his colleagues at UCLA have used animal models to show that DHA reduces Abeta accumulation.40 Researchers with the Framingham Heart Study used nine years of subject tracking to estimate that people in the top 25 per cent of plasma DHA levels had a 47 per cent reduction in the risk of developing dementia. To be in this top 25 per cent, the people in the study were consuming an average of 180mg/day of DHA via 2.9 fish servings per week. The bottom 25 per cent were at 90mg/day and 1.3 servings/week.41

As a bonus to the dementia results, reviews suggest that omega-3 fatty acids also have an antidepressive 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.42 A recent population study linked the dementia and depression effects: for 1,214 non- demented study participants, aged about 75 years and followed for four years, a higher plasma EPA concentration was associated with a 31 per cent lower risk of developing dementia; the reduction of risk was even greater in the subset of patients with diagnosed depression.43

Vitamin D & calcium in combination received massive negative press coverage in May 2007, as a result of a conference presentation by Martha Payne and co-investigators from Duke University and the University of North Carolina. Elderly subjects were examined by brain MRI. Higher vitamin-D and calcium 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 hypothesised that the nutrients could be promoting dietary-calcium absorption and subsequently calcification of blood vessels.44

In this study the highest vitamin-D intake from diet plus supplements was 1,014IU/day. The average for subjects with a high brain-lesions load was 355IU, and for subjects with low-lesion load, 326IU. The difference between the groups was statistically significant but numerically only a modest eight per cent 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.44

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 70 years is 600IU. If anything, there is a growing consensus that the RDA should be increased to 1,000IU. Two recent reviews defined serum vitamin-D levels of >75nmol/L as desirable, and estimated that intakes of >1,000IU/day are needed to move the majority of Americans to this range.45,46

According to the DRIs, abnormally elevated serum calcium — and thus the risk of calcification of blood vessels —?was seen after three months at 3,800IU/day but not at 2,400 IU/day. Thus the tolerable upper intake level of 2,000IU was set to be below the lowest known effect.47 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.48 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.49

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.50 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.45,46,51,52,53 Johnson notes that accelerated weight loss precedes diagnosis of Alzheimer's disease.54 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.

David A Mark, PhD, is president of dmark consulting LLC, a Boston-area science consulting firm. His 25 years of industry R&D experience includes functional foods, dietary supplements and medical nutrition products. www.dmarknutrition.com

St. John's wortMechanisms — and Ingredients of Interest
The functional ingredients and foods described in this article are a short selection from the litany of nutrients, foods and compounds, touted as having an effect on brain function. Here is a longer list, loosely sorted by mechanism.


Grape seed
Coenzyme Q10
Red wine
Tea or EGCG from tea
Tree nuts
Vitamin C
Vitamin E
Alpha-lipoic acid
Coenzyme Q10
Omega-3 fatty acids
Vitamin B6
Vitamin B12
Gotu cola
St. John's wort

Vitamins vs. pillsThe race is on: Supplements vs drugs
The pharmaceutical industry has not missed the boat on bringing products to market for Alzheimer's disease (AD). Sales of five FDA-approved drugs already exceed $2 billion dollars annually and are growing rapidly. For drug development, treatment is far more attractive than prevention, as the latter requires trials on the order of three to seven years and 1,000 to 5,000 individuals to be adequately powered for statistical analysis.1

Interestingly, there is little overlap in claimed mechanism of action between the dietary supplements and drugs targeting dementia, nor much thought that co-treatment with supplements might improve drug functionality. Drugs target treatment for AD-related changes to neurotransmitters or accumulation of amyloid-beta peptides. Many of the food and supplement products target antioxidant, anti-inflammatory, and vascular-health mechanisms making them more attractive to preventing vascular dementia (VaD) rather than treating AD. VaD is 50 per cent of all dementias in some eastern Asian countries.2,3

Acetylcholinesterase inhibitors such as Aricept or Exelon have been approved by the FDA for mild, moderate and severe Alzheimer's disease (AD). This class of drugs was developed based on observations that people with AD and VaD are deficient in acetylcholine — a central nervous system neurotransmitter. Initial FDA approval was in 1996.

NMDA (N-methyl-D-aspartate) receptor blockers are another class of FDA-approved drugs for AD. NMDA blockers guard against over-excitement of nerve cell NMDA receptors by neurotransmitter glutamate. Memantine (marketed under various brand names) was approved by the FDA in 2003. Other NMDA blockers are in development.

Slowing or stopping the accumulation of amyloid beta (Abeta) peptides in amyloid plaques in the brains of people with AD is a major drug target. Two drugs, Alzhemed and Flurizan, are expected to achieve FDA approval in 2009. Many other anti-Abeta drugs are in development.

There is conflicting evidence whether statin drugs, prescribed to lower blood cholesterol, provide any benefit for Alzheimer's disease. Clinical trials have reported both positive and negative results. Dr Benjamin Wolozin hypothesises that statins that can cross the blood-brain barrier, such as simvastatin, are more likely to be beneficial. Results from two major clinical trials on statins and AD (CLASP, LEADe) are expected in late 2008. Conclusive evidence for an anti-dementia effect of statins would not carry over to supplement- or diet-lowering of cholesterol.


1. Pfeifer M, et al. Effects of a long-term vitamin D and calcium supplementation on falls and parameters of muscle function in community-dwelling older individuals. Osteoporos Int 2008 (in press).
2. Jellinger KA. The pathology of "vascular dementia": a critical update. J Alzheimers Dis 2008;14:107-123.
3. Roman GC. Facts, myths, and controversies in vascular dementia. J Neuro Sci 2004;226:49-52.

Select suppliers: bringing you ingredients to entertain the brain

Artemis International
Standardized Nutritionals line includes a range of berry extracts, fruit powders and concentrates. Recently formed a co-marketing partnership with Linnea.

This krill-oil supplier has a distribution agreement with Enzymotec to supply an alternative to fish-sourced EPA/DHA.


BioFlaxElite is a branded combination of flax with beta-glucan. Offers a full EFA line from fish, flax, borage, evening primrose, blackcurrant, perilla and CLA.

Botanic Oil Innovations
Proprietary blends of cold-pressed seed oils and flours are rich in antioxidants to address neural health and much more.

Chemi Nutra
SerinAid PhosphatidylSerine (PS) is also part of OmegaAid PS, a combination product with DHA and EPA with PS.

Cypress Systems
SelenoExcell brand high-selenium yeast is a high-potency (1,200mg/g), 100 per cent organically bound selenium yeast product. It formulates well with capsules, tablets, hard gels or soft gels.

Cyvex Nutrition
Biovinca brand vinpocetine, Biovin whole-grape extract, CranLife cranberry extract, and PomActiv pomegranate extracts highlight a range of branded ingredients.

Denomega 100 and Denomega Powder are natural taste- and odour-free omega-3 oils from food-quality cod liver. They are finding a home in baked goods, dairy, beverages, margarines and spreads, fish, and meat products. Denotaste CLO is for supplements.

World's largest supplier can source resveratrol and most other ingredients.

Sharp-PS; Sharp-PS Silver, a concentrated blend of PS with DHA; Sharp-PS Gold, with PS and omega-3s. Crill is phospholipids-based and richer in DHA than krill oil.

Offers EPA and DHA concentrates for condition-specific formulations. Its Mood & Mind Health has high amounts of EPA.

Fluxome Sciences
Resveratrol is made by a fermentation process, which ensures a pure, white, crystalline powder. Suitable for supplements, functional foods, cosmetics and as a pharmaceutical ingredient.

Neuravena wild green-oat extract promotes mental health, cognitive function and aids stress-coping abilities.

Global dairy-foods and nutritional-ingredients group recently acquired Pizzey's Nutritionals, which produces omega-3 ingredients derived from flaxseed.

A world leader in identification, development and production of active principles derived from plants, including grape-seed extract.

Kyowa Hakko
Cognizin brand citicoline changes brain chemistry and activity in certain areas of the brain, enhancing attention, memory, mood, focus and concentration.

Marco Hi-Tech
Cranberry extracts and solids headline a large suite of ingredients that also includes green-tea extracts.

Ocean Nutrition Canada
Meg-3 omega-3 fish powder for foods uses a patented micro-encapsulation technology, Powder-loc, allowing taste- and odour-free incorporation into foods. Various Meg-3 concentrates are available for supplements.

Ocean Spray
King of the cranberries offers juice, sauces, craisins and produce — and not just cranberries, either.

Omega Protein Corporation
OmegaPure refined fish oil is derived from menhaden, rich in long-chain omega-3 fatty acids.

MegaNatural BP is a patent-pending grape-seed extract. MegaNatural Gold Grape Seed Extract guarantees a minimum 90 per cent polyphenols. Other brands include MegaNatural GSKE, GSKE040 grape extract, MegaNatural red-wine concentrate and grape-pomace extract.

SeleniumSelect contains a minimum of 40 per cent elemental selenium.

Taiyo International
Suntheanine brand L-theanine was the pioneer in supplying this amino acid, which promotes relaxation without drowsiness.

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2. Rodruguez JJL, et al. Prevalence of dementia in Latin America, India, and China: a population-based cross sectional survey. Lancet 2008;372:464-474.
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4. Jellinger KA. The pathology of "vascular dementia": a critical update. J Alzheimers Dis 2008;14:107-123.
5. Roman GC. Facts, myths, and controversies in vascular dementia. J Neuro Sci 2004;226:49-52.
6. Orgogozo JM, et al. Wine consumption and dementia in the elderly: a prospective community study in the Bordeaux area. Rev Neurol (Paris) 1997;153:185-192.
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11. USDA Database for the Proanthocyanidin Content of Selected Foods. http://www.nal.usda.gov/fnic/foodcomp/Data/PA/PA.pdf. Accessed on 9/12/08.
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13. Marambaud P, et al. Resveratrol promotes clearance of Alzheimer's disease amyloid-? peptides. J Biol Chem 2005;280:37377-82.
14. Syu KY, et al. Determination of theanine, GABA, and other amino acids in green, oolong, black and Pu-erh teas with dabsylation and high-performance liquid chromatography. J Agric Food Chem 2008 (in press).
15. Nobre AC, Rao A, Owen GN. L-theanine, a natural constituent in tea, and its effect on mental state. Asia Pac J Clin Nutr 2008;17(Suppl):167-168.
16. Lu K, Gray MA, et al. The acute effects of L-theanine in comparison with alprazolam on anticipatory anxiety in humans. Hum Psychopharmacol 2004;19:457-465.
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19. Kimura K, Ozeki M, Juneja LR, Ohira H. L-Theanine reduces psychological and physiological stress responses. Biol Psychol 2007;74:39-45.
20. Kakuda T, et al. Theanine, an ingredient of green tea, inhibits {3H]glutamine transport in neurons and astroglia in rat brain. J Neurosci Res 2008;86:1846-56.
21. Nathan PJ, et al. The neuropharmacology of L-theanine (N-ethyl-L-glutamine): a possibleneuroprotective and cognitive enhancing agent. J Herb Pharmacother 2006;6:21-30.
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24. Markesbery WR, Carney JM. Oxidative alterations in Alzheimer's disease. Brain Pathol 1999;9:133-146.
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27. Moshfegh AJ, et al. What We Eat in America, NHANES 2001-2002: Usual nutrient intakes from food compared to dietary reference intakes. U.S. Department of Agriculture, Agricultural Research Service. 56 pages. Published 2005.
28. Franco OH, et al. Higher dietary intake of lignans is associated with better cognitive performance in postmenopausal women. J Nutr 2005;135:1190-95.29.
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32. Williams CM, et al. Blueberry-induced changes in spatial working memory correlate with changes in hippocampal CREB phosphorylation and brain-derived neurotrophic factor (BDNF) levels. Free Radic Biol Med 2008;45:295-305.
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34. Wang J, et al. Grape-derived polyphenolics prevent A?oligomerization and attenuate cognitive deterioration in a mouse model of Alzheimer's disease. J Neurosci 2008;28:6388-92.
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36. Nutritional supplementation in cognitive aging. ClinicalTrials.gov #NCT00599508. Robert Krikorian, Univ Cincinnati. Clinical trial, completed in 2008.
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44. Sato
45. Wicherts IS, et al. Vitamin D status predicts physical performance and its decline in older patients. J Clin Endocrinol Metab 2007;92:2058-65.
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49. Doraiswamy PM, et al. Pharmacological strategies for the prevention of Alzheimer's disease. Expert Opin Pharmacother 2006;7:1-10.

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