Supporting Cognitive Function

Dementia occurs in several forms, including multi-infarct dementia and subcortical dementia. Multi-infarct dementia is the more common form, and is manifested in the elderly as confusion, loss of memory and heightened emotion, according to the National Institute of Neurological Disorders and Stroke (NINDS). This form of dementia is caused by blood clots in the brain that block small blood vessels and end up destroying brain tissue. Dementia can also occur as a symptom of Alzheimer’s disease (AD), two hallmarks of which are the formation of protein deposits (amyloid plaques) and tangled bundles of fibers (neurofibrillary tangles) composed of misplaced proteins in the brain, according to NINDS. In addition to dementia, symptoms of Alzheimer’s include forgetfulness, language deterioration, impaired judgment, restlessness and mood swings. Alzheimer’s affects an estimated 4.5 million Americans, according to the Alzheimer’s Association.

While cognition is often sharp in younger adults, memory often becomes fuzzy over time. This may be associated with age-related shrinkage of the hippocampus, the area of the brain responsible for processing, storing and recalling new information. In people with mild cognitive impairment (MCI), a risk factor for AD, the hippocampus shrinks at a faster rate, leading to short-term memory decline, despite continued sharpness in thinking and reasoning skills.

Whether customers are looking to bolster cognitive function and avoid problems in the future, or if they’re looking to regain some clarity of thought they had in youth, many nutritional and lifestyle options are available to help. One of the most simple things to do is exercise, as voluntary exercise may increase levels of brain-derived growth factors, improve mental performance and stimulate growth of neurons.¹ In addition, a healthy, balanced diet supports cognitive development, with studies showing positive results from an intake of nutrients such as long-chain polyunsaturated fatty acids, antioxidant vitamins and B vitamins.²

Consider the results of a Spanish study of 168 elderly subjects, in which researchers found those with “satisfactory” cognitive function typically had better dietary habits, with higher intakes of total food, fish, fatty acids and vitamins, as well as a lower intake of refined sweets.³ And a Japanese study found AD and dementia patients were more likely to have relative deficiencies of antioxidants and B vitamins, and an excess intake of omega-6 essential fatty acids (EFAs), which are linked to chronic inflammation.⁴

There are a host of “brain boosting” nutrients available in the dietary supplement market. One of the most studied categories is the area of antioxidants, which are believed to reduce free radical damage in the brain, thereby protecting cognitive function. Unfortunately, studies have noted the elderly are particularly at risk for marginal deficiencies of antioxidants, such as vitamins C and E, despite their ability to reduce the risk of degenerative diseases such as vascular dementia.⁵ A clinical study in elderly patients found those with AD or MCI had significantly lower antioxidant activity compared to control patients.6 The researchers further noted increased antioxidant activity in MCI patients could help lower the risk of progression into dementia.

Combinations of the antioxidant vitamins C and E have been examined for their possibly synergistic effect in protecting brain health. The Rotterdam Study, which examined dietary intake of more than 5,000 men and women, found a high intake of vitamins C and E was associated with a lower risk of AD.⁷ Similarly, a Hawaiian study of elderly men found those who took dietary supplements with vitamins C and E had a significantly reduced risk of developing vascular dementia, and had better cognitive performance than those who did not take supplements.⁸

The expected mechanism of action of the combination antioxidant is through reduction in free radical damage. Supplementation with vitamins C and E appears to increase plasma and cerebrospinal fluid (CSF) concentrations of those vitamins in AD patients.⁹ In addition, AD patients with abnormally low concentrations of vitamin C who received 1,000 mg/d of C saw their plasma and CSF levels return to normal.

The impacts of these antioxidant vitamins individually have also been investigated. A rat study conducted in Japan showed vitamin E prevented learning deficits commonly seen as a result of age-related oxidative stress.¹⁰ In addition, animals given vitamin E exhibited significantly accelerated learning functions compared to the control group. Human studies have shown similar positive results; for example, Spanish researchers investigating dietary intake of vitamin E found elderly men and women with higher plasma alpha-to-copherol levels had better results on tests of cognitive capacity.¹¹

Another human study, this one in Chicago, demonstrated protective effects with vitamin E intake.¹² Researchers analyzed data from a population-based study of almost 2,900 elderly community residents and reported those in the highest quintile of vitamin E intake had 36 percent less cognitive decline than subjects in the lowest quintile. A similar study conducted by the same researchers showed increasing vitamin E intake from foods reduced the risk of Alzheimer’s in a subgroup of subjects who tested negative for the APOE-e4 allele (a protein associated with an increased risk of late-onset Alzheimer’s disease).¹³

Vitamin C intake is also important to brain health. A case control study of institutionalized elderly patients found those with dementia had significantly lower plasma levels of vitamin C, compared to control patients.¹⁴ This was the case even when the two groups had similar dietary vitamin C intakes, leading researchers to conclude the difference was due to increased oxidative stress in the dementia patients depleting vitamin C levels. Similar conclusions were reached by researchers at the Portland Veteran’s Affairs Medical Center, Ore., who measured levels of antioxidants in CSF and plasma of AD patients and control patients.¹⁵ The CSF: plasma ratio of vitamin C was greater in AD patients, reflecting increased antioxidant requirements in the brain of AD patients.

There are many other antioxidant compounds being investigated for their benefits in brain health. Melatonin, for example, may lend a hand in protecting the brain against free radical damage. Spanish researchers conducted a study comparing the antioxidant effects of vitamin C and melatonin in neuroblastoma cells exposed to okadaic acid, and found melatonin was more efficient than vitamin C and could be used at a lower dosage to have the same effect.¹⁶ Other in vivo studies have shown melatonin prevents the oxidative effect of glutamate, which is responsible for a great deal of oxidative stress induction in the brain,¹⁷ and prevents lipid peroxidation from exposure to aluminum, a metal potentially involved in the pathogenesis of AD.¹⁸

Some of the most promising antioxidant compounds are found in the flavonoid family. These naturally-occurring, water-soluble phenolic compounds are found in a host of fruits, vegetables and herbs. Consider the power of flavonoids found in red wine, which were found in a population-based study to significantly decrease the risk of incident dementia.¹⁹

Red wine’s beneficial antioxidant properties are often delivered in the form of grapeseed extract or resveratrol, a compound found in grape skin. In vitro and in vivo research out of Creighton University in Omaha, Neb., indicated a grapeseed proanthocyanidin extract protected several types of cells, including neurons, against DNA damage and cell death.²⁰ And researchers at Seoul National University in South Korea concluded resveratrol may protect against AD by minimizing oxidative damage and betaamyloid-induced cell death.²¹

Another antioxidant source is green tea, which contains antioxidant catechins such as (-)-epigallocatechin 3-gallate (EGCG) that may protect against AD-related cognitive declines. Korean researchers have found EGCG may protect against AD by preventing hippocampal neuronal cells from amyloidbeta-induced apoptosis.²² And Chinese researchers found EGCG is even more protective against neuronal cell death than a mixture of green tea polyphenols.²³

Another source of antioxidant flavonoids is French maritime pine bark, available as Pycnogenol®. A review from Westfalische Wilhelms-Universitat Munster, Germany, noted Pycnogenol protects against oxidative stress by increasing the body’s production of endogenous antioxidant enzymes and regenerating vitamins C and E.²⁴ The researcher noted controlled animal experiments have shown an improvement in cognitive function with Pycnogenol supplementation. This is supported by in vitro work showing the ability of Pycnogenol to reduce Abeta-induced apoptosis, a pathological feature of AD.²⁵

Other botanicals are powerful sources of both flavonoids and other brain boosting compounds. Consider Ginkgo biloba, with its long history of use as a memory enhancing herb. A Cochrane Database Review noted ginkgo can increase blood supply by dilating blood vessels, as well as reduce blood viscosity, modify neurotransmitter systems and reduce the density of oxygen free radicals.²⁶ This meta-analysis of ginkgo studies indicated the botanical has overall promising evidence supporting its use for improving cognition.

The range of effects of ginkgo’s active constituents including flavonoids and terpene lactones led German researchers to conclude the herb is likely effective in treating subjects with mild and moderate dementia.²⁷ Another German study came to similar conclusions, noting ginkgo (as EGb 761®) may improve cognitive function in patients with dementia.²⁸

Another beneficial botanical is Vinca minor (periwinkle); its active constituent vinpocetine and the alkaloid vincamine increase blood circulation and metabolism in the brain. Animal research has shown it can reduce neuronal cell death caused by decreased blood flow, while human research shows vinpocetine can significantly improve attention, concentration and memory in adults with poor brain circulation or dementia-related disease.²⁹

Beyond Antioxidants

The nutrition arena offers more than just antioxidants to support brain health. Consider the research on the B vitamins, which have been widely studied for their ability to lower levels of homocysteine, as well as reducing cognitive decline with age. A study of almost 1,800 elderly subjects in California found supplementation with B complex protected against cognitive decline, possibly by reducing homocysteine.³⁰ In another study, this time in Sweden, researchers gave 30 elderly patients with MCI a high dose of vitamin B12, B6 and folate for 270 days.³¹ They found none of the patients progressed into dementia and homocysteine levels were normalized.

Researchers have also looked at the ability of the B vitamins individually to support brain function. Population studies have shown B12 levels decrease with age and are associated with greater cognitive impairment,³² and low serum levels of B12 may predispose dementia patients to greater negative outcomes, such as hallucinations.³³ Despite this, a meta-analysis did not find statistical support for B12 supplementation to prevent dementia or AD.³⁴

Reports on folate and cognitive function have been similarly inconclusive. Swiss researchers found in a study of 228 patients with normal cognitive functioning or MCI that relative folate deficiency may precede AD and dementia onset.³⁵ And a population study of AD patients found the patients consumed significantly less dietary folate than controls, and had higher homocysteine levels.³⁶

Other specialty compounds linked to cognitive health are naturally created in the body. Because they actively participate in the biology of the brain, certain naturally occurring phospholipids (key building blocks that make up cell membranes, including those in the brain) may boost cognitive ability and protect normal cognitive function in aging when taken supplementally. Phosphatidylserine (PS) is one such phospholipid.

“PS has known functions in all of our tissues and organs but is most concentrated in the brain,” wrote Parris M. Kidd, Ph.D., in Phosphatidylserine (Keats Publishing, 1998). “There it facilitates the entire complex diversity of activities that make the brain the sophisticated organ that it is. PS works to functionally integrate the brain’s different cells, tissue and regions into a unified whole.”

Studies into the effects of PS have shown possible effects in supporting memory. One Japanese animal study found administration of PS for 60 days to male rats significantly improved performance in the water maze test, and increased acetylcholine release in the brain.³⁷ And a 12-week study using plant-source derived PS (100 mg three times daily) in 18 human patients with MCI showed a significant positive effect on cognitive function.³⁸

Additional brain-specific phospholipids such as phosphatidylcholine (PC) and citicoline (or CDPcholine, a precursor of PC) are believed to promote the synthesis and transmission of neurotransmitters, such as acetylcholine, that are integral to memory function. Pharmaceutical treatments for AD increasingly are seeking to inhibit the breakdown of acetylcholine to increase its synaptic availability and boost cognition.³⁹

Fortunately, studies into citicoline have shown its natural ability to support brain function, serving as a choline donor for production of acetylcholine and PC.⁴⁰ Investigators at the Massachusetts Institute of Technology (MIT) in Cambridge conducted two human trials regarding citicoline and memory enhancement.⁴¹ In the first trial, 95 subjects were randomly assigned to either 1,000 mg/d of citicoline or placebo for three months, at which point researchers noted only subjects with relatively inefficient memories exhibited improvements in delayed recall and logical memory. With this data in hand, researchers organized a second study in which the subjects with inefficient memories were given placebo and 2,000 mg/d of citicoline for two months. The higher dose clearly improved immediate and delayed logical memory, leading researchers to conclude citicoline may be a logical treatment for agerelated cognitive decline. An unpublished animal study also showed citicoline’s ability to improve memory. Mice given a diet of 2 percent citicoline (as Cognizin™ from New York-based Kyowa Hakko USA) for four weeks exhibited enhanced memories compared to control mice.

Glycerophosphocholine (GPC), another naturally occurring ALC precursor, may also be of benefit against dementia, as well as improve cognition, mood and somatic symptoms in aging subjects.42 In addition to aiding patients with neurodegenerative disease, GPC can enhance general mental performance in elderly subjects, according to a review written by investigators at the University of Perugia in Italy.⁴³

Acetyl-L-carnitine is another ALC precursor that may improve cognitive function; the acetyl group found in acetyl-L-carnitine, which is similar in form and function to the amino acid L-carnitine, is partially responsible for the production of acetylcholine. Acetyl- L-carnitine has been seen to improve cognitive function compared to placebo in patients with AD as early as three months into a supplementation program with good tolerance.⁴⁴

Another important group of nutrients is the essential fatty acids (EFAs), which are not produced in the body, although they are necessary for proper cognitive function. The ratio in the body of omega-3 EFAs to omega-6 EFAs impacts cognitive functioning, in particular due to EFAs’ impact on neurotransmitters and inflammatory responses.⁴⁵

EFAs play an important role in brain health from gestation, when docosahexaenoic acid (DHA), arachidonic acid (AA) and eicasapentanoic acid (EPA) are used for brain development. Researchers have found adding DHA and AA to infant formula enhances intellectual development in infants.⁴⁶ Also, a study involving 76 infants found mothers taking supplemental omega-3s—as cod liver oil containing DHA and EPA—gave birth to children with superior mental development by 4 years of age compared with children born to mothers in the control group.⁴⁷

Manufacturers offer a range of products to supply EFAs to infants and children to enhance their cognitive development. For example, Watsonville, Calif.-based Nordic Naturals manufactures chewable Children’s DHA supplements and Arctic Cod Liver Oil supplements. “These products provide children with the DHA and EPA they need to support good health,” said Corinna Benoit, national sales manager. “DHA promotes proper brain development and visual function as it comprises 50 percent of the fat in the brain and is especially important in the prenatal and formative years. Since the body is unable to synthesize DHA, it must get this important nutrient from diet or supplementation.”

In addition to mental development, EFAs are thought to protect against cognitive decline. Population studies from The Netherlands and the United States have supported the role of omega-3 intake and cognitive performance. Dutch researchers examined data from more than 1,600 subjects, and found consumption of marine omega-3 EFAs was inversely related to the risk of impaired cognitive function.⁴⁸ The U.S. study examined dietary intake of omega-3 EFAs by 815 elderly residents, and found those with the highest intake of omega-3s had a reduced risk of AD.⁴⁹

Patients with AD were found in a Canadian study to have higher omega-6 EFA plasma levels, and lower plasma levels of omega-3 EFAs compared to control patients.⁵⁰ The researchers noted decreased plasma DHA was found in all patients, possibly linking DHA with general cognitive impairment with aging. Similar findings were reported by French researchers, who found higher levels of omega-6 EFAs were associated with a greater risk of cognitive decline in a study of more than 240 elderly men and women.⁵¹

According to Benoit, store demos are important to the sale of EFA products for children and adults. For example, many people are unaware of the benefits of fish-oil-based EFA supplements and are often hesitant to take them for fear of a “fishy” taste. Benoit recommended retailers offer taste samples and monthly promotions to draw interest and educate women who, according to Benoit, tend to be the primary purchasers for the family.

Research into the role of EFAs in cognition has led to new directions in ingredient development. For example, as omega-6 increases levels of inflammatory prostaglandins, there is increased interest in the role inflammation plays in cognitive dysfunction. This is leading some scientists to investigate compounds that control inflammation in the brain. Unigen Pharmaceuticals, for example, investigated the effects of more than 1,200 plant extracts on cycloxygenase (COX) and lipoxygenase (LOX) inhibitors before developing its Lasoperin™ ingredient. In house studies have shown humans taking 300 mg/d of Lasoperin had a marked improvement in speed and accuracy of processing complex information.

“During the aging process, the brain tissue produces inflammatory molecules,” said Bruce Burnett, Ph.D., director of discovery and screening with Unigen. “This ingredient controls inflammation to prevent age-related slowing in reaction times and information processing.” According to Burnett, the compound directly addresses a base cause of cognitive impairment, and can be taken to control inflammation and improve or maintain cognitive faculties.

Whether customers are looking to boost their brain power or avoid age-related cognitive decline, retailers have a number of scientifically-supported products that may aid in their quest. Providing the research behind the products can help them determine what course of action is best for them.

September 2004 Health Supplement Retailer
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