Cognitive Function

Cognitive Function

by Kim Schoenhals

Cognition is an expansive term covering various aspects of brain function, including learning, remembering, thinking and reasoning. These processes, imperative for daily life, can decline during the natural aging process or in the event of degenerative disease. Brain cells, and therefore cognition, can be affected by free radical damage that occurs as a natural part of aging, or they can be damaged by conditions such as dementia, Alzheimers or Parkinsons.

Dementia occurs in several forms, including multi-infarct dementia and subcortical dementia. Multi-infarct dementia is a common cause of dementia in the elderly that is manifested as confusion, loss of memory and heightened emotion, according to the National Institute of Neurological Disorders and Stroke (NINDS). Subcortical dementia, also known as Binswangers disease, is much more rare than multiinfarct dementia but has similar symptoms (i.e., memory loss, emotional changes).

Dementia can also occur as a symptom of Alzheimers disease, 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. Alzheimers affects an estimated 4.5 million Americans, according to the Alzheimers Association.

Like Alzheimers, Parkinsons disease is a neurodegenerative condition that can affect cognition, although dementia is not the most common symptom. More often, symptoms of Parkinsons include tremor and impaired coordination, although memory loss and confusion can occur as well. The disease affects more than 1.5 million Americans, according to the American Parkinson Disease Foundation.

Whether degenerative disease or the normal aging process are factors in reduced cognitive function, a healthy diet combined with supplement intake may benefit cognitive function. In a group of 168 elderly subjects, 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, according to Spanish researchers.¹ In another group of 176 elderly, independently living subjects, supplement use was correlated with a higher childhood IQ and better overall health, as noted by an investigation conducted by researchers from the Royal Cornhill Hospital in Aberdeen, England.²

Micronutrients

Those in the scientific and medical communities generally agree nutrition is an integral aspect of preserving healthy brain function. Nutrition has been linked with better cognitive abilities, and several nutrients have effects in the realm of memory and cognitive performance.

One antioxidant, vitamin E, may prevent cognitive decline. A rat study conducted in Japan showed vitamin E prevented learning deficits commonly seen as a result of age-related oxidative stress.⁵ In addition, animals given vitamin E exhibited significantly accelerated learning functions compared to the control group.

A human study conducted by researchers at the Rush Institute for Healthy Aging in Chicago also demonstrated protective effects with vitamin E intake.⁶ Researchers analyzed data from a longitudinal, population-based study of 2,889 community residents (ages 65 to 102) 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 Alzheimers in a subgroup of subjects who tested negative for the APOE-e4 allele (a protein associated with an increased risk of late-onset Alzheimers disease).⁷ A study conducted at Brigham and Womens Hospital in Boston further showed vitamin E supplements conferred modest cognitive benefits among elderly women, particularly among those who were also taking vitamin C,⁸ another antioxidant.

A large body of evidence shows that both vitamins E and C are important for the central nervous system and that a decrease in their concentrations causes structural and functional damage to the cells, according to a research review out of the Jean Mayer USDA (U.S. Department of Agriculture) Human Nutrition Research Center on Aging at Tufts University in Boston.⁹

Vitamin C was featured in an animal model of cognitive degeneration presented by researchers at the Universidad Federal do Rio Grande do Sul in Porto Alegre, Brazil.¹⁰ They noted oxidative damage may be involved in the neuropathology of propionic acidemia (a genetic disorder of branched-chain amino acid metabolism that hinders developmental growth), although vitamin C supplementation prevented a decline in the brains antioxidant systems.

Additional animal research out of the same Brazilian university was conducted with vitamins C and E to investigate the link between homocysteine-induced oxidative stress and memory decline.¹¹ According to the researchers, high levels of homocysteinean amino acid produced in the body that may increase the risk of Alzheimers disease when it occurs in high levelsare linked to an increase in free radical production, which can impair memory. The Brazilian researchers demonstrated how pretreatment with vitamins E and C prevented homocysteine-induced memory impairment.

More well-known than the antioxidants for homocysteine-lowering effects, the B vitamins have been widely studied for reducing cognitive decline associated with dementia and Alzheimers disease. Researchers at the University of California, Davis, concluded a B vitamin regimen may protect against cognitive decline in elderly populations.¹² Their study, which involved 1,789 elderly subjects, showed modest inverse associations between homocysteine concentrations and several indices of cognitive function. Additional research out of England showed B vitamins lowered homocysteine by 30 percent in a population at risk for dementia.¹³ And, researchers at Georgetown University Medical Center in Washington, D.C., concluded a high-dose combination of folic acid, vitamin B6 and vitamin B12 significantly reduced homocysteine levels in patients with Alzheimers disease.¹⁴

Despite these outcomes, there is some skepticism in the scientific community regarding whether B vitamins affect cognitive health beyond controlling homocysteine levels. Researchers in The Netherlands investigated 144 normal aging individuals during six years of follow-up and found that while elevated homocysteine levels were associated with lower cognitive performance, there was no relationship between folic acid or vitamin B12 and cognition.¹⁵ Research involving dementia sufferers indicated 10 mg/d of folic acid seemed to lower their performance on some cognitive tests, although the supplement was well tolerated.¹⁶ Additionally, several Cochrane reviews have failed to show cognitive benefits from vitamin B6,¹⁷ vitamin B12,¹⁸ or vitamin B12 plus folic acid.¹⁹

Some good news about B vitamins and cognitive function came out of Sahlgrenska University Hospital in Molndal, Sweden.²⁰ Of 30 patients with mild cognitive impairment and increased homocysteine levels, those taking a combination of B vitamins (including B6, B12 and folate) exhibited normalized homocysteine levels, leading researchers to conclude the vitamin regimen might stabilize cognitive status in this population. Additional promising research was reported from Case Western Reserve University in Cleveland, where researchers found Alzheimers patients consumed significantly less dietary vitamin B6 and folate after age 60 than controls.²¹

Specialty Ingredients

Unlike vitamins E and C and the Bs, several 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.

Image: U.S Sales for Supplements Used to Prevent Alzheimer's Disease & Memory Loss

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). PS works to functionally integrate the brains different cells, tissue and regions into a unified whole.

PS was included in a University of New Mexico, Albuquerque, research review that addressed several brain-specific compounds.²² Researchers mentioned animal studies showing PS attenuated several neuronal effects of aging and restored normal memory; however, human research cited by the reviewers did not show PS benefited Alzheimers patients and only modestly improved subjects with mild cognitive impairment. Two human trials conducted in The Netherlands showed that while PS is safe and welltolerated, ²³ it is ineffective for improving memory among elderly subjects with memory complaints.²⁴ Conversely, a prior Italian study showed treatment with 300 mg/d of PS for six months statistically improved behavioral and cognitive parameters in a group of 494 elderly patients with moderate to severe cognitive decline.²⁵

Researchers from Psychologix Inc. in Scottsdale, Ariz., compared a specific formulation of soy-derived PS (as LECI-PS, available from Champaign, Ill.-based Degussa Food Ingredients) with bovine-derived PS and placebo. The results of the study, which were reported in a review by Thomas H. Crook III, Ph.D.,²⁶ showed soy PS and bovine PS both improved memory in 50 elderly women significantly better than placebo, and the soy-derived PS actually performed slightly better. In the same paper, Crook described an additional 12-person study that indicated a 100 mg dose was as effective as a 300 mg dose over a 12-week period, although the higher dose was more effective after three weeks.

Like PS, the brain-specific phospholipid phosphatidylcholine (PC) was included in the research review published by investigators at the University of New Mexico.²⁷ PC, as well as citicoline (or CDP-choline, a precursor of PC), are believed to promote the synthesis and transmission of neurotransmitters integral to memory function, according to the researchers. They noted that while PC has little research to support its use for improving memory in Alzheimers patients, citicoline has been seen to improve memory recall in normally aging adults.

While the New Mexico reviewers did not cite promising PC research, there is scientific evidence linking the phospholipid to Alzheimers disease, as well as supporting its role in general brain health. Researchers in Amsterdam, The Netherlands, noted the cerebrospinal fluid taken from Alzheimers patients tended to have a lower lysophosphatidylcholine (lyso-PC)-to-PC ratio, suggesting an altered metabolism of choline-containing phospholipids.²⁸ And, animal research has shown PC supplementation can increase brain activity when used in combination with vitamin B12.²⁹

Citicoline research has also garnered some promising results for memory enhancement. Investigators at the Massachusetts Institute of Technology (MIT) in Cambridge conducted two human trials regarding citicoline and memory enhancement.³⁰ 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 age-related cognitive decline. An unpublished animal study also showed citicolines 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.

Animal research has elucidated citicolines mechanism of action. An MIT study showed mice treated with CDP-choline for 27 months exhibited a 19-percent increase in brain levels of PC, as well as an 18-percent increase in PS, which may explain citicolines benefits against neurologic disorders.³¹ Researchers at the University of Wisconsin, Madison, stated citicoline partially restores PC levels, attenuates lipid peroxidation and provides choline for the synthesis of acetylcholine (ALC), a neurotransmitter that assists in memory function and that, when it occurs in deficient levels, has been linked to the occurrence of Alzheimers disease.³²

Researchers at the Institute of Public Health in Cambridge, England, also touched on the link between ALC and Alzheimers disease, saying those with the disease tend to lack the enzyme responsible for converting choline to ALC.³³ Because lecithin is a major dietary source of choline, the researchers suggested enhanced consumption might reduce the progression of dementia, although they did not uncover any trials that clearly showed a clinical benefit of lecithin intake in Alzheimers or Parkinsons. However, they did note a dramatic result in favor of lecithin in patients with subjective memory problems.

Like the English investigators, researchers in Mexico City hypothesized that intake of an ALC precursor might improve cognitive function.³⁴ They randomly assigned 261 patients with Alzheimersrelated cognitive impairment to take either choline alfoscerate (an ALC precursor, sometimes called L-alpha-glycerylphosphorylcholine, or Lalpha- GPC) or placebo three times daily. Subjects in the treatment group exhibited consistent improvements in cognitive tests after 90 and 180 days compared with baseline values, while the control group either remained unchanged or worsened.

Aside from participating in ALC synthesis, acetyl-L-carnitine may act through additional mechanisms, according to researchers at the University of Massachusetts, Lowell.³⁸ Their in vitro research indicated acetyl-L-carnitine minimized oxidative stress and prevented the depletion of ATP (cellular energy manufactured in the bodys mitochondria), which may protect the compromised neuronal energy commonly seen in Alzheimers patients.

Acetyl-L-carnitine is a mitochondrial metabolite, as is alpha-lipoic acid, and both compounds were shown to reduce oxidative damage and reverse mitochondrial decay in old rats.³⁹ Researchers at the University of California, Berkeley, concluded these were the mechanisms behind improved memory in the elderly animals, which was observed after supplementation with the compounds individually and, more significantly, in combination.

Researchers in Hanover, Germany, hypothesized that because oxidative stress and energy depletion are hallmarks of Alzheimers disease, antioxidants with effects on glucose metabolismsuch as alpha-lipoic acidshould have positive effects in this population.⁴⁰ To investigate this possibility, researchers conducted an open study for which nine Alzheimers patients were given 600 mg/d of alpha-lipoic acid for approximately one year, after which time the treatment induced a stabilization of cognitive functions.

Like alpha-lipoic acid, coenzyme Q10 (CoQ10) is found in the bodys mitochondria and is known for its antioxidant properties. However, CoQ10 may not be a viable therapy for Alzheimers: Researchers in Madrid stated CoQ10 levels are similar between Alzheimers, dementia and healthy control subjects, suggesting the compound is not correlated with duration or severity of disease.⁴¹

While CoQ10 isnt necessarily applicable in the realm of Alzheimers treatment, its link to mitochondrial function and its antioxidant properties have piqued scientific interest in the study of Parkinsons disease. Parkinsons patients commonly exhibit defects in brain mitochondrial function, according to researchers at the University of North Dakota School of Medicine and Health Science, Grand Forks, and mitochondrial impairment may play a role in the degeneration of dopamine-producing neurons.⁴² They added that although CoQ10 levels appear to be normal in Parkinsons patients, the compound may attenuate the loss of dopamine-producing brain cells. Additional research out of New York Presbyterian Hospital indicated CoQ10 therapy targets mitochondrial dysfunction, as well as inflammation, which makes it a promising potential therapy for Parkinsons disease.⁴³ And, a review of clinical trials using CoQ10 for degenerative disease demonstrated the supplements benefits against functional declines in Parkinsons disease, Huntingtons disease and Friedreichs ataxia.⁴⁴

CoQ10 isnt the only naturally occurring compound that can modulate cellular metabolism and stave off oxidative damage, according to a research review out of New York Presbyterian Hospital.⁴⁵ The review cited CoQ10s efficacy in Parkinsons disease but also mentioned several animal studies that showed creatine can protect against neurodegenerative diseases such as Parkinsons. Similarly, a review conducted by researchers at Roche Vitamins AG in Basel, Switzerland, indicated creatine supplementation is protective in animal models of Parkinsons and Huntingtons disease.⁴⁶ According to the reviewers, these studies suggest creatine may delay neurodegenerative disease, as well as potentially strengthen memory function and intellectual capabilities.

In addition to being investigated for neuroprotective properties in degenerative disease, creatine has been studied for its potential to prevent mental fatigue. Because creatine is known for reducing muscle fatigue and improving physical performance, researchers at the University of Tokyo decided to test whether creatine could affect mental performance.⁴⁷ At a dose of 8 g/d for five days, creatine reduced mental fatigue and increased brain oxygen utilization in subjects performing simple mathematical calculations.

Fatty Acids & Botanicals

Unlike the specialty compounds mentioned above, the essential fatty acids (EFAs) are not produced in the body, although they are necessary for proper cognitive function. Long-chain polyunsaturated fatty acids (LC-PUFAs) are a group of healthy fats that contribute to normal brain function and must be supplied through the diet.

Dietary EFAs are of particular importance during gestation and infancy, when they are utilized for brain development. According to researchers at the Ross Products Division of Abbott Laboratories in Columbus, Ohio, two LC-PUFAs found in breast milkdocosahexaenoic acid (DHA) and arachidonic acid (AA)are of particular interest in infant nutrition because they rapidly accrue in the brain during the first postnatal year, and breast-fed infants are reported to have enhanced intellectual development.⁴⁸ In studying 157 infants, researchers concluded adding both DHA and AA to infant formula supports visual and cognitive development through 39 months of age. Contrarily, a study of 306 children conducted in The Netherlands failed to show benefits from DHA and/or AA supplementation at birth on cognitive performance by age 7.⁴⁹

Research focusing on DHA during infancy indicated the amount of DHA in human milk varies widely, although it is positively correlated with visual and language development in breast-fed infants.⁵⁰ A larger study involving 76 infants indicated mothers taking supplemental omega-3sas cod liver oil containing DHA and eicosapentaenoic acid (EPA)gave birth to children with superior mental development by 4 years of age compared with children born to mothers in the control group.⁵¹

In addition to mental development, LC-PUFAs are thought to possibly protect against cognitive decline related to dementia or Alzheimers. While research out of Laval University Geriatric Research Unit in Quebec failed to support a role of omega-3 polyunsaturated fatty acids in protecting against dementia and cognitive decline,⁵² research at Rush-Presbyterian-St. Lukes Medical Center in Chicago demonstrated a reduced risk of Alzheimers with dietary omega-3 and fish intake.⁵³ Researchers followed 815 residents for an average of just under four years, after which time participants consuming fish once a week or more had a 60-percent reduction in the risk for Alzheimers disease. Total omega-3 intakespecifically DHA intake was also linked with a reduced risk. Along these lines, research conducted at Shimane Medical University in Izumo, Japan, showed DHA administration had a profoundly beneficial effect in an animal model of Alzheimers disease.⁵⁴ Researchers added the DHA regimen also suppressed lipid peroxidation, possibly explaining the protective effect of the omega-3 in preventing Alzheimers-related learning deficiencies.

Additional research into the role EFAs play in brain function has shown DHA may affect general cognitive ability. Researchers at the National Institute on Alcohol Abuse and Alcoholism in Rockville, Md., reported animals fed a DHA-deficient diet had a 76-percent decrease in brain DHA levels, which was correlated with a deficit in higher order learning skills.⁵⁵ Another study conducted at Shimane Medical University showed elderly rats given DHA for 10 weeks exhibited improved learning abilities, as well as reductions in lipid peroxidation in the hippocampus (an area of the brain that regulates memory and emotion).⁵⁶

An investigation into the LC-PUFAs mechanism of action was conducted at the Hungarian Academy of Science in Szeged, where investigators reported reduced brain levels of DHA and AA are common in elderly subjects and patients with Alzheimers disease.⁵⁷ They also reported fish oil, which contains LC-PUFAs, acted in a manner similar to other agentssuch as Ginkgo bilobaby inducing transthyretin (TTR) expression. (TTR is a protein manufactured in the liver that acts as an amyloid beta scavenger, preventing amyloid deposits from collecting and thereby protecting against amyloidosisa class of diseases including Alzheimers that are characterized by abnormal protein deposits.)

In vitro research showed ginkgo does, in fact, upregulate TTR expression in the hippocampus, leading researchers to suggest ginkgo may have notable neuromodulatory effects.⁵⁸ Additional mechanisms of action were suggested by researchers at the University of Oxford in England.⁵⁹ They proposed 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. Their metaanalysis of ginkgo studies found promising evidence supporting its use for improving cognition.

Ginkgo supplements may be able to improve and/or protect cognitive function in subjects with neurodegenerative disease. Animal research conducted at the Oregon Health & Science University in Portland showed ginkgo supplementation for six months maintained cognitive function in an animal model of Alzheimers, comparably to wild-type healthy mice.⁶⁰

An analysis of the effects of several of ginkgos active constituents led researchers at Philipps University of Marburg in Ketzerbach, Germany, to conclude ginkgo should prove effective for treating patients with mild to moderate dementia.⁶¹ And, researchers in Berlin reviewing a 24-week double blind, placebo-controlled trial confirmed the benefit of ginkgo (as EGb 761, a standardized extract) for improving cognitive function in patients with dementia.⁶² Contradictory results were seen from a 12-week human trial that involved 214 dementia sufferers, all of whom performed similarly on cognitive function tests regardless of being in the treatment or placebo group.⁶³

Ginkgos cognitive benefits are also somewhat conflicting in healthy subjects. Researchers at Liberty University in Lynchburg, Va., conducted a six-week, randomized, placebo-controlled trial with 262 elderly subjects and found evidence that ginkgo supplementation enhanced certain neuropsychological and memory processes in cognitively intact older adults.⁶⁴ Similarly, of 24 healthy subjects in La Jolla, Calif., those given ginkgo plus vinpocetine exhibited improvements in shortterm working memory compared to subjects given placebo.⁶⁵ However, a study out of Umea University, Sweden, failed to show beneficial effects on memory in healthy adults taking either ginkgo or ginseng.⁶⁶

Like ginkgo, vinpocetine and ginseng have both been studied for their ability to potentially improve cognitive function. Vinpocetine increases blood circulation and metabolism in the brain, and animal research has shown it can reduce neuronal cell death caused by decreased blood flow, according to researchers from the University of New Mexico, Albuquerque.⁶⁷ They added that human research shows vinpocetine can significantly improve attention, concentration and memory in adults with poor brain circulation or dementia-related disease. As for ginseng, single doses have been shown to improve memory, although in incorrect doses, it can cause attention task deficits, according to a research review out of Northumbria University in England.⁶⁸ The researchers conclusion was evident in an earlier human trial they conducted with 20 healthy young volunteers.⁶⁹ Those given a single 400 mg dose of ginseng had significant improvements in quality of memory scores, although the 200 mg and 600 mg doses were correlated with reduced speed of attention scores.

Like ginseng, soy isoflavones are believed to affect memory, specifically verbal memory, according to a study of postmenopausal women conducted by researchers at the University of California, San Diego.⁷⁰ Researchers randomly divided 56 women into either a treatment (110 mg/d of total isoflavones) or placebo group for six months, at the end of which women taking soy isoflavones demonstrated consistently better scores compared to their own baseline results and the placebo group results. Another study of how soy affects womens cognitive function was conducted at Kings College, London, where researchers randomly assigned 33 postmenopausal women to receive 60 mg/d of isoflavones or placebo for 12 weeks.⁷¹ Compared to the placebo group, women taking soy demonstrated significantly better improvements in cognition, including picture recall, sustained attention, learning rule reversals and planning tasks.

Similar to soy, green tea contains active constituents that may improve certain aspects of cognitive function. Green teas antioxidant catechin (-)-epigallocatechin 3-gallate (EGCG), for example, is believed to protect against Alzheimers- and Parkinsons-related cognitive declines via its antioxidant properties. In vitro research conducted at the Keimyung University School of Medicine in Taegu, Korea, indicated EGCG may protect against Alzheimers disease by preventing hippocampal neuronal cells from amyloid-beta-induced apoptosis.⁷² EGCG may protect against Parkinsons disease in a similar manner, according to researchers at the Eve Topf and USA National Parkinson Foundation in Haifa, Israel.⁷³ Additional in vitro research conducted at the Institute of Biophysics in Beijing, China, indicated EGCG is even more protective against neuronal cell death than a mixture of green tea polyphenols, and the singular catechin has the potential to prevent neurodegenerative diseases such as Parkinsons, which is believed to be caused at least in part by oxidative damage.⁷⁴

Another antioxidant compound believed to protect against neuronal cell death is grapeseed extract. 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.⁷⁵

Additional in vitro research showed a black grape skin extract protected against oxidative damageand consequently prevented DNA fragmentationwhich suggests the natural compound could be used to slow the progression of Alzheimers disease, according to researchers at the University of Catania in Italy.⁷⁶ Similarly, researchers at Seoul National University in South Korea concluded resveratrol, a compound found in grape skin, may be protective against Alzheimers disease by minimizing oxidative damage and beta-amyloid-induced cell death.⁷⁷ Resveratrols antioxidant properties were also credited by researchers at McGill University in Montreal for the compounds neuroprotective effects.⁷⁸

Neuroprotection is afforded by several types of compounds, some naturally occurring in the body and others available through the diet. Regardless of the derivation of these compounds, one thing appears certain: Brain cells are fragile and can die from a number of causes, not the least of which are free radical damage and degenerative disease. By minimizing neuronal cell death, natural compounds appear to protect cognitive function and even slow the rate of progression of degenerative brain disease. While research continues to clarify the link between supplement intake, diet and brain health, results thus far offer hope that dietary supplements may have a place in improving cognitive function in America.

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