Neurology
(See Table 3 for a summary of the following neurology related studies.)
The brain is a prime target for free radical activity. It uses oxygen readily and the primary components of its cells are polyunsaturated fatty acids such as DHA, which are highly susceptible to lipid peroxidation. Unchecked, oxidation potentially compromises the health of brain cells, leading to adverse results, such as structural integrity loss, genetic damage, protein cross-linking, vascular damage, and ultimately, cell death. Older people may become more susceptible to such damage, as aging often results in poorer circulation and glucose uptake into cells.
Many investigators are examining whether antioxidants may help prevent and treat certain neurological problems. In this review article, the results of numerous epidemiological, experimental, and clinical studies which focused on antioxidants and cognitive function are analyzed. (Many of the individual studies are presented following this summary.) Some conclusions:
- Oxidative damage may play a role in neurodegenerative diseases which cause cognitive impairment, including dementia and stroke.
- Whether free radical activity causes or is merely the result of such neurological conditions is unclear. To make this distinction, new methods need to be developed to study free radical activity in vivo.
- Vitamin E deficiency is the only vitamin deficiency clearly linked to neurologic impairment.
- Inconsistent results exist in studies on the association of antioxidants and cognitive impairment or dementia. Problems in the methodology of current studies make interpreting their results difficult.
- Many questions remain, and further research is warranted.
Launer, L., Kalmijn, S. Anti-oxidants and Cognitive Function: A Review of Clinical and Epidemiologic Studies. Journal of Neural Transmission. Vol. 53 (suppl), pp.1-8, 1998.
Memory loss, the major disability in such neurological disorders as Alzheimer's disease, may be related to increased oxidative damage in the brain. This hypothesis is leading many researchers to investigate the association of antioxidant status and memory.
From 1988 to 1994, a national, multi-ethnic, cross-sectional survey was conducted in the United States. The Third National Health and Nutrition Examination Survey involved 4,809 non-Hispanic White, non-Hispanic Black, and Mexican-American elderly people. In this particular part of the study, blood samples were taken and serum levels of vitamin E, A, C, beta-carotene, and selenium were determined. Memory was also tested using delayed recall of six points from a story and three words. A combined score of less than 4 was defined as poor memory. After adjusting the results for age, education, income, vascular risk factors, and other trace elements and minerals, a significant association between low serum vitamin E concentrations and poor memory was found. No association between serum vitamin A, C, beta-carotene, and selenium levels were noted.
The authors state, "Increasing levels of vitamin E were associated with better memory performance for this ethnically diverse elderly population.
Perkins, A., Hendrie, H., Callahan, C. et al. Association of Antioxidants with Memory in a Multiethnic Elderly Sample Using the Third National Health and Nutrition Examination Survey. American Journal of Epidemiology. Vol. 150, pp.37-44, 1999.
In this study from the University of Basle, Switzerland, extensive memory tests were administered to 442 healthy, elderly, Swiss subjects (aged 65 to 94). Tests involved working-memory, free recall, recognition, and vocabulary. Blood samples were also taken and the concentrations of three antioxidants measured: vitamins E and C, and beta-carotene. The blood measurements of antioxidants correlated well with the levels found in the same subjects 22 years prior, showing that concentrations of these antioxidants do not change significantly over time. High concentrations of beta-carotene and vitamin C were significantly related to better recall, recognition, and vocabulary on the memory tests, even after adjusting for age, education, and gender. Vitamin E concentrations were not related to memory results, but the authors note that the vitamin E level in the subjects were unusually high. They speculate that a study group with lower vitamin E levels may show some correlation with memory performance.
The researchers conclude, "These results indicate the important role played by antioxidants in brain aging and may have implications for prevention of progressive cognitive impairments."
Perrig, W., Perrig, P., Stahelin, H. The Relation Between Antioxidants and Memory Performance in the Old and Very Old. Journal of the American Geriatric Society. Vol. 45, pp.718-24, 1997.
The Honolulu-Asia Aging Study, a sub-study of the larger Honolulu Heart Program, began in 1980 and continued on to 1993. This study involved 3,385 Japanese-American men (ages 71 to 93) living in Hawaii. Mailed surveys and telephone interviews established their vitamin E and C supplement usage, cognitive ability, and occurrence of dementia. Study participants who reported supplementing with vitamin E and/or C at least once a week were classified as users of that vitamin for the purpose of the analysis. Unfortunately, the researchers did not ask for the amount and duration of vitamin supplementation. Statistical analysis of the data revealed the following:
- Those who took both vitamin E and C supplements had 82% lower relative risk of developing vascular dementia (dementia due to multiple strokes), and 69% lower risk of other kinds of dementia (not including Alzheimer's).
- No protective effect was found for Alzheimer's dementia.
- In those who remained dementia-free, use of either vitamin E or C supplements was directly related to superior cognitive ability test scores, while use of both supplements had marginal benefit.
The authors conclude, "These results suggest that vitamin E and C supplements may protect against vascular dementia and may improve cognitive function in late life."
Masaki, K., Losonczy, K., Izmirlian, G., et al. Association of Vitamin E and C Supplement Use with Cognitive Function and Dementia in Elderly Men. Neurology. Vol. 54, pp.1265-72, 2000.
This study from Karl-Franzens University Graz, Austria, involved 1,769 subjects aged 50 to 75 with no history or signs of neurological disease or psychological disorder. Their cognitive ability was determined using the Mattis Dementia Rating Scale, based on a series of tests involving such things as attention, conceptualization, and verbal and nonverbal short-term memory. Plasma from blood samples were measured for a wide range of antioxidants including lutein/zeaxanthin, cryptoxanthin, canthaxanthin, lycopene, alpha- and beta-carotene, retinol (vitamin A), alpha- and gamma-tocopherol, and ascorbate (vitamin C). Notably, 16 subjects who regularly supplemented with vitamins were excluded from the blood tests, as the researchers were interested in antioxidants which were obtained from the diet alone.
The study found that low levels of beta-carotene and alpha-tocopherol were associated with lower test scores. After adjusting for such things as age, sex, years of education, smoking, lipid status, and stroke risk factors, only alpha-tocopherol's association remained significant, although modest. The authors suggest their results support the need for larger studies, and conclude, "These observations are compatible with the view that some dietary antioxidants may protect against cognitive impairment in older people."
Schmidt, R., Hayn, M., Reinhart, B. Plasma Antioxidants and Cognitive Performance in Middle-Aged and Older Adults: Results of the Austrian Stroke Prevention Study. Journal of the American Geriatrics Society. Vol. 46, pp.1407-10, 1998.
In this study from the Queen's University of Belfast, United Kingdom, the plasma levels of the antioxidants alpha- and beta-carotene, vitamin A, vitamin C, vitamin E, lycopene, and a measure of "total antioxidant capacity" were measured in 79 Alzheimer's patients, 37 vascular dementia patients, 18 Parkinson's disease and dementia patients, and 58 healthy controls. Also tested were 41 Parkinson's disease patients with 41 healthy controls. "Total antioxidant capacity" is a test measuring how quickly all the antioxidants in a blood sample neutralizes a controlled exposure to free radicals.
Compared to healthy controls, the results were as follows:
- In Alzheimer's patients, vitamins A, C, and E concentrations were significantly lower.
- In vascular dementia patients, vitamins A, C, and beta-carotene concentrations were significantly lower.
- In Parkinson's dementia patients, vitamin C and lycopene concentrations were significantly lower.
- Beta-carotene was lower in vascular dementia than in Alzheimer's.
- Lycopene was significantly lower in Parkinson's dementia than in Alzheimer's and vascular dementia.
- No significant differences were found for Parkinson's disease patients.
- No significant difference in total antioxidant capacity was found in all subjects.
The authors point out patients' medications could have increased oxidation in the body and thus decreased antioxidant levels. Thus, whether the low levels of antioxidants were a cause or an effect of the diseases could not be determined.
Foy, C., Passmore, A., Vahidassr, M., Young, I., Lawson, J. Plasma Chain-Breaking Antioxidants in Alzheimer's Disease, Vascular Dementia, and Parkinson's Disease. Q J Med (Monthly Journal of the Associations of Physicians). Vol. 92, Issue 1, pp.39-45, 1999.
In this study from the Erasmus University Medical School and the Netherlands Institute for Health Sciences, Rotterdam, Netherlands, 5,183 elderly subjects (ages 55 to 95) filled out questionnaires which semi-quantitatively assessed their dietary intake of 170 foods. The nutrient content was then calculated using the Dutch Food Composition Table. Vitamin supplement usage was also recorded. Then, each subject was tested with the 30-point Mini-Mental State Examination covering such aspects of mental function as orientation, memory, attention, language, and visual/spatial construction. After adjusting for age, education, gender, smoking, total caloric intake, and intake of other antioxidants, only dietary beta-carotene could be related to how well the subjects performed on the tests. Cognitive function was not related to vitamin C and E intake.
The study is limited by the reliability of the subjects' recall of dietary items, as well as the accuracy of current nutritional tables. The authors also point out they could not take into account natural changes in dietary and lifestyle habits which may have occurred and could only access dietary intake at a specific point in time. Thus, the results need to be interpreted in the broader context of other studies.
Jama, J., Launer, L., Witteman, J., et al. Dietary Antioxidants and Cognitive Function in a Population-based Sample of Older Persons. American Journal of Epidemiology. Vol. 144, pp.275-80, 1996.
In this unique study, blood samples were taken from 95 elderly (age 78 to 101) Catholic sisters, who lived in the same building and ate similar diets prepared from the same kitchen in a convent in Mankato, Minnesota. Their blood was analyzed for many different factors, including folate, other B-complex vitamins, vitamin E, carotenoids, minerals, and cholesterol. Thirty of the sisters subsequently died, and their brains were autopsied. A neuropathologist then determined the degree of atrophy of the brain's neocortex and the number of brain lesions. Only serum folate levels were strongly correlated with the severity of atrophy of the neocortex. In 15 nuns who had developed Alzheimer's, the correlation was especially strong. No correlation was found between any of the blood factors and the number of brain lesions.
While no causal connection can be made from the study results, the authors speculate that possibly low folate levels can reduce homocysteine levels, which may damage the vascular system. Alternatively, folate is also crucial in central nervous system development and may play a role in keeping the brain healthy later in life. Whether folate effectively prevents or treats Alzheimer disease has yet to be carefully examined.
Snowdon, D., Tully, C., Smith, C. Riley, K.,Markesbery, W. Serum Folate and the Severity of Atrophy of the Neocortex in Alzheimer Disease: Findings from the Nun Study. American Journal of Clinical Nutrition. Vol. 71, pp.993-8, 2000.
In this review article supporting the scientific basis for additional clinical trials using vitamin E in Alzheimer disease, the author points out several recent findings which are very encouraging.
- Beta-amyloid is a toxic substance found in high concentrations in the brains of Alzheimer's disease patients. In cell cultures, beta-amyloid destroys neuronal tissue via free radical mechanisms. Vitamin E prevents such oxidative damage in vitro. Moreover, in animal studies, it helps delay memory deficiencies.
- In the Alzheimer's Disease Cooperative Study based out of the University of California, San Diego, 341 subjects with moderately severe Alzheimer's received in a double-blind, randomized fashion 2000 IU vitamin E, 10 mg of the drug selegiline, both vitamin E and selegiline, or placebo daily. The subjects' progression of disease was followed until institutionalization, severe dementia, loss of basic skills, or death resulted. Vitamin E and selegiline, either alone or in combination, significantly reduced risk of these outcomes and delayed their onset. No extra benefit was found in those taking both, and fewer adverse effects were noted for those taking just vitamin E. However, no improvement of cognitive function was noted, possibly because of the subjects' advanced state of disease. A more detailed summary of this study is presented later.
- These encouraging observations warrants continued clinical investigations using vitamin E in Alzheimer disease.
Grundman, M. Vitamin E and Alzheimer Disease: The Basis for Additional Clinical Trials. American Journal of Clinical Nutrition. Vol. 71(suppl), pp.630S-6S, 2000.
Both vitamin E and the drug selegiline have been found in separate studies to benefit patients suffering neurodegenerative disorders such as Parkinson's and Huntington's diseases. Selegiline inhibits an enzyme that destroys catecholamines, necessary biochemicals found in the healthy brain. It is also an antioxidant. By increasing the levels of catecholamines and offer antioxidant protection, selegiline may benefit patients with Alzheimer disease. Both vitamin E and selegiline effectively slowed progression of Alzheimer disease in the present study, the Alzheimer's Disease Cooperative Study, which involved 23 medical centers throughout the United States.
In this double-blind, randomized, multicenter trial, 341 patients with moderately severe Alzheimer disease received 2000 IU vitamin E (synthetic "dl-alpha-tocopherol"), 10 mg of the drug seleginline, both vitamin E and selegiline, or placebo daily for 2 years. The progression of disease was followed until a subject required institutionalization, lost the ability to perform basic activities, developed severe dementia, or died.
The main results are:
- 22% of the vitamin E group, 28% of the selegiline group, and 31% of the placebo group lost the ability to perform basic activities.
- 26% of the vitamin E group, 33% of the selegiline group, and 39% of the placebo group needed institutionalization.
- The risk of reaching any of the outcomes was lower by 53% in the vitamin E group, 43% in the selegiline group, and 31% lower in the combination group compared to placebo.
- How long it took for a subject to develop any of the outcomes was greater than the placebo group by 230 days for the vitamin E group, 215 days for the selegiline group, and 145 days in the combination group.
The authors conclude, "Both selegiline and alpha-tocopherol delay functional deterioration, particularly as reflected by the need for institutionalization, and should be considered for use in patients with moderate dementia. Convenience and cost may play a part in treatment disorders, since both agents were effective."
Sano, M., Ernesto, C., Thomas, R. A Controlled Trial of Selegiline, Alpha-Tocopherol, or Both as Treatment for Alzheimer's Disease. New England Journal of Medicine. Vol. 336, pp.1216-22, 1997.
In East Boston, Massachusetts, during 1982-1983, 3,623 elderly (over age 65) subjects free from Alzheimer disease were interviewed in their homes on whether they took vitamin supplements. At this time, 23 persons reported taking vitamin C supplements; 27 persons, vitamin E supplements; 68, a multiple vitamin containing vitamin C; and 62, a multiple containing vitamin E. The typical vitamin E supplement provided 400 IU, and vitamin C, 500 mg. Multiples provided around 30 IU vitamin E and 60 mg vitamin C. Other supplements such as beta-carotene, selenium, and zinc could not be included in the study because few subjects took them.
Four years later, 633 of the original study population were re-interviewed and given neuropsychological exams. None of the 23 subjects taking vitamin C or 27 taking vitamin E developed Alzheimer disease. Of those taking multivitamins including E and/or C, 11 developed Alzheimer's. Of those taking no supplements, 80 developed the disease. Based on statistical analysis, at least 2 of the vitamin E and 3 of the vitamin C takers were expected to develop the disease. While the statistical strength of the small numbers in the study is weak, the findings were notable and "suggest that use of the higher-dose vitamin E and vitamin C supplements may lower the risk of Alzheimer disease."
Morris, M., Beckett, L., Scherr, P., et al. Vitamin E and Vitamin C Supplement Use and Risk of Incident Alzheimer Disease. Alzheimer Disease and Associated Disorders. Vol. 12, No.3, pp.121-6, 1998.
Tardive dyskinesia is a movement disorder that sometimes results from long-term psychiatric medication. While the mechanism of the disorder is still being investigated, it appears to involve excessive free radical activity which destroy neural receptors. Many studies have shown significant improvement of tardive dyskinesia with vitamin E supplementation of 1200 to 1600 IU per day. One double-blind study by Lohr and Caligiuri involved 35 subjects randomly assigned to take 800 IU vitamin E twice a day (total of 1600 IU per day) or placebo. After 2 months, those taking vitamin E showed significant improvement of abnormal involuntary movements. However, some studies do not show noticeable benefit of vitamin E supplementation, and further work in underway to help clarify the issue.
Vatassery, G., Bauer, T., Dysken, M. High Doses of Vitamin E in the Treatment of Disorders of the Central Nervous System in the Aged. American Journal of Clinical Nutrition. Vol. 70, pp.793-801, 1999.
Lohr, J., Caligiuri, M. A Double-Blind Placebo Controlled Study of Vitamin E Treatment of Tardive Dyskinesia. Journal of Clinical Psychiatry, Vol.57, pp.167-73, 1996.