Folate Intake and Risk of Parkinsons Disease
Honglei Chen1 ,
Shumin M. Zhang2,3,
Michael A. Schwarzschild4,
Miguel A. Hernán2,
Giancarlo Logroscino2,
Walter C. Willett1,2,5 and
Alberto Ascherio1,2,5
1 Department of Nutrition, Harvard School of Public Health, Boston, MA.
2 Department of Epidemiology, Harvard School of Public Health, Boston, MA.
3 Division of Preventive Medicine, Department of Medicine, Brigham and Womens Hospital and Harvard Medical School, Boston, MA.
4 Department of Neurology, Massachusetts General Hospital, Boston, MA.
5 Channing Laboratory, Department of Medicine, Brigham and Womens Hospital and Harvard Medical School, Boston, MA.
Received for publication December 15, 2003; accepted for publication March 2, 2004.
 |
ABSTRACT
|
---|
In clinical studies, individuals with Parkinsons disease have had higher concentrations of plasma homocysteine than did controls, and experimental evidence suggests that folate deficiency or focal administration of homocysteine sensitizes dopaminergic neurons to the neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. The authors thus prospectively investigated whether higher intake of folate, vitamin B6, or vitamin B12 was related to a lower risk of Parkinsons disease in the Health Professionals Follow-up Study (19862000) and the Nurses Health Study (19801998). They documented Parkinsons disease diagnoses in 248 men and 167 women during the follow-up. Folate intake was not associated with the risk of Parkinsons disease; the relative risks for the highest compared with the lowest quintiles were 1.0 (95% confidence interval: 0.7, 1.5) in men and 1.3 (95% confidence interval: 0.8, 2.3) in women. Neither did they find significant associations in analyses stratified by age, smoking, alcohol consumption, or lactose intake. Intake of vitamin B6 or vitamin B12 also was not related to the risk of Parkinsons disease. The current study does not support the hypothesis that higher intake of folate or related B vitamins lowers the risk of Parkinsons disease.
cohort studies; diet; folic acid; homocysteine; Parkinson disease
Abbreviations:
Abbreviations: CI, confidence interval; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.
 |
INTRODUCTION
|
---|
Low folate intake increases plasma homocysteine (1), which damages the vascular endothelium and increases the risk of cardiovascular diseases (2). Homocysteine is also neurotoxic, and hyperhomocysteinemia has been associated prospectively with higher risk of Alzheimers disease in the Framingham Study (3). A higher plasma homocysteine concentration has also been reported in Parkinsons disease patients than in controls (46), but this elevation could be a consequence rather than a cause of Parkinsons disease. The potential neurotoxicity of homocysteine to dopaminergic neurons was recently investigated in an animal model of Parkinsons disease, in which a folate-deficient diet or direct administration of homocysteine significantly enhanced the neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (7). The results suggest that folate deficiency and hyperhomocysteinemia may potentially contribute to Parkinsons disease pathogenesis. Therefore, we prospectively investigated whether intake of folate or of related B vitamins that are involved in folate and homocysteine metabolism was associated with Parkinsons disease risk in two large ongoing prospective cohorts: the Health Professionals Follow-up Study and the Nurses Health Study.
 |
MATERIALS AND METHODS
|
---|
Study population
The Health Professionals Follow-up Study cohort was established in 1986, when 51,529 male health professionals (dentists, optometrists, pharmacists, osteopaths, podiatrists, and veterinarians), aged 4075 years, responded to a mailed questionnaire that included a 131-item food frequency questionnaire (8), in addition to questions on history of diseases and lifestyle. The Nurses Health Study was established in 1976 when 121,700 registered nurses aged 3055 years in 11 states provided detailed information about their medical history and lifestyle practices (9). A 61-item food frequency questionnaire was added to the Nurses Health Study questionnaire to obtain dietary information in 1980 and was expanded to 116 items in 1984 and again to 136 items in 1986. In both cohorts, follow-up questionnaires have been mailed to participants every 2 years to update information on potential risk factors for chronic diseases and to ascertain whether major medical events have occurred, and dietary information has been updated every 24 years. A question on lifetime occurrence of Parkinsons disease was first included in the 1988 (Health Professionals Follow-up Study) and the 1994 (Nurses Health Study) questionnaires and subsequently updated every 2 years. Participants who reported Parkinsons disease (n = 178), stroke (n = 505), or cancer (other than nonmelanoma skin cancer, n = 5,572) at baseline were excluded from the analyses. In addition, we excluded from analyses participants with extreme daily energy intakes (<800 or >4,200 kcal for men; <500 or >3,500 for women) or incomplete food frequency questionnaire at baseline (>70 blanks for men or >10 for women). We followed 47,341 eligible men and 88,716 women from baseline (1986 and 1980, respectively) to the date that the first Parkinsons disease symptoms were noticed, the date of stroke diagnosis or death, or the end of the follow-up (January 31, 2000, in men and May 31, 1998, in women), whichever occurred first. These studies were approved by the human subjects committees at the Harvard School of Public Health (Health Professionals Follow-up Study) and Brigham and Womens Hospital (Nurses Health Study).
Parkinsons disease case ascertainment
Ascertainment of the Parkinsons disease cases in this study has been previously described (10). Briefly, after obtaining permission from participants who reported a new diagnosis of Parkinsons disease, we asked the treating neurologist (or internist if the neurologist did not respond) to complete a questionnaire to provide his/her judgment on the certainty of the diagnosis or to send a copy of the medical record. On the questionnaire, we also elicited the information on the date that the first symptoms of Parkinsons disease were noticed and the date when the disease was first clinically diagnosed. A case was confirmed if a diagnosis of Parkinsons disease was considered definite or probable by the treating neurologist or internist, or if the medical record included either a final diagnosis of Parkinsons disease made by a neurologist or evidence at a neurologic examination of at least two of the three cardinal signs (rest tremor, rigidity, bradykinesia) in the absence of features suggesting other diagnoses. The review of medical records was conducted by the investigators who were blind to the exposure status. Overall, the diagnosis was confirmed by the treating neurologist in 82.3 percent of the cases, by review of the medical records in 3.1 percent of the cases, and by the treating internist without further support in the remaining 14.6 percent of the cases.
Exposure assessment
In both cohorts, participants were asked how often, on average, they had consumed a specified amount of each food item in the food frequency questionnaire during the previous 12 months, with nine possible response categories ranging from "never" to "6 or more times per day." Information on the dose and duration of supplemental use of specific vitamins and multivitamins was collected at baseline in both cohorts and updated in the biennial surveys. The nutrient composition of foods was estimated from the Harvard University Food Composition Database that was derived from the US Department of Agriculture (11) and supplemented with information from manufacturers (8) and data from peer-reviewed literature. Validations studies have revealed high correlation coefficients between nutrient intakes estimated from the food frequency questionnaires and those from weighed dietary records. The coefficients were 0.77 for folate, 0.85 for vitamin B6, and 0.56 for vitamin B12 in the Health Professionals Follow-up Study (8) and 0.58 for vitamin B6 in the Nurses Health Study (12). Moreover, the correlation between total folate intake and erythrocyte folate concentration was 0.55 in a sample of 188 Nurses Health Study participants (13). In the control group of a recent Nurses Health Study on breast cancer (14), intake of these vitamins was also moderately correlated with their plasma concentrations, the coefficients being 0.49 for folate, 0.52 for vitamin B6, and 0.25 for vitamin B12.
Statistical analyses
In the primary analyses, baseline nutrient intake was classified into quintiles, adjusting for energy intake with the residual method (15). Multivariate-adjusted relative risks were derived from Cox proportional hazard models controlling for age (years), smoking status (never smoker, past smoker, or current smoker: cigarettes/day, 114 or
15), total energy intake (quintiles), caffeine intake (quintiles), alcohol consumption (g/day, men: 0, 19.9, 1019.9, 2029.9, or
30; women: 0, 14.9, 59.9, 1014.9, or
15), and lactose intake (quintiles). The p value for linear trend was calculated by using the median of each quintile category as a continuous variable in the Cox models. Log relative risks from the two cohorts were pooled by the inverse of their variances. For all relative risks, we calculated 95 percent confidence intervals and two-tailed p values. To examine the possibility that folate affects the risk of Parkinsons disease at only high or low levels, we further categorized folate intake into 10 categories, ranging from 200 or less µg to more than 1,000 µg per day. In a secondary analysis, we also compared participants with intakes of all three vitamins in the top tertile with those with intakes all in the bottom tertile. To take advantage of the repeatedly collected dietary information, we also conducted cumulative updated analyses by relating the average nutrient intake from all surveys prior to the beginning of each biennial questionnaire to the risk of Parkinsons disease in the following 2-year period (16). As Parkinsons disease may develop for many years before it can be clinically diagnosed, we also conducted 6-year lag analyses by excluding the first 6 years of follow-up in order to minimize the effect of dietary changes associated with undiagnosed Parkinsons disease on the analyses.
Since lactose intake was associated with an increased risk of Parkinsons disease in the Health Professionals Follow-up Study cohort (17), we repeated our primary analyses on folate and Parkinsons disease separately in individuals with high (quintiles 4 and 5) or low (quintiles 13) lactose intake. Further, as alcohol in many ways affects the absorption and metabolism of folate, we stratified folate analyses by baseline alcohol intake (<15 g and
15 g) in both men and women. Finally, stratified analyses were also conducted for all nutrients according to baseline age (<65 years vs.
65 years in men; <50 vs.
50 years in women) or smoking status (never smokers vs. ever smokers). The cutoff points for age group were selected on the basis of sample size considerations.
 |
RESULTS
|
---|
During an average of 12.7 years of follow-up in men and 17.3 years in women, we identified a total of 248 male and 167 female Parkinsons disease patients. The person-year contribution by each 5-year age group during the follow-up was 108,659 (<age 50 years), 103,624 (ages 5054 years), 96,994 (ages 5559 years), 92,607 (ages 6064 years), 84,294 (ages 6569 years), 64,388 (ages 7074 years), 36,589 (ages 7579 years), and 14,522 (age
80 years), respectively, in men, and 244,414 (ages <45 years), 254,099 (ages 4549 years), 310,993 (ages 5054 years), 306,213 (ages 5559 years), 229,013 (ages 6064 years), 137,721 (ages 6569 years), and 54,614 (age
70 years), respectively, in women. The average baseline intake of folate was 482 µg/day for men and 366 µg/day for women. Among both men and women, participants with higher folate intake were less likely to be current smokers, had lower coffee consumption, and had higher intakes of vitamins B6 and B12 (table 1).
View this table:
[in this window]
[in a new window]
|
TABLE 1. Age-adjusted population characteristics according to baseline total folate intake quintile in the Health Professionals Follow-up Study (1986) and the Nurses Health Study (1980)*
|
|
Baseline folate intake was not associated with the risk of Parkinsons disease (table 2). The pooled relative risks comparing the highest and the lowest intake quintiles were 1.1 (95 percent confidence interval (CI): 0.8, 1.5; ptrend = 0.8) for total folate and 1.2 (95 percent CI: 0.8, 1.7) for dietary folate. Additional analyses that restricted Parkinsons disease cases to definite cases or neurologist-diagnosed cases generated similar results. Individuals at either the low end or the high end of folate intake in our study population had a Parkinsons disease risk similar to the risk of those with normal folate intake (figure 1): Using folate intake of 400500 µg/day as the reference group, we found that the pooled relative risks were 1.1 (95 percent CI: 0.6, 1.9) for less than 200 µg/day and 0.9 (95 percent CI: 0.5, 1.6) for more than 1,000 µg/day. The pooled relative risks associated with cumulatively updated folate intake quintiles were 1.0 (referent), 0.9, 1.4, 1.3, and 1.0 for quintiles 15, and the corresponding relative risks in the 6-year lag analyses were 1.0, 0.9, 1.2, 1.0, and 1.1, respectively. As with folate intake, no significant association was found between intake of vitamin B6 or vitamin B12 and the risk of Parkinsons disease in our analysis. Although a slightly lower risk was found when a comparison was made of individuals whose intakes of all three vitamins were in the highest tertile and individuals whose intakes were in the lowest (relative risk = 0.8, 95 percent CI: 0.6, 1.3), the association was not statistically significant. Neither did we find a significant association between dietary intake of these vitamins and Parkinsons disease risk in the analyses stratified by age, smoking status, alcohol consumption (folate only), or lactose intake (folate only). Supplemental intake of these nutrients was also not related to the risk of Parkinsons disease (table 3). Compared with nonusers, individuals whose supplemental folate intake was more than 400 µg/day had a pooled relative risk of 1.0 (95 percent CI: 0.8, 1.2).
View this table:
[in this window]
[in a new window]
|
TABLE 2. Relative risk* of Parkinsons disease according to baseline intake of folate, vitamin B6, or vitamin B12 in the Health Professionals Follow-up Study (19862000) and the Nurses Health Study (19801998)
|
|

View larger version (14K):
[in this window]
[in a new window]
|
FIGURE 1. Multivariate relative risk and 95% confidence intervals of Parkinsons disease according to total folate intake in the Health Professionals Follow-up Study (19862000) and the Nurses Health Study (19801998), adjusting for age, smoking, alcohol consumption, caffeine intake, and lactose intake. RR, relative risk; PD, Parkinsons disease.
|
|
View this table:
[in this window]
[in a new window]
|
TABLE 3. Relative risk* of Parkinsons disease according to supplemental intake of folate, vitamin B6, or vitamin B12 in the Health Professionals Follow-up Study (19862000) and the Nurses Health Study (19801998)
|
|
 |
DISCUSSION
|
---|
In this large prospective analysis, we found no association between intake of folate, vitamin B6, or vitamin B12 and the risk of Parkinsons disease. Similar null results were found when we examined folate intake at very low or high levels or examined it together with intakes of vitamin B6 and vitamin B12.
Both the Health Professionals Follow-up Study cohort and the Nurses Health Study cohort are large prospective cohorts with validated dietary assessments and long follow-ups. Although participants of this study are health professionals who, on average, reported adequate folate intakes, the large size of these cohorts allowed us to explore the effects of folate over a wide range of intake that encompasses the consumption of the majority of the US population (18). Approximately 53 percent of men and 71 percent of women reported folate intakes lower than 400 µg/day, thus falling into the range in which the plasma homocysteine concentration increases as the folate intake decreases (1). Further, the folate intake assessed in our cohort was associated with lower risk of colon cancer, breast cancer, and coronary heart diseases (1921).
Previous epidemiologic studies have demonstrated an association between hyperhomocysteinemia and risk of Alzheimers disease (3). In the Framingham Cohort Study (3), individuals with plasma homocysteine greater than 14.0 µmol per liter had 90 percent higher risk of Alzheimers disease compared with those with normal concentrations. Elevated homocysteine may increase Alzheimers disease risk through its deleterious role in endothelial vascular pathogenesis as well as its direct neurotoxic effects (2227). It potentiates the neurotoxicity of ß-amyloid, enhances glutamate excitotoxicity, overstimulates N-methyl-D-aspartate receptors, and induces calcium influx into the neurons (2527). Further, a high homocysteine concentration as well as folate deficiency may decrease glutathione peroxidase activity and reduce tissue concentrations of antioxidant vitamins (28, 29), making neurons more vulnerable to oxidative attacks. Homocysteine may also induce neuron apoptosis by damaging neuron DNA and subsequently depleting neural energy reserves to repair the damages (27, 30). Although these mechanisms have been proposed to explain the association between folate and Alzheimers disease, most of them could also apply to other neurodegenerative diseases, including Parkinsons disease. In addition to folate, vitamin B6 and vitamin B12 also are important cofactors in the one-carbon metabolism, and individuals with low plasma concentrations of these B vitamins are more likely to have hyperhomocysteinemia (1). Although they have not been previously investigated in relation to dopaminergic neuron survival or to the risk of Parkinsons disease, low intakes of these two vitamins, particularly of vitamin B12, are probably associated with cognitive declines and the risk of Alzheimers disease in elder populations (3133).
Interestingly, individuals with Parkinsons disease have had higher plasma homocysteine concentrations than those without the disease (46). This increase may reflect dietary changes after Parkinsons disease diagnosis or may be related to the long-term use of levodopa in Parkinsons disease patients, which may deplete the intracellular methyl group, increase homocysteine concentrations, and promote its extracellular export (6, 34). However, the higher concentration of plasma homocysteine is also consistent with the possibility that homocysteine itself is neurotoxic to dopaminergic neurons and thus increases the risk of Parkinsons disease. In an experimental study (7), folate deficiency resulted in a high plasma homocysteine level in mice and significantly sensitized dopaminergic neurons to the neurotoxicity of a subtoxic dose of MPTP. This dose did not induce dopaminergic neuron death in mice with adequate folate intake, but it caused a significant decrease in the number of dopaminergic neurons and induced profound motor dysfunctions when combined with a folate-deficient diet. Moreover, focal administration of homocysteine into either striatum or substantia nigra also exacerbated the MPTP-induced motor dysfunctions and loss of striatal dopamine and its metabolites (7). Further, in vitro administration of homocysteine significantly enhanced the neurotoxicity of rotenone or ferrous iron to human dopaminergic neurons (7).
Some limitations should be considered in the interpretation of our findings. In both cohorts, we relied on the clinical diagnosis of the treating neurologist, which in a recent clinicopathologic investigation was found to be accurate in 90 percent of the cases (35). Thus, although the bias from diagnostic misclassification cannot be excluded, it is likely to be modest. Our previous reports on the well-known inverse associations between smoking and coffee consumption (in men only) and Parkinsons disease risk provide further indirect evidence against a substantial diagnostic inaccuracy in the study (10, 36). In studies on diet and chronic diseases, errors in dietary assessment are inevitable (37). We have tried to minimize the measurement error by using validated dietary data and by repeating analyses with cumulatively updated nutrient intake. Further, dietary intakes of folate and related B vitamins are only moderately correlated with plasma homocysteine concentration (1, 14). Therefore, although the results from our study suggest that folate intake is unlikely to be a major determinant of Parkinsons disease risk, they do not exclude the possibility of a mild to modest association between hyperhomocysteinemia and the risk of Parkinsons disease. It is advisable that future prospective studies examine directly the association of Parkinsons disease risk with plasma concentrations of homocysteine, folate, vitamin B6, or vitamin B12. Further, interactions between folate status and genetic polymorphisms of methylenetetrahydrofolate reductase should also be considered as individuals with these polymorphisms are more likely to have hyperhomocysteinemia, particularly when combined with low folate status (38). Because the participants of this study were health professionals, they were more likely to have adequate folate intake and less likely to have occupational or environmental exposures to neurotoxins, such as pesticides and heavy metals that have been related to Parkinsons disease risk (39, 40). Therefore, we were unable to detect any detrimental effects of very low folate intake or preventive effects of folate in the presence of occupational or environmental neurotoxins.
In summary, the results of this large prospective study among US health professionals suggest that dietary intake of folate, vitamin B6, or vitamin B12 is not related to risk of Parkinsons disease. If high intake of folate reduces the risk of Parkinsons disease, its beneficial effect is most likely restricted to individuals who are exposed to neurotoxins or who are genetically at risk of hyperhomocysteinemia.
 |
ACKNOWLEDGMENTS
|
---|
This study was supported by research grants NS35624 and CA87969 from the National Institutes of Health, Bethesda, Maryland, and by a gift from the Kinetics Foundation.
The authors are indebted to Drs. Frank E. Speizer and Graham A. Colditz, the principal investigators of the Nurses Health Study. They also thank Al Wing, Karen Corsano, Laura Sampson, Gary Chase, Barbara Egan, Mira Kaufman, Betsy Frost-Hawes, Stacey DeCaro, and Mitzi Wolff for their technical help.
 |
NOTES
|
---|
Correspondence to Dr. Honglei Chen, Department of Nutrition, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115 (e-mail: hchen{at}hsph.harvard.edu). 
 |
REFERENCES
|
---|
- Selhub J, Jacques PF, Wilson PW, et al. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA 1993;270:26938.[Abstract]
- Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA 2002;288:201522.[Abstract/Free Full Text]
- Seshadri S, Beiser A, Selhub J, et al. Plasma homocysteine as a risk factor for dementia and Alzheimers disease. N Engl J Med 2002;346:47683.[Abstract/Free Full Text]
- Kuhn W, Roebroek R, Blom H, et al. Elevated plasma levels of homocysteine in Parkinsons disease. Eur Neurol 1998;40:2257.[CrossRef][ISI][Medline]
- Yasui K, Kowa H, Nakaso K, et al. Plasma homocysteine and MTHFR C677T genotype in levodopa-treated patients with PD. Neurology 2000;55:43740.[Abstract/Free Full Text]
- Miller JW, Selhub J, Nadeau MR, et al. Effect of L-dopa on plasma homocysteine in PD patients: relationship to B-vitamin status. Neurology 2003;60:11259.[Abstract/Free Full Text]
- Duan W, Ladenheim B, Cutler RG, et al. Dietary folate deficiency and elevated homocysteine levels endanger dopaminergic neurons in models of Parkinsons disease. J Neurochem 2002;80:10110.[CrossRef][ISI][Medline]
- Rimm EB, Giovannucci EL, Stampfer MJ, et al. Reproducibility and validity of an expanded self-administered semiquantitative food frequency questionnaire among male health professionals (with discussion). Am J Epidemiol 1992;135:111436.[Abstract]
- Colditz GA, Manson JE, Hankinson SE. The Nurses Health Study: 20-year contribution to the understanding of health among women. J Womens Health 1997;6:4962.[ISI][Medline]
- Ascherio A, Zhang SM, Hernán MA, et al. Prospective study of caffeine consumption and risk of Parkinsons disease in men and women. Ann Neurol 2001;50:5663.[CrossRef][ISI][Medline]
- US Department of Agriculture. USDA national nutrient database for standard reference. Release 10. Beltsville, MD: Nutrient Data Laboratory, Agriculture Research Service, 1993. (http://www.nal.usda.gov/fnic/foodcomp).
- Willett WC, Sampson L, Stampfer MJ, et al. Reproducibility and validity of a semiquantitative food frequency questionnaire. Am J Epidemiol 1985;122:5165.[Abstract]
- Giovannucci E, Stampfer MJ, Colditz GA, et al. Folate, methionine, and alcohol intake and risk of colorectal adenoma. J Natl Cancer Inst 1993;85:87584.[Abstract]
- Zhang SM, Willett WC, Selhub J, et al. Plasma folate, vitamin B6, vitamin B12, homocysteine, and risk of breast cancer. J Natl Cancer Inst 2003;95:37380.[Abstract/Free Full Text]
- Willett WC, Howe GR, Kushi LH. Adjustment for total energy intake in epidemiologic studies (with discussion). Am J Clin Nutr 1997;65(suppl):1220S31S.
- Hu FB, Stampfer MJ, Rimm E, et al. Dietary fat and coronary heart disease: a comparison of approaches for adjusting for total energy intake and modeling repeated dietary measurements. Am J Epidemiol 1999;149:53140.[Abstract]
- Chen H, Zhang SM, Hernan MA, et al. Diet and Parkinsons disease: a potential role of dairy products in men. Ann Neurol 2002;52:793801.[CrossRef][ISI][Medline]
- Subar AF, Block G, James LD. Folate intake and food sources in the US population. Am J Clin Nutr 1989;50:50816.[Abstract]
- Giovannucci E, Stampfer MJ, Colditz GA, et al. Multivitamin use, folate, and colon cancer in women in the Nurses Health Study. Ann Intern Med 1998;129:51724.[Abstract/Free Full Text]
- Rimm EB, Willett WC, Hu FB, et al. Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women. JAMA 1998;279:35964.[Abstract/Free Full Text]
- Zhang S, Hunter DJ, Hankinson SE, et al. A prospective study of folate intake and the risk of breast cancer. JAMA 1999;281:16327.[Abstract/Free Full Text]
- Shea TB, Lyons-Weiler J, Rogers E. Homocysteine, folate deprivation and Alzheimer neuropathology. J Alzheimers Dis 2002;4:2617.[Medline]
- Mattson MP, Shea TB. Folate and homocysteine metabolism in neural plasticity and neurodegenerative disorders. Trends Neurosci 2003;26:13746.[CrossRef][ISI][Medline]
- Mattson MP. Will caloric restriction and folate protect against AD and PD? Neurology 2003;60:6905.[Abstract/Free Full Text]
- Ho PI, Collins SC, Dhitavat S, et al. Homocysteine potentiates beta-amyloid neurotoxicity: role of oxidative stress. J Neurochem 2001;78:24953.[CrossRef][ISI][Medline]
- Lipton SA, Kim WK, Choi YB, et al. Neurotoxicity associated with dual actions of homocysteine at the N-methyl-D-aspartate receptor. Proc Natl Acad Sci U S A 1997;94:59238.[Abstract/Free Full Text]
- Kruman II, Culmsee C, Chan SL, et al. Homocysteine elicits a DNA damage response in neurons that promotes apoptosis and hypersensitivity to excitotoxicity. J Neurosci 2000;20:69206.[Abstract/Free Full Text]
- Upchurch GR Jr, Welch GN, Fabian AJ, et al. Homocyst(e)ine decreases bioavailable nitric oxide by a mechanism involving glutathione peroxidase. J Biol Chem 1997;272:1701217.[Abstract/Free Full Text]
- Henning SM, Swendseid ME, Ivandic BT, et al. Vitamins C, E and A and heme oxygenase in rats fed methyl/folate-deficient diets. Free Radic Biol Med 1997;23:93642.[CrossRef][ISI][Medline]
- Kruman II, Kumaravel TS, Lohani A, et al. Folic acid deficiency and homocysteine impair DNA repair in hippocampal neurons and sensitize them to amyloid toxicity in experimental models of Alzheimers disease. J Neurosci 2002;22:175262.[Abstract/Free Full Text]
- Duthie SJ, Whalley LJ, Collins AR, et al. Homocysteine, B vitamin status, and cognitive function in the elderly. Am J Clin Nutr 2002;75:90813.[Abstract/Free Full Text]
- Riggs KM, Spiro A 3rd, Tucker K, et al. Relations of vitamin B-12, vitamin B-6, folate, and homocysteine to cognitive performance in the Normative Aging Study. Am J Clin Nutr 1996;63:30614.[Abstract]
- Wang HX, Wahlin A, Basun H, et al. Vitamin B(12) and folate in relation to the development of Alzheimers disease. Neurology 2001;56:118894.[Free Full Text]
- Liu XX, Wilson K, Charlton CG. Effects of L-dopa treatment on methylation in mouse brain: implications for the side effects of L-dopa. Life Sci 2000;66:227788.[CrossRef][ISI][Medline]
- Hughes AJ, Daniel SE, Lees AJ. Improved accuracy of clinical diagnosis of Lewy body Parkinsons disease. Neurology 2001;57:14979.[Abstract/Free Full Text]
- Hernan MA, Zhang SM, Rueda-deCastro AM, et al. Cigarette smoking and the incidence of Parkinsons disease in two prospective studies. Ann Neurol 2001;50:7806.[CrossRef][ISI][Medline]
- Willett WC. Nutritional epidemiology. New York, NY: Oxford University Press, 1998.
- Jacques PF, Bostom AG, Williams RR, et al. Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation 1996;93:79.[Abstract/Free Full Text]
- Gorell JM, Rybicki BA, Cole Johnson C, et al. Occupational metal exposures and the risk of Parkinsons disease. Neuroepidemiology 1999;18:3038.[CrossRef][ISI][Medline]
- Priyadarshi A, Khuder SA, Schaub EA, et al. A meta-analysis of Parkinsons disease and exposure to pesticides. Neurotoxicology 2000;21:43540.[ISI][Medline]