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 Channing Laboratory, Department of Medicine, Brigham and Womens Hospital and Harvard Medical School, Boston, MA.
Received for publication July 2, 2002; accepted for publication December 2, 2002.
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ABSTRACT |
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dietary fats; Parkinson disease; prospective studies
Abbreviations: Abbreviations: CI, confidence interval; FFQ, food frequency questionnaire; RR, relative risk.
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INTRODUCTION |
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MATERIALS AND METHODS |
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A specific question on lifetime occurrence of Parkinsons disease was first included in the 1988 (Health Professionals Follow-up Study) and 1994 (Nurses Health Study) questionnaires, and a question on a Parkinsons disease diagnosis within the previous 2 years was asked in the subsequent questionnaires. Participants who had been diagnosed with Parkinsons disease, stroke, or cancer (other than nonmelanoma skin cancer) at baseline were excluded from the analyses. In addition, we excluded participants whose daily energy intakes were extreme (<800 or >4,200 kcal for men; <500 or >3,500 kcal for women) or for whom the FFQ was incomplete at baseline (>70 blank responses for men and >10 for women). We followed 47,331 eligible men and 88,563 eligible women from baseline (1986 and 1980, respectively) to 1998 or date of Parkinsons disease diagnosis or death, whichever occurred first. These studies were approved by the Human Subjects Research Committees at the Harvard School of Public Health and the Brigham and Womens Hospital in Boston, Massachusetts.
Case ascertainment
Ascertainment of the Parkinsons disease cases in this study has been described previously (13). Briefly, after obtaining permission from participants who reported a new diagnosis of Parkinsons disease, we asked the treating neurologist (or the internist if the neurologist did not respond) to complete a questionnaire to confirm the diagnosis of Parkinsons disease and the certainty of the diagnosis or to supply a copy of the medical record. 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 of the disease (rest tremor, rigidity, bradykinesia) in the absence of features suggesting other diagnoses. The investigators, blinded to exposure status, reviewed the medical records. Overall, the diagnosis was confirmed by the treating neurologist for 82.3 percent of the cases, by review of the medical records for 3.1 percent of the cases, and by the treating internist without further support for the remaining 14.6 percent of the cases. Deaths in the cohorts were reported by family members, coworkers, or postal authorities, or they were identified by searching the National Death Index. If Parkinsons disease was listed as a cause of death on the death certificate, we requested permission from the family to contact the treating neurologist or physician and followed the same procedure as for the nonfatal cases. Fewer than 2 percent of the cases were ascertained by reviewing death certificates.
Exposure assessment
For each item on the FFQ, participants were asked how often, on average, they had consumed a specified amount during the previous 12 months; possible response categories were nine and ranged from "never" to "6 or more times per day." We also asked questions about the types of fat or oil used in the preparation of foods or at the table. The nutrient composition of foods was estimated by using the Harvard University Food Composition Database derived from the US Department of Agriculture (14, 15) and was supplemented with information from manufacturers (11) and data from peer-reviewed literature.
Dietary intakes assessed by using the Health Professionals Follow-up Study questionnaire have been validated previously among 127 men, who had also completed two 1-week weighed dietary records (11). After correction for day-to-day variability, the Pearsons correlation coefficients were 0.67 for total fat, 0.75 for saturated fat, 0.37 for polyunsaturated fat, 0.68 for monounsaturated fat, and 0.76 for cholesterol. In the Nurses Health Study cohort, similar validation studies were performed for the 1980 FFQ (16) and the 1986 FFQ (10). The corresponding 1980/1986 correlation coefficients were 0.53/0.57 for total fat, 0.59/0.68 for saturated fat, 0.48/0.48 for polyunsaturated fat, and 0.61/0.73 for cholesterol. In addition, intakes of poly- and trans-unsaturated fatty acids calculated from the FFQ were compared with their concentrations in adipose tissue (17, 18); the correlations between intake as a proportion of fat and the proportion in adipose tissue for men/women were 0.43/0.40 for polyunsaturated fat and 0.34/0.40 for trans-unsaturated fat. We used the 1984 intakes assessed in the Nurses Health Study as the baseline data for analyses involving specific polyunsaturated fatty acids because they provided greater details to calculate intakes of these nutrients.
Statistical analyses
Macronutrient intakes were expressed as percentage of energy, and quintile categories were used in the main analyses. Relative risks were calculated by dividing the incidence rate in an exposure category by the corresponding rate in the reference category. Age- and smoking-adjusted relative risks were calculated by using the Mantel-Haenszel method (19). The multivariate-adjusted relative risks were derived from a pooled logistic regression model. In this model, each 2-year interval of follow-up is considered as a separate cohort; the observations from each of these cohorts are pooled into a single large population, and the analyses are conducted by logistic regression (20). This method has been shown to be equivalent to a Cox proportional hazards analysis when the probability of an event within each interval is small (20). Covariates adjusted for in the models included age, smoking status, total energy intake, caffeine intake, and alcohol consumption. Because the age- and smoking-adjusted relative risks were similar to the multivariate relative risks, the latter are presented in this paper for simplicity. The effects of isocaloric substitution of polyunsaturated fat with saturated fat were estimated by fitting the multivariate models with saturated fat intake as a continuous variable and adjusting for total energy intake and all other sources of energy except for polyunsaturated fat (21). Log relative risks from the two cohorts were pooled by the inverse of their variances. All p values were two tailed.
Primary analyses involved use of baseline intakes. However, we also took advantage of the repeated dietary assessment by using the cumulative average intakes from all available questionnaires prior to the beginning of each 2-year follow-up period (22). The cumulative average was calculated, for example, for men in 1990 as the average of the 1986 and 1990 intakes and for men in 1994 as the average of the 1986, 1990, and 1994 intakes. To address the possibility that dietary changes caused by early symptoms of Parkinsons disease might affect the results, we also analyzed the data by excluding the first 6 years of follow-up.
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RESULTS |
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Because of the different physiologic effects of individual polyunsaturated fatty acids, intakes were examined separately (table 2). No significant associations were found between risk of Parkinsons disease and intake of linoleic, -linolenic, or long-chain
-3 fatty acids, including eicosapentaenoic acid and docosahexaenoic acid. A higher baseline intake of arachidonic acid tended to be associated with a lower risk of Parkinsons disease (pooled RR for the highest vs. lowest intake quintiles = 0.65, 95 percent CI: 0.46, 0.91; p for trend = 0.05), and the association remained in the cumulative average analyses (pooled RR = 0.62, 95 percent CI: 0.44, 0.88; p for trend = 0.02).
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DISCUSSION |
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Both the Health Professionals Follow-up Study and the Nurses Health Study were prospectively designed, with repeated dietary assessments and long follow-up periods. Intakes of total and individual fats derived from our dietary questionnaires reasonably reflected the long-term fat intakes of the study populations (10, 11, 1618) and have been found to predict the risk of coronary heart disease in a manner consistent with their metabolic effects (21, 23).
Previous epidemiologic results on dietary fats and risk of Parkinsons disease have been inconsistent. A higher risk of Parkinsons disease was found among participants with greater intakes of total fat (4, 9), animal fat (4) or foods high in animal fat (8), or cholesterol (9) in three case-control studies, with odds ratios ranging from 2 to 5 for the highest compared with the lowest categories. However, these studies were retrospectively designed, and each included fewer than 130 cases. In a larger case-control study (342 cases) (5) and a small prospective study among Hawaiian men (84 cases) (6), null associations between total or animal fat intake and risk of Parkinsons disease were reported. Compared with animal fat, vegetable fat and polyunsaturated fatty acids have been evaluated less often. Two of these previous case-control studies (4, 9) and the prospective investigation (6) have reported null associations between linoleic acid or vegetable fat intakes and risk of Parkinsons disease.
Although a slightly greater risk of Parkinsons disease was found among men in the current study whose intake of animal or saturated fat was higher, the increment was in the range of random error, and the association was attenuated in further analyses. Moreover, a nonsignificantly lower risk of Parkinsons disease was found among women in the highest quintile of animal or saturated fat intake compared with those in the lowest quintile. The greater risk of Parkinsons disease associated with isocaloric replacement of saturated fat with polyunsaturated fat by men was probably a result of its weak positive association with saturated fat and inverse association with polyunsaturated fat. Therefore, although we could not rule out the hypothesis that dietary intakes of animal or saturated fat in adult life increase the risk of Parkinsons disease, our results do not strongly support it. Intakes of most polyunsaturated fatty acids were not associated with risk of Parkinsons disease in this study. However, we found an inverse association between arachidonic acid intake and risk of Parkinsons disease among women and a similar, but nonsignificant association among men. Arachidonic acid has important physiologic functions in the central nervous system (24) and can stimulate dopamine release and inhibit its reuptake in the rat striatum (25); however, the relevance of this experimental finding to human Parkinsons disease is not clear, and we cannot exclude the possibility that our arachidonic acid results were due to chance.
Dietary fatty acids have been hypothesized to increase the risk of Parkinsons disease because they can potentially contribute to the oxidative stress that has been implicated in Parkinsons disease pathogenesis. Neural membranes are rich in polyunsaturated fatty acids, which are good substrates for the oxidative radicals. Cascades of lipid peroxidation will cause further oxidative damage and adversely modify the lipid composition of membranes, possibly contributing to neuron death (26). In addition, adverse essential fatty acid composition of mitochondrial membrane may also induce phosphorylation uncoupling, resulting in energy failure (27). Some support for lipid peroxidation in Parkinsons disease is found among persons who died of the disease. Compared with controls, these persons had higher concentrations of polyunsaturated fatty acid peroxidation metabolites but lower concentrations of polyunsaturated fatty acids and glutathione in the substantia nigra (2832). Saturated fat could modify the risk of Parkinsons disease by affecting polyunsaturated fatty acid metabolism and inducing adverse changes in cell membrane lipid composition (27), but these potential mechanisms remain speculative.
Lower energy intake may decrease free-radical production in the mitochondria, and experimental studies have shown that energy restriction made the midbrain dopaminergic neurons more resistant to the N-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP) neurotoxicity (33). Two case-control studies and one clinical observation found that Parkinsons disease patients reported higher energy intakes than controls (35). However, as noted by the authors (34), higher energy intake might be a consequence of the disease because of the higher energy expenditure associated with rigidity and tremor in Parkinsons disease patients. In this prospective study, we did not find any evidence to support that higher energy intake increases risk of Parkinsons disease, nor did we find any evidence to support a previous case-control finding that carbohydrate intake is positively associated with Parkinsons disease risk (5).
Potential limitations of this study include errors in outcome and exposure assessments. For the diagnosis of Parkinsons disease, we relied on the judgment of the patients treating physicians, in most cases their neurologists. Since we did not have a pathologic confirmation, we cannot exclude the possibility that a few cases were misdiagnosed. However, the results of a recent clinicopathologic study (35) suggest that the clinical Parkinson diagnosis (made by a neurologist in 86 percent of their case series) is accurate in 90 percent of the cases. The bias resulting from this source is therefore likely to have been small. The null results of our study could also be explained by error in assessing fat intakes. Although some error dietary assessment was inevitable in this as well as in previous studies, we minimized it by using an extensively validated FFQ and repeated dietary assessments. Nevertheless, modest or weak associations cannot be excluded. Finally, because the cohort participants were well-educated health professionals and not a random sample of the US general population, our results may not apply to persons whose fat intakes are outside the range of the current study or those who otherwise have markedly different dietary habits.
In summary, our study lends little support to the hypothesis that higher fat intakes increase risk of Parkinsons disease. The results suggest a possible adverse effect of replacing polyunsaturated fat with saturated fat for men and a potential beneficial effect of arachidonic acid, but these findings are preliminary and require further evaluation.
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ACKNOWLEDGMENTS |
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The authors thank 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.
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NOTES |
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REFERENCES |
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