In this large prospective investigation, we found no association between history of hypertension, hypercholesterolemia, or diabetes and risk of PD. These results are consistent with those of some previous studies,5,6,8
but not others in which a history of hypertension6,7,9
was associated with a decreased risk of PD. The inconsistency may be partially due to the retrospective exposure assessment of these conditions and the ambiguous time period of exposure classification in many of these studies. In a recent case–control study, a 40% lower risk of PD was estimated among subjects with diabetes, and a significant interaction between smoking status and diabetes was found among men but not women.10
In contrast, in a cohort study in Finland, risk of PD was 85% higher in men and women with Type 2 diabetes.21
However, we did not find an association between diabetes and risk of PD in either men or women and additional analyses restricted to nonsmokers or smokers did not suggest any differential effect.
Strengths of the current study include the large sample size, the prospective design, the high rate of follow-up, the availability of detailed and validated information on cigarette smoking and others potential confounders, and the multiple updated assessments of the exposures of interest, which provide a clear temporal sequence between vascular factors and PD diagnosis. PD patients may exhibit autonomic dysfunction,22,23
and changes in weight20
and physical activity19
have been documented to occur before diagnosis and could cause secondary changes in blood pressure, cholesterolemia, and risk of diabetes. To determine whether these conditions are risk factors for PD, it is therefore important that their presence is established before the onset of neurologic symptoms, and preferably several years earlier.
There are, however, some potential limitations. Exposures were assessed through self-reported doctor-diagnosed disease, rather than by direct clinical examinations. Although the use of self-reported history of hypertension, diabetes, and cholesterol has been validated,13,14
some misclassification may still occur. This would likely be nondifferential and may have attenuated possible existing relationships. However, the findings that self-reported history of hypertension, hypercholesterolemia, and diabetes are strong predictors of heart disease and stroke13,24
and self-reported total blood cholesterol predicts myocardial infarction (unpublished data) provide evidence of validity of the reported exposures and suggest that bias due to misclassification is likely to be modest. Some misclassification in PD diagnosis is also expected, but error from this source is also likely to be small. In recent clinicopathologic studies, the positive predictive value of clinical PD diagnosis was approximately 90% for diagnoses made by general neurologists25
and even higher for diagnoses made by movement disorder specialists.26
Finally, as in all observational studies, unmeasured confounding cannot be excluded, but it seems unlikely that this could account for the null results. All of the analyses were adjusted for the strongest risk factors for PD, including sex, age, and smoking history, the latter based on detailed, prospectively collected, and validated information. The role of other potential confounders, such as caffeine, alcohol consumption, BMI, physical activity, and use of NSAIDs were examined in multivariate models and were found to have little impact on effect estimates.
Average SBP and DBP among individuals who developed PD were similar to those of individuals without PD throughout the study period, which extended from 10 years before diagnosis to 8 years after diagnosis, except for a small but significant decline in SBP after the diagnosis. This decrease in SBP after diagnosis is consistent with the observation that autonomic dysregulation may be associated with PD in some patients22,23
and may increase with disease severity.27,28
Additionally, L-dopa and other treatments may result in resting hypotension, increased orthostatic hypotension, and increased autonomic dysfunction independent of disease severity.22,27,29–31
However, the trend of decreasing SBP after PD diagnosis was attenuated after exclusion of those on antihypertensive medications, and may thus reflect in part a stronger response to treatment of SBP in individuals with PD. Additionally, this trend after diagnosis may contribute to explain the decreased prevalence of measured hypertension in studies among diagnosed PD cases.
There was a suggestion of a potential protective effect of increasing total cholesterol, which was stronger in women than in men. These results should be interpreted with caution because the results were only marginally significant and could have occurred by chance. However, this finding is consistent with the report of lower levels of LDL cholesterol among patients with PD than controls32
and with the results of a recent prospective study of serum cholesterol levels and risk of PD in which a protective effect of increasing cholesterol was observed in women but not in men.33
Further investigation of the potential protective effect of high cholesterol and PD is nevertheless warranted, particularly because in this study we did not have individual information on specific cholesterol fractions. Of interest, plasma levels of uric acid have been found to be strongly inversely related to risk of PD,34–36
it would thus be important in future investigations to consider possible confounding by uricemia.
Overall, the results of this large prospective study do not support a role for hypertension, diabetes, or high total cholesterol as risk factors for PD. A possible decreased risk of PD associated with high plasma cholesterol, particularly in women, cannot be excluded and deserves further investigation.