In this large population of US older adults, higher levels of moderate to vigorous physical activities at ages 35-39 or in the past 10 years were associated with future lower risk of PD. This association was present in both men and women. The meta-analysis of prospective studies confirmed this relationship, and therefore the totality of epidemiologic evidence seems to support that higher levels of moderate to vigorous activities in mid or later life are associated with lower risk of PD.
The hypothesis that higher physical activity protects against PD originated from animal experiments in which forced exercise prior to or after dopamine-selective neurotoxicant treatments spared dopaminergic neurons and attenuated movement abnormalities.12–14
Examining this hypothesis in epidemiologic studies is difficult because the underlying PD pathogenesis might affect one's ability to exercise even in its preclinical stages. Previous analysis showed a persistent trend of decreasing activity level among patients with PD starting about 2-4 years prior to the diagnosis.8
Interestingly, the levels of physical activity among patients with PD were rather stable before that point. Therefore, etiologic research on physical activity and PD should be preferably conducted in large prospective cohorts with activity data collected years before the diagnosis.
To date, only a few prospective studies on physical activity and PD are available.8–11
In the HPFS and NHS cohorts,8
higher baseline vigorous activity was associated with lower PD risk in men, but not in women. Recalled participation in strenuous exercises in early life was, however, associated with lower PD risk in both men and women. In the male-only HAHS cohort,9
neither baseline nor recalled physical activity in earlier life was significantly associated with PD risk, although men with the highest energy expenditure had 37% lower PD risk than those in the lowest (RR = 0.63, 95% CI 0.36-1.12, p
for trend = 0.1). In the CPS-II Nutrition cohort,10
higher levels of moderate to vigorous activities were associated with lower future PD risk with a borderline statistical significance. No gender difference was found, but the gender-specific results were not significant due to small sample sizes. A fourth study in Finland reported in the text that leisure time physical activity was nonsignificantly associated with lower PD risk, but did not provide the data.11
Compared with previous studies, the current study is substantially larger with uniformly collected physical activity data for various time periods and includes substantially more female cases. The meta-analysis shows consistent results across studies and gender, suggesting the association between physical activity and PD is not likely due to chance. We could not exclude the possibility of reverse causality that low physical activity was a result of preclinical PD pathogenesis. However, several findings may argue against this as a primary explanation for the relationship between higher physical activity and lower PD risk. First, analysis with repeatedly measured physical activities showed no decrease in activity level among patients with PD until 2-4 years before the diagnosis.8
Second, the HPFS/NHS, CPS-II, and the current study all conducted analyses excluding the first several years of follow-up.8,10
Third, in the current analysis, recalled moderate to vigorous activities at ages 35-39 showed association with lower PD risk, as did strenuous exercises in early life in the HPFS and NHS studies.8
Finally, we demonstrated that decreasing physical activity between ages 35-39 and in the past 10 years was not related to a higher PD risk, suggesting activity levels in these life periods did not yet reflect changes as a result of undiagnosed PD.
The potential mechanisms that underlie the physical activity-PD relationship are yet to be elucidated. In animal experiments, forced exercise induced the secretion of neurotrophic factors which might in turn contribute to the neuroplasticity and survival of dopamine neurons.20,21
Further, exercise downregulates dopamine transporter14
and decreases its ratio to vesicular monoamine transporter. This may reduce cytosolic dopamine turnover and the susceptibility of dopaminergic neurons to neurotoxicants.12,22
Finally, vigorous, but not light, exercise induces lasting elevation of plasma urate,23
which in turn predicts lower PD risk24–27
and slower progression.28
The relevance of these proposed mechanisms needs to be evaluated in future clinical and experimental studies.
The study has several limitations. In this large prospective cohort, we had to rely on self-reports to identify patients with PD, and this inevitably introduced diagnostic and reporting errors. In our diagnostic confirmation effort, about 88% of the self-reported diagnoses were verified with medical information from their treating neurologists. Further, we excluded identified erroneous reports or misdiagnoses from the analysis. Physical activities were self-reported via a structured survey. Although the questionnaire was not directly validated, it contained key elements of the Physical Activity Scale for the Elderly that showed reasonable reliability and validity when compared against objectively measured energy expenditure using doubly labeled water.29,30
Physical activity assessed in this study has been previously linked to lower overall mortality31
and lower risk of colorectal cancer.32
Further, information on physical activity was collected prior to case identification and therefore the recall errors should be nondifferential and might have attenuated the true strengths of associations. Nevertheless, exposure misclassification is a concern as the accuracy of reporting physical activities was subject to participants' abilities of observation and memory. In particular, our findings that early life physical activities were not related to PD risk need cautious interpretations as the recall of activities in the distant past might have had more errors than that of recent activities. Despite the fact that we only included cases diagnosed at least 3 years after the exposure assessment and we presented several lines of evidence against the possibility of reverse causality, we could not entirely exclude the likelihood that our finding was due to decreased physical activities of patients with PD in early preclinical stages. Finally, most of our study participants were white; therefore the generalizability of our results to other ethnicities needs to be evaluated in future studies.