Our results provide evidence that moderate to vigorous physical activity may confer protection against the onset of Parkinson’s disease in both men and women. Men and women in our study in the highest baseline categories of moderate to vigorous activity, such as bicycling, aerobics, or tennis, had the lowest risk of PD during follow-up. On the other hand, risk among participants who reported only light activity at baseline, such as walking or dancing, was similar to that of individuals who reported no activity at all. Moderate to vigorous activity at age 40 was not associated with PD risk.
An important concern in interpreting the results of the present study is the possibility of a spurious inverse association between physical activity and PD risk due to an effect of early, pre-symptomatic PD on physical activity (reverse causation). In our study, the RR estimates were consistent over time and did not materially change after excluding the first four years of follow-up, providing some evidence against reverse causation, but a longer period of follow-up would help further address this possibility. Also, confounding by unmeasured factors cannot be excluded. These include personality traits such as introversion or low sensation seeking, which may predict less physical activity and increased risk of PD,12, 13
although these associations tend to be weak and seem unlikely to fully explain the results of this as well as previous investigations.
Previously, the protective potential of physical activity against PD risk was investigated in three prospective cohort studies, two restricted to men and one including both genders. In a nested case-control study within the College Alumni Health Study (men), based on 117 cases identified through questionnaires, of which 70% were physician-confirmed, and 20 cases identified through death certificates with no further confirmation, increased walking distance, participation in sports, and total energy expenditure were non-significantly associated with a lower PD incidence or mortality.3
A similar non-significant reduction in self-reported PD risk or mortality with increasing physical activity was found in a recent follow-up of a subset of participants in the same cohort.2
The third study was based on 387 physician-confirmed or medical record-confirmed cases from the combined HPFS (men) and NHS (women) cohorts, and was similar to the present study in measurement of physical activity and confirmation of PD cases.1
Among men in the HPFS, vigorous physical activity at baseline was inversely associated with PD risk, and so was strenuous physical activity in high school, in college, and at ages 30–40. Our results for baseline physical activity in men were similar to those in the HPFS, but we did not see an inverse association between physical activity at age 40 and PD risk in the present study. Women in the NHS had no decreased risk of PD regardless of their physical activity levels, except a nonsignificantly decreased risk associated with high levels of strenuous physical activity in early adulthood. The reasons for the gender difference observed between the men in the HPFS and the women in the NHS were not clear. Although a formal synthesis of the results of all the studies is difficult because of differences in methods, the epidemiological studies taken together provide reasonably consistent support for the hypothesis that physical activity is associated with modestly decreased PD risk among men, and possibly among women.
Our study has notable strengths, including prospective data collection, inclusion of both men and women, a large number of confirmed incident PD cases, and thorough data about variables that might have confounded the association between physical activity and PD. Our study also has some limitations. First, physical activity was measured solely by self-report, through a limited number of survey questions, and some level of misclassification was thus inevitable. Because of the longitudinal design of the study, this misclassification was most likely non-differential with respect to disease risk and thus likely attenuated the true relative risks. Physical activity has previously been shown to be inversely related to breast cancer and colon cancer in this cohort, indirectly supporting the validity of the exposure measurement.8, 9
Second, we may have had some diagnostic error by relying on neurological medical records and reports from treating physicians rather than in-person examinations of study participants. However, the clinical diagnosis of PD by neurologists10
and especially by movement disorders specialists11
has been found to be accurate, so bias from misdiagnosis is likely to be modest.
A causal link between physical activity and PD risk is supported by some experimental data, though the potential mechanisms have not been fully elucidated. Experiments in rodent models of PD have shown sparing of neurochemical and behavioral deficits through forced use of the contralateral (impaired) forelimb for seven days prior to administration of the neurotoxin 6-hydroxydopamine.14
These animals not only had attenuation of striatal dopamine loss, but also an exercise-induced increase in striatal glial cell-line derived neurotrophic factor (GDNF), suggesting that GDNF or another neural growth factor was involved in neuroprotection. Another plausible mechanism is provided by the effects of physical activity on plasma urate, an endogenous antioxidant which may be related to PD risk.15
Experimental studies in healthy men have shown that exercise increases plasma urate levels.16
High plasma urate is associated with reduced PD risk in well-designed prospective epidemiological cohorts,17, 18, 19
and predicts slower clinical progression in PD patients.20, 21
Whether physical activity influences PD risk through increasing plasma urate, increasing neural growth factors, or through some other means remains to be determined.
In summary, the results of our study favor a role for physical activity in the prevention of PD, and other prospective epidemiological studies on this topic have been reasonably consistent. PD is likely to have a multifactorial etiology, whereby environmental and genetic susceptibility factors interact to create the conditions leading to the onset of the disease.22
Under such a paradigm, individual factors may have only modest associations with PD risk. Recreational physical activity may be such a factor. Improved physical activity measurement in large research studies, additional data for women, and elucidation of biochemical pathways will advance our understanding of the importance of physical activity for neuroprotection.