Association of Physical Activity and Parkinson Disease in Women: Long-term Follow-up of the E3N Cohort Study

Abstract

Background and objectives: Previous cohort studies reported that a single measure of physical activity (PA) assessed at baseline was associated with lower Parkinson disease (PD) incidence, but a meta-analysis suggested that this association was restricted to men. Because of the long prodromal phase of the disease, reverse causation could not be excluded as a potential explanation. Our objective was to study the association between time-varying PA and PD in women using lagged analyses to address the potential for reverse causation and to compare PA trajectories in patients before diagnosis and matched controls.

Methods: We used data from the Etude Epidémiologique auprès de femmes de la Mutuelle Générale de l'Education Nationale (1990-2018), a cohort study of women affiliated with a national health insurance plan for persons working in education. PA was self-reported in 6 questionnaires over the follow-up. As questions changed across questionnaires, we created a time-varying latent PA (LPA) variable using latent process mixed models. PD was ascertained using a multistep validation process based on medical records or a validated algorithm based on drug claims. We set up a nested case-control study to examine differences in LPA trajectories using multivariable linear mixed models with a retrospective timescale. Cox proportional hazards models with age as the timescale and adjusted for confounders were used to estimate the association between time-varying LPA and PD incidence. Our main analysis used a 10-year lag to account for reverse causation; sensitivity analyses used 5-, 15-, and 20-year lags.

Results: Analyses of trajectories (1,196 cases and 23,879 controls) showed that LPA was significantly lower in cases than in controls throughout the follow-up, including 29 years before diagnosis; the difference between cases and controls started to increase ∼10 years before diagnosis (p interaction = 0.003). In our main survival analysis, of 95,354 women free of PD in 2000, 1,074 women developed PD over a mean follow-up of 17.2 years. PD incidence decreased with increasing LPA (p trend = 0.001), with 25% lower incidence in those in the highest quartile compared with the lowest (adjusted hazard ratio 0.75, 95% CI 0.63-0.89). Using longer lags yielded similar conclusions.

Discussion: Higher PA level is associated with lower PD incidence in women, not explained by reverse causation. These results are important for planning interventions for PD prevention.

Figure 1. Flowchart for Inclusion Into the Study Using 5-, 10-, 15-, and 20-Year Lags Between Physical Activity and PD Incidence in Survival Analyses

E3N = Etude Epidémiologique auprès de femmes de la Mutuelle Générale de l'Education Nationale; FU = follow-up; PD = Parkinson disease; Q = questionnaire.

Figure 2. Trajectories of Latent Physical Activity in Cases With PD and Matched Controls Up to 29 Years Before the Index Date

Figures A.a, B.a, and C.a show the trajectories (95% CI) of mean LPA in 1,196 PD cases and 23,879 matched controls based on a linear mixed model with a quadratic function of retrospective time; the model's coefficients are shown in eTable 5 (links.lww.com/WNL/C801). Figures A.b, B.b, and C.b show the differences (95% CI) between the mean trajectories of latent physical activity in PD cases and controls. Differences whose CI do not include 0 (horizontal dashed line) are statistically significant. We used a retrospective timescale, with T₀ (time = 0) representing the year of PD diagnosis in cases and the index date in controls. The model was adjusted for PD status, age at T₀, and 2-way interactions of time with PD status and age at T₀. It was further adjusted for baseline parity, place of residence, age at menarche, and time-varying smoking and menopausal status. Given the significant interaction between age at T₀ and time, trajectories were plotted for 3 different ages at T₀ (63, 73, and 83 years) and the most common profile of E3N participants (never smokers, age at menarche at 12–13 years, natural menopause, 2 children, and living in urban areas). E3N = Etude Epidémiologique auprès de femmes de la Mutuelle Générale de l'Education Nationale; LPA = latent physical activity; PD = Parkinson disease.

Figure 3. Cumulative Incidence Function of PD Over the Follow-up (2000–2018) According to LPA Assessed at Q1 (1990)

The cumulative incidence function of PD as a function of the quartiles of LPA assessed at Q1 (1990) is predicted by a Fine-Gray regression model for competing risks, with time since the beginning of the follow-up as the timescale and a 10-year lag (follow-up, 2000–2018). The model was adjusted for age (restricted cubic spline with 3 knots), parity, place of residence, age at menarche, smoking, and menopausal status (all assessed at the beginning of the follow-up). LPA = latent physical activity; PD = Parkinson disease.

Figure 4. HRs of PD in Relation to LPA (10-Year Lag)

HRs and 95% CIs calculated using Cox proportional hazards models for time-varying variables with age as the timescale and adjusted for baseline place of residence (rural/urban), age at menarche (≤11/12–13/≥14 years), parity (nulliparous/1 child/2 children/≥3 children), and time-varying smoking (never/ex/current) and menopausal status (premenopausal/natural menopause/artificial menopause/unknown type of menopause). The dots correspond to HRs for quartiles of LPA compared with the reference quartile (Table 2) together with their 95% CIs (vertical bars); HRs are plotted at the median of each quartile. The orange solid line represents the HR of PD for continuous LPA modeled as a linear variable, and the shaded area corresponds to the 95% CI. The HR of PD decreased linearly with an increasing level of LPA. The green solid line represents the HR of PD for continuous LPA modeled with restricted cubic splines, and the shaded area corresponds to 95% CI; 3 knots provided the best fit (lower AIC values). There was no significant departure from linearity (p = 0.25). AIC = Akaike information criterion; HR = hazard ratio; LPA = latent physical activity; PD = Parkinson disease.