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Objectives: Identifying the contribution of biological sex to the heterogeneity in presentation and progression of Parkinson's disease (PD). Background: The different prevalence of Parkinson's disease (PD) in men and women suggests that sex-associated mechanisms influence disease mechanisms. Investigating the contribution of sex to disease heterogeneity may uncover disease processes, and lead to new therapeutic targets. Also, understanding these differences in phenotypes will result in better patient management and the planning of more efficient clinical trials. Methods: We tested 40 clinical phenotypes using longitudinal clinic-based patient cohorts consisting of 5,946 patients with a median follow-up of 3.1 years. For continuous outcomes, we used linear regressions at baseline to test the sex-associated differences in presentation, and linear mixed-effects models to test the sex-associated differences in progression. For binomial outcomes, we used logistic regression models at baseline and Cox models for survival analyses. We adjusted for age, disease duration and dopaminergic medication usage. In the secondary analyses, data from 28,809 PD patients and 10,556 non-PD participants from Fox Insight, an online-only self-assessment cohort for PD research, were analyzed to check whether the sex-associated differences observed in the primary analyses were consistent in the cohort and whether the differences were unique to PD or not. Results: Female PD patients had a higher risk for developing dyskinesia early during the follow-up period; with a slower progression in their difficulties of activities of daily living as measured by the Unified Parkinson's Disease Rating Scale Part II (classic/MDS-revised version); and a lower risk of developing cognitive impairment than male patients. The findings in the longitudinal clinic-based cohorts were mostly consistent with the results in the online-only cohort. Conclusions: This large-scale analysis observed the sex contribution to the heterogeneity of Parkinson's disease. The results highlight the necessity of future research of the underlying mechanism and importance of personalized clinical management.

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