Abstract

Background: Sex differences in cognitive impairment in Parkinson’s disease (PD) have been reported, with several studies suggesting greater cognitive decline in males. However, evidence on long-term trajectories across specific cognitive domains is limited, as most prior work is cross-sectional. Aim: To investigate sex-specific longitudinal changes across multiple cognitive domains over 9 years in idiopathic PD, compared to age- and sex-matched controls. Methods: We analyzed data from the prospective ParkWest study, including n = 190 persons with PD (PwPs) and n = 202 controls. Regularly assessed cognitive domains included semantic fluency, processing speed, cognitive control, memory, and visuospatial ability. Linear mixed-effect models including a three-way interaction between time, disease status, and sex, to test whether sex-specific cognitive change in PD differed from that observed in controls, were estimated. Models were adjusted for age, years of education, baseline depression, and UPDRS part II. Results: Male PwPs showed faster decline than female PwPs in most cognitive measures, resulting in gradually increasing sex differences over 9 years. However, compared with controls, the differential sex-specific decline was statistically significant only for semantic fluency (p = 0.013) and processing speed (p = 0.027 and p = 0.035). These findings remained significant after covariate adjustment. Conclusions: PD was associated with increasing sex differences in semantic fluency and processing speed, likely driven by faster decline in males. Other domains did not show sex-specific divergence over time, suggesting that sex-specific vulnerabilities in cognitive trajectories are domain-specific rather than generalized among PwPs.

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