Objective: To study the interaction between GBA1 mutations, sex and other clinical factors in shaping depression outcomes in Parkinson’s Disease.

Background: Depression affects 35% of Parkinson’s disease (PD) patients and is closely linked to both motor and non-motor symptoms, making it one of the most significant predictors of reduced quality of life. Neuropsychiatric symptoms are common in PD carriers of GBA1 mutations (GBA-PD) although the impact of other clinical features and sex in predicting their severity remains unclear.

Method: This is a multicenter study involving 4 Italian centers. A cross-sectional analysis was conducted in 78 GBA-PD and 156 nonGBA-PD patients matched in a 1:2 ratio based on age, disease duration and cognitive profile (MoCA scores). Depressive features were explored using BDI-II scores and compared between PD groups and stratified by sex. A multivariate regression model was performed to identify predictors of depressive symptoms. Moreover, a longitudinal analysis on 57 GBA-PD and 83 nonGBA-PD patients with BDI-II scores available at 3-year follow-up was performed using a linear mixed-effects model.

Results: GBA-PD had worse BDI-II scores, with 3-times higher odds of clinically significant depression (BDI≥14) compared to nonGBA-PD. Assessing sex/genotype combined effect, depressive symptoms were significantly less prevalent in nonGBA-PD males compared to all other groups. In GBA-PD, only RBDSQ predicted depressive symptoms, whereas sex, UPDRS-IV, and MoCA emerged as predictors in nonGBA-PD. Longitudinally, GBA-PD patients showed faster progression of depressive symptoms than nonGBA-PD and these were more severe in those with clinically RBD at baseline, regardless of sex. Contrarily, sex had an impact on BDI-II scores overtime in nonGBA-PD, with females showing significantly higher scores than males.

Conclusion: GBA mutations are associated with a distinct pattern of depressive symptoms in PD, characterized by a stronger link with RBD and a faster progression of severity over time, regardless of sex differences.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/interplay-of-gba1-mutations-and-sex-on-determining-depressive-symptoms-in-parkinsons-disease/