Clinical and Biological Determinants of Longitudinal Cognitive Function in Patients With GBA1 Variants and Subthalamic Deep Brain Stimulation.

Abstract

Whether cognitive decline in patients with Parkinson's disease (PD) carrying GBA1 variants is accelerated after subthalamic deep brain stimulation (STN-DBS) remains controversial. Clarifying long-term cognitive outcomes is essential for informed decision making. We assembled matched cohorts of patients carrying GBA1 variants with STN-DBS (PD_GBA1+DBS+, n = 28) and without (PD_{G BA1+DBS-}, n = 28). Additional cohorts included non-carriers with STN-DBS (PD_GBA1-DBS+, n = 40) and without (PD_GBA1-DBS-, n = 43). Clinical, genetic, and cerebrospinal fluid (CSF) biomarkers (Aβ1-42, h-Tau, p181-Tau, and neurofilament light chain) were analyzed. Cognition was assessed using the Montreal Cognitive Assessment (MoCA). Cognitive slopes were estimated using linear mixed models and the minimally detectable slope difference at 3-year follow-up was 1.33 MoCA points enabling sensitivity to clinically meaningful changes. Secondarily, conversion to dementia was analyzed with Kaplan-Meier-analysis once the MoCA was < 21. There was no significant difference in cognitive decline between PD_GBA1+DBS+ and PD_GBA1+DBS- (-0.24 MoCA points/year; 95% confidence interval [CI] = -1.11 to 0.70) projecting to -0.72 MoCA points at 3-year-follow-up (p = 0.583). Secondarily, the risk for conversion to dementia did not differ between PD_GBA1+DBS+ and PD_GBA1+DBS- (HR = 0.55, 95% CI = 0.23-1.34, p = 0.119) or between PD_GBA1-DBS+ and PD_GBA1-DBS- (HR = 1.22, 95% CI = 0.53-2.83, p = 0.897). Dementia risk was associated with GBA1 status (HR = 3.04, 95% CI = 1.05-8.79, p = 0.041), baseline MoCA < 26 (HR = 3.05, 95% CI = 1.29-7.21, p = 0.011), and baseline age > 69 years (HR = 4.42, 95% CI = 1.79-10.89, p = 0.001). In GBA1 carriers, a visuospatial/executive domain score < 4/5 predicted dementia (HR = 4.71, 95% CI = 1.25-17.86, p = 0.022). GBA1 variant carriers meeting general STN-DBS indication criteria did not show accelerated cognitive decline in the presence of STN-DBS. In addition, exploratory predictors of dementia could support counseling of DBS candidates. ANN NEUROL 2026;99:976-988.