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

Ann Neurol · 2026-01-16

DOI: 10.1002/ana.78139PMID: 41542740

Open accessresearch-article; Journal ArticleOriginal source ↗

Research overview

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ObjectiveWhether 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.MethodsWe assembled matched cohorts of patients carrying GBA1 variants with STN-DBS (PDGBA1+DBS+, n = 28) and without (PDG BA1+DBS-, n = 28). Additional cohorts included non-carriers with STN-DBS (PDGBA1-DBS+, n = 40) and without (PDGBA1-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 ResultsThere was no significant difference in cognitive decline between PDGBA1+DBS+ and PDGBA1+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 PDGBA1+DBS+ and PDGBA1+DBS- (HR = 0.55, 95% CI = 0.23-1.34, p = 0.119) or between PDGBA1-DBS+ and PDGBA1-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  69 years (HR = 4.42, 95% CI = 1.79-10.89, p = 0.001). In GBA1 carriers, a visuospatial/executive domain score InterpretationGBA1 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.

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