Timing of Deep Brain Stimulation and Cognitive Trajectories in GBA1-Associated Parkinson's Disease.
Abstract
Background
Individuals with Parkinson's disease (PD) carrying GBA1 variants often develop advanced motor complications that prompt evaluation for deep brain stimulation (DBS). However, concerns about accelerated cognitive decline after DBS in GBA1 carriers complicate clinical decision making. A critical aspect that is increasingly gaining attention is the time at which DBS is performed.
Objective
The objective is to determine how the timing of DBS in relation to PD onset impacts cognitive trajectories across different GBA1 variant classes and in individuals without GBA1 variants.
Methods
A multicenter cohort study across 10 study sites in Europe and the USA was conducted. The study population comprised subjects with (GBA1-Associated Parkinson's Disease [GBA-PD]) and without GBA1 variants (nonGBA-PD), who were subjected to bilateral subthalamic nucleus (STN)-DBS. The main outcome measure was the Mattis Dementia Rating Scale (MDRS).
Results
A total of 343 individuals (91 GBA-PD and 252 nonGBA-PD) were included in this study. Percentile-based stratification into early and late STN-DBS treatment groups and linear mixed model analyses revealed that GBA-PD patients in the late DBS group had a significantly faster rate of cognitive decline independent of age, with sensitivity analyses identifying the 7- and 8-year cutoffs as the time points with a significant difference between early and late STN-DBS groups in GBA-PD. A negative correlation between MDRS scores and time from disease onset to STN-DBS was observed in GBA-PD, and was not present in nonGBA-PD. Cognitive trajectories were markedly worse in GBA-PD compared to nonGBA-PD, and this pattern was not influenced by the variant type.
Conclusions
In GBA-PD, STN-DBS treatment at later stages is associated with greater risk of cognitive decline. Earlier STN-DBS intervention in GBA-PD may extend the period of improved motor function before the onset of significant cognitive decline. These findings highlight the potential importance of early genetic testing and disease duration when considering STN-DBS in genetically defined PD populations. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.