Genotype-associated outcomes after deep brain stimulation in Parkinson's disease: a systematic review, meta-analysis and epigenetic implications.

Abstract

Introduction: Deep brain stimulation (DBS) is an established treatment for advanced Parkinson's disease (PD), but outcomes in genotype-defined PD remain debated. GBA1 variants are associated with faster cognitive decline, while their impact on DBS motor benefit is less clear.

State of the art: To assess whether DBS motor response differs by genotype in PD by pooling change in Unified Parkinson's Disease Rating Scale III (UPDRS III) (medication-OFF) from baseline to the first postoperative follow-up (T1, ~12 months). Secondary objectives were to summarise cognitive and quality-of-life outcomes after DBS across genotypes using structured narrative synthesis and to determine whether any clinical evidence links epigenetic biomarkers to DBS outcomes.

Material and methods: PubMed and Embase were searched (1 January 2000 to 3 November 2025). Eligible studies reported pos toperative outcomes stratified by GBA1, LRRK2 or PRKN carrier status in DBS-treated PD (any target). The primary endpoint was change in UPDRS III in the medication-OFF state from baseline to T1. A random-effects meta-analysis pooled genotype- -defined comparisons of variant carriers vs. non-carriers; because evidence was dominated by GBA1 cohorts, LRRK2/PRKN findings were summarised descriptively. A scoping search was performed for clinical epigenetic biomarker studies in DBS-treated PD.

Results: Eleven studies were included. Quantitative synthesis of five datasets (UPDRS III medication-OFF) showed no significant difference in motor improvement between variant carriers and non-carriers [standardised mean difference (SMD) = -0.124, 95% confidence interval (CI): -0.331 to 0.083; I2 = 22.3%). Similar non-significant results were observed for the medication-ON state. Cognitive and quality-of-life outcomes could not be pooled due to heterogeneous reporting; narrative synthesis suggested earlier cognitive decline in GBA1 carriers vs. non-carriers despite comparable short-term motor benefit. No clinical studies linking epigenetic biomarkers to DBS outcomes were identified.

Conclusions: At approximately 12 months, motor improvement after DBS appears broadly comparable between genotype- -defined variant carriers and non-carriers, with the most consistent evidence available for GBA1. Inference - particularly for cognition and quality of life - is constrained by gene/variant heterogeneity, observational study design, and the predominance of subthalamic nucleus-DBS (STN-DBS) cohorts. Clinical epigenetic predictors of DBS response remain unstudied, supporting the need for hypothesis-driven, genotype-stratified biomarker cohorts.