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

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.