Hikaru Kamo, Genko Oyama, Mai Shimizu, Haruka Takeshige‐Amano, Takashi Ogawa, Wataru Sako, Noriko Nishikawa, Taku Hatano, Yuanzhe Li, Hiroyo Yoshino, Manabu Funayama, Masanobu Ito, Hirokazu Iwamuro, Atsushi Umemura, Nobutaka Hattori
BACKGROUND: Deep brain stimulation (DBS) is effective for Parkinson's disease (PD); however, its efficacy varies with genetic background, such as the GBA1 variant-the causative gene of Gaucher disease-associated with increased PD risk and cognitive decline after subthalamic nucleus (STN)-DBS. OBJECTIVES: The aim of the study was to examine the relationship between outcomes after STN-DBS and GBA1 variants in PD patients undergoing bilateral STN-DBS. METHODS: Patients were retrospectively analyzed over 5 years, with clinical and genetic assessments, including GBA1 variant status performed at baseline and at 1-, 3-, and 5-years post-DBS. Longitudinal changes in motor, cognitive, and medication outcomes were evaluated using propensity score matching and linear mixed-effects models. RESULTS: A total of 371 PD patients undergoing bilateral STN-DBS were analyzed, including 54 GBA1 variant carriers and 253 noncarriers, after excluding other genetic variants. Propensity score matching yielded 2 groups with balanced baseline characteristics, with 50 patients each. Over time, no significant differences were observed in motor, cognitive, or neuropsychiatric assessments between groups. GBA1 carriers exhibited worsened medication OFF-DBS off state motor symptoms at 5 years postoperatively, whereas cognitive function, assessed by the Mini-Mental State Examination, remained stable in both groups. Levodopa-equivalent daily dose (LEDD) significantly decreased in both groups. Linear mixed-effects models showed progressive motor and cognitive decline and reduced medication use over 5 years, with no significant impact on GBA1 variant status. CONCLUSIONS: Findings from Japan's largest genetic cohort suggest that GBA1 variants may not significantly affect postoperative motor or cognitive trajectories following STN-DBS. Further validation through large-scale multinational and multicenter studies is warranted.