Unraveling the role of GBA1 genotype in axial signs response to subthalamic deep brain stimulation

Abstract

GBA1 variants represent the most common genetic risk factor for Parkinson's disease (PD) and are associated with higher risk of developing cognitive decline and axial motor impairment. While cognitive outcomes following subthalamic deep brain stimulation (STN-DBS) have recently received growing attention, axial signs progression remains poorly defined in this population. In this retrospective multicentric study, we analyzed a cohort of 353 PD patients who underwent bilateral STN-DBS surgery (75 GBA+ and 253 GBA-). 5-year follow-up data were available for 233 patients, including 43 mutated subjects. Lower off-medication UPDRS III score and levodopa responsiveness at baseline were identified as independent predictors of axial signs worsening after DBS, while GBA1 genotype was not identified as risk factor. The presence of GBA1 variants did not exert a detrimental effect on axial signs in PD patients up to five years following STN-DBS, supporting its consideration as a valid therapeutic option in this genetic subgroup.

Fig. 1. Outcome of the UPDRS III axial subscore after STN-DBS.

UPDRS III axial subscore before (T0) and after surgery (T1 = 1 year, T3 = 3 years, T5 = 5 years) in on-medication (A) and off-medication condition (B) in the two groups of PD patients carriers (GBA+ versus GBA−). * p < 0.05.

Fig. 2. Axial worsening-free survival curves.

Kaplan-Meier curves of axial worsening-free survival (reported with 95% upper and lower confidence interval) of GBA+ and GBA− in on-medication (A) and off-medication conditions (B). The “axial worsening-free survival” reflects axial impairment progression intended as the achievement of a ≥ 2-point higher UPDRS III axial subscore during the follow-up compared to the baseline score. Cross marks indicate censored data.