Long-term motor and cognitive outcome of Deep Brain Stimulation in GBA-PD: the Italian PARKNET study

Abstract Deep brain stimulation (DBS) is an established therapeutic option for Parkinson Disease (PD), with demonstrated efficacy on motor symptoms also in patients carrying GBA1 variants (GBA-PD). However, it was recently suggested that DBS may accelerate cognitive decline in this frequent genetic subgroup, raising major concerns on its indication. Primary aim of this study was to investigate the possible additive effects of GBA1 genotype and DBS implant on cognitive deterioration and other non-motor features in the long term. As secondary aims, we assessed the clinical outcomes of DBS-GBA-PD stratified by GBA1 variant classes (severe/complex, mild, risk, unknown), and by different DBS targets (subthalamic nucleus or globus pallidus). This is a multicenter retrospective, controlled, Italian cohort study involving 15 tertiary level Movement Disorder Centers contributing to the PARKNET cohort. Demographic, motor, cognitive and other non-motor features were collected at baseline after 1, 3 and 5 years, between years 2005 and 2021. We selected 615 PD participants who either underwent DBS surgery (430 DBS-nonGBA-PD and 109 DBS-GBA-PD) or fulfilled the same criteria for DBS eligibility but eventually were not operated (76 nonDBS-GBA-PD). Assessments included motor, cognitive and other non-motor features, as well as long-term complications, across all groups and time points. Within-group longitudinal outcome changes, between-group differences, and subgroups analyses stratified by GBA1 variant classes and DBS targets were performed. At baseline, the three cohorts were largely matched for demographic, motor, cognitive and other non-motor features. Longitudinally, both DBS groups showed marked improvements of motor symptoms and quality of life, a benefit which was absent in nonDBS-GBA-PD. Cognitive deterioration, as well as hallucinations and urinary problems, significantly increased in both GBA-PD groups compared to nonGBA-PD, regardless of DBS. No relevant differences in the clinical outcomes emerged upon stratification of GBA-PD for variant classes or for DBS targets, up to 3 years after surgery. DBS represents a valid therapeutic option for GBA-PD, as it generates prolonged benefits on motor symptoms and quality of life while not modifying the occurrence of cognitive deterioration and other non-motor features.