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. Competing Interest Statement MA, LA was supported by Ministry of University and Research (MUR), National Recovery 231 and Resilience Plan (NRRP), project MNESYS (PE0000006). Funding Statement This multicenter study was partly supported by the Italian Ministry of Health (Ricerca Corrente 2022-2024), Ricerca di Rete to the Italian Network for Neurosciences and Neurorehabilitation (RIN- RCR-2019-23669119_003 and RCR-2022-23 682 291) and National Recovery 231 and Resilience Plan (NRRP) project MAD-2022-12376496. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee of Full IRCCS Mondino, Pavia (IT) gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes