Parkinson Disease and Subthalamic Nucleus Deep Brain Stimulation: Cognitive Effects in GBA Mutation Carriers

Abstract

Objective This study was undertaken to compare the rate of change in cognition between glucocerebrosidase (GBA) mutation carriers and noncarriers with and without subthalamic nucleus deep brain stimulation (STN‐DBS) in Parkinson disease. Methods Clinical and genetic data from 12 datasets were examined. Global cognition was assessed using the Mattis Dementia Rating Scale (MDRS). Subjects were examined for mutations in GBA and categorized as GBA carriers with or without DBS (GBA+DBS+, GBA+DBS‐), and noncarriers with or without DBS (GBA‐DBS+, GBA‐DBS‐). GBA mutation carriers were subcategorized according to mutation severity (risk variant, mild, severe). Linear mixed modeling was used to compare rate of change in MDRS scores over time among the groups according to GBA and DBS status and then according to GBA severity and DBS status. Results Data were available for 366 subjects (58 GBA+DBS+, 82 GBA+DBS‐, 98 GBA‐DBS+, and 128 GBA‐DBS‐ subjects), who were longitudinally followed (range = 36–60 months after surgery). Using the MDRS, GBA+DBS+ subjects declined on average 2.02 points/yr more than GBA‐DBS‐ subjects (95% confidence interval [CI] = −2.35 to −1.69), 1.71 points/yr more than GBA+DBS‐ subjects (95% CI = −2.14 to −1.28), and 1.49 points/yr more than GBA‐DBS+ subjects (95% CI = −1.80 to −1.18). Interpretation Although not randomized, this composite analysis suggests that the combined effects of GBA mutations and STN‐DBS negatively impact cognition. We advise that DBS candidates be screened for GBA mutations as part of the presurgical decision‐making process. We advise that GBA mutation carriers be counseled regarding potential risks associated with STN‐DBS so that alternative options may be considered. ANN NEUROL 2022;91:424–435

Monogenic Parkinson’s Disease: Genotype, Phenotype, Pathophysiology, and Genetic Testing

“…Additionally, a recent study found that the rate of cognitive decline for GBA mutation carriers after bilateral subthalamic nucleus deep brain stimulation (STN-DBS) is higher than that of carriers of PRKN and LRRK2 mutations and those without identified disease-associated pathogenic variants [ 136 ] ( Figure 1 A). These findings were further corroborated by a new study which suggests that STN-DBS is associated with a greater rate of cognitive decline in GBA mutation carriers [ 137 ]. A recommendation that arose from this study is that PD patients should be screened for GBA pathogenic variants prior to DBS surgery, and that carriers of such variants should be counseled on the greater risk of cognitive decline [ 137 ].…”

“…These findings were further corroborated by a new study which suggests that STN-DBS is associated with a greater rate of cognitive decline in GBA mutation carriers [ 137 ]. A recommendation that arose from this study is that PD patients should be screened for GBA pathogenic variants prior to DBS surgery, and that carriers of such variants should be counseled on the greater risk of cognitive decline [ 137 ].…”

The Role of Genetic Data in Selecting Device-Aided Therapies in Patients With Advanced Parkinson’s Disease: A Mini-Review

“…However, post-operative cognitive impairment was found to be more common and severe in this group of patients (Lythe et al, 2017;Artusi et al, 2019;Mangone et al, 2020). Pal et al (2022) revealed that the combined effects of GBA mutation and STN DBS may increase the risk of cognitive decline (Pal et al, 2022). Also, non-motor symptoms (with cardiovascular symptoms as an exception) were found to be more prevalent and severe after surgery (Lythe et al, 2017).…”

“…Besides, the quality of life worsened significantly in GBA mutation carriers after receiving DBS surgery, with greatest deterioration in domains such as mobility, activities of daily living, cognition, and communication (Lythe et al, 2017). Furthermore, it appeared that the severity of the type of GBA mutation was not linked to a difference in the rate of cognitive decline after operation (Pal et al, 2022).…”

How Does Deep Brain Stimulation Change the Course of Parkinson's Disease?

“…In contrast, glucocerobrosidase ( GBA ) gene variants have been associated to poorer DBS outcomes in terms of cognitive decline and non‐motor symptom burden, but not response of motor symptoms to DBS 85,86 . According to a recent multicenter observational study, cognition in STN‐DBS treated PD patients with GBA mutations deteriorates faster compared with GBA patients without DBS, suggesting that patients should be screened for GBA variants as part of the pre‐surgical work‐up and counseled accordingly 87 . Beyond this latter study, however, there are no studies assessing patients with specific PD subtypes or genetic mutations treated with DBS and comparing their outcome to the patient groups with the same phenotype or genotype that are not treated by DBS.…”