Gian Pal1,2, Graziella Mangone3, Emily J Hill4, Bichun Ouyang2, Yuanqing Liu2, Vanessa Lythe5, Debra Ehrlich6, Rachel Saunders-Pullman7, Vicki Shanker7, Susan Bressman7, Roy N Alcalay8, Priscilla Garcia9, Karen S Marder8, Jan Aasly10, M Maral Mouradian1,11, Samantha Link2, Marc Rosenbaum2, Sharlet Anderson2, Bryan Bernard2, Robert Wilson2, Glenn Stebbins2, William C Nichols12, Marie-Laure Welter3,13, Sepehr Sani14, Mitra Afshari2, Leo Verhagen2, Rob M A de Bie15, Tom Foltynie5, Deborah Hall2, Jean-Christophe Corvol3, Christopher G Goetz2. 1. Department of Neurology, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ, USA. 2. Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA. 3. Sorbonne University, Public Hospital Network of Paris, Inserm, National Center for Scientific Research, Paris Brain Institute, Pitié-Salpêtrière Hospital, Department of Neurology, Center for Clinical Investigation Neurosciences, Paris, France. 4. Department of Neurology and Rehabilitation Medicine, University of Cincinnati, Cincinnati, OH, USA. 5. Department of Clinical and Movement Neurosciences, University College London Institute of Neurology, London, UK. 6. Parkinson's Disease Clinic, Office of the Clinical Director, National Institutes of Health/National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA. 7. Department of Neurology, Mount Sinai Beth Israel, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 8. Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA. 9. Department of Neurology, New York Medical College, Valhalla, NY, USA. 10. Department of Neurology, St Olavs Hospital and Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway. 11. Rutgers-Robert Wood Johnson Medical School Institute for Neurological Therapeutics, Biomedical and Health Sciences, Piscataway, NJ, USA. 12. Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. 13. Normandy University, Rouen University Hospital Center, Department of Neurophysiology, Rouen, France. 14. Department of Neurosurgery, Rush University Medical Center, Chicago, IL, USA. 15. Amsterdam University Medical Centers, University of Amsterdam, Department of Neurology, Amsterdam Neuroscience, Amsterdam, The Netherlands.
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.
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.
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