Joel Ramirez1, Allison A Dilliott2,3, Malcolm A Binns4, David P Breen5,6,7, Emily C Evans8, Derek Beaton4, Paula M McLaughlin9,10, Donna Kwan9, Melissa F Holmes1, Miracle Ozzoude1, Christopher J M Scott1, Stephen C Strother4, Sean Symons11, Richard H Swartz1,12, David Grimes13, Mandar Jog14, Mario Masellis1,12, Sandra E Black1,12, Anne Joutel15, Connie Marras16, Ekaterina Rogaeva17, Robert A Hegele2,3, Anthony E Lang16. 1. Hurvitz Brain Sciences Program, Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, Canada. 2. Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada. 3. Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada. 4. Rotman Research Institute, Baycrest, Toronto, Ontario, Canada. 5. Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom. 6. Anne Rowling Regenerative Neurology Clinic, University of Edinburgh, Edinburgh, United Kingdom. 7. Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, United Kingdom. 8. Mississauga Academy of Medicine, University of Toronto Mississauga, Mississauga, Ontario, Canada. 9. Queen's University, Centre for Neuroscience Studies, Kingston, Ontario. 10. Nova Scotia Health Authority, Dalhousie University, Department of Medicine-Geriatrics, Halifax, Nova Scotia, Canada. 11. Department of Medical Imaging, University of Toronto, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada. 12. Department of Medicine (Neurology), Sunnybrook Health Sciences Centre and University of Toronto, Ontario, Canada. 13. University of Ottawa Brain and Mind Research Institute, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada. 14. Department of Clinical Neurological Sciences, Western University, London, Canada. 15. Institute of Psychiatry and Neuroscience of Paris- Institut national de la santé et de la recherche médicale (INSERM), Paris Descartes University, Paris, France. 16. Edmond J. Safra Program in Parkinson's Disease and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, Toronto, Ontario, Canada. 17. Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Ontario, Canada.
Abstract
BACKGROUND: White matter hyperintensities (WMH) on magnetic resonance imaging may influence clinical presentation in patients with Parkinson's disease (PD), although their significance and pathophysiological origins remain unresolved. Studies examining WMH have identified pathogenic variants in NOTCH3 as an underlying cause of inherited forms of cerebral small vessel disease. METHODS: We examined NOTCH3 variants, WMH volumes, and clinical correlates in 139 PD patients in the Ontario Neurodegenerative Disease Research Initiative cohort. RESULTS: We identified 13 PD patients (~9%) with rare (<1% of general population), nonsynonymous NOTCH3 variants. Bayesian linear modeling demonstrated a doubling of WMH between variant negative and positive patients (3.1 vs. 6.9 mL), with large effect sizes for periventricular WMH (d = 0.8) and lacunes (d = 1.2). Negative correlations were observed between WMH and global cognition (r = -0.2). CONCLUSION: The NOTCH3 rare variants in PD may significantly contribute to increased WMH burden, which in turn may negatively influence cognition.
BACKGROUND: White matter hyperintensities (WMH) on magnetic resonance imaging may influence clinical presentation in patients with Parkinson's disease (PD), although their significance and pathophysiological origins remain unresolved. Studies examining WMH have identified pathogenic variants in NOTCH3 as an underlying cause of inherited forms of cerebral small vessel disease. METHODS: We examined NOTCH3 variants, WMH volumes, and clinical correlates in 139 PD patients in the Ontario Neurodegenerative Disease Research Initiative cohort. RESULTS: We identified 13 PD patients (~9%) with rare (<1% of general population), nonsynonymous NOTCH3 variants. Bayesian linear modeling demonstrated a doubling of WMH between variant negative and positive patients (3.1 vs. 6.9 mL), with large effect sizes for periventricular WMH (d = 0.8) and lacunes (d = 1.2). Negative correlations were observed between WMH and global cognition (r = -0.2). CONCLUSION: The NOTCH3 rare variants in PD may significantly contribute to increased WMH burden, which in turn may negatively influence cognition.