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Parkinson's Disease, NOTCH3 Genetic Variants, and White Matter Hyperintensities
Author(s) -
Ramirez Joel,
Dilliott Allison A.,
Binns Malcolm A.,
Breen David P.,
Evans Emily C.,
Beaton Derek,
McLaughlin Paula M.,
Kwan Donna,
Holmes Melissa F.,
Ozzoude Miracle,
Scott Christopher J.M.,
Strother Stephen C.,
Symons Sean,
Swartz Richard H.,
Grimes David,
Jog Mandar,
Masellis Mario,
Black Sandra E.,
Joutel Anne,
Marras Connie,
Rogaeva Ekaterina,
Hegele Robert A.,
Lang Anthony E.
Publication year - 2020
Publication title -
movement disorders
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.352
H-Index - 198
eISSN - 1531-8257
pISSN - 0885-3185
DOI - 10.1002/mds.28171
Subject(s) - hyperintensity , white matter , parkinson's disease , disease , medicine , magnetic resonance imaging , psychology , cohort , cognitive decline , population , neuroscience , cardiology , dementia , radiology , environmental health
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. © 2020 International Parkinson and Movement Disorder Society