Parkinson's Disease, NOTCH3 Genetic Variants, and White Matter Hyperintensities

Joel Ramirez¹, Allison A Dilliott^{2

3}, Malcolm A Binns⁴, David P Breen^{5

6

7}, Emily C Evans⁸, Derek Beaton⁴, Paula M McLaughlin^{9

10}, Donna Kwan⁹, Melissa F Holmes¹, Miracle Ozzoude¹, Christopher J M Scott¹, Stephen C Strother⁴, Sean Symons¹¹, Richard H Swartz^{1

12}, David Grimes¹³, Mandar Jog¹⁴, Mario Masellis^{1

12}, Sandra E Black^{1

12}, Anne Joutel¹⁵, Connie Marras¹⁶, Ekaterina Rogaeva¹⁷, Robert A Hegele^{2

3}, Anthony E Lang¹⁶; Ontario Neurodegenerative Disease Research Initiative Investigators

Affiliations

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.

PMID: 32573853
DOI: 10.1002/mds.28171

Parkinson's Disease, NOTCH3 Genetic Variants, and White Matter Hyperintensities

Joel Ramirez et al. Mov Disord. 2020 Nov.

. 2020 Nov;35(11):2090-2095.

doi: 10.1002/mds.28171. Epub 2020 Jun 23.

Authors

Affiliations

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.

PMID: 32573853
DOI: 10.1002/mds.28171

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. © 2020 International Parkinson and Movement Disorder Society.

Keywords: NOTCH3; CADASIL; ONDRI; Parkinson's disease; white matter hyperintensities.

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References

1. Wardlaw JM, Smith EE, Biessels GJ, et al. Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol 2013;12:822-838.
1. Bohnen NI, Albin RL. White matter lesions in Parkinson disease. NatRevNeurol 2011;7:229-236.
1. Foo H, Mak E, Yong TT, et al. Progression of small vessel disease correlates with cortical thinning in Parkinson's disease. Parkinsonism Relat Disord 2016;31:34-40.
1. Dunet V, Fartaria MJ, Deverdun J, et al. Episodic memory decline in Parkinson’ s disease: relation with white matter hyperintense lesions and influence of quantification method. Brain Imaging Behav 2019;13:810-818.
1. Toda K, Iijima M, Kitagawa K. Periventricular white matter lesions influence gait functions in Parkinson's disease. Eur Neurol 2019;81:120-127.

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Parkinson's Disease, NOTCH3 Genetic Variants, and White Matter Hyperintensities

Affiliations

Parkinson's Disease, NOTCH3 Genetic Variants, and White Matter Hyperintensities

Authors

Affiliations

Abstract

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous