Rare neurovascular genetic and imaging markers across neurodegenerative diseases

Allison A Dilliott; Stephanie A Berberian; Kelly M Sunderland; Malcolm A Binns; Julia Zimmer; Miracle Ozzoude; Christopher J M Scott; Fuqiang Gao; Anthony E Lang; David P Breen; Maria C Tartaglia; Brian Tan; Richard H Swartz; Ekaterina Rogaeva; Michael Borrie; Elizabeth Finger; Corinne E Fischer; Andrew Frank; Morris Freedman; Sanjeev Kumar; Stephen Pasternak; Bruce G Pollock; Tarek K Rajji; David F Tang-Wai; Agessandro Abrahao; John Turnbull; Lorne Zinman; Leanne Casaubon; Dar Dowlatshahi; Ayman Hassan; Jennifer Mandzia; Demetrios Sahlas; Gustavo Saposnik; David Grimes; Connie Marras; Thomas Steeves; Mario Masellis; Sali M K Farhan; Robert Bartha; Sean Symons; Robert A Hegele; Sandra E Black; Joel Ramirez; ONDRI Investigators

doi:10.1002/alz.13316

Rare neurovascular genetic and imaging markers across neurodegenerative diseases

Alzheimers Dement. 2023 Dec;19(12):5583-5595. doi: 10.1002/alz.13316. Epub 2023 Jun 5.

Authors

Allison A Dilliott¹, Stephanie A Berberian², Kelly M Sunderland³, Malcolm A Binns^{3

4}, Julia Zimmer¹, Miracle Ozzoude^{2

5}, Christopher J M Scott², Fuqiang Gao², Anthony E Lang⁶, David P Breen⁷, Maria C Tartaglia^{6

8}, Brian Tan³, Richard H Swartz^{2

9

10}, Ekaterina Rogaeva⁵, Michael Borrie^{11

12}, Elizabeth Finger¹¹, Corinne E Fischer¹³, Andrew Frank^{14

15}, Morris Freedman^{3

16}, Sanjeev Kumar^{17

18}, Stephen Pasternak¹⁹, Bruce G Pollock^{17

18}, Tarek K Rajji^{17

18

20}, David F Tang-Wai⁹, Agessandro Abrahao⁹, John Turnbull²¹, Lorne Zinman⁹, Leanne Casaubon⁹, Dar Dowlatshahi¹⁴, Ayman Hassan²², Jennifer Mandzia¹¹, Demetrios Sahlas²¹, Gustavo Saposnik^{23

24}, David Grimes¹⁴, Connie Marras⁶, Thomas Steeves²⁴, Mario Masellis^{2

9}, Sali M K Farhan¹, Robert Bartha¹⁹, Sean Symons²⁵, Robert A Hegele¹⁹, Sandra E Black^{2

3

9

10}, Joel Ramirez²; ONDRI Investigators

Affiliations

¹ Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montréal, Quebec, Canada.
² Dr. Sandra Black Centre for Brain Resilience and Recovery, LC Campbell Cognitive Neurology, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, Canada.
³ Rotman Research Institute, Baycrest Health Sciences, Toronto, Ontario, Canada.
⁴ Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
⁵ Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada.
⁶ Edmond J. Safra Program in Parkinson's Disease and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, Toronto, Ontario, Canada.
⁷ Centre for Clinical Brain Sciences, University of Edinburgh; Anne Rowling Regenerative Neurology Clinic, University of Edinburgh; Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.
⁸ Division of Neurology, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada.
⁹ Department of Medicine (Neurology), Sunnybrook Health Sciences and University of Toronto, Ontario, Canada.
¹⁰ Heart and Stroke Foundation Canadian Partnership for Stroke Recovery, Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, Toronto, Ontario, Canada.
¹¹ Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
¹² St. Joseph's Healthcare Centre, London, Ontario, Canada.
¹³ Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.
¹⁴ Department of Medicine (Neurology), University of Ottawa Brain and Mind Research Institute and Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
¹⁵ Bruyère Research Institute, Ottawa, Ontario, Canada.
¹⁶ Department of Medicine (Neurology), Baycrest Health Sciences, Mt. Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
¹⁷ Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
¹⁸ Adult Neurodevelopment and Geriatric Psychiatry, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
¹⁹ Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
²⁰ Toronto Dementia Research Alliance, University of Toronto, Toronto, Ontario, Canada.
²¹ Division of Neurology, Department of Medicine, Hamilton Health Sciences, McMaster University, Hamilton, Canada.
²² Thunder Bay Regional Health Research Institute, Thunder Bay, Ontario, Canada.
²³ Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.
²⁴ Division of Neurology, Department of Medicine, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.
²⁵ Department of Medical Imaging, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada.

PMID: 37272523
DOI: 10.1002/alz.13316

Abstract

Introduction: Cerebral small vessel disease (SVD) is common in patients with cognitive impairment and neurodegenerative diseases such as Alzheimer's and Parkinson's. This study investigated the burden of magnetic resonance imaging (MRI)-based markers of SVD in patients with neurodegenerative diseases as a function of rare genetic variant carrier status.

Methods: The Ontario Neurodegenerative Disease Research Initiative study included 520 participants, recruited from 14 tertiary care centers, diagnosed with various neurodegenerative diseases and determined the carrier status of rare non-synonymous variants in five genes (ABCC6, COL4A1/COL4A2, NOTCH3/HTRA1).

Results: NOTCH3/HTRA1 were found to significantly influence SVD neuroimaging outcomes; however, the mechanisms by which these variants contribute to disease progression or worsen clinical correlates are not yet understood.

Discussion: Further studies are needed to develop genetic and imaging neurovascular markers to enhance our understanding of their potential contribution to neurodegenerative diseases.

Keywords: HTRA1; NOTCH3; ONDRI; WMH; neurodegeneration; small vessel disease.

MeSH terms

Cerebral Small Vessel Diseases* / pathology
Cognitive Dysfunction*
Humans
Magnetic Resonance Imaging
Neurodegenerative Diseases* / diagnostic imaging
Neurodegenerative Diseases* / genetics