The protocol for an observational Australian cohort study of CADASIL: The AusCADASIL study

Danit G Saks; Beata Bajorek; Vibeke S Catts; Adam C Bentvelzen; Jiyang Jiang; Wei Wen; Karen A Mather; Anbupalam Thalamuthu; Jessie Huang-Lung; Lisa Nivison-Smith; Lyn R Griffiths; Robert A Smith; Adrienne Sexton; Paul James; Tharusha Jayasena; Anne Poljak; Gurpreet K Hansra; Satoshi Hosoki; Ashley Park; Claudia M Hillenbrand; Peter van Wijngaarden; Russell J Chander; Sam Humphrey; Rory Chen; Nicole A Kochan; Tessa J Helman; Christopher Levi; Amy Brodtmann; Michael J O'Sullivan; Romesh Markus; Ken Butcher; Mark Parsons; Jason C Kovacic; Perminder S Sachdev

doi:10.1016/j.cccb.2024.100225

The protocol for an observational Australian cohort study of CADASIL: The AusCADASIL study

Cereb Circ Cogn Behav. 2024 May 27:6:100225. doi: 10.1016/j.cccb.2024.100225. eCollection 2024.

Authors

Danit G Saks¹, Beata Bajorek^{2

3

4}, Vibeke S Catts¹, Adam C Bentvelzen¹, Jiyang Jiang¹, Wei Wen¹, Karen A Mather¹, Anbupalam Thalamuthu¹, Jessie Huang-Lung⁵, Lisa Nivison-Smith⁵, Lyn R Griffiths⁶, Robert A Smith⁶, Adrienne Sexton⁷, Paul James⁷, Tharusha Jayasena¹, Anne Poljak^{1

8}, Gurpreet K Hansra¹, Satoshi Hosoki¹, Ashley Park⁹, Claudia M Hillenbrand¹⁰, Peter van Wijngaarden^{11

12}, Russell J Chander¹, Sam Humphrey⁹, Rory Chen¹, Nicole A Kochan¹, Tessa J Helman¹, Christopher Levi^{13

14

15}, Amy Brodtmann⁹, Michael J O'Sullivan¹⁶, Romesh Markus¹⁷, Ken Butcher¹⁸, Mark Parsons¹⁹, Jason C Kovacic^{19

20

21}, Perminder S Sachdev^{1

22}

Affiliations

¹ Centre for Healthy Brain Ageing, Discipline of Psychiatry and Mental Health, School of Clinical Medicine, University of New South Wales, Sydney, 2052, Australia.
² Heart and Stroke Program, Hunter Medical Research Institute, Newcastle, 2305, Australia.
³ Pharmacy Department, John Hunter Hospital, Newcastle, 2305, Australia.
⁴ School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, 2308, Australia.
⁵ School of Optometry and Vision Science, University of New South Wales, Sydney, 2052, Australia.
⁶ Genomics Research Centre, Centre for Genomics and Personalised Health, Queensland University of Technology, Brisbane, 4059, Australia.
⁷ Genomic Medicine, Royal Melbourne Hospital, Melbourne, 3052, Australia.
⁸ Bioanalytical Mass Spectrometry Facility, University of New South Wales, Sydney, 2052, Australia.
⁹ Department of Neurology, Royal Melbourne Hospital, Melbourne, 3052, Australia.
¹⁰ Research Imaging NSW, University of New South Wales, Sydney, 2031, Australia.
¹¹ Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, 3002, Australia.
¹² Ophthalmology, Department of Surgery, University of Melbourne, Melbourne, 3052, Australia.
¹³ School of Medicine and Public Health, University of Newcastle, Newcastle, 2308, Australia.
¹⁴ John Hunter Health and Innovation Precinct (JHHIP), Newcastle, 2305, Australia.
¹⁵ Neurology Department, John Hunter Hospital, Newcastle, 2305, Australia.
¹⁶ Institute for Molecular Bioscience, University of Queensland, Brisbane, 4067, Australia.
¹⁷ Department of Neurology, St Vincent's Hospital, Sydney, 2010, Australia.
¹⁸ Department of Neurology, Prince of Wales Hospital, Sydney, 2031, Australia.
¹⁹ School of Clinical Medicine, University of New South Wales, Sydney, 2052, Australia.
²⁰ Victor Chang Cardiac Research Institute, Sydney, 2010, Australia.
²¹ Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
²² Neuropsychiatric Institute, Prince of Wales Hospital, Sydney, 2031, Australia.

Abstract

Introduction: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a rare genetic condition with a broad phenotypic presentation. This study aims to establish the first Australian cohort of individuals affected by CADASIL (AusCADASIL) and examine its clinical features and longitudinal course, and to investigate neuroimaging and blood biomarkers to assist in early diagnosis and identify disease progression.

Methods: Participants will be recruited from six study centres across Australia for an observational study of CADASIL. We aim to recruit 150 participants with diagnosed CADASIL, family history of CADASIL or suspected CADASIL symptoms, and 150 cognitively normal NOTCH3 negative individuals as controls. Participants will complete: 1) online questionnaires on medical and family history, mental health, and wellbeing; 2) neuropsychological evaluation; 3) neurological examination and brain MRI; 4) ocular examination and 5) blood sample donation. Participants will have annual follow-up for 4 years to assess their progression and will be asked to invite a study partner to corroborate their self-reported cognitive and functional abilities.Primary outcomes include cognitive function and neuroimaging abnormalities. Secondary outcomes include investigation of genetics and blood and ocular biomarkers. Data from the cohort will contribute to an international consortium, and cohort participants will be invited to access future treatment/health intervention trials.

Discussion: AusCADASIL will be the first study of an Australian cohort of individuals with CADASIL. The study will identify common pathogenic variants in this cohort, and characterise the pattern of clinical presentation and longitudinal progression, including imaging features, blood and ocular biomarkers and cognitive profile.

Keywords: Blood markers; CADASIL; Neuroimaging; Ocular imaging; Study protocol; Vascular dementia.