Unraveling the Earliest Phases of Vascular Cognitive Impairment and Dementia by Establishing a Large USA CADASIL Consortium
Michael Geschwind1, Jose Biller2, Jamie Elliott3, Suman Jayadev4, Stephen Salloway5, Jose Gutierrez6, Sudha Seshadri7, Jennifer Majersik8, Karen Orjuela9, David Liebeskind10, Helmi Lutsep11, Ihab Hajjar12, Fanny Elahi13, Henry Bockholt14, Jane Paulsen3
1Neurology, UCSF, 2Neurology, Loyola University Stritch School of Medicine, 3Neurology, University of Wisconsin, Madison, 4University of Washington Medical Center, 5Neurology, Brown Medical School, 6Neurology, Columbia University, 7Neurology, Glenn Biggs Institute for Alzheimer'S and Neurodegenerative Diseases, 8Neurology, University of Utah, 9Neurology, University of Colorado - Anschutz Medical Center, 10Neurology, Neurovascular Imaging Research Core at UCLA, 11Neurology, Oregon Health & Science University, 12Neurology, UTSW Medical Center, 13Neurology, Mt. Sinai School of Medicine, 14GSU
Objective:
To characterize the initial presentation and course of clinical, neuroimaging, and blood markers of presymptomatic to early/moderate symptomatic NOTCH3 carriers and compare them with non-carrier family member controls and to clarify genetic, health, and lifestyle factors which impact clinically meaningful outcomes in CADASIL.
Background:
CADASIL, caused by pathogenic variants in NOTCH3, is the most common monogenic cause of vascular dementia. Persons with CADASIL have a very high risk of developing vascular cognitive impairment and dementia (VCID), which can be studied in presymptomatic/early disease stages to detect the first changes in biological fluids, neuroimaging, and the emerging phenotype of VCID. Currently, there is little cross-sectional or longitudinal data from large USA CADASIL cohorts. Better understanding of the clinical progression and identifying biomarkers in CADASIL is needed to develop future treatment trials.
Design/Methods:
We are establishing an NIH/NIA-funded (RF1AG074608) longitudinal cohort of 400 NOTCH3 carriers and 100 non-carrier family members across 12 USA sites. Participants undergo systematic clinical, cognitive (standard & tablet-based), advanced neuroimaging, and blood-based phenotyping, to identify optimal biomarkers, with an aim to determine the lowest sample size estimates needed for clinical trials. Several assessments, including for quality of life (QOLs), will be compared to assess which best track disease progression.
Results:
Despite COVID-19-related issues, recruitment has begun at all 12 sites. Thus far, more than 140 participants have enrolled with most having all measures assessed. Initial imaging analyses are also being submitted for presentation.
Conclusions:
We hope to show that conducting such a large, multisite study in a rare disease is possible in the USA and will determine improved clinical outcome assessments in CADASIL. The data generated will be essential to design cost-effective, successful clinical trials in CADASIL and other vascular dementias.