Description (from grant):
Significance: This project investigates the link between cerebral microvascular health and brain function in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) patients. CADASIL is the most common monogenic cause of stroke and Vascular contributions to Cognitive Impairment and Dementia (VCID). Preclinical studies have indicated that NOTCH3 mutations are associated with structural and functional changes in the vascular smooth muscle cells and the loss of pericyte function. Thus, studying CADASIL patients with NOTCH3 mutations is an ideal approach to investigate early physiologyl changes associated with VCID in gene mutation carriers, prior to onset of clinical symptoms. We will examine cerebrovascular reactivity (CVR), a cerebral small vessel disease (SVD) functional marker, in a subset of participants from the first North American longitudinal cohort (CADASIL Consortium). This Consortium includes 400 adults with CADASIL NOTCH3 mutations and 100 non-carrier controls. A key feature of CADASIL and other SVD is the early development of often irreversible white matter (WM) hyperintensities. Functional declines in microvascular health are thought to occur earlier in the development of the disease and may underlie the WM changes in CADASIL. CVR is a sensitive measure of microvascular function and the objective of this application is to determine the impact of NOTCH3 mutations on CVR, and explore potential associations with clinical, neuropsychological, neuroimaging, and biofluid markers of VCID. To achieve this, we will leverage participants and data from the longitudinal cohort with NOTCH3 mutation carriers (CADASIL Consortium) and compare with healthy non-carriers. In Aim 1 we will examine if CVR is lower in NOTCH3 mutation carriers with varying disease severity (asymptomatic, symptomatic, and symptomatic with functional decline) when compared with healthy non-carrier controls. In Aim 2 we will determine if CVR in NOTCH3 mutation carriers is associated with other biomarkers of VCID and CADASIL phenotypic markers. In Aim 3 we will characterize the trajectory of change in CVR in NOTCH3 mutation carriers and non-carrier controls (over 18 months) and determine the association with other biomarkers of VCID and CADASIL phenotypic markers. This application will provide critical information on the pathogenesis of VCID using participants with a SVD autosomal dominant source, expanding beyond patients of the rare disease CADASIL. This approach aligns with recent NIH recommendations emphasizing the need for human studies to identify and confirm biomarkers of vascular processes related to cognitive impairment.