Thursday, April 3, 2025
4/3/2025
Non-Invasive MRI Markers to Elicit the Role of Vascular Disease in CADASIL Compared to Normal Aging - Project Summary/Abstract: The project addresses vascular contributions to cognitive impairment and dementia (VCID) using a design that enrolls persons with the autosomal dominant gene for Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). Exploration of VCID by focusing on the rare heritable monogenic disorder, CADASIL, will advance knowledge of the full spectrum of this vascular dementia from asymptomatic gene carriers through dementia and will facilitate studies evaluating vascular contributions in different neurodegenerative processes including Alzheimer’s disease (AD) and related dementias (ADRD). CADASIL is caused by a mutation in the gene Notch3, which encodes a receptor protein expressed in vascular smooth muscle cells and pericytes. When mutated, expression of the gene leads to generalized degeneration of vascular smooth muscle cells affecting small and medium sized arteries. To provide insights into the impact of small vessel disease (SVD) in CADASIL (and AD, ADRD, and VCID more generally) on parenchymal damage and cognitive decline, non-invasive Magnetic Resonance Imaging (MRI) provides quantification of brain structure, function, and some measures of vascular health; however, current clinically available MRI techniques lack sensitivity and specificity to address key vascular hypotheses as many measures only indirectly study cerebrovascular disease, primarily focusing on the damage already caused by SVD, not the vessels themselves. Our group is uniquely positioned to address these key gaps in our knowledge base, both due to our MRI technology and as a member of the first CADASIL consortium study in North America. We propose an ensemble of novel MRI techniques optimized to provide vascular specific measures in a non-invasive imaging protocol. By characterizing in vivo measures of vascular stiffening at the macrovascular and microvascular levels in CADASIL, we will provide insights into the degree and mechanisms of VCID and establish baseline data to compare the longitudinal time course of CADASIL with normal age-related cerebrovascular changes, including SVD. We previously found that our MRI stiffness measures can detect vascular changes in amyloid positive AD participants even prior to demonstrating cognitive dysfunction. Our pilot data in CADASIL suggests pronounced vascular disease involving all levels of the cerebrovascular system. In close collaboration with three additional CADASIL consortium sites, a multidisciplinary team at the University of Wisconsin will first utilize newly developed, state- of-the art, quantitative MRI vascular imaging methods to understand the distribution and severity of vascular changes in CADASIL (Aim 1). We will then study the influence of altered intracranial vasculature on CADASIL neurodegeneration and cognition (Aim 2), and finally, we will study the degree of vascular involvement in CADASIL in comparison to cognitively unimpaired, normal aging participants (Aim 3). Upon completion we will be uniquely positioned to incorporate these techniques into large cohort studies investigating SVD, VCID, and extending into other ADRD vascular mechanisms as well as evaluate risk and protective factors.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).