DEVELOPMENT AND VALIDATION OF A FUNCTIONAL MRI BIOMARKER OF CEREBRAL SMALL VESSELS DYSFUNCTION IN CADASIL – fMRI-BioSVD

Cerebral Small Vessel Diseases (SVDs) are among the most prevalent disorders that impact brain health at the population level and contribute to increased disability and mortality with aging. A major hurdle to the development of disease-modifying drugs in SVDs is that, today, these conditions are only monitored on the basis of clinical manifestations and imaging aspects of their resulting cerebral tissue injuries, without any indicator of the alterations in dynamics of microvessels. Neurovascular coupling alterations have been repeatedly observed at early stage of SVDs in animal models, and recently, in humans, using functional MRI (fMRI). The identification of CADASIL, the most common genetic form of SVDs offers an unprecedented opportunity to develop dedicated tools in highly selected and homogeneous samples of SVDs and at a target stage of evolution allowing therapeutic development. In this project, our goal is to develop a novel fMRI biomarker for CADASIL to monitor and quantify the cerebral microvascular dysfunction both in patients and in the corresponding disease mouse model for future clinical and preclinical trials. Using a dedicated MRI protocol at 3T with short visual stimuli, recent results provided a promising biomarker able to discriminate patients and healthy individuals. In this research project based on 3 distinct work-packages, we aim: 1) to optimize and validate a reproducible fMRI study protocol and automate extraction of the hyperaemic response and calculation of a derived biomarker in healthy individuals; 2) to measure the magnitude of this fMRI biomarker change during the course of CADASIL and detect potential correlates with clinical or imaging manifestations; 3) to develop a similar fMRI biomarker in mice for aligning future preclinical trials in the CADASIL mouse model with clinical trials in patients.