Early biomarkers of vascular brain dysfunction

Abstract

AbstractCerebral small vessel disease (cSVD) is a major cause of brain degeneration and dementia for which we have no therapies. My lab applies new molecular omics technology to human biospecimen for an initial unbiased approach to discovery of clinically‐relevant dysregulated molecular pathways in humans living with disease. A major obstacle is lack of in vivo gold standards. As such, we have focused our efforts on an autosomal dominant form of disease–CADASIL (Cerebral Autosomal Dominant Arteriopathy Subcortical Infarcts and Leukoencephalopathy) caused by mutations in NOTCH3. Given its autosomal dominant nature, CADASIL provides a unique opportunity to build an all‐in‐human modeling pipeline for discovery of biomarkers and therapeutics for VCID. We take a systems biology approach, using brain tissue, plasma and patient‐derived stem cells to model disease and uncover biomarkers as well as therapeutic targets. We then perform cross‐disease comparisons with other cSVD subtypes, such as hypertensive cSVD and Cerebral Amyloid Angiopathy to identify shared pathologies. Finally, we investigate the relevance of uncovered molecular pathways to brain dysfunction and degeneration in prevalent neurodegenerative disease syndromes such as AD, FTD, and PD.