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CADASIL: a clinical model of ischemic small vessel disease (ID 1295)
Abstract BodyCADASIL represents a unique model to investigate clinical features, imaging correlates, and prognostic factors in ischemic cerebral small vessel disease. During the last decades, studies in different CADASIL cohorts provided crucial results: 1) to capture the natural history and exact clinical spectrum related to specific functional and structural alterations of smooth muscle cells and pericytes in the cerebral microvasculature, 2) to understand the variable mechanisms and clinical consequences of MRI lesions developing during the course of the disease; 3) to investigate the factors that can modulate the clinical progression and development of white-matter lesions, lacunes, microbleeds or cerebral atrophy detected at imaging level; 4) to develop innovative markers that can be used in future therapeutic development. Imaging studies in CADASIL also illustrated how subcortical lesions can impact the cortex structure and morphology in a pure ischemic small vessel disease, questioning the concept of subcortical ischemic vascular dementia. Altogether the results obtained in CADASIL have illuminated the field of clinical and imaging research in cerebral small vessel disease. Additional studies are now warranted for obtaining robust and reproducible markers, the best clinical outcomes and molecular targets for developing innovative disease-modifying drugs in the most frequent hereditary small vessel disease of the brain.
Pathogenesis of small vessel diseases of the Brain: new insights from genetic models (ID 1296)
Cerebral small vessel diseases (SVD) account for ~25% of ischemic strokes, ~ 90% of intracerebral hemorrhages (ICH) and are a leading cause of cognitive decline and disability. Our limited understanding of the pathogenesis of SVD is a major obstacle to the development of treatments. Monogenic forms of SVD, such as CADASIL, an ischemic form of SVD caused by highly stereotyped mutations in the Notch3 receptor, provide a window into the mechanism underlying much more common, but largely indistinguishable, sporadic forms of SVD.
Over the past years, we have generated and characterized several mouse models of CADASIL. We established that aggregation/accumulation of the extracellular domain of Notch3 in brain vessels is a central event, promoting the abnormal recruitment of functionally important extracellular matrix proteins that ultimately cause multifactorial toxicity. We identified a novel mechanism linking pathological alterations of the vascular extracellular matrix and a channelopathy-like defect that underlies cerebrovascular dysfunction. Recently, we obtained preliminary evidence of efficacy of passive immunization targeting Notch3 in a proof-of-concept study.