The pathogenesis of cerebral small vessel disease and vascular cognitive impairment

Cerebral small vessel disease (cSVD) is the broadly accepted term nowadays to designate a heterogeneous group of diseases caused by in situ damage of small brain vessels commonly related to aging, hypertension, or genetic factors. Cardinal neuroimaging features include small (<20 mm) infarcts or lacunes, cerebral microbleeds, white matter hyperintensities, enlarged perivascular spaces, and brain atrophy. Overall, cSVD represents one of the major problems facing global society today, causing a quarter of all ischemic strokes and the vast majority of spontaneous hemorrhages and accounting for 20% or more of all dementias. Yet mechanisms of cSVD are still incompletely understood, and we have no effective proven treatments other than risk factor modification. Recently, major progress in understanding the underlying disease mechanisms has occurred thanks to novel approaches including advanced molecular, genetic, and imaging tools. Here, we provide a comprehensive and critical appraisal of the biggest advances in our understanding of how cSVD affects the structure and function of small brain vessels, causes brain lesions, and alters cognition. To set the stage, we begin by reviewing the molecular anatomy and physiology of healthy small brain vessels and report on the milestones from the medical literature, starting in the 1850s, that have laid the foundation for the "modern" definition of cSVD. We conclude by discussing the framework for clinical interventions that will emerge from these novel insights. We also highlight the outstanding questions to address and challenges to tackle to move the field forward.