Emerging Evidence for Pathogenesis of Sporadic Cerebral Small Vessel Disease

Cerebral small vessel disease (SVD), which affects small arteries, arterioles, venules, and capillaries in the brain, has long been associated with cognitive impairment and dementia. Pathologically, characteristic features include (1) vasculopathy of the small cerebral vessels,1 (2) lacunar infarcts,2 (3) microbleeds (lobar or deep),3 (4) widened perivascular spaces (Virchow–Robin spaces),4,5 (5) focal or diffuse white matter (WM) changes (often seen as hyperintensities on magnetic resonance imaging),6 and (6) microinfarcts.7,8 SVD is a spectrum of abnormalities, with the majority of patients experiencing symptoms from both ischemic and hemorrhagic changes in varying degrees as the disease progresses.9 WM damage is commonly found in SVD, and enlarged perivascular spaces, lacunar infarction, and deep microbleeds coexist with lipohyalinosis,10 whereas cortical microinfarcts and lobar microbleeds are more frequently found in cerebral amyloid angiopathy.11 Such pathological changes also frequently accompany the hallmarks of Alzheimer’s disease and previously were only evident by postmortem histopathological examinations12 but now often visible with modern neuroimaging.13 Despite improvements in clinical/radiological markers available for the characterization of SVD, none are specific for SVD and there remain other factors yet to be identified. Here, we aim to review 4 emerging factors involved in the pathogenesis of SVD, with particular emphasis on the endothelial dysfunction that leads to blood–brain barrier (BBB) disruption, as well as discuss potential future therapeutic strategies. The 4 factors covered in our topical review are (1) hypertension and salt intake, (2) infection and inflammation, (3) large and small artery cross talk, and (4) cell–cell interaction in the BBB. For a comprehensive view of SVD pathogenesis, readers may refer to the already published reviews.1,10,14 The most common risk factor of SVD is hypertension, but multiple factors frequently coexist,15 as is …