Tan Rhea, Traylor Matthew, Rutten-Jacobs Loes, Markus Hugh
Stroke Research Group, Department of Clinical Neurosciences, University of Cambridge, Box 83, R3 Neurosciences, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0QQ, U.K.
Department of Medical and Molecular Genetics, King's College London, 8th Floor, Tower Wing, Guys Hospital, Great Maze Pond, London SE1 9RT, U.K.
Clin Sci (Lond). 2017 Apr 1;131(7):515-531. doi: 10.1042/CS20160825.
Cerebral small vessel disease (SVD) is a common cause of lacunar strokes, vascular cognitive impairment (VCI) and vascular dementia. SVD is thought to result in reduced cerebral blood flow, impaired cerebral autoregulation and increased blood-brain barrier (BBB) permeability. However, the molecular mechanisms underlying SVD are incompletely understood. Recent studies in monogenic forms of SVD, such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and 'sporadic' SVD have shed light on possible disease mechanisms in SVD. Proteomic and biochemical studies in post-mortem monogenic SVD patients, as well as in animal models of monogenic disease have suggested that disease pathways are shared between different types of monogenic disease, often involving the impairment of extracellular matrix (ECM) function. In addition, genetic studies in 'sporadic' SVD have also shown that the disease is highly heritable, particularly among young-onset stroke patients, and that common variants in monogenic disease genes may contribute to disease processes in some SVD subtypes. Genetic studies in sporadic lacunar stroke patients have also suggested distinct genetic mechanisms between subtypes of SVD. Genome-wide association studies (GWAS) have also shed light on other potential disease mechanisms that may be shared with other diseases involving the white matter, or with pathways implicated in monogenic disease. This review brings together recent data from studies in monogenic SVD and genetic studies in 'sporadic' SVD. It aims to show how these provide new insights into the pathogenesis of SVD, and highlights the possible convergence of disease mechanisms in monogenic and sporadic SVD.
脑小血管病（SVD）是腔隙性卒中、血管性认知障碍（VCI）和血管性痴呆的常见病因。人们认为SVD会导致脑血流量减少、脑自动调节功能受损以及血脑屏障（BBB）通透性增加。然而，SVD潜在的分子机制尚未完全明确。最近对单基因形式的SVD（如伴有皮质下梗死和白质脑病的脑常染色体显性动脉病，CADASIL）以及“散发性”SVD的研究，为SVD可能的发病机制提供了线索。对死后单基因SVD患者以及单基因疾病动物模型进行的蛋白质组学和生化研究表明，不同类型的单基因疾病存在共同的疾病途径，通常涉及细胞外基质（ECM）功能受损。此外，对“散发性”SVD的遗传学研究还表明，该疾病具有高度遗传性，尤其是在年轻起病的卒中患者中，单基因疾病基因中的常见变异可能在某些SVD亚型的疾病进程中起作用。对散发性腔隙性卒中患者的遗传学研究也提示了SVD各亚型之间不同的遗传机制。全基因组关联研究（GWAS）也揭示了其他可能与涉及白质的其他疾病或与单基因疾病相关途径共享的潜在疾病机制。本综述汇集了单基因SVD研究和“散发性”SVD遗传学研究的最新数据。其目的是展示这些研究如何为SVD的发病机制提供新的见解，并强调单基因和散发性SVD疾病机制可能的趋同性。
