New Insight Into the Pathogenesis of Cerebral Small-Vessel Diseases
New Insight Into the Pathogenesis of Cerebral Small-Vessel Diseases
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DOI：
10.1161/strokeaha.116.012888
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发表时间：
2017-02-01
期刊：
影响因子：
8.3
通讯作者：
Schwaninger, Markus
中科院分区：
文献类型：
--
作者：
Mueller, Kristin;Courtois, Gilles;Schwaninger, Markus
Müller 等人研究了脑小血管疾病的发病机制第 521 部分：NOTCH3 (N3ECD) 的细胞外结构域，并导致含有 N3ECD 的颗粒状嗜锇物质在细胞外积聚。 16 突变的 N3ECD 似乎获得了有毒蛋白功能（见下文）。尸检研究显示血管平滑肌细胞减少、血管壁增厚以及小动脉管腔狭窄。 16 据报道，在毛细血管水平，内皮细胞和周细胞丢失（图 1）。 18 临床前研究提供了周细胞稳定血脑屏障的良好证据。 19 因此，周细胞的丧失可以解释病例报告和该疾病的小鼠模型中描述的血脑屏障的破坏。 20, 21 在家庭之间甚至在家庭内部，临床表现是异质的，22 大多数 CADASIL 患者都存在 4 个主要症状，即复发性皮质下缺血发作、先兆偏头痛、认知能力下降和情绪障碍。近 85% 的患者患有短暂性脑缺血发作或腔隙性缺血性中风，平均发病时间为 50 岁或 60 岁。 22, 23 有先兆偏头痛影响五分之一到三分之二的患者，其发病率至少比一般人群高 5 倍。 22, 23 在短暂性脑缺血发作和中风发生之后，有时甚至在发生之前，一些患者的记忆力受损。 16 在精神表现中，抑郁和冷漠最为常见。 23 迄今为止，基因检测是诊断该疾病的金标准，只能对症治疗。 23
Müller et al Pathogenesis of Cerebral Small-Vessel Diseases 521 in the extracellular domain of NOTCH3 (N3ECD) and lead to the extracellular accumulation of granular osmiophilic material containing N3ECD. 16 The mutated N3ECD seems to gain a toxic protein function (see below). Postmortem studies have shown a loss of vascular smooth muscle cells, thickening of the vessel wall, and luminal stenosis of arterioles. 16 At the capillary level, a loss of endothelial cells and pericytes has been reported (Figure 1). 18 Preclinical studies provide good evidence that pericytes stabilize the BBB. 19 Thus, the loss of pericytes may explain the disruption of the BBB that has been described in case reports and in a mouse model of the disease. 20, 21 Between and even within families, the clinical picture is heterogeneous, 22 but 4 major symptoms are present in most CADASIL patients, ie, recurrent subcortical ischemic attacks, migraine with aura, cognitive decline, and mood disorders. Almost 85% of patients have transient ischemic attacks or lacunar ischemic strokes with a mean onset in the fifth or sixth decade. 22, 23 Migraine with aura affects one fifth to two thirds of patients and is at least 5× more frequent than in the general population. 22, 23 After and sometimes even before transient ischemic attacks and stroke occur, some patients have impaired memory. 16 Among psychiatric manifestations, depression and apathy are most common. 23 To date, genetic testing serves as the gold standard for diagnosing this disease, and only symptomatic treatment is available. 23