Frontal white matter hyperintensities, clasmatodendrosis and gliovascular abnormalities in ageing and post-stroke dementia.
Frontal white matter hyperintensities, clasmatodendrosis and gliovascular abnormalities in ageing and post-stroke dementia.
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DOI：
10.1093/brain/awv328
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发表时间：
2016-01
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通讯作者：
Kalaria RN
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作者：
Chen A;Akinyemi RO;Hase Y;Firbank MJ;Ndung'u MN;Foster V;Craggs LJ;Washida K;Okamoto Y;Thomas AJ;Polvikoski TM;Allan LM;Oakley AE;O'Brien JT;Horsburgh K;Ihara M;Kalaria RN
白色高信号与卒中后认知功能障碍有关，但其潜在机制尚不清楚。Chen等人提供了来自人类和实验研究的证据，表明在死于血管性痴呆的受试者的额叶白色物质中，类枝胶质细胞增多症（一种不可逆星形胶质细胞损伤的标志物）和神经胶质血管异常增加。 白色高信号与卒中后认知功能障碍有关，但其潜在机制尚不清楚。Chen等人提供了来自人类和实验研究的证据，表明在死于血管性痴呆的受试者的额叶白色物质中，类枝胶质细胞增多症（一种不可逆星形胶质细胞损伤的标志物）和神经胶质血管异常增加。 脑T 2加权磁共振成像上所见的白色高信号与中风、脑小血管疾病和痴呆中不同程度的认知功能障碍有关。白色物质内认知功能障碍的病理生理机制尚不清楚。假设在白色高信号高负荷的受试者中，胶质血管相互作用受损，我们对卒中后幸存者进行了临床病理学研究，这些幸存者表现出更大的额叶白色高信号体积，预测痴呆发作的时间更短。组织学方法被用来确定基板的白色的问题，将区分中风后痴呆症与中风后非痴呆症的主题。我们专注于反应性细胞标记物胶质细胞酸性蛋白（GFAP），研究不可逆损伤的星形胶质细胞的形态学属性，即类枝胶质细胞变性的发生率和位置。与正常出现的GFAP+星形胶质细胞相反，clasmatodendrocytes肿胀，细胞体空泡化。其他标志物如醛脱氢酶1家族成员L1（ALDH 1 L1）显示星形胶质细胞的细胞质解体。脑卒中后痴呆患者的额叶和颞叶白色物质中的GFAP+细胞总数并不比脑卒中后非痴呆患者多。然而，在额叶白色物质中，中风后痴呆的受试者与中风后非痴呆的受试者相比，类突胶质细胞的百分比增加了2倍以上（P = 0.026），老年对照组与年轻对照组相比增加了11倍（P < 0.023）。额叶白色物质中高比例的类突胶质细胞与总星形胶质细胞的比例与卒中后痴呆受试者较低的简易精神状态检查和修订的剑桥认知检查评分一致。双重免疫荧光染色显示水通道蛋白4（AQP 4）在收缩的GFAP+星形胶质细胞中的异常共定位，破坏了与微血管并列的终足。为了探讨这是否与中断的胶质血管相互作用或血脑屏障损伤，我们评估了共同定位的GFAP和AQP 4免疫反应性在死后的大脑从成年狒狒脑低灌注损伤，引起闭塞的三个主要血管供应血液到大脑。对闭塞后存活1-28天的动物的灌注脑中的额叶白色物质的分析显示，纤维蛋白原免疫反应性的最高强度是在14天。在这个生存时间点，我们还注意到AQP 4和GFAP+星形胶质细胞转化为clasmatodendrocytes惊人相似的再分布。我们的研究结果表明，不可逆的星形胶质细胞损伤和额叶白色物质中血脑屏障的胶质血管相互作用的破坏与老年卒中后幸存者的认知障碍之间存在新的联系。我们认为，clasmatodendrosis是另一种病理底物，与白色物质高信号和额叶白色物质的变化，这可能有助于中风后或小血管疾病痴呆。
White matter hyperintensities are associated with post-stroke cognitive dysfunction, but the underlying mechanisms are unclear. Chen et al. provide evidence from human and experimental studies that clasmatodendrosis – a marker of irreversible astrocyte damage – and gliovascular abnormalities are increased in the frontal white matter of subjects who succumb to vascular dementia. White matter hyperintensities are associated with post-stroke cognitive dysfunction, but the underlying mechanisms are unclear. Chen et al. provide evidence from human and experimental studies that clasmatodendrosis – a marker of irreversible astrocyte damage – and gliovascular abnormalities are increased in the frontal white matter of subjects who succumb to vascular dementia. White matter hyperintensities as seen on brain T 2 -weighted magnetic resonance imaging are associated with varying degrees of cognitive dysfunction in stroke, cerebral small vessel disease and dementia. The pathophysiological mechanisms within the white matter accounting for cognitive dysfunction remain unclear. With the hypothesis that gliovascular interactions are impaired in subjects with high burdens of white matter hyperintensities, we performed clinicopathological studies in post-stroke survivors, who had exhibited greater frontal white matter hyperintensities volumes that predicted shorter time to dementia onset. Histopathological methods were used to identify substrates in the white matter that would distinguish post-stroke demented from post-stroke non-demented subjects. We focused on the reactive cell marker glial fibrillary acidic protein (GFAP) to study the incidence and location of clasmatodendrosis, a morphological attribute of irreversibly injured astrocytes. In contrast to normal appearing GFAP+ astrocytes, clasmatodendrocytes were swollen and had vacuolated cell bodies. Other markers such as aldehyde dehydrogenase 1 family, member L1 (ALDH1L1) showed cytoplasmic disintegration of the astrocytes. Total GFAP+ cells in both the frontal and temporal white matter were not greater in post-stroke demented versus post-stroke non-demented subjects. However, the percentage of clasmatodendrocytes was increased by >2-fold in subjects with post-stroke demented compared to post-stroke non-demented subjects ( P = 0.026) and by 11-fold in older controls versus young controls ( P < 0.023) in the frontal white matter. High ratios of clasmotodendrocytes to total astrocytes in the frontal white matter were consistent with lower Mini-Mental State Examination and the revised Cambridge Cognition Examination scores in post-stroke demented subjects. Double immunofluorescent staining showed aberrant co-localization of aquaporin 4 (AQP4) in retracted GFAP+ astrocytes with disrupted end-feet juxtaposed to microvessels. To explore whether this was associated with the disrupted gliovascular interactions or blood–brain barrier damage, we assessed the co-localization of GFAP and AQP4 immunoreactivities in post-mortem brains from adult baboons with cerebral hypoperfusive injury, induced by occlusion of three major vessels supplying blood to the brain. Analysis of the frontal white matter in perfused brains from the animals surviving 1–28 days after occlusion revealed that the highest intensity of fibrinogen immunoreactivity was at 14 days. At this survival time point, we also noted strikingly similar redistribution of AQP4 and GFAP+ astrocytes transformed into clasmatodendrocytes. Our findings suggest novel associations between irreversible astrocyte injury and disruption of gliovascular interactions at the blood–brain barrier in the frontal white matter and cognitive impairment in elderly post-stroke survivors. We propose that clasmatodendrosis is another pathological substrate, linked to white matter hyperintensities and frontal white matter changes, which may contribute to post-stroke or small vessel disease dementia.