Association of cerebral microvascular dysfunction and white matter injury in Alzheimer's disease
Association of cerebral microvascular dysfunction and white matter injury in Alzheimer's disease
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DOI：
10.1007/s11357-022-00585-5
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发表时间：
2022-05-25
期刊：
影响因子：
5.6
通讯作者：
Back, Stephen A.
中科院分区：
文献类型：
--
作者：
Bagi, Zsolt;Kroenke, Christopher D.;Back, Stephen A.
阿尔茨海默病（AD）患者常在MRI上表现为脑白色物质（WM）高信号，病理学上表现为推测起源于微血管的微梗死。在这里，我们确定是否WM穿透性小动脉的血管舒张功能障碍与病理学定义的WM损伤和定量MRI定义的WM完整性在混合微血管和AD病理的患者的干扰。我们分析了28个连续收集的人脑组织，这些人脑来自诊断为不同程度的AD神经病理学改变（ADNC）伴或不伴脑微梗死（mVBI）的研究供体。WM穿透和软膜表面小动脉的内皮依赖性激动剂缓激肽的反应进行定量离体与视频显微镜。定量PCR检测血管内皮型一氧化氮合酶（eNOS）和NAD（P）H氧化酶（Nox1、2和4亚型）表达。胶质细胞酸性蛋白（GFAP）标记的星形胶质细胞进行定量的无偏体视学方法在邻近的WM穿透血管收集的网站。死后采用扩散张量成像（DTI）测量平均表观扩散系数（ADC）和各向异性分数（FA），量化指标的WM完整性。与软脑膜表面小动脉相反，与其他组相比，诊断为高ADNC和mVBI的供体的白色物质穿透小动脉对缓激肽的反应显著降低。AD和mVBI患者WM小动脉eNOS表达减少，而Nox 1表达增加。WM星形胶质细胞密度在AD和mVBI中增加，这与WM小动脉中血管舒张减少相关。此外，在ADNC低的病例中，缓激肽诱导的WM小动脉扩张与较低的ADC和较高的FA值相关。共病ADNC和mVBI似乎协同相互作用，选择性损害缓激肽诱导的血管舒张WM穿透性小动脉，这可能与减少一氧化氮和过量活性氧介导的血管内皮功能障碍。WM小动脉血管扩张功能障碍与WM损伤相关，这得到反应性星形胶质细胞增生和MRI定义的WM微结构完整性破坏的支持。
Patients with Alzheimer's disease (AD) often have cerebral white matter (WM) hyperintensities on MRI and microinfarcts of presumed microvascular origin pathologically. Here, we determined if vasodilator dysfunction of WM-penetrating arterioles is associated with pathologically defined WM injury and disturbances in quantitative MRI-defined WM integrity in patients with mixed microvascular and AD pathology. We analyzed tissues from 28 serially collected human brains from research donors diagnosed with varying degrees of AD neuropathologic change (ADNC) with or without cerebral microinfarcts (mVBI). WM-penetrating and pial surface arteriolar responses to the endothelium-dependent agonist bradykinin were quantified ex vivo with videomicroscopy. Vascular endothelial nitric oxide synthase (eNOS) and NAD(P)H-oxidase (Nox1, 2 and 4 isoforms) expression were measured with quantitative PCR. Glial fibrillary acidic protein (GFAP)-labeled astrocytes were quantified by unbiased stereological approaches in regions adjacent to the sites of WM-penetrating vessel collection. Post-mortem diffusion tensor imaging (DTI) was used to measure mean apparent diffusion coefficient (ADC) and fractional anisotropy (FA), quantitative indices of WM integrity. In contrast to pial surface arterioles, white matter-penetrating arterioles from donors diagnosed with high ADNC and mVBI exhibited a significantly reduced dilation in response to bradykinin when compared to the other groups. Expression of eNOS was reduced, whereas Nox1 expression was increased in WM arterioles in AD and mVBI cases. WM astrocyte density was increased in AD and mVBI, which correlated with a reduced vasodilation in WM arterioles. Moreover, in cases with low ADNC, bradykinin-induced WM arteriole dilation correlated with lower ADC and higher FA values. Comorbid ADNC and mVBI appear to synergistically interact to selectively impair bradykinin-induced vasodilation in WM-penetrating arterioles, which may be related to reduced nitric oxide- and excess reactive oxygen species-mediated vascular endothelial dysfunction. WM arteriole vasodilator dysfunction is associated with WM injury, as supported by reactive astrogliosis and MRI-defined disrupted WM microstructural integrity.