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.

阿尔茨海默病 (AD) 患者通常在 MRI 上有脑白质 (WM) 高信号，在病理学上有推测为微血管起源的微梗死。在这里，我们确定了 WM 穿透小动脉的血管扩张功能障碍是否与病理学定义的 WM 损伤和混合微血管和 AD 病理患者的定量 MRI 定义的 WM 完整性紊乱有关。我们分析了 28 个连续收集的人类大脑的组织，这些人类大脑来自被诊断患有不同程度的 AD 神经病理学改变 (ADNC) 伴或不伴脑微梗塞 (mVBI) 的研究供体。WM 穿透和软脑膜表面小动脉对内皮依赖性激动剂缓激肽的反应在体外用视频显微镜进行量化。血管内皮一氧化氮合酶 (eNOS) 和 NAD(P)H-氧化酶 (Nox1, 2 和 4 同种型）表达用定量 PCR 测量。神经胶质纤维酸性蛋白 (GFAP) 标记的星形胶质细胞通过无偏体视学方法在 WM 穿透血管收集部位附近的区域进行量化。死后扩散张量成像 (DTI) 用于测量平均表观扩散系数 (ADC) 和分数各向异性 (FA)，WM 完整性的定量指标。与软脑膜表面小动脉相比，与其他组相比，来自诊断为高 ADNC 和 mVBI 的供体的白质穿透小动脉对缓激肽的反应显着减少。eNOS 的表达减少，而在 AD 和 mVBI 病例的 WM 小动脉中 Nox1 表达增加。WM 星形胶质细胞密度在 AD 和 mVBI 中增加，这与 WM 小动脉的血管舒张减少相关。此外，在低 ADNC 的情况下，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，选择性地损害 WM 穿透小动脉中缓激肽诱导的血管舒张，这可能与一氧化氮减少和活性氧过多介导的血管内皮功能障碍有关。WM 小动脉血管扩张功能障碍与 WM 损伤相关，反应性星形胶质细胞增生和 MRI 定义的 WM 微观结构完整性破坏支持这一点。共病 ADNC 和 mVBI 似乎协同相互作用，选择性地损害 WM 穿透小动脉中缓激肽诱导的血管舒张，这可能与一氧化氮减少和活性氧过多介导的血管内皮功能障碍有关。WM 小动脉血管扩张功能障碍与 WM 损伤相关，反应性星形胶质细胞增生和 MRI 定义的 WM 微观结构完整性破坏支持这一点。共病 ADNC 和 mVBI 似乎协同相互作用，选择性地损害 WM 穿透小动脉中缓激肽诱导的血管舒张，这可能与一氧化氮减少和活性氧过多介导的血管内皮功能障碍有关。WM 小动脉血管扩张功能障碍与 WM 损伤相关，反应性星形胶质细胞增生和 MRI 定义的 WM 微观结构完整性破坏支持这一点。