Institute of Neuroscience, Newcastle University, Newcastle Upon Tyne, UK.
School of Biology, University of St Andrews, Fife, UK.
Brain Pathol. 2019 May;29(3):414-424. doi: 10.1111/bpa.12685. Epub 2019 Jan 29.
The blood-brain barrier (BBB) regulates cerebrovascular permeability and leakage of blood-derived fibrinogen. Dysfunction of the BBB has been associated with cerebral arteriolosclerosis small vessel disease (SVD) and white matter lesions (WML). Furthermore, BBB dysfunction is associated with the pathogenesis of Alzheimer's disease (AD) with the presence of CSF plasma proteins suggested to be a potential biomarker of AD. We aimed to determine if extravascular fibrinogen in the white matter was associated with the development of AD hallmark pathologies, i.e., hyperphosphorylated tau (HPτ) and amyloid-β (Aβ), as well as SVD, cerebral amyloid angiopathy (CAA) and measures of white matter damage. Using human post-mortem brains, parietal tissue from 20 AD and 22 non-demented controls was quantitatively assessed for HPτ, Aβ, white matter damage severity, axonal density, demyelination and the burden of extravascular fibrinogen in both WML and normal appearing white matter (NAWM). SVD severity was determined by calculating sclerotic indices. WML- and NAWM fibrinogen burden was not significantly different between AD and controls nor was it associated with the burden of HPτ or Aβ pathology, or any measures of white matter damage. Increasing severity of SVD was associated with and a predictor of both higher WML- and NAWM fibrinogen burden (all P < 0.05) in controls only. In cases with minimal SVD NAWM fibrinogen burden was significantly higher in the AD cases (P < 0.05). BBB dysfunction was present in both non-demented and AD brains and was not associated with the burden of AD-associated cortical pathologies. BBB dysfunction was strongly associated with SVD but only in the non-demented controls. In cases with minimal SVD, BBB dysfunction was significantly worse in AD cases possibly indicating the influence of CAA. In conclusion, extravascular fibrinogen is not associated with AD hallmark pathologies but indicates SVD, suggesting that the presence of fibrinogen in the CSF is not a surrogate marker for AD pathology.
血脑屏障 (BBB) 调节脑血管通透性和血液来源纤维蛋白原的渗漏。BBB 功能障碍与脑小血管疾病 (SVD) 和白质病变 (WML) 小动脉粥样硬化有关。此外，BBB 功能障碍与阿尔茨海默病 (AD) 的发病机制有关，CSF 血浆蛋白的存在被认为是 AD 的潜在生物标志物。我们旨在确定血管外白质中的纤维蛋白原是否与 AD 标志性病理的发展有关，即磷酸化 tau (HPτ) 和淀粉样蛋白-β (Aβ) 以及 SVD、脑淀粉样血管病 (CAA) 和白质损伤程度有关。使用人类死后大脑，定量评估 20 例 AD 和 22 例非痴呆对照者的顶叶组织中 HPτ、Aβ、白质损伤严重程度、轴突密度、脱髓鞘和血管外纤维蛋白原在 WML 和正常外观白质 (NAWM) 中的负担。SVD 严重程度通过计算硬化指数来确定。AD 和对照组之间 WML 和 NAWM 纤维蛋白原负担没有显著差异，也与 HPτ 或 Aβ 病理负担或任何白质损伤测量值无关。SVD 严重程度的增加与对照组中更高的 WML 和 NAWM 纤维蛋白原负担相关且是其预测因素（均 P < 0.05）。在 SVD 最小的情况下，AD 病例的 NAWM 纤维蛋白原负担明显更高（P < 0.05）。非痴呆和 AD 脑均存在 BBB 功能障碍，与 AD 相关皮质病变的负担无关。BBB 功能障碍与 SVD 密切相关，但仅在非痴呆对照组中。在 SVD 最小的情况下，AD 病例的 BBB 功能障碍明显更差，可能表明 CAA 的影响。总之，血管外纤维蛋白原与 AD 标志性病理无关，但表明 SVD 的存在，提示 CSF 中纤维蛋白原不是 AD 病理的替代标志物。
