Fernando Malee S, Simpson Julie E, Matthews Fiona, Brayne Carol, Lewis Claire E, Barber Robert, Kalaria Raj N, Forster Gill, Esteves Filomena, Wharton Stephen B, Shaw Pamela J, O'Brien John T, Ince Paul G
Division of Genomic Medicine, University of Sheffield, United Kingdom.
Stroke. 2006 Jun;37(6):1391-8. doi: 10.1161/01.STR.0000221308.94473.14. Epub 2006 Apr 20.
"Incidental" MRI white matter (WM) lesions, comprising periventricular lesions (PVLs) and deep subcortical lesions (DSCLs), are common in the aging brain. Direct evidence of ischemia associated with incidental WM lesions (WMLs) has been lacking, and their pathogenesis is unresolved.
A population-based, postmortem cohort (n=456) of donated brains was examined by MRI and pathology. In a subsample of the whole cohort, magnetic resonance images were used to sample and compare WMLs and nonlesional WM for molecular markers of hypoxic injury.
PVL severity was associated with loss of ventricular ependyma (P=0.004). For DSCLs, there was arteriolar sclerosis compared with normal WM (vessel wall thickness and perivascular enlargement; both P<0.001). Capillary endothelial activation (ratio of intercellular adhesion molecule to basement membrane collagen IV; P<0.001) and microglial activation (CD68 expression; P=0.002) were elevated in WMLs. Immunoreactivity for hypoxia-inducible factors (HIFs) HIF1alpha and HIF2alpha was elevated in DSCLs (P=0.003 and P=0.005). Other hypoxia-regulated proteins were also increased in WMLs: matrix metalloproteinase-7 (PVLs P<0.001; DSCLs P=0.009) and the number of neuroglobin-positive cells (WMLs P=0.02) reaching statistical significance. The severity of congophilic amyloid angiopathy was associated with increased HIF1alpha expression in DSCLs (P=0.04).
The data support a hypoxic environment within MRI WMLs. Persistent HIF expression may result from failure of normal adaptive mechanisms. WM ischemia appears to be a common feature of the aging brain.
在衰老大脑中，“偶然发现的”MRI白质（WM）病变很常见，包括脑室周围病变（PVL）和深部皮质下病变（DSCL）。与偶然发现的WM病变（WML）相关的缺血的直接证据一直缺乏，其发病机制尚未明确。
通过MRI和病理学检查了一个基于人群的死后捐赠大脑队列（n = 456）。在整个队列的一个子样本中，使用磁共振图像对WML和非病变WM进行采样，并比较缺氧损伤分子标志物。
PVL严重程度与脑室室管膜缺失相关（P = 0.004）。对于DSCL，与正常WM相比存在小动脉硬化（血管壁厚度和血管周围扩大；P均<0.001）。WML中毛细血管内皮激活（细胞间粘附分子与基底膜胶原蛋白IV的比率；P<0.001）和小胶质细胞激活（CD68表达；P = 0.002）升高。DSCL中缺氧诱导因子（HIF）HIF1α和HIF2α的免疫反应性升高（P = 0.003和P = 0.005）。其他缺氧调节蛋白在WML中也增加：基质金属蛋白酶-7（PVL中P<0.001；DSCL中P = 0.009）和神经球蛋白阳性细胞数量（WML中P = 0.02）达到统计学意义。嗜刚果红性淀粉样血管病的严重程度与DSCL中HIF1α表达增加相关（P = 0.04）。
数据支持MRI WML内存在缺氧环境。正常适应性机制失效可能导致HIF持续表达。WM缺血似乎是衰老大脑的一个常见特征。
