期刊
STROKE
卷 37, 期 6, 页码 1391-1398出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.STR.0000221308.94473.14
关键词
hypoxia; magnetic resonance imaging; pathology; white matter
资金
- MRC [G0502157, G9901400, G0400074, G0300126, G0500247] Funding Source: UKRI
- Medical Research Council [G9901400, G0300126, G0400074, G0500247, G0502157] Funding Source: researchfish
- Medical Research Council [G9901400, G0500247, G0400074, G0502157, MC_U105292687, G0300126] Funding Source: Medline
Background and Purpose - 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. Methods - 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. Results - 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) HIF1 alpha and HIF2 alpha 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 HIF1 alpha expression in DSCLs ( P = 0.04). Conclusion - 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.
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