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White matter lesions in an unselected cohort of the elderly: Molecular pathology suggests origin from chronic hypoperfusion injury

Lookup NU author(s): Professor Carol Brayne, Dr Robert Barber, Professor Raj Kalaria, Professor John O'Brien


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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) HIF1α and HIF2α 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 HIF1α 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. © 2006 American Heart Association, Inc.

Publication metadata

Author(s): Fernando MS, Simpson JE, Matthews F, Brayne C, Lewis CE, Barber R, Kalaria RN, Forster G, Esteves F, Wharton SB, Shaw PJ, O'Brien JT, Ince PG, On behalf of the MRC Cognitive Function and Ageing Neuropathology Study Group

Publication type: Article

Publication status: Published

Journal: Stroke

Year: 2006

Volume: 37

Issue: 6

Pages: 1391-1398

ISSN (print): 0039-2499

ISSN (electronic): 1524-4628

Publisher: Lippincott Williams & Wilkins


DOI: 10.1161/01.STR.0000221308.94473.14

PubMed id: 16627790


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Funder referenceFunder name
G0400074Medical Research Council
G0300126Medical Research Council
G0500247Medical Research Council
G0502157Medical Research Council
G9901400Medical Research Council
MC_U105292687Medical Research Council