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

Abstract:

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) 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). CONCLUSIONS: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.

journal_name

Stroke

journal_title

Stroke

authors

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,MRC Cognitive Function and Ageing Neuropathology Study Group.

doi

10.1161/01.STR.0000221308.94473.14

subject

Has Abstract

pub_date

2006-06-01 00:00:00

pages

1391-8

issue

6

eissn

0039-2499

issn

1524-4628

pii

01.STR.0000221308.94473.14

journal_volume

37

pub_type

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