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on April 20, 2006

A more recent version of this article appeared on June 1, 2006

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Submitted on December 23, 2005
Accepted on January 10, 2006

White Matter Lesions in an Unselected Cohort of the Elderly. Molecular Pathology Suggests Origin From Chronic Hypoperfusion Injury

Malee S. Fernando PhD; Julie E. Simpson PhD; Fiona Matthews PhD; Carol Brayne MD; Claire E. Lewis PhD; Robert Barber MD; Raj N. Kalaria PhD; Gill Forster BSc; Filomena Esteves PhD; Stephen B. Wharton MB; Pamela J. Shaw MD; John T. O’Brien MD; Paul G. Ince MD^*; on behalf of the MRC Cognitive Function and Ageing Neuropathology Study Group

From the Academic Unit of Pathology (M.S.F., J.E.S., C.E.L., G.F., F.E., S.B.W., P.G.I.) and Academic Unit of Neurology (P.J.S.), Division of Genomic Medicine, University of Sheffield, United Kingdom; MRC Biostatistics Unit (F.M.), University of Cambridge and Institute of Public Health (C.B.), University of Cambridge, United Kingdom; and Institute for Health and Ageing (R.B., R.N.K., J.T.O.), University of Newcastle upon Tyne, United Kingdom.

^* To whom correspondence should be addressed. E-mail: p.g.ince{at}shef.ac.uk.

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 and HIF2 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 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.

Key words: hypoxia • magnetic resonance imaging • pathology • white matter

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