title: White matter lesions in an unselected cohort of the elderly: molecular pathology suggests origin from chronic hypoperfusion injury.
abstract: OBJECTIVE
  "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.
authors.affiliation: Division of Genomic Medicine, University of Sheffield, United Kingdom.
authors.forename: Malee S
authors.initials: MS
authors.lastname: Fernando
authors.forename: Julie E
authors.initials: JE
authors.lastname: Simpson
authors.forename: Fiona
authors.initials: F
authors.lastname: Matthews
authors.forename: Carol
authors.initials: C
authors.lastname: Brayne
authors.forename: Claire E
authors.initials: CE
authors.lastname: Lewis
authors.forename: Robert
authors.initials: R
authors.lastname: Barber
authors.forename: Raj N
authors.initials: RN
authors.lastname: Kalaria
authors.forename: Gill
authors.initials: G
authors.lastname: Forster
authors.forename: Filomena
authors.initials: F
authors.lastname: Esteves
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Wharton
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Shaw
authors.forename: John T
authors.initials: JT
authors.lastname: O'Brien
authors.forename: Paul G
authors.initials: PG
authors.lastname: Ince
mesh_terms: D000368:Aged; D051792:Basic Helix-Loop-Helix Proteins; D001808:Blood Vessels / Q000473:pathology; D001921:Brain / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology*; D002545:Brain Ischemia / Q000150:complications / Q000175:diagnosis* / Q000378:metabolism* / Q000473:pathology; D002102:Cadaver; D015815:Cell Adhesion Molecules / Q000378:metabolism; D016657:Cerebral Amyloid Angiopathy / Q000150:complications; D002908:Chronic Disease; D015331:Cohort Studies; D024141:Collagen Type IV / Q000378:metabolism; D004805:Ependyma / Q000473:pathology; D006801:Humans; D002534:Hypoxia, Brain / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D017628:Microglia / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D015815:Cell Adhesion Molecules; D024141:Collagen Type IV; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009419:Nerve Tissue Proteins; D014157:Transcription Factors; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human