title: White matter pathology and disconnection in the frontal lobe in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).
abstract: BACKGROUND
  Magnetic resonance imaging indicates diffuse white matter (WM) changes are associated with cognitive impairment in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). We examined whether the distribution of axonal abnormalities is related to microvascular pathology in the underlying WM.
  
  
  METHODS
  We used post-mortem brains from CADASIL subjects and similar age cognitively normal controls to examine WM axonal changes, microvascular pathology, and glial reaction in up to 16 different regions extending rostro-caudally through the cerebrum. Using unbiased stereological methods, we estimated length densities of affected axons immunostained with neurofilament antibody SMI32. Standard immunohistochemistry was used to assess amyloid precursor protein immunoreactivity per WM area. To relate WM changes to microvascular pathology, we also determined the sclerotic index (SI) in WM arterioles.
  
  
  RESULTS
  The degree of WM pathology consistently scored higher across all brain regions in CADASIL subjects (P<0.01) with the WM underlying the primary motor cortex exhibiting the most severe change. SMI32 immunoreactive axons in CADASIL were invariably increased compared with controls (P<0.01), with most prominent axonal abnormalities observed in the frontal WM (P<0.05). The SIs of arterioles in CADASIL were increased by 25-45% throughout the regions assessed, with the highest change in the mid-frontal region (P=0.000).
  
  
  CONCLUSIONS
  Our results suggest disruption of either cortico-cortical or subcortical-cortical networks in the WM of the frontal lobe that may explain motor deficits and executive dysfunction in CADASIL. Widespread WM axonal changes arise from differential stenosis and sclerosis of arterioles in the WM of CADASIL subjects, possibly affecting some axons of projection neurones connecting to targets in the subcortical structures.
authors.affiliation: Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, UK.
authors.forename: Lucinda J L
authors.initials: LJ
authors.lastname: Craggs
authors.forename: Yumi
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Masafumi
authors.initials: M
authors.lastname: Ihara
authors.forename: Richard
authors.initials: R
authors.lastname: Fenwick
authors.forename: Matthew
authors.initials: M
authors.lastname: Burke
authors.forename: Arthur E
authors.initials: AE
authors.lastname: Oakley
authors.forename: Sigrun
authors.initials: S
authors.lastname: Roeber
authors.forename: Marco
authors.initials: M
authors.lastname: Duering
authors.forename: Hans
authors.initials: H
authors.lastname: Kretzschmar
authors.forename: Raj N
authors.initials: RN
authors.lastname: Kalaria
mesh_terms: D000328:Adult; D000368:Aged; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D001369:Axons / Q000378:metabolism / Q000473:pathology*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D046589:CADASIL / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009415:Nerve Net / Q000473:pathology; D066127:White Matter / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*
chemical_list: D016564:Amyloid beta-Protein Precursor
keywords: CADASIL; cognitive impairment; disconnection; stroke; vascular dementia; white matter changes