title: Neuropathologic evidence of endothelial changes in cerebral small vessel disease.
abstract: OBJECTIVE
  Cerebral small vessel disease (SVD) is common in aged brains and causes lacunar stroke, diffuse white matter lesions (leukoaraiosis), and vascular cognitive impairment. The pathogenesis is unknown. Endothelial dysfunction is a possible causal factor, and circulating markers of endothelial activation (intercellular adhesion molecule-1, thrombomodulin) and inflammation (interleukin [IL]-6) are elevated in patients with SVD. In this case-control study, we tested whether brain endothelial ICAM1, thrombomodulin, and IL-6 are altered in SVD.
  
  
  METHODS
  We examined small penetrating cerebral arteries of pathologically diagnosed SVD cases, aged controls without SVD, young control cases with no brain pathology, and cases with early-onset hereditary SVD (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy [CADASIL]). All tissues had minimal cerebral amyloid angiopathy or other Alzheimer pathology.
  
  
  RESULTS
  Thrombomodulin immunoreactivity was present in all aged SVD, aged control, and CADASIL cases, primarily in small artery endothelium. Thrombomodulin was augmented in aged SVD cases compared with aged controls (p = 0.012) and in vessels with higher sclerotic index (an indicator of SVD severity; p < 0.01). Thrombomodulin was sparse/absent in young controls. Endothelial ICAM1 and IL-6 were rarely seen, and were not related to SVD.
  
  
  CONCLUSIONS
  Our data suggest that cerebral endothelial activation in deep penetrating arteries is not associated with SVD. Endothelial thrombomodulin increased with SVD severity, and CADASIL data suggest that this may be a cerebral response to SVD. Elevated thrombomodulin may be a protective agent in SVD. Our data confirm endothelial involvement in SVD.
authors.affiliation: Stroke and Dementia Research Centre, St Georges University of London, London, UK.
authors.forename: M O
authors.initials: MO
authors.lastname: Giwa
authors.forename: J
authors.initials: J
authors.lastname: Williams
authors.forename: K
authors.initials: K
authors.lastname: Elderfield
authors.forename: N S
authors.initials: NS
authors.lastname: Jiwa
authors.forename: L R
authors.initials: LR
authors.lastname: Bridges
authors.forename: R N
authors.initials: RN
authors.lastname: Kalaria
authors.forename: H S
authors.initials: HS
authors.lastname: Markus
authors.forename: M M
authors.initials: MM
authors.lastname: Esiri
authors.forename: A H
authors.initials: AH
authors.lastname: Hainsworth
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism* / Q000473:pathology*; D059345:Cerebral Small Vessel Diseases / Q000378:metabolism* / Q000473:pathology*; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D006801:Humans; D008297:Male; D018180:Thrombomodulin / Q000378:metabolism*
chemical_list: D018180:Thrombomodulin