Pathophysiology of white matter perfusion in Alzheimer's disease and vascular dementia

Rachel Barker, Emma L. Ashby, Dannielle Wellington, Vivienne M. Barrow, Jennifer C. Palmer, Patrick G. Kehoe, Margaret M. Esiri, Seth Love*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

58 Citations (Scopus)

Abstract

Little is known about the contributors and physiological responses to white matter hypoperfusion in the human brain. We previously showed the ratio of myelin-associated glycoprotein to proteolipid protein 1 in post-mortem human brain tissue correlates with the degree of ante-mortem ischaemia. In age-matched post-mortem cohorts of Alzheimer's disease (n = 49), vascular dementia (n = 17) and control brains (n = 33) from the South West Dementia Brain Bank (Bristol), we have now examined the relationship between the ratio of myelin-associated glycoprotein to proteolipid protein 1 and several other proteins involved in regulating white matter vascularity and blood flow. Across the three cohorts, white matter perfusion, indicated by the ratio of myelin-associated glycoprotein to proteolipid protein 1, correlated positively with the concentration of the vasoconstrictor, endothelin 1 (P = 0.0005), and negatively with the concentration of the pro-angiogenic protein, vascular endothelial growth factor (P = 0.0015). The activity of angiotensin-converting enzyme, which catalyses production of the vasoconstrictor angiotensin II was not altered. In samples of frontal white matter from an independent (Oxford, UK) cohort of post-mortem brains (n = 74), we confirmed the significant correlations between the ratio of myelin-associated glycoprotein to proteolipid protein 1 and both endothelin 1 and vascular endothelial growth factor. We also assessed microvessel density in the Bristol (UK) samples, by measurement of factor VIII-related antigen, which we showed to correlate with immunohistochemical measurements of vessel density, and found factor VIII-related antigen levels to correlate with the level of vascular endothelial growth factor (P = 0.0487), suggesting that upregulation of vascular endothelial growth factor tends to increase vessel density in the white matter. We propose that downregulation of endothelin 1 and upregulation of vascular endothelial growth factor in the context of reduced ratio of myelin-associated glycoprotein to proteolipid protein 1 are likely to be protective physiological responses to reduced white matter perfusion. Further analysis of the Bristol cohort showed that endothelin 1 was reduced in the white matter in Alzheimer's disease (P
Original languageEnglish
Pages (from-to)1524-1532
Number of pages9
JournalBrain
Volume137
Issue number5
DOIs
Publication statusPublished - 10 May 2014

Keywords

  • Alzheimer's disease
  • brain ischaemia
  • cerebral blood flow
  • dementia
  • neuropathology
  • ENDOTHELIAL GROWTH-FACTOR
  • CEREBRAL AMYLOID ANGIOPATHY
  • CONVERTING ENZYME ACE
  • ACUTE ISCHEMIC STROKE
  • BETA-PEPTIDE
  • BLOOD-FLOW
  • RAT-BRAIN
  • ANGIOGENESIS
  • VEGF
  • PLASMA

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