title: Pathophysiology of white matter perfusion in Alzheimer's disease and vascular dementia.
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 < 0.05) compared with control subjects, but not in vascular dementia, in which endothelin 1 tended to be elevated, perhaps reflecting abnormal regulation of white matter perfusion in vascular dementia. Our findings demonstrate the potential of post-mortem measurement of myelin proteins and mediators of vascular function, to assess physiological and pathological processes involved in the regulation of cerebral perfusion in Alzheimer's disease and vascular dementia.
authors.affiliation: 1 Dementia Research Group, Institute of Clinical Neurosciences, School of Clinical Sciences, University of Bristol, Bristol, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Barker
authors.forename: Emma L
authors.initials: EL
authors.lastname: Ashby
authors.forename: Dannielle
authors.initials: D
authors.lastname: Wellington
authors.forename: Vivienne M
authors.initials: VM
authors.lastname: Barrow
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Palmer
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Kehoe
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Esiri
authors.forename: Seth
authors.initials: S
authors.lastname: Love
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000473:pathology*; D001921:Brain / Q000473:pathology*; D015331:Cohort Studies; D015140:Dementia, Vascular / Q000473:pathology*; D019332:Endothelin-1 / Q000378:metabolism; D005169:Factor VIII / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018992:Myelin-Associated Glycoprotein / Q000378:metabolism; D009413:Nerve Fibers, Myelinated / Q000473:pathology / Q000502:physiology*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D019332:Endothelin-1; D018992:Myelin-Associated Glycoprotein; D042461:Vascular Endothelial Growth Factor A; D005169:Factor VIII; D007703:Peptidyl-Dipeptidase A
keywords: Alzheimer’s disease; brain ischaemia; cerebral blood flow; dementia; neuropathology