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Publication - Dr Scott Miners

    Biochemical Evidence Of Cerebral Hypoperfusion in Dementia: Associated With β-Secretase, Endothelin-1 And Arteriolosclerosis

    Citation

    Tayler, H, MacLachlan, R, Miners, S & Love, S, 2019, ‘Biochemical Evidence Of Cerebral Hypoperfusion in Dementia: Associated With β-Secretase, Endothelin-1 And Arteriolosclerosis’.

    Abstract

    We have developed biochemical methods to quantify ante-mortem white matter oxygenation, microvascular content and blood-brain barrier disruption. Their value in determining the disease processes responsible for dementia remains to be established. To assess this, we have analysed frontal and parietal cortex and white matter from 104 donors with a neuropathologically-confirmed diagnosis of Alzheimer’s disease, 21 with vascular dementia, 33 with mixed pathology, and 57 controls. All had previously had comprehensive quantitative/semiquantitative assessment of neurodegenerative and cerebral vascular disease pathologies.
    Ante-mortem oxygenation was assessed by measuring the ratio of myelin associated glycoprotein (MAG) to proteolipid protein-1 (PLP1) (Barker et al, J Cereb Blood Flow Metab 2013;33:1050), and the concentration of vascular endothelial growth factor-A (VEGFA) (Thomas et al, Brain 2015;138:1059). We also measured multiple other vascular markers including endothelin-1; von Willebrand factor, to indicate microvessel density; the pericyte marker, platelet-derived growth factor receptor-β; fibrinogen, to assess blood-brain barrier leakage; and β-secretase activity, known to be important for maintenance of blood vessels (Cai et al. EMBO Mol Med 2012;4:980).
    Stepwise logistic multivariable regression analysis showed the main independent predictors of dementia in this cohort to be Braak tangle stage, frontal Aβ plaque load, frontal white matter MAG:PLP1, frontal arteriolosclerosis and frontal cerebral amyloid angiopathy (area under ROC curve >0.97). Further analysis indicated that reduction in MAG:PLP1 was associated with increased β-secretase activity, endothelin-1, VEGFA and, to a lesser extent, arteriolosclerosis.
    Our findings support the use of biochemical methods to quantify vascular disease processes in post-mortem brains, and highlight the importance of altered expression of vasoregulatory factors such as endothelin-1 in reduced cerebral oxygenation and the development of dementia.

    Full details in the University publications repository