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

• Published in: Brain (London, England : 1878) England : 1878), 2014-05, Vol.137 (5), p.1524-1532
• Main Authors: Barker, Rachel, Ashby, Emma L., Wellington, Dannielle, Barrow, Vivienne M., Palmer, Jennifer C., Kehoe, Patrick G., Esiri, Margaret M., Love, Seth
• Format: Article
• Language: English
• Subjects: Adult and adolescent clinical studies; Aged; Aged, 80 and over; Alzheimer Disease - pathology; Biological and medical sciences; Brain - pathology; Cohort Studies; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Dementia, Vascular - pathology; Endothelin-1 - metabolism; Factor VIII - metabolism; Female; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy; Humans; Male; Medical sciences; Middle Aged; Myelin-Associated Glycoprotein - metabolism; Nerve Fibers, Myelinated - pathology; Nerve Fibers, Myelinated - physiology; Nervous system (semeiology, syndromes); Neurology; Organic mental disorders. Neuropsychology; Original; Peptidyl-Dipeptidase A - metabolism; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Vascular diseases and vascular malformations of the nervous system; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 0006-8950; 1460-2156
• DOI: 10.1093/brain/awu040

The pathophysiology of white matter hypoperfusion is poorly understood. Barker et al. quantify ante-mortem hypoperfusion by measuring myelin proteins differentially susceptible to ischaemia, and assess the extent to which vasoregulatory factors protect from or contribute to ischaemic white matter injury in Alzheimer’s disease and vascular dementia. 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 matt