Journal Article

Mediators of cerebral hypoperfusion and blood‐brain barrier leakiness in Alzheimer’s disease, vascular dementia and mixed dementia

Miners, J. Scott, MacLachlan, Rob, Tayler, Hannah, Güzel, Özge, Love, Seth

2021

Overview

In vascular dementia (VaD) and Alzheimer’s disease (AD), cerebral hypoperfusion and blood‐brain barrier (BBB) leakiness contribute to brain damage. In this study, we have measured biochemical markers and mediators of cerebral hypoperfusion and BBB in the frontal (BA6) and parietal (BA7) cortex and underlying white matter, to investigate the pathophysiology of vascular dysfunction in AD, VaD and mixed dementia. The ratio of myelin‐associated glycoprotein to proteolipid protein‐1 (MAG:PLP1), a post‐mortem biochemical indicator of the adequacy of ante‐mortem cerebral perfusion; the concentration of fibrinogen adjusted for haemoglobin level, a marker of blood‐brain barrier (BBB) leakiness; the level of vascular endothelial growth factor‐A (VEGF), a marker of tissue hypoxia; and endothelin‐1 (EDN1), a potent vasoconstrictor, were measured by ELISA in the frontal and parietal cortex and underlying white matter in 94 AD, 20 VaD, 33 mixed dementia cases and 58 age‐matched controls. All cases were assessed neuropathologically for small vessel disease (SVD), cerebral amyloid angiopathy (CAA) severity, Aβ and phospho‐tau parenchymal load, and Braak tangle stage. Aβ40 and Aβ42 were measured by ELISA in guanidine‐HCl tissue extracts. We found biochemical evidence of cerebral hypoperfusion in AD, VaD and mixed dementia to be associated with SVD, Aβ level, plaque load, EDN1 level and Braak tangle stage, and to be most widespread in mixed dementia. There was evidence of BBB leakiness in AD—limited to the cerebral cortex and related to EDN1 level. In conclusion, abnormalities of cerebral perfusion and BBB function in common types of dementia can largely be explained by a combination of arteriolosclerosis, and Aβ‐, tau‐ and endothelin‐related vascular dysfunction. The relative contributions of these processes vary considerably both between and within the diseases. Tayler et al. used post‐mortem biochemical methods to determine the severity of chronic and acute hypoperfusion of the cerebral cortex and white matter in Alzheimer's disease (AD), vascular dementia (VaD) and mixed dementia (Mixed). The two myelin proteins myelin‐associated protein (MAG) and proteolipid protein‐1 (PLP‐1), which have a similar slow turnover in vivo, are differentially susceptible to changes in tissue oxygenation such that a fall in the ratio of these proteins indicates reduced perfusion of the tissue over a period of several months prior to death. In contrast, vascular endothelial growth factor‐A (VEGF‐A) is upregulated acutely in response to tissue hypoxia. By measuring these proteins, the authors showed the severity of cerebral hypoperfusion in AD, VaD and mixed dementia to be associated with multiple factors (small vessel disease severity, Aβ level, plaque load, endothelin‐1 level and Braak tangle stage) and to be most widespread in mixed dementia.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: Abnormalities / Adequacy / Advertising executives / Aged / Aged, 80 and over / Alzheimer Disease - complications / Alzheimer Disease - pathology / Alzheimer's disease / Amyloid / Amyloid beta-Peptides - metabolism / Binswanger's disease / Biochemical markers / Biochemistry / Blood vessels / Blood-brain barrier / Blood-Brain Barrier - metabolism / Blood-Brain Barrier - pathology / Brain / Brain - metabolism / Brain - pathology / Brain damage / Brain injury / Cerebral amyloid angiopathy / Cerebral Amyloid Angiopathy - complications / Cerebral Amyloid Angiopathy - pathology / Cerebral cortex / cerebral hypoperfusion / Cerebrovascular Disorders - complications / Cerebrovascular Disorders - pathology / Cortex (frontal) / Cortex (parietal) / Dementia / Dementia disorders / Dementia, Vascular - pathology / Endothelins / Female / Fibrinogen / Glycoproteins / Growth factors / Guanidine hydrochloride / Hemoglobin / Humans / Hypoxia / Male / Markers / Medical research / Medicine, Experimental / mixed dementia / Myelin / Myelin proteolipid protein / Myelin-associated glycoprotein / Neurodegenerative diseases / pathophysiology / Perfusion / Plaque, Amyloid - complications / Plaque, Amyloid - pathology / Substantia alba / Tau protein / Vascular dementia / Vascular endothelial growth factor