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

Abstract

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.

Blood–Brain Barrier Breakdown: An Emerging Biomarker of Cognitive Impairment in Normal Aging and Dementia

“…It is a progressive neurological disease associated with impairments in cognition and deterioration of the everyday life activities of an affected individual (Mills et al, 2007 ; Kirshner, 2009 ). In dementia, BBB breakdown and cerebral hypoperfusion cause brain damage and a decline in cognition (Nation et al, 2019 ; Tayler et al, 2021 ). Dementia is a considerable health complication affecting millions of people worldwide.…”

“…Figure 1 shows the difference between young or normal BBB and aged or dysfunctional BBB. (Bell and Zlokovic, 2009;Grinberg and Thal, 2010;Richardson et al, 2012;Rouhl et al, 2012;Sagare et al, 2012) Yes (Salmina et al, 2010;Villar-Vesga et al, 2020;Chacón-Quintero et al, 2021;González-Molina et al, 2021) Yes (Wardlaw et al, 2003;Zhang et al, 2014;Rajani et al, 2018;Wang et al, 2018;Tayler et al, 2021;Zhu et al, 2021) Extracellular components…”

“…• Thickness increase Yes (Grinberg and Thal, 2010;Richardson et al, 2012;Rouhl et al, 2012) Yes (Zlokovic, 2011;Morris et al, 2014) Yes (Ueno et al, 2002;Iadecola, 2013;Rosenberg, 2017) Pericytes • Pericytes number decrease • PDGFRβ in CSF increase Yes (Bell et al, 2010;Montagne et al, 2015;Sagare et al, 2015;Duncombe et al, 2017;Erdo et al, 2017;Goodall et al, 2018;Nation et al, 2019) Yes (Sengillo et al, 2013;Halliday et al, 2016;Montagne et al, 2018;Miners et al, 2019;Uemura et al, 2020) Yes (Iadecola, 2013;Montagne et al, 2018;Yang et al, 2018;Uemura et al, 2020) Astrocytes • Vascular coverage reduction • GFAP upregulation • AQP4 downregulation Yes (Middeldorp and Hol, 2011;Duncombe et al, 2017;Goodall et al, 2018;Heithoff et al, 2021) Yes (Abbott et al, 2006;Yang Y. et al, 2011;Kimbrough et al, 2015;Ahmad et al, 2019) Yes (Wardlaw et al, 2003;Iadecola, 2013;Saggu et al, 2016;Price et al, 2018;Wang et al, 2018;Tayler et al, 2021)...…”

Tongxinluo Exerts Inhibitory Effects on Pyroptosis and Amyloid-β Peptide Accumulation after Cerebral Ischemia/Reperfusion in Rats

“…On the other hand, studies have indicated that A β toxicity acts as a trigger of pyroptosis and BBB damage [ 14 , 15 , 34 ]. Therefore, a vicious circle is considered to form between astrocytic pyroptosis and A β accumulation in cerebral I/R injuries, exacerbating BBB damage which is a vital trigger of both AD and vascular dementia (VD), the two main types of dementia [ 35 ]. In the present study, our results exhibited the AQP-4 polarization loss with obvious dispersion accompanied with A β accumulation around astrocytes in ischemic cortex and hippocampus as well as increased A β 1–42 oligomers (the main form of A β toxicity) after cerebral I/R.…”

Interplay between Brain Pericytes and Endothelial Cells in Dementia

“…70 However, increased VEGF has been found in the white matter in patients with cSVD and AD without apparent rescue, suggesting that a more complex signaling mechanism is involved. 24 Loss of pericytes leads to increased VEGF-A expression in endothelial cells, 18 which may be a compensatory endothelial cell response to promote cell survival. However, it may also be attributable to loss of pericyte VEGF receptor 1, which regulates VEGF signaling by sequestration 110 or a combination of both mechanisms.…”