Theranostics 2022; 12(4):1639-1658. doi:10.7150/thno.68304 This issue

Review

Pathophysiology of blood brain barrier dysfunction during chronic cerebral hypoperfusion in vascular cognitive impairment

Vismitha Rajeev1, David Y. Fann2,3,4, Quynh Nhu Dinh5, Hyun Ah Kim5, T. Michael De Silva5, Mitchell K.P. Lai1, Christopher Li-Hsian Chen1, Grant R. Drummond5, Christopher G. Sobey5, Thiruma V. Arumugam5,6✉

1. Memory Aging and Cognition Centre, Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
2. Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
3. Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
4. Centre for Healthy Longevity, National University Health System (NUHS), Singapore
5. Centre for Cardiovascular Biology and Disease Research, Department of Physiology, Anatomy and Microbiology, School of Life Sciences, La Trobe University, Bundoora, VIC, Australia
6. School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Citation:
Rajeev V, Fann DY, Dinh QN, Kim HA, De Silva TM, Lai MKP, Chen CLH, Drummond GR, Sobey CG, Arumugam TV. Pathophysiology of blood brain barrier dysfunction during chronic cerebral hypoperfusion in vascular cognitive impairment. Theranostics 2022; 12(4):1639-1658. doi:10.7150/thno.68304. Available from https://www.thno.org/v12p1639.htm

File import instruction

Abstract

Graphic abstract

The prevalence of cerebrovascular disease increases with age, placing the elderly at a greater lifetime risk for dementia. Vascular cognitive impairment (VCI) encompasses a spectrum of cognitive deficits from mild cognitive impairment to dementia. VCI and its most severe form, vascular dementia (VaD), is becoming a major public health concern worldwide. As growing efforts are being taken to understand VCI and VaD in animal models and humans, the pathogenesis of the disease is being actively explored. It is postulated that chronic cerebral hypoperfusion (CCH) is a major cause of VCI. CCH activates a molecular and cellular injury cascade that leads to breakdown of the blood brain barrier (BBB) and neurodegeneration. The BBB tightly regulates the movement of substances between the blood and the brain, thereby regulating the microenvironment within the brain parenchyma. Here we illustrate how BBB damage is causal in the pathogenesis of VCI through the increased activation of pathways related to excitotoxicity, oxidative stress, inflammation and matrix metalloproteinases that lead to downstream perivascular damage, leukocyte infiltration and white matter changes in the brain. Thus, CCH-induced BBB damage may initiate and contribute to a vicious cycle, resulting in progressive neuropathological changes of VCI in the brain. This review outlines the molecular and cellular mechanisms that govern BBB breakdown during CCH and highlights the clinical evidence in identifying at-risk VCI patients.