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

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.

Figure 1

In a healthy state, tight junctions (TJs) zonula occludens (ZO-1), Claudin-5, Occludin and junctional adhesion molecules (JAMs) are involved at the apical end of the endothelial cells. Adherens junctions such as VE-cadherins are involved at the basolateral end of the endothelial cells. Collectively, these proteins provide for a continuous intercellular barrier between the endothelial cells. Pericytes, astrocytic end feet and the basement membrane are associated with the endothelial cells that collectively form the blood brain barrier (BBB) and are involved in the tightly regulated movements of molecules between the blood and the brain. In a chronic cerebral hypoperfused state, the reduced cerebral blood flow (CBF) triggers a myriad of effects on the BBB such as the reduced expression, modification and weakened assembly of the TJ proteins between the endothelial cells. Other effects of a reduced CBF are the induction of increased excitotoxicity, inflammation, oxidative stress and expression of matrix metalloproteinases. Collectively, these effects increase the permeability of the BBB at the endothelial cells and therefore increase the movement of substances between the blood and the brain. Secondary effects of increased BBB permeability include leukocyte infiltration, unregulated transcytosis, damaged pericytes, increased perivascular space and astrogliosis.

Figure 2

Chronic cerebral hypoperfusion or reduced cerebral blood flow (CBF) results in various mechanisms triggered in endothelial and neighbouring cells of the neurovascular unit including excitotoxicity. Excitotoxicity is induced in endothelial cells in response to a decreased glucose intake. Abnormally high levels of cytosolic Ca²⁺ induces the disruption of metabolism, mitochondrial dysfunction, activation of proteases and phospholipases, and production of reactive oxidative species (ROS) that collectively contribute to cell membrane damage and vascular cell death leading to disruption of BBB integrity. Astrocytes of the BBB are adversely affected by excitotoxins, as the interaction between astrocytes and the extracellular matrix (ECM) is rapidly disrupted. Astrocytic dysfunction or astrogliosis coupled with increased transendothelial pinocytosis contributes mostly to BBB breakdown after excitotoxicity.

Figure 3

Oxidative Stress induces endothelial cell dysfunction. Increased reactive oxygen species (ROS) and reactive nitrogen species (RNS) from sources such as NADPH oxidases, cyclooxygenases and mitochondria. Increased oxidative stress can modify TJs directly, cause endothelial dysfunction, and activate MMPs.

Figure 4

Inflammation is induced via the release of pro-inflammatory cytokines and chemokines. This release can activate various cell types including endothelial cells. These cytokines can directly damage the BBB, and increase permeability at the endothelial cell interface via either weakening assembly or endocytosis of tight junctions (TJs). They can also activate apoptotic pathways; unregulated transcytosis across the endothelial cells and also occur in response to inflammation. MMPs are activated by inflammation and can affect ECM and TJ disruption. Leukocyte infiltration is a downstream effect of increased cell adhesion pathways during inflammation. ECM edema can also cause other downstream effects such as white matter lesions (WMLs) and perivascular damage.

Figure 5

Clinical Detection Method for BBB Breakdown. In patients, there are three main ways that BBB breakdown is measured. The first detection method is via neuroimaging techniques. The most sensitive and commonly used method is T1-weighted dynamic contrast-enhanced MRI (DCE-MRI), to image for low molecular weight paramagnetic tracers in the blood. Positron emission tomography (PET) imaging visualises the movement of radiolabelled tracers injected such as gallium. However, these methods are quite invasive in nature. A non-invasive MRI method known as diffusion-prepared arterial spin labelling (DP-ASL) is an effective technique to measures subtle dysfunctions associated with altered water exchange rates across the BBB. Another detection method of BBB permeability is through the measurement of fluid biomarkers. While cerebral spinal fluid (CSF) albumin and transthyretin have been studied to be effective markers of BBB permeability, their invasive nature proves to be ineffective. Hence blood biomarkers Albumin and S100b have gained much interest lately in measuring BBB breakdown.