Envisaging Blood Brain Barrier Dysfunction as Secondary to Reduced Blood Flow to the Brain

The blood-brain barrier is a layer of specialized cells that tightly control passage of cells and molecules from the vasculature to the central nervous system. When the blood-brain barrier becomes dysfunctional and leaky with age, this contributes to chronic inflammation in brain tissue. The paper here provides an interesting discussion of the degree to which blood-brain barrier dysfunction in aging is secondary to reduced blood flow to the brain. A combination of factors lead to reduced circulation in the brain: loss of capillary density; small vessel disease in which the vessels narrow and weaken; heart failure; loss of physical fitness and reduced level of exercise; and so forth.

Vascular cognitive impairment (VCI) covers an entire spectrum of vascular pathologies that contribute to cognitive impairment, from pre-clinical subjective states to the manifestation of a severe state of cognitive decline such as vascular dementia (VaD). Even without the presence of risk factors, vascular aging leads to chronic cerebral hypoperfusion (CCH) that induces phenotypical changes in the brain and therefore makes the brain more vulnerable to disease. This emphasizes the importance of cerebral blood flow (CBF) regulation under physiological and pathological conditions. Cerebral blood vessels are responsible for the delivery of many important substances to the brain such as nutrients and oxygen, which is necessary for neuronal oxidative metabolism of energy substrates. Neurons have limited capacity for anaerobic metabolism, thus adequate CBF is critically important for function and viability of neurons.

CCH was reported to be a common feature in all subtypes of VCI. In fact, CCH was reported to begin at early stages of VCI and continue till the late demented state of VaD. Furthermore, in a severe state of VaD, global CBF reduction in patients was reported to be more extensive than age-matched controls and Alzheimer's disease patients. VaD patient cohorts reportedly showed decreased CBF to all parts of the brain. A study reported a 31% decrease in CBF at the frontal cortex and a 39% decrease in CBF at the parietal cortex.

It is postulated that 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.

Link: https://doi.org/10.7150/thno.68304

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