The impact of cerebrovascular aging on vascular cognitive impairment and dementia

Abstract

As human life expectancy rises, the aged population will increase. Aging is accompanied by changes in tissue structure, often resulting in functional decline. For example, aging within blood vessels contributes to a decrease in blood flow to important organs, potentially leading to organ atrophy and loss of function. In the central nervous system, cerebral vascular aging can lead to loss of the integrity of the blood-brain barrier, eventually resulting in cognitive and sensorimotor decline. One of the major of types of cognitive dysfunction due to chronic cerebral hypoperfusion is vascular cognitive impairment and dementia (VCID). In spite of recent progress in clinical and experimental VCID research, our understanding of vascular contributions to the pathogenesis of VCID is still very limited. In this review, we summarize recent findings on VCID, with a focus on vascular age-related pathologies and their contribution to the development of this condition.

Keywords: Blood-brain barrier; Hypoperfusion; Vascular aging; White matter.

Fig. 1. Anatomical structures of the cerebral vasculature

(A) Brain artery branch from the circle of Willis. The vessel wall contains three layers. The tunica externa is composed of connective tissue and elastic fibers. The tunica media is a thick layer of smooth muscle cells that control vessel tone. In the inner layer, the tunica intima consists of a monolayer of endothelial cells that rest on the basement membrane. (B) Brain arteries branch into a dense network of arterioles within the pia mater. These arterioles lack the tunica externa but contain the thinner media layer. As the major switch that controls the CBF, these arterioles are exposed to both blood in the lumen and the CSF rushing through the subarachnoid space. (C) The structure of the NVU is unique to the brain. Pericytes are contractile cells sitting outside the endothelial monolayer. The endothelial cells and neurons are connected by astrocyte endfeet. Microglial cells migrate around the NVU. Complex cell-cell interactions exist within the NVU and are integrated to control CBF and cellular function. SMCs: smooth muscle cells.

Fig. 2. Vascular and neural pathology underlying VCID

The left panel represents diverse vascular pathologies in VCID. Large vessel diseases, including atherosclerosis and arterial occlusion, cause neuronal death (middle upper panel) or cerebral infarction. SVDs (left lower panel) typically cause neuritic injuries (middle lower panel), such as demyelination and axonal injuries. According to neuroimaging studies, VCID lesions can be observed in both gray and white matters (right panel). Among the lesions, cortical infarcts (typically multi-infarcts) are common in post-stroke VCID, while lacunar infarcts and leukoaraiosis are mainly located at periventricular regions. SVDs: small vessel diseases; Aβ: amyloid-β; GOM: granular osmiophilic material.

Fig. 3. Pathophysiology of WM injury in VCID

Vascular risk factors such as aging, hypertension, and diabetes result in systemic oxidative stress, which may induce cerebrovascular disorders. Two major consequences of cerebrovascular dysfunction are CBF reduction and BBB breakdown, leading to brain tissue hypoxia and inflammation. WM is particularly vulnerable to hypoxia, leading to damaged oligodendrocytes and OPCs. Loss of trophic coupling facilitates demyelination and interrupts remyelination, thereby predisposing axons to atrophy. Due to increased energy consumption during the action potential, tissue hypoxia is exacerbated. Injured OPCs secrete MMP, which amplifies BBB breakdown, leading to a feed-forward cycle that is vascular-oriented and culminates in WM injury.