Chronic cerebral hypoperfusion: a critical feature in unravelling the etiology of vascular cognitive impairment

Abstract

Vascular cognitive impairment (VCI) describes a wide spectrum of cognitive deficits related to cerebrovascular diseases. Although the loss of blood flow to cortical regions critically involved in cognitive processes must feature as the main driver of VCI, the underlying mechanisms and interactions with related disease processes remain to be fully elucidated. Recent clinical studies of cerebral blood flow measurements have supported the role of chronic cerebral hypoperfusion (CCH) as a major driver of the vascular pathology and clinical manifestations of VCI. Here we review the pathophysiological mechanisms as well as neuropathological changes of CCH. Potential interventional strategies for VCI are also reviewed. A deeper understanding of how CCH can lead to accumulation of VCI-associated pathology could potentially pave the way for early detection and development of disease-modifying therapies, thus allowing preventive interventions instead of symptomatic treatments.

Keywords: Chronic cerebral hypoperfusion; Neuronal cell death; Vascular dementia; White matter lesions.

Fig. 1

Stepwise progression to VaD. The road from risk factors to disease manifestation in VCI is a complicated one, as the multiple demographics, lifestyle and comorbid disease risk and mitigating factors interact through the progression from asymptomatic vascular lesions, cognitive impairment, and finally to VaD. Furthermore, these complex interactions give rise to several distinct cerebrovascular diseases underlying different forms of vascular brain injuries, leading to the clinical heterogeneity of VaD. However, regardless of the specific nature of vascular injury (occlusive, thrombotic, etc.), a state of chronic cerebral hypoperfusion can be considered to be the common etiological link. *See Table 1 for details and summary of supporting research

Fig. 2

Pathological drivers of CCH-associated VCI. Several CCH-induced pathological drivers have been long associated with the pathogenesis of VaD including energy imbalance, inflammation, endoplasmic reticulum (ER) stress, oxidative stress and mitochondrial dysfunction. Decreased ATP production impairs ATPase pumps, results in neuronal depolarization, and leads to a deregulation in the glutamate homeostasis at the synaptic cleft and excitotoxicity in the brain. Low cerebral blood flow triggers the brain to utilize anaerobic respiration to produce ATP and this results in the accumulation of lactate within the neurons, leading to acidosis. Neuronal death following CCH is primarily attributed to the increase in the pro-inflammatory cytokine release during the chronic inflammatory response. Danger associated molecular patterns (DAMPs) released by the brain cells can also trigger glial activation and leukocyte infiltration, both of which can also produce pro-inflammatory cytokines. At the cellular level, increase in the reactive oxidative species from various sources, including the mitochondria, induces the oxidative stress state. While the increase in reactive oxygen species can contribute to the redox dynamics and hemodynamics imbalance, it can also induce chronic ER stress. Persistent ER stress leads to an accumulation of misfolded proteins and can have fatal effects on neuronal survival and integrity via the terminal unfolded protein response (UPR) pathway, as well as contributing to Ca²⁺ homeostatic imbalance. Mitochondrial deterioration causes a further decrease in the ATP production, leading to proteosomal dysfunction, as well as contributing to the frequency of mutagenesis events at the mitochondrial DNA. In a chronic state of CCH, these drivers are pathological and ultimately pave the way for downstream disease mechanisms