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

Rajeev, Vismitha; Chai, Yuek Ling; Poh, Luting; Selvaraji, Sharmelee; Fann, David Y.; Jo, Dong-Gyu; De Silva, T. Michael; Drummond, Grant R.; Sobey, Christopher G.; Arumugam, Thiruma V.; Chen, Christopher P.; Lai, Mitchell K. P. · 2023 · DOAJ

DOI: 10.1186/s40478-023-01590-1

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Summary

This review article addresses the etiology of vascular cognitive impairment (VCI), a spectrum of cognitive deficits ranging from subjective decline to vascular dementia. The authors identify chronic cerebral hypoperfusion (CCH)—chronically inadequate brain perfusion—as the critical, unifying driver of VCI pathology. While VCI is heterogeneous and associated with various risk factors such as hypertension, diabetes, and stroke, the underlying mechanisms linking these factors to cognitive decline remain incompletely understood. The paper posits that CCH serves as the common etiological link across different VCI subtypes, motivating a comprehensive review of its pathophysiological mechanisms, neuropathological consequences, and potential interventional strategies. The authors conducted a narrative review of existing literature, synthesizing data from clinical studies, longitudinal observations, and animal models. They analyzed the relationship between CCH and structural brain changes, such as white matter lesions and lacunes, and examined molecular pathways including energy imbalance, oxidative stress, endoplasmic reticulum stress, and neuroinflammation. The review also cataloged current pharmacotherapeutic options, such as antihypertensives and antiplatelet agents, to contextualize potential treatments within the framework of CCH-driven pathology. The findings indicate that CCH is a central mediator of VCI progression, leading to a cascade of cellular and molecular events. Reduced cerebral blood flow causes energy imbalance by compromising ATP production, which impairs sodium-potassium pumps and leads to glutamate excitotoxicity. CCH also induces oxidative stress through disrupted calcium homeostasis and increased reactive oxygen species production, further damaging vascular tone and promoting neuronal apoptosis. These mechanisms contribute to blood-brain barrier dysfunction, neuroinflammation, and the accumulation of neuropathological lesions like white matter injury. Clinically, CCH is associated with significant reductions in cerebral blood flow, particularly in frontal and parietal cortices, and predicts the development of white matter lesions. The review highlights that while current treatments manage risk factors, they do not directly address the underlying CCH mechanisms. The significance of this work lies in establishing CCH as a pivotal target for early detection and disease-modifying therapies in VCI. By elucidating how CCH drives the accumulation of pathology, the authors argue that interventions aimed at restoring perfusion or mitigating hypoperfusion-induced damage could prevent cognitive decline rather than merely treating symptoms. This perspective shifts the focus from symptomatic management to preventive strategies, potentially reducing the socioeconomic burden of VCI. The review underscores the need for further research into therapies that specifically address the pathophysiological cascade initiated by chronic hypoperfusion.

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• cognitive impairment