Neurovascular coupling impairment as a mechanism for cognitive deficits in COVID-19

Abstract

Components that comprise our brain parenchymal and cerebrovascular structures provide a homeostatic environment for proper neuronal function to ensure normal cognition. Cerebral insults (e.g. ischaemia, microbleeds and infection) alter cellular structures and physiologic processes within the neurovascular unit and contribute to cognitive dysfunction. COVID-19 has posed significant complications during acute and convalescent stages in multiple organ systems, including the brain. Cognitive impairment is a prevalent complication in COVID-19 patients, irrespective of severity of acute SARS-CoV-2 infection. Moreover, overwhelming evidence from in vitro, preclinical and clinical studies has reported SARS-CoV-2-induced pathologies in components of the neurovascular unit that are associated with cognitive impairment. Neurovascular unit disruption alters the neurovascular coupling response, a critical mechanism that regulates cerebromicrovascular blood flow to meet the energetic demands of locally active neurons. Normal cognitive processing is achieved through the neurovascular coupling response and involves the coordinated action of brain parenchymal cells (i.e. neurons and glia) and cerebrovascular cell types (i.e. endothelia, smooth muscle cells and pericytes). However, current work on COVID-19-induced cognitive impairment has yet to investigate disruption of neurovascular coupling as a causal factor. Hence, in this review, we aim to describe SARS-CoV-2's effects on the neurovascular unit and how they can impact neurovascular coupling and contribute to cognitive decline in acute and convalescent stages of the disease. Additionally, we explore potential therapeutic interventions to mitigate COVID-19-induced cognitive impairment. Given the great impact of cognitive impairment associated with COVID-19 on both individuals and public health, the necessity for a coordinated effort from fundamental scientific research to clinical application becomes imperative. This integrated endeavour is crucial for mitigating the cognitive deficits induced by COVID-19 and its subsequent burden in this especially vulnerable population.

Keywords: SARS-CoV-2; cognitive impairment; endothelium; neurovascular uncoupling; oxidative stress.

Graphical Abstract

Figure 1

NVC response and SARS-CoV-2-mediated neurovascular disruption. (A) NVC response at the arteriolar level (left) and capillary level (right). Arrows with question marks indicate hypothesized pathways yet to be uncovered. Sharp arrows indicate cellular signaling within the NVU. Flathead arrows indicate inhibitory action on NVU pathways. (B) Hypothesized SARS-CoV-2-mediated neurovascular uncoupling. SARS-CoV-2 known action of persistent endothelial dysfunction is hypothesized as a causal factor that underlies vasodilatory impairment, neuroinflammation, capillary rarefaction, and glial activation–all known factors that contribute to neurovascular uncoupling. Created with BioRender.com. 20-HETE = 20-hydroxyeicosatetraenoic acid; cGMP = cyclic guanosine monophosphate; sGC = soluble guanylate cyclase; nNOS = neuronal nitric oxide synthase; PGE₂ = prostaglandin E₂; P2X = purinergic ligand-gated ion channel; AA = arachidonic acid; CYP450 = cytochrome P450; P2Y₁, P2Y₁₂ = purinergic G protein-coupled receptors.

Figure 2

Therapeutics targeting neurovascular uncoupling in COVID-19 induced cognitive impairment. This schematic figure illustrates four key categories, each addressing specific aspects of neurovascular function affected by COVID-19: (i) Mitochondrial Function: Metformin, Anti-oxidants, Rapamycin and life-style interventions, such as time restricted eating; (ii) Senescence: Senolytics, Rapamycin and Metformin; (iii) Inflammation: Anti-oxidants Rapamycin, Statins, ACEI/ARBs and brain stimulation; (iv) Vasodilation Interventions: Anti-oxidants, Statins, ACEI/ARBs, brain stimulation, and metformin. While these interventions have shown promise in preclinical and clinical studies, further research is needed to fully elucidate their effects and potential benefits in the context of COVID-19-related cognitive decline. Created with BioRender.com.