Vascular Dysfunctions Contribute to the Long-Term Cognitive Deficits Following COVID-19

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a single-stranded RNA virus and a member of the corona virus family, primarily affecting the upper respiratory system and the lungs. Like many other respiratory viruses, SARS-CoV-2 can spread to other organ systems. Apart from causing diarrhea, another very common but debilitating complication caused by SARS-CoV-2 is neurological symptoms and cognitive difficulties, which occur in up to two thirds of hospitalized COVID-19 patients and range from shortness of concentration and overall declined cognitive speed to executive or memory function impairment. Neuro-cognitive dysfunction and "brain fog" are frequently present in COVID-19 cases, which can last several months after the infection, leading to disruption of daily life. Cumulative evidence suggests that SARS-CoV-2 affects vasculature in the extra-pulmonary systems directly or indirectly, leading to impairment of endothelial function and even multi-organ damage. The post COVID-19 long-lasting neurocognitive impairments have not been studied fully and their underlying mechanism remains elusive. In this review, we summarize the current understanding of the effects of COVID-19 on vascular dysfunction and how vascular dysfunction leads to cognitive impairment in patients.

Keywords: SARS-CoV-2; blood-brain barrier; cognitive dysfunction; endothelial cells; long COVID; neuro-inflammation.

Figure 1

Schematic representation of SARS-CoV-2 infection causing vascular dysfunction and BBB disruption. Proinflammatory cytokines result in VEGF production in astrocytes via allowing immune cells to pass through the BBB. VEGF is able to disrupt TJ proteins in brain capillary endothelial cells by triggering the phosphoinositide 3 (PI3)-kinase and AKT signaling pathways and MMP-9 upregulation, leading to BBB breakdown.

Figure 2

Schematic representation of indirect BBB disruption resulting from vascular dysfunction in COVID-19. The virus acts via binding of the spike glycoprotein of the virus to the angiotensin converting enzyme 2 (ACE2) on the cell surface. Disharmonic and disturbed immune reaction in COVID-19 patients lead to wide local and systemic inflammation by generating cytokine storm, leading to ARDS and vascular coagulation. Alternatively, it may lead to the formation of neutrophil extracellular traps (NETs), composed of chromatin and microbicidal proteins, which participate in the pathobiology of thrombosis and platelets aggregation. Activation of the complement system results in the generation of C5a and C5b, which are involved in the inflammation and activation of platelets. This C5b forms the membrane attack complex (MAC) to activate microvascular coagulation and inflammation.