COVID-19 and cognitive impairment: neuroinvasive and blood‒brain barrier dysfunction

Abstract

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to a global pandemic. Although COVID-19 was initially described as a respiratory disease, there is growing evidence that SARS-CoV-2 is able to invade the brains of COVID-19 patients and cause cognitive impairment. It has been reported that SARS-CoV-2 may have invasive effects on a variety of cranial nerves, including the olfactory, trigeminal, optic, and vagus nerves, and may spread to other brain regions via infected nerve endings, retrograde transport, and transsynaptic transmission. In addition, the blood-brain barrier (BBB), composed of neurovascular units (NVUs) lining the brain microvasculature, acts as a physical barrier between nerve cells and circulating cells of the immune system and is able to regulate the transfer of substances between the blood and brain parenchyma. Therefore, the BBB may be an important structure for the direct and indirect interaction of SARS-CoV-2 with the brain via the blood circulation. In this review, we assessed the potential involvement of neuroinvasion under the SARS-CoV-2 infection, and the potential impact of BBB disorder under SARS-CoV-2 infection on cognitive impairment.

Keywords: BBB; COVID-19; Cognitive; Neuroinvasion; SARS-CoV-2.

Fig. 1

Potential routes of SARS-CoV-2 entry into the brain via the olfactory pathway. Once SARS-CoV-2 is inhaled into the nasal cavity, the virus spreads to the central nervous system along the retrograde axons of the olfactory nerve via the olfactory epithelial receptors ACE2 and TMPRSS2

Fig. 2

Possible pathways by which SARS-CoV-2 enters the brain through other neural invasions. In addition to infection through the olfactory route, SARS-CoV-2 can also be transmitted through direct or indirect contact with the eyes and oral mucosa. SARS-CoV-2 may enter cells through receptors such as ACE2 on the nasal cavity, eyes, respiratory epithelium, lung parenchyma, and gut and in turn affect multiple cranial nerves (including trigeminal, optic, and vagus nerves). SARS-CoV-2 may infect nerve endings, be transported retrogradely, and spread to other brain regions via synapses

Fig. 3

Possible mechanism of SARS-CoV-2 infection of the brain via the haematogenous route. Pulmonary infection with SARS-CoV-2 leads to vascular endothelial damage and increase capillary permeability, allowing virus transfer from the lungs to the pulmonary microcirculation. After reaching the BBB, SARS-CoV-2 may enter the CNS through direct interaction with ACE2 receptors or by altering tight junction proteins formed by BBB endothelial cells. Infection with SARS-CoV-2 increases circulating concentrations of proinflammatory cytokines (IL-1, IL-1β, TNF-α, IL-6, IL-12, etc.), thrombin, fibrinogen, and plasmin, and induced hypoxia to disrupt the BBB may lead to paracellular passage of SARS-CoV-2 as a means of entry into the CNS. In addition, infected leukocytes can carry SARS-CoV-2 across the BBB to infect the CNS through a “Trojan horse” mechanism