Cognitive Sequelae of COVID-19: Mechanistic Insights and Therapeutic Approaches

Abstract

Background: The COVID-19 pandemic has left an indelible mark on the world, with mounting evidence suggesting that it not only posed acute challenges to global healthcare systems but has also unveiled a complex array of long-term consequences, particularly cognitive impairment (CI). As the persistence of post-COVID-19 neurological syndrome could evolve into the next public health crisis, it is imperative to gain a better understanding of the intricate pathophysiology of CI in COVID-19 patients and viable treatment strategies.

Methods: This comprehensive review explores the pathophysiology and management of cognitive impairment across the phases of COVID-19, from acute infection to Long-COVID, by synthesizing findings from clinical, preclinical, and mechanistic studies to identify key contributors to CI, as well as current therapeutic approaches.

Results: Key mechanisms contributing to CI include persistent neuroinflammation, cerebrovascular complications, direct neuronal injury, activation of the kynurenine pathway, and psychological distress. Both pharmacological interventions, such as anti-inflammatory therapies and agents targeting neuroinflammatory pathways, and non-pharmacological strategies, including cognitive rehabilitation, show promise in addressing these challenges. Although much of the current evidence is derived from preclinical and animal studies, these findings provide foundational insights into potential treatment approaches.

Conclusion: By synthesizing current knowledge, this review highlights the importance of addressing COVID-19-related cognitive impairment and offers actionable insights for mitigation and recovery as the global community continues to grapple with the pandemic's long-term impact.

Keywords: COVID‐19; brain; cognitive impairment; pathophysiology; pharmacological treatment.

FIGURE 1

Proposed pathways for SARS‐CoV‐2 entry into the brain. A cartoon model illustrates four potential routes through which SARS‐CoV‐2 may enter the brain: (1) examining the potential for viral entry through the olfactory system, (2) exploring the possibility of retrograde transmission from peripheral nerves, (3) highlighting the potential entry through the bloodstream, and (4) demonstrating the role of the choroid plexus in viral entry.

FIGURE 2

Pathophysiology of cognitive impairment in COVID‐19 patients. A cartoon figure outlines the potential pathophysiological mechanisms contributing to cognitive impairment in COVID‐19 patients, including: (1) direct viral entry induced brain injury. (2) Hypoxia induced reduction of oxygen levels may contribute to cognitive decline. (3) Highlighting the role of widespread systemic inflammation in cognitive impairment.

FIGURE 3

Impact of SARS‐CoV‐2 on the renin–angiotensin system (RAS). This flowchart illustrates the consequences of SARS‐CoV‐2 attachment to cells, which results in the downregulation of ACE‐2 receptor expression. This downregulation leads to the suppression of the regulatory RAS pathway and the overactivation of the classical RAS pathway.

FIGURE 4

Mechanism of leaky ryanodine receptor 2 channels in cognitive impairment after SARS‐CoV‐2 infection. A cartoon illustration offers a concise explanation of the potential mechanism underlying leaky ryanodine channels, which regulate cellular calcium overload and contribute to cognitive impairment in individuals affected by SARS‐CoV‐2.

FIGURE 5

Vascular dysfunction and cognitive impairment in COVID‐19 patients. A cartoon figure demonstrates (1) the cascade of events triggered by endothelial damage, leading to the activation of the intrinsic pathway and bone morphogenetic protein (BMP) activation. (2) The consequences of decreased ACE2 receptor levels, resulting in increased Angiotensin II (Ang II) levels and the release of vasoactive compounds such as prostaglandins (PG), thromboxane (TXA2), serotonin, and adenosine diphosphate (ADP). These factors collectively contribute to additional endothelial injury, which may potentially lead to cognitive impairment in individuals with COVID‐19.

FIGURE 6

Impact of SARS‐CoV‐2 on the kynurenine pathway in the peripheral and central nervous system which leads to cognitive impairment. A visual representation depicts the impact of SARS‐CoV‐2 on the kynurenine pathway in both the peripheral and central nervous systems, potentially leading to cognitive impairment or cognitive symptoms following SARS‐CoV‐2 infection.

FIGURE 7

Mechanisms for ameliorating cognitive impairment caused by elevated kynurenine metabolites. A cartoon figure demonstrates three mechanisms for inhibiting cognitive impairment caused by elevated kynurenine metabolites: (1) KMO inhibitors, (2) KAT inhibitors, and (3) Brain‐permeable KMO inhibitors.