Molecular and systemic mechanisms of cognitive impairment associated with coronavirus infection

Cognitive dysfunction represents a prevalent and long-lasting non-respiratory symptom following a protracted course of coronavirus infection, yet its molecular basis remains inadequately characterized. This review aims to present a comprehensive and systematic examination of the pathogenic mechanisms underlying cognitive impairment associated with COVID-19 and to consolidate current evidence on the critical processes linking SARS-CoV-2 infection to long-term neurological outcomes. Evidence indicates that cognitive deficits resulting from COVID-19 arise from a multifaceted interplay, including the virus's direct neurotropic effects, the emergence of neuroinflammation characterized by microglial and astrogliosis activation, disruption of the blood-brain barrier, and cerebrovascular complications. Additionally, systemic neuroendocrine alterations - including dysfunctions of the autonomic nervous system, hypothalamic-pituitary-adrenal axis, and monoamine metabolism - as well as diminished glymphatic clearance, are significant in the pathogenesis and are intricately associated with neuropsychiatric symptoms, thereby perpetuating the pathological processes. The notable molecular similarities with the early stages of neurodegenerative diseases suggest a potential risk for long-term acceleration of neurodegenerative processes in individuals experiencing post-COVID syndrome. Future research should focus on developing integrative diagnostic algorithms that combine biomarkers representative of various pathogenic processes with advanced neuroimaging techniques, organizing longitudinal studies to assess the time course of cognitive disorders, and formulating personalized therapeutic strategies to address key components of the identified pathogenic mechanisms.