Neurological Manifestations of COVID-19: Unraveling the Pathogenesis and Long-Term Implications


The association between COVID-19 and neurological manifestations, both in the acute phase and post-infection, has been a subject of intense research and scrutiny. Studies have shown that patients with COVID-19 exhibit signs of central nervous system (CNS) involvement, highlighted by the presence of neurological symptoms and changes in biomarkers indicative of neuronal and glial damage.

One significant area of focus has been on the biomarkers neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP), which serve as indicators of neuronal and glial degeneration, respectively. These biomarkers have been traditionally used in neurodegenerative diseases and are now being applied to understand the neurological impact of COVID-19. Elevated levels of NfL and GFAP have been reported in both hospitalized and non-hospitalized COVID-19 patients, pointing to an ongoing process of CNS injury that transcends the severity of respiratory symptoms.

Recent studies have reinforced these findings, showing elevated levels of NfL and GFAP in patients with severe COVID-19 and in those with milder cases. This suggests a broad spectrum of neurological involvement irrespective of the overall disease severity. For instance, in a study involving critically ill COVID-19 patients, it was found that GFAp and NfL levels decreased over time, but changes in cognitive function and fatigue persisted for months following the acute phase of the infection. This persistence of symptoms underscores the need for long-term monitoring of COVID-19 survivors for potential lingering cognitive and neurological effects​​​​​​.

Moreover, the relationship between these biomarkers and cognitive outcomes has been explored, with findings indicating that cognitive impairments can occur even in those with milder forms of the disease and without significant changes in inflammatory markers. This is particularly concerning given the vast spread of COVID-19 globally and the potential for a substantial number of individuals to experience such cognitive deficits post-infection. The cognitive decline, encompassing issues like executive functioning deficits, has been documented across various age groups, not just older adults, highlighting the indiscriminate nature of COVID-19’s neurological impact​​.

The evolving research underscores the importance of continued investigation into the neurological consequences of COVID-19, including the development of cognitive impairments and the role of biomarkers like NfL and GFAP in predicting and understanding these outcomes. Given the global reach of the pandemic and the significant number of individuals affected, the implications of these findings are vast, necessitating a comprehensive approach to monitoring and addressing the long-term neurological and cognitive sequelae of COVID-19.


The study highlights the persistent elevation of serum biomarkers for neuronal (sNfL) and glial (sGFAP) damage observed one week after the resolution of asymptomatic or mild COVID-19, which remained elevated 10 months post-infection. Interestingly, cognitive impairment was reported to worsen over this period, despite the reduction in biomarker levels, indicating a potential disconnection between early neuronal/glial damage and long-term cognitive outcomes.

The study emphasizes the half-lives of sNfL and sGFAP to interpret their levels correctly, noting that sNfL peaks 7-10 days post-nervous system injury and has a longer half-life than sGFAP, which peaks within 24 hours of CNS injury. The findings suggest ongoing neuronal and astrocytic damage post-COVID-19, with higher biomarker levels 10 months post-infection in those with persistent symptoms, highlighting a complex pathophysiology that may involve ongoing axonal pathology and glial responses.

Cognitive deficits, especially in executive functions, attention, and memory, were commonly observed post-COVID-19, with a significant percentage of patients experiencing cognitive failures immediately after recovery. The study underscores the potential impact of mild COVID-19 on cognitive function, advocating for neuropsychological evaluations in occupational settings to monitor and address cognitive impairments in workers returning post-infection.

The study also notes a correlation between alcohol consumption and elevated levels of sNfL and sGFAP, suggesting chronic alcoholism as a risk factor for more severe COVID-19 and related brain injury. This aligns with previous findings linking alcohol use disorders with increased sNfL levels, indicating a potential marker for alcohol-induced brain injury.

Limitations of the study include reliance on self-reported cognitive performance measures and the inability to correlate alcohol consumption with serum neurofilament levels in healthy controls. Furthermore, the study acknowledges the challenge in distinguishing the origin of NfL between the central and peripheral nervous systems, with most NfL in blood presumed to originate from the CNS, although peripheral contributions cannot be excluded.

Overall, the study calls for further research to explore the long-term neurological and cognitive consequences of COVID-19, especially in relation to mild cases and asymptomatic infections, and the role of various factors like alcohol consumption in influencing these outcomes.

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