Understanding the Association Between Neurological Symptoms and Blood Biomarkers in Mild-to-Moderate COVID-19 and Long COVID


The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has been associated with various neurological complications ranging from mild to severe. While these neurological symptoms are commonly observed during the acute phase of the infection, emerging evidence suggests that they may persist for months, independent of the initial severity of the infection.

This prolonged symptom burden has led to the establishment of a post-COVID-19 syndrome, known as Long COVID or post-acute sequelae of SARS-CoV-2 infection (PASC).

The World Health Organization (WHO) defines Long COVID as symptoms lasting for at least two months, starting three months from the onset of the infection, without an alternative explanation.

Detection of Neurological Injury Biomarkers

Ultrasensitive Single Molecular Array (Simoa) Assays have provided a breakthrough in detecting various cerebrovascular injuries through blood samples of acute and post-acute COVID-19 patients with high accuracy. These assays have identified specific biomarkers, such as glial fibrillary acidic protein (GFAP) and neurofilaments (Nfs), which are indicative of brain injury.

GFAP is a major protein component of glial intermediate filaments in astrocytes and plays a crucial role in regulating their function. Astrocytes are integral to the blood-brain barrier, and damage to this barrier leads to increased GFAP levels in the bloodstream. Therefore, elevated GFAP levels in the blood suggest astrocytic damage or activation.

Neurofilaments (Nfs) are exclusively expressed in neurons and provide structural stability to the central and peripheral nervous system. Among the various types of Nfs, neurofilament light chain (NfL) has been identified as a reliable biomarker for neuro-axonal injury.

In response to CNS axonal damage, NfL is released into the interstitial fluid, which freely communicates with cerebrospinal fluid (CSF) and blood. As NfL has a low molecular weight, it can diffuse from the brain parenchyma to the CSF and subsequently enter the bloodstream, making it a useful biomarker for neuro-axonal injury.

Blood Biomarkers in Severe COVID-19 Cases

Previous studies have reported elevated levels of GFAP and NfL in the blood samples of patients with severe SARS-CoV-2 infections requiring hospitalization in intensive care units (ICU). However, limited research has investigated blood biomarkers of brain injury in patients with mild-to-moderate COVID-19 symptoms, both during the acute phase and after its resolution.

Association of Biomarkers with Neurological Symptoms: A study involving non-hospitalized adolescents with mild-to-moderate COVID-19 symptoms found increased levels of serum NfL (sNfL) and serum GFAP (sGFAP). Another study involving adult healthcare workers with similar symptom severity reported elevated sNfL levels. However, the association between increased biomarker levels and neurological symptoms in these groups remains poorly understood.

Current Study Findings

To address these gaps, a follow-up study was conducted on patients who had experienced mild-to-moderate SARS-CoV-2 infections. The study aimed to investigate possible associations between sGFAP, sNfL, and neurological symptoms and to assess longitudinal changes in these biomarkers over time.

The findings revealed that participants with moderate SARS-CoV-2 infections experienced a longer-lasting acute infection phase with several symptoms and were more frequently affected by Long COVID compared to those with mild infections. Both sub-groups reported neurological symptoms at similar frequencies. However, no association was found between neurological symptoms and serum biomarkers of brain injury (sNfL/sGFAP).

The study also examined individuals suffering from Long COVID after a mild-to-moderate infection. Interestingly, it was discovered that sGFAP levels were associated with Long COVID, suggesting a unique relationship between sGFAP and Long COVID. In contrast, no significant association was observed between sNfL and Long COVID in the cohort.

Comparison with Previous Studies

These findings differ from earlier studies. Some studies had reported elevated NfL levels in adult healthcare workers and non-hospitalized adolescents with mild-to-moderate COVID-19 infections. The disparities in findings could be attributed to differences in sample sizes, study designs, investigation timing (acute vs. post-acute infection), age demographics, and pre-analytical sample handling methods.

Implications and Future Directions

The ultrasensitive detection of brain injury biomarkers in blood samples enables non-invasive monitoring of neurological damage associated with COVID-19 infections. This may aid in understanding the disease’s progression and improving patient management in clinical practice. However, before implementing these biomarkers in routine clinical settings, larger studies are required to validate their effectiveness and reliability, especially in Long COVID patients.

Furthermore, exploring additional central nervous system-derived analytes may enhance the accuracy of non-invasive monitoring for CNS disorders related to COVID-19.

Strengths and Limitations

The strengths of this study include a well-defined group of unvaccinated individuals from the general population with mild-to-moderate COVID-19 infections. The study also provided longitudinal data with a follow-up period of 10 months post-infection. Additionally, the inclusion of individuals with Long COVID following mild-to-moderate infections provided valuable insights into the association between brain injury biomarkers and this condition.

However, the study had some limitations. The small sample size of participants with moderate infections prevented subgroup analysis based on disease severity. The reliance on self-reported symptoms introduced the potential for recall bias. Moreover, detailed clinical data during hospitalization, such as oxygen status, were unavailable. Additionally, the study lacked data from the acute phase of infection, limiting the investigation of biomarkers to the post-acute setting. Despite these limitations, the findings provide valuable insights into the relationship between neurological symptoms, blood biomarkers, and different stages of COVID-19 infection.


In conclusion, this study indicates that post-acute, mild-to-moderate COVID-19 cases from the general population are not associated with serum brain injury biomarkers. Neurological symptoms reported in these individuals may not result from neuro-axonal or astroglial damage. However, individuals with mild-to-moderate infections suffering from Long COVID exhibit increased serum biomarkers of astroglial injury, suggesting an association between Long COVID and brain injury. Further research involving larger cohorts is necessary to confirm these findings and shed more light on the role of biomarkers in COVID-19 and Long COVID.


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