Neuron-specific Biomarkers Associated With Neurological Manifestations In COVID-19: An Evidence Mapping Systematic Review

ABSTRACT

Introduction. We aimed to map and synthesize the available evidence on neuron-specific biomarkers related to COVID-19. Methods. A systematic review and qualitative evidence mapping synthesis was performed (PROSPERO-CRD42021266995). Searches were conducted in PubMed and Scopus, and complemented by manual search (July 2021). We included observational studies of any design assessing neurological biomarkers in adult patients (>18 years;with or without neurological comorbidities) diagnosed with COVID-19. Methodological quality of nonrandomized studies (case-control, cohorts) was assessed using the Newcastle-Ottawa Scale. Results. Overall, 14 studies (n=485 patients) conducted in Sweden (n=4 articles, 28.5%), Germany (n=3;21.4%), USA (n=3;21.4%), Canada, France, Italy and Norway (n=1 study each) were included. The most reported neurological symptoms (n=13 studies, 92.8%) were headache, confusion, general weakness, loss of smell/taste, cognitive impairments and behavioral changes. Prevalent neurological conditions included encephalopathies, neuropathies, myopathies, and delirium;most critical cases presented cerebrovascular events (n=4 studies, 28.5%). Hypertension, diabetes, obesity, dyslipidemia, and chronic lung disease were the most reported comorbidities. Eight different neuron-specific biomarkers were found in primary studies neurofilament-light chain - NfL (n=10 studies;71.4%), glial fibrillary acidic-protein - GFAp (n=5;35.7%), tau protein (n=5;35.7%), neurofilament-heavy chain - NfH, S100B protein, ubiquitin C-terminal hydrolase L1 - UCH-L1, neuronspecific enolase and beta protein-amyloid - Abeta (n=1 study each). These biomarkers were found both in cerebrospinal fluid and blood/ plasma samples even without an evident cytokine storm. In patients with COVID-19, NfL and GFAp can act as sensitive indicators of neuroaxonal and astrocytic damages, respectively. Increased levels of NfL were significantly associated with severe COVID-19, unconsciousness and longer stay in the intensive care unit (p<0.05). Studies had an overall poor to moderate methodological quality. Conclusions. We identified eight neuron-specific biomarkers that should be further studied as prognostic factors of COVID-19. These findings can also guide the development of targeted therapies against SARS-CoV-2. Additional well-designed clinical trials are needed to strengthen this evidence and help understand the mechanisms of neurological symptoms and sequelae after COVID-19 infection.