Transient Changes in the Plasma of Astrocytic and Neuronal Injury Biomarkers in COVID-19 Patients without Neurological Syndromes.

The levels of several glial and neuronal plasma biomarkers have been found to increase during the acute phase in COVID-19 patients with neurological symptoms. However, replications in patients with minor or non-neurological symptoms are needed to understand their potential as indicators of CNS injury or vulnerability. Plasma levels of glial fibrillary acidic protein (GFAP), neurofilament light chain protein (NfL), and total Tau (T-tau) were determined by Single molecule array (Simoa) immunoassays in 45 samples from COVID-19 patients in the acute phase of infection [moderate (n = 35), or severe (n = 10)] with minor or non-neurological symptoms; in 26 samples from fully recovered patients after ~2 months of clinical follow-up [moderate (n = 23), or severe (n = 3)]; and in 14 non-infected controls. Plasma levels of the SARS-CoV-2 receptor, angiotensin-converting enzyme 2 (ACE2), were also determined by Western blot. Patients with COVID-19 without substantial neurological symptoms had significantly higher plasma concentrations of GFAP, a marker of astrocytic activation/injury, and of NfL and T-tau, markers of axonal damage and neuronal degeneration, compared with controls. All these biomarkers were correlated in COVID-19 patients at the acute phase. Plasma GFAP, NfL and T-tau levels were all normalized after recovery. Recovery was also observed in the return to normal values of the quotient between the ACE2 fragment and circulating full-length species, following the change noticed in the acute phase of infection. None of these biomarkers displayed differences in plasma samples at the acute phase or recovery when the COVID-19 subjects were sub-grouped according to occurrence of minor symptoms at re-evaluation 3 months after the acute episode (so called post-COVID or "long COVID"), such as asthenia, myalgia/arthralgia, anosmia/ageusia, vision impairment, headache or memory loss. Our study demonstrated altered plasma GFAP, NfL and T-tau levels in COVID-19 patients without substantial neurological manifestation at the acute phase of the disease, providing a suitable indication of CNS vulnerability; but these biomarkers fail to predict the occurrence of delayed minor neurological symptoms.

Plasma biomarkers of brain injury in COVID-19 patients with neurological symptoms.

OBJECTIVE: Neurological symptoms (NS) were often reported in COVID-19 infection. We examined the plasma levels of glial fibrillary acidic protein (GFAP) and S100B together, as brain injury biomarkers, in relation to persistent NS in a cohort of patients with COVID-19 during the acute phase of the disease. METHODS: A total of 20 healthy controls and 58 patients with confirmed COVID-19 were enrolled in this prospective study. Serum GFAP and S100B levels were measured by using enzymle linked immunoassay method from blood samples. RESULTS: Serum GFAP levels were found to be significantly higher in the severe group than in the controls (p = 0.007). However, serum S100B levels were similar between control and disease groups (p > 0.05). No significant results for GFAP and S100B were obtained between the disease groups depending on whether the sampling time was below or above 5 days (p > 0.05). We did not find a correlation between serum GFAP and S100B levels and the presence of NS (p > 0.05). However, serum S100B levels were slightly higher in patients with multiple NS than in those with a single symptom (p = 0.044). CONCLUSIONS: Elevated GFAP was associated with disease severity but not with NS in COVID-19 patients. Whereas, high serum S100B was associated with the multipl NS in these patients. Our data suggest that GFAP and S100B may be of limited value currently in order to represent the neuronal damage, though serving a basis for the future work.

Serum glial fibrillary acidic protein is a body fluid biomarker: A valuable prognostic for neurological disease - A systematic review.

Astrocytes are the most abundant cell type in the human central nervous system, and they play an important role in the regulation of neuronal physiology. In neurological disorders, astrocyte disintegration leads to the release of glial fibrillary acidic protein (GFAP) from tissue into the bloodstream. Elevated serum levels of GFAP can serve as blood biomarkers, and a useful prognostic tool to facilitate the early diagnosis of several neurological diseases ranging from stroke to neurodegenerative disorders. This systematic review synthesizes studies published between January 2012 and September 2021 that used GFAP as a potential blood biomarker to detect neurological disorders. The following electronic databases were accessed: MEDLINE, Scopus, and Web of Science. In all the databases, the following search strategy was used: ¨GFAP¨ OR ¨glial fibrillary acidic protein¨ AND ¨neurological¨ OR ¨neurodegenerative¨ AND ¨plasma¨ OR ¨serum¨. The initial search identified 1152 articles. After the exclusion criteria were applied, 48 publications that reported GFAP levels in neurological disorders were identified. A total of16 different neurological disorders that have plasmatic GFAP levels as a possible biomarker for the disease were described in the articles, being: multiple sclerosis, frontotemporal lobar degeneration, Alzheimer's disease, Parkinson disease, COVID-19, epileptic seizures, Wilson Disease, diabetic ketoacidosis, schizophrenia, autism spectrum disorders, major depressive disorder, glioblastoma, spinal cord injury, asthma, neuromyelitis optica spectrum disorder and Friedreich's ataxia. Our review shows an association between GFAP levels and the disease being studied, suggesting that elevated GFAP levels are a potentially valuable diagnostic biomarker in the evaluation of different neurological diseases.

Oxidative stress and inflammatory markers in patients with COVID-19: Potential role of RAGE, HMGB1, GFAP and COX-2 in disease severity.

BACKGROUND: SARS-CoV-2 infection can lead to the abnormal induction of cytokines and a dysregulated hyperinflammatory state that is implicated in disease severity and risk of death. There are several molecules present in blood associated with immune cellular response, inflammation, and oxidative stress that could be used as severity markers in respiratory viral infections such as COVID-19. However, there is a lack of clinical studies evaluating the role of oxidative stress-related molecules including glial fibrillary acidic protein (GFAP), the receptor for advanced glycation end products (RAGE), high mobility group box-1 protein (HMGB1) and cyclo-oxygenase-2 (COX-2) in COVID-19 pathogenesis. AIM: To evaluate the role of oxidative stress-related molecules in COVID-19. METHOD: An observational study with 93 Brazilian participants from September 2020 to April 2021, comprising 23 patients with COVID-19 admitted to intensive care unit (ICU), 19 outpatients with COVID-19 with mild to moderate symptoms, 17 individuals reporting a COVID-19 history, and 34 healthy controls. Blood samples were taken from all participants and western blot assay was used to determine the RAGE, HMGB1, GFAP, and COX-2 immunocontent. RESULTS: We found that GFAP levels were higher in patients with severe or critical COVID-19 compared to outpatients (p = 0.030) and controls (p < 0.001). A significant increase in immunocontents of RAGE (p < 0.001) and HMGB1 (p < 0.001) were also found among patients admitted to the ICU compared to healthy controls, as well as an overexpression of the inducible COX-2 (p < 0.001). In addition, we found a moderate to strong correlation between RAGE, GFAP and HMGB1 proteins. CONCLUSION: SARS-CoV-2 infection induces the upregulation of GFAP, RAGE, HMGB1, and COX-2 in patients with the most severe forms of COVID-19.

Neurochemical signs of astrocytic and neuronal injury in acute COVID-19 normalizes during long-term follow-up.

BACKGROUND: Neurologic manifestations are well-recognized features of coronavirus disease 2019 (COVID-19). However, the longitudinal association of biomarkers reflecting CNS impact and neurological symptoms is not known. We sought to determine whether plasma biomarkers of CNS injury were associated with neurologic sequelae after COVID-19. METHODS: Patients with confirmed acute COVID-19 were studied prospectively. Neurological symptoms were recorded during the acute phase of the disease and at six months follow-up, and blood samples were collected longitudinally. Healthy age-matched individuals were included as controls. We analysed plasma concentrations of neurofilament light-chain (NfL), glial fibrillary acidic protein (GFAp), and growth differentiation factor 15 (GDF-15). FINDINGS: One hundred patients with mild (n = 24), moderate (n = 28), and severe (n = 48) COVID-19 were followed for a median (IQR) of 225 (187-262) days. In the acute phase, patients with severe COVID-19 had higher concentrations of NfL than all other groups (all p < 0·001), and higher GFAp than controls (p < 0·001). GFAp was also significantly increased in moderate disease (p < 0·05) compared with controls. NfL (r = 0·53, p < 0·001) and GFAp (r = 0·39, p < 0·001) correlated with GDF-15 during the acute phase. After six months, NfL and GFAp concentrations had normalized, with no persisting group differences. Despite this, 50 patients reported persistent neurological symptoms, most commonly fatigue (n = 40), "brain-fog" (n = 29), and changes in cognition (n = 25). We found no correlation between persistent neurological symptoms and CNS injury biomarkers in the acute phase. INTERPRETATION: The normalization of CNS injury biomarkers in all individuals, regardless of previous disease severity or persisting neurological symptoms, indicates that post COVID-19 neurological sequelae are not accompanied by ongoing CNS injury. FUNDING: The Swedish State Support for Clinical Research, SciLifeLab Sweden, and the Knut and Alice Wallenberg Foundation have provided funding for this project.