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

Nelly Kanberg,Bengt Nellgård,Henrik Zetterberg,Nicholas J Ashton,Staffan Nilsson,Kaj Blennow,Pär-Daniel Sundvall,Lars-Magnus Andersson,Arvid Edén,Joel Simrén,Magnus Gisslén

doi:10.1016/j.ebiom.2021.103512

Nelly Kanberg, Bengt Nellgård + Show 9 more

Open Access

https://doi.org/10.1016/j.ebiom.2021.103512

Copy DOI

Journal: eBioMedicine	Publication Date: Jul 29, 2021
Citations: 116	License type: cc-by

Affiliation: University of Gothenburg, Primary Health Care

Abstract

BackgroundNeurologic 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.MethodsPatients 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).FindingsOne 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.InterpretationThe 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.FundingThe Swedish State Support for Clinical Research, SciLifeLab Sweden, and the Knut and Alice Wallenberg Foundation have provided funding for this project.

Highlights

Central nervous system (CNS) involvement has been described in coronavirus disease 2019 (COVID-19) patients since the beginning of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic.[1,2] Headache, fatigue, dysgeusia, and anosmia are common in both mild and severe cases of COVID-19, while signs of CNS dysfunction, and inflammatory CNS disorders have primarily been reported in patients with severe COVID-19 [2À5]
We have prospectively examined the dynamic changes in plasma biomarkers of CNS injury (GFAp and neurofilament light-chain (NfL)) and persistent neurological symptoms in a cohort of patients with mild, moderate, or severe COVID-19 during the acute phase of the disease, and in subsequent follow-up in comparison with uninfected controls to determine the long-term CNS impact of COVID-19
In the acute phase of COVID-19 (< 21 days after symptom onset; n = 92), NfL and glial fibrillary acidic protein (GFAp) were significantly correlated with age (NfL: r = 0¢63, GFAp: r = 0¢55), and with each other (r = 0¢48) in the whole sample (Fig. S1)

Summary

Introduction

Central nervous system (CNS) involvement has been described in coronavirus disease 2019 (COVID-19) patients since the beginning of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic.[1,2] Headache, fatigue, dysgeusia, and anosmia are common in both mild and severe cases of COVID-19, while signs of CNS dysfunction, (including encephalopathy) and inflammatory CNS disorders (including encephalitis) have primarily been reported in patients with severe COVID-19 [2À5]. We concluded that changes in these CNS damage biomarkers were more pronounced in hospitalized patients compared to non-hospitalized individuals and healthy controls [8]. Results confirming this have subsequently been reported in other studies [9,10]. 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). 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.

Methods

Results

Conclusion