Normalisation of central nervous system (CNS) injury biomarkers in all individuals, regardless of previous disease severity or persisting neurological symptoms, indicates that post coronavirus disease 2019 (COVID-19) neurological sequelae are not accompanied by ongoing CNS injury, according to a study published in EBioMedicine.
“To the best of our knowledge, this is the first study reporting longitudinal data on plasma biomarkers (neurofilament light-chain [NfL], glial fibrillary acidic protein [GFAp]) of CNS injury in relation to neurological symptoms in patients recovering from COVID-19,” wrote Nelly Kanberg, University of Gothenburg, Gothenburg, Sweden, and colleagues. “We found that CNS injury biomarkers increase with greater disease severity during the acute phase of COVID-19 but normalise in all patients at follow-up. Persisting self-reported neurological and cognitive symptoms were common in patients, regardless of disease severity, but were not associated with biomarker evidence of CNS injury.”
The study involved 100 patients with mild (n = 24), moderate (n = 28), and severe (n = 48) COVID-19 with a median age of 55 years. In addition, 51 healthy age-matched individuals were included as controls.
Neurological symptoms were recorded during the acute phase of the disease and at 6 months follow-up. Meanwhile, baseline blood samples were collected at a median of 10 days after symptom onset. All patients had blood samples collected at a median of 3 time points and were followed for a median of 225 (interquartile range [IQR] 187– 262) days. Plasma concentrations of NfL, GFAp, and growth differentiation factor 15 (GDF-15) were analysed.
At baseline, the most frequently reported neurological symptoms were headache (41%) and dysgeusia (11%). At follow-up, self-reported symptom questionnaires were completed by 97 patients at a median of 225 days after onset of symptoms. In total, 50 (50%) patients reported one or more neurological symptoms across the mild (n =11), moderate (n =14), severe (n = 25) disease groups. The most common symptoms reported at follow-up were fatigue (41%), “brain-fog” (30%), and cognitive impairment such as memory loss and lack of concentration (26%). However, no significant differences in the frequency of any symptoms were found among the groups.
In the acute phase, patients with severe COVID-19 had higher concentrations of NfL than all other groups (all P< 0·001, ANCOVA), and higher GFAp than controls (P< 0·001, ANCOVA). GFAp was also higher in patients with moderate disease compared to controls (P = 0·028, ANCOVA). In addition, plasma NfL concentrations in severely ill patients continued to increase in blood samples taken 30–70 days after symptom onset, as compared to acute phase sampling (n = 18) (P< 0·001, t-test), whereas GFAp decreased among patients with severe (P< 0·05, t-test) and moderate (P< 0·001, t-test) disease. During the acute phase of COVID-19, patients with severe and moderate disease had markedly higher GDF-15 concentrations compared to individuals with mild disease and to controls (P< 0·001, ANCOVA).
At 6-month follow-up, researchers observed that NfL and GFAp concentrations had normalised, with no persisting group differences, whereas GDF-15 concentration remained significantly higher in the severe and moderate COVID-19 groups, compared to patients with mild COVID-19 and controls.
When assessing the impact of the degree of CNS injury during the acute phase using binary logistic regression (reflected by NfL and GFAp concentrations), the researchers found no correlation between persistent neurological symptoms and CNS injury biomarkers in the acute phase.
“The normalisation of CNS injury biomarkers in all individuals, regardless of previous disease severity or persistent neurological symptoms, suggests that common post COVID-19 neurological sequelae are not due to active neurodegeneration or astroglial activation. However, considering the rapidly increasing number of individuals who do suffer from post-infectious neurological sequelae while recovering from COVID-19, further studies of the underlying causes and tenacious pathological processes that severe acute respiratory syndrome coronavirus 2 infection may initiate are urgently needed,” the authors concluded.