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

Abstract

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.

Dynamic Changes in Central and Peripheral Neuro-Injury vs. Neuroprotective Serum Markers in COVID-19 Are Modulated by Different Types of Anti-Viral Treatments but Do Not Affect the Incidence of Late and Early Strokes

“…Elevations in serum NF-L levels were reported inconsistently in studies plagued with small fibers, unadjusted for comorbidities, or limited to the most sick patients [ 12 , 32 , 35 , 94 , 119 , 120 , 121 ]. Gisslen et al reported the normalization of GFAP and NF-L six months after the resolution of COVID-19, but their patients continued to exhibit neurological symptoms and their study was limited to these markers [ 34 ]. Persistent elevations of several neurodegeneration markers suggest an ongoing pathological process in COVID survivors that is heterogeneous [ 38 , 43 , 44 , 46 , 51 , 52 , 55 , 87 , 94 , 111 , 122 ].…”

“…These interactions can trigger the aggregation of the brain’s proteins when protective anti-folding mechanisms are impaired, potentially exacerbating ongoing neurodegeneration processes and effects of the non-specific inflammatory response [ 26 , 27 , 28 , 29 , 30 ]. Several case reports, case series, and research projects provided conflicting data regarding the levels of τ, Amyloid β1-42, and Amyloid β2-41 in COVID-19 [ 6 , 31 , 32 , 33 , 34 , 35 ]. In silica, analyses suggested molecular mimicry between the compromising of SARS-CoV-2 and nervous system proteins, but clinical correlations are not described [ 3 , 36 ].…”

“…Furthermore, rather than their absolute levels, the dynamics of markers are more important for predicting cognitive outcomes than isolated measurements [ 56 , 57 ]. However, only a few of these markers were studied in COVID-19, but even fewer look at them longitudinally in COVID-19 survivors [ 12 , 34 ].…”

Neuropsychiatric manifestations of COVID-19, potential neurotropic mechanisms, and therapeutic interventions

“…Higher serum NfL concentrations were associated with worse clinical outcomes, such as mechanical ventilation and ICU admission, in hospitalized COVID-19 patients [ 79 ]. A longitudinal study showed that elevated NfL and GFAP concentrations normalized at 6-month follow-up, regardless of prior disease severity or persisting neurological symptoms, in all COVID-19 patients [ 80 ]. A longitudinal cohort study with time-series design to estimate the spectrum of biochemical dataset suggests two other biochemical markers, C-reactive protein (CRP) and urea nitrogen, are associated with the risk of COVID-19-related acute respiratory failure and death [ 81 ].…”

TOM70 in Glial Cells as a Potential Target for Treatment of COVID-19

“…Acute neurological signs include anosmia, ageusia, headache, altered mental status, seizures, and stroke (Iadecola et al, 2020;Balcom et al, 2021). Interestingly, headache, fatigue, dysgeusia, and anosmia are common in both mild and severe cases (Kanberg et al, 2021). However, it is yet to be established whether altered mental health is a result from an encephalopathy caused by a systemic inflammatory condition or an encephalitis caused by SARS-CoV-2 neuroinvasion (Iadecola et al, 2020;Balcom et al, 2021).…”