The authors from the United Kingdom investigated the concentrations of brain injury markers, inflammatory mediators, and autoantibodies in two cohorts of patients during the acute and late convalescent phases of COVID-19. The results showed alterations of brain injury markers in both the acute and convalescent phases of COVID-19. Dysregulation of inflammatory mediators, as indicators of systemic innate and adaptive immune responses, has been found only in the acute phase of the disease. Importantly, serum levels of some markers of brain injury and innate inflammatory mediators, as well as levels of autoantibodies against certain antigens of the central nervous system (CNS), showed a robust differentiation between COVID-19 participants with impaired consciousness, defined as a Glasgow Coma Scale (GCS) score, and those with a normal GCS score.
The neurological sequelae of COVID-19 are frequently mild, such as headache and myalgia. However, severe neurological manifestations were reported, such as encephalitis/encephalopathies, Guillain-Barre Syndrome, seizures, and stroke.
The authors suggested that direct viral invasion is unlikely a cause of neurological dysfunction in vivo. Some previous postmortem studies failed to detect viral infection in the brain by immunohistochemistry, although in vitro studies confirmed that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can infect neurons and astrocytes. However, the authors stated that SARS-CoV-2 more likely affects the brain indirectly through peripherally generated inflammatory mediators, immune cells, autoantibodies and/or changes in the blood-brain barrier associated with endothelial damage.
According to the results of a previous proton magnetic resonance spectroscopy study, the alterations in neurometabolites, indicators of neuronal damage and glial dysfunction, can be detected in the brains of patients diagnosed with long COVID syndrome. https://discovermednews.com/alterations-neurometabolites-neuronal-damage-glial-dysfunction-the-brains-long-covid/
About the study
Participants were recruited prospectively during their hospitalization with COVID-19. All patients were stratified according to GCS scores. Healthy controls were recruited from the Cambridge Biomedical Research Centre before the COVID-19 pandemic. They did not have SARS-CoV-2 infection or neurological diagnoses.
The convalescent participants were recruited for the COVID-Clinical Neuroscience Study. The inclusion criteria were the onset of neurological complications within 6 weeks of acute COVID-19 and the absence of other associated causes.
Serum samples from both groups of patients were collected in the early phase (under six weeks after a COVID-19 positive test) or in the late convalescent phase (after six weeks from a COVID-19 positive test). Researchers investigated the concentrations of brain injury markers, including GFAP (glial fibrillary acidic protein, marker of astrocyte injury), UCH-L1 (a marker of neuronal cell body injury), and NfL (neurofilament light) and Tau (both markers of axonal and dendritic injury). They also evaluated serum levels of 48 inflammatory mediators and autoantibodies.
Results
The study included 111 patients with acute COVID-19. The sera samples were taken one to eleven days after the hospital admission. The study also included 60 healthy controls (20–79 years old). The convalescent cohort included 92 participants. In 56 of them, a new neurological diagnosis developed as a complication of COVID-19, and this group was labeled as “neuro-COVID”, while 36 participants had no neurological complications.
Out of 111 patients with acute COVID-19, 76 had normal GCS scores, and 35 had impaired consciousness and abnormal GCS scores (GCS≤ 14).
Patients with acute COVID-19 had higher concentrations of all four markers of brain injury (GFAP, NfL, tTau, and UCH-L1) than controls. The highest serum levels of NfL were found in individuals with cerebrovascular diseases, whereas tTau was elevated in those with cerebrovascular diseases, CNS inflammation, and peripheral neuropathies. In addition, patients with acute COVID-19 had autoantibody responses to a number of both neural and non-neural antigens.
During the convalescent period of six weeks, NfL and GFAP were elevated in all COVID-19 patients. After six weeks, the levels of NfL and GFAP remained elevated only in those who developed acute neurological complications (the “neuro-COVID” group), indicating ongoing neuro-glial injury. Similarly, tTau remained elevated overall in those with neurological complications, and its levels correlated with eight immune mediators including CCL2, IL-1RA, IL-2Rα, and M-CSF along with CCL7, stem cell factor (SCF), IL-16, and IL-18. These results show that elevated levels of brain injury markers reflect clinical neurological complications during both, the acute and convalescent phases of COVID-19. Patients with neuro-COVID also had different cytokine networks and specific autoantibody responses to the gonadotrophin-releasing hormone receptor (GnRHR) and several HLA antigens. Interestingly, during the late phase, patients who had or had not experienced a neurological complication after COVID-19 differed by the presence of autoantibodies against HLA antigens, and not against neural antigens.
All patients with acute COVID-19 had elevated levels of interleukin (IL)-6, hepatocyte growth factor (HGF), IL-12p40, IL-1RA, CCL2, and macrophage colony-stimulating factor (M-CSF). IL-12p40 has a key role in controlling Th1 responses and is involved in central and peripheral neuroinflammation.
The correlation analysis showed that brain injury biomarkers GFAP and UCL-H1 correlated with several mediators, including the IL-1 family, interferons, and M-CSF, whereas tTau and NfL correlated strongly with HGF and IL-12p40.
Importantly, serum levels of some markers of brain injury and innate inflammatory mediators, as well as levels of autoantibodies against certain antigens of the CNS showed a robust differentiation between COVID-19 patients with impaired consciousness, defined by GCS score, and those with a normal GCS score. COVID-19 patients with impaired consciousness had increased levels of axonal and neuronal body injury markers NfL and UCH-L1. The levels of HGF and IL-12p40 also demonstrated a robust differentiation between participants with and without impaired consciousness. Interestingly, patients with acute COVID-19 and impaired consciousness had higher levels of various autoantibodies, including the CNS antigens UCH-L1, glutamate (NMDA) receptor subunit 3B (GRIN3B) and dopamine receptor D2 (DRD2), as well as the cardiac antigen, myosin light chain (MYL)-7, but also the SARS-CoV-2 spike protein. The autoantibody responses to the neural antigens UCH-L1, GRIN3B, and DRD2 were more common in participants with impaired consciousness at presentation.
Conclusion
In the acute phase of COVID-19, the altered markers of brain injury were associated with dysregulated systemic innate and adaptive immune responses. The changes in serum levels of neuro-glial damage markers were more pronounced in COVID-19 participants with neurological dysfunction in the acute phase of the disease. They persisted in convalescent patients with defined acute neurological complications. Serum levels of some markers of brain injury, innate inflammatory mediators, and autoantibodies against certain CNS antigens, showed a robust differentiation between COVID-19 participants with impaired consciousness and those with a normal GCS score.
This article was published in Nature Communications.
Journal Reference
Hampshire A, Sieradzki A, Seed AW, et al. Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses. Nature Communications ( 2023) 14:8487. https://www.nature.com/articles/s41467-023-42320-4
