Characterization and Biomarker Analyses of Post-COVID-19 Complications and Neurological Manifestations

Abstract

As the SARS-CoV-2 pandemic continues, reports have demonstrated neurologic sequelae following COVID-19 recovery. Mechanisms to explain long-term neurological sequelae are unknown and need to be identified. Plasma from 24 individuals recovering from COVID-19 at 1 to 3 months after initial infection were collected for cytokine and antibody levels and neuronal-enriched extracellular vesicle (nEV) protein cargo analyses. Plasma cytokine IL-4 was increased in all COVID-19 participants. Volunteers with self-reported neurological problems (nCoV, n = 8) had a positive correlation of IL6 with age or severity of the sequalae, at least one co-morbidity and increased SARS-CoV-2 antibody compared to those COVID-19 individuals without neurological issues (CoV, n = 16). Protein markers of neuronal dysfunction including amyloid beta, neurofilament light, neurogranin, total tau, and p-T181-tau were all significantly increased in the nEVs of all participants recovering from COVID-19 compared to historic controls. This study suggests ongoing peripheral and neuroinflammation after COVID-19 infection that may influence neurological sequelae by altering nEV proteins. Individuals recovering from COVID-19 may have occult neural damage while those with demonstrative neurological symptoms additionally had more severe infection. Longitudinal studies to monitor plasma biomarkers and nEV cargo are warranted to assess persistent neurodegeneration and systemic effects.

The Role of Exosomes in the Treatment, Prevention, Diagnosis, and Pathogenesis of COVID-19

“…86 Although no differences were found between COVID-19 patients with and without reported neurological symptoms, this study confirmed that COVID-19 alters the cargo of neuronal-enriched exosomes, with high levels of toxic proteins that were still found altered in patients who have recovered from COVID-19. 86 Studies correlating these findings in the plasma of COVID-19 patients and their neurological status are underway.…”

“…86 Interestingly, compared with the historic cohort, all COVID-19 patients had increased protein markers of neuronal dysfunction, such as amyloid β, neurofilament light, neurogranin, total tau, and p-T181-tau. 86 Although no differences were found between COVID-19 patients with and without reported neurological symptoms, this study confirmed that COVID-19 alters the cargo of neuronal-enriched exosomes, with high levels of toxic proteins that were still found altered in patients who have recovered from COVID-19. 86 Studies correlating these findings in the plasma of COVID-19 patients and their neurological status are underway.…”

“…86 The authors analyzed the plasma neuron-derived exosomes in patients who had recovered from acute illness due to SARS-CoV-2 virus infection and had presented with (n ¼ 8) or without (n ¼ 16) neurological symptoms and compared them with the plasma of 12 prepandemic healthy controls. 86 Interestingly, compared with the historic cohort, all COVID-19 patients had increased protein markers of neuronal dysfunction, such as amyloid β, neurofilament light, neurogranin, total tau, and p-T181-tau. 86 Although no differences were found between COVID-19 patients with and without reported neurological symptoms, this study confirmed that COVID-19 alters the cargo of neuronal-enriched exosomes, with high levels of toxic proteins that were still found altered in patients who have recovered from COVID-19.…”

“…85 Another study showed that plasma exosomes could be biomarkers for the neurologic sequelae following COVID-19 recovery. 86 The authors analyzed the plasma neuron-derived exosomes in patients who had recovered from acute illness due to SARS-CoV-2 virus infection and had presented with (n ¼ 8) or without (n ¼ 16) neurological symptoms and compared them with the plasma of 12 prepandemic healthy controls. 86 Interestingly, compared with the historic cohort, all COVID-19 patients had increased protein markers of neuronal dysfunction, such as amyloid β, neurofilament light, neurogranin, total tau, and p-T181-tau.…”

Neurological sequelae of COVID-19: a review

“…Infection with SARS-CoV-2 may also initiate protein aggregation via heparin-binding sites and/or spike-derived peptides, leading to amyloid fibrils that may produce similar pathology to Alzheimer’s disease [ 10 ]. Elevated levels of amyloid-beta, neurofilament light, neurogranin, and tau in patients 1–3 months after recovery from COVID-19 suggest generation of neurotoxic proteins may contribute as well [ 11 ].…”