Abstract
The balance between neurodegeneration, neuroinflammation, neuroprotection, and COVID-19-directed therapy may underly the heterogeneity of SARS-CoV-2′s neurological outcomes. A total of 105 patients hospitalized with a diagnosis of COVID-19 had serum collected over a 6 month period to assess neuroinflammatory (MIF, CCL23, MCP-1), neuro-injury (NFL, NCAM-1), neurodegenerative (KLK6, τ, phospho τ, amyloids, TDP43, YKL40), and neuroprotective (clusterin, fetuin, TREM-2) proteins. These were compared to markers of nonspecific inflammatory responses (IL-6, D-dimer, CRP) and of the overall viral burden (spike protein). Data regarding treatment (steroids, convalescent plasma, remdasavir), pre-existing conditions, and incidences of strokes were collected. Amyloid β42, TDP43, NF-L, and KLK6 serum levels declined 2–3 days post-admission, yet recovered to admission baseline levels by 7 days. YKL-40 and NCAM-1 levels remained elevated over time, with clusters of differential responses identified among TREM-2, TDP43, and YKL40. Fetuin was elevated after the onset of COVID-19 while TREM-2 initially declined before significantly increasing over time. MIF serum level was increased 3–7 days after admission. Ferritin correlated with TDP-43 and KLK6. No treatment with remdesivir coincided with elevations in Amyloid-β40. A lack of convalescent plasma resulted in increased NCAM-1 and total tau, and steroidal treatments did not significantly affect any markers. A total of 11 incidences of stroke were registered up to six months after initial admission for COVID-19. Elevated D-dimer, platelet counts, IL-6, and leukopenia were observed. Variable MIF serum levels differentiated patients with CVA from those who did not have a stroke during the acute phase of COVID-19. This study demonstrated concomitant and opposite changes in neurodegenerative and neuroprotective markers persisting well into recovery.
Highlights
We investigate if the initial increase in neurodegeneration markers will be accompanied by a decline in neuroprotective proteins, creating conditions that could promote the release of neurodysfunctional markers and their potential long-term outcomes
We found that several neurodegeneration markers (YKL40, NCAM-1, C-C motif ligand 23 (CCL23)) were elevated in survivors of COVID-19 in a sustained fashion
The sustained elevation of YKL40, NCAM-1, and CCL23 may represent an ongoing pathological process in the survivors of COVID-19 as the levels did not decline below those recorded at admission [46,51,107]
Summary
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been linked to abnormalities in the central nervous system such as the loss of smell and taste, cognitive creativecommons.org/licenses/by/ 4.0/). The heterogeneity of symptoms remains puzzling [1,3,7,8,9,10] The development of these abnormalities often occurs within two days from the onset of symptoms [1,5,7,11,12]. SARS-CoV-2 co-localizes with the phosphorylated tau (τ) protein, triggering neuronal death or interfering with the distribution of τ [21]. The latter effect persists, suggesting a potential chronic mechanism for neurodegeneration.
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