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. 2024 Mar 8;13(6):478.
doi: 10.3390/cells13060478.

Blood Markers Show Neural Consequences of LongCOVID-19

Norina Tang  1 , Tatsuo Kido  1 , Jian Shi  2   3 , Erin McCafferty  1 , Judith M Ford  4   5 , Kaitlyn Dal Bon  4 , Lynn Pulliam  1   6
Affiliations

Blood Markers Show Neural Consequences of LongCOVID-19

Norina Tang et al. Cells. .

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) persists throughout the world with over 65 million registered cases of survivors with post-COVID-19 sequelae, also known as LongCOVID-19 (LongC). LongC survivors exhibit various symptoms that span multiple organ systems, including the nervous system. To search for neurological markers of LongC, we investigated the soluble biomolecules present in the plasma and the proteins associated with plasma neuronal-enriched extracellular vesicles (nEVs) in 33 LongC patients with neurological impairment (nLongC), 12 COVID-19 survivors without any LongC symptoms (Cov), and 28 pre-COVID-19 healthy controls (HC). COVID-19 positive participants were infected between 2020 and 2022, not hospitalized, and were vaccinated or unvaccinated before infection. IL-1β was significantly increased in both nLongC and Cov and IL-8 was elevated in only nLongC. Both brain-derived neurotrophic factor and cortisol were significantly elevated in nLongC and Cov compared to HC. nEVs from people with nLongC had significantly elevated protein markers of neuronal dysfunction, including amyloid beta 42, pTau181 and TDP-43. This study shows chronic peripheral inflammation with increased stress after COVID-19 infection. Additionally, differentially expressed nEV neurodegenerative proteins were identified in people recovering from COVID-19 regardless of persistent symptoms.

Keywords: BDNF; LongCOVID-19; blood markers; cognition; cortisol; neuronal extracellular vesicles.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
nLongC and Cov participants were infected over a period of three years with, likely, different SARS-CoV-2 variants. The COVID-19 cases described in this study are shown as black and white bars superimposed onto a background of SARS-CoV-2 variants described by Wang et al., 2022 [12] and Lam et al., 2020 [13].
Figure 2
Figure 2
Plasma cytokines. (A) Meso Scale Discovery (MSD) analysis for seven cytokines showed a significant increase in IL-1β for both Cov and nLongC groups. IL-8 was increased only in the nLongC group. Horizontal bars indicate group medians which were compared using Kruskal–Wallis tests followed by post-hoc Dunn tests. p value symbols are as follows: ns = p > 0.05, * p ≤ 0.05) and **** p ≤ 0.0001. HC (n = 28), Cov (n = 12) and nLongC (n = 33). (B) Receiver-operating characteristic (ROC) curves for significantly differentially expressed plasma cytokines, Il-1β and IL-8. Area under curve (AUC) is shown in graphs. Significantly differentially expressed cytokines are displayed for each pair of groups: IL-1β (solid red line) and IL-8 (solid black line).
Figure 3
Figure 3
Plasma levels of brain-derived neurotrophic factor (BDNF), C-reactive protein (CRP) and cortisol. (A) People with Cov and nLongC had elevated levels of BDNF and cortisol without increased CRP (Kruskal–Wallis tests followed by post-hoc Dunn’s tests). ns = p > 0.05, ** p ≤ 0.01, *** p ≤ 0.001 and **** p ≤ 0.0001. BDNF had a moderate positive correlation with IL-1β in the nLongC group (B) (Spearman r = 0.39, p = 0.03) and a moderate negative correlation with cortisol (C) (Spearman r = −0.45, p = 0.0087). (D) Cortisol decreased over time in Cov subjects but not in nLongC individuals. For all panels, HC (n = 28), Cov (n = 12) and nLongC (n = 33).
Figure 4
Figure 4
Characterization of nEVs. (A) Nanoparticle tracking analysis (NTA) showed larger and more abundant nEVs for nLongC. (B) nEV tetraspanins CD9, CD63 and CD81 were all increased in both Cov and nLongC groups. (C) Exosomal protein Alix was increased in both Cov and nLongC groups while NeuN was present in all nEVs at similar levels between the three groups. For NeuN, there were fewer values in each group due to insufficient sample availability: HC (n = 8), Cov (n = 3), nLongC (n = 13). Kruskal–Wallis tests followed by post-hoc Dunn’s tests were performed for all comparisons. ns = p > 0.05, * p ≤ 0.05, ** p ≤ 0.01, *** p ≤ 0.001 and **** p ≤ 0.0001. Group sample sizes for all (except NeuN) were HC (n = 28), Cov (n = 12) and nLongC (n = 33).
Figure 5
Figure 5
Neuronal protein cargo in nEVs. nEV lysates were analyzed using a 9-plex Luminex neurodegeneration panel and ELISA for HMGB1. Concentrations were normalized to plasma volume. All of the proteins except Aβ40 and tTau were increased in nEVs from the nLongC group. For the Cov group, only four proteins were elevated (Aβ40, NCAM-1, NRGN, tTau). Kruskal–Wallis tests followed by post-hoc Dunn’s tests were performed for all comparisons. ns = p > 0.05, * p ≤ 0.05, ** p ≤ 0.01, *** p ≤ 0.001 and **** p ≤ 0.0001. Group sample sizes were HC (n = 28), Cov (n = 12) and nLongC (n = 33), except for HMGB1 which were HC (n = 15) and nLongC (n = 25).
Figure 6
Figure 6
Blood biomolecules and informatics classification analyses for nLongC. (A) Venn diagram delineating the differentially expressed blood biomolecules identified in this study. (B) Heatmap of eight critical blood protein levels, with samples from healthy controls (HC) on the left, Cov in the middle, and nLongC on the right. Red represents higher expression and green represents lower expression. (C) Chord diagram depicting the connections between the genes and their associated GO and HP terms, providing insights into the biological processes and functions related to nLongC pathogenesis. GO and HP terms, along with their respective biological processes, indicated in red, represent potential pathological mechanisms of nLongC, some of which show associations to AD.
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References

    1. Davis H.E., McCorkell L., Vogel J.M., Topol E.J. Long COVID: Major findings, mechanisms and recommendations. Nat. Rev. Microbiol. 2023;21:133–146. doi: 10.1038/s41579-022-00846-2. - DOI - PMC - PubMed
    1. Fischer A., Zhang L., Elbéji A., Wilmes P., Oustric P., Staub T., Nazarov P.V., Ollert M., Fagherazzi G. Long COVID Symptomatology After 12 Months and Its Impact on Quality of Life According to Initial Coronavirus Disease 2019 Disease Severity. Open Forum Infect. Dis. 2022;9:ofac397. doi: 10.1093/ofid/ofac397. - DOI - PMC - PubMed
    1. FAIR Health . Patients Diagnosed with Post-COVID-19 Conditions: An Analysis of Private Healthcare Claims Using the Official ICD-10 Diagnostic Code. FAIR Health, Inc.; New York, NY, USA: 2022. white paper.
    1. Nalbandian A., Sehgal K., Gupta A., Madhavan M.V., McGroder C., Stevens J.S., Cook J.R., Nordvig A.S., Shalev D., Sehrawat T.S., et al. Post-acute COVID-19 syndrome. Nat. Med. 2021;27:601–615. doi: 10.1038/s41591-021-01283-z. - DOI - PMC - PubMed
    1. Stefanou M.I., Palaiodimou L., Bakola E., Smyrnis N., Papadopoulou M., Paraskevas G.P., Rizos E., Boutati E., Grigoriadis N., Krogias C., et al. Neurological manifestations of long-COVID syndrome: A narrative review. Ther. Adv. Chronic Dis. 2022;13:20406223221076890. doi: 10.1177/20406223221076890. - DOI - PMC - PubMed

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