Characterization and Biomarker Analyses of Post-COVID-19 Complications and Neurological Manifestations
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Participants
2.2. SARS-CoV-2 IgG Antibody Test
2.3. APOE4 Genotyping
2.4. Plasma Multiplex Cytokine Analysis and NFL by MSD Assays
2.5. nEV Isolation
2.6. Characterization of nEVs by NTA and electron microscopy
2.7. Neuronal-Enriched EV Protein Cargo Analyses
2.8. Statistics and Bioinformatics
3. Results
3.1. Participant Demographic and Clinical Data
3.2. Plasma Cytokines, NFL, and IgG Levels
3.3. Neuronal Enriched EV Characterization
3.4. Neuronal enriched EV protein cargo
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Control (%) † | CoV (%) | nCoV (%) | p-Value | |||||
---|---|---|---|---|---|---|---|---|
Sex | Female (N = 22) | 4 | (33.3) | 12 | (75.0) | 6 | (75.0) | 0.053 |
Male (N = 14) | 8 | (66.7) | 4 | (25.0) | 2 | (25.0) | ||
Race | Asian | 2 | (16.7) | 0 | (0.0) | 1 | (12.5) | 0.154 |
Black | 4 | (33.3) | 2 | (12.5) | 1 | (12.5) | ||
White | 6 | (50.0) | 11 | (68.8) | 5 | (62.5) | ||
American Indian | 0 | (0.0) | 0 | (0.0) | 1 | (12.5) | ||
Undisclosed | 0 | (0.0) | 3 | (18.8) | 0 | (0.0) | ||
Ethnicity | Hispanic | 1 | (8.3) | 3 | (18.8) | 4 | (50.0) | 0.081 |
Non-Hispanic | 11 | (91.7) | 13 | (81.3) | 4 | (50.0) | ||
APOE genotype | ε2, ε3 | NA | NA | 2 | (12.5) | 0 | (0.0) | 0.615 |
ε3, ε3 | NA | NA | 9 | (56.3) | 6 | (75.0) | ||
ε3, ε4 | NA | NA | 4 | (25.0) | 2 | (25.0) | ||
ε4, ε4 | NA | NA | 1 | (6.3) | 0 | (0.0) | ||
Comorbidity | NA | NA | 7 | (43.8) | 8 | (100) | 0.0095 | |
Days till visit, Mean (SD) | NA | 56.6 (20.3) | 76.5 (27.2) | 0.094 | ||||
Age in years, Mean (SD) | 52.3 (12.4) | 45.2 (13.2) | 45.6 (12.3) | 0.316 |
ID | Age | Sex | Race/Ethnicity | Mobility Issues ‡ | Selfcare Issues ‡ | Activity Issues ‡ | Hospitalized | Days Till visit § | IgG | ApoE Genotype | Neuro Symptoms | Comorbidity |
---|---|---|---|---|---|---|---|---|---|---|---|---|
1 | 34 | F | AI/L | 2 | 1 | 1 | No | 36 | 4.2 | ε3,ε3 | DV | LD |
2 † | 69 | M | W | 3 | 3 | 3 | No | 62 | 8.3 | ε3,ε3 | M/C | HT,LD,O |
3 | 38 | F | Asian | 2 | 2 | 2 | Yes | 103 | 8.6 | ε3,ε3 | H | AID, DM,O |
4 † | 59 | M | W | 3 | 3 | 3 | Yes | 80 | 7.5 | ε3,ε3 | M/C | HT,LD |
5 | 33 | F | W/L | 2 | 1 | 3 | No | 97 | 3.3 | ε3,ε3 | M/C | HT |
6 | 43 | F | B/L | 2 | 1 | 3 | Yes | 99 | 9.4 | ε3,ε4 | M/C | HT,LD,O |
7 | 46 | F | W/L | 2 | 2 | 3 | Yes | 95 | 5.9 | ε3,ε4 | M/C | DM,O |
8 | 43 | F | W | 2 | 2 | 2 | No | 40 | 9.1 | ε3,ε3 | M/C | O |
9 | 30 | F | W | 1 | 2 | 3 | No | 38 | 2 | ε2,ε3 | None | |
10 | 37 | F | W | 1 | 1 | 1 | No | 30 | 0.4 | ε3,ε3 | None | |
11 | 30 | F | W | 1 | 1 | 1 | No | 31 | 3.9 | ε3,ε3 | None | |
12 | 43 | F | W | 3 | 2 | 3 | No | 52 | 1.1 | ε3,ε4 | None | |
13 | 35 | F | W | 2 | 1 | 2 | No | 41 | 8.8 | ε3,ε4 | None | |
14 | 30 | F | W | 2 | 1 | 1 | No | 44 | 6.1 | ε3,ε4 | None | |
15 | 66 | F | W | 3 | 2 | 3 | No | 49 | 8.4 | ε3,ε3 | None | LD |
16 | 40 | F | B | 1 | 1 | 1 | No | 38 | 4.9 | ε3,ε4 | None | O |
17 | 33 | F | W | 1 | 2 | 1 | No | 60 | 3.5 | ε3,ε3 | None | O |
18 | 67 | M | W | 2 | 1 | 2 | No | 64 | 2.6 | ε4,ε4 | None | O |
19 | 43 | F | B | 1 | 3 | 2 | No | 70 | 7.3 | ε3,ε3 | None | HT |
20 | 59 | F | W | 2 | 2 | 2 | No | 60 | 0.3 | ε2,ε3 | None | |
21 | 40 | F | W | 2 | 1 | 2 | No | 60 | 7.2 | ε3,ε3 | None | |
22 | 52 | M | Dc/L | 3 | 3 | 3 | Yes | 88 | 5.8 | ε3,ε3 | None | DM |
23 | 65 | M | Dc/L | 3 | 3 | 3 | Yes | 84 | 6.7 | ε3,ε3 | None | DM,O |
24 | 52 | M | Dc/L | 2 | 1 | 1 | Yes | 97 | 4.2 | ε3,ε3 | None |
Term | p Value | Genes |
---|---|---|
Gene Ontology | ||
GO:0030182~neuron differentiation | 0.0002 | APP, IL6, NCAM1, MAPT, HMGB1, KLK6 |
GO:0050803~regulation of synapse structure or activity | 0.0002 | APP, NCAM1, SYP, NRGN |
GO:0007399~nervous system development | 0.0003 | APP, IL6, NCAM1, MAPT, HMGB1, NRGN, KLK6 |
GO:0070997~neuron death | 0.0003 | APP, IL6, FGF21, KLK6 |
GO:0022008~neurogenesis | 0.0004 | APP, IL6, NCAM1, MAPT, HMGB1, KLK6 |
GO:0031175~neuron projection development | 0.0006 | APP, IL6, NCAM1, MAPT, HMGB1 |
GO:0008219~cell death | 0.0018 | APP, IL6, HMGB1, TARDBP, FGF21, KLK6 |
GO:0048167~regulation of synaptic plasticity | 0.0024 | NCAM1, SYP, NRGN |
GO:0006935~chemotaxis | 0.0026 | APP, IL6, NCAM1, HMGB1 |
GO:0030424~axon | 0.0050 | APP, MAPT, NRGN |
Uniprotein: Neurodegeneration | 0.0068 | APP, MAPT, TARDBP |
GO:0006915~apoptotic process | 0.0096 | APP, IL6, HMGB1, TARDBP, FGF21 |
GO:0048812~neuron projection morphogenesis | 0.0323 | APP, NCAM1, MAPT |
GO:0099536~synaptic signaling | 0.0393 | NCAM1, SYP, NRGN |
Genetic Association Database | ||
Dementia | 0.0009 | APP, IL6, MAPT |
Alzheimer’s Disease | 0.0013 | APP, IL6, MAPT, TARDBP |
Schizophrenia | 0.0141 | IL6, NCAM1, MAPT, NRGN |
Neuroinflammation Signaling Pathway † | 0.0000 | APP, IL6, HMGB1, MAPT |
Neuroprotective Role of THOP1 in Alzheimer’s Disease † | 0.0000 | APP, KLK6, MAPT |
Transcription factor binding site | ||
NFKB | 0.0298 | APP, IL6, NCAM1, SYP, MAPT, TARDBP, NRGN, KLK6 |
STAT3 | 0.0217 | APP, NCAM1, SYP, MAPT, TARDBP, FGF21, NRGN, KLK6 |
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Sun, B.; Tang, N.; Peluso, M.J.; Iyer, N.S.; Torres, L.; Donatelli, J.L.; Munter, S.E.; Nixon, C.C.; Rutishauser, R.L.; Rodriguez-Barraquer, I.; et al. Characterization and Biomarker Analyses of Post-COVID-19 Complications and Neurological Manifestations. Cells 2021, 10, 386. https://doi.org/10.3390/cells10020386
Sun B, Tang N, Peluso MJ, Iyer NS, Torres L, Donatelli JL, Munter SE, Nixon CC, Rutishauser RL, Rodriguez-Barraquer I, et al. Characterization and Biomarker Analyses of Post-COVID-19 Complications and Neurological Manifestations. Cells. 2021; 10(2):386. https://doi.org/10.3390/cells10020386
Chicago/Turabian StyleSun, Bing, Norina Tang, Michael J. Peluso, Nikita S. Iyer, Leonel Torres, Joanna L. Donatelli, Sadie E. Munter, Christopher C. Nixon, Rachel L. Rutishauser, Isabel Rodriguez-Barraquer, and et al. 2021. "Characterization and Biomarker Analyses of Post-COVID-19 Complications and Neurological Manifestations" Cells 10, no. 2: 386. https://doi.org/10.3390/cells10020386
APA StyleSun, B., Tang, N., Peluso, M. J., Iyer, N. S., Torres, L., Donatelli, J. L., Munter, S. E., Nixon, C. C., Rutishauser, R. L., Rodriguez-Barraquer, I., Greenhouse, B., Kelly, J. D., Martin, J. N., Deeks, S. G., Henrich, T. J., & Pulliam, L. (2021). Characterization and Biomarker Analyses of Post-COVID-19 Complications and Neurological Manifestations. Cells, 10(2), 386. https://doi.org/10.3390/cells10020386