Severe Neuro-COVID is associated with peripheral immune signatures, autoimmunity and neurodegeneration: a prospective cross-sectional study

  1. Manina M. Etter
  2. Tomás A. Martins
  3. Laila Kulsvehagen
  4. Elisabeth Pössnecker
  5. Wandrille Duchemin
  6. Sabrina Hogan
  7. Gretel Sanabria-Diaz
  8. Jannis Müller
  9. Alessio Chiappini
  10. Jonathan Rychen
  11. Noëmi Eberhard
  12. Raphael Guzman
  13. Luigi Mariani
  14. Lester Melie-Garcia
  15. Emanuela Keller
  16. Ilijas Jelcic
  17. Hans Pargger
  18. Martin Siegemund
  19. Jens Kuhle
  20. Johanna Oechtering
  21. Caroline Eich
  22. Alexandar Tzankov
  23. Matthias S. Matter
  24. Sarp Uzun
  25. Özgür Yaldizli
  26. Johanna M. Lieb
  27. Marios-Nikos Psychogios
  28. Karoline Leuzinger
  29. Hans H. Hirsch
  30. Cristina Granziera
  31. Anne-Katrin Pröbstel
  32. Gregor Hutter

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Abstract

Growing evidence links COVID-19 with acute and long-term neurological dysfunction. However, the pathophysiological mechanisms resulting in central nervous system involvement remain unclear, posing both diagnostic and therapeutic challenges. Here we show outcomes of a cross-sectional clinical study (NCT04472013) including clinical and imaging data and corresponding multidimensional characterization of immune mediators in the cerebrospinal fluid (CSF) and plasma of patients belonging to different Neuro-COVID severity classes. The most prominent signs of severe Neuro-COVID are blood-brain barrier (BBB) impairment, elevated microglia activation markers and a polyclonal B cell response targeting self-antigens and non-self-antigens. COVID-19 patients show decreased regional brain volumes associating with specific CSF parameters, however, COVID-19 patients characterized by plasma cytokine storm are presenting with a non-inflammatory CSF profile. Post-acute COVID-19 syndrome strongly associates with a distinctive set of CSF and plasma mediators. Collectively, we identify several potentially actionable targets to prevent or intervene with the neurological consequences of SARS-CoV-2 infection.

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  1. Version published to 10.1038/s41467-022-34068-0
  2. Version published to 10.21203/rs.3.rs-1385593/v1 on Research Square
  3. ScreenIT

    SciScore for 10.1101/2022.02.18.22271039: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Ethicsnot detected.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    The analysis was performed using JASP (https://jasp-stats.org/) and MATLAB (‘partialcorri.m’ function) (https://www.mathworks.com/).
    JASP
    suggested: (JASP, RRID:SCR_015823)
    MATLAB
    suggested: (MATLAB, RRID:SCR_001622)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    This result comes with the caveat that we included only 6 class III patients for CPV analysis (39). Decreased GMVs in class II/III patients were associated with overexpression of the immune checkpoint protein PD-L1. Potentially, PD-L1 blockade would counteract this immune dysregulation and their associated structural brain changes (40). Conversely, HGF, reported to mediate tissue-regenerative responses in COVID-19-induced lung damage (8), might serve as a counter-regulatory factor promoting neuroregeneration upon neuronal damage. In contrast, lower plasma levels of neuroprotective GDF-8 (20) and BMP-4 (21), were associated with class II/III-related GMV loss, emphasizing the impact of COVID-19-induced soluble factors on distinct brain regions. Taken together, these GMV-associated CSF/plasma parameters may serve as targets to prevent long-term Neuro-COVID.

    Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT04472013Active, not recruitingSystematic Assessment of SARS-CoV-2 Neurotropic Capacity in …

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a protocol registration statement.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

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  4. Version published to 10.1101/2022.02.18.22271039v1 on medRxiv