Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses

Data Availability Statement: The individual-level data from these studies is not publicly available to main confidentiality. Data generated by the ISARIC4C consortium is available for collaborative analysis projects through an independent data and materials access committee at isaric4c.net/sample_access. Data and samples from the COVID-Clinical Neuroscience Study are available through collaborative research by application through the NIHR bioresource at https://bioresource.nihr.ac.uk/using-our-bioresource/apply-for-bioresource-data-access/. Brain injury marker and immune mediator data are present in the paper and in the source data file. Source data are provided with this paper.To understand neurological complications of COVID-19 better both acutely and for recovery, we measured markers of brain injury, inflammatory mediators, and autoantibodies in 203 hospitalised participants; 111 with acute sera (1–11 days post-admission) and 92 convalescent sera (56 with COVID-19-associated neurological diagnoses). Here we show that compared to 60 uninfected controls, tTau, GFAP, NfL, and UCH-L1 are increased with COVID-19 infection at acute timepoints and NfL and GFAP are significantly higher in participants with neurological complications. Inflammatory mediators (IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) are associated with both altered consciousness and markers of brain injury. Autoantibodies are more common in COVID-19 than controls and some (including against MYL7, UCH-L1, and GRIN3B) are more frequent with altered consciousness. Additionally, convalescent participants with neurological complications show elevated GFAP and NfL, unrelated to attenuated systemic inflammatory mediators and to autoantibody responses. Overall, neurological complications of COVID-19 are associated with evidence of neuroglial injury in both acute and late disease and these correlate with dysregulated innate and adaptive immune responses acutely.National Institute for Health and Care Research (NIHR) (CO-CIN-01) and jointly by NIHR and UK Research and Innovation (CV220-169, MC_PC_19059). B.D.M. is supported by the UKRI/MRC (MR/V03605X/1), the MRC/UKRI (MR/V007181/1), MRC (MR/T028750/1) and Wellcome (ISSF201902/3). C.D. is supported by MRC (MC_PC_19044). We would like to thank the University of Liverpool GCP laboratory facility team for Luminex assistance and the Liverpool University Biobank team for all their help, especially Dr. Victoria Shaw, Lara Lavelle-Langham, and Sue Holden. We would like to acknowledge the Liverpool Experimental Cancer Medicine Centre for providing infrastructure support for this research (Grant Reference: C18616/A25153). We acknowledge the Liverpool Centre for Cell Imaging (CCI) for provision of imaging equipment (Dragonfly confocal microscope) and excellent technical assistance (BBSRC grant number BB/R01390X/1). Tom Solomon is supported by The Pandemic Institute and the NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool. D.K.M. and E.N. are supported by the NIHR Cambridge Biomedical Centre and by NIHR funding to the NIHR BioResource (RG94028 and RG85445), and by funding from Brain Research UK 201819-20. We thank NIHR BioResource volunteers for their participation, and gratefully acknowledge NIHR BioResource centres, NHS Trusts and staff for their contribution. We thank the National Institute for Health and Care Research, NHS Blood and Transplant, and Health Data Research UK as part of the Digital Innovation Hub Programme. Support for title page creation and format was provided by AuthorArranger, a tool developed at the National Cancer Institute. The authors would like to acknowledge the eDRIS team (Public Health Scotland) for their support in obtaining approvals, the provisioning and linking of data and facilitating access to the National Safe Haven. The views expressed are those of the author(s) and not necessarily those of the UKRI, NHS, the NIHR or the Department of Health and Social Care

Posthospitalization COVID-19 cognitive deficits at 1 year are global and associated with elevated brain injury markers and gray matter volume reduction

\ua9 The Author(s) 2024.The spectrum, pathophysiology and recovery trajectory of persistent post-COVID-19 cognitive deficits are unknown, limiting our ability to develop prevention and treatment strategies. We report the 1-year cognitive, serum biomarker and neuroimaging findings from a prospective, national study of cognition in 351 COVID-19 patients who required hospitalization, compared with 2,927 normative matched controls. Cognitive deficits were global, associated with elevated brain injury markers and reduced anterior cingulate cortex volume 1 year after COVID-19. Severity of the initial infective insult, postacute psychiatric symptoms and a history of encephalopathy were associated with the greatest deficits. There was strong concordance between subjective and objective cognitive deficits. Longitudinal follow-up in 106 patients demonstrated a trend toward recovery. Together, these findings support the hypothesis that brain injury in moderate to severe COVID-19 may be immune-mediated, and should guide the development of therapeutic strategies

Posthospitalization COVID-19 cognitive deficits at 1 year are global and associated with elevated brain injury markers and gray matter volume reduction

Data availability: Individual-level data and samples from the COVID-Clinical Neuroscience Study are available for collaborative research by application through the NIHR BioResource Data Access Committee https://bioresource.nihr.ac.uk/using-our-bioresource/apply-for-bioresource-data-access/. The Committee decide on academic applications, with escalation to the NIHR BioResource Steering Committee for contentious applications, and/or applications from industry. Participants in the NIHR BioResource have all consented to the sharing of de-identified data with bona fide researchers worldwide, for research in the public interest. There are limits to these consents both by expectation and legal—some datasets may not be shared beyond a safe setting in the UK. The Data Access Committee aim to process data-only requests as quickly as possible and meet fortnightly to consider applications. Once approved, timeframes for data availability vary from 2 weeks to 6 months depending on the nature of the data requested.Code availability: Code is publicly available via https://github.com/tnggroup/covidcns.Extended data are available online at: https://www.nature.com/articles/s41591-024-03309-8#Sec24 .Supplementary information is available online at: https://www.nature.com/articles/s41591-024-03309-8#Sec25 .The spectrum, pathophysiology and recovery trajectory of persistent post-COVID-19 cognitive deficits are unknown, limiting our ability to develop prevention and treatment strategies. We report the 1-year cognitive, serum biomarker and neuroimaging findings from a prospective, national study of cognition in 351 COVID-19 patients who required hospitalization, compared with 2,927 normative matched controls. Cognitive deficits were global, associated with elevated brain injury markers and reduced anterior cingulate cortex volume 1 year after COVID-19. Severity of the initial infective insult, postacute psychiatric symptoms and a history of encephalopathy were associated with the greatest deficits. There was strong concordance between subjective and objective cognitive deficits. Longitudinal follow-up in 106 patients demonstrated a trend toward recovery. Together, these findings support the hypothesis that brain injury in moderate to severe COVID-19 may be immune-mediated, and should guide the development of therapeutic strategies.Members of the COVID-CNS Study Group are supported to conduct COVID-19 neuroscience research by the UK Research and Innovation/Medical Research Council (UKRI/MRC; grant no. MR/V03605X/1). G.K.W. is funded by the UK NIHR as an NIHR Academic Clinical Fellow (ACF-2022-07-007). B.D.M., G.B. and other investigators are supported by NIHR Health Protection Research Unit in Emerging and Zoonotic Infections at University of Liverpool, NIHR/Wellcome Trust King’s Clinical Research Facility, NIHR Maudsley Biomedical Research Centre at South London, Maudsley NHS Foundation Trust and King’s College London. B.D.M. is also supported for additional neurological inflammation research due to viral infection by grants from: the NIHR (award CO-CIN-01), the MRC (MC_PC_19059), the UKRI/MRC (MR/V007181/1), MRC (MR/T028750/1) and Wellcome (ISSF201902/3). J.-P.T. is supported by the Newcastle NIHR Biomedical Research Centre and the NIHR Dementia Translational Research Collaboration. This publication was supported by the Association of British Neurologists, British Paediatric Neurology Association, British Association of Stroke Physicians and the Royal College of Psychiatrists

Author Correction: Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses (Nature Communications, (2023), 14, 1, (8487), 10.1038/s41467-023-42320-4)

Correction to: Nature Communications https://doi.org/10.1038/s41467-023-42320-4, published online 22 December 2023.The author correction has been noted on the original BURA record at https://bura.brunel.ac.uk/handle/2438/28104 .Correction to: Nature Communicationshttps://doi.org/10.1038/s41467-023-42320-4, published online 22 December 2023 The original version of this article omitted three members of the COVID-CNS Consortium. Alex Berry and Obioma Orazulume, who are from the ‘University College London, London, UK’, and Ian Galea, who is from the ‘University of Southampton, Southampton, UK’ were added to the list of COVID-CNS Consortium members. This has been corrected in both the PDF and HTML versions of the article