Autoantibody landscapes in neurological Long COVID and post-COVID cognitive impairment show heterogeneity without a shared disease signature
Background: Neurological Long COVID (n-LC) includes persistent cognitive and autonomic symptoms after SARS-CoV-2 infection. Prior studies of post-COVID conditions have described diverse humoral autoreactivity, but findings are heterogeneous, and it remains unclear whether n-LC is associated with a consistent CNS-directed humoral signature. Methods: We performed a cross-cohort case-control analysis to detect autoantibodies in cerebrospinal fluid (CSF) and serum from n-LC participants. In the Yale COVID Mind Study cohort, CSF from n-LC participants and from pre-pandemic and post-COVID asymptomatic controls was assessed by mouse brain immunofluorescence and proteome-wide phage immunoprecipitation sequencing (PhIP-Seq), with candidate reactivities evaluated by orthogonal assays and supervised modeling. In the Epidemiology, Immunology, and Clinical Characteristics of Emerging Infectious Diseases with Pandemic Potential (IDCRP EPICC) cohort, post-COVID sera collected prior to iPhone- or iPad-based cognitive screening were profiled by PhIP-Seq and compared between participants with and without cognitive impairment. Results: CSF immunoreactivity on mouse brain tissue was observed in both n-LC and controls, with similar overall frequencies, although n-LC participants more often showed nuclear-predominant staining patterns. PhIP-Seq identified sparse, largely patient-specific peptide reactivities to nuclear and neuronal proteins in CSF and serum. Supervised models provided limited discrimination between cases and controls. Candidate autoantigens had limited disease specificity on orthogonal testing. EPICC serum autoantibody profiling similarly failed to distinguish individuals with and without cognitive impairment. Conclusions: Across cohorts and compartments, n-LC did not exhibit a shared autoantibody signature. These findings support the absence of a dominant, common CNS autoantibody-mediated mechanism in n-LC.
### Competing Interest Statement
SDP reports that the Uniformed Services University (USU) Infectious Diseases Clinical Research Program (IDCRP), a US Department of Defense institution, and the Henry M. Jackson Foundation (HJF) were funded under a Cooperative Research and Development Agreement to conduct an unrelated phase III COVID-19 monoclonal antibody immunoprophylaxis trial sponsored by AstraZeneca. The HJF, in support of the USU IDCRP, was funded by the Department of Defense Joint Program Executive Office for Chemical, Biological, Radiological, and Nuclear Defense to augment the conduct of an unrelated phase III vaccine trial sponsored by AstraZeneca. Both of these trials were part of the US Government COVID-19 response. Neither is related to the work presented here. MRW has received research-unrelated grant funding from Roche/Genentech, Novartis, and Kyverna Therapeutics, consulting fees from Ouro Medicines, Indapta Therapeutics, Vertex Pharmaceuticals, and Pfizer, and is a co-founder and on the Board of Directors for Delve Bio.
### Funding Statement
This EPICC protocol was supported by awards from the Defense Health Program (HU00012020067 and HU00012120103) and the National Institute of Allergy and Infectious Disease (HU00011920111), the National Institute of Neurological Disorders and Stroke (R01NS125693) and the Westridge Foundation. The protocol was executed by the Infectious Disease Clinical Research Program (IDCRP), a Department of War (DoW) program executed by the Uniformed Services University of the Health Sciences (USUHS) through a cooperative agreement by the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. (HJF). The Yale COVID mind study was supported by National Institute of Mental Health (R01MH125737); National Institute of Allergy and Infectious Disease (R01AI157488); the National Institute of Neurological Disorders and Stroke (K23NS133488). This project has been funded in part by the National Institute of Allergy and Infectious Diseases at the National Institutes of Health, under an interagency agreement (Y1-AI-5072), and the National Multiple Sclerosis Society Postdoctoral Fellowship for DC. Sequencing was performed at the UCSF CAT, supported by UCSF PBBR, RRP IMIA, and NIH 1S10OD028511-01 grants.
### Author Declarations
I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.
Yes
The details of the IRB/oversight body that provided approval or exemption for the research described are given below:
All studies in the Yale COVID Mind study cohort were approved by the Yale University IRB (HIC#1502015318), and written consent was obtained from all participants. All EPICC participants also provided informed consent, and the EPICC protocol was approved by the Uniformed Services University (USU) Institutional Review Board (Protocol number- IDCRP-085).The protocol was executed by the Infectious Disease Clinical Research Program (IDCRP), a Department of War (DoW) program executed by the Uniformed Services University of the Health Sciences (USUHS) through a cooperative agreement by the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. (HJF).
I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.
Yes
I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).
Yes
I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.
Yes
All PhIP-seq data are available for download at Dryad and code is deposited in GitHub.
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