Brain cortical changes are related to inflammatory biomarkers in hospitalized SARS-CoV-2 patients with neurological symptoms

Increasing evidence shows that the brain is a target of SARS-CoV-2. However, the consequences of the virus on the cortical regions of hospitalized patients are currently unknown. The purpose of this study was to assess brain cortical gray matter volume (GMV), thickness (Th), and surface area (SA) characteristics in SARS-CoV-2 hospitalized patients with a wide range of neurological symptoms and their association with clinical indicators of inflammatory processes. A total of 33 patients were selected from a prospective, multicenter, cross-sectional study during the ongoing pandemic (August 2020-April 2021) at Basel University Hospital. Retrospectively biobank healthy controls with the same image protocol served as controls group. For each anatomical T1w MPRAGE image, the Th and GMV segmentation were performed with the FreeSurfer-5.0. Cortical measures were compared between groups using a linear regression model. The covariates were age, gender, age*gender, MRI magnetic field strength, and total intracranial volume/mean Th/Total SA. The association between cortical features and laboratory variables was assessed using partial correlation adjusting for the same covariates. P-values were adjusted using false discovery rate (FDR). Our findings revealed a lower cortical gray matter volume in orbitofrontal and cingulate regions in patients compared to controls. The orbitofrontal grey matter volume was negatively associated with protein levels, CSF-blood/albumin ratio and CSF EN-RAGE level. CSF EN-RAGE and CSF/Blood-albumin ratio, which are neuroinflammatory biomarkers, were associated with cortical alterations in gray matter volume and thickness in frontal, orbitofrontal, and temporal regions. Our data suggest that viral-triggered inflammation leads to increased neurotoxic damage in some cortical areas. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The study was funded by the BOTNAR Fast Track Call foundation grant (FTC-2020-10) awarded to G.H., Other research support to G.H. for this project include a Swiss National Science Foundation Professorial Fellowship (PP00P3\_176974); the ProPatient Forschungsstiftung, University Hospital Basel (Annemarie Karrasch Award 2019); the Department of Surgery, University Hospital Basel, to G.H. G.H. has equity in, and is a cofounder of Incephalo Inc. CG is supported by the Swiss National Science Foundation (SNSF) grant PP00P3\_176984, the Stiftung zur Forderung der gastroenterologischen und allgemeinen klinischen Forschung and the EUROSTAR E!113682 HORIZON2020. ### 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: The trial ([NCT04472013][1]) was registered under clinicaltrials.gov and approved by the local institutional review board (Ethikkommission Nordwest- und Zentralschweiz, EKNZ 2020-01503) 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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors * SARS-CoV-2 : severe acute respiratory syndrome coronavirus 2 CSF : cerebrospinal fluid GMV : gray matter volume Th : cortical thickness SA : surface area TRANCE : tumor necrosis factor -related activation-induced cytokine EN-RAGE : receptor for advanced glycation end-products binding protein OPG (TNFRSF11B) : osteoprotegerin rRT-PCR : quantitative reverse transcriptase polymerase chain reaction FDR : false discovery rate [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04472013&atom=%2Fmedrxiv%2Fearly%2F2022%2F02%2F15%2F2022.02.13.22270662.atom