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

Growing evidence suggests that coronavirus disease 2019 (COVID-19) is associated with acute and long-term neurological sequelae. However, the underlying pathophysiological mechanisms resulting in central nervous system (CNS) derogation remain unclear, posing both diagnostic and therapeutic challenges. Here, we performed a cross-sectional study (NCT04472013) and multidimensional characterization of cerebrospinal fluid (CSF) and plasma-targeted proteomics in different Neuro-COVID severity classes with corresponding clinical and imaging data. COVID-19 patients displayed a plasma cytokine storm but a non-inflammatory CSF profile. Severely affected patients displayed signs of blood-brain barrier (BBB) impairment, elevated microglia activation markers and a polyclonal B cell response targeting self- and non-self antigens. Also, COVID-19 patients had decreased regional brain volumes associated with specific CSF and plasma parameters. We provide a multiparametric framework of Neuro-COVID severity classifiers. Collectively, this data identified several potentially actionable targets that may be addressed to prevent COVID-19-related neurological sequelae.

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

Importance Growing evidence suggests that coronavirus disease 2019 (COVID-19) is associated with neurological sequelae. However, the underlying pathophysiological mechanisms resulting in central nervous system (CNS) derogation remain unclear. Objective To identify severity-dependent immune mechanisms in the cerebrospinal fluid (CSF) and plasma of COVID-19 patients and their association with brain imaging alterations. Design Prospective cross-sectional cohort study. Setting This study was performed from August 2020 to April 2021. Participants were enrolled in the outpatient clinics, hospital wards and intensive care units (ICU) of two clinical sites in Basel and Zurich, Switzerland. Participants Age >18 years and a positive SARS-CoV-2 test result were inclusion criteria. Potentially matching individuals were identified (n=310), of which 269 declined to participate and 1 did not match inclusion criteria. Paired CSF and plasma samples, as well as brain images, were acquired. The COVID-19 cohort (n=40; mean [SD] age, 54 [20] years; 17 women (42%)) was prospectively assorted by neurological symptom severity (classes I, II and III). Age/sex-matched inflammatory (n=25) and healthy (n=25) CSF and plasma control samples were obtained. For volumetric brain analysis, a healthy age/sex-matched control cohort (n=36) was established. Exposures Lumbar puncture, blood sampling and cranial MRI and/or CT. Main outcomes and measures Proteomics, standard parameters and antibody profiling of paired CSF and plasma samples in COVID-19 patients and controls. Brain imaging and gray matter volumetric analysis in association with biomarker profiles. Follow-up after 10-months. Results COVID-19 patients displayed a plasma cytokine storm but a non-inflammatory CSF profile. Class III patients displayed signs of blood-brain barrier (BBB) impairment and a polyclonal B cell response targeting self- and non-self antigens. Decreased regional brain volumes were present in COVID-19 patients and associated with specific CSF and plasma parameters. Conclusion and relevance Neuro-COVID class III patients had a strong, peripheral immune response resulting in (1) BBB impairment (2) ingress of (auto-)antibodies, (3) microglia activation and neuronal damage signatures. Our data point towards several potentially actionable targets that may be addressed to prevent COVID-19-related neurological sequelae. Trial registration

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

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 (clinicaltrials.gov NCT04472013). Retrospectively biobank, age- and sex-matched 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 no significant differences between groups in age, gender, Total GMV, Th, and SA (all P>.05). Patients showed lower GMV in orbitofrontal and cingulate regions. In a subgroup of patients (with CSF-study), we found a significant association between a decreased cortical volume and thickness in frontal, fronto-orbital, and temporal regions and increased CSF protein, CSF blood/albumin ratio, and CSF EN-RAGE levels. Our data suggest that viral-triggered inflammation leads to increased neurotoxic damage in some cortical areas.