SARS-CoV-2 Triggered Inflammation Leads To Increased Neurotoxic Damage In Cortical Areas Of The Human Brain

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Researchers from the University Hospital Basel and University of Basel-Switzerland have in a new shockingly found that SARS-CoV-2 triggered inflammation leads to increased neurotoxic damage in cortical areas of the human brain.

The study findings were published on a preprint server and are currently being peer reviewed. https://www.medrxiv.org/content/10.1101/2022.02.13.22270662v1

ncreasing 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.

Map of the brain regions with a significant association between gray matter volume and cortical thickness clinical variables in severly affected SARS-CoV-2 patients. Panel A) show the 27 brain regions with significant correlation values for gray matter volume and cortical thickness after multiple comparison corrections (False Discovery Rate-FDR). Panel B) and C) shows the matrices representing the association significance (significant p-corrected<0.05 in red squares).CSF=Cerebrospinal fluid, leuk=leukocytes, lact=lactate, prot=protein, albR=Albumin CSF-blood ratio, Cen_Rage: CSF EN-RAGE = extracellular receptor for advanced glycation end-products binding protein, R= right, L= left.

Discussion

This study shows a GMV decrease in orbitofrontal and cingulate regions in a sample of hospitalized SARS-CoV-2 patients with a wide range of neurological symptoms. These findings are in agreement and extend previous reported multifocal MRI abnormalities in hospitalized patients (4).

Interestingly, the GMV in the orbitofrontal area– a region that has been described as metabolic affected in hospitalized patients (5) -was consistently negatively associated with with protein levels, CSF/blood-albumin ratio and CSF EN-RAGE.

One hypothesis for the brain alteration in SARS-CoV-2 infection is a neuroinflammatory response (6). Our results confirmed a significant association between (i) a decreased GMV and Th in frontal, fronto-orbital, and temporal regions and (ii) increased CSF levels of indirect inflammatory markers (protein, blood/albumin ratio, and EN-RAGE).

Elevation in CSF protein levels has been used to indicate the inflammatory response (7). The CSF/blood-albumin ratio increase suggests a BBB breakdown. EN-RAGE is a cytokine that activates an inflammatory cascade, including accelerated atherosclerosis (8).

The relationship between ENRAGE and CSF/blood-albumin ratio with increased volumes in some cortical areas suggests a viral-triggered inflammatory process as a consequence of a secondary parainfectious complication or after direct invasion (less probable) (9).

In summary, CSF inflammatory marker levels were associated with GMV and Th changes in frontal, orbitofrontal, and temporal regions in hospitalized SARS-CoV-2 patients with different levels of neurological involvement. Future longitudinal studies in larger cohorts should further confirm and expand these findings.

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