Multiple sclerosis as a model to investigate SARS‐CoV‐2 effect on brain atrophy

Abstract Introduction Data on structural brain changes after infection with SARS‐CoV‐2 is sparse. We postulate multiple sclerosis as a model to study the effects of SARS‐CoV‐2 on brain atrophy due to the unique availability of longitudinal imaging data in this patient group, enabling assessment of intraindividual brain atrophy rates. Methods Global and regional cortical gray matter volumes were derived from structural MRIs using FreeSurfer. A linear model was fitted to the measures of the matching pre‐SARS‐CoV‐2 images with age as an explanatory variable. The residuals were used to determine whether the post‐SARS‐CoV‐2 volumes differed significantly from the baseline. Results Fourteen RRMS patients with a total of 113 longitudinal magnetic resonance images were retrospectively analyzed. We found no acceleration of brain atrophy after infection with SARS‐CoV‐2 for global gray matter volume (p = 0.17). However, on the regional level, parahippocampal gyri showed a tendency toward volume reduction (p = 0.0076), suggesting accelerated atrophy during or after infection. Conclusions Our results illustrate the opportunity of using longitudinal MRIs from existing MS registries to study brain changes associated with SARS‐CoV‐2 infections. We would like to address the global MS community with a call for action to use the available cohorts, reproduce the proposed analysis, and pool the results.

(MRI) examinations, a greater reduction in gray matter thickness and tissue contrast in the orbitofrontal cortex and parahippocampal gyrus was observed. The authors underlined the need for additional follow-up data to determine whether those findings are reversible or persistent in the long term. However, reliably deriving intraindividual brain atrophy rates requires multiple imaging examinations before the infection, which is not available with only two MRIs from the UK Biobank.
Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease of the central nervous system with inflammatory and degenerative components. 2 In individuals with MS, the risk of a severe course of SARS-CoV-2 infection is linked to age, certain immunotherapies, and patient characteristics such as ambulatory disability. 3,4 In our view, MS represents an ideal model for studying the potential effects of infection with SARS-CoV-2 on brain structure for several reasons. The main advantage of MS cohorts lies in the availability of imaging data with multiple scans at short follow-up intervals both before and after infection with SARS-CoV-2 obtained with standardized imaging protocols. This allows adjustment for the intraindividual brain atrophy rate prior to SARS-CoV-2 infection. Thus, it is possible to determine whether the brain atrophy in a given individual accelerates either temporarily during the infection or persistently after the infection. Furthermore, brain atrophy in individuals with MS has been extensively studied and increased atrophy rates and differences in atrophy patterns in comparison to healthy individuals are well documented. 5,6 In particular, increased atrophy rates in spinal, striatal, pallidal, thalamic, and cortical areas as well as in the white matter and the corpus callosum have been described. 7,8 The orbitofrontal cortex and parahippocampal gyrus, which seem to be most affected by SARS-CoV-2 infection in the general population according to the UK Biobank study, 1 are not known to be affected by MS. With this brief report, we propose to use MS registries worldwide to study SARS-CoV-2-related brain atrophy specifically, by analyzing longitudinal MRI data on a patient level along the approach presented here.  with our standardized MS protocol. 10 Atrophy was quantified on unenhanced, high-resolution magnetization-prepared rapid acquisition with gradient echo sequence (MPRAGE) images. MRI data were processed using the freely available software packages FreeSurfer (version 6.0.0) and DL+DiReCT to derive global and regional cortical gray matter (GM) volume and thickness. 11-13

| ME THODS
Patient-specific atrophy rates prior to infection were calculated individually for every patient with at least three pre-SARS-CoV-2 MRI scans that matched with at least one post-SARS-CoV-2 scan with respect to field strength, repetition time, and inversion time ( Figure S2), leading to the final cohort of 14 patients ( Figure S1). A linear model was fitted to the global and regional GM volumes of the matching pre-SARS-CoV-2 images using patient age as the explanatory variable. Standardized residuals were derived from matched pre-and post-SARS-CoV-2 images and subjected to a two-sided t test to determine whether the post-SARS-CoV-2 residuals were significantly different from baseline residuals.

| RE SULTS
Fourteen patients with relapsing-remitting MS with a total of 113 eligible MR scans were finally included ( Figure S3). The included patients had an average of 6.7 MRI scans (range 3-13) before and Using standardized residuals from the linear pre-SARS-CoV-2 fits to adjust for the region-and person-specific brain atrophy rate, the global GM volume showed no indication of accelerated brain atrophy during or after infection with SARS-CoV-2 (p = 0.17). However, the residuals of the parahippocampal gyri tended toward negative values (p = 0.0076), suggesting accelerated regional atrophy (Figure 1). These FreeSurfer-generated results were confirmed with DL + DiReCT, 12 an independent, deep learning-based morphometry tool ( Figure S4) and are in line with the findings from the UK Biobank study 1 despite the younger age F I G U R E 1 An increased atrophy rate of the parahippocampal gyri after SARS-CoV-2 infection using FreeSurfer for atrophy analysis. Longitudinal atrophy rates for individual patients are depicted in Figure S3. Analogous results from the DL+DiReCT software are presented in Figure S4.

| CON CLUS I ON AND D ISCUSS I ON
We analyzed brain atrophy rates in patients with MS after infection with SARS-CoV-2. A patient-specific baseline was derived from longitudinal preinfection MRIs and compared with postinfection measures. No evidence for an increased global atrophy rate was observed, but regional atrophy in the parahippocampal gyri was increased, confirming the main finding of the UK Biobank study. 1 Our proposed approach allows adjustment for the intraindividual brain atrophy rate prior to SARS-CoV-2 infection and shows whether the brain atrophy accelerates during or after SARS-CoV-2 infection.
Such an analysis can complement results from studies like those presented by Douaud et al., 1 where a single MRI scan before and after SARS-CoV-2 infection was available for a large number of subjects but offered no possibility to adjust for the intraindividual and regional atrophy rate. We call for further studies to reproduce these investigations in MS registries worldwide. We also encour-