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Review 1: "Brain Imaging and Neuropsychological Assessment of Individuals Recovered from Mild to Moderate SARS-CoV-2 Infection"

Published onNov 21, 2022
Review 1: "Brain Imaging and Neuropsychological Assessment of Individuals Recovered from Mild to Moderate SARS-CoV-2 Infection"
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key-enterThis Pub is a Review of
Brain imaging and neuropsychological assessment of individuals recovered from a mild to moderate SARS-CoV-2 infection

AbstractAs SARS-CoV-2 infections have been shown to affect the central nervous system, the investigation of associated alterations of brain structure and neuropsychological sequelae is crucial to help address future health care needs. Therefore, we performed a comprehensive neuroimaging and neuropsychological assessment of 223 non-vaccinated individuals recovered from a mild to moderate SARS-CoV-2 infection (100 female/123 male, age [years], mean ± SD, 55.54 ± 7.07; median 9.7 months after infection) in comparison with 223 matched controls (93 female/130 male, 55.74 ± 6.60) within the framework of the Hamburg City Health Study. Primary study outcomes were advanced diffusion magnetic resonance imaging (MRI) measures of white matter microstructure, cortical thickness, white matter hyperintensity load and neuropsychological test scores. Among all 11 MRI markers tested, significant differences were found in global measures of mean diffusivity and extracellular free-water which were elevated in the white matter of post-SARS-CoV-2 individuals comparing to matched controls (free-water: 0.148 ± 0.018 vs. 0.142 ± 0.017,P<.001; mean diffusivity [10−3mm2/s]: 0.747 ± 0.021 vs. 0.740 ± 0.020,P<.001). Group classification accuracy based on diffusion imaging markers was up to 80%. Neuropsychological test scores did not significantly differ between groups. Collectively, our findings suggest that subtle changes in white matter extracellular water content last beyond the acute infection with SARS-CoV-2. However, in our sample, a mild to moderate SARS-CoV-2 infection was not associated with neuropsychological deficits, significant changes in cortical structure or vascular lesions several months after recovery. External validation of our findings and longitudinal follow-up investigations are needed.Significance statementIn this case-control study, we demonstrate that non-vaccinated individuals recovered from a mild to moderate SARS-CoV-2 infection show significant alterations of the cerebral white matter identified by diffusion weighted imaging, such as global increases in extracellular free-water and mean diffusivity. Despite the observed brain white matter alterations in this sample, a mild to moderate SARS-CoV-2 infection was not associated with worse cognitive functions within the first year after recovery. Collectively, our findings indicate the presence of a prolonged neuroinflammatory response to the initial viral infection. Further longitudinal research is necessary to elucidate the link between brain alterations and clinical features of post-SARS-CoV-2 individuals.

RR:C19 Evidence Scale rating by reviewer:

  • Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.



This study investigated differences in a range of cognitive (i.e., several neuropsychological tests) and structural magnetic resonance imaging outcome measures (e.g., cortical thickness, white matter lesion load and microstructural integrity) between two large samples (n > 200) of participants who either had never been infected by the SARS-Cov-2 virus or had recovered from mild-to-moderate infection. The main aim of this cross-sectional study was to ascertain whether people who had COVID-19 without severe symptoms showed any signs of neurocognitive deficits compared to matched healthy individuals. Overall, the methods used by the authors appear to be sound and appropriate to answer the research question. The main finding of this study relates to the lack of differences in cognitive performance and most of the brain imaging parameters between the two samples of participants who had and who never had COVID-19. However, some microstructural alterations were detected in people who recovered from mild-to-moderate SARS-Cov-2 infections, partially in line with what had been observed by one previous longitudinal study on the UK Biobank cohort. In particular, widespread increases in mean diffusivity and in extracellular free water levels were observed in the white matter of participants who had COVID-19. As suggested by the authors, these changes may be compatible with inflammatory consequences associated with SARS-Cov-2 infection. Conclusions are generally supported by the data and methods used. However, this study has some limitations that have already been substantially highlighted by the authors. First, the use of a cross-sectional design and the lack of neuroimaging and cognitive data before SARS-Cov-2 infection prevent any definite conclusions on whether COVID-19 has played a prominent role in driving white matter microstructural differences found between the two groups. Second, participants have been assessed several months after recovering from the infection, thus effects of COVID-19 might have been diluted over time. Regression analyses of the association between the number of days from infection and the neurocognitive outcome measures may help clarify this issue. Third, assessing whether any associations can be detected between brain imaging and cognitive variables may offer complementary results to support the interpretation of the clinical relevance of between-group differences. Fourth, no information was provided on the persistence of COVID-19 symptoms, the so-called “long COVID”, at the time of assessment. Indeed, patients who experience symptoms over a longer period of time may be more likely to show neural alterations. Fifth, the literature discussed in this study did not cover any of the findings regarding the impact of SARS-Cov-2 infection on functional brain alterations (e.g., glucose hypometabolism and alterations in resting-state connectivity across different networks of functionally related brain areas) that may be more closely associated with some of the symptoms experienced by patients. The authors recommended caution with interpreting the results of this study and suggested that future longitudinal investigations are necessary to validate and clarify the clinical relevance of these findings. For this reasons, decision-makers should consider the claims in this study actionable with limitations based on the methods and data, since no definite conclusions can be drawn on the complete lack of neurocognitive consequences in patients who experienced mild-to-moderate SARS-Cov-2 infection.

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