Widespread white matter oedema in subacute COVID-19 patients with neurological symptoms - PubMed (original) (raw)

. 2022 Sep 14;145(9):3203-3213.

doi: 10.1093/brain/awac045.

Nils Schroeter 2, Ganna Blazhenets 3, Andrea Dressing 2 4, Lea I Walter 2, Elias Kellner 5, Tobias Bormann 2 4, Hansjörg Mast 1, Dirk Wagner 6, Horst Urbach 1, Cornelius Weiller 2 4, Philipp T Meyer 3, Marco Reisert 5 7, Jonas A Hosp 2

Affiliations

Widespread white matter oedema in subacute COVID-19 patients with neurological symptoms

Alexander Rau et al. Brain. 2022.

Abstract

While neuropathological examinations in patients who died from COVID-19 revealed inflammatory changes in cerebral white matter, cerebral MRI frequently fails to detect abnormalities even in the presence of neurological symptoms. Application of multi-compartment diffusion microstructure imaging (DMI), that detects even small volume shifts between the compartments (intra-axonal, extra-axonal and free water/CSF) of a white matter model, is a promising approach to overcome this discrepancy. In this monocentric prospective study, a cohort of 20 COVID-19 inpatients (57.3 ± 17.1 years) with neurological symptoms (e.g. delirium, cranial nerve palsies) and cognitive impairments measured by the Montreal Cognitive Assessment (MoCA test; 22.4 ± 4.9; 70% below the cut-off value <26/30 points) underwent DMI in the subacute stage of the disease (29.3 ± 14.8 days after positive PCR). A comparison of whole-brain white matter DMI parameters with a matched healthy control group (n = 35) revealed a volume shift from the intra- and extra-axonal space into the free water fraction (V-CSF). This widespread COVID-related V-CSF increase affected the entire supratentorial white matter with maxima in frontal and parietal regions. Streamline-wise comparisons between COVID-19 patients and controls further revealed a network of most affected white matter fibres connecting widespread cortical regions in all cerebral lobes. The magnitude of these white matter changes (V-CSF) was associated with cognitive impairment measured by the MoCA test (r = -0.64, P = 0.006) but not with olfactory performance (r = 0.29, P = 0.12). Furthermore, a non-significant trend for an association between V-CSF and interleukin-6 emerged (r = 0.48, P = 0.068), a prominent marker of the COVID-19 related inflammatory response. In 14/20 patients who also received cerebral 18F-FDG PET, V-CSF increase was associated with the expression of the previously defined COVID-19-related metabolic spatial covariance pattern (r = 0.57; P = 0.039). In addition, the frontoparietal-dominant pattern of neocortical glucose hypometabolism matched well to the frontal and parietal focus of V-CSF increase. In summary, DMI in subacute COVID-19 patients revealed widespread volume shifts compatible with vasogenic oedema, affecting various supratentorial white matter tracts. These changes were associated with cognitive impairment and COVID-19 related changes in 18F-FDG PET imaging.

Keywords: 18F-FDG PET; COVID-19; Montreal Cognitive Assessment; cognition; diffusion microstructure imaging.

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Figures

Figure 1

Figure 1

Comparison of whole white matter DMI parameters between COVID-19 patients and controls. Box plots show the distribution of volume fractions within the entire white matter. In COVID-19 patients, a significant decrease of V-intra and V-extra was accompanied by a highly significant increase of V-CSF. Thus, there is a global volume shift from intra- and extra-axonal space into the V-CSF. Group comparisons were performed by ANCOVAs with covariates ‘age’ and ‘sex’. *P < 0.05; ***P < 0.001.

Figure 2

Figure 2

Spatial distribution and weights of COVID-19-related changes. The standardized regression coefficients of the factor V-CSF were extracted from regression models attained by voxel-wise comparisons between COVID-19 patients and controls (with covariates ‘age’, ‘sex’ and ‘tissue probability value’) and were superimposed onto a T1-weighted MRI template. Colour-coding indicates the coefficient values as a measure of effect size of the factor ‘COVID-19’ on V-CSF (hot colours: large effect size versus cold colours: small effect size). Please note that all coefficients monodirectionally indicated an increase in V-CSF. Radiological orientation, i.e. left image side corresponds to patient’s right body side; numbers denote the axial (z) position in millimetres.

Figure 3

Figure 3

Network of most affected white matter fibres. (A) Streamline-wise comparisons between COVID-19 patients and controls (with nuisance covariates ‘age’ and ‘sex’; exploratory threshold of P < 0.001) reveal a widespread network of white matter fibres in MNI space that were most affected by COVID-19-related V-CSF increase. (B) To display the distribution and extent of the aforementioned network in the white matter, 3D streamlines were rendered to generate a visiting map in MNI space (blue shading) that is superimposed onto a transversal T1-weighted template. Depicted in radiological orientation, i.e. left image side corresponds to patient’s right body side; numbers denote the axial (z) position in millimetres.

Figure 4

Figure 4

Association of whole white matter V-CSF with clinical parameters and cerebral glucose metabolism assessed by 18F-FDG PET imaging. (A) Associations were assessed using partial Spearman’s correlations with ‘age’ and ‘sex’ as covariates. Each dot represents an individual patient’s data. In case of a significant correlation, a linear regression was fitted (black line) and dotted lines indicate the 95% confidence interval. For MoCA performance, a significant inverse correlation with V-CSF emerged. No significant correlation was present between olfactory performance and V-CSF. Between IL-6 peak values and V-CSF, a non-significant trend for a correlation was present. The pattern expression score (PES) as a measure of COVID-19-related changes in cerebral glucose metabolism was significantly correlated with V-CSF. Please note that only 14 of 23 patients underwent 18F-FDG PET imaging. (B) COVID-19-related spatial covariance pattern of cerebral glucose metabolism established by Hosp and colleagues.3 Displayed were voxels of the highest quartile of negative voxel weights (i.e. relative hypometabolism) overlaid onto a T1-weighted MRI-based volume mesh.

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