Long-term microstructure and cerebral blood flow changes in patients recovered from COVID-19 without neurological manifestations

Abstract

BACKGROUNDThe coronavirus disease 2019 (COVID-19) rapidly progressed to a global pandemic. Although some patients totally recover from COVID-19 pneumonia, the disease's long-term effects on the brain still need to be explored.METHODSWe recruited 51 patients with 2 subtypes of COVID-19 (19 mild and 32 severe) with no specific neurological manifestations at the acute stage and no obvious lesions on the conventional MRI 3 months after discharge. Changes in gray matter morphometry, cerebral blood flow (CBF), and white matter (WM) microstructure were investigated using MRI. The relationship between brain imaging measurements and inflammation markers was further analyzed.RESULTSCompared with healthy controls, the decrease in cortical thickness/CBF and the changes in WM microstructure were more severe in patients with severe disease than in those with mild disease, especially in the frontal and limbic systems. Furthermore, changes in brain microstructure, CBF, and tract parameters were significantly correlated (P < 0.05) with the inflammatory markers C-reactive protein, procalcitonin, and interleukin 6.CONCLUSIONIndirect injury related to inflammatory storm may damage the brain, altering cerebral volume, CBF, and WM tracts. COVID-19-related hypoxemia and dysfunction of vascular endothelium may also contribute to neurological changes. The abnormalities in these brain areas need to be monitored during recovery, which could help clinicians understand the potential neurological sequelae of COVID-19.FUNDINGNatural Science Foundation of China.

Keywords: COVID-19; Neuroimaging; Neuroscience.

Conflict of interest statement

Conflict of interest: The authors have declared that no conflict of interest exists.

Figures

Figure 1. Flow diagram of the experimental design.

MG, mild group; SG, severe group; CRP, C-reactive protein; IL-6, interleukin-6; PCT, procalcitonin; MRI, magnetic resonance imaging; BRAVO, brain volume; pcASL, pseudo-continuous arterial spin labeling; DTI, diffusion tensor imaging; NC, normal control.

Figure 2. Cortical and subcortical morphology analyses of recovered COVID-19 patients.

(A) Significant cortical thickness differences between the NC group and SG. (B) Significant negative correlations between the left hippocampus thickness and inflammatory marker PCT values in the SG (r = –0.38, P = 0.0420). Results of subcortical nuclei volume comparisons between the NC group and the SG (C) (left: NC; right: SG), and the MG and SG (D) (left: MG; right: SG), as exhibited in the violin plot. The trunk size shows the probability density of the data at different values; the bigger the trunk, the denser the values appeared at that level. The notch indicates the 25% median and 75% interquartile range. The mean value of the group is shown by solid line. The bigger the standard deviation, the thinner the violin plot. The brain slices of subcortical nuclei were extracted from a subject. Left violin plots indicate the NC/MG; right violin plots indicate the SG. STG, superior temporal gyrus. Sample sizes: NC, n = 31; MG, n = 19; SG, n = 32. Permutation test, P < 0.05.

Figure 3. Significant differences in cortical and subcortical CBF between groups.

(A) NC group (n = 31) and SG (n = 32). (B) MG (n = 19) and SG (n = 32). (C) Significant positive correlation between the left insula CBF and inflammatory marker PCT values in the SG (r = 0.3738, P = 0.0458). Results of the comparisons of the CBF in the subcortical nuclei between groups: (D) NC group and SG; (E) MG and SG. SMFG, superior medial frontal gyrus. The left of the brain images is actually the right side of the brain. Accu, accumbens; Amy, amygdala; Cau, caudate; GP, globus pallidus; Hippo, hippocampus; Pu, putamen; L, left; R, right. Left violin plots indicate NC/MG, right violin plots indicate SG. Permutation test, P < 0.05.

Figure 4. Group comparisons and correlation analyses in the MG.

(A) Significant difference in tract volume between the NC group (n = 31) and the MG (n = 19). Permutation test, P < 0.05. The brain slice of a specific tract from HCP population is displayed in the right corner. For standardization, these tracts were extracted from the HCP population instead of the subjects’ specific tracts. The PC1 (B) and the volumes of the right ATR (C) and right ILF (D) showed a significant correlation with the PCT level in the MG (P < 0.05). Left violin plots indicate the NC group; right violin plots indicate the MG.

Figure 5. Significant difference of the tracts’ volume between the NC group and the SG.

Violin plots for the NC group (left plots, n = 31) and the SG (right plots, n = 32). Permutation test, P < 0.05. The brain slice of a specific tract from the HCP population is displayed in the right corner. For standardization, these tracts were extracted from the HCP population instead of the subjects’ specific tracts.

Figure 6. Correlations between the significantly different tracts and inflammatory markers in the SG.

Correlations between the PC1 (A), FA of left MDLF (B), volume of the left CST (C), volume of the right OR (D), and IL-6 respectively. L, left; R, right. n = 32; P < 0.05.

Figure 7. Workflow of ANTs cortical thickness estimation.

ANTs cortical thickness pipeline yielded clear-cut brain extraction and 6-tissue segmentation, as well as nearly perfect estimation of thickness in the native space and accurate warping into the MNI space.

Figure 8. Illustration of the method of XTRACT automated tractography.

(A) Diagram of the steps for the XTRACT automated tractography, with an example of the left IFO. Tractography protocol masks were defined in standard space (FSL_HCP1065 FA atlas, derived from the HCP data set) with seed (start point, blue), exclusion (rejection, black), target (destination, green), and stop (termination, red) masks. The native and standard tractography maps were extracted from a subject from the current sample. (B) Illustration of the projections of the HCP population tract atlases. Association fiber bundles: arcuate fascic-ulus (AF), FAT, ILF, IFO, middle longitudinal fasciculus (MdLF), SLF1, 2, and 3, uncinate fasciculus (UF), and vertical occipital fasciculus (VOF). Projection fiber bundles: AR, ATR, CST, OR, and superior thalamic radiation (STR). Limbic fiber bundles: cingulum bundle, perigenual (CBP), cingulum bundle, temporal (CBT), CBD, and FX. Commissural fiber bundles: anterior commissure (AC), forceps major (FMA), and FMI.