Subacute frontoinsular-cingulate tract changes in unvaccinated COVID-19 survivors: A tract-based spatial statistics study of diffusion tensor imaging.

BACKGROUND AND

OBJECTIVES

Post-recovery brain changes following Coronavirus Disease 2019 (COVID-19) have been reported using various imaging techniques. The objective was to identify microstructural abnormalities between groups in specific fiber tracts using tract-based spatial statistics (TBSS) of diffusion tensor imaging (DTI), along with region-specific quantitative analysis of T1 relaxation times (qT1) and volumes.

METHODS

This single-center, prospective, observational case-control study included adults ≥ 3 months after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigen positivity, matched by age and gender with seronegative controls, and categorized by initial infection severity and an age cut-off of 40. MRI included: (1) 2 mm DTI generating fractional anisotropy (FA), mean (MD), radial (RD), and axial diffusivity (AD) maps; (2) two 3D 1 mm³ gradient-echo datasets for mapping T1 relaxation times (qT1) and creating synthetic high-resolution T1 images; (3) 3 mm 2D fluid-attenuated inversion recovery (FLAIR) images. Baseline characteristics and neuro(psycho)logical assessments including olfactory function, Beck Depression Inventory, Epworth Sleepiness Scale, Pittsburgh Sleep Quality Index, EQ-5D, and Montreal cognitive assessment were also recorded.

RESULTS

Between November 2020 and December 2021, 145 unvaccinated subjects (median age, 46 years [IQR, 33.5-53]; 73 women) were consecutively evaluated. TBSS showed no significant FA differences between all 69 cases and 76 age- and sex-matched controls. However, participants ≥ 40 years that required hospitalization due to COVID-19 (n = 23) had decreased FA, increased RD, and reduced qT1 values (all P ≤ 0.001) in specific voxels compared to controls ≥ 40 years (n = 47). These microstructural measures appeared in predominantly right-sided lateral orbitofrontal, frontal inferior, anterior insular, and rostral anterior cingulate white matter (WM) regions, without visually detectable abnormalities or region-specific volume loss in WM or cortical gray matter. This subgroup also showed significantly higher presence of fatigue, depressive symptoms, poorer sleep quality and reduced health-related quality of life.

DISCUSSION: Advanced MRI revealed microstructural abnormalities along frontoinsular-cingulate WM fiber tracts in unvaccinated participants aged ≥ 40 with a history of COVID-19 requiring hospitalization. These findings may suggest ongoing reduced fiber integrity and persistent oxidative stress within the salience network, potentially contributing to functional sequelae.