Impact on the microstructure of deep gray matter in unvaccinated patients after moderate-to-severe COVID-19: insights from MRI T1 mapping

Abstract

Background: To determine changes in quantitative T1 relaxation times (qT1) in deep gray matter in patients recovered from coronavirus disease 2019 (COVID-19).

Methods: Unvaccinated COVID-19 participants ≥ 3 months after seropositivity and age- and sex-matched controls were examined using 3-T magnetic resonance imaging. Bilateral measures of thalamus, pallidum, putamen, caudate and accumbens nuclei, and hippocampus were extracted from qT1 maps after automated segmentation. Baseline characteristics and results of tests assessing neurological functions (standardized exam), ability to smell (4-Item Pocket Smell Test), depression (Beck Depression Inventory-II), sleepiness (Epworth Sleepiness Scale), sleep quality (Pittsburgh Sleep Quality Index), health-related quality of life (EQ-5D), and cognitive performance (Montreal Cognitive Assessment) were evaluated.

Results: One hundred forty-five subjects (median age, 46 years; 73 females) were included (11/2020-12/2021): 69 recovered after COVID-19 and 76 controls (age, p = 0.532; sex, p = 0.799), without significant differences in qT1 values overall (all p-values > 0.050). Subgroup analysis of participants aged ≥ 40 (age, p = 0.675; sex, p = 0.447) revealed higher qT1 values in previously hospitalized COVID-19 subjects (23/69) compared to controls (47/76) in left and right caudate nuclei (p = 0.009; p = 0.027), left accumbens nucleus (p = 0.017), right putamen (p = 0.041), and right hippocampus (p = 0.020). No correlations were found with macroscopic imaging findings, pre-existing conditions, time since COVID-19 diagnosis, inpatient treatment duration, or test results.

Conclusion: T1 mapping revealed microstructural changes in striatal and hippocampal regions of unvaccinated individuals aged ≥ 40 who recovered from moderate-to-severe COVID-19 during the pre-Omicron era.

Relevance statement: This study elucidates brain involvement following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, underscoring the need for further longitudinal analyses to assess the potential reversibility, stability or deterioration of these findings.

Key points: We hypothesized altered T1 relaxation times in deep gray matter after COVID-19. Unvaccinated participants ≥ 40 years exhibited higher striatal, hippocampal qT1 after moderate-to-severe COVID-19. No qT1 correlations were found with hospitalization duration, pre-existing conditions, or neuro-(psycho)logical tests.

Keywords: Brain mapping; COVID-19; Gray matter; Magnetic resonance imaging; SARS-CoV-2.

Fig. 1

Box plots of qT1 values in five regions of interest, showing compelling trends of increased values in previously hospitalized COVID-19 patients versus controls, all of whom were unvaccinated and aged 40 years or older. Data were analyzed using Wilcoxon–Mann–Whitney U tests, stratified by age and controlled for false discoveries by the Benjamini-Hochberg method. Five deep gray matter regions (x-axis) showed significant differences (Δ) in qT1 values (y-axis; [ms]) between the subgroup of controls (n = 47; box plots further to the left) and recovered COVID-19 patients (n = 23; box plots further to the right). COVID-19, Coronavirus disease 2019; qT1, Quantitative T1 relaxation times

Fig. 2

Representative case of a recovered COVID-19 patient with MRI-detectable macro- and microstructural brain changes. The 66-year-old male subject was hospitalized for over 3 months due to COVID-19. The MRI protocol included a conventional FLAIR sequence (a) and a synthetic anatomical MP-RAGE sequence (b), the latter of which was also used for software-based automatic segmentation of multiple deep gray matter structures. The visually interpreted images (a, b) revealed a lacuna in the left dorsal putamen (white arrowheads), which was excluded from the qT1 measurements (threshold exceeded). MRI qT1 maps showed increased qT1 values predominantly in the left caudate and accumbens nuclei (subject’s median qT1: 1,563 ms and 1,818 ms versus median qT1 of the never-infected controls aged ≥ 40: 1,398 ms and 1,644 ms), without any apparent lesions on conventional images. COVID-19, Coronavirus disease 2019; FLAIR, Fluid-attenuated inversion recovery; MP-RAGE, Magnetization-prepared rapid acquisition gradient-echo; MRI, Magnetic resonance imaging; qT1, Quantitative T1 relaxation times