Patterns of brain atrophy in recently-diagnosed relapsing-remitting multiple sclerosis

Abstract

Recurrent neuroinflammation in relapsing-remitting MS (RRMS) is thought to lead to neurodegeneration, resulting in progressive disability. Repeated magnetic resonance imaging (MRI) of the brain provides non-invasive measures of atrophy over time, a key marker of neurodegeneration. This study investigates regional neurodegeneration of the brain in recently-diagnosed RRMS using volumetry and voxel-based morphometry (VBM). RRMS patients (N = 354) underwent 3T structural MRI <6 months after diagnosis and 1-year follow-up, as part of the Scottish multicentre 'FutureMS' study. MRI data were processed using FreeSurfer to derive volumetrics, and FSL for VBM (grey matter (GM) only), to establish regional patterns of change in GM and normal-appearing white matter (NAWM) over time throughout the brain. Volumetric analyses showed a decrease over time (q<0.05) in bilateral cortical GM and NAWM, cerebellar GM, brainstem, amygdala, basal ganglia, hippocampus, accumbens, thalamus and ventral diencephalon. Additionally, NAWM and GM volume decreased respectively in the following cortical regions, frontal: 14 out of 26 regions and 16/26; temporal: 18/18 and 15/18; parietal: 14/14 and 11/14; occipital: 7/8 and 8/8. Left GM and NAWM asymmetry was observed in the frontal lobe. GM VBM analysis showed three major clusters of decrease over time: 1) temporal and subcortical areas, 2) cerebellum, 3) anterior cingulum and supplementary motor cortex; and four smaller clusters within the occipital lobe. Widespread GM and NAWM atrophy was observed in this large recently-diagnosed RRMS cohort, particularly in the brainstem, cerebellar GM, and subcortical and occipital-temporal regions; indicative of neurodegeneration across tissue types, and in accord with limited previous studies in early disease. Volumetric and VBM results emphasise different features of longitudinal lobar and loco-regional change, however identify consistent atrophy patterns across individuals. Atrophy measures targeted to specific brain regions may provide improved markers of neurodegeneration, and potential future imaging stratifiers and endpoints for clinical decision making and therapeutic trials.

Fig 1. Overview of data exclusions.

Fig 2. Manhattan plot of longitudinal brain volume change.

Each point represents a tissue region within the given brain area category (x-axis). P-values were inverse log transformed (y-axis). Insignificant p-values (p>0.05) are shown in blue. Significant (p<0.05) false discovery rate (FDR) corrected p-values at q = 0.05 are shown in pink, and in red for q = 0.001. Regardless of significance, the direction of all effects – but one frontal NAWM area (in grey)—showed a longitudinal volume decrease. BS = brainstem, GM=grey matter, NAWM = normal-appearing white matter.

Fig 3. Volumetric results.

For illustration purposes, regional grey matter (GM) (A) and normal-appearing white matter (NAWM) (B) areas with significant volume decrease (w1-w0; q<0.05) are shown on an example subject’s axial T1-weighted image. Colours were chosen to emphasise borders between regions and have no further meaning in terms of results. This figure was created using MRIcron (https://www.nitrc.org/projects/mricron).

Fig 4. Voxel-based morphometry (VBM) results.

VBM results for significant grey matter (GM) change over time (w1-w0; p_corrected<0.001; N = 351) in RRMS are shown in blue on a template axial (top row) and sagittal (bottom row) T1-weighted image. This figure was created using MRIcron (https://www.nitrc.org/projects/mricron) and the implemented ‘ch2’ template (http://www.bic.mni.mcgill.ca/ServicesAtlases/Colin27).

Fig 5. Comparison of voxel-based morphometry (VBM) and volumetric results in relapsing-remitting multiple sclerosis (RRMS).

For illustration purposes, VBM results for significant grey matter (GM) change over time (w1-w0; p_corrected<0.001) (green) are overlaid on volumetric results (red) for regional GM, cerebellar GM and subcortical areas with significant volume decrease (w1-w0; q<0.05) (red). Areas where VBM and volumetry overlap are shown in yellow. Overlays are shown on an example subject’s axial (top row) and sagittal (bottom row) T1-weighted image. This figure was created using MRIcron (https://www.nitrc.org/projects/mricron).