Disability-Specific Atlases of Gray Matter Loss in Relapsing-Remitting Multiple Sclerosis

Abstract

Importance: Multiple sclerosis (MS) is characterized by progressive gray matter (GM) atrophy that strongly correlates with clinical disability. However, whether localized GM atrophy correlates with specific disabilities in patients with MS remains unknown.

Objective: To understand the association between localized GM atrophy and clinical disability in a biology-driven analysis of MS.

Design, setting, and participants: In this cross-sectional study, magnetic resonance images were acquired from 133 women with relapsing-remitting MS and analyzed using voxel-based morphometry and volumetry. A regression analysis was used to determine whether voxelwise GM atrophy was associated with specific clinical deficits. Data were collected from June 28, 2007, to January 9, 2014.

Main outcomes and measures: Voxelwise correlation of GM change with clinical outcome measures (Expanded Disability Status Scale and Multiple Sclerosis Functional Composite scores).

Results: Among the 133 female patients (mean [SD] age, 37.4 [7.5] years), worse performance on the Multiple Sclerosis Functional Composite correlated with voxelwise GM volume loss in the middle cingulate cortex (P < .001) and a cluster in the precentral gyrus bilaterally (P = .004). In addition, worse performance on the Paced Auditory Serial Addition Test correlated with volume loss in the auditory and premotor cortices (P < .001), whereas worse performance on the 9-Hole Peg Test correlated with GM volume loss in Brodmann area 44 (Broca area; P = .02). Finally, voxelwise GM loss in the right paracentral lobulus correlated with bowel and bladder disability (P = .03). Thus, deficits in specific clinical test results were directly associated with localized GM loss in clinically eloquent locations.

Conclusions and relevance: These biology-driven data indicate that specific disabilities in MS are associated with voxelwise GM loss in distinct locations. This approach may be used to develop disability-specific biomarkers for use in future clinical trials of neuroprotective treatments in MS.

Fig. 1.

Direct association between the Multiple Sclerosis Functional Composite (MSFC) and voxelwise gray matter volume. The significance clusters are located in the middle cingulate cortex, the left precentral, and inferior frontal gyrus, the right precentral and middle frontal gyrus, and the right inferior temporal gyrus. Positive association indicated by lower scores (poorer performance) on the MSFC correlate with less gray matter volume (more atrophy).

Fig. 2.

Significant associations between performance on clinical tests and voxelwise gray matter volume. A) The significance clusters are located the primary auditory cortex bilaterally, the left precentral gyrus, the middle cingulate gyrus bilaterally, and the left superior frontal gyrus. Direct association indicates lower scores (poorer performance) on PASAT2 correlate with less gray matter volume (more atrophy). B) The significance cluster is located in left Brodmann area 44. Indirect association indicates higher number of seconds (poorer performance) on 9-HPT correlate with less gray matter volume (more atrophy). C) The significance clusters are located in the right paracentral lobulus and the left anterior-basal insula. Indirect association indicates disability on bowel and bladder function correlates with less gray matter volume (more atrophy).

Fig. 3.

Heat map showing positive and negative correlations and their clustering. A graphical representation of relationship among whole gray matter volumes, the MSFC and its component sub-tests, and the EDSS and its functional sub-scores. In the heat map, yellow indicates a positive (direct) correlation and red indicates a negative (indirect) correlation between the values. Gray matter volumes and all clinical disability scores are clustered in both row and column, as shown in the dendrograms.