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Original Investigation |

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

Allan MacKenzie-Graham, PhD1; Florian Kurth, MD, PhD1; Yuichiro Itoh, PhD1; He-Jing Wang, MD2; Michael J. Montag, MS1; Robert Elashoff, PhD2; Rhonda R. Voskuhl, MD1
[+] Author Affiliations
1Department of Neurology, David Geffen School of Medicine at University of California, Los Angeles
2Department of Biomathematics, David Geffen School of Medicine at University of California, Los Angeles
JAMA Neurol. 2016;73(8):944-953. doi:10.1001/jamaneurol.2016.0966.
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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.

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Figure 1.
Direct Association Between the Multiple Sclerosis Functional Composite (MSFC) Scores and Voxelwise Gray Matter (GM) Volume

Maximum intensity projections of GM loss superimposed on the sagittal (A), coronal (B), and axial (C) planes of the SPM standard glass brain. The significance clusters (red) 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. A positive association indicated by lower scores (worse performance) on the MSFC correlate with less GM volume (more atrophy). Surface GM loss is displayed on the left (D) and right (E) hemispheres of a rendering of the mean template. Hot colormap indicates areas of greater statistical significance.

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Figure 2.
Significant Associations Between Performance on Clinical Tests and Voxelwise Gray Matter (GM) Volume

Maximum intensity projections of GM loss superimposed on the SPM standard glass brain together with surface GM loss displayed on a rendering of the mean template. Hot colormap indicates areas of greater statistical significance in yellow. A, The significance clusters (red) are located in the primary auditory cortex bilaterally, the left precentral gyrus, the middle cingulate gyrus bilaterally, and the left superior frontal gyrus. Direct association indicates that lower scores (worse performance) on the Paced Auditory Serial Addition Test at 2 seconds (PASAT2) correlate with less GM volume (more atrophy). B, The significance cluster is located in left Brodmann area 44. Indirect association indicates a higher number of seconds (worse performance) on the 9-Hole Peg Test (9-HPT) correlate with less GM 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 the Expanded Disability Status Scale (EDSS) bowel and bladder functional system correlates with less GM volume (more atrophy).

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Figure 3.
Heat Map of Positive and Negative Correlations and Their Clustering

The associations among whole–gray matter (GM) volumes, the Multiple Sclerosis Functional Composite (MSFC) and its component subtests (9-Hole Peg Test [9-HPT], Timed 25-Foot Walk [T25-FW], and Paced Auditory Serial Addition Test at 2 [PASAT2] and 3 [PASAT3] seconds), and the Expanded Disability Status Scale (EDSS) and its functional system subscores are illustrated. 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 rows and columns, as shown in the dendrograms.

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