Mapping the Progressive Treatment-Related Reduction of Active MRI Lesions in Multiple Sclerosis

Abstract

Objective: To assess treatment-related spatio-temporal dynamics of active MRI lesions in relapsing-remitting multiple sclerosis (RRMS) patients. Methods: We performed a post-hoc analysis of MRI data acquired at weeks 4, 8, 12, and 16, in RRMS patients from the multicenter randomized IMPROVE study, which compares patients treated with 44 mcg subcutaneous interferon β-1a three times weekly (n = 120) versus placebo (n = 60). We created lesion probability maps (LPMs) of the cumulative combined unique active (CUA) lesions in each patient group at each time point. Group differences were tested in terms of lesion spatial distribution and frequency of occurrence. Results: Spatial distribution of CUA lesions throughout the study was less widespread in the treated than placebo group, with a 50% lower lesion accrual (24 vs. 48 cm3/month). Similar results were obtained with the WM tract analysis, with a reduction ranging from -47 to -66% in the treated group (p < 0.001). On voxel-wise analysis, CUA lesion frequency was lower in the treated group than the placebo group at week 4 (p = 0.07, corrected), becoming particularly pronounced (p ≤ 0.03, corrected) from week 8 onwards in large clusters of WM tracts, with peaks along fronto-parietal parts of the corticospinal tract, thalamic radiation, and superior longitudinal fascicle. Conclusion: LPM showed, in the short term, a treatment-related reduction of MRI lesion activity in RRMS patients in specific, clinically relevant brain locations. Such a quantitative approach might be a promising additional endpoint in future MS studies alongside the number and volume of WM lesions. Clinical Trial Registration: ClinicalTrials.gov identifier NCT00441103.

Keywords: MRI; brain; lesion probability map; multiple sclerosis; white matter.

Copyright © 2020 Giorgio, Battaglini, Gentile, Stromillo, Gasperini, Visconti, Paolillo and De Stefano.

Figures

Figure 1

Registration workflow for the creation of the study template in standard space (A), registration onto the template of T1-weighted images, (B) and combined unique active (CUA) lesion masks (C) of all study patients. See text for details.

Figure 2

Illustrative slices of lesion probability map (LPM) of the spatial distribution of active MRI lesions, expressed as combined unique active (CUA) lesions, in the placebo and interferon (IFN) β-1a groups at weeks 4, 8, 12, and 16. Red-to-yellow represents the frequency of CUA lesion occurrence (range: 0.1–10%). The background image is the study template in standard space (MNI 2 mm3). An animated version of this figure regarding data visualization of the entire brains of each group at each time point is available as Supplementary Material.

Figure 3

Lesion probability map (LPM) of the spatial distribution of active MRI lesions, expressed as combined unique active (CUA) lesions, mapped on some representative white matter (WM) tracts (in white: corticospinal tract [CST], superior longitudinal fascicle [SLF], cingulum [Cg]). Red-to-yellow represents the frequency of CUA lesion occurrence (range: 0.1–10%). The background image is the study template in standard space (MNI 2 mm3).

Figure 4

Clusters of active MRI lesions, expressed as combined unique active (CUA) lesions, showing lower frequency in the interferon (IFN) β-1a than placebo group at weeks 4, 8, 12, and 16. Red-to-yellow represents the significance level (p-value, range: 0.07–0.001, corrected for multiple comparisons across space). Crosshair points at local maxima, representing the highest reduction in CUA lesion frequency (see Table 2). Background image is the study template in standard space (MNI 2 mm3). The most informative slices are shown.

Figure 5

Clusters of on-study active MRI lesions, expressed as combined unique active (CUA) lesions averaged across all follow-up time points (week 4, 8, 12, and 16), showing lower frequency in the interferon (IFN) β-1a than placebo group. Red-to-yellow color represents the significance level (p-value, range: 0.05–0.0002, corrected for multiple comparisons across space). The background image is the study template in standard space (MNI 2 mm3). The most informative slices are shown.