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Published on: April 14, 2014
Remyelination varies between and within lesions in multiple sclerosis following bexarotene
J William L Brown1,2,3, Ferran Prados2,4,5, Daniel R Altmann6
1Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
Objective:
In multiple sclerosis chronic demyelination is associated with axonal loss, and ultimately contributes to irreversible progressive disability. Enhancing remyelination may slow, or even reverse, disability. We recently trialled bexarotene versus placebo in 49 people with multiple sclerosis. While the primary MRI outcome was negative, there was converging neurophysiological and MRI evidence of efficacy. Multiple factors influence lesion remyelination. In this study we undertook a systematic exploratory analysis to determine whether treatment response - measured by change in magnetisation transfer ratio - is influenced by location (tissue type and proximity to CSF) or the degree of abnormality (using baseline magnetisation transfer ratio and T1 values).
Methods:
We examined treatment effects at the whole lesion level, the lesion component level (core, rim and perilesional tissues) and at the individual lesion voxel level.
Results:
At the whole lesion level, significant treatment effects were seen in GM but not WM lesions. Voxel-level analyses detected significant treatment effects in WM lesion voxels with the lowest baseline MTR, and uncovered gradients of treatment effect in both WM and CGM lesional voxels, suggesting that treatment effects were lower near CSF spaces. Finally, larger treatment effects were seen in the outer and surrounding components of GM lesions compared to inner cores.
Interpretation:
Remyelination varies markedly within and between lesions. The greater remyelinating effect in GM lesions is congruent with neuropathological observations. For future remyelination trials, whole GM lesion measures require less complex post-processing compared to WM lesions (which require voxel level analyses) and markedly reduce sample sizes.
Insights
Bexarotene treatment showed remyelination effects in multiple sclerosis (MS) gray matter lesions, particularly in outer regions. White matter lesion remyelination varied by location and baseline abnormality, suggesting future trials should focus on gray matter measures.
Area of Science:
- Neuroscience
- Radiology
- Clinical Trials
Background:
- Chronic demyelination in multiple sclerosis (MS) leads to axonal loss and progressive disability.
- Enhancing remyelination offers a potential strategy to slow or reverse MS-related disability.
Purpose of the Study:
- To explore factors influencing bexarotene treatment response in MS lesions, specifically location and baseline abnormality.
- To determine if remyelination effects vary by tissue type (gray matter vs. white matter) and proximity to cerebrospinal fluid (CSF).
Main Methods:
- Exploratory analysis of bexarotene versus placebo trial data in 49 MS patients.
- Assessment of treatment effects using magnetisation transfer ratio (MTR) changes at whole lesion, component, and voxel levels.
- Analysis of lesion location (tissue type, CSF proximity) and baseline MTR/T1 values.
Main Results:
- Significant bexarotene treatment effects were observed in gray matter (GM) lesions but not white matter (WM) lesions at the whole lesion level.
- Voxel-level analysis revealed treatment effects in WM lesions with the lowest baseline MTR.
- Treatment effects showed gradients in both WM and cortical gray matter (CGM) lesions, decreasing near CSF spaces.
- Larger treatment effects were noted in the outer and surrounding components of GM lesions compared to their inner cores.
Conclusions:
- Remyelination efficacy varies significantly within and between MS lesions.
- Gray matter lesions exhibit a greater remyelination response compared to white matter lesions.
- Future remyelination trials could benefit from focusing on whole GM lesion measures, which require less complex analysis and smaller sample sizes than WM lesion voxel-level analyses.
