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Randomized Controlled Trial
. 2023 Sep;29(10):1257-1265.
doi: 10.1177/13524585231187289. Epub 2023 Aug 3.

Effect of ibudilast on thalamic magnetization transfer ratio and volume in progressive multiple sclerosis

Kunio Nakamura  1 , Yufan Zheng  1 , Kedar R Mahajan  1 , Jeffrey A Cohen  1 , Robert J Fox  1 , Daniel Ontaneda  1
Affiliations
Randomized Controlled Trial

Effect of ibudilast on thalamic magnetization transfer ratio and volume in progressive multiple sclerosis

Kunio Nakamura et al. Mult Scler. 2023 Sep.

Abstract

Background: Thalamic volume (TV) is a sensitive biomarker of disease burden of injury in multiple sclerosis (MS) and appears to reflect overall lesion loads. Ibudilast showed significant treatment effect on brain atrophy and magnetization transfer ratio (MTR) of normal-appearing brain tissue but not in new/enlarging T2 lesion in the SPRINT-MS randomized clinical trial.

Objective: To evaluate the effect of ibudilast on thalamic tissue integrity and volume in the SPRINT-MS.

Methods: A total of 255 participants with progressive MS were randomized to oral ibudilast or placebo, and thalamic MTR and normalized TV over 96 weeks were quantified. Mixed-effect modeling assessed treatment effects on the thalamic MTR and TV, separately. Similarly, the measures were compared between the participants with confirmed disability progression (CDP).

Results: Ibudilast's treatment effect was observed compared to placebo for thalamic MTR (p = 0.03) but not for TV (p = 0.68) while TV correlated with T2 lesion volume (p < 0.001). CDP associated with thalamic MTR (p = 0.04) but not with TV (p = 0.7).

Conclusion: Ibudilast showed an effect on thalamic MTR, which was associated with CDP, suggesting a clinically relevant effect on thalamic tissue integrity. However, the treatment effect was not observed in TV, suggesting that thalamic atrophy is more closely associated with global inflammatory activity than local tissue integrity.

Clinicaltrials.gov: NCT01982942.

Keywords: Progressive multiple sclerosis; ibudilast; magnetic resonance imaging; randomized clinical trial; thalamic damage.

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Figures

Figure 1.
Figure 1.
Example of thalamic segmentation and MTR map from 2 participants. The first participant (top) had the normalized thalamic volume of 13.3 mL (94th percentile) and mean thalamic MTR of 43.4% (77th percentile), while the second (bottom) participant was 17.7 mL (19th percentile) and 45.5% (19th percentile), respectively. (a) Thalamus segmentation. (b) MTR map. (c) Thalamus segmentation. (d) MTR map. MTR: magnetization transfer ratio.
Figure 2.
Figure 2.
(a) Pearson correlation matrix of baseline MRI measures. (b) A scatterplot of baseline scanner-vendor-adjusted thalamic MTR and volume showing a small but significant association. MTR: magnetization transfer ratio; BPF: brain parenchymal fraction; T2LV: T2 lesion volume; PPMS: primary progressive multiple sclerosis; SPMS: secondary progressive multiple sclerosis; MRI: magnetic resonance imaging. *p < 0.05, **p < 0.01.
Figure 3.
Figure 3.
(a) Scanner-vendor-adjusted thalamic MTR for ibudilast (solid black) and placebo (gray dotted) showing significant treatment effect (p = 0.03) while (b) normalized thalamic volume did not show significant treatment effect (p = 0.68). Thick lines are the linear regression, and the filled area indicates 95% confidence interval. MTR: magnetization transfer ratio.
Figure 4.
Figure 4.
Scanner-vendor-adjusted thalamic MTR during the study, grouped by disability progression status showing a significant difference (p = 0.04): dotted = progressed, solid = not progressed. Thick lines are the linear regression lines, and the filled area indicates 95% confidence interval. MTR: magnetization transfer ratio.
See this image and copyright information in PMC

References

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