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

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 thalamic damage randomized clinical trial

Get full access to this article

View all access options for this article.

References

Ontaneda

Raza

Mahajan

, et al. Deep grey matter injury in multiple sclerosis: A NAIMS consensus statement. Brain 2021; 144: 1974–1984.

Cifelli

Arridge

Jezzard

, et al. Thalamic neurodegeneration in multiple sclerosis. Ann Neurol 2002; 52: 650–653.

Ranjeva

Audoin

Au Duong

, et al. Local tissue damage assessed with statistical mapping analysis of brain magnetization transfer ratio: Relationship with functional status of patients in the earliest stage of multiple sclerosis. AJNR Am J Neuroradiol 2005; 26(1): 119–127.

Audoin

Ranjeva

Au Duong

, et al. Voxel-based analysis of MTR images: A method to locate gray matter abnormalities in patients at the earliest stage of multiple sclerosis. J Magn Reson Imaging 2004; 20(5): 765–771.

Davies

Altmann

Rashid

, et al. Emergence of thalamic magnetization transfer ratio abnormality in early relapsing—Remitting multiple sclerosis. Mult Scler 2005; 11(3): 276–281.

Wylezinska

Cifelli

Jezzard

, et al. Thalamic neurodegeneration in relapsing-remitting multiple sclerosis. Neurology 2003; 60: 1949–1954.

Fisher

Chang

Fox

, et al. Imaging correlates of axonal swelling in chronic multiple sclerosis brains. Ann Neurol 2007; 62(3): 219–228.

Schmierer

Scaravilli

Altmann

, et al. Magnetization transfer ratio and myelin in postmortem multiple sclerosis brain. Ann Neurol 2004; 56(3): 407–415.

Henry

Shieh

Okuda

, et al. Regional grey matter atrophy in clinically isolated syndromes at presentation. J Neurol Neurosurg Psychiatry 2008; 79(11): 1236–1244.

10.

Azevedo

Overton

Khadka

, et al. Early CNS neurodegeneration in radiologically isolated syndrome. Neurol Neuroimmunol Neuroinflamm 2015; 2(3): e102.

11.

Mahajan

Nakamura

Cohen

, et al. Intrinsic and extrinsic mechanisms of thalamic pathology in multiple sclerosis. Ann Neurol 2020; 88(1): 81–92.

12.

Eshaghi

Prados

Brownlee

, et al. Deep gray matter volume loss drives disability worsening in multiple sclerosis. Ann Neurol 2018; 83(2): 210–222.

13.

Azevedo

Cen

Khadka

, et al. Thalamic atrophy in multiple sclerosis: A magnetic resonance imaging marker of neurodegeneration throughout disease. Ann Neurol 2018; 83(2): 223–234.

14.

Calabrese

Rinaldi

Grossi

, et al. Basal ganglia and frontal/parietal cortical atrophy is associated with fatigue in relapsing-remitting multiple sclerosis. Mult Scler 2010; 16(10): 1220–1228.

15.

Mesaros

Rocca

Pagani

, et al. Thalamic damage predicts the evolution of primary-progressive multiple sclerosis at 5 years. AJNR Am J Neuroradiol 2011; 32(6): 1016–1020.

16.

Zivadinov

Bergsland

Dolezal

, et al. Evolution of cortical and thalamus atrophy and disability progression in early relapsing-remitting MS during 5 years. AJNR Am J Neuroradiol 2013; 34(10): 1931–1939.

17.

Gaetano

Häring

Radue

E-W

, et al. Fingolimod effect on gray matter, thalamus, and white matter in patients with multiple sclerosis. Neurology 2018; 90: e1324–e1332.

18.

Filippi

Rocca

Pagani

, et al. Placebo-controlled trial of oral laquinimod in multiple sclerosis: MRI evidence of an effect on brain tissue damage. J Neurol Neurosurg Psychiatry 2014; 85(8): 851–858.

19.

Nakamura

Sun

Hara-Cleaver

, et al. Natalizumab reduces loss of gray matter and thalamic volume in patients with RRMS: Analysis from the AFFIRM trial. Mult Scler J 2022; 28: 130–131.

20.

Arnold

Sprenger

Bar-Or

, et al. Ocrelizumab reduces thalamic volume loss in patients with RMS and PPMS. Mult Scler 2022; 28(12): 1927–1936.

21.

Comi

Kappos

Selmaj

, et al. Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (SUNBEAM): A multicentre, randomised, minimum 12-month, phase 3 trial. Lancet Neurol 2019; 18(11): 1009–1020.

22.

Arnold

Piani-Meier

Bar-Or

, et al. Effect of siponimod on magnetic resonance imaging measures of neurodegeneration and myelination in secondary progressive multiple sclerosis: Gray matter atrophy and magnetization transfer ratio analyses from the EXPAND phase 3 trial. Mult Scler 2022; 28(10): 1526–1540.

23.

York

Thrippleton

Meijboom

, et al. Quantitative magnetization transfer imaging in relapsing-remitting multiple sclerosis: A systematic review and meta-analysis. Brain Commun 2022; 4(2): fcac088.

24.

Fox

Coffey

Conwit

, et al. Phase 2 trial of ibudilast in progressive multiple sclerosis. N Engl J Med 2018; 379: 846–855.

25.

Naismith

Bermel

Coffey

, et al. Effects of ibudilast on MRI measures in the phase 2 SPRINT-MS study. Neurology 2021; 96: e491–e500.

26.

Barkhof

Hulst

Drulovic

, et al. Ibudilast in relapsing-remitting multiple sclerosis: A neuroprotectant? Neurology 2010; 74: 1033–1040.

27.

Avants

Epstein

Grossman

, et al. Symmetric diffeomorphic image registration with cross-correlation: Evaluating automated labeling of elderly and neurodegenerative brain. Med Image Anal 2008; 12(1): 26–41.

28.

Fonov

Evans

McKinstry

, et al. Unbiased nonlinear average age-appropriate brain templates from birth to adulthood. Neuroimage 2009; 47: S102.

29.

Nakamura

Guizard

Fonov

, et al. Jacobian integration method increases the statistical power to measure gray matter atrophy in multiple sclerosis. Neuroimage Clin 2014; 4: 10–17.

30.

Andorra

Nakamura

Lampert

, et al. Assessing biological and methodological aspects of brain volume loss in multiple sclerosis. JAMA Neurology 2018; 75: 1246–1255.

31.

Arnold

Sheffield

Montalban

, et al. Whole brain, cortical grey matter, and thalamic volume changes during 3 to five years of ozanimod in relapsing MS. Eur J Neurol 2021; 28: 122–123.

32.

Schoonheim

Ciccarelli

. The value of including thalamic atrophy as a clinical trial endpoint in multiple sclerosis. Neurology 2018; 90: 677.

33.

Conway

Planchon

, et al. Measures of thalamic integrity are associated with cognitive functioning in fingolimod-treated multiple sclerosis patients. Mult Scler Relat Disord 2021; 47: 102635.

34.

Nakamura

Brown

Araujo

, et al. Correlation between brain volume change and T2 relaxation time induced by dehydration and rehydration: Implications for monitoring atrophy in clinical studies. Neuroimage Clin 2014; 6: 166–170.

35.

Nakamura

Brown

Narayanan

, et al. Diurnal fluctuations in brain volume: Statistical analyses of MRI from large populations. Neuroimage 2015; 118: 126–132.

36.

Smith

Bulte

van Zijl

. Direct saturation MRI: Theory and application to imaging brain iron. Magn Reson Med 2009; 62(2): 384–393.

37.

Absinta

Maric

Gharagozloo

, et al. A lymphocyte–microglia–astrocyte axis in chronic active multiple sclerosis. Nature 2021; 597(7878): 709–714.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.03 MB