Characterization of patients with Becker muscular dystrophy by histology, magnetic resonance imaging, function, and strength assessments

Giacomo P Comi, Erik H Niks, Claudia M Cinnante, Hermien E Kan, Krista Vandenborne, Rebecca J Willcocks, Daniele Velardo, Michela Ripolone, Jules J van Benthem, Nienke M van de Velde, Simone Nava, Laura Ambrosoli, Sara Cazzaniga, Paolo U Bettica, Giacomo P Comi, Erik H Niks, Claudia M Cinnante, Hermien E Kan, Krista Vandenborne, Rebecca J Willcocks, Daniele Velardo, Michela Ripolone, Jules J van Benthem, Nienke M van de Velde, Simone Nava, Laura Ambrosoli, Sara Cazzaniga, Paolo U Bettica

Abstract

Introduction/aims: Becker muscular dystrophy (BMD) is characterized by variable disease severity and progression, prompting the identification of biomarkers for clinical trials. We used data from an ongoing phase II study to provide a comprehensive characterization of a cohort of patients with BMD, and to assess correlations between histological and magnetic resonance imaging (MRI) markers with muscle function and strength.

Methods: Eligible patients were ambulatory males with BMD, aged 18 to 65 years (200 to 450 meters on 6-minute walk test). The following data were obtained: function test results, strength, fat-fraction quantification using chemical shift-encoded MRI (whole thigh and quadriceps), and fibrosis and muscle fiber area (MFA) of the brachial biceps.

Results: Of 70 patients screened, 51 entered the study. There was substantial heterogeneity between patients in muscle morphology (histology and MRI), with high fat replacement. Total fibrosis correlated significantly and mostly moderately with all functional endpoints, including both upper arm strength assessments (left and right elbow flexion rho -.574 and -.588, respectively [both P < .0001]), as did MRI fat fraction (whole thigh and quadriceps), for example, with four-stair-climb velocity -.554 and -.550, respectively (both P < .0001). Total fibrosis correlated significantly and moderately with both MRI fat fraction assessments (.500 [P = .0003] and .423 [.0024], respectively).

Discussion: In this BMD cohort, micro- and macroscopic morphological muscle parameters correlated moderately with each other and with functional parameters, potentially supporting the use of MRI fat fraction and histology as surrogate outcome measures in patients with BMD, although additional research is required to validate this.

Keywords: Becker muscular dystrophy; correlation; function; histology; magnetic resonance imaging.

Conflict of interest statement

G.P.C. has served on scientific advisory boards of Avexis, PTC Therapeutics, Italfarmaco, Sarepta, Roche, and Biogen. E.H.N. has worked as an investigator on the Italfarmaco SpA clinical trial described in this article. He also reports ad hoc consultancies for BioMarin, Summit, WAVE, and Regenxbio, and worked as an investigator in clinical trials for BioMarin, GSK, Lilly, Santhera, WAVE, Roche, NS Pharma, Reveragen, and Sarepta, all outside the submitted work. All reimbursements were received by the LUMC. H.E.K. reports grants from Netherlands Organization for Health Research and Development, grant 91716490, research support from Philips Healthcare, trial support from ImagingDMD‐UF, and has served as a consultant for Esperare and PTC Therapeutics (no personal fees collected, all payments to the LUMC). KV reports grants from the National Institutes of Health (R01 AR056973) and research service support from Sarepta Therapeutics, Catabasis Pharmaceuticals, PTC Therapeutics, Eli Lilly, Summit Therapeutics, ML Bio/VCU directed to the University of Florida. N.M.v.d.V. has worked as a subinvestigator in clinical trials of givinostat, WAVE, Roche, and NS Pharma, all outside the submitted work. All reimbursements were received by the LUMC (no personal fees collected). S.C. and P.U.B. are employees of Italfarmaco SpA, the sponsor of the study. The remaining authors have no conflicts of interest to disclose.

© 2021 The Authors. Muscle & Nerve published by Wiley Periodicals LLC.

Figures

FIGURE 1
FIGURE 1
A, Correlation analyses for total fibrosis (from arm biopsy) vs right elbow flexion. B, Correlation analyses for MRI fat fraction in the whole thigh vs four‐stair‐climb velocity. Dotted line is locally estimated scatterplot smoothing (LOESS)‐fitted line showing relation between variables. MRI, magnetic resonance imaging

References

    1. Clarke A, Johnson M, Harris JB. Improved diagnosis of Becker muscular dystrophy by dystrophin testing. Neurology. 1989;39:1011‐1017.
    1. Wilson K, Faelan C, Patterson‐Kane JC, et al. Duchenne and Becker muscular dystrophies: a review of animal models, clinical end points, and biomarker quantification. Toxicol Pathol. 2017;45:961‐976.
    1. Mah JK, Korngut L, Dykeman J, Day L, Pringsheim T, Jette N. A systematic review and meta‐analysis on the epidemiology of Duchenne and Becker muscular dystrophy. Neuromuscul Disord. 2014;24:482‐491.
    1. Naarding KJ, Reyngoudt H, van Zwet EW, et al. MRI vastus lateralis fat fraction predicts loss of ambulation in Duchenne muscular dystrophy. Neurology. 2020;94:e1386‐e1394.
    1. Barnard AM, Willcocks RJ, Triplett WT, et al. MR biomarkers predict clinical function in Duchenne muscular dystrophy. Neurology. 2020;94:e897‐e909.
    1. Rooney WD, Berlow YA, Triplett WT, et al. Modeling disease trajectory in Duchenne muscular dystrophy. Neurology. 2020;94:E1622‐E1633.
    1. McDonald CM, Henricson EK, Han JJ, et al. The 6‐minute walk test in Duchenne/Becker muscular dystrophy: longitudinal observations. Muscle Nerve. 2010;42:966‐974.
    1. Bérard C, Payan C, Hodgkinson I, Fermanian J. A motor function measure scale for neuromuscular diseases. Construction and validation study. Neuromuscul Disord. 2005;15:463‐470.
    1. Fischer D, Hafner P, Rubino D, et al. The 6‐minute walk test, motor function measure and quantitative thigh muscle MRI in Becker muscular dystrophy: a cross‐sectional study. Neuromuscul Disord. 2016;26:414‐422.
    1. Vuillerot C, Girardot F, Payan C, et al. Monitoring changes and predicting loss of ambulation in Duchenne muscular dystrophy with the motor function measure. Dev Med Child Neurol. 2010;52:60‐65.
    1. Peverelli L, Testolin S, Villa L, et al. Histologic muscular history in steroid‐treated and untreated patients with Duchenne dystrophy. Neurology. 2015;85:1886‐1893.
    1. Hu HH, Yokoo T, Bashir MR, et al. Linearity and bias of proton density fat fraction as a quantitative imaging biomarker: a multicenter, multiplatform, multivendor phantom study. Radiology. 2021;298:640‐651.
    1. Triplett WT, Baligand C, Forbes SC, et al. Chemical shift‐based MRI to measure fat fractions in dystrophic skeletal muscle. Magn Reson Med. 2014;72:8‐19.
    1. Schober P, Boer C, Schwarte LA. Correlation coefficients: appropriate use and interpretation. Anesth Analg. 2018;126:1763‐1768.
    1. Clemens PR, Niizawa G, Feng J, et al. The CINRG Becker natural history study: baseline characteristics. Muscle Nerve. 2020;62:369‐376.
    1. Barp A, Bello L, Caumo L, et al. Muscle MRI and functional outcome measures in Becker muscular dystrophy. Sci Rep. 2017;7:16060.
    1. Faridian‐Aragh N, Wagner KR, Leung DG, Carrino JA. Magnetic resonance imaging phenotyping of Becker muscular dystrophy. Muscle Nerve. 2014;50:962‐967.
    1. Tasca G, Iannaccone E, Monforte M, et al. Muscle MRI in Becker muscular dystrophy. Neuromuscul Disord. 2012;22(Suppl):S100‐106.
    1. Hooijmans MT, Froeling M, Koeks Z, et al. Multi‐parametric MR in Becker muscular dystrophy patients. NMR Biomed. 2020;33:e4385.
    1. Wokke BH, Hooijmans MT, van den Bergen JC, Webb AG, Verschuuren JJ, Kan HE. Muscle MRS detects elevated PDE/ATP ratios prior to fatty infiltration in Becker muscular dystrophy. NMR Biomed. 2014;27:1371‐1377.
    1. Van Den Bergen JC, Wokke BH, Janson AA, et al. Dystrophin levels and clinical severity in Becker muscular dystrophy patients. J Neurol Neurosurg Psychiatry. 2014;85:747‐753.
    1. Løkken N, Hedermann G, Thomsen C, Vissing J. Contractile properties are disrupted in Becker muscular dystrophy, but not in limb girdle type 2I. Ann Neurol. 2016;80:466‐471.
    1. Loughran T, Higgins DM, McCallum M, Coombs A, Straub V, Hollingsworth KG. Improving highly accelerated fat fraction measurements for clinical trials in muscular dystrophy: origin and quantitative effect of R2* changes. Radiology. 2015;275:570‐578.
    1. Hollingsworth KG, Higgins DM, McCallum M, Ward L, Coombs A, Straub V. Investigating the quantitative fidelity of prospectively undersampled chemical shift imaging in muscular dystrophy with compressed sensing and parallel imaging reconstruction. Magn Reson Med. 2014;72:1610‐1619.
    1. Bonati U, Schmid M, Hafner P, et al. Longitudinal 2‐point Dixon muscle magnetic resonance imaging in Becker muscular dystrophy. Muscle Nerve. 2015;51:918‐921.
    1. van de Velde NM, Hooijmans MT, Sardjoe Mishre ASD, et al. Selection approach to identify the optimal biomarker using quantitative muscle MRI and functional assessments in Becker muscular dystrophy. Neurology. 2021;97:e513‐e522.
    1. Forbes SC, Arora H, Willcocks RJ, et al. Upper and lower extremities in Duchenne muscular dystrophy evaluated with quantitative MRI and proton MR spectroscopy in a multicenter cohort. Radiology. 2020;295:616‐625.
    1. European Medicines Agency . Guideline on the Clinical Investigation of Medicinal Products for the Treatment of Duchenne and Becker Muscular Dystrophy. 2015.

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