Upper Limb Evaluation in Duchenne Muscular Dystrophy: Fat-Water Quantification by MRI, Muscle Force and Function Define Endpoints for Clinical Trials

Objective A number of promising experimental therapies for Duchenne muscular dystrophy (DMD) are emerging. Clinical trials currently rely on invasive biopsies or motivation-dependent functional tests to assess outcome. Quantitative muscle magnetic resonance imaging (MRI) could offer a valuable alternative and permit inclusion of non-ambulant DMD subjects. The aims of our study were to explore the responsiveness of upper-limb MRI muscle-fat measurement as a non-invasive objective endpoint for clinical trials in non-ambulant DMD, and to investigate the relationship of these MRI measures to those of muscle force and function. Methods 15 non-ambulant DMD boys (mean age 13.3 y) and 10 age-gender matched healthy controls (mean age 14.6 y) were recruited. 3-Tesla MRI fat-water quantification was used to measure forearm muscle fat transformation in non-ambulant DMD boys compared with healthy controls. DMD boys were assessed at 4 time-points over 12 months, using 3-point Dixon MRI to measure muscle fat-fraction (f.f.). Images from ten forearm muscles were segmented and mean f.f. and cross-sectional area recorded. DMD subjects also underwent comprehensive upper limb function and force evaluation. Results Overall mean baseline forearm f.f. was higher in DMD than in healthy controls (p<0.001). A progressive f.f. increase was observed in DMD over 12 months, reaching significance from 6 months (p<0.001, n = 7), accompanied by a significant loss in pinch strength at 6 months (p<0.001, n = 9) and a loss of upper limb function and grip force observed over 12 months (p<0.001, n = 8). Conclusions These results support the use of MRI muscle f.f. as a biomarker to monitor disease progression in the upper limb in non-ambulant DMD, with sensitivity adequate to detect group-level change over time intervals practical for use in clinical trials. Clinical validity is supported by the association of the progressive fat transformation of muscle with loss of muscle force and function.

[1]  K. Lim,et al.  Eteplirsen in the treatment of Duchenne muscular dystrophy , 2017, Drug design, development and therapy.

[2]  H. Kan,et al.  T2 relaxation times are increased in Skeletal muscle of DMD but not BMD patients , 2016, Muscle & nerve.

[3]  T. Yousry,et al.  MRI biomarker assessment of neuromuscular disease progression: a prospective observational cohort study , 2016, The Lancet Neurology.

[4]  L. Servais,et al.  Quantitative NMRI and NMRS identify augmented disease progression after loss of ambulation in forearms of boys with Duchenne muscular dystrophy , 2015, NMR in biomedicine.

[5]  O. Bieri,et al.  Quantitative muscle MRI: A powerful surrogate outcome measure in Duchenne muscular dystrophy , 2015, Neuromuscular Disorders.

[6]  C. Senesac,et al.  Magnetic Resonance Assessment of Hypertrophic and Pseudo-Hypertrophic Changes in Lower Leg Muscles of Boys with Duchenne Muscular Dystrophy and Their Relationship to Functional Measurements , 2015, PloS one.

[7]  Wei Zhang,et al.  Progression and variation of fatty infiltration of the thigh muscles in Duchenne muscular dystrophy, a muscle magnetic resonance imaging study , 2015, Neuromuscular Disorders.

[8]  L. Servais,et al.  Upper Limb Strength and Function Changes during a One-Year Follow-Up in Non-Ambulant Patients with Duchenne Muscular Dystrophy: An Observational Multicenter Trial , 2015, PloS one.

[9]  Volker Straub,et al.  Investigating the quantitative fidelity of prospectively undersampled chemical shift imaging in muscular dystrophy with compressed sensing and parallel imaging reconstruction , 2014, Magnetic resonance in medicine.

[10]  R. Finkel,et al.  Correction: Magnetic Resonance Imaging and Spectroscopy Assessment of Lower Extremity Skeletal Muscles in Boys with Duchenne Muscular Dystrophy: A Multicenter Cross Sectional Study , 2014, PloS one.

[11]  J. Mendell,et al.  T.P.1 Pilot study evaluating motivation on the performance of timed walking in boys with Duchenne muscular dystrophy , 2014, Neuromuscular Disorders.

[12]  V. Ricotti,et al.  Safety and efficacy of drisapersen for the treatment of Duchenne muscular dystrophy (DEMAND II): an exploratory, randomised, placebo-controlled phase 2 study , 2014, The Lancet Neurology.

[13]  G. Comi,et al.  Ataluren treatment of patients with nonsense mutation dystrophinopathy , 2014, Muscle & nerve.

[14]  R. Finkel,et al.  Examination of effects of corticosteroids on skeletal muscles of boys with DMD using MRI and MRS , 2014, Neurology.

[15]  W. Triplett,et al.  Longitudinal measurements of MRI-T2 in boys with Duchenne muscular dystrophy: Effects of age and disease progression , 2014, Neuromuscular Disorders.

[16]  M. Versluis,et al.  Quantitative MRI and strength measurements in the assessment of muscle quality in Duchenne muscular dystrophy , 2014, Neuromuscular Disorders.

[17]  E. Bertini,et al.  Reliability of the Performance of Upper Limb assessment in Duchenne muscular dystrophy , 2014, Neuromuscular Disorders.

[18]  Elizabeth Vroom,et al.  Development of the Performance of the Upper Limb module for Duchenne muscular dystrophy , 2013, Developmental medicine and child neurology.

[19]  R. Finkel,et al.  Skeletal muscles of ambulant children with Duchenne muscular dystrophy: validation of multicenter study of evaluation with MR imaging and MR spectroscopy. , 2013, Radiology.

[20]  K. Bushby,et al.  Magnetic resonance imaging in duchenne muscular dystrophy: Longitudinal assessment of natural history over 18 months , 2013, Muscle & nerve.

[21]  Juliet A. Ellis,et al.  International Workshop : Newborn screening for Duchenne muscular dystrophy 14 – 16 th December , 2012 , Naarden , The Netherlands , 2013 .

[22]  B. Wong,et al.  Analysis of fatty infiltration and inflammation of the pelvic and thigh muscles in boys with Duchenne muscular dystrophy (DMD): grading of disease involvement on MR imaging and correlation with clinical assessments , 2013, Pediatric Radiology.

[23]  T. Voit,et al.  Innovative methods to assess upper limb strength and function in non-ambulant Duchenne patients , 2013, Neuromuscular Disorders.

[24]  V. Ricotti,et al.  Long-term benefits and adverse effects of intermittent versus daily glucocorticoids in boys with Duchenne muscular dystrophy , 2012, Journal of Neurology, Neurosurgery & Psychiatry.

[25]  Volker Straub,et al.  Towards harmonization of protocols for MRI outcome measures in skeletal muscle studies: Consensus recommendations from two TREAT-NMD NMR workshops, 2 May 2010, Stockholm, Sweden, 1–2 October 2009, Paris, France , 2012, Neuromuscular Disorders.

[26]  Volker Straub,et al.  TREAT-NMD workshop: Pattern recognition in genetic muscle diseases using muscle MRI 25–26 February 2011, Rome, Italy , 2012, Neuromuscular Disorders.

[27]  C. Senesac,et al.  Relationships of thigh muscle contractile and non-contractile tissue with function, strength, and age in boys with Duchenne muscular dystrophy , 2012, Neuromuscular Disorders.

[28]  M. Gaeta,et al.  Muscle fat-fraction and mapping in Duchenne muscular dystrophy: evaluation of disease distribution and correlation with clinical assessments , 2012, Skeletal Radiology.

[29]  J. Bourke,et al.  Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: an open-label, phase 2, dose-escalation study , 2011, The Lancet.

[30]  G. van Ommen,et al.  Systemic administration of PRO051 in Duchenne's muscular dystrophy. , 2011, The New England journal of medicine.

[31]  Craig McDonald,et al.  Diagnosis and management of Duchenne muscular dystrophy, part 2: implementation of multidisciplinary care , 2010, The Lancet Neurology.

[32]  R. Finkel,et al.  Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management , 2010, The Lancet Neurology.

[33]  Vicente Gilsanz,et al.  Three-point technique of fat quantification of muscle tissue as a marker of disease progression in Duchenne muscular dystrophy: preliminary study. , 2008, AJR. American journal of roentgenology.

[34]  Guido Gerig,et al.  User-guided 3D active contour segmentation of anatomical structures: Significantly improved efficiency and reliability , 2006, NeuroImage.

[35]  Vicente Gilsanz,et al.  Fat quantification using three-point dixon technique: in vitro validation. , 2005, Academic radiology.

[36]  A. Manzur,et al.  Glucocorticoid corticosteroids for Duchenne muscular dystrophy. , 2004, The Cochrane database of systematic reviews.

[37]  E. Mattsson,et al.  Validity of the EK scale: a functional assessment of non-ambulatory individuals with Duchenne muscular dystrophy or spinal muscular atrophy. , 2001, Physiotherapy research international : the journal for researchers and clinicians in physical therapy.

[38]  G. Glover.  Multipoint dixon technique for water and fat proton and susceptibility imaging , 1991, Journal of magnetic resonance imaging : JMRI.

[39]  G H Glover,et al.  Three‐point dixon technique for true water/fat decomposition with B0 inhomogeneity correction , 1991, Magnetic resonance in medicine.