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. 2016 Sep 20;11(9):e0162542.
doi: 10.1371/journal.pone.0162542. eCollection 2016.

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

Valeria Ricotti  1 , Matthew R B Evans  2   3 , Christopher D J Sinclair  2   3 , Jordan W Butler  1 , Deborah A Ridout  4 , Jean-Yves Hogrel  5 , Ahmed Emira  2   3 , Jasper M Morrow  2 , Mary M Reilly  2 , Michael G Hanna  2 , Robert L Janiczek  6 , Paul M Matthews  2   7 , Tarek A Yousry  2   3 , Francesco Muntoni  1   2 , John S Thornton  2   3
Affiliations

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

Valeria Ricotti et al. PLoS One. .

Abstract

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.

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Conflict of interest statement

RLJ is an employee of GlaxoSmithKline. PMM was an employee of GlaxoSmithKline during design and initial implementation stages of this study. FM also received funding from GlaxoSmithKline. TAY has received honoraria and travel expenses for advisory committee work from Bayer Schering, Biogen Idec, and Novartis; and research grants (held by University College London) from Biogen Idec, GlaxoSmithKline, Novartis, and Schering AG for analysis of data from MS trials. MMR received grant funding from the National Institute of Neurological Disorders and Stroke/Office of Rare Diseases and the Medical Research Council (MRC). MGH is supported by the MRC Centre and by The Myositis Support Group. FM has served on scientific advisory boards for Acceleron Pharma, Genzyme,AVI BioPharma, Debiopharma Group, GlaxoSmithKline, Prosensa, Servier, Summit and Santhera Pharmaceutical, receives research support from Trophos, and GlaxoSmithKline, and has received funding for trials from AVI, and PTC. JST has received research support from GlaxoSmithKline, Medtronic and Siemens. JYH is an inventor of the MyoGrip (patent pending, PCT/FR2013/050694), MyoPinch (patent pending, PCT/2013/052106) and MoviPlate (patent pending, PCT/2013/050353) devices. VR is currently an employee of Biomarin Europe. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The other authors have no conflict of interest to declare.

Figures

Fig 1
Fig 1. Muscle segmentation (A) and raw 3-point Dixon (B) of the central slice in the dominant forearm of a healthy control.
DORSAL compartment: Extensor carpi ulnaris (ECU), extensor digiti minimi (EDM), extensor digitorum (ED), extensor pollicis longus (EPL), abductor pollicis longus (APL), extensor carpi radialis longus/brevis and brachioradialis (ECRLB Br). VOLAR compartment: flexor digitorum profundus and flexor pollicis longus (FDP), flexor digitorum superficialis and palmaris longus (FDS), flexor carpi ulnaris (FCU), flexor carpi radialis (FCR).
Fig 2
Fig 2. 3-point Dixon fat-fraction (f.f.) maps of dominant forearm central slice at baseline (left images) and 12 months (right images).
Top: 13 y.o. DMD, non-ambulant for 40 months, and on daily steroids. Overall mean f.f. at baseline = 7.6% (A) and 12 months = 9.7% (B). Bottom: 11 y.o. DMD, non-ambulant for 14 months, not on steroid therapy. Mean f.f. at baseline = 30.7% (C) and 12 months = 43.3% (D). (Grey-level bars represent f.f. from 0 to 100%).
Fig 3
Fig 3. Plots of individual trajectories for (A) central slice overall muscle %fat fraction, (B) proximal slice overall muscle %fat fraction, (C) distal slice overall muscle %fat fraction, (D) MyoPinch, (E) total score for Performance of Upper limb, (F) PUL Shoulder domain score, (G) MoviPlate and (H) MyoGrip.
f.f. = fat fraction. PUL = Performance of upper limb.
See this image and copyright information in PMC

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