title: Upper Limb Evaluation in Duchenne Muscular Dystrophy: Fat-Water Quantification by MRI, Muscle Force and Function Define Endpoints for Clinical Trials.
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.
authors.affiliation: Dubowitz Neuromuscular Centre, UCL Institute of Child Health and Great Ormond Street Hospital, London, United Kingdom.
authors.forename: Valeria
authors.initials: V
authors.lastname: Ricotti
authors.affiliation: MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, United Kingdom.|Neuroradiological Academic Unit, UCL Institute of Neurology, London, United Kingdom.
authors.forename: Matthew R B
authors.initials: MR
authors.lastname: Evans
authors.affiliation: MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, United Kingdom.|Neuroradiological Academic Unit, UCL Institute of Neurology, London, United Kingdom.
authors.forename: Christopher D J
authors.initials: CD
authors.lastname: Sinclair
authors.affiliation: Dubowitz Neuromuscular Centre, UCL Institute of Child Health and Great Ormond Street Hospital, London, United Kingdom.
authors.forename: Jordan W
authors.initials: JW
authors.lastname: Butler
authors.affiliation: Population, Policy and Practice Programme, UCL Institute of Child Health and Great Ormond Street Hospital, London, United Kingdom.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Ridout
authors.affiliation: Institut de Myologie, GH Pitié-Salpêtrière, Paris, France.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Hogrel
authors.affiliation: MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, United Kingdom.|Neuroradiological Academic Unit, UCL Institute of Neurology, London, United Kingdom.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Emira
authors.affiliation: MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, United Kingdom.
authors.forename: Jasper M
authors.initials: JM
authors.lastname: Morrow
authors.affiliation: MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, United Kingdom.
authors.forename: Mary M
authors.initials: MM
authors.lastname: Reilly
authors.affiliation: MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, United Kingdom.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Hanna
authors.affiliation: GlaxoSmithKline, London, United Kingdom.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Janiczek
authors.affiliation: MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, United Kingdom.|Division of Brain Sciences and Centre for Neurotechnology, Imperial College London, United Kingdom.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Matthews
authors.affiliation: MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, United Kingdom.|Neuroradiological Academic Unit, UCL Institute of Neurology, London, United Kingdom.
authors.forename: Tarek A
authors.initials: TA
authors.lastname: Yousry
authors.affiliation: Dubowitz Neuromuscular Centre, UCL Institute of Child Health and Great Ormond Street Hospital, London, United Kingdom.|MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, United Kingdom.
authors.forename: Francesco
authors.initials: F
authors.lastname: Muntoni
authors.affiliation: MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, United Kingdom.|Neuroradiological Academic Unit, UCL Institute of Neurology, London, United Kingdom.
authors.forename: John S
authors.initials: JS
authors.lastname: Thornton
mesh_terms: D000293:Adolescent; D002648:Child; D005223:Fats / Q000378:metabolism; D005542:Forearm / Q000000981:diagnostic imaging / Q000503:physiopathology; D006801:Humans; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D053580:Muscle Strength / Q000502:physiology; D018482:Muscle, Skeletal / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000503:physiopathology; D020388:Muscular Dystrophy, Duchenne / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000503:physiopathology; D013997:Time Factors; D034941:Upper Extremity / Q000000981:diagnostic imaging* / Q000503:physiopathology; D014867:Water / Q000378:metabolism
chemical_list: D005223:Fats; D014867:Water