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

<div><p>Objective</p><p>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.</p><p>Methods</p><p>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.</p><p>Results</p><p>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).</p><p>Conclusions</p><p>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.</p></div

MRI and clinical indices mean changes (95% CI) from baseline from analysis of variance.

<p>MRI and clinical indices mean changes (95% CI) from baseline from analysis of variance.</p

3-point Dixon fat-fraction (f.f.) maps of dominant forearm central slice at baseline (left images) and 12 months (right images).

<p><b>Top:</b> 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). <b>Bottom:</b> 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%).</p

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.

<p>f.f. = fat fraction. PUL = Performance of upper limb.</p

Muscle segmentation (A) and raw 3-point Dixon (B) of the central slice in the dominant forearm of a healthy control.

<p><b>DORSAL compartment</b>: 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). <b>VOLAR compartment</b>: flexor digitorum profundus and flexor pollicis longus (FDP), flexor digitorum superficialis and palmaris longus (FDS), flexor carpi ulnaris (FCU), flexor carpi radialis (FCR).</p

Quantitative Muscle MRI as an Assessment Tool for Monitoring Disease Progression in LGMD2I: A Multicentre Longitudinal Study

<div><p>Background</p><p>Outcome measures for clinical trials in neuromuscular diseases are typically based on physical assessments which are dependent on patient effort, combine the effort of different muscle groups, and may not be sensitive to progression over short trial periods in slow-progressing diseases. We hypothesised that quantitative fat imaging by MRI (Dixon technique) could provide more discriminating quantitative, patient-independent measurements of the progress of muscle fat replacement within individual muscle groups.</p><p>Objective</p><p>To determine whether quantitative fat imaging could measure disease progression in a cohort of limb-girdle muscular dystrophy 2I (LGMD2I) patients over a 12 month period.</p><p>Methods</p><p>32 adult patients (17 male;15 female) from 4 European tertiary referral centres with the homozygous c.826C>A mutation in the fukutin-related protein gene (<i>FKRP</i>) completed baseline and follow up measurements 12 months later. Quantitative fat imaging was performed and muscle fat fraction change was compared with (i) muscle strength and function assessed using standardized physical tests and (ii) standard T1-weighted MRI graded on a 6 point scale.</p><p>Results</p><p>There was a significant increase in muscle fat fraction in 9 of the 14 muscles analyzed using the quantitative MRI technique from baseline to 12 months follow up. Changes were not seen in the conventional longitudinal physical assessments or in qualitative scoring of the T₁w images.</p><p>Conclusions</p><p>Quantitative muscle MRI, using the Dixon technique, could be used as an important longitudinal outcome measure to assess muscle pathology and monitor therapeutic efficacy in patients with LGMD2I.</p></div

Percentage of LGMD2I patients in each category of each semi-quantitative grade for individual muscle groups using the Mercuri et al. scale, with the median grade for each muscle.

<p>Percentage of LGMD2I patients in each category of each semi-quantitative grade for individual muscle groups using the Mercuri et al. scale, with the median grade for each muscle.</p

Quantitative Magnetic Resonance Imaging in Limb-Girdle Muscular Dystrophy 2I: A Multinational Cross-Sectional Study

<div><p>We conducted a prospective multinational study of muscle pathology using magnetic resonance imaging (MRI) in patients with limb-girdle muscular dystrophy 2I (LGMD2I). Thirty eight adult ambulant LGMD2I patients (19 male; 19 female) with genetically identical mutations (c.826C>A) in the fukutin-related protein (<i>FKRP</i>) gene were recruited. In each patient, T1-weighted (T₁w) imaging was assessed by qualitative grading for 15 individual lower limb muscles and quantitative Dixon imaging was analysed on 14 individual lower limb muscles by region of interest analysis. We described the pattern and appearance of muscle pathology and gender differences, not previously reported for LGMD2I. Diffuse fat infiltration of the gastrocnemii muscles was demonstrated in females, whereas in males fat infiltration was more prominent in the medial than the lateral gastrocnemius (p = 0.05). In the anterior thigh of males, in contrast to females, median fat infiltration in the vastus medialis muscle (45.7%) exceeded that in the vastus lateralis muscle (11.2%) (p<0.005). MRI is non-invasive, objective and does not rely on patient effort compared to clinical and physical measures that are currently employed. We demonstrated (i) that the quantitative Dixon technique is an objective quantitative marker of disease and (ii) new observations of gender specific patterns of muscle involvement in LGMD2I.</p></div

Summary table of the clinical characteristics of the LGMD2I cohort (n = 38).

<p>Summary table of the clinical characteristics of the LGMD2I cohort (n = 38).</p

The median values of fat fraction (%) in the patient group and the control group.

<p>The p values represent Mann-Whitney U test between patients and controls.</p