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INTRODUCTION: This two-part study explored the safety, feasibility, and efficacy of a mild-moderate resistance isometric leg exercise program in ambulatory boys with Duchenne Muscular Dystrophy (DMD). METHODS: First, we used a dose escalation paradigm with varying intensity and frequency of leg isometric exercise to determine the dose response and safety in 10 boys. Second, we examined safety and feasibility of a 12-week in-home, remotely-supervised, mild-moderate intensity strengthening program in 8 boys. Safety measures included T(2) MRI, creatine kinase levels, and pain. Peak strength and function (time to ascend/descend 4 stairs) were also measured. RESULTS: Dose-escalation revealed no signs of muscle damage. Seven of the 8 boys completed the 12-week in-home program with a compliance of 84.9%, no signs of muscle damage, and improvements in strength (knee extensors p < 0.01; knee flexors p < 0.05) and function (descending steps p < 0.05). DISCUSSION: An in-home, mild-moderate intensity leg exercise program is safe with potential to positively impact both strength and function in ambulatory boys with DMD.

Duchenne muscular dystrophy (DMD) is a muscle degenerative disorder that manifests in early childhood and results in progressive muscle weakness. Physical therapists have long been an important component of the multidisciplinary team caring for people with DMD, providing expertise in areas of disease assessment, contracture management, assistive device prescription, and exercise prescription. Over the last decade, magnetic resonance imaging of muscles in people with DMD has led to an improved understanding of the muscle pathology underlying the clinical manifestations of DMD. Findings from magnetic resonance imaging (MRI) studies in DMD, paired with the clinical expertise of physical therapists, can help guide research that leads to improved physical therapist care for this unique patient population. The 2 main goals of this perspective article are to (1) summarize muscle pathology and disease progression findings from qualitative and quantitative muscle MRI studies in DMD and (2) link MRI findings of muscle pathology to the clinical manifestations observed by physical therapists with discussion of any potential implications of MRI findings on physical therapy management.

BACKGROUND: Upper extremity MRI and proton MR spectroscopy are increasingly considered to be outcome measures in Duchenne muscular dystrophy (DMD) clinical trials. PURPOSE: To demonstrate the feasibility of acquiring upper extremity MRI and proton ((1)H) MR spectroscopy measures of T2 and fat fraction in a large, multicenter cohort (ImagingDMD) of ambulatory and nonambulatory individuals with DMD; compare upper and lower extremity muscles by using MRI and (1)H MR spectroscopy; and correlate upper extremity MRI and (1)H MR spectroscopy measures to function. MATERIALS AND METHODS: In this prospective cross-sectional study, MRI and (1)H MR spectroscopy and functional assessment data were acquired from participants with DMD and unaffected control participants at three centers (from January 28, 2016, to April 24, 2018). T2 maps of the shoulder, upper arm, forearm, thigh, and calf were generated from a spin-echo sequence (repetition time msec/echo time msec, 3000/20–320). Fat fraction maps were generated from chemical shift-encoded imaging (eight echo times). Fat fraction and (1)H(2)O T2 in the deltoid and biceps brachii were measured from single-voxel (1)H MR spectroscopy (9000/11–243). Groups were compared by using Mann-Whitney test, and relationships between MRI and (1)H MR spectroscopy and arm function were assessed by using Spearman correlation. RESULTS: This study evaluated 119 male participants with DMD (mean age, 12 years ± 3 [standard deviation]) and 38 unaffected male control participants (mean age, 12 years ± 3). Deltoid and biceps brachii muscles were different in participants with DMD versus control participants in all age groups by using quantitative T2 MRI (P < .001) and (1)H MR spectroscopy fat fraction (P < .05). The deltoid, biceps brachii, and triceps brachii were affected to the same extent (P > .05) as the soleus and medial gastrocnemius. Negative correlations were observed between arm function and MRI (T2: range among muscles, ρ = −0.53 to −0.73 [P < .01]; fat fraction, ρ = −0.49 to −0.70 [P < .01]) and (1)H MR spectroscopy fat fraction (ρ = −0.64 to −0.71; P < .01). CONCLUSION: This multicenter study demonstrated early and progressive involvement of upper extremity muscles in Duchenne muscular dystrophy (DMD) and showed the feasibility of MRI and (1)H MR spectroscopy to track disease progression over a wide range of ages in participants with DMD. © RSNA, 2020 Online supplemental material is available for this article.

ObjectiveTo quantify disease progression in individuals with Duchenne muscular dystrophy (DMD) using magnetic resonance biomarkers of leg muscles.MethodsMRI and magnetic resonance spectroscopy (MRS) biomarkers were acquired from 104 participants with DMD and 51 healthy controls using a prospective observational study design with patients with DMD followed up yearly for up to 6 years. Fat fractions (FFs) in vastus lateralis and soleus muscles were determined with 1H MRS. MRI quantitative T2 (qT2) values were measured for 3 muscles of the upper leg and 5 muscles of the lower leg. Longitudinal changes in biomarkers were modeled with a cumulative distribution function using a nonlinear mixed-effects approach.ResultsMRS FF and MRI qT2 increased with DMD disease duration, with the progression time constants differing markedly between individuals and across muscles. The average age at half-maximal muscle involvement (μ) occurred 4.8 years earlier in vastus lateralis than soleus, and these measures were strongly associated with loss-of-ambulation age. Corticosteroid treatment was found to delay μ by 2.5 years on average across muscles, although there were marked differences between muscles with more slowly progressing muscles showing larger delay.ConclusionsMRS FF and MRI qT2 provide sensitive noninvasive measures of DMD progression. Modeling changes in these biomarkers across multiple muscles can be used to detect and monitor the therapeutic effects of corticosteroids on disease progression and to provide prognostic information on functional outcomes. This modeling approach provides a method to transform these MRI biomarkers into well-understood metrics, allowing concise summaries of DMD disease progression at individual and population levels.ClinicalTrials.gov identifier:NCT01484678.

Background The lack of dystrophin in cardiomyocytes in Duchenne muscular dystrophy (DMD) is associated with progressive decline in cardiac function eventually leading to death by 20–40 years of age. The aim of this prospective study was to determine rate of progressive decline in left ventricular (LV) function in Duchenne muscular dystrophy (DMD) over 5 years. Methods Short axis cine and grid tagged images of the LV were acquired in individuals with DMD (n = 59; age = 5.3–18.0 years) yearly, and healthy controls at baseline (n = 16, age = 6.0–18.3 years) on a 3 T MRI scanner. Grid-tagged images were analyzed for composite circumferential strain (ℇcc%) and ℇcc% in six mid LV segments. Cine images were analyzed for left ventricular ejection fraction (LVEF), LV mass (LVM), end-diastolic volume (EDV), end-systolic volume (ESV), LV atrioventricular plane displacement (LVAPD), and circumferential uniformity ratio estimate (CURE). LVM, EDV, and ESV were normalized to body surface area for a normalized index of LVM (LVMI), EDV (EDVI) and ESV (ESVI). Results At baseline, LV ℇcc% was significantly worse in DMD compared to controls and five of the six mid LV segments demonstrated abnormal strain in DMD. Longitudinal measurements revealed that ℇcc% consistently declined in individuals with DMD with the inferior segments being more affected. LVEF progressively declined between 3 to 5 years post baseline visit. In a multivariate analysis, the use of cardioprotective drugs trended towards positively impacting cardiac measures while loss of ambulation and baseline age were associated with negative impact. Eight out of 17 cardiac parameters reached a minimal clinically important difference with a threshold of 1/3 standard deviation. Conclusion The study shows a worsening of circumferential strain in dystrophic myocardium. The findings emphasize the significance of early and longitudinal assessment of cardiac function in DMD and identify early biomarkers of cardiac dysfunction to help design clinical trials to mitigate cardiac pathology. This study provides valuable non-invasive and non-contrast based natural history data of cardiac changes which can be used to design clinical trials or interpret the results of current trials aimed at mitigating the effects of decreased cardiac function in DMD.

BACKGROUND: Expiratory muscle weakness and impaired airway clearance are early signs of respiratory dysfunction in Duchenne muscular dystrophy (DMD), a degenerative muscle disorder in which muscle cells are damaged and replaced by fibrofatty tissue. Little is known about expiratory muscle pathology and its relationship to cough and airway clearance capacity; however, the level of muscle replacement by fat can be estimated using MRI and expressed as a fat fraction (FF). RESEARCH QUESTION: How does abdominal expiratory muscle fatty infiltration change over time in DMD and relate to clinical expiratory function? STUDY DESIGN AND METHODS: Individuals with DMD underwent longitudinal MRI of the abdomen to determine FF in the internal oblique, external oblique, and rectus abdominis expiratory muscles. FF data were used to estimate a model of expiratory muscle degeneration by using nonlinear mixed effects and a cumulative distribution function. FVC, maximal inspiratory and expiratory pressures, and peak cough flow were collected as clinical correlates to MRI. RESULTS: Forty individuals with DMD (aged 6-18 years at baseline) participated in up to five visits over 36 months. Modeling estimated the internal oblique progresses most quickly and reached 50% replacement by fat at a mean patient age of 13.0 years (external oblique, 14.0 years; rectus abdominis, 16.2 years). Corticosteroid-untreated individuals (n = 4) reached 50% muscle replacement by fat 3 to 4 years prior to treated individuals. Individuals with mild clinical dystrophic phenotypes (n = 3) reached 50% muscle replacement by fat 4 to 5 years later than corticosteroid-treated individuals. Internal and external oblique FFs near 50% were associated with maximal expiratory pressures < 60 cm H(2)O and peak cough flows < 270 L/min. INTERPRETATION: These data improve understanding of the early phase of respiratory compromise in DMD, which typically presents as airway clearance dysfunction prior to the onset of hypoventilation, and links expiratory muscle fatty infiltration to pulmonary function measures.

OBJECTIVE: Duchenne muscular dystrophy (DMD) is characterized by damage to muscles including the muscles involved in respiration. Dystrophic muscles become weak and infiltrated with fatty tissue, resulting in progressive respiratory impairment. The objective of this study was to assess respiratory muscle quality and function in DMD using magnetic resonance imaging and to determine the relationship to clinical respiratory function. METHODS: Individuals with DMD (n=36) and unaffected controls (n=12) participated in this cross-sectional magnetic resonance imaging study. Participants underwent dynamic imaging of the thorax to assess diaphragm and chest wall mobility and chemical shift-encoded imaging of the chest and abdomen to determine fatty infiltration of the accessory respiratory muscles. Additionally, clinical pulmonary function measures were obtained. RESULTS: Thoracic cavity area was decreased in individuals with DMD compared to controls during tidal and maximal breathing. Individuals with DMD had reduced chest wall movement in the anterior-posterior direction during maximal inspirations and expirations, but diaphragm descent during maximal inspirations (normalized to height) was only decreased in a subset of individuals with maximal inspiratory pressures less than 60% predicted. Muscle fat fraction was elevated in all three expiratory muscles assessed (p

INTRODUCTION: In this study we explored walking activity in a large cohort of boys with Duchenne muscular dystrophy (DMD). METHODS: Step activity (monitored for 7 days), functional ability, and strength were quantified in ambulatory boys (5-12.9 years of age) with DMD and unaffected boys. Ambulatory status was determined 2 years later. RESULTS: Two to 5 days of activity monitoring predicted weekly step activity (adjusted R(2) = 0.80-0.95). Age comparisons revealed significant declines for step activity with increasing age, and relationships were found between step activity with both function and strength (P < .01). Our regression model predicted 36.5% of the variance in step activity. Those who were still ambulatory after 2 years demonstrated baseline step activity nearly double that of those who were no longer walking 2 years later (P < .01). DISCUSSION: Step activity for DMD is related to and predictive of functional declines, which may be useful for clinical trials.

ObjectiveTo investigate the potential of lower extremity magnetic resonance (MR) biomarkers to serve as endpoints in clinical trials of therapeutics for Duchenne muscular dystrophy (DMD) by characterizing the longitudinal progression of MR biomarkers over 48 months and assessing their relationship to changes in ambulatory clinical function.MethodsOne hundred sixty participants with DMD were enrolled in this longitudinal, natural history study and underwent MR data acquisition of the lower extremity muscles to determine muscle fat fraction (FF) and MRI T2 biomarkers of disease progression. In addition, 4 tests of ambulatory function were performed. Participants returned for follow-up data collection at 12, 24, 36, and 48 months.ResultsLongitudinal analysis of the MR biomarkers revealed that vastus lateralis FF, vastus lateralis MRI T2, and biceps femoris long head MRI T2 biomarkers were the fastest progressing biomarkers over time in this primarily ambulatory cohort. Biomarker values tended to demonstrate a nonlinear, sigmoidal trajectory over time. The lower extremity biomarkers predicted functional performance 12 and 24 months later, and the magnitude of change in an MR biomarker over time was related to the magnitude of change in function. Vastus lateralis FF, soleus FF, vastus lateralis MRI T2, and biceps femoris long head MRI T2 were the strongest predictors of future loss of function, including loss of ambulation.ConclusionsThis study supports the strong relationship between lower extremity MR biomarkers and measures of clinical function, as well as the ability of MR biomarkers, particularly those from proximal muscles, to predict future ambulatory function and important clinical milestones.ClinicalTrials.gov identifierNCT01484678.

Introduction Tests of ambulatory function are common clinical trial endpoints in Duchenne muscular dystrophy (DMD). Using these tests, the ImagingDMD study has generated a large data set that can describe the contemporary natural history of DMD in 5-12.9-year-olds. Methods Ninety-two corticosteroid-treated boys with DMD and 45 controls participated in this longitudinal study. Participants performed the 6-minute walk test (6MWT) and timed function tests (TFT: 10-m walk/run, climbing 4 stairs, supine to stand). Results Boys with DMD had impaired functional performance even at 5-6.9 years old. Boys older than 7 had significant declines in function over 1 year for 10-m walk/run and 6MWT. Eighty percent of participants could perform all functional tests at 9 years old. TFTs appear to be slightly more responsive and predictive of disease progression than the 6MWT in 7-12.9 year olds. Discussion This study provides insight into the contemporary natural history of key functional endpoints in DMD. Muscle Nerve 58: 631-638, 2018.

Lack of sarcolemma-localized neuronal nitric oxide synthase mu (nNOSμ) contributes to muscle damage and fatigue in dystrophic muscle. In this study, we examined the effects of compensating for lack of nNOSμ with a phosphodiesterase type 5 (PDE5) inhibitor in mdx mice following downhill running and endurance training. Dystrophic mice ( mdx) were treated with sildenafil citrate and compared with untreated mdx and wild-type mice after an acute bout of downhill running and during a progressive low-intensity treadmill running program (5 days/wk, 4 wk). Magnetic resonance imaging (MRI) and spectroscopy (MRS) transverse relaxation time constant (T2) of hindlimb and forelimb muscles were measured as a marker of muscle damage after downhill running and throughout training. The MRI blood oxygenation level dependence (BOLD) response and 31phosphorus MRS (31P-MRS) data were acquired after stimulated muscle contractions. After downhill running, the increase in T2 was attenuated ( P < 0.05) in treated mdx and wild-type mice compared with untreated mdx. During training, resting T2 values did not change in wild-type and mdx mice from baseline values; however, the running distance completed during training was greater ( P < 0.05) in treated mdx (>90% of target distance) and wild-type (100%) than untreated mdx (60%). The post-contractile BOLD response was greater ( P < 0.05) in treated mdx that trained than untreated mdx, with no differences in muscle oxidative capacity, as measured by 31P-MRS. Our findings indicate that PDE5 inhibition reduces muscle damage after a single bout of downhill running and improves performance during endurance training in dystrophic mice, possibly because of enhanced microvascular function. NEW & NOTEWORTHY This study examined the combined effects of PDE5 inhibition and exercise in dystrophic muscle using high-resolution magnetic resonance imaging and spectroscopy. Our findings demonstrated that sildenafil citrate reduces muscle damage after a single bout of downhill running, improves endurance-training performance, and enhances microvascular function in dystrophic muscle. Collectively, the results support the combination of exercise and PDE5 inhibition as a therapeutic approach in muscular dystrophies lacking nNOSμ.

Background Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disease characterized by progressive muscle weakness, multiple system involvement and premature mortality. Effective treatments for DMD through clinical trials and natural history studies are currently underway. Clinical trials in DMD typically include several outcome measures of motor function. Research sites and studies have been found to have slightly different operational definitions for a given functional outcome resulting in different procedures and protocols for these measurements. Objective The goal of this study is to establish agreement among experts in the field around best practices in collecting functional outcome data in DMD providing researchers and clinicians with guidance on best practices. Methods A group of 30 experts in Duchenne Muscular Dystrophy (DMD) with experience in the development and/ or execution of lower extremity outcome measures for this population met face to face to identify incongruences in the collection of this data. This effort was based in the United States (US) and sponsored by Parent Project Muscular Dystrophy. Several discrepancies were categorized for each outcome which included: 6-minute walk test, 10-meter walk/run, supine to stand, ascend 4 stairs, sit to stand, and the NorthStar Ambulatory Assessment. Following this meeting an additional 32 experts in DMD (28 from the United States and 11 international participants) consented to participate in a Delphi Survey to reach consensus on the protocols and execution of lower extremity outcomes. Results Round one: 70 operationally defined questions were surveyed with 45 (64%) reaching >70% consensus. Round two: 27 questions were operational, with 20 (74%) reaching >70% consensus. Those questions that did not reach consensus appear minor. Conclusion With minor modifications in the collection of data across sites, outcomes could potentially be normalized across research studies. This would reduce excessive training for evaluators in trials and produce minimal differences between protocols. Consistency in protocols will promote more efficient study start up, less errors between administration of items across studies, and ultimately improve quality and reliability of the functional outcomes. The authors strongly advocate for the establishment of a "research network library" that could be utilized by all those performing clinical assessments and trials in DMD.

OBJECTIVE The main objective of this study was to examine the effect of disease on strength in two functionally important lower limb muscles for a period of 2 yrs in children with Duchene muscular dystrophy. DESIGN Seventy-seven Duchene muscular dystrophy children participated in this study. Plantar flexors, knee extensors, strength, and performance on timed tests (6-min walk, 4-stairs, 10-m walk, supine-up) were assessed yearly for 2 yrs. Multivariate normal regression was used to assess changes in strength over time in the Duchene muscular dystrophy group. Spearman correlations were computed to examine relationship between strength and function. RESULTS Normalized plantar flexor and knee extensor strength showed a significant decrease (P < 0.05) over 2 yrs, with larger declines in knee extensor. At baseline, knee extensor strongly correlated with performance on timed tests. However, plantar flexor strength was found to be a stronger predictor of loss in ambulatory function. Modest correlations (r = 0.19-0.34) were found between the decline in strength and functional performance over 2 yrs. CONCLUSIONS This study describes the loss of lower limb strength in a large cohort of Duchene muscular dystrophy children for 2 yrs. The findings support that lower limb strength alone cannot account for the decline in performance on functional tests, and the role of other contributing factors, such as compensatory strategies, should be considered.

Objective The aim of this study was to describe Duchenne muscular dystrophy (DMD) disease progression in the lower extremity muscles over 12 months using quantitative magnetic resonance (MR) biomarkers, collected across three sites in a large cohort. Methods A total of 109 ambulatory boys with DMD (8.7 ± 2.0 years; range, 5.0–12.9) completed baseline and 1-year follow-up quantitative MR imaging (transverse relaxation time constant; MRI-T2), MR spectroscopy (fat fraction and 1H2O T2), and 6-minute walk test (6MWT) measurements. A subset of boys completed additional measurements after 3 or 6 months. Results MRI-T2 and fat fraction increased significantly over 12 months in all age groups, including in 5- to 6.9-year-old boys. Significant increases in vastus lateralis (VL) fat fraction were observed in 3 and 6 months. Even in boys whose 6MWT performance improved or remained stable over 1 year, significant increases in MRI-T2 and fat fraction were found. Of all the muscles examined, the VL and biceps femoris long head were the most responsive to disease progression in boys with DMD. Interpretation MR biomarkers are responsive to disease progression in 5- to 12.9-year-old boys with DMD and able to detect subclinical disease progression in DMD, even within short (3–6 months) time periods. The measured sensitivity of MR biomarkers in this multicenter study may be critically important to future clinical trials, allowing for smaller sample sizes and/or shorter study windows in this fatal rare disease. Ann Neurol 2016;79:535–547

To validate a multicenter protocol that examines lower extremity skeletal muscles of children with Duchenne muscular dystrophy (DMD) by using magnetic resonance (MR) imaging and MR spectroscopy in terms of reproducibility of these measurements within and across centers.This HIPAA-compliant study was approved by the institutional review boards of all participating centers, and informed consent was obtained from each participant or a guardian. Standardized procedures with MR operator training and quality assurance assessments were implemented, and data were acquired at three centers by using different 3-T MR imaging instruments. Measures of maximal cross-sectional area (CSAmax), transverse relaxation time constant (T2), and lipid fraction were compared among centers in two-compartment coaxial phantoms and in two unaffected adult subjects who visited each center. Also, repeat MR measures were acquired twice on separate days in 30 boys with DMD (10 per center) and 10 unaffected boys. Coefficients of variation (CVs) were computed to examine the repeated-measure variabilities within and across centers.CSAmax, T2 from MR imaging and MR spectroscopy, and lipid fraction were consistent across centers in the phantom (CV,3%) and in the adult subjects who traveled to each site (CV, 2%-7%). High day-to-day reproducibility in MR measures was observed in boys with DMD (CSAmax, CV = 3.7% [25th percentile, 1.3%; 75th percentile, 5.1%]; contractile area, CV = 4.2% [25th percentile, 0.8%; 75th percentile, 4.9%]; MR imaging T2, CV = 3.1% [25th percentile, 1.2%; 75th percentile, 4.7%]; MR spectroscopy T2, CV = 3.9% [25th percentile, 1.5%; 75th percentile, 5.1%]; and lipid fraction, CV = 4.7% [25th percentile, 1.0%; 75th percentile, 5.3%]).The MR protocol implemented in this multicenter study achieved highly reproducible measures of lower extremity muscles across centers and from day to day in ambulatory boys with DMD.

Purpose The relationship between fat fractions (FFs) determined based on multiple TE, unipolar gradient echo images and 1H magnetic resonance spectroscopy (MRS) was evaluated using different models for fat-water decomposition, signal-to-noise ratios, and excitation flip angles. Methods A combination of single-voxel proton spectroscopy (1H-MRS) and gradient echo imaging was used to determine muscle FFs in both normal and dystrophic muscles. In order to cover a large range of FFs, the soleus and vastus lateralis muscles of 22 unaffected control subjects, 16 subjects with collagen VI deficiency (COL6), and 71 subjects with Duchenne muscular dystrophy (DMD) were studied. 1H-MRS–based FF were corrected for the increased muscle 1H2O T1 and T2 values observed in dystrophic muscles. Results Excellent agreement was found between coregistered FFs derived from gradient echo images fit to a multipeak model with noise bias correction and the relaxation-corrected 1H-MRS FFs (y = 0.93x + 0.003; R2 = 0.96) across the full range of FFs. Relaxation-corrected 1H-MRS FFs and imaging-based FFs were significantly elevated (P < 0.01) in the muscles of COL6 and DMD subjects. Conclusion FFs, T2, and T1 were all sensitive to muscle involvement in dystrophic muscle. MRI offered an additional advantage over single-voxel spectroscopy in that the tissue heterogeneity in FFs could be readily determined. Magn Reson Med 72:8–19, 2014. © 2013 Wiley Periodicals, Inc.

Purpose Skeletal muscles of children with Duchenne muscular dystrophy (DMD) have enhanced susceptibility to damage and progressive lipid infiltration, which contribute to an increase in magnetic resonance proton transverse relaxation time (T2). Therefore, examining T2 changes in individual muscles may be useful for monitoring disease progression in DMD. In this study we utilized mean T2, percent elevated pixels, and T2 heterogeneity to assess changes in composition of dystrophic muscles. In addition, we used fat saturation (fatsat) to distinguish T2 changes due to edema and inflammation from fat infiltration in muscles.

The purpose of this study was to evaluate skeletal muscle composition of lower extremity muscles in a manifesting female carrier of Duchenne muscular dystrophy (MFC DMD ) using magnetic resonance imaging (MRI) and spectroscopy (MRS). MRI/MRS was performed on the lower extremities and heart of a MFC DMD (47years, 51kg) on four occasions within 21months and in a control subject. Heterogeneity and asymmetry among muscles in the MFC DMD was observed in lipid fraction and mean transverse relaxation time (T 2 ) of lower extremity muscles with some muscles presenting as unaffected (e.g., rectus femoris) and others showing substantial deterioration and lipid infiltration (e.g., vasti muscles). There was an association of abnormal MRI findings and strength and motor function. Over the 21months a small decrease in CSA max and increase in lipid fraction and T 2 was observed in the MFC DMD in some muscles. In summary, this MFC DMD revealed significant imaging evidence of pathologic heterogeneity among muscles. Furthermore, this study shows the feasibility of combining various quantitative MRI and MRS approaches to monitor skeletal muscle involvement.

There is a pressing need for biomarkers and outcomes that can be used across disease stages in Duchenne muscular dystrophy (DMD), to facilitate the inclusion of a wider range of participants in clinical trials and to improve our understanding of the natural history of DMD. Quantitative magnetic resonance imaging (qMRI) and spectroscopy (MRS) biomarkers show considerable promise in both the legs and forearms of individuals with DMD, but have not yet been examined in functionally important proximal upper extremity muscles such as the biceps brachii and deltoid. The primary objective of this study was to examine the feasibility of implementing qMRI and MRS biomarkers in the proximal upper extremity musculature, and the secondary objective was to examine the relationship between MR measures of arm muscle pathology and upper extremity functional endpoints. Biomarkers included MRS and MRI measures of fat fraction and transverse relaxation time (T 2). The MR exam was well tolerated in both ambulatory and non-ambulatory boys. qMR biomarkers differentiated affected and unaffected participants and correlated strongly with upper extremity function (r = 0.91 for biceps brachii T 2 versus performance of upper limb score). These qMR outcome measures could be highly beneficial to the neuromuscular disease community, allowing measurement of the quality of functionally important muscles across disease stages to understand the natural history of DMD and particularly to broaden the opportunity for clinical trial participation.

Mathur S, Lott DJ, Senesac C, Germain SA, Vohra RS, Sweeney HL, Walter GA, Vandenborne K. Age-related differences in lower-limb muscle cross-sectional area and torque production in boys with Duchenne muscular dystrophy. Objective To examine the relationship between lower-extremity muscle cross-sectional area, muscle strength, specific torque, and age in ambulatory boys with Duchenne muscular dystrophy (DMD) compared with controls. Design Observational cross-sectional study. Setting University research setting. Participants Volunteer sample of boys with DMD (n=22) and healthy control boys (n=10), ages 5 through 14 years. Interventions Not applicable. Main Outcome Measures Maximal muscle cross-sectional area (CSA max ) assessed by magnetic resonance imaging of quadriceps, plantarflexors (PFs) and dorsiflexors (DFs), peak isometric torque from dynamometry, and timed functional tests. Results The average CSA max of the triceps surae muscle group was approximately 60% higher in boys with DMD compared with controls (39.1±13.6 cm 2 vs 24.5±9.3 cm 2 ; P =.002), while the tibialis anterior muscle showed age-appropriate increases in CSA max . The increase in quadriceps CSA max was also distinctly different in boys with DMD compared with controls. Specific torque (ie, peak torque/CSA max ) was impaired in all 3 muscles groups, with the knee extensor (KE) and PF muscles showing 4-fold, and the DF muscles 2-fold, higher values in controls compared with boys with DMD. Large age-related gains in specific torque were observed in all 3 muscle groups of control subjects, which were absent in ambulatory boys with DMD. Correlations were observed between performance on functional tasks and quadriceps and PF torque production ( r =−.45 to −.57, P Conclusions Age-related changes in muscle cross-sectional area and specific torque production in lower-extremity muscles showed distinctly different patterns in the KE, PF, and DF muscles of boys with DMD compared with controls.

Objective To provide evidence for quantitative magnetic resonance (qMR) biomarkers in Duchenne muscular dystrophy by investigating the relationship between qMR measures of lower extremity muscle pathology and functional endpoints in a large ambulatory cohort using a multicenter study design. Methods MR spectroscopy and quantitative imaging were implemented to measure intramuscular fat fraction and the transverse magnetization relaxation time constant (T2) in lower extremity muscles of 136 participants with Duchenne muscular dystrophy. Measures were collected at 554 visits over 48 months at one of three imaging sites. Fat fraction was measured in the soleus and vastus lateralis using MR spectroscopy, while T2 was assessed using MRI in eight lower extremity muscles. Ambulatory function was measured using the 10m walk/run, climb four stairs, supine to stand, and six minute walk tests. Results Significant correlations were found between all qMR and functional measures. Vastus lateralis qMR measures correlated most strongly to functional endpoints (|ρ| = 0.68–0.78), although measures in other rapidly progressing muscles including the biceps femoris (|ρ| = 0.63–0.73) and peroneals (|ρ| = 0.59–0.72) also showed strong correlations. Quantitative MR biomarkers were excellent indicators of loss of functional ability and correlated with qualitative measures of function. A VL FF of 0.40 was an approximate lower threshold of muscle pathology associated with loss of ambulation. Discussion Lower extremity qMR biomarkers have a robust relationship to clinically meaningful measures of ambulatory function in Duchenne muscular dystrophy. These results provide strong supporting evidence for qMR biomarkers and set the stage for their potential use as surrogate outcomes in clinical trials.

Objective: To evaluate the effects of corticosteroids on the lower extremity muscles in boys with Duchenne muscular dystrophy (DMD) using MRI and magnetic resonance spectroscopy (MRS). Methods: Transverse relaxation time (T2) and fat fraction were measured by MRI/MRS in lower extremity muscles of 15 boys with DMD (age 5.0–6.9 years) taking corticosteroids and 15 corticosteroid-naive boys. Subsequently, fat fraction was measured in a subset of these boys at 1 year. Finally, MRI/MRS data were collected from 16 corticosteroid-naive boys with DMD (age 5–8.9 years) at baseline, 3 months, and 6 months. Five boys were treated with corticosteroids after baseline and the remaining 11 served as corticosteroid-naive controls. Results: Cross-sectional comparisons demonstrated lower muscle T2 and less intramuscular (IM) fat deposition in boys with DMD on corticosteroids, suggesting reduced inflammation/damage and fat infiltration with treatment. Boys on corticosteroids demonstrated less increase in IM fat infiltration at 1 year. Finally, T2 by MRI/MRS detected effects of corticosteroids on leg muscles as early as 3 months after drug initiation. Conclusions: These results demonstrate the ability of MRI/MRS to detect therapeutic effects of corticosteroids in reducing inflammatory processes in skeletal muscles of boys with DMD. Our work highlights the potential of MRI/MRS as a biomarker in evaluating therapeutic interventions in DMD.

Background Duchenne muscular dystrophy (DMD), an inherited recessive X chromosome-linked disease, is the most severe childhood form of muscular dystrophy. Boys with DMD experience muscle loss, with infiltration of intramuscular fat into muscles. Objectives This case series describes the progression of DMD in boys using magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS). Magnetic resonance results are then compared with an established functional timed test. Methods Four boys with DMD and 4 healthy age-matched controls were chosen from a larger cohort. Boys with DMD were assessed at 4 time points over 2 years, with controls assessed at baseline only. Progression of the disease was documented by assessing the plantar flexors using MRI and MRS techniques and by assessing ambulation using the 30-Foot Fast Walk Test. Results Transverse relaxation time (T2) values were elevated in all boys with DMD at baseline. The lipid ratio increased rapidly as the disease progressed in 2 boys. Discrete changes in T2 in the other 2 boys with DMD indicated a slower disease progression. Magnetic resonance imaging and MRS allowed monitoring of the disease over all time periods regardless of ambulation status. Limitations The magnetic resonance data were collected with 2 different magnets at 2 different field strengths (1.5 and 3.0 T). Although we corrected for this difference, care must be taken in interpreting data when different image collection systems are used. This was a case series of 4 boys with DMD taken from a larger cohort study. Conclusions Magnetic resonance imaging and MRS are objective, noninvasive techniques for measuring muscle pathology and can be used to detect discrete changes in both people who are ambulatory and those who are nonambulatory. These techniques should be considered when monitoring DMD progression and assessing efficacy of therapeutic interventions.

The purpose of this study was to use proton magnetic resonance spectroscopy to assess intramuscular lipid and metabolites of lower leg muscles in boys with Duchenne muscular dystrophy (DMD) and determine its relationship with strength and functional ability. Spectroscopic measurements were obtained from four muscles of the lower leg in 25 boys with DMD (9.2±3.1 years) and 10 healthy boys (10.2±2.6 years). Lipid fractions and metabolite concentrations were also determined. Muscle strength, a timed functional test, and the Modified Brooke Lower Extremity Functional Scale were also determined. Lipid fractions were higher (p

While most studies of Duchenne muscular dystrophy (DMD) have focused on physical impairment, there is a need to explore how impairment impacts real-life experiences in order to provide intervention strategies focused on participation. Objectives were: (1) to investigate the domains of participation in a sample of boys with DMD; (2) to compare a younger (10 years) and older (≥10 years) group of boys with DMD with regard to participation; (3) to investigate strength and timed functional tests in a sample of boys with DMD; (4) to compare a younger (10 years) and older (≥10 years) group of boys with DMD with regard to strength and timed functional tests; and (5) to explore associations between participation and strength and timed functional tests for our DMD cohorts.This cross-sectional study included 60 boys with DMD (mean 9.3 years ± 0.3). Boys completed strength testing, timed functional tests, the Children's Assessment of Participation and Enjoyment and the ACTIVLIM. Independent samples t-tests were used to test for differences in all measures between our younger and older cohorts; Spearman's (rank) correlation was used to assess relationships between participation and strength and time functional tests.Significant differences were found between our younger and older boys with DMD in the areas of recreational (p 0.01), social (p 0.001), and skill-based activities (p 0.05), as well as with whom and where the activities were performed (p 0.05 and 0.001, respectively). Older boys with DMD report lower levels of participation in these areas, as well as less engagement in activities with individuals other than family members and less participation outside of the home. Lower levels of strength and slower rates of functional performance correlate with participation in fewer physical activities for our younger cohort and fewer physical and social activities for our older cohort.Strength and function relate to the variability and type of activities in which boys with DMD participate. A key finding is the significant decline in social activities and community-based engagement as the boys with DMD age. The ultimate goal of an intervention is for our children to be as actively engaged in life as they desire. This requires addressing participation when measuring outcomes in order to more fully understand limitations and provide appropriate strategies for continued participation for boys and their families.Duchenne muscular dystrophy is a devastating progressive neuromuscular disorder that leads to significant strength and functional limitations, which affect physical and social participation for these boys. The ability to move beyond clinically-based outcomes and assess and monitor a child's daily activities through participation measures may provide information for therapeutic interventions. Rehabilitation specialists have a role as advocates for social and community engagement for children with physical limitations. Providing families with information on community-based opportunities, and the strategies and environmental modifications available may increase social participation for our youth growing up with a neuromuscular disorder.

Duchenne muscular dystrophy (DMD) is characterized by an increased muscle damage and progressive replacement of muscle by noncontractile tissue. Both of these pathological changes can lengthen the MRI transverse proton relaxation time (T 2 ). The current study measured longitudinal changes in T 2 and its distribution in the lower leg of 16 boys with DMD (5–13years, 15 ambulatory) and 15 healthy controls (5–13years). These muscles were chosen to allow extended longitudinal monitoring, due to their slow progression compared with proximal muscles in DMD. In the soleus muscle of boys with DMD, T 2 and the percentage of pixels with an elevated T 2 (⩾2SD above control mean T 2 ) increased significantly over 1year and 2years, while the width of the T 2 histogram increased over 2years. Changes in soleus T 2 variables were significantly greater in 9–13years old compared with 5–8years old boys with DMD. Significant correlations between the change in all soleus T 2 variables over 2years and the change in functional measures over 2years were found. MRI measurement of muscle T 2 in boys with DMD is sensitive to disease progression and shows promise as a clinical outcome measure.

The purpose of this study was to assess the contractile and non-contractile content in thigh muscles of patients with Duchenne muscular dystrophy (DMD) and determine the relationship with functional abilities. Magnetic resonance images of the thigh were acquired in 28 boys with DMD and 10 unaffected boys. Muscle strength, timed functional tests, and the Brookes Lower Extremity scale were also assessed. Non-contractile content in the DMD group was significantly greater than in the control group for six muscles, including rectus femoris, biceps femoris-long head and adductor magnus. Non-contractile content in the total thigh musculature assessed by MRI correlated with the Brookes scale (r(s)=0.75) and supine-up test (r(s)=0.68), as well as other functional measures. An age-related specific torque increase was observed in the control group (r(s)=0.96), but not the DMD (r(s)=0.06). These findings demonstrate that MRI measures of contractile and non-contractile content can provide important information about disease progression in DMD.

IntroductionDuchenne muscular dystrophy (DMD) is an X-linked recessive disorder that results in functional deficits. However, these functional declines are often not able to be quantified in clinical trials for DMD until after age 7. In this study, we hypothesized that (1)H2O T2 derived using (1)H-MRS and MRI-T2 will be sensitive to muscle involvement at a young age (5-7 years) consistent with increased inflammation and muscle damage in a large cohort of DMD subjects compared to controls.MethodsMR data were acquired from 123 boys with DMD (ages 5-14 years; mean 8.6 SD 2.2 years) and 31 healthy controls (age 9.7 SD 2.3 years) using 3-Tesla MRI instruments at three institutions (University of Florida, Oregon Health & Science University, and Children's Hospital of Philadelphia). T2-weighted multi-slice spin echo (SE) axial images and single voxel 1H-MRS were acquired from the lower leg and thigh to measure lipid fraction and (1)H2O T2.ResultsMRI-T2, (1)H2O T2, and lipid fraction were greater (pDiscussionOverall, MR measures of T2 and lipid fraction revealed differences between DMD and Controls. Furthermore, MRI-T2 was greater in the older age group compared to the young age group, which was associated with higher lipid fractions. Overall, MR measures of T2 and lipid fraction show excellent sensitivity to DMD disease pathologies and potential therapeutic interventions in DMD, even in the younger boys.

Boys with Duchenne muscular dystrophy (DMD) have an increased incidence of fracture and low bone mineral density (BMD). Previous studies of bone in DMD have utilized dual-emission X-ray absorptiometry (DXA); however, this technique yields monoplanar bone density. Magnetic resonance imaging (MRI) techniques on the other hand provide 3-dimensional structural information regarding bone structure and composition. Subjects for this cross-sectional analysis were drawn from the milticenter ImagingDMD study and included 14 boys with DMD (age 7–11 years, mean 9.3 ± 1.6 years) and 7 control subjects (age 7–11 years, mean 9.4 ± 1.5 years). MRI T1-weighted images taken at the mid-tibia were used to determine the following bone volumetric measures: overall bone cross-sectional area (CSA), cortical bone cross-sectional area (cCSA) and trabecular bone cross-sectional area (tCSA). Mid-tibia trabecular bone composition was assessed using the same T1-weighted cross-sectional image with and without fat suppression to determine average trabecular bone fat signal intensity. Boys with DMD had lower mean tibial CSA compared to controls (p = 0.001), lower mean cCSA (p = 0.0005) and lower mean tCSA (p = .03). The mean tibial trabecular fat content was not significantly different between the two groups (p = 0.38). This study demonstrates that boys with DMD have significant differences in measures of bone cross-sectional area, affecting both the cortical and trabecular bone, with the reduction in cortical bone being the most marked (∼30% reduced). There is a clear need to better characterize the abnormalities in bone of boys with DMD in order to improve both direct medical management of osteoporoesis in this population as well as inform the development of clinical trials to address this issue.