Longitudinal changes in cardiac function in Duchenne muscular dystrophy population as measured by magnetic resonance imaging.

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.

Safety, feasibility, and efficacy of strengthening exercise in Duchenne muscular dystrophy.

BACKGROUND: 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-wk in-home, remotely supervised, mild-moderate intensity strengthening program in eight boys. Safety measures included T2 MRI, creatine kinase levels, and pain. Peak strength and function (time to ascend/descend four stairs) were also measured. RESULTS: Dose-escalation revealed no signs of muscle damage. Seven of the eight boys completed the 12-wk in-home program with a compliance of 84.9%, no signs of muscle damage, and improvements in strength (knee extensors P < .01; knee flexors P < .05) and function (descending steps P < .05). CONCLUSIONS: 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.

Walking activity in a large cohort of boys with Duchenne muscular dystrophy.

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 R2 = 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.

Upper and Lower Extremities in Duchenne Muscular Dystrophy Evaluated with Quantitative MRI and Proton MR Spectroscopy in a Multicenter Cohort.

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 (1H) 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 1H MR spectroscopy; and correlate upper extremity MRI and 1H MR spectroscopy measures to function. Materials and Methods In this prospective cross-sectional study, MRI and 1H 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 1H2O T2 in the deltoid and biceps brachii were measured from single-voxel 1H MR spectroscopy (9000/11-243). Groups were compared by using Mann-Whitney test, and relationships between MRI and 1H 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 1H 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 1H 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 1H 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.

Electrical impedance myography in individuals with collagen 6 and laminin α-2 congenital muscular dystrophy: a cross-sectional and 2-year analysis.

INTRODUCTION: Electrical impedance myography (EIM) is a noninvasive electrophysiological technique that characterizes muscle properties through bioimpedance. We compared EIM measurements to function, strength, and disease severity in a population with congenital muscular dystrophy (CMD). METHODS: Forty-one patients with CMD, either collagen 6 related disorders (COL6-RD; n = 21) or laminin α-2-related disorders (LAMA2-RD; n = 20), and 21 healthy pediatric controls underwent 2 yearly EIM exams. In the CMD cohorts, EIM was compared with functional and strength measurements. RESULTS: Both CMD cohorts exhibited change over time and had correlation with disease severity. The 50-kHZ phase correlated well with function and strength in the COL6-RD cohort but not in the LAMA2-RD cohort. DISCUSSION: EIM is a potentially useful measure in clinical studies with CMD because of its sensitivity to change over a 1-year period and correlation with disease severity. For COL6-RD, there were also functional and strength correlations. Muscle Nerve 57: 54-60, 2018.

Longitudinal timed function tests in Duchenne muscular dystrophy: ImagingDMD cohort natural history.

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.

Multicenter prospective longitudinal study of magnetic resonance biomarkers in a large duchenne muscular dystrophy cohort.

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 (1) H2 O 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.

Chemical shift-based MRI to measure fat fractions in dystrophic skeletal muscle.

PURPOSE: The relationship between fat fractions (FFs) determined based on multiple TE, unipolar gradient echo images and (1) H 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 ((1) H-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. (1) H-MRS-based FF were corrected for the increased muscle (1) H2 O 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 (1) H-MRS FFs (y = 0.93x + 0.003; R(2) = 0.96) across the full range of FFs. Relaxation-corrected (1) H-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.

Clinical importance of changes in magnetic resonance biomarkers for Duchenne muscular dystrophy.

OBJECTIVE: Magnetic resonance (MR) measures of muscle quality are highly sensitive to disease progression and predictive of meaningful functional milestones in Duchenne muscular dystrophy (DMD). This investigation aimed to establish the reproducibility, responsiveness to disease progression, and minimum clinically important difference (MCID) for multiple MR biomarkers at different disease stages in DMD using a large natural history dataset. METHODS: Longitudinal MR imaging and spectroscopy outcomes and ambulatory function were measured in 180 individuals with DMD at three sites, including repeated measurements on two separate days (within 1 week) in 111 participants. These data were used to calculate day-to-day reproducibility, responsiveness (standardized response mean, SRM), minimum detectable change, and MCID. A survey of experts was also performed. RESULTS: MR spectroscopy fat fraction (FF), as well as MR imaging transverse relaxation time (MRI-T2 ), measures performed in multiple leg muscles, and had high reproducibility (Pearson's R > 0.95). Responsiveness to disease progression varied by disease stage across muscles. The average FF from upper and lower leg muscles was highly responsive (SRM > 0.9) in both ambulatory and nonambulatory individuals. MCID estimated from the distribution of scores, by anchoring to function, and via expert opinion was between 0.01 and 0.05 for FF and between 0.8 and 3.7 ms for MRI-T2 . INTERPRETATION: MR measures of FF and MRI T2 are reliable and highly responsive to disease progression. The MCID for MR measures is less than or equal to the typical annualized change. These results confirm the suitability of these measures for use in DMD and potentially other muscular dystrophies.

Skeletal muscles of ambulant children with Duchenne muscular dystrophy: validation of multicenter study of evaluation with MR imaging and MR spectroscopy.

PURPOSE: 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. MATERIALS AND METHODS: 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. RESULTS: 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%]). CONCLUSION: 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.

T2 mapping provides multiple approaches for the characterization of muscle involvement in neuromuscular diseases: a cross-sectional study of lower leg muscles in 5-15-year-old boys with Duchenne muscular dystrophy.

Skeletal muscles of children with Duchenne muscular dystrophy (DMD) show enhanced susceptibility to damage and progressive lipid infiltration, which contribute to an increase in the MR proton transverse relaxation time (T2). Therefore, the examination of T2 changes in individual muscles may be useful for the monitoring of disease progression in DMD. In this study, we used the mean T2, percentage of elevated pixels and T2 heterogeneity to assess changes in the composition of dystrophic muscles. In addition, we used fat saturation to distinguish T2 changes caused by edema and inflammation from fat infiltration in muscles. Thirty subjects with DMD and 15 age-matched controls underwent T2 -weighted imaging of their lower leg using a 3-T MR system. T2 maps were developed and four lower leg muscles were manually traced (soleus, medial gastrocnemius, peroneal and tibialis anterior). The mean T2 of the traced regions of interest, width of the T2 histograms and percentage of elevated pixels were calculated. We found that, even in young children with DMD, lower leg muscles showed elevated mean T2, were more heterogeneous and had a greater percentage of elevated pixels than in controls. T2 measures decreased with fat saturation, but were still higher (P < 0.05) in dystrophic muscles than in controls. Further, T2 measures showed positive correlations with timed functional tests (r = 0.23-0.79). The elevated T2 measures with and without fat saturation at all ages of DMD examined (5-15 years) compared with unaffected controls indicate that the dystrophic muscles have increased regions of damage, edema and fat infiltration. This study shows that T2 mapping provides multiple approaches that can be used effectively to characterize muscle tissue in children with DMD, even in the early stages of the disease. Therefore, T2 mapping may prove to be clinically useful in the monitoring of muscle changes caused by the disease process or by therapeutic interventions in DMD.

Antisense oligonucleotide targeting DMPK in patients with myotonic dystrophy type 1: a multicentre, randomised, dose-escalation, placebo-controlled, phase 1/2a trial.

BACKGROUND: Myotonic dystrophy type 1 results from an RNA gain-of-function mutation, in which DM1 protein kinase (DMPK) transcripts carrying expanded trinucleotide repeats exert deleterious effects. Antisense oligonucleotides (ASOs) provide a promising approach to treatment of myotonic dystrophy type 1 because they reduce toxic RNA levels. We aimed to investigate the safety of baliforsen (ISIS 598769), an ASO targeting DMPK mRNA. METHODS: In this dose-escalation phase 1/2a trial, adults aged 20-55 years with myotonic dystrophy type 1 were enrolled at seven tertiary referral centres in the USA and randomly assigned via an interactive web or phone response system to subcutaneous injections of baliforsen 100 mg, 200 mg, or 300 mg, or placebo (6:2 randomisation at each dose level), or to baliforsen 400 mg or 600 mg, or placebo (10:2 randomisation at each dose level), on days 1, 3, 5, 8, 15, 22, 29, and 36. Sponsor personnel directly involved with the trial, participants, and all study personnel were masked to treatment assignments. The primary outcome measure was safety in all participants who received at least one dose of study drug up to day 134. This trial is registered with ClinicalTrials.gov (NCT02312011), and is complete. FINDINGS: Between Dec 12, 2014, and Feb 22, 2016, 49 participants were enrolled and randomly assigned to baliforsen 100 mg (n=7, one patient not dosed), 200 mg (n=6), 300 mg (n=6), 400 mg (n=10), 600 mg (n=10), or placebo (n=10). The safety population comprised 48 participants who received at least one dose of study drug. Treatment-emergent adverse events were reported for 36 (95%) of 38 participants assigned to baliforsen and nine (90%) of ten participants assigned to placebo. Aside from injection-site reactions, common treatment-emergent adverse events were headache (baliforsen: ten [26%] of 38 participants; placebo: four [40%] of ten participants), contusion (baliforsen: seven [18%] of 38; placebo: one [10%] of ten), and nausea (baliforsen: six [16%] of 38; placebo: two [20%] of ten). Most adverse events (baliforsen: 425 [86%] of 494; placebo: 62 [85%] of 73) were mild in severity. One participant (baliforsen 600 mg) developed transient thrombocytopenia considered potentially treatment related. Baliforsen concentrations in skeletal muscle increased with dose. INTERPRETATION: Baliforsen was generally well tolerated. However, skeletal muscle drug concentrations were below levels predicted to achieve substantial target reduction. These results support the further investigation of ASOs as a therapeutic approach for myotonic dystrophy type 1, but suggest improved drug delivery to muscle is needed. FUNDING: Ionis Pharmaceuticals, Biogen.

Participation and quality of life in children with Duchenne muscular dystrophy using the International Classification of Functioning, Disability, and Health.

BACKGROUND: Duchenne muscular dystrophy (DMD) is characterized by muscle damage and progressive loss of muscle function in male children. DMD is one of the most devastating genetically linked neuromuscular diseases for which there is currently no cure. Most clinical studies for DMD utilize a standard protocol for measurement exploring pathophysiology, muscle strength and timed tasks. However, we propose that examining broader components of health as emphasized by the International Classification of Functioning, Disability and Health-Children and Youth Version (ICF-CY) may be of great value to children and their families, and important outcomes for future clinical trials. METHODS: Fifty boys with DMD and 25 unaffected age-matched boys completed two self-report measures: the Children's Assessment of Participation and Enjoyment and the Pediatric Quality of Life InventoryTM 4.0. We investigated differences between the two groups with regard to participation in life activities and perceived quality of life (QoL). Additionally, we compared participation in activities and QoL in both cohorts of younger and older boys. RESULTS: Participation in physical activities was significantly lower in boys with DMD than unaffected boys. Perceived QoL was markedly diminished in children with DMD relative to unaffected controls, except in the emotional domain. The amount of time boys engage in an activity, as well as participation in social activities, declined for our older boys with DMD but no changes were observed for our older unaffected boys. For both groups, QoL remained constant over time. CONCLUSIONS: The ICF-CY provides a conceptual framework and specific terminology that facilitates investigation of the consequences of impairment in children and youth. Our study is one of the first to explore participation in a cohort of boys with DMD. It was not surprising that activities of choice for boys with DMD were less physical in nature than unaffected boys their age, but the consequences of less social engagement as the boys with DMD age is of great concern. Results from our study underscore the need to further evaluate activities that children elect to participate in, with special emphasis on facilitators and barriers to participation and how participation changes throughout the course of a disease.

Characterizing Expiratory Respiratory Muscle Degeneration in Duchenne Muscular Dystrophy Using MRI.

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 H2O 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.

Step Activity Monitoring in Boys with Duchenne Muscular Dystrophy and its Correlation with Magnetic Resonance Measures and Functional Performance.

BACKGROUND: Muscles of boys with Duchenne muscular dystrophy (DMD) are progressively replaced by fatty fibrous tissues, and weakness leads to loss of ambulation (LoA). Step activity (SA) monitoring is a quantitative measure of real-world ambulatory function. The relationship between quality of muscle health and SA is unknown in DMD. OBJECTIVE: To determine SA in steroid treated boys with DMD across various age groups, and to evaluate the association of SA with quality of muscle health and ambulatory function. METHODS: Quality of muscle health was measured by magnetic resonance (MR) imaging transverse magnetization relaxation time constant (MRI-T2) and MR spectroscopy fat fraction (MRS-FF). SA was assessed via accelerometry, and functional abilities were assessed through clinical walking tests. Correlations between SA, MR, and functional measures were determined. A threshold value of SA was determined to predict the future LoA. RESULTS: The greatest reduction in SA was observed in the 9- < 11years age group. SA correlated with all functional and MR measures.10m walk/run test had the highest correlation with SA. An increase in muscle MRI-T2 and MRS-FF was associated with a decline in SA. Two years prior to LoA, SA in boys with DMD was 32% lower than age matched boys with DMD who maintained ambulation for more than two-year period. SA monitoring can predict subsequent LoA in Duchenne, as a daily step count of 3200 at baseline was associated with LoA over the next two-years. CONCLUSION: SA monitoring is a feasible and accessible tool to measure functional capacity in the real-world environment.

Development of Contractures in DMD in Relation to MRI-Determined Muscle Quality and Ambulatory Function.

BACKGROUND: Joint contractures are common in boys and men with Duchenne muscular dystrophy (DMD), and management of contractures is an important part of care. The optimal methods to prevent and treat contractures are controversial, and the natural history of contracture development is understudied in glucocorticoid treated individuals at joints beyond the ankle. OBJECTIVE: To describe the development of contractures over time in a large cohort of individuals with DMD in relation to ambulatory ability, functional performance, and muscle quality measured using magnetic resonance imaging (MRI) and spectroscopy (MRS). METHODS: In this longitudinal study, range of motion (ROM) was measured annually at the hip, knee, and ankle, and at the elbow, forearm, and wrist at a subset of visits. Ambulatory function (10 meter walk/run and 6 minute walk test) and MR-determined muscle quality (transverse relaxation time (T2) and fat fraction) were measured at each visit. RESULTS: In 178 boys with DMD, contracture prevalence and severity increased with age. Among ambulatory participants, more severe contractures (defined as greater loss of ROM) were significantly associated with worse ambulatory function, and across all participants, more severe contractures significantly associated with higher MRI T2 or MRS FF (ρ: 0.40-0.61 in the lower extremity; 0.20-0.47 in the upper extremity). Agonist/antagonist differences in MRI T2 were not strong predictors of ROM. CONCLUSIONS: Contracture severity increases with disease progression (increasing age and muscle involvement and decreasing functional ability), but is only moderately predicted by muscle fatty infiltration and MRI T2, suggesting that other changes in the muscle, tendon, or joint contribute meaningfully to contracture formation in DMD.

Evaluating Genetic Modifiers of Duchenne Muscular Dystrophy Disease Progression Using Modeling and MRI.

BACKGROUND AND OBJECTIVES: Duchenne muscular dystrophy (DMD) is a progressive muscle degenerative disorder with a well-characterized disease phenotype but considerable interindividual heterogeneity that is not well understood. The aim of this study was to evaluate the effects of dystrophin variations and genetic modifiers of DMD on rate and age of muscle replacement by fat. METHODS: One hundred seventy-five corticosteroid treated participants from the ImagingDMD natural history study underwent repeated magnetic resonance spectroscopy (MRS) of the vastus lateralis (VL) and soleus (SOL) to determine muscle fat fraction (FF). MRS was performed annually in most instances; however, some individuals had additional visits at 3 or 6 monthss intervals. FF changes over time were modeled using nonlinear mixed effects to estimate disease trajectories based on the age that the VL or SOL reached half-maximum change in FF (mu) and the time required for FF change (sigma). Computed mu and sigma values were evaluated for dystrophin variations that have demonstrated the ability to lead to a mild phenotype as well as compared between different genetic polymorphism groups. RESULTS: Participants with dystrophin gene deletions amenable to exon 8 skipping (n = 4) had minimal increases in SOL FF and had an increase in VL mu value by 4.4 years compared with a reference cohort (p = 0.039). Participants with nonsense variations within exons that may produce milder phenotypes (n = 11) also had minimal increases in SOL and VL FFs. No differences in estimated FF trajectories were seen for individuals amenable to exon 44 skipping (n = 10). Modeling of the SPP1, LTBP4, and thrombospondin-1 (THBS1) genetic modifiers did not result in significant differences in muscle FF trajectories between genotype groups (p > 0.05); however, trends were noted for the polymorphisms associated with long-range regulation of LTBP4 and THBS1 that deserve further follow-up. DISCUSSION: The results of this study link the historically mild phenotypes seen in individuals amenable to exon 8 skipping and with certain nonsense variations with alterations in trajectories of lower extremity muscle replacement by fat.

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<.05), but not with DF strength. 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.

Magnetic Resonance Imaging Studies in Duchenne Muscular Dystrophy: Linking Findings to the Physical Therapy Clinic.

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.