Becker muscular dystrophy (BMD) is a progressive disorder and impairs upper extremity (UE) function. The Performance of Upper Limb (PUL) measures UE function in muscular dystrophy, but has a ceiling effect in high-functioning subjects. Yet, fat fraction (FF) values via quantitative magnetic resonance (qMRI) have been used as biomarkers of muscle deterioration. Thus, the study aims to 1) determine if the PUL or qMRI FF can discriminate between functional groups of men with BMD and controls, and 2) assess relationships between PUL scores and qMRI FF. In a cross-sectional study, 56 men with BMD and 9 controls (18-63 yrs) completed PUL 2.0 and whole-body qMRI. Composite FF values for UE (deltoid, biceps & triceps) and whole-body were calculated. To understand the impact of mobility on UE performance, men with BMD were grouped using the 10-m run/walk test. Functional groups were: A) non-ambulatory B) walks – with no increase in speed possible; C) fast walking or jog; or D) run. One-way ANOVA/Kruskal-Wallis and Spearman's rho were used to assess differences between groups and correlations, respectively. Men with BMD scored 18-42 on the PUL. The PUL only detects differences between non-ambulatory (Group A) and high-functioning (Group C: p<0.001; Group D: p=0.02; Controls: p<0.001) groups. However, qMRI UE FF composite can discriminate between low-functioning (Groups A-B) and high-functioning (Groups C-D) men with BMD and whole-body FF composite can discriminate between all BMD functional groups (p<0.001 to 0.02). Higher PUL scores were associated with lower qMRI FF (p<0.05; rho =-0.70 to -0.50) only in low-functioning men with BMD (Groups A&B). Thus, the PUL has utility in assessing UE function in low-functioning men with BMD. Because the PUL may provide limited information about UE impairment in high-functioning men with BMD, it should be used cautiously or together with other biomarkers such as qMRI FF.

North Star Ambulatory Assessment (NSAA) is increasingly being utilized to assess efficacy of interventions in muscular dystrophies. Furthermore, proton magnetic resonance spectroscopy (1H-MRS) measures of fat fraction have been shown to be sensitive to disease progression and treatments in Duchenne muscular dystrophy (DMD). However, the relationship between NSAA and MR measures of fat fraction are less established. Therefore, in this study we evaluated NSAA and fat fraction measures of lower extremity muscles in a longitudinal study of DMD. A total of 90 subjects (age 5-17 at baseline) with DMD from the ImagingNMD project were included in this study with time points acquired yearly for up to 3 years. Single voxel 1H-MRS data were acquired at 3T using stimulated echo acquisition mode (STEAM) with relaxation corrections to measure fat fraction from the soleus and vastus lateralis. Relationships among measures were evaluated using non-parametric correlation and probability analyses. There was a strong relationship between NSAA total score and fat fraction of the soleus (ρ = -.78, p<0.01) and vastus lateralis (ρ = -.85, p<0.01). Three-year longitudinal changes in fat fraction correlated with NSAA total score changes (ρ = -.37, p=0.01). Further, the loss of ability to perform the more difficult tasks in the NSAA occurred at a lower fat fraction (e.g., running, 50% probability to perform task, vastus lateralis fat fraction 0.35) than less challenging tasks (e.g., standing, vastus lateralis fat fraction 0.60). Overall, NSAA was strongly correlated with muscle fat fraction evaluated with 1H-MRS, and our findings are consistent with the notion that muscle fat fraction can be used to predict functional abilities included in NSAA.

Becker muscular dystrophy (BMD) results in fat replacement of skeletal muscle and impaired functional performance. Quantitative magnetic resonance (qMR) imaging of muscle fat fraction (FF) has been used as a biomarker of muscle deterioration in muscular dystrophies. Specifically, qMR whole-body imaging (WBI) can quickly analyze multiple muscles and develop FF composites. The North Star Assessment for limb-girdle type muscular dystrophies (NSAD), has the potential to assess motor function in men with BMD across a wide range of abilities. Thus, we aimed to 1) assess the relationship between qMR FF and NSAD scores, and 2) determine qMR FF cut-off values for loss of performance on NSAD tasks that require gluteal and thigh muscle contractions. 41 men with BMD (18-62 years) completed 3-point Dixon qMR WBI and the NSAD. GlutThigh was calculated as the average FF of the right gluteus maximus, gluteus medius/minimus, quadriceps femoris, and hamstrings. The relationship between GlutThigh and function was assessed using Spearman's rho. GlutThigh cut-off values to discriminate men able or unable to perform each NSAD task were calculated using the receiver operating characteristic (ROC) and the Youden Index. Men with BMD had GlutThigh values from 0.08-0.89 (median: 0.58). Higher GlutThigh was strongly associated with lower NSAD scores (rho=-0.93; p<0.001). GlutThigh cut-off values ranged from 0.27 for rise from squat and running to 0.82 for standing and showed 83-100% sensitivity and 67-100% specificity. In men with BMD, higher GlutThigh values are strongly associated with poorer NSAD performance and more challenging NSAD tasks have lower GlutThigh cut-offs. GlutThigh cut-off values have high sensitivity and specificity to detect NSAD task failures across a wide range of men with BMD. Thus, qMR WBI GlutThigh provides important insight into functional performance in men with BMD and may serve as a functionally relevant biomarker of disease status in future clinical trials.

Magnetic resonance (MR) biomarkers that quantify increases in intramuscular fat are highly sensitive to disease progression and predictive of meaningful functional milestones in DMD. However, the minimum clinically important difference (MCID), defined as "the smallest change that is important to patients" has not been established. The purpose of this investigation was to estimate the MCID for both muscle fat fraction measured using MR spectroscopy and bulk muscle T2 measured using MRI. As part of the multicenter ImagingDMD study, localized 1H-MR spectra (TE=108 ms; TR=3000 ms) and multi-echo T2 weighted images were collected longitudinally in 180 males with DMD, with 0-8 annual follow up visits. Spectra from the vastus lateralis and soleus muscles were integrated and relaxation-corrected then used to estimate fat fraction (fat:(fat+water)). Spin-echo images were used to calculate T2 maps, which were manually segmented to obtain T2 measurements for 7 leg muscles. Ambulatory function groups were defined as: able to rise from the floor - Group I; able to walk - Group II; nonambulatory - Group III. MCID was estimated using 1) the standard error of measurement method, incorporating the group variance and day-to-day reproducibility of the measurement from 111 study participants, 2) the 1/3 standard deviation method, and 3) a survey of experts. Combining results from the three estimation methods, ranges for MCID for fat fraction were 0.02-0.05 in the vastus lateralis and 0.01-0.05 in the soleus. For MRI T2, MCID ranged between 1.9 and 3.0 ms for the vastus lateralis and 0.9 and 2.4 ms for the soleus. The average annual change in fat fraction or T2 exceeds the MCID in Groups I, II, and III for vastus lateralis fat fraction, Groups I and II for vastus lateralis T2, Groups II and III for soleus fat fraction, and Group II for soleus T2. Expected change, expected variability, and estimated MCID in the target population should all be considered when selecting a primary MR measure to use in clinical trials.

Duchenne muscular dystrophy (DMD) causes progressive weakness and disability, including the loss of arm function. Magnetic resonance imaging (MRI) and spectroscopy (MRS) provide insight into the progression of this disease in the legs and show promise as quantitative biomarkers, but these methods have not been used to examine the upper arm or shoulder in DMD. There is a critical need for robust noninvasive biomarkers for nonambulatory as well as ambulatory boys with DMD to facilitate the inclusion of a wider range of patients in clinical trials. In this preliminary study, we performed MRI and MRS examinations as well as strength and functional testing of the arms of 12 boys with DMD (11 ± 3 years, 10 ambulatory) and 5 unaffected controls (12 ± 3 years). Quantitative measures of muscle quality (fat fraction, MRI transverse relaxation time (T2) and water T2 measured using MRS) were significantly altered in DMD, even in boys as young as 7 years. Biceps brachii water T2 was higher in DMD than control subjects (29.5 ± 2.8 ms vs 25.8 ± 0.9 ms). MRI T2 was elevated in the deltoid (DMD: 44.4 ± 8.7 ms control: 30.9 ± 1.1 ms), biceps brachii (BB, DMD: 48.4 ± 12.1 ms, control: 30.2 ± 2.4 ms), and triceps brachii (DMD: 46.3 ± 8.4 ms, control: 31.4 ± 0.9 ms). Finally, BB fat fraction (FF) was 0.29 ± 0.11 in DMD and 0.14 ± 0.03 in controls. BB FF was also significantly correlated with total Performance of Upper Limb test score (r = 0.89), which measures proximal and distal arm function, in boys with DMD. These preliminary data suggest that MR measures of muscle quality in the arms have potential to be used as biomarkers in both ambulatory and nonambulatory boys with DMD.

Genetic modifiers contribute to variability in the rate of disease progression in Duchenne muscular dystrophy (DMD), a progressive muscle-wasting disease. Single nucleotide polymorphisms in the genes SPP1 (osteopontin) and LTBP4 (latent TGF-β binding protein 4) are associated with delayed loss of ambulation in DMD. The present study aimed to determine if SPP1 and LTBP4 polymorphisms impact the rate of intramuscular fat infiltration, a measure of disease severity in DMD. Eighty-four subjects with DMD (ages 5–14 years) were genotyped using fibroblasts. Intramuscular fat fraction (FF) was measured in the vastus lateralis (VL) and soleus at baseline and 12 months using 1H magnetic resonance spectroscopy. Age at 50% FF in the VL was estimated using a sigmoidal model of disease progression based on longitudinal FF data. Subjects with both the TT genotype of SPP1 and the IAAM/IAAM haplotype of LTBP4 demonstrated no significant change in soleus and VL FF across 1 year (p > 0.5). Subjects with either TT or IAAM/IAAM, but not both, had moderate increases in muscle FF (Δ 2.5% in the soleus; Δ 6.8% in the VL), while subjects who lacked both TT and IAAM/IAAM had the highest increase in FF in both the soleus (Δ 3.5%, p < 0.001) and VL (Δ 8.8%, p < 0.0001), indicating significant disease progression. Based on the disease progression model, subjects with both TT and IAAM/IAAM had an older age at 50% VL FF (16.0 years old) compared to boys with neither TT nor IAAM/IAAM (12.3 years old, p < 0.05). The TT genotype of SPP1 and the homozygous IAAM haplotype of LTBP4 slowed the rate of muscle fat infiltration, a marker of disease progression in DMD. The effect of having both protective genotypes appears to be additive. Genetic polymorphisms may be important covariates for consideration when designing clinical trials of therapeutics for DMD. Families and physicians can also use genotype information to assist in disease course planning.

A multi-center study is being implemented to evaluate the potential of magnetic resonance imaging (MRI) and spectroscopy (MRS) to monitor the progression of disease in children with Duchenne muscular dystrophy (DMD) and ultimately to serve as a surrogate outcome measure for clinical trials. Longitudinal MRI/MRS measures are being acquired over five years at three geographically distributed sites with a centralized data analysis center. In addition to MR, a battery of timed functional tests and muscle strength are assessed and immortalized fibroblasts deposited in tissue repositories. Initial efforts of this study have focused on establishing quality assurance procedures and minimizing variability in MR measures across sites, and from day-to-day. This has been accomplished using two-compartment coaxial phantoms and human subjects that visited each site. To date, 21 children have been enrolled in the study: 5 controls (9.2 ± 2.4 years, 29.2 ± 6.7 kg) and 16 ambulatory boys with DMD (9.3 ± 2.0 years, 32.4 ± 9.6 kg). MR scans include fat suppressed and unsuppressed transaxial 3D-gradient echo and spin echo images as well as localized 1H-spectroscopy. During the initial visit MR measures are being performed twice on separate days to test reproducibility. The MR data acquisition is performed on a Philips 3T Achieva, Siemens Verio, or Siemens TIM Trio system. Reproducibility of the MR measures have been evaluated for the soleus using MRI-T2 (Day 1: 43 ± 9 ms, Day 2: 44 ± 9 ms; CV 2.2 ± 1.9%), T2 of 1H2O from spectroscopic relaxometry (Day 1: 30.3 ± 2.6 ms, Day 2: 30.4 ± 2.9 ms; CV 2.1 ± 1.5%), and the ratio of lipid/(lipid + water) using 1H-spectroscopy (Day 1: 0.32 ± 0.23 ms, Day 2: 0.32 ± 0.22 ms; CV 4.8 ± 2.8%). In summary, the MR measures implemented in this multisite study are highly reproducible in children with DMD and controls. These noninvasive measures show promise for evaluating disease progression and treatment in DMD subjects, and are continuing to be evaluated in this multi-center study.

Objectives: To examine longitudinal changes in muscle size, damage, lipid content, and function in boys with Duchenne's muscular dystrophy (DMD) and to compare this with controls. Design: Cohort study, with 6- to 12-month follow-up. Setting: Research lab. Participants: Volunteer sample, boys with DMD (n=6; age range, 6−13y); age- and sex-matched controls (n=6). Interventions: Not applicable. Main Outcome Measures: Magnetic resonance imaging (MRI) and spectroscopy (MRS) (at 1.5T or 3.0T) were used to quantify muscle cross-sectional area (CSA), T2 relaxation time (muscle damage), and lipid content of the lower leg. Functional tests included timed 30-foot walk and isometric muscle strength. Results: Increases of 2% to 32% in lipid and 2% to 11% in T2 of the soleus were observed in boys with DMD. These values were higher than in controls (P<.05). Time to walk 30ft increased an average of 30% over time in boys with DMD and was longer than for controls (P<.01). CSA of the plantar- and dorsiflexors was 15% to 143% higher, whereas strength was 49% to 74% lower in boys with DMD compared with controls (P<.01). Conclusions: MRI and MRS provide unique, noninvasive quantification of progressive muscle pathology in boys with DMD and may be applicable in clinical trials examining new therapies for DMD.