Rebecca J. Willcocks

Longitudinal measurements of MRI-T2 in boys with Duchenne muscular dystrophy: effects of age and disease progression.

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 (T2). The current study measured longitudinal changes in T2 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, T2 and the percentage of pixels with an elevated T2 (⩾2SD above control mean T2) increased significantly over 1year and 2years, while the width of the T2 histogram increased over 2years. Changes in soleus T2 variables were significantly greater in 9-13years old compared with 5-8years old boys with DMD. Significant correlations between the change in all soleus T2 variables over 2years and the change in functional measures over 2years were found. MRI measurement of muscle T2 in boys with DMD is sensitive to disease progression and shows promise as a clinical outcome measure.

Examination of effects of corticosteroids on skeletal muscles of boys with DMD using MRI and MRS

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.

Magnetic Resonance Imaging and Spectroscopy Assessment of Lower Extremity Skeletal Muscles in Boys with Duchenne Muscular Dystrophy: A Multicenter Cross Sectional Study

Introduction Duchenne 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 1H2O T2 derived using 1H-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. Methods MR 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 1H2O T2. Results MRI-T2, 1H2O T2, and lipid fraction were greater (p<0.05) in DMD compared to controls. In the youngest age group, DMD values were different (p<0.05) than controls for the soleus MRI-T2, 1H2O T2 and lipid fraction and vastus lateralis MRI-T2 and 1H2O T2. In the boys with DMD, MRI-T2 and lipid fraction were greater (p<0.05) in the oldest age group (11–14 years) than the youngest age group (5–6.9 years), while 1H2O T2 was lower in the oldest age group compared to the young age group. Discussion Overall, 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.

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

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.

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.

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

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.

MRI quantifies neuromuscular disease progression

Several studies provide compelling support for the use of MRI as a sensitive non-invasive method to assess skeletal muscle disease progression in various neuromuscular diseases, including Duchenne muscular dystrophy1,2 and limb girdle muscular dystrophy type 2I.3 In The Lancet Neurology, Jasper Morrow and colleagues4 now report the sensitivity of MRI to track disease progression in 20 patients with Charcot-Marie-Tooth disease 1A and 20 patients with inclusion body myositis. The investigators used a comprehensive study design that included magnetic resonance measures of muscle fat fraction, transverse relaxation time constant (T2), and magnetisation transfer ratio (MTR), along with relevant clinical functional tests (lower limb myometry, Medical Research Council score, Short-Form 36 Quality of Life Score, and Charcot-Marie-Tooth examination score or inclusion body myositis functional rating scale). In this study, the validity of the magnetic resonance measures was supported by strong correlations with clinical functional measures and the responsiveness to disease progression over 1 year was shown to be better with MRI than with the clinical functional tests. Notably, standardised response mean values were greater than 1 in inclusion body myositis and greater than 0·8 in Charcot-Marie-Tooth disease 1A, indicating that magnetic resonance measures are highly sensitive to disease progression and more responsive than established clinical measures. Even though Charcot-Marie-Tooth disease 1A progresses slowly, magnetic resonance measures detected substantial increases in disease pathological changes in 1 year. Thus, the encouraging results of Morrow and colleagues’ study might have a profound effect on clinical trials, potentially leading to a need for fewer participants to show efficacy or futility, shorter trials, and ultimately more rapid approval of treatments. An additional advantage of magnetic resonance measures compared with timed functional and strength measures, which are highly relevant to paediatric neuromuscular diseases, is that they are not dependent on participant motivation, an issue that has been of concern in Duchenne muscular dystrophy trials.5 Along with showing that MRI is a sensitive measure of disease progression in Charcot-Marie-Tooth disease 1A and inclusion body myositis, Morrow and colleagues also report that MRI-measured T2 and MTR are abnormal in these diseases even when fat fraction values are within normal limits. The authors interpret this to suggest that tissue water distribution changes before fat infiltration. Because MRI-measured T2 and MTR are affected by both fat and water content, the interpretation of these measures can be difficult in the context of neuromuscular diseases, and several analysis approaches are being developed to address this concern.6–8 Alternatively, magnetic resonance spectroscopy (MRS) could be used to more directly measure 1H2O T2 (figure) and MTR, and this would avoid the influence of fat.9 This method has already been applied to neuromuscular diseases10,11 1H2O T2 has been shown to differentiate boys with Duchenne muscular dystrophy and healthy individuals, even at a young age, when muscle fat fraction levels are normal.10 Furthermore, 1H2O T2 measured with MRS decreases with corticosteroid treatment in Duchenne muscular dystrophy, presumably because of reduced inflammation.11 Therefore, although lacking in spatial resolution, MRS is a high-fidelity approach to calculate 1H2O T2 and MTR measurements in neuromuscular diseases. Figure MRI and magnetic resonance spectroscopy of skeletal muscle in Duchenne muscular dystrophy In view of the low prevalence of neuromuscular diseases, standardisation of methods over several sites will be crucial to the successful implementation of magnetic resonance biomarkers in clinical trials. Although challenging, when standardised protocols are carefully implemented across sites, several important magnetic resonance measures can be reproducibly obtained, including MRI-measured T2 and MRS measures of fat fraction and 1H2O T2.12 Similar to neuroimaging and musculoskeletal studies, for larger trials, incorporation of an infrastructure that enables automated or semi-automated processing, analysis, and quality control procedures that can detect and correct for system deviations, including instrument modifications and upgrades, will be particularly important. Importantly, Morrow and colleagues showed the effectiveness of monitoring disease progression using magnetic resonance sequences commonly available on clinical scanners. Although the measures used were highly effective in tracking progression, future studies might include some developments. For example, the accuracy of fat fraction from the Dixon fat-water imaging sequence might be further improved by correcting for T2*, accounting for noise bias, and using a multipeak Dixon model specific to skeletal muscle.13,14 As suggested by Morrow and colleagues, the optimum outcome measures will depend on the pathophysiology, stage of disease, muscles affected, and intervention to be tested. This could include different types of magnetic resonance measures and analysis procedures. For example, targeting of specific muscles might be optimum for certain stages of a particular disease. Also, use of large regions of interest that encompass the entire muscle might be needed to detect pathological changes and improve responsiveness in some diseases, by contrast with small portions of the muscle, as used by Morrow and colleagues to measure T2 and MTR. Overall, this study by Morrow and colleagues clearly shows the value of MRI to monitor disease progression and sets the stage for its potential use in clinical trials for Charcot-Marie-Tooth disease 1A and inclusion body myositis. With increased evidence of the validity and sensitivity of magnetic resonance biomarkers in neuromuscular diseases, the path for biomarker qualification (eg, their approval by the Food and Drug Administration) should be carefully explored, with the ultimate goal of using magnetic resonance measures as surrogate endpoints in clinical trials.

Longitudinal timed function tests in Duchenne muscular dystrophy: Imagingdmd cohort natural history: Functional Outcomes in DMD

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

Skeletal muscle magnetic resonance biomarkers correlate with function and sentinel events in Duchenne muscular dystrophy

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.

Leg muscle MRI in identical twin boys with duchenne muscular dystrophy: MRI in Twins with DMD

Significant variability in disease progression has been documented in patients with Duchenne muscular dystrophy (DMD). This variability has been attributed to differences in the disease causing mutation or in genetic modifiers. and to differences in treatment, including corticosteroid regime. Whereas female twins with dystrophin mutations have been shown to differ phenotypically due to differences in X-inactivation, male twins with DMD have been reported to have identical ages at diagnosis, loss of ambulation, and death. The purpose of this study is to present a set of identical male twins with DMD whose lower limb muscles have been extensively characterized by MRI and MR spectroscopy (MRS) over a period of 12 months.