The muscular dystrophies are rare orphan diseases, characterized by progressive muscle weakness: the most common and well known is Duchenne muscular dystrophy which affects young boys and progresses ...quickly during childhood. However, over 70 distinct variants have been identified to date, with different rates of progression, implications for morbidity, mortality, and quality of life. There are presently no curative therapies for these diseases, but a range of potential therapies are presently reaching the stage of multi-centre, multi-national first-in-man clinical trials. There is a need for sensitive, objective end-points to assess the efficacy of the proposed therapies. Present clinical measurements are often too dependent on patient effort or motivation, and lack sensitivity to small changes, or are invasive. Quantitative MRI to measure the fat replacement of skeletal muscle by either chemical shift imaging methods (Dixon or IDEAL) or spectroscopy has been demonstrated to provide such a sensitive, objective end-point in a number of studies. This review considers the importance of the outcome measures, discusses the considerations required to make robust measurements and appropriate quality assurance measures, and draws together the existing literature for cross-sectional and longitudinal cohort studies using these methods in muscular dystrophy.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The muscular dystrophies are made up of a diverse group of rare genetic diseases characterized by progressive loss of muscle strength and muscle damage. Since there is no cure for muscular dystrophy ...and clinical outcome measures are limited, it is critical to assess the progression of MD objectively. Imaging muscle replacement by fibrofatty tissue has been shown to be a robust biomarker to monitor disease progression in DMD. In magnetic resonance imaging (MRI) data, specific texture patterns are found to correlate to certain MD subtypes and thus present a potential way for automatic assessment. In this paper, we first apply state-of-the-art convolutional neural networks (CNNs) to perform accurate MD image classification and then propose an effective visualization method to highlight the important image textures. With a dystrophic MRI dataset, we found that the best CNN model delivers an 91.7% classification accuracy, which significantly outperforms non-deep learning methods, e.g., > 40% improvement has been found over the traditional mean fat fraction (MFF) criterion for DMD and CMD classification. After investigating every single neuron at the top layer of CNN model, we found the superior classification ability of CNN can be explained by its 91 and 118 neurons were performing better than the MFF criterion under the measurements of Euclidean and Chi-square distance, respectively. In order to further interpret CNNs predictions, we tested an improved class activation mapping (ICAM) method to visualize the important regions in the MRI images. With this ICAM, CNNs are able to locate the most discriminative texture patterns of DMD in soleus, lateral gastrocnemius, and medial gastrocnemius; for CMD, the critical texture patterns are highlighted in soleus, tibialis posterior, and peroneus.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPUK, ZAGLJ, ZRSKP
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.
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.
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.
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.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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 (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.
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 (1)H2O T2.
MRI-T2, (1)H2O 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, (1)H2O T2 and lipid fraction and vastus lateralis MRI-T2 and (1)H2O 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.
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.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Genetic modifiers alter disease progression in both preclinical models and subjects with Duchenne muscular dystrophy (DMD). Using multiparametric magnetic resonance (MR) techniques, we compared the ...skeletal and cardiac muscles of two different dystrophic mouse models of DMD, which are on different genetic backgrounds, the C57BL/10ScSn-Dmdmdx (B10-mdx) and D2.B10-Dmdmdx (D2-mdx). The proton transverse relaxation constant (T2) using both MR imaging and spectroscopy revealed significant age-related differences in dystrophic skeletal and cardiac muscles as compared with their age-matched controls. D2-mdx muscles demonstrated an earlier and accelerated decrease in muscle T2 compared with age-matched B10-mdx muscles. Diffusion-weighted MR imaging indicated differences in the underlying muscle structure between the mouse strains. The fractional anisotropy, mean diffusion, and radial diffusion of water varied significantly between the two dystrophic strains. Muscle structural differences were confirmed by histological analyses of the gastrocnemius, revealing a decreased muscle fiber size and increased fibrosis in skeletal muscle fibers of D2-mdx mice compared with B10-mdx and control. Cardiac involvement was also detected in D2-mdx myocardium based on both decreased function and myocardial T2. These data indicate that MR parameters may be used as sensitive biomarkers to detect fibrotic tissue deposition and fiber atrophy in dystrophic strains.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPUK, ZAGLJ, ZRSKP
The primary objectives of this study were to evaluate contractile and non-contractile content of lower leg muscles of boys with Duchenne muscular dystrophy (DMD) and determine the relationships ...between non-contractile content and functional abilities.
Lower leg muscles of thirty-two boys with DMD and sixteen age matched unaffected controls were imaged. Non-contractile content, contractile cross sectional area and non-contractile cross sectional area of lower leg muscles (tibialis anterior, extensor digitorum longus, peroneal, medial gastrocnemius and soleus) were assessed by magnetic resonance imaging (MRI). Muscle strength, timed functional tests and the Brooke lower extremity score were also assessed.
Non-contractile content of lower leg muscles (peroneal, medial gastrocnemius, and soleus) was significantly greater than control group (p<0.05). Non-contractile content of lower leg muscles correlated with Brooke score (rs = 0.64-0.84) and 30 feet walk (rs = 0.66-0.80). Dorsiflexor (DF) and plantarflexor (PF) specific torque was significantly different between the groups.
Overall, non-contractile content of the lower leg muscles was greater in DMD than controls. Furthermore, there was an age dependent increase in contractile content in the medial gastrocnemius of boys with DMD. The findings of this study suggest that T1 weighted MR images can be used to monitor disease progression and provide a quantitative estimate of contractile and non-contractile content of tissue in children with DMD.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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.
(13)C NMR has many advantages for a metabolomics study, including a large spectral dispersion, narrow singlets at natural abundance, and a direct measure of the backbone structures of metabolites. ...However, it has not had widespread use because of its relatively low sensitivity compounded by low natural abundance. Here we demonstrate the utility of high-quality (13)C NMR spectra obtained using a custom (13)C-optimized probe on metabolomic mixtures. A workflow was developed to use statistical correlations between replicate 1D (13)C and (1)H spectra, leading to composite spin systems that can be used to search publicly available databases for compound identification. This was developed using synthetic mixtures and then applied to two biological samples, Drosophila melanogaster extracts and mouse serum. Using the synthetic mixtures we were able to obtain useful (13)C-(13)C statistical correlations from metabolites with as little as 60 nmol of material. The lower limit of (13)C NMR detection under our experimental conditions is approximately 40 nmol, slightly lower than the requirement for statistical analysis. The (13)C and (1)H data together led to 15 matches in the database compared to just 7 using (1)H alone, and the (13)C correlated peak lists had far fewer false positives than the (1)H generated lists. In addition, the (13)C 1D data provided improved metabolite identification and separation of biologically distinct groups using multivariate statistical analysis in the D. melanogaster extracts and mouse serum.
Full text
Available for:
IJS, KILJ, NUK, PNG, UL, UM
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.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
PDF
