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Quantitative muscle ultrasound detects disease progression in Duchenne muscular dystrophy.

ABSTRACT: We assessed changes in quantitative muscle ultrasound data in boys with Duchenne muscular dystrophy (DMD) and healthy controls to determine whether ultrasound can serve as a biomarker of disease progression. Two approaches were used: gray scale level (GSL), measured from the ultrasound image, and quantitative backscatter analysis (QBA), measured directly from the received echoes.GSL and QBA were obtained from 6 unilateral arm/leg muscles in 36 boys with DMD and 28 healthy boys (age?=?2-14 years) for up to 2 years. We used a linear mixed effects model with random intercept and slope terms to compare trajectories of GSL, QBA, and functional assessments. We analyzed separately a subset of boys who initiated corticosteroids.Compared to healthy boys, increasing GSL in DMD boys >7.0 years old was first identified at 6 months (eg, anterior forearm slope difference of 1.16 arbitrary units/mo, p?=?0.004, 95% confidence interval [CI]?=?0.38-1.94); in boys???7 years old, differences in GSL first appeared at 12 months (0.82 arbitrary units/mo, p?=?0.04, 95% CI?=?0.075-1.565, in rectus femoris). QBA performed similarly to GSL (eg, DMD boys?>?7 years old: 0.41dB/mo, p?=?0.01, 95% CI?=?0.096-0.72, in anterior forearm at 6 months). Ultrasound identified differences earlier than functional measures including 6-minute walk and supine-to-stand tests. However, neither QBA nor GSL showed an effect of corticosteroid initiation.QBA performs similarly to GSL, and both appear more sensitive than functional assessments for detecting muscle deterioration in DMD. Additional studies will be required to determine whether quantitative muscle ultrasound can detect therapeutic efficacy. Ann Neurol 2017;81:633-640.

SUBMITTER: Zaidman CM

PROVIDER: S-EPMC5444989 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Quantitative muscle ultrasound detects disease progression in Duchenne muscular dystrophy.

Zaidman Craig M CM Wu Jim S JS Kapur Kush K Pasternak Amy A Madabusi Lavanya L Yim Sung S Pacheck Adam A Szelag Heather H Harrington Tim T Darras Basil T BT Rutkove Seward B SB

Annals of neurology 20170504 5

<h4>Objective</h4>We assessed changes in quantitative muscle ultrasound data in boys with Duchenne muscular dystrophy (DMD) and healthy controls to determine whether ultrasound can serve as a biomarker of disease progression. Two approaches were used: gray scale level (GSL), measured from the ultrasound image, and quantitative backscatter analysis (QBA), measured directly from the received echoes.<h4>Methods</h4>GSL and QBA were obtained from 6 unilateral arm/leg muscles in 36 boys with DMD and ...[more]

PMID: 28241384

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Project description:Duchenne muscular dystrophy (DMD) causes progressive disability in 1 of every 5,000 boys due to the lack of functional dystrophin protein. Despite much advancement in knowledge about DMD disease presentation and progression-attributable in part to studies using mouse and canine models of the disease-current DMD treatments are not equally effective in all patients. There remains, therefore, a need for translational animal models in which novel treatment targets can be identified and evaluated. Golden Retriever muscular dystrophy (GRMD) is a phenotypically and genetically homologous animal model of DMD. As with DMD, speed of disease progression in GRMD varies substantially. However, unlike DMD, all GRMD dogs possess the same causal mutation; therefore genetic modifiers of phenotypic variation are relatively easier to identify. Furthermore, the GRMD dogs used in this study reside within the same colony, reducing the confounding effects of environment on phenotypic variation. To detect modifiers of disease progression, we developed gene expression profiles using RNA sequencing for 9 dogs: 6 GRMD dogs (3 with faster-progressing and 3 with slower-progressing disease, based on quantitative, objective biomarkers) and 3 control dogs from the same colony. All dogs were evaluated at 2 time points: early disease onset (3 months of age) and the point at which GRMD stabilizes (6 months of age) using quantitative, objective biomarkers identified as robust against the effects of relatedness/inbreeding. Across all comparisons, the most differentially expressed genes fell into 3 categories: myogenesis/muscle regeneration, metabolism, and inflammation. Our findings are largely in concordance with DMD and mouse model studies, reinforcing the utility of GRMD as a translational model. Novel findings include the strong up-regulation of chitinase 3-like 1 (CHI3L1) in faster-progressing GRMD dogs, suggesting previously unexplored mechanisms underlie progression speed in GRMD and DMD. In summary, our findings support the utility of RNA sequencing for evaluating potential biomarkers of GRMD progression speed, and are valuable for identifying new avenues of exploration in DMD research.

Dataset Information

Quantitative muscle ultrasound detects disease progression in Duchenne muscular dystrophy.

Publications

Quantitative muscle ultrasound detects disease progression in Duchenne muscular dystrophy.

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