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Measurements of Motor Function and Other Clinical Outcome Parameters in Ambulant Children with Duchenne Muscular Dystrophy
Published on: January 12, 2019
Selection Approach to Identify the Optimal Biomarker Using Quantitative Muscle MRI and Functional Assessments in
Nienke M van de Velde1, Melissa T Hooijmans1, Aashley S D Sardjoe Mishre1
1From the Department of Neurology (N.M.v.d.V., K.R.K., Z.K., J.J.G.M.V., E.H.N.), C.J. Gorter Center for High-Field MRI, Department of Radiology (M.T.H., A.S.D.S.M., K.R.K., T.T.J.V., J.-W.M.B., H.E.K.), Department of Orthopaedics, Rehabilitation and Physical Therapy (I.A.), Department of Biomedical Data Sciences (E.W.v.Z.), and Department of Ophthalmology (J.-W.M.B.), Leiden University Medical Center, the Netherlands; and Duchenne Center Netherlands (N.M.v.d.V., J.J.G.M.V., H.E.K., E.H.N.), the Netherlands.
Objective:
To identify the best quantitative fat-water MRI biomarker for disease progression of leg muscles in Becker muscular dystrophy (BMD) by applying a stepwise approach based on standardized response mean (SRM) over 24 months, correlations with baseline ambulatory tests, and reproducibility.
Methods:
Dixon fat-water imaging was performed at baseline (n = 24) and 24 months (n = 20). Fat fractions (FF) were calculated for 3 center slices and the whole muscles for 19 muscles and 6 muscle groups. Contractile cross-sectional area (cCSA) was obtained from the center slice. Functional assessments included knee extension and flexion force and 3 ambulatory tests (North Star Ambulatory Assessment [NSAA], 10-meter run, 6-minute walking test). MRI measures were selected using SRM (≥0.8) and correlation with all ambulatory tests (ρ ≤ -0.8). Measures were evaluated based on intraclass correlation coefficient (ICC) and SD of the difference. Sample sizes were calculated assuming 50% reduction in disease progression over 24 months in a clinical trial with 1:1 randomization.
Results:
Median whole muscle FF increased between 0.2% and 2.6% without consistent cCSA changes. High SRMs and strong functional correlations were found for 8 FF but no cCSA measures. All measures showed excellent ICC (≥0.999) and similar SD of the interrater difference. Whole thigh 3 center slices FF was the best biomarker (SRM 1.04, correlations ρ ≤ -0.81, ICC 1.00, SD 0.23%, sample size 59) based on low SD and acquisition and analysis time.
Conclusion:
In BMD, median FF of all muscles increased over 24 months. Whole thigh 3 center slices FF reduced the sample size by approximately 40% compared to NSAA.
