Background and Objectives To study the potential of quantitative MRI (qMRI) fat fraction (FF) as a biomarker in nonambulant patients with Duchenne muscular dystrophy (DMD), we assessed the additive... Show moreBackground and Objectives To study the potential of quantitative MRI (qMRI) fat fraction (FF) as a biomarker in nonambulant patients with Duchenne muscular dystrophy (DMD), we assessed the additive predictive value of elbow flexor FF to age at loss of hand-to-mouth movement. Methods Nonambulant patients with DMD (age >= 8 years) were included. Four-point Dixon MRI scans of the right upper arm were performed at baseline and at the 12-, 18-, or 24-month follow-up. Elbow flexor FFs were determined from 5 central slices. Loss of hand-to-mouth movement was determined at study visits and by phone calls every 4 months. FFs were fitted to a sigmoidal curve by use of a mixed model with random slope to predict individual trajectories. The added predictive value of elbow flexor FF to age at loss of hand-to-mouth movement was calculated from a Cox model with the predicted FF as a time-varying covariate, yielding a hazard ratio. Results Forty-eight MRIs of 20 patients with DMD were included. The hazard ratio of a percent-point increase in elbow flexor FF for the time to loss of hand-to-mouth movement was 1.12 (95% confidence interval 1.04-1.21; p = 0.002). This corresponded to a 3.13-fold increase in the instantaneous risk of loss of hand-to-mouth movement in patients with a 10-percent points higher elbow flexor FF at any age. Discussion In this prospective study, elbow flexor FF predicted loss of hand-to-mouth movement independently of age. qMRI-measured elbow flexor FF can be used as a surrogate endpoint or stratification tool for clinical trials in nonambulant patients with DMD. Classification of Evidence This study provides Class II evidence that qMRI FF of elbow flexor muscles in patients with DMD predicts loss of hand-to-mouth movement independently of age. Show less
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... Show moreObjective 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 (rho <= -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 rho <= -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. Show less
ObjectiveWe studied the potential of quantitative MRI (qMRI) as a surrogate endpoint in Duchennemuscular dystrophy by assessing the additive predictive value of vastus lateralis (VL) fat fraction... Show moreObjectiveWe studied the potential of quantitative MRI (qMRI) as a surrogate endpoint in Duchennemuscular dystrophy by assessing the additive predictive value of vastus lateralis (VL) fat fraction(FF) to age on loss of ambulation (LoA).MethodsVL FFs were determined on longitudinal Dixon MRI scans from 2 natural history studies inLeiden University Medical Center (LUMC) and Cincinnati Children’s Hospital MedicalCenter (CCHMC). CCHMC included ambulant patients, while LUMC included a mixedambulant and nonambulant population. We fitted longitudinal VL FF values to a sigmoidalcurve using a mixed model with random slope to predict individual trajectories. The additivevalue of VL FF over age to predict LoA was calculated from a Cox model, yielding a hazard ratio.ResultsEighty-nine MRIs of 19 LUMC and 15 CCHMC patients were included. At similar age,6-minute walking test distances were smaller and VL FFs were correspondingly higher inLUMC compared to CCHMC patients. Hazard ratio of a percent-point increase in VL FF forthe time to LoA was 1.15 for LUMC (95% confidence interval [CI] 1.05–1.26; p = 0.003) and0.96 for CCHMC (95% CI 0.84–1.10; p = 0.569).ConclusionsThe hazard ratio of 1.15 corresponds to a 4.11-fold increase of the instantaneous risk of LoA inpatients with a 10% higher VL FF at any age. Although results should be confirmed in a largercohort with prospective determination of the clinical endpoint, this added predictive value ofVL FF to age on LoA supports the use of qMRI FF as an endpoint or stratification tool inclinical trials. Show less
ObjectiveWe studied the potential of quantitative MRI (qMRI) as a surrogate endpoint in Duchennemuscular dystrophy by assessing the additive predictive value of vastus lateralis (VL) fat fraction... Show moreObjectiveWe studied the potential of quantitative MRI (qMRI) as a surrogate endpoint in Duchennemuscular dystrophy by assessing the additive predictive value of vastus lateralis (VL) fat fraction(FF) to age on loss of ambulation (LoA).MethodsVL FFs were determined on longitudinal Dixon MRI scans from 2 natural history studies inLeiden University Medical Center (LUMC) and Cincinnati Children’s Hospital MedicalCenter (CCHMC). CCHMC included ambulant patients, while LUMC included a mixedambulant and nonambulant population. We fitted longitudinal VL FF values to a sigmoidalcurve using a mixed model with random slope to predict individual trajectories. The additivevalue of VL FF over age to predict LoA was calculated from a Cox model, yielding a hazard ratio.ResultsEighty-nine MRIs of 19 LUMC and 15 CCHMC patients were included. At similar age,6-minute walking test distances were smaller and VL FFs were correspondingly higher inLUMC compared to CCHMC patients. Hazard ratio of a percent-point increase in VL FF forthe time to LoA was 1.15 for LUMC (95% confidence interval [CI] 1.05–1.26; p = 0.003) and0.96 for CCHMC (95% CI 0.84–1.10; p = 0.569).ConclusionsThe hazard ratio of 1.15 corresponds to a 4.11-fold increase of the instantaneous risk of LoA inpatients with a 10% higher VL FF at any age. Although results should be confirmed in a largercohort with prospective determination of the clinical endpoint, this added predictive value ofVL FF to age on LoA supports the use of qMRI FF as an endpoint or stratification tool inclinical trials. Show less
