Selection Approach to Identify the Optimal Biomarker Using Quantitative Muscle MRI and Functional Assessments in Becker Muscular Dystrophy

Abstract

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.

Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Figures

Figure 1. Heterogenous Fat Distribution in Vastus Lateralis (VL) and Semitendinosus (ST)

Example of regions of interest (B) and of heterogenous fat distribution from distal (A) to proximal (C) in the VL (A–D) and ST (A–C, E). (B) An example of heterogenous fat distribution in the axial plane of the quadriceps. To enhance visualization of the fat differences along the proximodistal axis of the muscles, patients are grouped according to their weighted fat of the whole muscle (light gray: 65% fat). The muscles are aligned based on the insertion of the biceps femoris short head (BFS) (marked as “center”) in D and E. Distal and proximal muscle parts are depicted in the left and right part of the figure, respectively. Blue lines: healthy controls; black/grey lines: Becker muscular dystrophy patients. Each line represents one individual participant. AL = adductor longus; AM = adductor magnus; BFL = biceps femoris long head; GR = gracilis; RF = rectus femoris; SM = semimembranosus; SR = sartorius; VI = vastus intermedius; VM = vastus medialis.

Figure 2. Flowchart of the Stepwise Process for Selection of MRI Measures

*Correlation with baseline North Star Ambulatory Assessment, 10-meter run test, and 6-minute walk test. 3C slices = 3 center slices; cCSA = contractile cross-sectional area; FF = fat fraction; SRM = standardized response mean; WM = whole muscle.

Figure 3. Mean Change in Fat in Thigh and Lower Leg Whole Muscles per Patient

Each patient is represented by a black and gray bar stitched together. Black and gray bars indicate mean change over thigh and lower leg muscles, respectively. Patients are subdivided in 4 groups based on their average weighted fat over all thigh and lower leg muscles (60% fat). *Mean change of zero.

Figure 4. Change in Fat and Contractile Cross-Sectional Area (cCSA) Over 24 Months

(A) Change in fat over 24 months. (B) Change in cCSA over 24 months. Boxes show median (IQR). The lines represent the 10th–90th percentile with diamonds indicating values outside this window. Median baseline values are given at the left border. AL = adductor longus; AM = adductor magnus; BFL = biceps femoris long head; BFS = biceps femoris short head; EDL = extensor digitorum longus; GL = gastrocnemius lateralis; GM = gastrocnemius medialis; GR = gracilis; PR = peroneus; RF = rectus femoris; SM = semimembranosus; SOL = soleus; SR = sartorius; ST = semitendinosus; TA = tibialis anterior; TP = tibialis posterior; VI = vastus intermedius; VL = vastus lateralis; VM = vastus medialis.

Figure 5. Relation Between Change in Function Tests and Fat Fraction (FF)

Change in whole thigh FF of 3 center slices vs (A) North Star Ambulatory Assessment (NSAA) and (B) 10-meter run test (TMR) velocity. Closed arrows: patients with baseline and follow-up measurements. Open triangles: patients with only 1 measurement (baseline). Horizontal arrows indicate functionally stable patients but with a change in FF.