Multicenter prospective longitudinal study of magnetic resonance biomarkers in a large duchenne muscular dystrophy cohort

Rebecca J Willcocks, William D Rooney, William T Triplett, Sean C Forbes, Donovan J Lott, Claudia R Senesac, Michael J Daniels, Dah-Jyuu Wang, Ann T Harrington, Gihan I Tennekoon, Barry S Russman, Erika L Finanger, Barry J Byrne, Richard S Finkel, Glenn A Walter, H Lee Sweeney, Krista Vandenborne, Rebecca J Willcocks, William D Rooney, William T Triplett, Sean C Forbes, Donovan J Lott, Claudia R Senesac, Michael J Daniels, Dah-Jyuu Wang, Ann T Harrington, Gihan I Tennekoon, Barry S Russman, Erika L Finanger, Barry J Byrne, Richard S Finkel, Glenn A Walter, H Lee Sweeney, Krista Vandenborne

Abstract

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 (1) H2 O 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.

Conflict of interest statement

Potential Conflicts of Interest

Nothing to report.

© 2016 American Neurological Association.

Figures

FIGURE 1
FIGURE 1
Raw data from an unaffected control subject, illustrating data analysis. For MRI-T2 mapping analysis, regions of interest were outlined on eight leg muscles on the image acquired with a TE of 20 ms. To avoid contamination from subcutaneous fat, bone, or other tissue, boundaries were traced slightly inside of the muscle boundaries. Rectangular 1H-MRS voxels were selected in the Sol and VL muscles, and used to measure both 1H20T2, by fitting water peak height to a monoexponential curve, and FF, by integrating the water and lipid peaks. BFLH=long head of the biceps femoris; GRA=gracilis; 1H-MRS=proton magnetic resonance spectroscopy; MG=medial gastrocnemius; MRI=magnetic resonance imaging; MRS=magnetic resonance spectroscopy; PER=peroneals; SOL=soleus; TA=tibialis anterior; TE=echo time; TP=tibialis posterior; VL=vastus lateralis.
FIGURE 2
FIGURE 2
Relationship between clinical status (Modified Brooke Lower Extremity Score) and VL FF in boys with DMD at baseline and 12 months. A moderate significant relationship was noted (r=0.54; p < 0.0001). Low FFs were noted in boys who are able to climb stairs without using hand rails (Brooke Score 1), whereas high FFs were observed in boys who climb stairs slowly (Brooke score 3), do not climb stairs at all (Brooke score 5), or are unable to walk (Brooke score 9). DMD=Duchenne muscular dystrophy; FF=fat fraction; VL=vastus lateralis.
FIGURE 3
FIGURE 3
3D gradient echo images acquired in the upper leg of an unaffected control subject and a boy with DMD at baseline and 12-month follow-up time points show increases in intramuscular fat (top). Spectra show the quantitative increase in fat, whereas MRI-T2 maps show increased T2 concomitant with increased fat fraction. 3D=three-dimensional; BFLH=long head of the biceps femoris; DMD=Duchenne muscular dystrophy; BFLH=long head of the biceps femoris; GRA=gracilis; GRE=gradient refocused echo; 1H-MRS=proton magnetic resonance spectroscopy; MRI=magnetic resonance imaging; VL=vastus lateralis.
FIGURE 4
FIGURE 4
Representative MR images (fat saturated gradient echo images) of the lower (A) and upper leg (B) showing the changes in muscle composition in the different age groups. MR=magnetic resonance.
FIGURE 5
FIGURE 5
FF and MRI-T2 in the SOL and VL muscle were greater in DMD than control at all ages and were higher at 12 months than baseline. This increase was significant in all groups except SOL FF in 5- to 6.9-year-old boys. Data are presented as mean±standard error. DMD=Duchenne muscular dystrophy; FF=fat fraction; MRI=magnetic resonance imaging; SOL-=soleus; VL=vastus lateralis.
FIGURE 6
FIGURE 6
Changes in VL FF over 3, 6, and 12 months in 5- to 12.9-year-old boys. Each bar represents an individual subject. FF increased significantly over 3 (p=0.03), 6 (p=0.0004), and 12 months (p < 0.0001). FF=fat fraction; VL=vastus lateralis.
FIGURE 7
FIGURE 7
(A) Boys were divided into quartiles based on the 1-year change in 6MWD. The first quartile comprised boys whose 6MWD increased, the second quartile comprised boys whose 6MWD was stable, and the third and fourth quartiles included boys whose 6MWD decreased in 1 year. Boys who lost ambulation are shown in open circles. (B and C) VL and SOL FF and T2 and BFLH T2 increased over 1 year in boys whose 6MWD was stable or improved over 1 year. 6MWT=6-minute walk test; BFLH=long head of the biceps femoris; FF=fat fraction; SOL=soleus; VL=vastus lateralis.
FIGURE 8
FIGURE 8
Standardized Response Mean for MR Measures in Age Subgroups

Source: PubMed

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