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Assessing Functional Performance in the Mdx Mouse Model
Published on: March 27, 2014
Modeling disease trajectory in Duchenne muscular dystrophy
William D Rooney1, Yosef A Berlow2, William T Triplett2
1From the Advanced Imaging Research Center (W.D.R., Y.A.B., I.A., E.O., B.M.), Department of Neurology (W.D.R., I.A., B.S.R., E.L.F.), Department of Biomedical Engineering (W.D.R.), Department of Behavioral Neuroscience (W.D.R., Y.A.B.), and Department of Pediatrics (B.S.R., E.L.F.), Oregon Health & Science University, Portland; Departments of Physical Therapy (W.T.T., S.C.F., R.J.W., H.A., C.S., D.J.L., K.V.), Statistics (S.C., M.J.D.), Physiology and Functional Genomics (A.B., G.A.W.), and Pharmacology & Therapeutics (H.L.S.), University of Florida, Gainesville; Department of Radiology (D.-J.W.) and Division of Neurology (G.T.), Children's Hospital of Philadelphia, PA; Department of Pediatrics (R.F.), Nemours Children's Hospital, Orlando, FL; and Shriners Hospital (B.S.R., E.L.F.), Portland, OR. rooneyw@ohsu.edu.
Objective:
To quantify disease progression in individuals with Duchenne muscular dystrophy (DMD) using magnetic resonance biomarkers of leg muscles.
Methods:
MRI and magnetic resonance spectroscopy (MRS) biomarkers were acquired from 104 participants with DMD and 51 healthy controls using a prospective observational study design with patients with DMD followed up yearly for up to 6 years. Fat fractions (FFs) in vastus lateralis and soleus muscles were determined with 1H MRS. MRI quantitative T2 (qT2) values were measured for 3 muscles of the upper leg and 5 muscles of the lower leg. Longitudinal changes in biomarkers were modeled with a cumulative distribution function using a nonlinear mixed-effects approach.
Results:
MRS FF and MRI qT2 increased with DMD disease duration, with the progression time constants differing markedly between individuals and across muscles. The average age at half-maximal muscle involvement (μ) occurred 4.8 years earlier in vastus lateralis than soleus, and these measures were strongly associated with loss-of-ambulation age. Corticosteroid treatment was found to delay μ by 2.5 years on average across muscles, although there were marked differences between muscles with more slowly progressing muscles showing larger delay.
Conclusions:
MRS FF and MRI qT2 provide sensitive noninvasive measures of DMD progression. Modeling changes in these biomarkers across multiple muscles can be used to detect and monitor the therapeutic effects of corticosteroids on disease progression and to provide prognostic information on functional outcomes. This modeling approach provides a method to transform these MRI biomarkers into well-understood metrics, allowing concise summaries of DMD disease progression at individual and population levels.
Clinicaltrialsgov Identifier:
NCT01484678.
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