Skeletal muscle magnetic resonance biomarkers correlate with function and sentinel events in Duchenne muscular dystrophy

Abstract

ObjectiveTo provide evidence for quantitative magnetic resonance (qMR) biomarkers in Duchenne muscular dystrophy by investigating the relationship between qMR measures of lower extremity muscle pathology and functional endpoints in a large ambulatory cohort using a multicenter study design.MethodsMR spectroscopy and quantitative imaging were implemented to measure intramuscular fat fraction and the transverse magnetization relaxation time constant (T2) in lower extremity muscles of 136 participants with Duchenne muscular dystrophy. Measures were collected at 554 visits over 48 months at one of three imaging sites. Fat fraction was measured in the soleus and vastus lateralis using MR spectroscopy, while T2 was assessed using MRI in eight lower extremity muscles. Ambulatory function was measured using the 10m walk/run, climb four stairs, supine to stand, and six minute walk tests.ResultsSignificant correlations were found between all qMR and functional measures. Vastus lateralis qMR measures correlated most strongly to functional endpoints (|ρ| = 0.68–0.78), although measures in other rapidly progressing muscles including the biceps femoris (|ρ| = 0.63–0.73) and peroneals (|ρ| = 0.59–0.72) also showed strong correlations. Quantitative MR biomarkers were excellent indicators of loss of functional ability and correlated with qualitative measures of function. A VL FF of 0.40 was an approximate lower threshold of muscle pathology associated with loss of ambulation.DiscussionLower extremity qMR biomarkers have a robust relationship to clinically meaningful measures of ambulatory function in Duchenne muscular dystrophy. These results provide strong supporting evidence for qMR biomarkers and set the stage for their potential use as surrogate outcomes in clinical trials.

Diaphragm Involvement in Duchenne Muscular Dystrophy (DMD): An MRI Study

“…Third, we found that the fat fraction and the functional ability of the diaphragm were strongly correlated. Prior studies have found high degrees of correlation between MRI measures of fat fraction of quickly degenerating proximal muscles and ambulatory function, measured using the 10‐m walk/run, the climb four stairs, supine to stand, and 6‐minute walk tests . With respect to these studies, we directly related the fat fraction increase of the diaphragm to its excursion function; thus, the structure–function relationship was investigated free from any compensatory mechanisms.…”

“…Prior studies have found high degrees of correlation between MRI measures of fat fraction of quickly degenerating proximal muscles and ambulatory function, measured using the 10-m walk/run, the climb four stairs, supine to stand, and 6-minute walk tests. 15,[37][38][39] With respect to these studies, we directly related the fat fraction increase of the diaphragm to its excursion function; thus, the structure-function relationship was investigated free from any compensatory mechanisms. Studies performed by using ultrasonography (US) showed a progressive diaphragm atrophy with age and reduced excursion.…”

Advancements in magnetic resonance imaging‐based biomarkers for muscular dystrophy

“…Cross‐sectional studies in DMD have shown strong correlations of quantitative fat fraction and T2 values with the 6‐minute walk test . Another recent study in DMD patients used MRI‐derived fat fractions and T2 values to classify patients according to loss of motor milestones such as the ability to climb stairs and stand from supine . Other studies have sought to establish a correlation between imaging biomarkers and disease‐specific clinical scales .…”

“…An additional advantage of using MRS rather than T2‐weighted imaging is that the contributions of fat and free water to the T2 signal can be more clearly partitioned by using MRS. Researchers using 1 H MRS in DMD have been able to detect larger lipid metabolite peaks associated with smaller water peaks in older age groups; these studies have also demonstrated that fat fractions calculated from MRS correlate significantly with muscle strength and functional endpoints …”

“…Researchers using 1 H MRS in DMD have been able to detect larger lipid metabolite peaks associated with smaller water peaks in older age groups; these studies have also demonstrated that fat fractions calculated from MRS correlate significantly with muscle strength and functional endpoints. [55][56][57] 3 | EVALUATING EDEMA Fluid-sensitive sequences are among the most widely used MRI sequences and are included in most muscle scanning protocols. These sequences are typically variations of T2-weighted sequences that are modified to suppress the hyperintense signal from fat (which would otherwise be indistinguishable from free water).…”