MRI vastus lateralis fat fraction predicts loss of ambulation in Duchenne muscular dystrophy

Abstract

ObjectiveWe studied the potential of quantitative MRI (qMRI) as a surrogate endpoint in Duchenne muscular 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 in Leiden University Medical Center (LUMC) and Cincinnati Children's Hospital Medical Center (CCHMC). CCHMC included ambulant patients, while LUMC included a mixed ambulant and nonambulant population. We fitted longitudinal VL FF values to a sigmoidal curve using a mixed model with random slope to predict individual trajectories. The additive value 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 in LUMC compared to CCHMC patients. Hazard ratio of a percent-point increase in VL FF for the time to LoA was 1.15 for LUMC (95% confidence interval [CI] 1.05–1.26; p = 0.003) and 0.96 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 in patients with a 10% higher VL FF at any age. Although results should be confirmed in a larger cohort with prospective determination of the clinical endpoint, this added predictive value of VL FF to age on LoA supports the use of qMRI FF as an endpoint or stratification tool in clinical trials.

The feasibility of quantitative MRI of extra‐ocular muscles in myasthenia gravis and Graves' orbitopathy

“…All scans except one were free from visible motion artefacts, indicating that all subjects could adhere to the protocol. The mean bias in FF between the segmentations of two independent observers was low (0.3%) and the limits of agreement were within ±3% in FF, which is in the same range as previously reported values in segmentation of the vastus lateralis in patients with Duchenne muscular dystrophy (bias: 0.1%, limits of agreement: ±1.1%), 28 in healthy controls and patients with type 2 diabetes in all leg muscle compartments (bias: −0.2, limits of agreement:…”

“…All scans except one were free from visible motion artefacts, indicating that all subjects could adhere to the protocol. The mean bias in FF between the segmentations of two independent observers was low (0.3%) and the limits of agreement were within ±3% in FF, which is in the same range as previously reported values in segmentation of the vastus lateralis in patients with Duchenne muscular dystrophy (bias: 0.1%, limits of agreement: ±1.1%), 28 in healthy controls and patients with type 2 diabetes in all leg muscle compartments (bias: −0.2, limits of agreement: ±2.6%), 29 and in patients with myotonic dystrophy type 1 in lower leg muscles (limits of agreement: ±2.5%) 30 . The scan‐to‐scan reproducibility between the two Dixon scans with different resolutions showed a low average bias in FF (−0.7%) and narrow limits of agreement (−3.4% to 1.8%), which is lower than the difference found between the patients and the healthy controls (ie, ~4%), indicating the feasibility of assessing FFs using this method to detect affected muscles.…”

Multiexponential Analysis of the Water T2‐Relaxation in the Skeletal Muscle Provides Distinct Markers of Disease Activity Between Inflammatory and Dystrophic Myopathies

“…4 Particularly, fat-fraction mapping methods allow to quantitatively monitor the replacement of muscle by fat, the common final pathway in most NMDs, thus providing an objective marker of disease progression. 5,6 However, precise measures allowing monitoring the different pathophysiological processes and the histopathological alterations involved in the degenerative process would significantly improve the assessment of the effects and efficacy of therapies. 7 The water T 2 -relaxation in skeletal muscle has been shown to be sensitive, although not specific, to several pathological and even physiological processes affecting the water distribution and protein hydration in tissue, such as exercise, injury, interstitial edema, inflammation, necrosis, cell swelling, and acidification.…”

“…In this context, quantitative magnetic resonance imaging (MRI) has been playing an important role in clinical trials 4 . Particularly, fat‐fraction mapping methods allow to quantitatively monitor the replacement of muscle by fat, the common final pathway in most NMDs, thus providing an objective marker of disease progression 5,6 . However, precise measures allowing monitoring the different pathophysiological processes and the histopathological alterations involved in the degenerative process would significantly improve the assessment of the effects and efficacy of therapies 7 …”

Quantitative Imaging in Muscle Diseases with Focus on Non-proton MRI and Other Advanced MRI Techniques

“…23,24 A large number of studies showed a good to very good correlation of MFF with strength and function measures cross-sectionally in a wide range of muscle diseases, 12,19,[25][26][27][28] and recently MFF was even shown to be able to predict future function in Duchenne muscular dystrophy (DMD). 29,30 This represents an important step forward in the road to a surrogate end point in clinical trials. 13,31 A second approach for the reliable assessment of degenerative disease activity in muscle tissue including fatty degeneration represents T2 mapping of skeletal muscle.…”