Benjamin Marty

Skeletal Muscle Quantitative Nuclear Magnetic Resonance Imaging and Spectroscopy as an Outcome Measure for Clinical Trials

Recent years have seen tremendous progress towards therapy of many previously incurable neuromuscular diseases. This new context has acted as a driving force for the development of novel non-invasive outcome measures. These can be organized in three main categories: functional tools, fluid biomarkers and imagery. In the latest category, nuclear magnetic resonance imaging (NMRI) offers a considerable range of possibilities for the characterization of skeletal muscle composition, function and metabolism. Nowadays, three NMR outcome measures are frequently integrated in clinical research protocols. They are: 1/ the muscle cross sectional area or volume, 2/ the percentage of intramuscular fat and 3/ the muscle water T2, which quantity muscle trophicity, chronic fatty degenerative changes and oedema (or more broadly, “disease activity”), respectively. A fourth biomarker, the contractile tissue volume is easily derived from the first two ones. The fat fraction maps most often acquired with Dixon sequences have proven their capability to detect small changes in muscle composition and have repeatedly shown superior sensitivity over standard functional evaluation. This outcome measure will more than likely be the first of the series to be validated as an endpoint by regulatory agencies. The versatility of contrast generated by NMR has opened many additional possibilities for characterization of the skeletal muscle and will result in the proposal of more NMR biomarkers. Ultra-short TE (UTE) sequences, late gadolinium enhancement and NMR elastography are being investigated as candidates to evaluate skeletal muscle interstitial fibrosis. Many options exist to measure muscle perfusion and oxygenation by NMR. Diffusion NMR as well as texture analysis algorithms could generate complementary information on muscle organization at microscopic and mesoscopic scales, respectively. 31P NMR spectroscopy is the reference technique to assess muscle energetics non-invasively during and after exercise. In dystrophic muscle, 31P NMR spectrum at rest is profoundly perturbed, and several resonances inform on cell membrane integrity. Considerable efforts are being directed towards acceleration of image acquisitions using a variety of approaches, from the extraction of fat content and water T2 maps from one single acquisition to partial matrices acquisition schemes. Spectacular decreases in examination time are expected in the near future. They will reinforce the attractiveness of NMR outcome measures and will further facilitate their integration in clinical research trials.

Simultaneous muscle water T2 and fat fraction mapping using transverse relaxometry with stimulated echo compensation

Skeletal muscle inflammation/necrosis and fat infiltration are strong indicators of disease activity and progression in many neuromuscular disorders. They can be assessed by muscle T2 relaxometry and water‐fat separation techniques, respectively. In the present work, we exploited differences between water and fat T1 and T2 relaxivities by applying a bi‐component extended phase graph (EPG) fitting approach to simultaneously quantify the muscle water T2 and fat fraction from standard multi‐slice multi‐echo (MSME) acquisitions in the presence of stimulated echoes. Experimental decay curves were adjusted to the theoretical model using either an iterative non‐negative least‐squares (NNLS) procedure or a pattern recognition approach. Twenty‐two patients (age, 49 ± 18 years) were selected to cover a large range of muscle fat infiltration. Four cases of chronic or subchronic juvenile dermatomyositis (age, 8 ± 3 years) were investigated before and 3 months following steroid treatment. For control, five healthy volunteers (age, 25 ± 2 years) were recruited. All subjects underwent the MSME sequence and EPG fitting procedure. The EPG fitting algorithm allowed a precise estimation of water T2 and fat fraction in diseased muscle, even in the presence of large B1+ inhomogeneities. In the whole cohort of patients, there was no overall correlation between water T2 values obtained with the proposed method and the fat fraction estimated inside muscle tissues (R2 = 0.02). In the patients with dermatomyositis, there was a significant decrease in water T2 (‐4.09 ± 3.7 ms) consequent to steroid treatment. The pattern recognition approach resulted in a 20‐fold decrease in processing time relative to the iterative NNLS procedure. The fat fraction derived from the EPG fitting approach correlated well with the fat fraction derived from a standard three‐point Dixon method (≈1.5% bias). The bi‐component EPG fitting analysis is a precise tool to monitor muscle tissue disease activity and is able to handle bias introduced by fat infiltration and B1+ inhomogeneities. Copyright

Bloch Equations-Based Reconstruction of Myocardium T1 Maps from Modified Look-Locker Inversion Recovery Sequence

Modified Look-Locker Inversion recovery (MOLLI) sequence is increasingly performed for myocardial T1 mapping but is known to underestimate T1 values. The aim of the study was to quantitatively analyze several sources of errors when T1 maps are derived using standard post-processing of the sequence and to propose a reconstruction approach that takes into account inversion efficacy (η), T2 relaxation during balanced steady-state free-precession readouts and B1+ inhomogeneities. Contributions of the different sources of error were analyzed using Bloch equations simulations of MOLLI sequence. Bloch simulations were then combined with the acquisition of fast B1+ and T2 maps to derive more accurate T1 maps. This novel approach was evaluated on phantoms and on five healthy volunteers. Simulations show that T2 variations, B1+ heterogeneities and inversion efficiency represent major confounders for T1 mapping when MOLLI is processed with standard 3-parameters fitting. In vitro data indicate that T1 values are accurately derived with the simulation approach and in vivo data suggest that myocardium T1 are 15% underestimated when processed with the standard 3-parameters fitting. At the cost of additional acquisitions, this method might be suitable in clinical research protocols for precise tissue characterization as it decorrelates T1 and T2 effects on parametric maps provided by MOLLI sequence and avoids inaccuracies when B1+ is not homogenous throughout the myocardium.

Characterization of Benign Myocarditis Using Quantitative Delayed-Enhancement Imaging Based on Molli T1 Mapping.

AbstractDelayed contrast enhancement after injection of a gadolinium-chelate (Gd-chelate) is a reference imaging method to detect myocardial tissue changes. Its localization within the thickness of the myocardial wall allows differentiating various pathological processes such as myocardial infarction (MI), inflammatory myocarditis, and cardiomyopathies. The aim of the study was first to characterize benign myocarditis using quantitative delayed-enhancement imaging and then to investigate whether the measure of the extracellular volume fraction (ECV) can be used to discriminate between MI and myocarditis.In 6 patients with acute benign myocarditis (32.2 ± 13.8 year-old, subepicardial late gadolinium enhancement [LGE]) and 18 patients with MI (52.3 ± 10.9 year-old, subendocardial/transmural LGE), myocardial T1 was determined using the Modified Look-Locker Imaging (MOLLI) sequence at 3 Tesla before and after Gd-chelate injection. T1 values were compared in LGE and normal regions of the myocardium. The myocardial T1 values were normalized to the T1 of blood, and the ECV was calculated from T1 values of myocardium and blood pre- and post-Gd injection.In both myocarditis and MI, the T1 was lower in LGE regions than in normal regions of the left ventricle. T1 of LGE areas was significantly higher in myocarditis than in MI (446.8 ± 45.8 vs 360.5 ± 66.9 ms, P = 0.003) and ECV was lower in myocarditis than in MI (34.5 ± 3.3 vs 53.8 ± 13.0 %, P = 0.004).Both inflammatory process and chronic fibrosis induce LGE (subepicardial in myocarditis and subendocardial in MI). The present study demonstrates that the determination of T1 and ECV is able to differentiate the 2 histological patterns.Further investigation will indicate whether the severity of ECV changes might help refine the predictive risk of LGE in myocarditis.

G.P.119

Fatty infiltration of muscles is a marker of disease progression in many neuromuscular disorders. Muscle MRI is capable of revealing patterns of muscles involvement that are disease specific and facilitates the diagnostic workup of patients. Although routine T1-weighted (T1w) imaging can give an indication of the presence or absence of muscular fat infiltration, it is difficult to extract quantitative data from these images. On the contrary, Dixon methods provide quantitative measure of fat fraction. Usually, whole-body (WB) exams consist in the acquisition of T1w images, followed by Dixon acquisitions on targeted regions to quantitatively assess fat infiltration. With the aim of improving and accelerating the qualitative assessment of neuromuscular disorders, we propose to avoid the T1w acquisition altogether, by allowing to perform the visual diagnosis workup on a WB Dixon imaging. 20 patients underwent WB MRI at 3T. WB T1w images were acquired with a 2D TSE sequence (resolution=1.1×1.1mm 2 , slice thickness=6mm, T acq =5min 40s). WB Dixon acquisition consisted in a 3D VIBE sequence with 3 echoes (resolution=1×1×5mm 3 , T acq =14min 5s). Quantitative fat fraction maps were derived using a standard 3-points Dixon reconstruction method. A customed lookup table was embedded in the DICOM file to provide a colored lecture of fat fraction maps corresponding to the Mercuris scale. Our results show that the acquisition of a high resolution WB Dixon imaging is possible in less than 15min using an optimized VIBE sequence. This provides quantitative data that are more suitable than T1w images for longitudinal natural history studies, or therapeutic clinical trials. Moreover, the color representation renders the visual grading of the muscles more convenient and less operator dependent as it is based on actual fat fraction measurements. WB Dixon might then overcome the use of WB T1w images for diagnostic of neuromuscular disorders.

Monitoring skeletal muscle chronic fatty degenerations with fast T1-mapping

ObjectivesTo develop a fast, high-resolution T1-mapping sequence dedicated to skeletal muscle imaging, and to evaluate the potential of T1 as a robust and sensitive biomarker for the monitoring of chronic fatty degenerations in a dystrophic disease.MethodsThe magnetic resonance imaging sequence consisted of the acquisition of a 1,000-radial-spokes FLASH echo-train following magnetisation inversion, resulting in 10s scan time per slice. Temporal image series were reconstructed using compressed sensing and T1 maps were computed using Bloch simulations. Ten healthy volunteers and 30 patients suffering from Becker muscular dystrophy (BMD) participated in this prospective study, in order to evaluate the repeatability, the precision and the sensitivity of the proposed approach. Intramuscular fat fraction (FF) was also measured using a standard three-point Dixon method. The protocol was approved by a local ethics committee.ResultsThe mean T1 evaluated in the thighs muscles of healthy volunteers was 1,199 ± 45 ms, with a coefficient of reproducibility of 2.3%. Mean T1 values were statistically decreased in the thighs of BMD patients and were linearly correlated with intramuscular FF (R = -0.98).ConclusionsT1-mapping is a good candidate for fast, sensitive and quantitative monitoring of fatty infiltrations in neuromuscular disorders.Key Points• A T1 mapping sequence dedicated to skeletal muscle imaging was implemented.• The acquisition time was 10 s per slice.• Muscle T1 values were significantly decreased in dystrophic muscles compared to healthy muscles.• T1 values correlated with intramuscular fat fraction measured by three-point Dixon.• T1 represents an alternative biomarker for monitoring fatty infiltrations in neuromuscular disorders.

Acute changes in extracellular volume fraction in skeletal muscle monitored by 23Na NMR spectroscopy

In this article, we induced acute changes in extracellular volume fraction in skeletal muscle tissue and compared the sensitivity of a standard 1H T2 imaging method with different 23Na‐NMR spectroscopy parameters within acquisition times compatible with clinical investigations. First, we analyzed the effect of a short ischemia on the sodium distribution in the skeletal muscle. Then, the lower leg of 21 healthy volunteers was scanned under different vascular filling conditions (vascular draining, filling, and normal condition) expected to modify exclusively the extracellular volume. The first experiment showed no change in the total sodium content during a 15 min ischemia, but the intracellular weighted 23Na signal slowly decreased. For the second part, significant variations of total sodium content, sodium distribution, and T1 and T2∗ of 23Na signal were observed between different vascular filling conditions. The measured sodium distribution correlates significantly with sodium T1 and with the short and long T2∗ fractions. In contrast, significant changes in the proton T2w signal were observed only in three muscles. Altogether, the mean T2w signal intensity of all muscles as well as their mean T2 did not vary significantly with the extracellular volume changes. In conclusion, at the expense of giving up spatial resolution, the proposed 23Na spectroscopic method proved to be more sensitive than standard 1H T2 approach to monitor acute extracellular compartment changes within muscle tissue.

Myocardial characterisation in Becker muscular dystrophy using T1 and T2 mapping

Methods From April 2012 to May 2014, 84 consecutive patients (age=38,6 ± 13,6 years) with Becker muscular dystrophy (BMD) and 12 control subjects underwent cardiac magnetic imaging (MRI) on a 3-T clinical scanner (Magnetom Trio Tim, Siemens Healthcare). T1 maps and apparent extracellular volume fraction (appECV) preand post-GdDOTA injection was performed with a prototype modified Look-Locker sequence (MOLLI, 3, 3 and 5 image acquisitions). T2 maps were generated with a T2 prepared TrueFISP sequence acquired with 3 preparation times (0, 25 and 55 ms). Late Gadolinium enhancement (LGE), T1, T2, appECV were assessed according to the classification of the AHA segmentation.

Cardiac dyssynchrony in a Becker cohort: preliminary results

Background We previously reported the early detection of cardiac motion dyssynchrony in GRMD dogs (a model for Duchenne myopathy with cardiac involvement). In this new work, we applied the same dyssynchrony index in a cohort of 88 Becker patients of various age (38,7 ±13,6 years; range from 18 to 68) and disease burden (number of segment count with any Gd late enhancement : 4,37 ± 3,14 ; range from 0 to 12). We compared the data obtained to those in 10 control subjects.