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La deuxième édition de l’École Balte de Neuromyologie s’est tenue du 26 au 27 août 2022 à Riga (Lettonie) dans une ambiance un peu particulière étant donné la situation internationale. Ce fut l’occasion pour les auteurs de mesurer le chemin parcouru par leurs homologues baltes tant dans le domaine du diagnostic que celui de la prise en charge des maladies neuromusculaires. Cette entreprise difficile mais couronnée de succès a conduit à l’intégration de trois centres de référence neuromusculaire baltes au sein de l’ERN (réseau européen des maladies rares) Euro-NMD. Au-delà de cette forme de consécration, et même si beaucoup reste à faire, au niveau de l’histopathologie musculaire notamment, les différentes équipes baltes ont présenté des travaux de recherche clinique tout à fait remarquables et utiles à l’ensemble de la communauté myologique.

Background Quantitative MRI is increasingly proposed in clinical trials related to neuromuscular disorders (NMDs). Purpose To investigate the potential of an MR fingerprinting sequence for water and fat fraction (FF) quantification (MRF T1-FF) for providing markers of fatty replacement and disease activity in patients with NMDs and to establish the sensitivity of water T1 as a marker of disease activity compared with water T2 mapping. Materials and Methods Data acquired between March 2018 and March 2020 from the legs of patients with NMDs were retrospectively analyzed. The MRI examination comprised fat-suppressed T2-weighted imaging, mapping of the FF measured with the three-point Dixon technique (FFDixon), water T2 mapping, and MRF T1-FF, from which the FF measured with MRF T1-FF (FFMRF) and water T1 were derived. Data from the legs of healthy volunteers were prospectively acquired between January and July 2020 to derive abnormality thresholds for FF, water T2, and water T1 values. Kruskal-Wallis tests and receiver operating characteristic curve analysis were performed, and linear models were used. Results A total of 73 patients (mean age ± standard deviation, 47 years ± 12; 45 women) and 15 healthy volunteers (mean age, 33 years ± 8; three women) were evaluated. A linear correlation was observed between FFMRF and FFDixon (R2 = 0.97, P < .001). Water T1 values were higher in muscles with high signal intensity at fat-suppressed T2-weighted imaging than in muscles with low signal intensity (mean value, 1281 msec [95% CI: 1165, 1604] vs 1198 msec [95% CI: 1099, 1312], respectively; P < .001), and a correlation was found between water T1 and water T2 distribution metrics (R2 = 0.66 and 0.79 for the median and 90th percentile values, respectively; P < .001). Water T1 classified the patients' muscles as abnormal based on quantitative water T2, with high sensitivity (93%; 68 of 73 patients) and specificity (80%; 53 of 73 patients) (area under the receiver operating characteristic curve, 0.92 [95% CI: 0.83, 0.97]; P < .001). Conclusion Water-fat separation in MR fingerprinting is robust for deriving quantitative imaging markers of intramuscular fatty replacement and disease activity in patients with neuromuscular disorders. © RSNA, 2021 Online supplemental material is available for this article.

Imaging is an important tool in the evaluation of idiopathic inflammatory myopathies. It plays a role in diagnosis, assessment of disease activity and follow-up, and as a non-invasive biomarker. Among the different modalities, nuclear magnetic resonance imaging (MRI), ultrasound (US), and positron emission tomography (PET) may have the most clinical utility in myositis. MRI is currently the best modality to evaluate skeletal muscle and provides excellent characterization of muscle edema and fat replacement through the use of T1-weighted and T2-weighted fat suppressed/STIR sequences. Although MRI can be read qualitatively for the presence of abnormalities, a more quantitative approach using Dixon sequences and the generation of water T2 parametric maps would be preferable for follow-up. Newer protocols such as diffusion-weighted imaging, functional imaging measures, and spectroscopy may be of interest to provide further insights into myositis. Despite the advantages of MRI, image acquisition is relatively time-consuming, expensive, and not accessible to all patients. The use of US to evaluate skeletal muscle in myositis is gaining interest, especially in chronic disease, where fat replacement and fibrosis are detected readily by this modality. Although easily deployed at the bedside, it is heavily dependent on operator experience to recognize disease states. Further, systematic characterization of muscle edema by US is still needed. PET provides valuable information on muscle function at a cellular level. Fluorodeoxyglucose (FDG-PET) has been the most common application in myositis to detect pathologic uptake indicative of inflammation. The use of neurodegenerative markers is now also being utilized for inclusion body myositis. These different modalities may prove to be complementary methods for myositis evaluation.

OBJECTIVE: To characterize the natural history of spinal muscular atrophy (SMA) over 24 months using innovative measures such as wearable devices, and to provide evidence for the sensitivity of these measures to determine their suitability as endpoints in clinical trials. METHODS: Patients with Type 2 and 3 SMA (N = 81) with varied functional abilities (sitters, nonsitters, nonambulant, and ambulant) who were not receiving disease-modifying treatment were assessed over 24 months: motor function (Motor Function Measure [MFM]), upper limb strength (MyoGrip, MyoPinch), upper limb activity (ActiMyo® ), quantitative magnetic resonance imaging (fat fraction [FFT2 ] mapping and contractile cross-sectional area [C-CSA]), pulmonary function (forced vital capacity [FVC], peak cough flow, maximum expiratory pressure, maximum inspiratory pressure, and sniff nasal inspiratory pressure), and survival of motor neuron (SMN) protein levels. RESULTS: MFM32 scores declined significantly over 24 months, but not 12 months. Changes in upper limb activity could be detected over 6 months and continued to decrease significantly over 12 months, but not 24 months. Upper limb strength decreased significantly over 12 and 24 months. FVC declined significantly over 12 months, but not 24 months. FFT2 increased over 12 and 24 months, although not with statistical significance. A significant increase in C-CSA was observed at 12 but not 24 months. Blood SMN protein levels were stable over 12 and 24 months. INTERPRETATION: These data demonstrate that the MFM32, MyoGrip, MyoPinch, and ActiMyo® enable the detection of a significant decline in patients with Type 2 and 3 SMA over 12 or 24 months. ispartof: ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY vol:8 issue:2 pages:359-373 ispartof: location:United States status: published

Background Quantitative nuclear magnetic resonance imaging (NMRI) is an objective and precise outcome measure for evaluating disease progression in neuromuscular disorders. We aimed to investigate predictive 'disease activity' NMR indices, including water T2 and 31P NMR spectroscopy (NMRS), and its relation to NMR markers of 'disease progression', such as the changes in fat fraction (ΔFat%) and contractile cross-sectional area (ΔcCSA), in GNE myopathy (GNEM) patients. Methods NMR was performed on a 3T clinical scanner, at baseline and at a 1-year interval, in 10 GNEM patients and 29 age-matched controls. Dixon-based fat-water imaging and water T2 mapping were acquired in legs and thighs, and in the dominant forearm. 31P NMRS was performed at the level of quadriceps and hamstring. Water T2 and 31P NMRS indices were determined for all muscle groups and visits. Correlations were performed with 'disease progression' indices ΔFat%, ΔcCSA and the muscle fat transformation rate (Rmuscle_transf). Results In quadriceps, known to be relatively preserved in GNEM, water T2 at baseline was significantly higher compared to controls, and correlated strongly with the one-year evolution of Fat% and cCSA and Rmuscle_transf. Various 31P NMRS indices showed significant differences in quadriceps and hamstring compared to controls and correlations existed between these indices and ΔFat%, ΔcCSA and Rmuscle_transf. Conclusions This study demonstrates that disease activity indices such as water T2 and 31P NMRS may predict disease progression in skeletal muscles of GNEM patients, and suggests that these measures may be considered to be valuable surrogate endpoints in the assessment of GNEM disease progression.

Magnetic resonance signals from different nuclei can be excited or received at the same time,rendering simultaneous or rapidly interleaved multi-nuclear acquisitions feasible. The advan-tages are a reduction of total scan time compared to sequential multi-nuclear acquisitions or that additional information from heteronuclear data is obtained at thesame time and anatomical position. Information content can be qualitatively increased by delivering a more comprehensive MR-based picture of a transient state (such as an exercise bout). Also, combiningnon-proton MR acquisitions with

The widespread use of magnetic resonance imaging (MRI) in the diagnosis of myopathies has made it possible to clarify the typical MRI pattern of dysferlinopathy. However, sufficient attention has not been given to the variability of MRI patterns in dysferlinopathy. Materials and methods Twenty-five patients with the clinical manifestations of dysferlinopathy were examined. For all patients, creatine phosphokinase levels were measured and molecular genetics were examined. In two patients, immunohistochemical examinations of muscle biopsies were performed. MRI scanning was included T2 multi-slice multi-echo, T1 weighted, T2 weighted and Short Tau Inversion Recovery T2 weighted sequences. Quantitative and semi-quantitative evaluations of fatty replacement and swelling of the muscles were undertaken. Results Variability in the MRI patterns was lowest in the pelvis and leg muscles and highest in the thigh muscles. Three main types of MRI patterns were distinguished: posterior-dominant (80%), anterior-dominant (16%), and diffuse (4%). Among patients with the anterior-dominant pattern, the collagen-like variant (4%), proximal variant (4%) and pseudo-myositis (8%) were separately distinguished. Conclusions Awareness of atypical MRI patterns in dysferlinopathy is important for increasing the efficiency of routine diagnostics and optimizing the search for causative gene mutations.

Context Cardiovascular disease is the leading cause of death in patients with Cushing syndrome. Cortisol excess and adverse metabolic profile could increase cardiac fat, which can subsequently impair cardiac structure and function. Objective We aimed to evaluate cardiac fat mass and distribution in patients with Cushing syndrome. Methods In this prospective, cross-sectional study, 23 patients with Cushing syndrome and 27 control individuals of comparable age, sex, and body mass index were investigated by cardiac magnetic resonance imaging and proton spectroscopy. Patients were explored before and after biochemical disease remission. Myocardial fat measured by the Dixon method was the main outcome measure. The intramyocardial triglyceride/water ratio measured by spectroscopy and epicardial and pericardial fat volumes were secondary outcome measures. Results No difference was found between patients and controls in intramyocardial lipid content. Epicardial fat mass was increased in patients compared to controls (30.8 g/m2 [20.4-34.8] vs 17.2 g/m2 [13.1-23.5], P Conclusion Intramyocardial fat stores are not increased in patients with Cushing syndrome, despite highly prevalent metabolic syndrome, suggesting increased cortisol-mediated lipid consumption. Cushing syndrome is associated with marked accumulation of epicardial and pericardial fat. Epicardial adiposity may exert paracrine proinflammatory effects promoting cardiomyopathy.

BACKGROUND AND OBJECTIVE: To identify the most responsive and sensitive clinical outcome measures in GNE myopathy. METHODS: ClinBio-GNE is a natural history study in GNE myopathy. Patients were assessed prospectively by clinical, functional and quantitative nuclear magnetic resonance imaging (qNMRI) evaluations. Strength and functional tests included Myogrip, Myopinch, MoviPlate and Brooke assessments for upper limb and the 6-min walk distance for lower limb. qNMRI was performed for determining the degree of fatty infiltration and trophicity in leg, thigh, forearm and hand skeletal muscles. Ten GNE myopathy patients were included. Three patients were non-ambulant. Age and gender-matched healthy subjects were used as controls. RESULTS: Fatty infiltration and contractile cross-sectional area changed inversely and significantly in lower distal limbs and in proximal lower and distal upper limbs over 1 year. qNMRI indices and functional assessment results were strongly correlated. CONCLUSIONS: Even in a limited number of patients, qNMRI could detect a significant change over a 1-year period in GNE myopathy, which suggests that qNMRI could constitute a surrogate endpoint in this slowly progressive disease. Quantitative NMRI outcome measures can monitor intramuscular fat accumulation with high responsiveness. Longer follow-up should improve our understanding of GNE myopathy evolution and also lead to the identification of non-invasive outcome measures with the highest discriminant power for upcoming clinical trials.

BACKGROUND Duchenne muscular dystrophy (DMD) is a hereditary neuromuscular disease leading to progressive muscle wasting. Since there is a need for MRI variables that serve as early sensitive indicators of response to treatment, several quantitative MRI methods have been suggested for disease monitoring. PURPOSE To evaluate the potential of sodium (23 Na) and proton (1 H) MRI methods to assess early pathological changes in skeletal muscle of DMD. STUDY TYPE Prospective clinical study. POPULATION 23 Na and 1 H MRI of the right leg were performed in 13 patients with DMD (age 7.8 ± 2.4) and 14 healthy boys (age 9.5 ± 2.2). FIELD STRENGTH/SEQUENCE 3 T including a multiecho-spin-echo sequence, diffusion-weighted sequences, 1 H spectroscopy, 3-pt Dixon, and 23 Na ultrashort echo time sequences. ASSESSMENT We obtained water T2 maps, fat fraction (FF), pH, and diffusion properties of the skeletal muscle tissue. Moreover, total tissue sodium concentration (TSC) was calculated from the 23 Na sequence. Intracellular-weighted 23 Na signal (ICwS) was derived from 23 Na inversion-recovery imaging. STATISTICAL TESTS Results from DMD patients and controls were compared using Wilcoxon rank-sum tests and repeated analysis of variance (ANOVA). Spearman-rank correlations and area under the curve (AUC) were calculated to assess the performance of the different MRI methods to distinguish dystrophic from healthy muscle tissue. RESULTS FF, water T2 , and pH were higher in DMD patients (0.07 ± 0.03, 39.4 ± 0.8 msec, 7.06 ± 0.03, all P

Objective Our aim was to assess the role of quantitative 1H and 23Na MRI methods in providing imaging biomarkers of disease activity and severity in patients with Facioscapulohumeral muscular dystrophy (FSHD). Methods We imaged the lower leg muscles of 19 FSHD patients and 12 controls with a multimodal MRI protocol to obtain STIR-T2w images, fat fraction (FF), water T2 (wT2), water T1 (wT1), tissue sodium concentration (TSC), and intracellular-weighted sodium signal (inversion recovery (IR) and triple quantum filter (TQF) sequence). In addition, the FSHD patients underwent muscle strength testing. Results Imaging biomarkers related with water mobility (wT1 and wT2) and ion homeostasis (TSC, IR, TQF) were increased in muscles of FSHD patients. Muscle groups with FF > 10% had higher wT2, wT1, TSC, IR, and TQF values than muscles with FF 1 was increased in few muscles without fat replacement. Furthermore, few STIR-negative muscles (n = 11/76) exhibited increased wT1, TSC, IR or TQF. Increased wT1 as well as 23Na signals were also present in muscles with normal wT2. Muscle strength was related to the mean FF and all imaging biomarkers of tibialis anterior except wT2 were correlated with dorsal flexion. Conclusion The newly evaluated imaging biomarkers related with water mobility (wT1) and ion homeostasis (TSC, IR, TQF) showed different patterns compared to the established markers like FF in muscles of FSHD patients. These quantitative biomarkers could thus contain valuable complementary information for the early characterization of disease progression.

Fibrosis is a key pathological feature in muscle disorders, but its quantification mainly relies on histological and biochemical assays. Muscle fibrosis most frequently is entangled with other pathological processes, as cell membrane lesions, inflammation, necrosis, regeneration, or fatty infiltration, making in vivo assessment difficult. Here, we (1) describe a novel mouse model with variable levels of induced skeletal muscle fibrosis displaying minimal inflammation and no fat infiltration, and (2) report how fibrosis affects non-invasive metrics derived from nuclear magnetic resonance (NMR) and ultrasound shear-wave elastography (SWE) associated with a passive biomechanical assay. Our findings show that collagen fraction correlates with multiple non-invasive metrics. Among them, muscle stiffness as measured by SWE, T2, and extracellular volume (ECV) as measured by NMR have the strongest correlations with histology. We also report that combining metrics in a multi-modality index allowed better discrimination between fibrotic and normal skeletal muscles. This study demonstrates that skeletal muscle fibrosis leads to alterations that can be assessed in vivo with multiple imaging parameters. Furthermore, combining NMR and SWE passive biomechanical assay improves the non-invasive evaluation of skeletal muscle fibrosis and may allow disentangling it from co-occurring pathological alterations in more complex scenarios, such as muscular dystrophies.

Summary Background Inclusion body myositis is the most frequent myositis in patients older than 50 years. Classical immunosuppressants are ineffective in treating inclusion body myositis, and to date there are no recommendations for pharmacological approaches to treatment. When used after organ transplantation, sirolimus can block the proliferation of effector T cells, while preserving T regulatory cells, and induce autophagy, all of which are processes that are impaired in inclusion body myositis. In this pilot study, we aimed to test the efficacy of sirolimus in patients with inclusion body myositis. Methods This randomised, double-blind, placebo-controlled, proof-of-concept, phase 2b trial was done at a single hospital in Paris, France. The study included men and women (aged 45–80 years) who had a defined diagnosis of inclusion body myositis according to established criteria. Eligible participants were randomly assigned (1:1) to receive once-daily oral sirolimus 2 mg or placebo. Centralised balanced block randomisation (blocks of four) was computer generated without stratification. The study comprised a 15-day screening period (days −15 to 0) and a 52-week treatment period (day 0 to month 12). The primary endpoint was the relative percentage change from baseline to month 12 in maximal voluntary isometric knee extension strength. Secondary endpoints included the following assessments at months 6 and 12: 6-min walking distance, isometric muscle strength for hand grip (finger flexors), knee flexion and elbow flexion and extension, forced vital capacity, muscle replacement with fat measured by quantitative nuclear MRI, Inclusion Body Myositis Weakness Composite Index (IBMWCI), Inclusion Body Myositis Functional Rating Scale (IBMFRS), Health Assessment Questionnaire without Disability Index (HAQ-DI), and analyses of T-cell subpopulations by mass cytometry. The primary analysis was done on the intention-to-treat population. The trial is registered at ClinicalTrials.gov , NCT02481453 . Findings Between July 15, 2015, and May 13, 2016, we screened 285 patients, 44 of whom were randomly allocated to sirolimus (22 patients) or placebo (22 patients). We observed no difference in the primary outcome of relative percentage change from baseline to month 12 of the maximal voluntary isometric knee extension strength (median difference 3·78, 95% CI −10·61 to 17·31; p=0·85). For secondary outcomes, differences between the groups were not significant for changes in strength of other muscle groups (grip, elbow flexion and extension, or knee flexion), IBMWCI, IBMFRS, and lower limb muscle fat fraction. However, we observed significant differences in favour of sirolimus between the study groups for HAQ-DI, forced vital capacity, thigh fat fraction, and 6-min walking distance. Ten (45%) of 22 patients in the sirolimus group had a serious adverse event compared with six (27%) of 22 patients in the placebo group. Four (18%) patients in the sirolimus group stopped their treatment because of adverse events (severe mouth ulcers, aseptic pneumonia, renal insufficiency, and peripheral lower limb oedema), which resolved after treatment discontinuation. Canker sores were the most frequent side-effect and were mainly mild or moderate in ten patients. Interpretation We found no evidence for efficacy of sirolimus for treating inclusion body myositis based on maximal voluntary isometric knee extension strength and other muscle strength measures, and the side-effects of treatment were substantial for some patients. However, we believe there was enough evidence of benefit in certain secondary outcomes to pursue a multicentre phase 3 trial to further assess the safety and efficacy of sirolimus. Funding Institut national de la sante et de la recherche medicale, Direction generale de l'offre de soins, and Association Francaise contre les Myopathies.

International audience; Background: Our objective was to define the pattern and severity of muscle damage in immune-mediated necrotizing myopathy (IMNM) and its relationship with clinical and serological features.Methods: IMNM patients with a whole-body MRI (n=42) were included and compared to sporadic inclusion-body myositis (s-IBM) patients (n=60). Fat replacement was estimated using the Mercuri score in 55 muscles. Overall lesion load was defined as the sum of all abnormal Mercuri scores (reported in % maximal score) and lesion load quotient was defined as the overall lesion load divided by disease duration. Linear relationships between variables were assessed and multidimensional analysis was performed to define homogenous groups of patients.Results: IMNM patients were aged 48.1±15.8 years and had a disease duration of 9.8±8.1 years. Most severely affected muscle groups were located in the pelvifemoral and lumbar region. Unsupervised analysis showed two subgroups of patients: one with mild lesion load (15±10%, n=32/42) and another with severe lesion load (60±10%, n=10/42: p

BACKGROUND: Quantitative nuclear magnetic resonance imaging (NMRI) is an objective and precise outcome measure for evaluating disease progression in neuromuscular disorders. We aimed to investigate predictive ‘disease activity’ NMR indices, including water T(2) and (31)P NMR spectroscopy (NMRS), and its relation to NMR markers of ‘disease progression’, such as the changes in fat fraction (ΔFat%) and contractile cross-sectional area (ΔcCSA), in GNE myopathy (GNEM) patients. METHODS: NMR was performed on a 3T clinical scanner, at baseline and at a 1-year interval, in 10 GNEM patients and 29 age-matched controls. Dixon-based fat-water imaging and water T(2) mapping were acquired in legs and thighs, and in the dominant forearm. (31)P NMRS was performed at the level of quadriceps and hamstring. Water T(2) and (31)P NMRS indices were determined for all muscle groups and visits. Correlations were performed with ‘disease progression’ indices ΔFat%, ΔcCSA and the muscle fat transformation rate (R(muscle_transf)). RESULTS: In quadriceps, known to be relatively preserved in GNEM, water T(2) at baseline was significantly higher compared to controls, and correlated strongly with the one-year evolution of Fat% and cCSA and R(muscle_transf). Various (31)P NMRS indices showed significant differences in quadriceps and hamstring compared to controls and correlations existed between these indices and ΔFat%, ΔcCSA and R(muscle_transf). CONCLUSIONS: This study demonstrates that disease activity indices such as water T(2) and (31)P NMRS may predict disease progression in skeletal muscles of GNEM patients, and suggests that these measures may be considered to be valuable surrogate endpoints in the assessment of GNEM disease progression.

Magnetic resonance imaging (MRI) constitutes a powerful outcome measure in neuromuscular disorders, yet there is a broad diversity of approaches in data acquisition and analysis. Since each neuromuscular disease presents a specific pattern of muscle involvement, the recommended analysis is assumed to be the muscle-by-muscle approach. We, therefore, performed a comparative analysis of different segmentation approaches, including global muscle segmentation, to determine the best strategy for evaluating disease progression. In 102 patients (21 immune-mediated necrotizing myopathy/IMNM, 21 inclusion body myositis/IBM, 10 GNE myopathy/GNEM, 19 Duchenne muscular dystrophy/DMD, 12 dysferlinopathy/DYSF, 7 limb-girdle muscular dystrophy/LGMD2I, 7 Pompe disease, 5 spinal muscular atrophy/SMA), two MRI scans were obtained at a 1-year interval in thighs and lower legs. Regions of interest (ROIs) were drawn in individual muscles, muscle groups, and the global muscle segment. Standardized response means (SRMs) were determined to assess sensitivity to change in fat fraction (ΔFat%) in individual muscles, muscle groups, weighted combinations of muscles and muscle groups, and in the global muscle segment. Global muscle segmentation gave high SRMs for ΔFat% in thigh and lower leg for IMNM, DYSF, LGMD2I, DMD, SMA, and Pompe disease, and only in lower leg for GNEM and thigh for IBM. Global muscle segment Fat% showed to be sensitive to change in most investigated neuromuscular disorders. As compared to individual muscle drawing, it is a faster and an easier approach to assess disease progression. The use of individual muscle ROIs, however, is still of interest for exploring selective muscle involvement. • MRI-based evaluation of fatty replacement in muscles is used as an outcome measure in the assessment of 1-year disease progression in 8 different neuromuscular diseases. • Different segmentation approaches, including global muscle segmentation, were evaluated for determining 1-year fat fraction changes in lower limb skeletal muscles. • Global muscle segment fat fraction has shown to be sensitive to change in lower leg and thigh in most of the investigated neuromuscular diseases.

The goal of this study was to evaluate the reproducibility and repeatability of tissue sodium concentration (TSC) measurements using 23 Na MRI in skeletal muscle tissue. 23 Na MRI was performed at 3 T on the right lower leg of eight healthy volunteers (aged 28 ± 4 years). The examinations were repeated at the same site after ~ 22 weeks to assess the variability over a medium-term period. Additionally, they were scanned at a second site shortly before or shortly after the first visit (within 3 weeks) to evaluate the inter-site reproducibility. Moreover, we analysed the effect of B0 correction on the variability. Coefficients of variations (CVs) from mean TSC values as well as Bland-Altman plots were used to assess intra-site repeatability and inter-site reproducibility. In phantom measurements, the B0 correction improved the quantitative accuracy. We observed differences of up to 4.9 mmol/L between the first and second visit and a difference of up to 3.7 mmol/L between the two different sites. The CV for the medium-term repeatability was 15% and the reproducibility CV was 9%. The Bland-Altman plots indicated high agreement between the visits in all muscle regions. The systematic bias of -0.68 mmol/L between site X and Y (P = 0.03) was slightly reduced to -0.64 mmol/L after B0 correction (P = 0.04). This work shows that TSC measurements in healthy skeletal muscle tissue can be performed with good repeatability and reproducibility, which is of importance for future longitudinal or multicentre studies.

BACKGROUND The monoexponential water T2 (T2-mono ) is a proven biomarker of disease activity in neuromuscular disorders (NMDs). However, it lacks specificity, being elevated in the presence of several pathological processes and pathomorphological alterations in the muscle tissue. PURPOSE To investigate the multiexponential behavior of the water T2 -relaxation in the skeletal muscle of NMD patients, aiming to identify more sensitive and specific biomarkers of disease activity. STUDY TYPE Retrospective case-control. POPULATION Thirty Duchenne muscular dystrophy and 114 inclusion body myositis patients and 55 control subjects. FIELD STRENGTH/SEQUENCE 3T/Single-voxel proton spectroscopy (1 H-MRS) and multispin-echo (MSE) imaging. ASSESSMENT Water T2 -decay curves generated from 1 H-MRS data acquired at 14 echo-times were fitted to mono- and biexponential models and the adjusted R2 of each fit was computed. Additionally, T2 spectra were generated from a regularized inverse Laplace transform. For comparison, water T2 maps were generated from the MSE data. The performances of the different variables at identifying patients were assessed via receiver operating characteristic (ROC)-curve analysis. STATISTICAL TESTS Chi-square, Kruskal-Wallis, and Mann-Whitney with Bonferroni correction for multiple comparisons. RESULTS T2-mono was elevated in patients (P

International audience; Nemaline myopathies are clinically and genetically heterogeneous muscle diseases characterized by the presence of nemaline bodies (rods) in muscle fibers. Mutations in the KLHL40 (kelch-like family member 40) gene (NEM 8) are common cause of severe/lethal nemaline myopathy. We report an 8-year-old girl born to consanguineous Moroccan parents, who presented with hypotonia and poor sucking at birth, delayed motor development, and further mild difficulties in walking and fatigability. A muscle biopsy revealed the presence of nemaline bodies. KLHL40 gene Sanger sequencing disclosed a never before reported pathogenic homozygous mutation which resulted in absent KLHL40 protein expression in the muscle. This further expands the phenotypical spectrum of KLHL40 related nemaline myopathy.

Autosomal dominant pathogenic variants in the filamin C gene (FLNC) have been associated with myofibrillar myopathies, distal myopathies, and isolated cardiomyopathies. Mutations in different functional domains of FLNC can cause various clinical phenotypes. A novel heterozygous missense variant c.608G>A, p.(Cys203Tyr) in the actin binding domain of FLCN was found to cause an upper limb distal myopathy (MIM #614065). The muscle MRI findings are similar to those observed in FLNC-myofibrillar myopathy (MIM #609524). However, the muscle biopsy revealed >20% of muscle fibers with nemaline bodies, in addition to numerous ring fibers and a predominance of type 1 fibers. Overall, this case shows some unique and rare aspects of FLNC-myopathy constituting a new morphologic phenotype of FLNC-related myopathies.

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.

AimsBecker muscular dystrophy (BMD) is a genetic neuromuscular disease characterized by an alteration of the dystrophin protein. Myocardial involvement is frequent, eventually progressing to a dilated cardiomyopathy, and represents the most common cause of death for this pathology. We performed a comprehensive evaluation of myocardial functional and structural alterations encountered in a large cohort of BMD patients using quantitative cardiac magnetic resonance (CMR) imaging.Methods and resultsEighty-eight BMD patients and 26 age-matched volunteers underwent standard cine and tag imaging to assess myocardial function and dyssynchrony, while native T1, T2, and extracellular volume fraction (ECV) were measured for tissue characterization. The left ventricular ejection fraction (LV-EF) was significantly reduced in 26% of the BMD patients. Patients exhibited higher dyssynchrony index than controls (6.94 ± 3.17 vs. 5.09 ± 1.25, P = 0.005). Diastolic dyssynchrony also exists in patients where systolic function was normal. BMD subjects, compared with controls, had significantly higher native T1, T2, and ECV (1183 ± 60 ms vs. 1164 ± 22 ms, 47.5 ± 4.5 ms vs. 45.6 ± 3.4 ms, 0.282 ± 0.050 vs. 0.231 ± 0.027, respectively, P ConclusionQuantitative CMR represents a powerful tool to evaluate structural and functional impairments in the myocardium of BMD subjects. Native T1, T2, and ECV provided quantitative biomarkers related to inflammation and fibrosis, and could stratify disease severity.

To 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. The 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. The 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). T1-mapping is a good candidate for fast, sensitive and quantitative monitoring of fatty infiltrations in neuromuscular disorders. • 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.

The purpose of this study was to examine exercise effects on muscle water T2 in patients with Duchenne muscular dystrophy (DMD). In 12 DMD subjects and 19 controls, lower leg muscle fat (%) was measured by Dixon and muscle water T2 and R2 (1/T2) by the tri-exponential model. Muscle water R2 was measured again at 3 hours after an ankle dorsiflexion exercise. The muscle fat fraction was higher in DMD participants than in controls (p < .001) except in the tibialis posterior muscle. Muscle water T2 was measured independent of the degree of fatty degeneration in DMD muscle. At baseline, muscle water T2 was higher in all but the extensor digitorum longus muscles of DMD participants than controls (p < .001). DMD participants had a lower muscle torque (p < .001) and exerted less power (p < .01) during exercise than controls. Nevertheless, muscle water R2 decreased (T2 increased) after exercise from baseline in DMD subjects and controls with greater changes in the target muscles of the exercise than in ankle plantarflexor muscles. Skeletal muscle water T2 is a sensitive biomarker of the disease status in DMD and of the exercise response in DMD patients and controls.

Purpose Quantitative cardiac MRI, and more particularly T1 mapping, has become a most important modality to characterize myocardial tissue. In this work, the value of a radial variant of the conventional modified Look-Locker inversion recovery sequence (raMOLLI) is demonstrated. Methods The raMOLLI acquisition scheme consisted of five radial echo trains of 80 spokes acquired using either a fast low-angle shot (FLASH) or a true fast imaging with steady-state-precession (TrueFISP) readout at different time points after a single magnetization inversion. View sharing combined with a compressed sensing algorithm allowed the reconstruction of 50 images along the T1 relaxation recovery curve, to which a dictionary-fitting approach was applied to estimate T1 . The sequence was validated on a nine-vial phantom, on 19 healthy subjects, and one patient suffering from dilated cardiomyopathy. Results The raMOLLI sequence allowed a significant decrease of myocardial T1 map acquisition time down to five heartbeats, while exhibiting a higher degree of accuracy and a comparable precision on T1 value estimation than the conventional modified Look-Locker inversion recovery sequence. The FLASH readout demonstrated a better robustness to B0 inhomogeneities than TrueFISP, and was therefore preferred for in vivo acquisitions. Conclusions This sequence represents a good candidate for ultrafast acquisition of myocardial T1 maps. Magn Reson Med 79:1387-1398, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Introduction Patients with anoctamin-5 (ANO5) mutations may present not only with limb-girdle muscular dystrophy type 2L or adult-onset Miyoshi-type myopathy but also with asymptomatic hyperCKemia, exercise intolerance, or rhabdomyolysis. Materials and methods Data from 38 patients in France with ANO5 mutations with and without muscle weakness on first examination were compared. Results Twenty patients presented without muscle weakness. Median age at symptom onset or discovery of hyperCKemia was 23 years. Creatine kinase levels ranged from 200 to 40,000 U/L. Electromyography showed a myopathic pattern in 5 patients, and muscle imaging showed involvement of posterior calf muscles in 10 patients. Mild cardiac involvement was observed in 2 patients. Sixteen patients remain free of weakness after a median follow-up period of 5 years. Discussion Asymptomatic, sometimes mild hyperCKemia or exercise intolerance is a presentation of ANO5-related myopathy and may remain isolated or precede muscle weakness by many years. Muscle Nerve 56: 1096-1100, 2017.