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Background: Finding sensitive clinical outcome measures has become crucial in natural history studies and therapeutic trials of neuromuscular disorders. Here, we focus on 1-year longitudinal data from quantitative magnetic resonance imaging (MRI) and phosphorus magnetic resonance spectroscopy ( 31 P MRS) in a placebo-controlled study of sirolimus for inclusion body myositis (IBM), also examining their links to functional, strength, and clinical parameters in lower limb muscles., Methods: Quantitative MRI and 31 P MRS data were collected at 3 T from a single site, involving 44 patients (22 on placebo, 22 on sirolimus) at baseline and year-1, and 21 healthy controls. Assessments included fat fraction (FF), contractile cross-sectional area (cCSA), and water T 2 in global leg and thigh segments, muscle groups, individual muscles, as well as 31 P MRS indices in quadriceps or triceps surae. Analyses covered patient-control comparisons, annual change assessments via standard t-tests and linear mixed models, calculation of standardized response means (SRM), and exploration of correlations between MRI, 31 P MRS, functional, strength, and clinical parameters., Results: The quadriceps and gastrocnemius medialis muscles had the highest FF values, displaying notable heterogeneity and asymmetry, particularly in the quadriceps. In the placebo group, the median 1-year FF increase in the quadriceps was 3.2% (P < 0.001), whereas in the sirolimus group, it was 0.7% (P = 0.033). Both groups experienced a significant decrease in cCSA in the quadriceps after 1 year (P < 0.001), with median changes of 12.6% for the placebo group and 5.5% for the sirolimus group. Differences in FF and cCSA changes between the two groups were significant (P < 0.001). SRM values for FF and cCSA were 1.3 and 1.4 in the placebo group and 0.5 and 0.8 in the sirolimus group, respectively. Water T 2 values were highest in the quadriceps muscles of both groups, significantly exceeding control values in both groups (P < 0.001) and were higher in the placebo group than in the sirolimus group. After treatment, water T 2 increased significantly only in the sirolimus group's quadriceps (P < 0.01). Multiple 31 P MRS indices were abnormal in patients compared to controls and remained unchanged after treatment. Significant correlations were identified between baseline water T 2 and FF at baseline and the change in FF (P < 0.001). Additionally, significant correlations were observed between FF, cCSA, water T 2 , and functional and strength outcome measures., Conclusions: This study has demonstrated that quantitative MRI/ 31 P MRS can discern measurable differences between placebo and sirolimus-treated IBM patients, offering promise for future therapeutic trials in idiopathic inflammatory myopathies such as IBM., (© 2024 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC.)

Background: Dysferlinopathy is a phenotypically heterogeneous group of hereditary diseases caused by mutations in the DYSF gene. Early contractures are considered rare, and rigid spine syndrome in dysferlinopathy has been previously reported only once., Case Presentation: We describe a 23-year-old patient with Miyoshi myopathy with a rigid spine and multiple contractures, a rare phenotypic variant. The disease first manifested when the patient was 13 years old, with fatigue of the gastrocnemius muscles and the development of pronounced contractures of the Achilles tendons, flexors of the fingers, and extensors of the toes, followed by the involvement of large joints and the spine. Magnetic resonance imaging revealed signs of connective tissue and fatty replacement of the posterior muscles of the thighs and lower legs. Edema was noted in the anterior and medial muscle groups of the thighs, lower legs, and the multifidus muscle of the back. Whole genome sequencing revealed previously described mutations in the DYSF gene in exon 39 (c.4282 C > T) and intron 51 (c.5785-824 C > T). An immunohistochemical analysis and Western blot showed the complete absence of dysferlin protein expression in the muscle fibers., Conclusions: This case expands the range of clinical and phenotypic correlations of dysferlinopathy and complements the diagnostic search for spine rigidity., (© 2024. The Author(s).)

Background: The reference standard for assessing water T 2 (T 2,H2O ) at high fat fraction (FF) is 1 H MRS. T 2,H2O (T 2,H2O,MRS ) dependence on FF (FF MRS ) has recently been demonstrated in muscle at high FF (i.e. ≥60%)., Purpose: To investigate the relationship between T 2,H2O,MRS and FF MRS in the thigh/leg muscles of patients with neuromuscular diseases and to compare with quantitative MRI., Study Type: Retrospective case-control study., Population: A total of 151 patients with neuromuscular disorders (mean age ± standard deviation = 52.5 ± 22.6 years, 54% male), 44 healthy volunteers (26.5 ± 13.0 years, 57% male)., Field Strength/sequence: A 3-T; single-voxel stimulated echo acquisition mode (STEAM) MRS, multispin echo (MSE) imaging (for T 2 mapping, T 2,H2O,MRI ), three-point Dixon imaging (for FF MRI and R 2 * mapping)., Assessment: Mono-exponential and bi-exponential models were fitted to water T 2 decay curves to extract T 2,H2O,MRS and FF MRS . Water resonance full-width-at-half-maximum (FWHM) and B 0 spread (∆B 0 ) values were calculated. T 2,H2O,MRI (mean), FF MRI (mean, kurtosis, and skewness), and R 2 * (mean) values were estimated in the MRS voxel., Statistical Tests: Mann-Whitney U tests, Kruskal-Wallis tests. A P-value <0.05 was considered statistically significant., Results: Normal T 2,H2O,MRS threshold was defined as the 90 th percentile in healthy controls: 30.3 msec. T 2,H2O,MRS was significantly higher in all patients with FF MRS  < 60% compared to healthy controls. We discovered two subgroups in patients with FF MRS  ≥ 60%: one with T 2,H2O,MRS  ≥ 30.3 msec and one with T 2,H2O,MRS  < 30.3 msec including abnormally low T 2,H2O,MRS . The latter subgroup had significantly higher water resonance FWHM, ∆B 0 , FF MRI kurtosis, and skewness values but nonsignificantly different R 2 * (P = 1.00) and long T 2,H2O,MRS component and its fraction (P > 0.11) based on the bi-exponential analysis., Data Conclusion: The findings suggest that the cause for (abnormally) T 2,H2O,MRS at high FF MRS is biophysical, due to differences in susceptibility between muscle and fat (increased FWHM and ∆B 0 ), rather than pathophysiological such as compartmentation changes, which would be reflected by the bi-exponential analysis., Evidence Level: 3 TECHNICAL EFFICACY: Stage 3., (© 2023 International Society for Magnetic Resonance in Medicine.)

Duchenne muscular dystrophy (DMD) is one of the most common forms of hereditary muscular dystrophies in childhood and is characterized by steady progression and early disability. It is known that physical therapy can slow down the rate of progression of the disease. According to global recommendations, pool exercises, along with stretching, are preferable for children with DMD, as these types of activities have a balanced effect on skeletal muscles and allow simultaneous breathing exercises. The present study aimed to evaluate the effectiveness of regular pool exercises in patients with Duchenne muscular dystrophy who are capable of independent movement during 4 months of training. 28 patients with genetically confirmed Duchenne muscular dystrophy, who were aged 6.9 ± 0.2 years, were examined. A 6-min distance walking test and timed tests, namely, rising from the floor, 10-meter running, and stair climbing and descending, muscle strength of the upper and lower extremities were assessed on the baseline and during dynamic observation at 2 and 4 months. Hydrorehabilitation course lasted 4 months and was divided into two stages: preparatory and training (depend on individual functional heart reserve (IFHR)). Set of exercises included pool dynamic aerobic exercises. Quantitative muscle MRI of the pelvic girdle and thigh was performed six times: before training (further BT) and after training (further AT) during all course. According to the results of the study, a statistically significant improvement was identified in a 6-min walking test, with 462.7 ± 6.2 m on the baseline and 492.0 ± 6.4 m after 4 months ( p < 0.001). The results from the timed functional tests were as follows: rising from the floor test, 4.5 ± 0.3 s on the baseline and 3.8 ± 0.2 s after 4 months ( p < 0.001); 10 meter distance running test, 4.9 ± 0.1 s on the baseline and 4.3 ± 0.1 s after 4 months ( p < 0.001); 4-stair climbing test, 3.7 ± 0.2 s on the baseline and 3.2 ± 0.2 s after 4 months ( p < 0.001); and 4-stair descent test, 3.9 ± 0.1 s on the baseline and 3.2 ± 0.1 s after 4 months ( p < 0.001). Skeletal muscle quantitative MRI was performed in the pelvis and the thighs in order to assess the impact of the procedures on the muscle structure. Muscle water T2, a biomarker of disease activity, did not show any change during the training period, suggesting the absence of deleterious effects and negative impact on disease activity. Thus, a set of dynamic aerobic exercises in water can be regarded as effective and safe for patients with DMD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Suslov, Lieberman, Carlier, Ponomarenko, Ivanov, Rudenko, Suslova and Adulas.)

Dysferlinopathy is a muscle disease characterized by a variable clinical presentation and is caused by mutations in the DYSF gene. The Jain Clinical Outcome Study for Dysferlinopathy (COS) followed the largest cohort of patients (n=187) with genetically confirmed dysferlinopathy throughout a three-year natural history study, in which the patients underwent muscle function tests and muscle magnetic resonance imaging (MRI). We previously described the pattern of muscle pathology in this population and established a series of imaging criteria for diagnosis. In this paper, we describe the muscle imaging and clinical features of a subgroup of COS participants whose muscle imaging results did not completely meet the diagnostic criteria. We reviewed 184 T1-weighted (T1w) muscle MRI scans obtained at the baseline visit of the COS study, of which 106 were pelvic and lower limb only and 78 were whole-body scans. We identified 116 of the 184 patients (63%) who did not meet at least one of the established imaging criteria. The highest number found of unmet criteria was four per patient. We identified 24 patients (13%) who did not meet three or more of the nine established criteria and considered them as "outliers". The most common unmet criterion (27.3% of cases) was the adductor magnus being equally or more affected than the adductor longus. We compared the genetic, demographic, clinical and muscle function data of the outlier patients with those who met the established criteria and observed that the outlier patients had an age of disease onset that was significantly older than the whole group (29.3 vs 20.5 years, p=0.0001). This study expands the phenotypic muscle imaging spectrum of patients with dysferlinopathy and can help to guide the diagnostic process in patients with limb girdle weakness of unknown origin., Competing Interests: Declarations of Competing Interest Authors have no conflict of interest related to the content of this paper., (Copyright © 2023. Published by Elsevier B.V.)

Myostatin is a myokine which acts upon skeletal muscle to inhibit growth and regeneration. Myostatin is endogenously antagonised by follistatin. This study assessed serum myostatin and follistatin concentrations as monitoring or prognostic biomarkers in dysferlinopathy, an autosomal recessively inherited muscular dystrophy. Myostatin was quantified twice with a three-year interval in 76 patients with dysferlinopathy and 38 controls. Follistatin was quantified in 62 of these patients at the same timepoints, and in 31 controls. Correlations with motor function, muscle fat fraction and contractile cross-sectional area were performed. A regression model was used to account for confounding variables. Baseline myostatin, but not follistatin, correlated with baseline function and MRI measures. However, in individual patients, three-year change in myostatin did not correlate with functional or MRI changes. Linear modelling demonstrated that function, serum creatine kinase and C-reactive protein, but not age, were independently related to myostatin concentration. Baseline myostatin concentration predicted loss of ambulation but not rate of change of functional or MRI measures, even when relative inhibition with follistatin was considered. With adjustment for extra-muscular causes of variation, myostatin could form a surrogate measure of functional ability or muscle mass, however myostatin inhibition does not form a promising treatment target in dysferlinopathy., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023. Published by Elsevier B.V.)

Anti-MuSK myasthenia gravis (Anti-MuSK MG) is a chronic autoimmune disease caused by complement-independent dysfunction of the agrin-MuSK-Lrp4 complex, accompanied by the development of the pathological muscle fatigue and sometimes muscle atrophy. Fatty replacement of the tongue, mimic, masticatory and paravertebral muscles, revealed by muscle MRI and proton magnetic resonance spectroscopy (MRS), is considered to be a consequence of the myogenic process in anti-MuSK antibody MG in the patients with a plenty long course of the disease. However, in most experimental studies on animal models with anti-MuSK MG, complex presynaptic and postsynaptic changes are revealed, accompanied by the functional denervation of masticatory and paravertebral muscles predominantly. This study presents the MRI, nerve conduction studies (NCS), repetitive nerve stimulation (RNS) and electromyography (EMG) of neurogenic lesions of the axial muscles (m. Multifidus Th12, L3-L5; m. Erector spinae L4-L5) in two patients K. (51 years old), and P. (44 years old), both of whom were having weakness of the paravertebral muscles for 2-4 months due to anti-MuSK MG. The clinical manifestations, as well as the edematous changes in the paravertebral muscles, regressed after therapy. Thus, these clinical examples may confirm the presence of the neurogenic changes at an early stage of anti-MuSK myasthenia gravis and indicate importance of immediate initiation of therapy to avoid the development of muscle atrophy and fatty infiltration., (©2022 Gaetano Conte Academy - Mediterranean Society of Myology, Naples, Italy.)

The second edition of the Baltic School of Neuromyology took place on August 26-27, 2022 in Riga (Latvia), in a somewhat peculiar atmosphere given the international situation. An opportunity for the authors to measure the accomplishments made by their Baltic counterparts in the diagnosis and management of neuromuscular disorders, a successful although challenging venture, which led to the integration of three Baltic neuromuscular reference centers to the European Reference Network Euro-NMD. Beyond this form of consecration, and even though a lot remains to be achieved, notably in the field of muscle histopathology, various Baltic teams showed truly remarkable pieces of clinical research that will be useful to the whole myology community worldwide., (© 2022 médecine/sciences – Inserm.)

Background: Water T2 (T2 H2O ) mapping is increasingly being used in muscular dystrophies to assess active muscle damage. It has been suggested as a surrogate outcome measure for clinical trials. Here, we investigated the prognostic utility of T2 H2O to identify changes in muscle function over time in limb girdle muscular dystrophies., Methods: Patients with genetically confirmed dysferlinopathy were assessed as part of the Jain Foundation Clinical Outcomes Study in dysferlinopathy. The cohort included 18 patients from two sites, both equipped with 3-tesla magnetic resonance imaging (MRI) systems from the same vendor. T2 H2O value was defined as higher or lower than the median in each muscle bilaterally. The degree of deterioration on four functional tests over 3 years was assessed in a linear model against covariates of high or low T2 H2O at baseline, age, disease duration, and baseline function., Results: A higher T2 H2O at baseline significantly correlated with a greater decline on functional tests in 21 out of 35 muscles and was never associated with slower decline. Higher baseline T2 H2O in adductor magnus, vastus intermedius, vastus lateralis, and vastus medialis were the most sensitive, being associated bilaterally with greater decline in multiple timed tests. Patients with a higher than median baseline T2 H2O (>40.6 ms) in the right vastus medialis deteriorated 11 points more on the North Star Ambulatory Assessment for Dysferlinopathy and lost an additional 86 m on the 6-min walk than those with a lower T2 H2O (<40.6 ms). Optimum sensitivity and specificity thresholds for predicting decline were 39.0 ms in adductor magnus and vastus intermedius, 40.0 ms in vastus medialis, and 40.5 ms in vastus lateralis from different sites equipped with different MRI systems., Conclusions: In dysferlinopathy, T2 H2O did not correlate with current functional ability. However, T2 H2O at baseline was higher in patients who worsened more rapidly on functional tests. This suggests that inter-patient differences in functional decline over time may be, in part, explained by different severities of the active muscle damage, assessed by T2 H2O measure at baseline. Significant challenges remain in standardizing T2 H2O values across sites to allow determining globally applicable thresholds. The results from the present work are encouraging and suggest that T2 H2O could be used to improve prognostication, patient selection, and disease modelling for clinical trials., (© 2022 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

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 1 Hinformation (e.g., dynamic shim updates and motion correction) can be used to improve data quality during long scans and benefits image coregistration. This work reviews the literature on interleaved and simultaneous multi-nuclear MRI and MRS in vivo. Prominent use cases for this methodology in clinical and research applications are brain and muscle, but studies have also been carried out in other targets, including the lung, knee, breast and heart. Simultaneous multi-nuclear measurements in the liver and kidney have also been performed, but exclusively in rodents. In this review, a consistent nomenclature is proposed, to help clarify the terminology used for this principle throughout the literature on in-vivo MR. An overview covers the basic principles, the technical requirements on the MR scanner and the implementations realised either by MR system vendors or research groups, from the early days until today. Considerations regarding the multi-tuned RF coils required and heteronuclear polarisation interactions are briefly discussed, and fields for future in-vivo applications for interleaved multi-nuclear MR pulse sequences are identified., (© 2022 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.)

Background: Natural history studies in neuromuscular disorders are vital to understand the disease evolution and to find sensitive outcome measures. We performed a longitudinal assessment of quantitative magnetic resonance imaging (MRI) and phosphorus magnetic resonance spectroscopy ( 31 P MRS) outcome measures and evaluated their relationship with function in lower limb skeletal muscle of dysferlinopathy patients., Methods: Quantitative MRI/ 31 P MRS data were obtained at 3 T in two different sites in 54 patients and 12 controls, at baseline, and three annual follow-up visits. Fat fraction (FF), contractile cross-sectional area (cCSA), and muscle water T 2 in both global leg and thigh segments and individual muscles and 31 P MRS indices in the anterior leg compartment were assessed. Analysis included comparisons between patients and controls, assessments of annual changes using a linear mixed model, standardized response means (SRM), and correlations between MRI and 31 P MRS markers and functional markers., Results: Posterior muscles in thigh and leg showed the highest FF values. FF at baseline was highly heterogeneous across patients. In ambulant patients, median annual increases in global thigh and leg segment FF values were 4.1% and 3.0%, respectively (P < 0.001). After 3 years, global thigh and leg FF increases were 9.6% and 8.4%, respectively (P < 0.001). SRM values for global thigh FF were over 0.8 for all years. Vastus lateralis muscle showed the highest SRM values across all time points. cCSA decreased significantly after 3 years with median values of 11.0% and 12.8% in global thigh and global leg, respectively (P < 0.001). Water T 2 values in ambulant patients were significantly increased, as compared with control values (P < 0.001). The highest water T 2 values were found in the anterior part of thigh and leg. Almost all 31 P MRS indices were significantly different in patients as compared with controls (P < 0.006), except for pH w , and remained, similar as to water T 2 , abnormal for the whole study duration. Global thigh water T 2 at baseline was significantly correlated to the change in FF after 3 years (ρ = 0.52, P < 0.001). There was also a significant relationship between the change in functional score and change in FF after 3 years in ambulant patients (ρ = -0.55, P = 0.010)., Conclusions: This multi-centre study has shown that quantitative MRI/ 31 P MRS measurements in a heterogeneous group of dysferlinopathy patients can measure significant changes over the course of 3 years. These data can be used as reference values in view of future clinical trials in dysferlinopathy or comparisons with quantitative MRI/S data obtained in other limb-girdle muscular dystrophy subtypes., (© 2022 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

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., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction/aims: There is debate about whether and to what extent either respiratory or cardiac dysfunction occurs in patients with dysferlinopathy. This study aimed to establish definitively whether dysfunction in either system is part of the dysferlinopathy phenotype., Methods: As part of the Jain Foundation's International Clinical Outcome Study (COS) for dysferlinopathy, objective measures of respiratory and cardiac function were collected twice, with a 3-y interval between tests, in 188 genetically confirmed patients aged 11-86 y (53% female). Measures included forced vital capacity (FVC), electrocardiogram (ECG), and echocardiogram (echo)., Results: Mean FVC was 90% predicted at baseline, decreasing to 88% at year 3. FVC was less than 80% predicted in 44 patients (24%) at baseline and 48 patients (30%) by year 3, including ambulant participants. ECGs showed P-wave abnormalities indicative of delayed trans-atrial conduction in 58% of patients at baseline, representing a risk for developing atrial flutter or fibrillation. The prevalence of impaired left ventricular function or hypertrophy was comparable to that in the general population., Discussion: These results demonstrate clinically significant respiratory impairment and abnormal atrial conduction in some patients with dysferlinopathy. Therefore, we recommend that annual or biannual follow-up should include FVC measurement, enquiry about arrhythmia symptoms and peripheral pulse palpation to assess cardiac rhythm. However, periodic specialist cardiac review is probably not warranted unless prompted by symptoms or abnormal pulse findings., (© 2022 The Authors. Muscle & Nerve published by Wiley Periodicals LLC.)

Dysferlinopathy is a muscular dystrophy with a highly variable functional disease progression in which the relationship of function to some patient reported outcome measures (PROMs) has not been previously reported. This analysis aims to identify the suitability of PROMs and their association with motor performance.Two-hundred and four patients with dysferlinopathy were identified in the Jain Foundation's Clinical Outcome Study in Dysferlinopathy from 14 sites in 8 countries. All patients completed the following PROMs: Individualized Neuromuscular Quality of Life Questionnaire (INQoL), International Physical Activity Questionnaire (IPAQ), and activity limitations for patients with upper and/or lower limb impairments (ACTIVLIMs). In addition, nonambulant patients completed the Egen Klassifikation Scale (EK). Assessments were conducted annually at baseline, years 1, 2, 3, and 4. Data were also collected on the North Star Assessment for Limb Girdle Type Muscular Dystrophies (NSAD) and Performance of Upper Limb (PUL) at these time points from year 2. Data were analyzed using descriptive statistics and Rasch analysis was conducted on ACTIVLIM, EK, INQoL. For associations, graphs (NSAD with ACTIVLIM, IPAQ and INQoL and EK with PUL) were generated from generalized estimating equations (GEE). The ACTIVLIM appeared robust psychometrically and was strongly associated with the NSAD total score (Pseudo R 2 0.68). The INQoL performed less well and was poorly associated with the NSAD total score (Pseudo R 2 0.18). EK scores were strongly associated with PUL (Pseudo R 2 0.69). IPAQ was poorly associated with NSAD scores (Pseudo R 2 0.09). This study showed that several of the chosen PROMs demonstrated change over time and a good association with functional outcomes. An alternative quality of life measure and method of collecting data on physical activity may need to be selected for assessing dysferlinopathy., Competing Interests: MJ receives fee support for PhD studies from the Jain Foundation. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Mayhew, James, Moore, Sutherland, Jacobs, Feng, Lowes, Alfano, Muni Lofra, Rufibach, Rose, Duong, Bello, Pedrosa-Hernández, Holsten, Sakamoto, Canal, Sánchez-Aguilera Práxedes, Thiele, Siener, Vandevelde, DeWolf, Maron, Gordish-Dressman, Hilsden, Guglieri, Hogrel, Blamire, Carlier, Spuler, Day, Jones, Bharucha-Goebel, Salort-Campana, Pestronk, Walter, Paradas, Stojkovic, Mori-Yoshimura, Bravver, Díaz-Manera, Pegoraro, Mendell and Straub.)

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., (©2021 Gaetano Conte Academy - Mediterranean Society of Myology, Naples, Italy.)

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 < .001). Similarly, pericardial fat mass was increased in patients compared to controls (28.3 g/m2 [17.9-38.0] vs 11.4 g/m2 [7.5-19.4], P = .003). Sex, glycated hemoglobin A1c, and the presence of hypercortisolism were independent determinants of epicardial fat. Pericardial fat was associated with sex, impaired glucose homeostasis and left ventricular wall thickness. Disease remission decreased epicardial fat mass without affecting pericardial fat., 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., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To understand the natural disease upper limb progression over 3 years of ambulatory and non-ambulatory patients with Duchenne muscular dystrophy (DMD) using functional assessments and quantitative magnetic resonance imaging (MRI) and to exploratively identify prognostic factors., Methods: Forty boys with DMD (22 non-ambulatory and 18 ambulatory) with deletions in dystrophin that make them eligible for exon 53-skipping therapy were included. Clinical assessments, including Brooke score, motor function measure (MFM), hand grip and key pinch strength, and upper limb distal coordination and endurance (MoviPlate), were performed every 6 months and quantitative MRI of fat fraction (FF) and lean muscle cross sectional area (flexor and extensor muscles) were performed yearly., Results: In the whole population, there were strong nonlinear correlations between outcome measures. In non-ambulatory patients, annual changes over the course of 3 years were detected with high sensitivity standard response mean (|SRM| ≥0.8) for quantitative MRI-based FF, hand grip and key pinch, and MFM. Boys who presented with a FF<20% and a grip strength >27% were able to bring a glass to their mouth and retained this ability in the following 3 years. Ambulatory patients with grip strength >35% of predicted value and FF <10% retained ambulation 3 years later., Interpretation: We demonstrate that continuous decline in upper limb strength, function, and MRI measured muscle structure can be reliably measured in ambulatory and non-ambulatory boys with DMD with high SRM and strong correlations between outcomes. Our results suggest that a combination of grip strength and FF can be used to predict important motor milestones., (© 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

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 (FF Dixon ), water T2 mapping, and MRF T1-FF, from which the FF measured with MRF T1-FF (FF MRF ) 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 FF MRF and FF Dixon ( R 2 = 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 ( R 2 = 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 .

Purpose: To evaluate the repeatability of multinuclear interleaved 1 H/ 31 P NMR dynamic acquisitions in skeletal muscle and the impact of nuclear Overhauser enhancement (nOe) on the 31 P results at 3T in exercise-recovery and ischemia-hyperemia paradigms., Methods: A 1 H/ 31 P interleaved pulse sequence was used to measure every 2.5 s a perfusion-weighted image, a T 2 ∗ map, a 31 P spectrum and 32 1 H spectra sensitive to deoxymyoglobin. 21 subjects performed a plantar flexion exercise and after recovery underwent an 8-min lower leg ischemia. The procedure was repeated in visit 2 with 12 subjects. An additional exercise bout without 1 H excitation was appended to visit 1. Individual 1 H RF pulse nOe was measured at rest in every visit., Results: Repeatability scores (coefficient of variation, Bland-Altman analysis) were similar to those found in the literature using similar mono-nuclear acquisitions. |Pi]/[PCr], pH drop, creatine rephosphorylation rate (τ PCr ), maximum perfusion, time to peak perfusion, and blood flow post-exercise showed high reliability (intraclass correlation coefficient > 0.7), whereas hemodynamic results from reactive hyperemia showed higher repeatability. After accounting for nOe, which increased Pi and PCr signal-to-noise ratio by 30%, no differences in 31 P results were observed between interleaved and 31 P MRS-only acquisitions. τ PCr was unaffected by nOe., Conclusion: The method shows good repeatability for both paradigms while simultaneously providing multiple dynamic data sets on a clinical scanner. The nOe effects were accounted for on a per-subject and per-visit basis using a short 31 P reference scan. This multiparametric approach has a multitude of applications for the study of oxygen utilization and ATP turnover in the muscle., (© 2021 International Society for Magnetic Resonance in Medicine.)

Objectives: 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., Methods: 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., Results: 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., Conclusions: 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., Key Points: • 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.

Objective: Dysferlinopathy is a muscular dystrophy with a highly variable clinical presentation and currently unpredictable progression. This variability and unpredictability presents difficulties for prognostication and clinical trial design. The Jain Clinical Outcomes Study of Dysferlinopathy aims to establish the validity of the North Star Assessment for Limb Girdle Type Muscular Dystrophies (NSAD) scale and identify factors that influence the rate of disease progression using NSAD., Methods: We collected a longitudinal series of functional assessments from 187 patients with dysferlinopathy over 3 years. Rasch analysis was used to develop the NSAD, a motor performance scale suitable for ambulant and nonambulant patients. Generalized estimating equations were used to evaluate the impact of patient factors on outcome trajectories., Results: The NSAD detected significant change in clinical progression over 1 year. The steepest functional decline occurred during the first 10 years after symptom onset, with more rapid decline noted in patients who developed symptoms at a younger age (p = 0.04). The most rapidly deteriorating group over the study was patients 3 to 8 years post symptom onset at baseline., Interpretation: The NSAD is the first validated limb girdle specific scale of motor performance, suitable for use in clinical practice and clinical trials. Longitudinal analysis showed it may be possible to identify patient factors associated with greater functional decline both across the disease course and in the short-term for clinical trial preparation. Through further work and validation in this cohort, we anticipate that a disease model incorporating functional performance will allow for more accurate prognosis for patients with dysferlinopathy. ANN NEUROL 2021;89:967-978., (© 2021 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

This study aims to determine clinically relevant phenotypic differences between the two most common phenotypic classifications in dysferlinopathy, limb girdle muscular dystrophy R2 (LGMDR2) and Miyoshi myopathy (MMD1). LGMDR2 and MMD1 are reported to involve different muscles, with LGMDR2 showing predominant limb girdle weakness and MMD1 showing predominant distal lower limb weakness. We used heatmaps, regression analysis and principle component analysis of functional and Magnetic Resonance Imaging data to perform a cross-sectional review of the pattern of muscle involvement in 168 patients from the Jain Foundation's international Clinical Outcomes Study for Dysferlinopathy. We demonstrated that there is no clinically relevant difference in proximal vs distal involvement between diagnosis. There is a continuum of distal involvement at any given degree of proximal involvement and patients do not fall into discrete distally or proximally affected groups. There appeared to be geographical preference for a particular diagnosis, with MMD1 being more common in Japan and LGMDR2 in Europe and the USA. We conclude that the dysferlinopathies do not form two distinct phenotypic groups and therefore should not be split into separate cohorts of LGMDR2 and MM for the purposes of clinical management, enrolment in clinical trials or access to subsequent treatments., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Our aim was to assess the role of quantitative 1 H and 23 Na 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-T 2 w images, fat fraction (FF), water T 2 (wT 2 ), water T 1 (wT 1 ), 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 (wT 1 and wT 2 ) and ion homeostasis (TSC, IR, TQF) were increased in muscles of FSHD patients. Muscle groups with FF > 10% had higher wT 2 , wT 1 , TSC, IR, and TQF values than muscles with FF < 10%. Muscles with FF < 10% resembled muscles of healthy controls for these MRI disease activity measures. However, wT 1 was increased in few muscles without fat replacement. Furthermore, few STIR-negative muscles (n = 11/76) exhibited increased wT 1 , TSC, IR or TQF. Increased wT 1 as well as 23 Na signals were also present in muscles with normal wT 2 . Muscle strength was related to the mean FF and all imaging biomarkers of tibialis anterior except wT 2 were correlated with dorsal flexion., Conclusion: The newly evaluated imaging biomarkers related with water mobility (wT 1 ) 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.

Background: The availability of non-invasive, accessible, and reliable methods for estimating regional skeletal muscle volume is paramount in conditions involving primary and/or secondary muscle wasting. This work aimed at (i) optimizing serial bioelectrical impedance analysis (S BIA ) by computing a conductivity constant based on quantitative magnetic resonance imaging (MRI) data and (ii) investigating the potential of S BIA for estimating lean regional thigh muscle volume in patients with severe muscle disorders., Methods: Twenty healthy participants with variable body mass index and 20 patients with idiopathic inflammatory myopathies underwent quantitative MRI. Anatomical images and fat fraction maps were acquired in thighs. After manual muscle segmentation, lean thigh muscle volume (lV MRI ) was computed. Subsequently, multifrequency (50 to 350 kHz) serial resistance profiles were acquired between current skin electrodes (i.e. ankle and hand) and voltage electrodes placed on the anterior thigh. In vivo values of the muscle electrical conductivity constant were computed using data from S BIA and MRI gathered in the right thigh of 10 healthy participants. Lean muscle volume (lV BIA ) was derived from S BIA measurements using this newly computed constant. Between-day reproducibility of lV BIA was studied in six healthy participants., Results: Electrical conductivity constant values ranged from 0.82 S/m at 50 kHz to 1.16 S/m at 350 kHz. The absolute percentage difference between lV BIA and lV MRI was greater at frequencies >270 kHz (P < 0.0001). The standard error of measurement and the intra-class correlation coefficient for lV BIA computed from measurements performed at 155 kHz (i.e. frequency with minimal difference) against lV MRI were 6.1% and 0.95 in healthy participants and 9.4% and 0.93 in patients, respectively. Between-day reproducibility of lV BIA was as follows: standard error of measurement = 4.6% (95% confidence interval [3.2, 7.8] %), intra-class correlation coefficient = 0.98 (95% confidence interval [0.95, 0.99])., Conclusions: These findings demonstrate a strong agreement of lean muscle volume estimated using S BIA against quantitative MRI in humans, including in patients with severe muscle wasting and fatty degeneration. S BIA shows promises for non-invasive, fast, and accessible estimation and follow-up of lean regional skeletal muscle volume for transversal and longitudinal studies., (© 2020 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

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, T 2 , 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.

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 santé et de la recherche médicale, Direction générale de l'offre de soins, and Association Française contre les Myopathies., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: The monoexponential water T 2 (T 2-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 T 2 -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 T 2 -decay curves generated from 1 H-MRS data acquired at 14 echo-times were fitted to mono- and biexponential models and the adjusted R 2 of each fit was computed. Additionally, T 2 spectra were generated from a regularized inverse Laplace transform. For comparison, water T 2 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: T 2-mono was elevated in patients (P<0.05), but could not distinguish inclusion body myositis (IBM) from Duchenne muscular dystrophy (DMD). While 79% of IBM data presented a biexponential behavior, this was only 16% and 10% for DMD and control data, respectively (P<0.05). All T 2 spectra presented an intermediate-T 2 peak characterized by an elevated T 2 in patients (P<0.05) and by a relative fraction that was abnormally smaller in IBM patients (P<0.05). Also, a long-T 2 peak was exclusively observed in IBM patients. A combination of T 2 -spectrum variables performed best at identifying patients., Data Conclusion: T 2 spectra not only provided more sensitive and specific markers of disease presence than the T 2-mono , but also allowed distinguishing IBM from DMD patients. This must reflect distinct predominant pathological alterations between these diseases, suggesting that these markers provide additional pathophysiological/histopathological information that are missing from T 2-mono ., Level of Evidence: 3 TECHNICAL EFFICACY STAGE: 3., (© 2020 International Society for Magnetic Resonance in Medicine.)

Practice of sports during childhood or adolescence correlates with an earlier onset and more rapidly progressing phenotype in dysferlinopathies. To determine if this correlation relates to greater muscle pathology that persists into adulthood, we investigated the effect of exercise on the degree of muscle fatty replacement measured using muscle MRI. We reviewed pelvic, thigh and leg T1W MRI scans from 160 patients with genetically confirmed dysferlinopathy from the Jain Foundation International clinical outcomes study in dysferlinopathy. Two independent assessors used the Lamminen-Mercuri visual scale to score degree of fat replacement in each muscle. Exercise intensity for each individual was defined as no activity, minimal, moderate, or intensive activity by using metabolic equivalents and patient reported frequency of sports undertaken between the ages of 10 and 18. We used ANCOVA and linear modeling to compare the mean Lamminen-Mercuri score for the pelvis, thigh, and leg between exercise groups, controlling for age at assessment and symptom duration. Intensive exercisers showed greater fatty replacement in the muscles of the pelvis than moderate exercisers, but no significant differences of the thigh or leg. Within the pelvis, Psoas was the muscle most strongly associated with this exercise effect. In patients with a short symptom duration of <15 years there was a trend toward greater fatty replacement in the muscles of the thigh. These findings define key muscles involved in the exercise-phenotype effect that has previously been observed only clinically in dysferlinopathy and support recommendations that pre-symptomatic patients should avoid very intensive exercise., Competing Interests: UM, MJa, LR, AB, and AP reports the grant from the Jain Foundation. JD reports the grant from the Jain Foundation, personal fees from Biogen, Ionis, Avexis, Roche, Sarepta, Sanofi, Genzyme, Scholar Rock, Pfizer plus patents from Athena Diagnostics. DB-G reports membership of the Gene Therapy Network (Avexis). MW reports advisory board membership for Avexis, Biogen, Novartis, Roche, Santhera, Sarepta, PTC Therapeutics, Ultragenyx, Wave Sciences, plus personal fees from Novartis, Biogen, Ultragenyx, Santhera, PTC Therapeutics, Ask Bio, Audentes Therapeutics, Fulcrum Therapeutics, GIG Consul, Guidepoint Global, Novartis, PTC, Gruenthal Pharma. EP reports grants, personal fees, and non-financial support from Santhera, personal fees, and non-financial support from Sarepta, Personal fees, and non-financial support from PTC pharmaceuticals all outside this submitted work. VS reports the Jain Foundation grant and other grants and personal fees from Sarepta Therapeutics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Moore, Jacobs, Fernandez-Torron, LLauger Rossello, Smith, James, Mayhew, Rufibach, Carlier, Blamire, Day, Jones, Bharucha-Goebel, Salort-Campana, Pestronk, Walter, Paradas, Stojkovic, Mori-Yoshimura, Bravver, Pegoraro, Mendell, Bushby, Straub and Diaz-Manera.)

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<0.001) associated with a mean disease duration of 6.8±6.0 years and 19.5±5.7 years, respectively (p<0.0001). Correlational studies confirmed that disease duration was the most important predictor of muscle damage. Multivariate analyses demonstrated a more severe involvement in select muscle groups in females and seropositive patients. No difference was found in overall lesion load quotient of IMNM compared to IBM (p=0.07) but with a distinct muscle pattern., Conclusion: IMNM is associated with severe axial and pelvifemoral muscle damage. Disease duration is an important predictor of muscle damage. IMNM and s-IBM patients have a comparable damage burden., Competing Interests: Declaration of Competing Interest None., (Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.)

Magnetic resonance fingerprinting (MRF) provides a unique concept for simultaneous and fast acquisition of multiple quantitative MR parameters. Despite acquisition efficiency, adoption of MRF into the clinics is hindered by its dictionary matching-based reconstruction, which is computationally demanding and lacks scalability. Here, we propose a convolutional neural network-based reconstruction, which enables both accurate and fast reconstruction of parametric maps, and is adaptable based on the needs of spatial regularization and the capacity for the reconstruction. We evaluated the method using MRF T1-FF, an MRF sequence for T1 relaxation time of water (T1 H 2 O ) and fat fraction (FF) mapping. We demonstrate the method's performance on a highly heterogeneous dataset consisting of 164 patients with various neuromuscular diseases imaged at thighs and legs. We empirically show the benefit of incorporating spatial regularization during the reconstruction and demonstrate that the method learns meaningful features from MR physics perspective. Further, we investigate the ability of the method to handle highly heterogeneous morphometric variations and its generalization to anatomical regions unseen during training. The obtained results outperform the state-of-the-art in deep learning-based MRF reconstruction. The method achieved normalized root mean squared errors of 0.048  ±  0.011 for T1 H 2 O maps and 0.027  ±  0.004 for FF maps when compared to the dictionary matching in a test set of 50 patients. Coupled with fast MRF sequences, the proposed method has the potential of enabling multiparametric MR imaging in clinically feasible time., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier B.V.)

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., (© 2020 American Association of Neuropathologists, Inc. All rights reserved.)

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&#95;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&#95;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&#95;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., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/qims-20-39). AB reports personal fees from Ultragenyx pharmaceutical, during the conduct of the study; LS reports grants and personal fees from Avexis, grants and personal fees from Biogen, grants and personal fees from Roche, personal fees from Cytokinetics, personal fees from Sarepta, personal fees from Biophytis, personal fees from Pfizer, personal fees from Catabasis, personal fees from Lupin, grants and personal fees from Dynacure, personal fees from Audentes, outside the submitted work; PGC reports personal fees from Santhera, personal fees from Sanofi, personal fees from Sarepta, outside the submitted work. The authors have no other conflicts of interest to declare., (2020 Quantitative Imaging in Medicine and Surgery. All rights reserved.)

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 B 0 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 B 0 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 B 0 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., (© 2020 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.)

Objective: We 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)., Methods: VL 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., Results: Eighty-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)., Conclusions: The 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., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Purpose: To develop a fast MR fingerprinting (MRF) sequence for simultaneous estimation of water T1 (T1 H2O ) and fat fraction (FF) in fat infiltrated skeletal muscles., Methods: The MRF sequence for T1 H2O and FF quantification (MRF T1-FF) comprises a 1400 radial spokes echo train, following nonselective inversion, with varying echo and repetition time, as well as prescribed flip angle. Undersampled frames were reconstructed at different acquisition time-points by nonuniform Fourier transform, and a bi-component model based on Bloch simulations applied to adjust the signal evolution and extract T1 H2O and FF. The sequence was validated on a multi-vial phantom, in three healthy volunteers and five patients with neuromuscular diseases. We evaluated the agreement between MRF T1-FF parameters and reference values and confounding effects due to B0 and B1 inhomogeneities., Results: In phantom, T1 H2O and FF were highly correlated with references values measured with multi-inversion time inversion recovery-stimulated echo acquisition mode and Dixon, respectively (R 2 > 0.99). In vivo, T1 H2O and FF determined by the MRF T1-FF sequence were also correlated with reference values (R 2 = 0.98 and 0.97, respectively). The precision on T1 H2O was better than 5% for muscles where FF was less than 0.4. Both T1 H2O and FF values were not confounded by B0 nor B1 inhomogeneities., Conclusion: The MRF T1-FF sequence derived T1 H2O and FF values in voxels containing a mixture of water and fat protons. This method can be used to comprehend and characterize the effects of tissue water compartmentation and distribution on muscle T1 values in patients affected by chronic fat infiltration., (© 2019 International Society for Magnetic Resonance in Medicine.)

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 T 2 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 T 2 , and pH were higher in DMD patients (0.07 ± 0.03, 39.4 ± 0.8 msec, 7.06 ± 0.03, all P < 0.05) than in controls (0.02 ± 0.01, 36.0 ± 0.4 msec, 7.03 ± 0.02). No difference was observed in diffusion properties. TSC (26.0 ± 1.3 mM, P < 0.05) and ICwS (0.69 ± 0.05 a.u., P < 0.05) were elevated in DMD (controls: 16.5 ± 1.3 mM and 0.47 ± 0.04 a.u.). The ICwS was frequently abnormal in DMD even when water T 2 , FF, and pH were in the normal range. 23 Na MRI showed higher AUC values in comparison to the 1 H methods., Data Conclusion: Sodium anomalies were regularly observed in patients with DMD compared with controls, and were present even in absence of fatty degenerative changes and water T 2 increases., Level of Evidence: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:1103-1113., (© 2019 International Society for Magnetic Resonance in Medicine.)

Early studies have demonstrated that (total) magnesium was decreased in skeletal muscle of Duchenne muscular dystrophy (DMD) patients. Free intramuscular Mg 2+ can be derived from 31 P NMRS measurements. The value of free intramuscular magnesium concentration ([Mg 2+ ]) is highly dependent on precise knowledge of intracellular pH, which is abnormally alkaline in dystrophic muscle, possibly due to an expanded interstitial space, potentially causing an underestimation of [Mg 2+ ]. We have recently shown that intracellular pH can be derived using 1 H NMRS of carnosine. Our aim was to determine whether 31 P NMRS-based [Mg 2+ ] is, in fact, abnormally low in DMD patients, taking advantage of the 1 H NMRS-based pH. A comparative analysis was, therefore, made between [Mg 2+ ] values calculated with both 1 H and 31 P NMRS-based approaches to determine pH in 25 DMD patients, on a 3-T clinical NMR scanner. [Mg 2+ ] was also assessed with 31 P NMRS only in (forearm or leg) skeletal muscle of 60 DMD patients and 63 age-matched controls. Additionally, phosphodiester levels as well as quantitative NMRI indices including water T 2 , fat fraction, contractile cross-sectional area and one-year changes were evaluated. The main finding was that the significant difference in [Mg 2+ ] between DMD patients and controls was preserved even when the intracellular pH determined with 1 H NMRS was similar in both groups. Consequently, we observed that [Mg 2+ ] is significantly lower in DMD patients compared with controls in the larger database where only 31 P NMRS data were obtained. Significant yet weak correlations existed between [Mg 2+ ] and PDE, water T 2 and fat fraction. We concluded that low [Mg 2+ ] is an actual finding in DMD, whether intracellular pH is normal or alkaline, and that it is a likely consequence of membrane leakiness. The response of Mg 2+ to therapeutic treatment remains to be investigated in neuromuscular disorders. Free [Mg 2+ ] determination with 31 P NMRS is highly dependent on a precise knowledge of intracellular pH. The pH of Duchenne muscular dystrophy (DMD) patients, as determined by 31 P NMRS, is abnormally alkaline. We have recently shown that intracellular pH could be determined using 1 H NMRS of carnosine, and that intracellular pH was alkaline in a proportion of, but not all, DMD patients with a 31 P NMRS-based alkaline pH. Taking advantage of this 1 H NMRS-based intracellular pH, we found that free intramuscular [Mg 2+ ] is in fact abnormally low in DMD patients., (© 2019 John Wiley & Sons, Ltd.)

Aims: Becker 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 Results: Eighty-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 < 0.05). Native T1, T2, and ECV correlated with LV-EF (R = -0.79, -0.70, and -0.71, respectively, P < 0.001) and N-terminal-pro brain natriuretic peptide (R = 0.51, 0.58, and 0.44, respectively, P < 0.001)., Conclusion: Quantitative 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., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.)

Objective: Limb girdle muscular dystrophy type R9 (LGMD R9) is an autosomal recessive muscle disease for which there is currently no causative treatment. The development of putative therapies requires sensitive outcome measures for clinical trials in this slowly progressing condition. This study extends functional assessments and MRI muscle fat fraction measurements in an LGMD R9 cohort across 6 years., Methods: Twenty-three participants with LGMD R9, previously assessed over a 1-year period, were re-enrolled at 6 years. Standardized functional assessments were performed including: myometry, timed tests, and spirometry testing. Quantitative MRI was used to measure fat fraction in lower limb skeletal muscle groups., Results: At 6 years, all 14 muscle groups assessed demonstrated significant increases in fat fraction, compared to eight groups in the 1-year follow-up study. In direct contrast to the 1-year follow-up, the 6-min walk test, 10-m walk or run, timed up and go, stair ascend, stair descend and chair rise demonstrated significant decline. Among the functional tests, only FVC significantly declined over both the 1- and 6-year studies., Interpretation: These results further support fat fraction measurements as a primary outcome measure alongside functional assessments. The most appropriate individual muscles are the vastus lateralis, gracilis, sartorius, and gastrocnemii. Using composite groups of lower leg muscles, thigh muscles, or triceps surae, yielded high standardized response means (SRMs). Over 6 years, quantitative fat fraction assessment demonstrated higher SRM values than seen in functional tests suggesting greater responsiveness to disease progression., Competing Interests: APM, JM, JD, TS, CS, SW, MH, LL, JVH, and PC report no conflict of interest. Professor Willis has served on advisory boards for PTC pharmaceuticals, Genzyme Sanofi, Sarepta and Biogen and has received honorariums for lectures and symposium from PTC pharmaceuticals, Genzyme Sanofi and Biogen. Yousry has received honoraria and travel expenses for advisory committee work from Bayer Schering, Biogen Idec, and Novartis; and research grants (held by University College London) from Biogen Idec, GlaxoSmithKline, Novartis, and Schering AG for analysis of data from MS trials. James performs consultancy work (training physiotherapists) for: Roche, Pfizer, PTC, Summit, Sarepta, Santhera, Italfarmaco, Amicus and has participated in advisory boards for PTC Therapeutics. Mayhew performs consultancy work (training physiotherapists) for: Roche, Avexis, Biogen, Pfizer, PTC, Summit, Sarepta, Santhera, Italfarmaco, Amicus, Tamoxifen noncommercial study for DMD and has participated in advisory boards for: PTC, AMO Pharma, Roche, Summit, Biogen, Modus, Novartis. Eagle performs consultancy work for: Biomarin, GSK, Prosensa, Italfarmaco, Amicus, Capricor, Catabasis, Eli Lilly, Fibrogen, MNK, PTC, Santhera, Solid, Summit, Sarepta, Theracon, Reveragen and Wave. Thornton has received research support from GlaxoSmithKline, Medtronic, and Siemens. Vissing has received research and travel support, and speaker honoraria from Sanofi Genzyme, Ultragenyx Pharmaceuticals, Santhera Pharmaceuticals and aTyr Pharma, and served as consultant on advisory boards for Sanofi/Genzyme, aTyr pharma, Ultragenyx Pharmaceuticals, Santhera Pharmaceuticals, Sarepta Therapeutics, Audentes Therapeutics and Stealth Biotherapeutics within the last 3 years. Hollingsworth reports grants from the United Kingdom Medical Research Council, Diabetes UK, the European Union (H2020, 667078) and the Newcastle Healthcare Charity, consultancy for Summit pharmaceuticals and trial support from ImagingDMD outside the submitted work. All reimbursements were received by Newcastle University, no personal benefits were received. Straub has or had been a chief/principal investigator for trials sponsored by Sanofi Genzyme, GSK, Prosensa/Biomarin, Ionis Pharmceuticals, and Sarepta and a subinvestigator for many other commercial studies. He received speaker honoraria from Sanofi Genzyme and is or has been on advisory boards for Audentes Therapeutics, Biogen, Biomarin, Bristol‐Myer Squibb, Exonics Therapeutics, Italfarmaco S.p.A., Nicox, Sanofi Genzyme, Santhera Pharmaceuticals, Sarepta Therapeutics, Summit Therapeutics, Tivorsan, TrophyNOD, and Wave Therapeutics. He received funding for research collaboration with Ultragenyx and Sanofi Genzyme.

We investigated the response of skeletal muscle global T1 under different physiological and pathological conditions using an inversion-recovery radial T1 mapping sequence. Thirty five healthy volunteers, seven patients with Becker muscular dystrophy (BMD) and seven patients with sporadic inclusion body myositis (IBM) were investigated in order to evaluate the effects of gender, age, muscle group, exercise and pathological processes on global T1 values. In addition, the intramuscular fat content was measured using 3-point Dixon and the global T2 and water T2 (T2 H2O ) were determined with a multi-spin-echo sequence. In the muscles of healthy volunteers, there was no impact of age on global T1. However, we measured a significant effect of sex and muscle group. After exercise, a significant 7.7% increase of global T1 was measured in the recruited muscles, and global T1 variations were highly correlated to T2 H2O variations (R = 0.91). In pathologies, global T1 values were reduced in fat infiltrated muscles. When fat fraction was taken into account, global T1 values were higher in IBM patients compared to BMD. Global T1 variations are a sensitive indicator of tissue changes in skeletal muscle related to several physiological and pathological events.

Objective: To assess the ability of functional measures to detect disease progression in dysferlinopathy over 6 months and 1 year., Methods: One hundred ninety-three patients with dysferlinopathy were recruited to the Jain Foundation's International Clinical Outcome Study for Dysferlinopathy. Baseline, 6-month, and 1-year assessments included adapted North Star Ambulatory Assessment (a-NSAA), Motor Function Measure (MFM-20), timed function tests, 6-minute walk test (6MWT), Brooke scale, Jebsen test, manual muscle testing, and hand-held dynamometry. Patients also completed the ACTIVLIM questionnaire. Change in each measure over 6 months and 1 year was calculated and compared between disease severity (ambulant [mild, moderate, or severe based on a-NSAA score] or nonambulant [unable to complete a 10-meter walk]) and clinical diagnosis., Results: The functional a-NSAA test was the most sensitive to deterioration for ambulant patients overall. The a-NSAA score was the most sensitive test in the mild and moderate groups, while the 6MWT was most sensitive in the severe group. The 10-meter walk test was the only test showing significant change across all ambulant severity groups. In nonambulant patients, the MFM domain 3, wrist flexion strength, and pinch grip were most sensitive. Progression rates did not differ by clinical diagnosis. Power calculations determined that 46 moderately affected patients are required to determine clinical effectiveness for a hypothetical 1-year clinical trial based on the a-NSAA as a clinical endpoint., Conclusion: Certain functional outcome measures can detect changes over 6 months and 1 year in dysferlinopathy and potentially be useful in monitoring progression in clinical trials., Clinicaltrialsgov Identifier: NCT01676077., (Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Neuromuscular diseases are characterized by progressive muscle degeneration and muscle weakness resulting in functional disabilities. While each of these diseases is individually rare, they are common as a group, and a large majority lacks effective treatment with fully market approved drugs. Magnetic resonance imaging and spectroscopy techniques (MRI and MRS) are showing increasing promise as an outcome measure in clinical trials for these diseases. In 2013, the European Union funded the COST (co-operation in science and technology) action BM1304 called MYO-MRI (www.myo-mri.eu), with the overall aim to advance novel MRI and MRS techniques for both diagnosis and quantitative monitoring of neuromuscular diseases through sharing of expertise and data, joint development of protocols, opportunities for young researchers and creation of an online atlas of muscle MRI and MRS. In this report, the topics that were discussed in the framework of working group 3, which had the objective to: Explore new contrasts, new targets and new imaging techniques for NMD are described. The report is written by the scientists who attended the meetings and presented their data. An overview is given on the different contrasts that MRI can generate and their application, clinical needs and desired readouts, and emerging methods.

Objectives: 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., Methods: 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., Results: 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)., Conclusions: T1-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.

Background and Objective: Dysferlinopathies are a group of muscle disorders caused by mutations in the DYSF gene. Previous muscle imaging studies describe a selective pattern of muscle involvement in smaller patient cohorts, but a large imaging study across the entire spectrum of the dysferlinopathies had not been performed and previous imaging findings were not correlated with functional tests., Methods: We present cross-sectional T1-weighted muscle MRI data from 182 patients with genetically confirmed dysferlinopathies. We have analysed the pattern of muscles involved in the disease using hierarchical analysis and presented it as heatmaps. Results of the MRI scans have been correlated with relevant functional tests for each region of the body analysed., Results: In 181 of the 182 patients scanned, we observed muscle pathology on T1-weighted images, with the gastrocnemius medialis and the soleus being the most commonly affected muscles. A similar pattern of involvement was identified in most patients regardless of their clinical presentation. Increased muscle pathology on MRI correlated positively with disease duration and functional impairment., Conclusions: The information generated by this study is of high diagnostic value and important for clinical trial development. We have been able to describe a pattern that can be considered as characteristic of dysferlinopathy. We have defined the natural history of the disease from a radiological point of view. These results enabled the identification of the most relevant regions of interest for quantitative MRI in longitudinal studies, such as clinical trials., Clinical Trial Registration: NCT01676077., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Purpose: Quantitative cardiac MRI, and more particularly T 1 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 T 1 relaxation recovery curve, to which a dictionary-fitting approach was applied to estimate T 1 . 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 T 1 map acquisition time down to five heartbeats, while exhibiting a higher degree of accuracy and a comparable precision on T 1 value estimation than the conventional modified Look-Locker inversion recovery sequence. The FLASH readout demonstrated a better robustness to B 0 inhomogeneities than TrueFISP, and was therefore preferred for in vivo acquisitions., Conclusions: This sequence represents a good candidate for ultrafast acquisition of myocardial T 1 maps. Magn Reson Med 79:1387-1398, 2018. © 2017 International Society for Magnetic Resonance in Medicine., (© 2017 International Society for Magnetic Resonance in Medicine.)