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1. Effect of sirolimus on muscle in inclusion body myositis observed with magnetic resonance imaging and spectroscopy

Author: Harmen Reyngoudt, Pierre‐Yves Baudin, Ericky Caldas de Almeida Araújo, Damien Bachasson, Jean‐Marc Boisserie, Kubéraka Mariampillai, Mélanie Annoussamy, Yves Allenbach, Jean‐Yves Hogrel, Pierre G. Carlier, Benjamin Marty, and Olivier Benveniste
Subjects: 31P MRS, Biomarkers, Inclusion body myositis, Quantitative MRI, Treatment, Diseases of the musculoskeletal system, RC925-935, Human anatomy, QM1-695
Abstract: Abstract 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 (31P 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 31P 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 T2 in global leg and thigh segments, muscle groups, individual muscles, as well as 31P 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, 31P 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
Published: 2024
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2. Miyoshi myopathy associated with spine rigidity and multiple contractures: a case report

Author: Sergey N. Bardakov, Angelina A. Titova, Sergey S. Nikitin, Valentin Nikitins, Margarita O. Sokolova, Vadim A. Tsargush, Elena A. Yuhno, Oleg V. Vetrovoj, Pierre G. Carlier, Yana V. Sofronova, Аrtur А. Isaev, and Roman V. Deev
Subjects: Contractures, DYSF, Dysferlinopathy, Limb-girdle muscle dystrophy R2, Spine rigidity, Diseases of the musculoskeletal system, RC925-935
Abstract: Abstract 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.
Published: 2024
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3. Water T2 could predict functional decline in patients with dysferlinopathy

Author: Ursula Moore, Ericky Caldas de Almeida Araújo, Harmen Reyngoudt, Heather Gordish‐Dressman, Fiona E. Smith, Ian Wilson, Meredith James, Anna Mayhew, Laura Rufibach, John W. Day, Kristi J. Jones, Diana X. Bharucha‐Goebel, Emmanuelle Salort‐Campana, Alan Pestronk, Maggie C. Walter, Carmen Paradas, Tanya Stojkovic, Madoka Mori‐Yoshimura, Elena Bravver, Elena Pegoraro, Jerry R. Mendell, The Jain COS Consortium, Kate Bushby, Andrew M. Blamire, Volker Straub, Pierre G. Carlier, and Jordi Diaz‐Manera
Subjects: Magnetic resonance imaging, Water T2, Limb girdle muscular dystrophy, Limb girdle muscular dystrophy R2, Limb girdle muscular dystrophy 2B, Diseases of the musculoskeletal system, RC925-935, Human anatomy, QM1-695
Abstract: Abstract Background Water T2 (T2H2O) 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 T2H2O 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. T2H2O 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 T2H2O at baseline, age, disease duration, and baseline function. Results A higher T2H2O 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 T2H2O 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 T2H2O (>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 T2H2O (
Published: 2022
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4. Three‐year quantitative magnetic resonance imaging and phosphorus magnetic resonance spectroscopy study in lower limb muscle in dysferlinopathy

Author: Harmen Reyngoudt, Fiona E. Smith, Ericky Caldas de Almeida Araújo, Ian Wilson, Roberto Fernández‐Torrón, Meredith K. James, Ursula R. Moore, Jordi Díaz‐Manera, Benjamin Marty, Noura Azzabou, Heather Gordish, Laura Rufibach, Tim Hodgson, Dorothy Wallace, Louise Ward, Jean‐Marc Boisserie, Julien Le Louër, Heather Hilsden, Helen Sutherland, Aurélie Canal, Jean‐Yves Hogrel, Marni Jacobs, Tanya Stojkovic, Kate Bushby, Anna Mayhew, Jain Clinical Outcome Study for Dysferlinopathy consortium, Volker Straub, Pierre G. Carlier, and Andrew M. Blamire
Subjects: Dysferlinopathy, Quantitative MRI, 31P MRS, Longitudinal, Outcome measures, Diseases of the musculoskeletal system, RC925-935, Human anatomy, QM1-695
Abstract: Abstract 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 (31P MRS) outcome measures and evaluated their relationship with function in lower limb skeletal muscle of dysferlinopathy patients. Methods Quantitative MRI/31P 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 T2 in both global leg and thigh segments and individual muscles and 31P 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 31P 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
Published: 2022
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5. Lean regional muscle volume estimates using explanatory bioelectrical models in healthy subjects and patients with muscle wasting

Author: Damien Bachasson, Alper Carras Ayaz, Jessie Mosso, Aurélie Canal, Jean‐Marc Boisserie, Ericky C.A. Araujo, Olivier Benveniste, Harmen Reyngoudt, Benjamin Marty, Pierre G. Carlier, and Jean‐Yves Hogrel
Subjects: Skeletal muscle, Bioelectrical impedance analysis, Myopathies, Muscle mass, Muscle volume, Muscle atrophy, Diseases of the musculoskeletal system, RC925-935, Human anatomy, QM1-695
Abstract: Abstract 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 (SBIA) by computing a conductivity constant based on quantitative magnetic resonance imaging (MRI) data and (ii) investigating the potential of SBIA 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 (lVMRI) 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 SBIA and MRI gathered in the right thigh of 10 healthy participants. Lean muscle volume (lVBIA) was derived from SBIA measurements using this newly computed constant. Between‐day reproducibility of lVBIA 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 lVBIA and lVMRI was greater at frequencies >270 kHz (P
Published: 2021
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6. Non-invasive assessment of skeletal muscle fibrosis in mice using nuclear magnetic resonance imaging and ultrasound shear wave elastography

Author: Aurea B. Martins-Bach, Damien Bachasson, Ericky C. A. Araujo, Lucas Soustelle, Paulo Loureiro de Sousa, Yves Fromes, and Pierre G. Carlier
Subjects: Medicine, Science
Abstract: Abstract Fibrosis is a key pathological feature in muscle disorders, but its quantification mainly relies on histological and biochemical assays. Muscle fibrosis most frequently is entangled with other pathological processes, as cell membrane lesions, inflammation, necrosis, regeneration, or fatty infiltration, making in vivo assessment difficult. Here, we (1) describe a novel mouse model with variable levels of induced skeletal muscle fibrosis displaying minimal inflammation and no fat infiltration, and (2) report how fibrosis affects non-invasive metrics derived from nuclear magnetic resonance (NMR) and ultrasound shear-wave elastography (SWE) associated with a passive biomechanical assay. Our findings show that collagen fraction correlates with multiple non-invasive metrics. Among them, muscle stiffness as measured by SWE, T2, and extracellular volume (ECV) as measured by NMR have the strongest correlations with histology. We also report that combining metrics in a multi-modality index allowed better discrimination between fibrotic and normal skeletal muscles. This study demonstrates that skeletal muscle fibrosis leads to alterations that can be assessed in vivo with multiple imaging parameters. Furthermore, combining NMR and SWE passive biomechanical assay improves the non-invasive evaluation of skeletal muscle fibrosis and may allow disentangling it from co-occurring pathological alterations in more complex scenarios, such as muscular dystrophies.
Published: 2021
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7. Assessing the Relationship of Patient Reported Outcome Measures With Functional Status in Dysferlinopathy: A Rasch Analysis Approach

Author: Anna G. Mayhew, Meredith K. James, Ursula Moore, Helen Sutherland, Marni Jacobs, Jia Feng, Linda Pax Lowes, Lindsay N. Alfano, Robert Muni Lofra, Laura E. Rufibach, Kristy Rose, Tina Duong, Luca Bello, Irene Pedrosa-Hernández, Scott Holsten, Chikako Sakamoto, Aurélie Canal, Nieves Sánchez-Aguilera Práxedes, Simone Thiele, Catherine Siener, Bruno Vandevelde, Brittney DeWolf, Elke Maron, Heather Gordish-Dressman, Heather Hilsden, Michela Guglieri, Jean-Yves Hogrel, Andrew M. Blamire, Pierre G. Carlier, Simone Spuler, John W. Day, Kristi J. Jones, Diana X. Bharucha-Goebel, Emmanuelle Salort-Campana, Alan Pestronk, Maggie C. Walter, Carmen Paradas, Tanya Stojkovic, Madoka Mori-Yoshimura, Elena Bravver, Jordi Díaz-Manera, Elena Pegoraro, Jerry R. Mendell, and Volker Straub
Subjects: limb girdle muscular dystrophy, dysferlinopathy, PROMs, quality of life, clinical outcome assessments, Neurology. Diseases of the nervous system, RC346-429
Abstract: 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 R2 0.68). The INQoL performed less well and was poorly associated with the NSAD total score (Pseudo R2 0.18). EK scores were strongly associated with PUL (Pseudo R2 0.69). IPAQ was poorly associated with NSAD scores (Pseudo R2 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.
Published: 2022
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8. Natural history of limb girdle muscular dystrophy R9 over 6 years: searching for trial endpoints

Author: Alexander P. Murphy, Jasper Morrow, Julia R. Dahlqvist, Tanya Stojkovic, Tracey A. Willis, Christopher D. J. Sinclair, Stephen Wastling, Tarek Yousry, Michael S. Hanna, Meredith K. James, Anna Mayhew, Michelle Eagle, Laurence E. Lee, Jean‐Yves Hogrel, Pierre G. Carlier, John S. Thornton, John Vissing, Kieren G. Hollingsworth, and Volker Straub
Subjects: Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract: Abstract 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.
Published: 2019
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9. Intensive Teenage Activity Is Associated With Greater Muscle Hyperintensity on T1W Magnetic Resonance Imaging in Adults With Dysferlinopathy

Author: Ursula Moore, Marni Jacobs, Roberto Fernandez-Torron, Jaume LLauger Rossello, Fiona E. Smith, Meredith James, Anna Mayhew, Laura Rufibach, Pierre G. Carlier, Andrew M. Blamire, John W. Day, Kristi J. Jones, Diana X. Bharucha-Goebel, Emmanuelle Salort-Campana, Alan Pestronk, Maggie C. Walter, Carmen Paradas, Tanya Stojkovic, Madoka Mori-Yoshimura, Elena Bravver, Elena Pegoraro, Jerry R. Mendell, Kate Bushby, Volker Straub, and Jordi Diaz-Manera
Subjects: dysferlinopathy, Magnetic Resonace Imaging (MRI), Miyoshi myopathy, LGMDR2, limb girdle muscle dystrophy, exercise, Neurology. Diseases of the nervous system, RC346-429
Abstract: 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
Published: 2020
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10. Dmdmdx/Largemyd: a new mouse model of neuromuscular diseases useful for studying physiopathological mechanisms and testing therapies

Author: Poliana C. M. Martins, Danielle Ayub-Guerrieri, Aurea B. Martins-Bach, Paula Onofre-Oliveira, Jackeline M. Malheiros, Alberto Tannus, Paulo L. de Sousa, Pierre G. Carlier, and Mariz Vainzof
Subjects: Medicine, Pathology, RB1-214
Abstract: SUMMARY Although muscular dystrophies are among the most common human genetic disorders, there are few treatment options available. Animal models have become increasingly important for testing new therapies prior to entering human clinical trials. The Dmdmdx mouse is the most widely used animal model for Duchenne muscular dystrophy (DMD), presenting the same molecular and protein defect as seen in humans with the disease. However, this mouse is not useful for clinical trials because of its very mild phenotype. The mouse model for congenital myodystrophy type 1D, Largemyd, harbors a mutation in the glycosyltransferase Large gene and displays a severe phenotype. To help elucidate the role of the proteins dystrophin and LARGE in the organization of the dystrophin-glycoprotein complex in muscle sarcolemma, we generated double-mutant mice for the dystrophin and LARGE proteins. The new Dmdmdx/Largemyd mouse model is viable and shows a severe phenotype that is associated with the lack of dystrophin in muscle. We tested the usefulness of our new mouse model for cell therapy by systemically injecting them with normal murine mesenchymal adipose stem cells (mASCs). We verified that the mASCs were hosted in the dystrophic muscle. The new mouse model has proven to be very useful for the study of several other therapies, because injected cells can be screened both through DNA and protein analysis. Study of its substantial muscle weakness will also be very informative in the evaluation of functional benefits of these therapies.
Published: 2013
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11. Natural history of Type 2 and 3 spinal muscular atrophy: 2‐year NatHis‐SMA study

Author: Jean-Yves Hogrel, Myriam Ly-Le Moal, A. Daron, Teresa Gidaro, Timothy Seabrook, Laurent Servais, Carole Vuillerot, Vincent Laugel, Emmanuel Fournier, Pierre G. Carlier, Ulrike Schara, Yann Péréon, Nicole Hellbach, Andreea Mihaela Seferian, Claude Cances, Ksenija Gorni, M. Annoussamy, Linda Lowes, C. Lilien, Ricardo Hermosilla, Christian Czech, Liesbeth De Waele, Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), SYSNAV, Centre Hospitalier Universitaire de Liège (CHU-Liège), Centre de reference des maladies neuromusculaires Nantes-Angers, CHU d'Angers et Nantes, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL), Institut NeuroMyoGène (INMG), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University Hospitals Leuven [Leuven], KU Leuven Campus Kulak Kortrijk [Belgium], CIC Strasbourg (Centre d’Investigation Clinique Plurithématique (CIC - P) ), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Nouvel Hôpital Civil de Strasbourg-Hôpital de Hautepierre [Strasbourg], University of Duisburg-Essen, University of Oxford, Nationwide Children's Hospital, Hoffman-La Roche Ltd, Translational Medicine, Neuroscience, Institut ROCHE [Boulogne-Billancourt], Roche S.A.S, Roche Innovation Center [Basel, Switzerland], Pfizer, Gestionnaire, Hal Sorbonne Université, Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), CHU Toulouse [Toulouse], Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA)-Hôpital de Hautepierre [Strasbourg]-Nouvel Hôpital Civil de Strasbourg, University of Oxford [Oxford], and Universität Duisburg-Essen = University of Duisburg-Essen [Essen]
Subjects: 0301 basic medicine, Vital capacity, Time Factors, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Medizin, MESH: Respiratory Function Tests, NASAL INSPIRATORY PRESSURE, Severity of Illness Index, Pulmonary function testing, MESH: Magnetic Resonance Imaging, Disability Evaluation, 0302 clinical medicine, MESH: Muscular Atrophy, Spinal, MESH: Child, Longitudinal Studies, MESH: Nerve Tissue Proteins, Child, MESH: Longitudinal Studies, Research Articles, VALUES, General Neuroscience, MESH: Muscle Strength, MESH: Disability Evaluation, RNA-Binding Proteins, SMA, Magnetic Resonance Imaging, MESH: Motor Activity, Respiratory Function Tests, medicine.anatomical_structure, MESH: Young Adult, Child, Preschool, Anesthesia, Disease Progression, Upper limb, MESH: Disease Progression, Erratum, Life Sciences & Biomedicine, RC321-571, Research Article, Adult, Adolescent, Clinical Neurology, Neurosciences. Biological psychiatry. Neuropsychiatry, Nerve Tissue Proteins, Motor Activity, Muscular Atrophy, Spinal, Upper Extremity, Young Adult, 03 medical and health sciences, FEV1/FVC ratio, Statistical significance, MESH: Severity of Illness Index, medicine, Humans, Muscle Strength, RC346-429, MESH: Adolescent, Science & Technology, MESH: Humans, business.industry, MESH: Time Factors, MESH: Child, Preschool, Neurosciences, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Survival of motor neuron, MESH: Adult, Spinal muscular atrophy, MESH: Upper Extremity, medicine.disease, 030104 developmental biology, MESH: RNA-Binding Proteins, Neurology. Diseases of the nervous system, Neurology (clinical), Neurosciences & Neurology, business, 030217 neurology & neurosurgery
Abstract: OBJECTIVE: To characterize the natural history of spinal muscular atrophy (SMA) over 24 months using innovative measures such as wearable devices, and to provide evidence for the sensitivity of these measures to determine their suitability as endpoints in clinical trials. METHODS: Patients with Type 2 and 3 SMA (N = 81) with varied functional abilities (sitters, nonsitters, nonambulant, and ambulant) who were not receiving disease-modifying treatment were assessed over 24 months: motor function (Motor Function Measure [MFM]), upper limb strength (MyoGrip, MyoPinch), upper limb activity (ActiMyo® ), quantitative magnetic resonance imaging (fat fraction [FFT2 ] mapping and contractile cross-sectional area [C-CSA]), pulmonary function (forced vital capacity [FVC], peak cough flow, maximum expiratory pressure, maximum inspiratory pressure, and sniff nasal inspiratory pressure), and survival of motor neuron (SMN) protein levels. RESULTS: MFM32 scores declined significantly over 24 months, but not 12 months. Changes in upper limb activity could be detected over 6 months and continued to decrease significantly over 12 months, but not 24 months. Upper limb strength decreased significantly over 12 and 24 months. FVC declined significantly over 12 months, but not 24 months. FFT2 increased over 12 and 24 months, although not with statistical significance. A significant increase in C-CSA was observed at 12 but not 24 months. Blood SMN protein levels were stable over 12 and 24 months. INTERPRETATION: These data demonstrate that the MFM32, MyoGrip, MyoPinch, and ActiMyo® enable the detection of a significant decline in patients with Type 2 and 3 SMA over 12 or 24 months. ispartof: ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY vol:8 issue:2 pages:359-373 ispartof: location:United States status: published
Published: 2020
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12. Epicardial and Pericardial Adiposity Without Myocardial Steatosis in Cushing Syndrome

Author: Séverine Trabado, Pierre G. Carlier, Benjamin Marty, Jacques Young, Christel Jublanc, Peter Kamenický, Hélène Agostini, Bruno Fève, Philippe Chanson, Céline Droumaguet, Nadjia Kachenoura, Anne-Lise Lecoq, Alban Redheuil, Mikaël Prigent, Sylvie Salenave, Khaoula Bouazizi, Christiane Ajzenberg, Celine Piedvache, Anne Blanchard, Peter Wolf, Emmanuelle Kuhn, Hôpital Bicêtre, Physiologie et physiopathologie endocriniennes (PHYSENDO), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Medizinische Universität Wien = Medical University of Vienna, Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Résonance Magnétique Nucléaire (LRMN), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Imagerie Biomédicale [Paris] (LIB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), CIC - HEGP (CIC 1418), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de médecine interne [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], CHU Saint-Antoine [AP-HP], Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), Feve, Bruno, Laboratoire d'Imagerie Biomédicale (LIB), École pratique des hautes études (EPHE), Service d'Endocrinologie, diabétologie et endocrinologie de la reproduction [CHU Saint-Antoine], Centre National de Référence des Pathologies Rares de l'Insulino-Sécrétion et de l'Insulino-Sensibilité [CHu Saint-Antoine] (PRISIS), and Service de Radiologie cardiovasculaire et interventionnelle [CHU Pitié-Salpêtrière]
Subjects: pericardial and epicardial fat, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Clinical Biochemistry, cardiac magnetic resonance imaging, Cardiomyopathy, Context (language use), Biochemistry, Cushing syndrome, chemistry.chemical_compound, Endocrinology, Cardiac magnetic resonance imaging, Internal medicine, medicine, Glucose homeostasis, Triglyceride, medicine.diagnostic_test, business.industry, Biochemistry (medical), medicine.disease, proton magnetic resonance spectroscopy, [SDV] Life Sciences [q-bio], chemistry, cardiac steatosis, Cardiology, Metabolic syndrome, business, Body mass index, cardiomyopathy
Abstract: Context Cardiovascular disease is the leading cause of death in patients with Cushing syndrome. Cortisol excess and adverse metabolic profile could increase cardiac fat, which can subsequently impair cardiac structure and function. Objective We aimed to evaluate cardiac fat mass and distribution in patients with Cushing syndrome. Methods In this prospective, cross-sectional study, 23 patients with Cushing syndrome and 27 control individuals of comparable age, sex, and body mass index were investigated by cardiac magnetic resonance imaging and proton spectroscopy. Patients were explored before and after biochemical disease remission. Myocardial fat measured by the Dixon method was the main outcome measure. The intramyocardial triglyceride/water ratio measured by spectroscopy and epicardial and pericardial fat volumes were secondary outcome measures. Results No difference was found between patients and controls in intramyocardial lipid content. Epicardial fat mass was increased in patients compared to controls (30.8 g/m2 [20.4-34.8] vs 17.2 g/m2 [13.1-23.5], P Conclusion Intramyocardial fat stores are not increased in patients with Cushing syndrome, despite highly prevalent metabolic syndrome, suggesting increased cortisol-mediated lipid consumption. Cushing syndrome is associated with marked accumulation of epicardial and pericardial fat. Epicardial adiposity may exert paracrine proinflammatory effects promoting cardiomyopathy.
Published: 2021
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13. Quantitative 1H and 23Na muscle MRI in Facioscapulohumeral muscular dystrophy patients

Author: Katharina Porzelt, Matthias Türk, Pierre G. Carlier, Michael Uder, Lena V. Gast, Teresa Gerhalter, Stefan Schwab, Armin M. Nagel, Benjamin Marty, and Rafael Heiss
Subjects: congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Pathology, Neurology, Water T1, Triple quantum filter, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Facioscapulohumeral muscular dystrophy, Sodium MRI, medicine, Humans, In patient, ddc:610, Muscle, Skeletal, Neuroradiology, Leg, Original Communication, Muscle mri, business.industry, Sodium, Quantitative MRI, Dorsal flexion, medicine.disease, Magnetic Resonance Imaging, Muscular Dystrophy, Facioscapulohumeral, Ion homeostasis, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract: Objective Our aim was to assess the role of quantitative 1H and 23Na MRI methods in providing imaging biomarkers of disease activity and severity in patients with Facioscapulohumeral muscular dystrophy (FSHD). Methods We imaged the lower leg muscles of 19 FSHD patients and 12 controls with a multimodal MRI protocol to obtain STIR-T2w images, fat fraction (FF), water T2 (wT2), water T1 (wT1), tissue sodium concentration (TSC), and intracellular-weighted sodium signal (inversion recovery (IR) and triple quantum filter (TQF) sequence). In addition, the FSHD patients underwent muscle strength testing. Results Imaging biomarkers related with water mobility (wT1 and wT2) and ion homeostasis (TSC, IR, TQF) were increased in muscles of FSHD patients. Muscle groups with FF > 10% had higher wT2, wT1, TSC, IR, and TQF values than muscles with FF 1 was increased in few muscles without fat replacement. Furthermore, few STIR-negative muscles (n = 11/76) exhibited increased wT1, TSC, IR or TQF. Increased wT1 as well as 23Na signals were also present in muscles with normal wT2. Muscle strength was related to the mean FF and all imaging biomarkers of tibialis anterior except wT2 were correlated with dorsal flexion. Conclusion The newly evaluated imaging biomarkers related with water mobility (wT1) and ion homeostasis (TSC, IR, TQF) showed different patterns compared to the established markers like FF in muscles of FSHD patients. These quantitative biomarkers could thus contain valuable complementary information for the early characterization of disease progression.
Published: 2021

14. Non-invasive assessment of skeletal muscle fibrosis in mice using nuclear magnetic resonance imaging and ultrasound shear wave elastography

Author: Ericky C. A. Araujo, Lucas Soustelle, A.B. Martins-Bach, Damien Bachasson, Yves Fromes, Pierre G. Carlier, Paulo Loureiro de Sousa, Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Réseau nanophotonique et optique, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Matériaux et nanosciences d'Alsace (FMNGE), Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, and Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, 0301 basic medicine, Science, Muscle disorder, Article, 030218 nuclear medicine & medical imaging, Skeletal muscle fibrosis, Mice, 03 medical and health sciences, Magnetic resonance imaging, 0302 clinical medicine, Nuclear magnetic resonance, In vivo, Fibrosis, medicine, Animals, Muscle, Skeletal, Ultrasonography, Multidisciplinary, medicine.diagnostic_test, business.industry, Regeneration (biology), Ultrasound, Diagnostic markers, Neuromuscular disease, Muscle stiffness, medicine.disease, 030104 developmental biology, Elasticity Imaging Techniques, Medicine, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Elastography, business
Abstract: Fibrosis is a key pathological feature in muscle disorders, but its quantification mainly relies on histological and biochemical assays. Muscle fibrosis most frequently is entangled with other pathological processes, as cell membrane lesions, inflammation, necrosis, regeneration, or fatty infiltration, making in vivo assessment difficult. Here, we (1) describe a novel mouse model with variable levels of induced skeletal muscle fibrosis displaying minimal inflammation and no fat infiltration, and (2) report how fibrosis affects non-invasive metrics derived from nuclear magnetic resonance (NMR) and ultrasound shear-wave elastography (SWE) associated with a passive biomechanical assay. Our findings show that collagen fraction correlates with multiple non-invasive metrics. Among them, muscle stiffness as measured by SWE, T2, and extracellular volume (ECV) as measured by NMR have the strongest correlations with histology. We also report that combining metrics in a multi-modality index allowed better discrimination between fibrotic and normal skeletal muscles. This study demonstrates that skeletal muscle fibrosis leads to alterations that can be assessed in vivo with multiple imaging parameters. Furthermore, combining NMR and SWE passive biomechanical assay improves the non-invasive evaluation of skeletal muscle fibrosis and may allow disentangling it from co-occurring pathological alterations in more complex scenarios, such as muscular dystrophies.
Published: 2021
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15. Sirolimus for treatment of patients with inclusion body myositis: a randomised, double-blind, placebo-controlled, proof-of-concept, phase 2b trial

Author: Harmen Reyngoudt, Jean-Yves Hogrel, Yves Allenbach, Anthony Behin, Lisa Belin, Océane Landon-Cardinal, Pascal Laforêt, Noël Zahr, Bruno Eymard, Gaëlle Dzangué-Tchoupou, Baptiste Hervier, Steven A. Greenberg, Jean-Sébastien Hulot, Pierre G. Carlier, Aude Rigolet, Akinori Uruha, Lee S. Nguyen, Joe-Elie Salem, Damien Amelin, Olivier Benveniste, Damien Bachasson, Edith Guilloux, Tanya Stojkovic, M. Annoussamy, Kuberaka Mariampillai, Benjamin Marty, Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), CHU Trousseau [APHP], Centre d'investigation clinique Paris Est [CHU Pitié Salpêtrière] (CIC Paris-Est), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Université de Montréal (UdeM), Harvard Medical School [Boston] (HMS), Institut national de la santé et de la recherche médicale, Direction générale de l'offre de soins, and Association Française contre les Myopathies., Centre National de Référence du Lupus Systémique, Syndrome des Anticorps Anti-phospholipides et Maladies Auto-immunes Systémiques Rares [CHU Pitié Salpêtrière], Service de Médecine Interne 2, maladies auto-immunes et systémiques [CHU Pitié-Salpêtrière], Institut E3M [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut E3M [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de médecine interne [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de pharmacologie médicale [CHU Pitié-Salpêtrière], CIC AP-HP [CHU Pitié-Salpêtrière], Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut E3M [CHU Pitié-Salpêtrière], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: medicine.medical_specialty, Vital capacity, Immunology, Population, Isometric exercise, Placebo, 03 medical and health sciences, 0302 clinical medicine, Rheumatology, Internal medicine, medicine, Clinical endpoint, Immunology and Allergy, 10. No inequality, education, Myositis, 030304 developmental biology, 0303 health sciences, education.field_of_study, business.industry, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, medicine.disease, 3. Good health, Discontinuation, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Inclusion body myositis, business, 030217 neurology & neurosurgery
Abstract: Summary Background Inclusion body myositis is the most frequent myositis in patients older than 50 years. Classical immunosuppressants are ineffective in treating inclusion body myositis, and to date there are no recommendations for pharmacological approaches to treatment. When used after organ transplantation, sirolimus can block the proliferation of effector T cells, while preserving T regulatory cells, and induce autophagy, all of which are processes that are impaired in inclusion body myositis. In this pilot study, we aimed to test the efficacy of sirolimus in patients with inclusion body myositis. Methods This randomised, double-blind, placebo-controlled, proof-of-concept, phase 2b trial was done at a single hospital in Paris, France. The study included men and women (aged 45–80 years) who had a defined diagnosis of inclusion body myositis according to established criteria. Eligible participants were randomly assigned (1:1) to receive once-daily oral sirolimus 2 mg or placebo. Centralised balanced block randomisation (blocks of four) was computer generated without stratification. The study comprised a 15-day screening period (days −15 to 0) and a 52-week treatment period (day 0 to month 12). The primary endpoint was the relative percentage change from baseline to month 12 in maximal voluntary isometric knee extension strength. Secondary endpoints included the following assessments at months 6 and 12: 6-min walking distance, isometric muscle strength for hand grip (finger flexors), knee flexion and elbow flexion and extension, forced vital capacity, muscle replacement with fat measured by quantitative nuclear MRI, Inclusion Body Myositis Weakness Composite Index (IBMWCI), Inclusion Body Myositis Functional Rating Scale (IBMFRS), Health Assessment Questionnaire without Disability Index (HAQ-DI), and analyses of T-cell subpopulations by mass cytometry. The primary analysis was done on the intention-to-treat population. The trial is registered at ClinicalTrials.gov , NCT02481453 . Findings Between July 15, 2015, and May 13, 2016, we screened 285 patients, 44 of whom were randomly allocated to sirolimus (22 patients) or placebo (22 patients). We observed no difference in the primary outcome of relative percentage change from baseline to month 12 of the maximal voluntary isometric knee extension strength (median difference 3·78, 95% CI −10·61 to 17·31; p=0·85). For secondary outcomes, differences between the groups were not significant for changes in strength of other muscle groups (grip, elbow flexion and extension, or knee flexion), IBMWCI, IBMFRS, and lower limb muscle fat fraction. However, we observed significant differences in favour of sirolimus between the study groups for HAQ-DI, forced vital capacity, thigh fat fraction, and 6-min walking distance. Ten (45%) of 22 patients in the sirolimus group had a serious adverse event compared with six (27%) of 22 patients in the placebo group. Four (18%) patients in the sirolimus group stopped their treatment because of adverse events (severe mouth ulcers, aseptic pneumonia, renal insufficiency, and peripheral lower limb oedema), which resolved after treatment discontinuation. Canker sores were the most frequent side-effect and were mainly mild or moderate in ten patients. Interpretation We found no evidence for efficacy of sirolimus for treating inclusion body myositis based on maximal voluntary isometric knee extension strength and other muscle strength measures, and the side-effects of treatment were substantial for some patients. However, we believe there was enough evidence of benefit in certain secondary outcomes to pursue a multicentre phase 3 trial to further assess the safety and efficacy of sirolimus. Funding Institut national de la sante et de la recherche medicale, Direction generale de l'offre de soins, and Association Francaise contre les Myopathies.
Published: 2021
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16. Severe axial and pelvifemoral muscle damage in immune-mediated necrotizing myopathy evaluated by whole-body MRI

Author: Benjamin Granger, Mathieu Vautier, Yves Allenbach, Harmen Reyngoudt, Pierre G. Carlier, Nicolas Champtiaux, Baptiste Hervier, Cedi Koumako, Olivier Benveniste, Jean-Marc Boisserie, Perrine Guillaume-Jugnot, Océane Landon-Cardinal, Aude Rigolet, Giulia Hardouin, Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université du Québec à Montréal = University of Québec in Montréal (UQAM), Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), Laboratoire RMN AIM-CEA, Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Myologie, Departement Hospitalo- Universitaire - Inflammation, Immunopathologie, Biothérapie [Paris] (DHU - I2B), Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Trousseau [APHP], and Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU)
Subjects: medicine.medical_specialty, Myopathy, [SDV]Life Sciences [q-bio], Whole body mri, Muscle damage, Gastroenterology, Immune-mediated necrotizing myopathy, Autoimmune Diseases, Lesion load, 03 medical and health sciences, 0302 clinical medicine, Lumbar, Rheumatology, Internal medicine, Whole-body MRI, Humans, Medicine, 030212 general & internal medicine, Muscle, Skeletal, Myositis, 030203 arthritis & rheumatology, business.industry, Immune mediated necrotizing myopathy, medicine.disease, Magnetic Resonance Imaging, Muscle imaging, Anesthesiology and Pain Medicine, Female, Necrotizing myopathy, medicine.symptom, business
Abstract: International audience; Background: Our objective was to define the pattern and severity of muscle damage in immune-mediated necrotizing myopathy (IMNM) and its relationship with clinical and serological features.Methods: IMNM patients with a whole-body MRI (n=42) were included and compared to sporadic inclusion-body myositis (s-IBM) patients (n=60). Fat replacement was estimated using the Mercuri score in 55 muscles. Overall lesion load was defined as the sum of all abnormal Mercuri scores (reported in % maximal score) and lesion load quotient was defined as the overall lesion load divided by disease duration. Linear relationships between variables were assessed and multidimensional analysis was performed to define homogenous groups of patients.Results: IMNM patients were aged 48.1±15.8 years and had a disease duration of 9.8±8.1 years. Most severely affected muscle groups were located in the pelvifemoral and lumbar region. Unsupervised analysis showed two subgroups of patients: one with mild lesion load (15±10%, n=32/42) and another with severe lesion load (60±10%, n=10/42: p
Published: 2020
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17. Spatially regularized parametric map reconstruction for fast magnetic resonance fingerprinting

Author: Fabian Balsiger, Benjamin Marty, Mauricio Reyes, Olivier Scheidegger, Alain Jungo, Pierre G. Carlier, Center for Biomedical Engineering Research (ARTORG), University of Bern, CEA- Saclay (CEA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Bern University Hospital [Berne] (Inselspital), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)
Subjects: FOS: Computer and information sciences, Magnetic Resonance Spectroscopy, Matching (graph theory), Computer Vision and Pattern Recognition (cs.CV), Computer Science - Computer Vision and Pattern Recognition, Health Informatics, 610 Medicine & health, Iterative reconstruction, Regularization (mathematics), Convolutional neural network, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, FOS: Electrical engineering, electronic engineering, information engineering, Image Processing, Computer-Assisted, Humans, Radiology, Nuclear Medicine and imaging, [INFO]Computer Science [cs], Parametric statistics, Radiological and Ultrasound Technology, business.industry, Phantoms, Imaging, Deep learning, Perspective (graphical), Image and Video Processing (eess.IV), Brain, Pattern recognition, Electrical Engineering and Systems Science - Image and Video Processing, Computer Graphics and Computer-Aided Design, Magnetic Resonance Imaging, 3. Good health, Test set, 570 Life sciences, biology, Computer Vision and Pattern Recognition, Artificial intelligence, business, 030217 neurology & neurosurgery, Algorithms
Abstract: 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 (T1H2O) 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 $\pm$ 0.011 for T1H2O maps and 0.027 $\pm$ 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., Accepted to Medical Image Analysis
Published: 2020
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18. Assessing the variability of 23Na MRI in skeletal muscle tissue: Reproducibility and repeatability of tissue sodium concentration measurements in the lower leg at 3 T

Author: Michael Uder, Lena V. Gast, Teresa Gerhalter, Pierre G. Carlier, Benjamin Marty, and Armin M. Nagel
Subjects: Reproducibility, business.industry, Sodium, Right lower leg, chemistry.chemical_element, Repeatability, Quantitative accuracy, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, chemistry, Healthy volunteers, Skeletal Muscle Tissue, Sodium MRI, Molecular Medicine, Medicine, Radiology, Nuclear Medicine and imaging, ddc:610, Nuclear medicine, business, 030217 neurology & neurosurgery, Spectroscopy
Abstract: The goal of this study was to evaluate the reproducibility and repeatability of tissue sodium concentration (TSC) measurements using 23 Na MRI in skeletal muscle tissue. 23 Na MRI was performed at 3 T on the right lower leg of eight healthy volunteers (aged 28 ± 4 years). The examinations were repeated at the same site after ~ 22 weeks to assess the variability over a medium-term period. Additionally, they were scanned at a second site shortly before or shortly after the first visit (within 3 weeks) to evaluate the inter-site reproducibility. Moreover, we analysed the effect of B0 correction on the variability. Coefficients of variations (CVs) from mean TSC values as well as Bland-Altman plots were used to assess intra-site repeatability and inter-site reproducibility. In phantom measurements, the B0 correction improved the quantitative accuracy. We observed differences of up to 4.9 mmol/L between the first and second visit and a difference of up to 3.7 mmol/L between the two different sites. The CV for the medium-term repeatability was 15% and the reproducibility CV was 9%. The Bland-Altman plots indicated high agreement between the visits in all muscle regions. The systematic bias of -0.68 mmol/L between site X and Y (P = 0.03) was slightly reduced to -0.64 mmol/L after B0 correction (P = 0.04). This work shows that TSC measurements in healthy skeletal muscle tissue can be performed with good repeatability and reproducibility, which is of importance for future longitudinal or multicentre studies.
Published: 2020

19. Mild clinical presentation in KLHL40-related nemaline myopathy (NEM 8)

Author: John Rendu, Julien Fauré, Laurent Pelletier, Pierre G. Carlier, Laurent Servais, Norma B. Romero, Andreea Mihaela Seferian, Véronique Forin, Edoardo Malfatti, Teresa Gidaro, Jessica Taytard, E. Gargaun, C Bosson, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de référence des maladies rares neuromusculaires, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de recherche en myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unit of Neuromuscular Morphology [CHU Pitié-Salpêtrière], Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Pneumologie pédiatrique [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de réhabilitation pédiatrique [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), NMR Laboratory, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Institut de Myologie (U153 Inserm - IM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Centre de référence des maladies rares neuromusculaires [CHU Pitié-Salpétriêre], and HAL-UPMC, Gestionnaire
Subjects: 0301 basic medicine, Pathology, medicine.medical_specialty, Muscle Proteins, KLHL40, Biology, medicine.disease_cause, Myopathies, Nemaline, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Nemaline myopathy, medicine, Humans, Nemaline bodies, Child, Muscle, Skeletal, Genetics (clinical), Sanger sequencing, Mutation, Muscle biopsy, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, medicine.diagnostic_test, Genetic heterogeneity, medicine.disease, Hypotonia, 3. Good health, 030104 developmental biology, Phenotype, Neurology, Pediatrics, Perinatology and Child Health, symbols, Female, Neurology (clinical), Presentation (obstetrics), medicine.symptom, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Nemaline myopathies are clinically and genetically heterogeneous muscle diseases characterized by the presence of nemaline bodies (rods) in muscle fibers. Mutations in the KLHL40 (kelch-like family member 40) gene (NEM 8) are common cause of severe/lethal nemaline myopathy. We report an 8-year-old girl born to consanguineous Moroccan parents, who presented with hypotonia and poor sucking at birth, delayed motor development, and further mild difficulties in walking and fatigability. A muscle biopsy revealed the presence of nemaline bodies. KLHL40 gene Sanger sequencing disclosed a never before reported pathogenic homozygous mutation which resulted in absent KLHL40 protein expression in the muscle. This further expands the phenotypical spectrum of KLHL40 related nemaline myopathy.
Published: 2020
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20. MRI vastus lateralis fat fraction predicts loss of ambulation in Duchenne muscular dystrophy

Author: I. Rybalsky, Julien Le Louër, Karin J. Naarding, Harmen Reyngoudt, Erik W. van Zwet, Pierre G. Carlier, K. Shellenbarger, Melissa T. Hooijmans, Cuixia Tian, Brenda Wong, Hermien E. Kan, and Erik H. Niks
Subjects: Male, medicine.medical_specialty, Duchenne muscular dystrophy, Population, Article, 030218 nuclear medicine & medical imaging, Quadriceps Muscle, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Clinical endpoint, Medicine, Humans, Mobility Limitation, education, Child, education.field_of_study, Surrogate endpoint, Proportional hazards model, business.industry, Hazard ratio, medicine.disease, Magnetic Resonance Imaging, Confidence interval, Muscular Dystrophy, Duchenne, Adipose Tissue, Cohort, Cardiology, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract: ObjectiveWe studied the potential of quantitative MRI (qMRI) as a surrogate endpoint in Duchenne muscular dystrophy by assessing the additive predictive value of vastus lateralis (VL) fat fraction (FF) to age on loss of ambulation (LoA).MethodsVL FFs were determined on longitudinal Dixon MRI scans from 2 natural history studies in Leiden University Medical Center (LUMC) and Cincinnati Children's Hospital Medical Center (CCHMC). CCHMC included ambulant patients, while LUMC included a mixed ambulant and nonambulant population. We fitted longitudinal VL FF values to a sigmoidal curve using a mixed model with random slope to predict individual trajectories. The additive value of VL FF over age to predict LoA was calculated from a Cox model, yielding a hazard ratio.ResultsEighty-nine MRIs of 19 LUMC and 15 CCHMC patients were included. At similar age, 6-minute walking test distances were smaller and VL FFs were correspondingly higher in LUMC compared to CCHMC patients. Hazard ratio of a percent-point increase in VL FF for the time to LoA was 1.15 for LUMC (95% confidence interval [CI] 1.05–1.26;p= 0.003) and 0.96 for CCHMC (95% CI 0.84–1.10;p= 0.569).ConclusionsThe hazard ratio of 1.15 corresponds to a 4.11-fold increase of the instantaneous risk of LoA in patients with a 10% higher VL FF at any age. Although results should be confirmed in a larger cohort with prospective determination of the clinical endpoint, this added predictive value of VL FF to age on LoA supports the use of qMRI FF as an endpoint or stratification tool in clinical trials.
Published: 2020

21. Whole-Body Muscle Magnetic Resonance Imaging in Glycogen-Storage Disease Type III

Author: Marion Masingue, Luca Bello, Andrea Barp, David Tobaly, Ariane Perry, Pascal Laforêt, Robert-Yves Carlier, Pierre G. Carlier, Valérie Decostre, Philippe Labrune, Dalila Habes, and François Petit
Subjects: 0301 basic medicine, Adult, Male, glycogen-storage disease type III, heatmap, Mercuri, muscle MRI, pattern recognition, whole-body MRI, Adolescent, Female, Glycogen Storage Disease Type III, Humans, Magnetic Resonance Imaging, Middle Aged, Muscle, Skeletal, Severity of Illness Index, Vital Capacity, Walk Test, Whole Body Imaging, Young Adult, Physiology, Fatty replacement, 030105 genetics & heredity, Glycogen storage disease type III, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Muscle nerve, Physiology (medical), medicine, medicine.diagnostic_test, business.industry, Magnetic resonance imaging, Anatomy, Skeletal, medicine.disease, Patient management, Coronal plane, Muscle, Neurology (clinical), Whole body, business, Relevant information, 030217 neurology & neurosurgery
Abstract: INTRODUCTION The main objective of this study was to describe muscle involvement on whole-body magnetic resonance imaging scans in adults at different stages of glycogen-storage disease type III (GSDIII). METHODS Fifteen patients, 16-59 years of age, were examined on a 3-T system. The examinations consisted of coronal and axial T1-weighted images or fat images with a Dixon technique, and were scored for 47 muscles using Mercuri's classification. Muscle changes consisted of internal bright signals of fatty replacement. RESULTS Distribution across muscles showed predominant signal alteration in the lower limbs and postural muscles. This finding is consistent with the overall clinical presentation of GSDIII and the results of heatmap scores. Review of the MRI scans provided new information regarding recurrent muscle changes, particularly in the soleus, gastrocnemius medial head, and thoracic extensor muscles. DISCUSSION Whole-body muscle imaging provides clinically relevant information regarding muscle involvement in GSDIII. A severity score may contribute to improved patient management. Muscle Nerve, 2019.
Published: 2019

22. Muscle MRI in patients with dysferlinopathy: pattern recognition and implications for clinical trials

Author: Tim Hodgson, Dorothy Wallace, Madoka Mori-Yoshimura, Kate Bushby, Diana Bharucha-Goebel, Carmen Paradas, John W. Day, Roberto Stramare, Jean-Yves Hogrel, Elena Bravver, Bruce Harwick, Mark Smith, Andrew M. Blamire, Claudio Semplicini, Emmanuelle Salort-Campana, Pierre G. Carlier, Marni Jacobs, Alessandro Rampado, Laura E. Rufibach, Matthew B. Harms, Olivia Schreiber-Katz, Plavi Mittal, Jerry R. Mendell, Eva Coppenrath, Fiona E. Smith, Sheryl Foster, Stanley T. Fricke, Anna Mayhew, David Bendahan, Tanya Stojkovic, Hanns Lochmüller, Anthony Peduto, Jordi Díaz-Manera, Michelle Eagle, Noriko Sato, Yann Le Fur, H. Hilsden, Suna Turk, U. Moore, Simone Spuler, Kristi J. Jones, Shin'ichi Takeda, Anne M. Sawyer, Volker Straub, Glenn Foster, Elena Pegoraro, Sabine Krause, Louise Ward, Susan Sparks, Hansel J. Otero, Carolina Tesi Rocha, M. James, Luca Bello, Takeshi Tamaru, Alan Pestronk, Jaume Llauger, Roberto Fernández-Torrón, Ulrike Grieben, Susana Rico Gala, Maggie C. Walter, CIBER de Enfermedades Raras (CIBERER), Newcastle University [Newcastle], Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Georgetown University [Washington] (GU), Università degli Studi di Padova = University of Padua (Unipd), Ludwig Maximilian University [Munich] (LMU), Aix Marseille Université (AMU), Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), The University of Sydney, Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, National Institute of Neurological Disorders and Stroke [Bethesda] (NINDS), National Institutes of Health [Bethesda] (NIH), Neurologie, maladies neuro-musculaires [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Washington University in Saint Louis (WUSTL), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Universita degli Studi di Padova, Stanford University School of Medicine [Stanford], Stanford University [Stanford], Max Delbrück Center for Molecular Medicine (MDC), Helmholtz-Gemeinschaft, Washington University in St Louis, Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), United Kingdom Met Office [Exeter], Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Neurology, Solid State NMR Group, University of Warwick, University of Warwick [Coventry], Max Delbrück Center, Computer Science Department [Boston] (Boston University), Boston University [Boston] (BU), Centre de référence des maladies neuromusculaires et de la SLA, Hôpital de la Timone [CHU - APHM] (TIMONE), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Hospital Universitario Virgen del Rocío [Sevilla]
Subjects: 0301 basic medicine, muscular dystrophy, Adult, Male, medicine.medical_specialty, Dysferlinopathy, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, Disease, Muscle disorder, Muscle MRI, Outcome measures, 03 medical and health sciences, outcome measures, 0302 clinical medicine, medicine, Humans, In patient, Longitudinal Studies, Muscular dystrophy, Muscle, Skeletal, ComputingMilieux_MISCELLANEOUS, dysferlinopathy, muscle MRI, Surgery, Neurology (clinical), Psychiatry and Mental Health, Muscle mri, business.industry, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Clinical trial, 030104 developmental biology, Cross-Sectional Studies, Muscular Dystrophies, Limb-Girdle, Neuromuscular, Pattern recognition (psychology), [SDV.IB]Life Sciences [q-bio]/Bioengineering, Female, Radiology, Function and Dysfunction of the Nervous System, business, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Background and objectiveDysferlinopathies 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.MethodsWe 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.ResultsIn 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.ConclusionsThe 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 registrationNCT01676077.
Published: 2018
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23. Long-term microdystrophin gene therapy is effective in a canine model of Duchenne muscular dystrophy

Author: Virginie François, Oumeya Adjali, Jean-Yves Hogrel, George Dickson, Thibaut Larcher, Maeva Dutilleul, Taeyoung Koo, Marie Montus, Stéphane Ederhy, Stéphane Blot, M. Allais, Carole Masurier, Alberto Malerba, Marie Devaux, B. Matot, Karim Wahbi, Sophie Moullec, Bernard Gjata, Bodvael Fraysse, Laurent Servais, Fulvio Mavilio, Inès Barthélémy, Pierre G. Carlier, Takis Athanasopoulos, Isabelle Testault, Samia Martin, Jack-Yves Deschamps, Philippe Moullier, Federico Mingozzi, Philippe Veron, Christophe Georger, Johanne Le Duff, Caroline Le Guiner, Thomas Voit, Jean-Laurent Thibaut, U1089, Institut National de la Santé et de la Recherche Médicale (INSERM), Service of Clinical Trials and Databases, Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Généthon, Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Laboratoire de Thérapie Génique Translationnelle des Maladies Génétiques (Inserm UMR 1089), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre de Boisbonne, Atlantic Gene Therapies, Ecole Nationale Vétérinaire Agroalimentaire et de l'Alimentation Nantes Atlantique (ONIRIS), Thérapie génique translationnelle pour les maladies neuromusculaires et de la rétine, Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie Animale et bioThérapie du muscle et du système nerveux (PAnTher), Institut National de la Recherche Agronomique (INRA)-École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Royal Holloway, University of London, Laboratoire de Résonance Magnétique Nucléaire (LRMN), Modélisation thérapeutique en neurologie: myologie et biothérapies des myopathies canines, Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Chercheur indépendant, Centre Hospitalier Vétérinaire Atlantia, Service de Cardiologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire des Sciences de l'Information et des Systèmes (LSIS), Aix Marseille Université (AMU)-Université de Toulon (UTLN)-Arts et Métiers Paristech ENSAM Aix-en-Provence-Centre National de la Recherche Scientifique (CNRS), Approches génétiques intégrées et nouvelles thérapies pour les maladies rares (INTEGRARE), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Généthon, University of Wolverhampton, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Thérapie des maladies du muscle strié, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), UMR1089, Laboratoire de Thérapie Génique, Université de Nantes (UN), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Service de Cardiologie [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre National de la Recherche Scientifique (CNRS)-Arts et Métiers Paristech ENSAM Aix-en-Provence-Université de Toulon (UTLN)-Aix Marseille Université (AMU), École pratique des hautes études (EPHE), Laboratoire RMN, Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de recherche en myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), UMR 1089, Atlantic Gene Therapies, Développement et Pathologie du Tissu Musculaire (DPTM), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Nantes, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Association française contre les myopathies (AFM-Téléthon), École pratique des hautes études (EPHE)-Université d'Évry-Val-d'Essonne (UEVE)-GENETHON 3-Institut National de la Santé et de la Recherche Médicale (INSERM), UMR 1089, Atlantic Gene Therapies & Genethon, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Université Pierre et Marie Curie - Paris 6 (UPMC), Recherche et développement [Généthon, Evry] (R & D Généthon), Généthon [Evry], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Généthon-École pratique des hautes études (EPHE), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)
Subjects: 0301 basic medicine, Male, myopathie de duchenne, Duchenne muscular dystrophy, Genetic enhancement, medicine.medical_treatment, General Physics and Astronomy, Bioinformatics, Dystrophin, Muscular Dystrophy, Vector (molecular biology), Transgenes, Muscular dystrophy, Multidisciplinary, biology, Gene Transfer Techniques, Immunosuppression, Skeletal, Dependovirus, 3. Good health, thérapie génique, Administration, Muscle, Administration, Intravenous, Intravenous, ITGA7, musculoskeletal diseases, congenital, hereditary, and neonatal diseases and abnormalities, Neuromuscular disease, Science, Genetic Vectors, Animals, Disease Models, Animal, Dogs, Genetic Therapy, Muscle, Skeletal, Muscular Dystrophy, Animal, Muscular Dystrophy, Duchenne, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, medicine, Animal, business.industry, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, General Chemistry, Duchenne, medicine.disease, 030104 developmental biology, Disease Models, biology.protein, business
Abstract: Duchenne muscular dystrophy (DMD) is an incurable X-linked muscle-wasting disease caused by mutations in the dystrophin gene. Gene therapy using highly functional microdystrophin genes and recombinant adeno-associated virus (rAAV) vectors is an attractive strategy to treat DMD. Here we show that locoregional and systemic delivery of a rAAV2/8 vector expressing a canine microdystrophin (cMD1) is effective in restoring dystrophin expression and stabilizing clinical symptoms in studies performed on a total of 12 treated golden retriever muscular dystrophy (GRMD) dogs. Locoregional delivery induces high levels of microdystrophin expression in limb musculature and significant amelioration of histological and functional parameters. Systemic intravenous administration without immunosuppression results in significant and sustained levels of microdystrophin in skeletal muscles and reduces dystrophic symptoms for over 2 years. No toxicity or adverse immune consequences of vector administration are observed. These studies indicate safety and efficacy of systemic rAAV-cMD1 delivery in a large animal model of DMD, and pave the way towards clinical trials of rAAV–microdystrophin gene therapy in DMD patients., Duchenne muscular dystrophy is a progressive degenerative disease of muscles caused by mutations in the dystrophin gene. Here the authors use AAV vectors to deliver microdystrophin to dogs with muscular dystrophy, and show restoration of dystrophin expression and reduction of symptoms up to 26 months of age.
Published: 2017
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24. Stimulated echo DTI of skeletal muscle in Becker muscular dystrophy: a pilot study

Author: Andrew M. Blamire, Hermien E. Kan, J.J.G. Verschuuren, O. Scheidegger, Erik H. Niks, Jedrzej Burakiewicz, Celine Baligand, Paola Porcari, Chris A. Clark, Pierre G. Carlier, Matthew Hall, and Melissa T. Hooijmans
Subjects: medicine.anatomical_structure, Neurology, business.industry, Pediatrics, Perinatology and Child Health, medicine, Skeletal muscle, Neurology (clinical), Stimulated echo, Anatomy, Muscular dystrophy, medicine.disease, business, Genetics (clinical)
Published: 2017

25. Affected female carriers of MTM1 mutations display a wide spectrum of clinical and pathological involvement: delineating diagnostic clues

Author: Anne Boland, Marguerite Miguet, Jocelyn Laporte, Julie Dawn Thompson, Robert-Yves Carlier, Nicol C. Voermans, Pierre G. Carlier, Nicolas Dondaine, Nasim Vasli, Sophie Scheidecker, Xavière Lornage, Edmar Zanoteli, Nadège Calmels, Shay Ben-Shachar, Raphaël Schneider, Pascal Laforêt, Curtis Rogers, Annie Laquerrière, Benno Küsters, Laurent Pasquier, Michel Fardeau, Valérie Kremer, Tanya Stojkovic, Erik-Jan Kamsteeg, Celia Boutte, Laura Tanner, Valérie Biancalana, Claire Gasnier, Elise Schaefer, Alexandre Moerman, Norma B. Romero, Armelle Magot, Julie Perrier, Pascale Marcorelle, Bruno Eymard, Jean Pouget, Jean-François Deleuze, Elisabeth Ollagnon-Roman, Christine Tranchant, Osorio Abath Neto, Nathalie Streichenberger, Sandra Mercier, Karine Nguyen, Helen Roper, Service d'Anatomie et Cytologie Pathologique [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Université Toulouse - Jean Jaurès (UT2J), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Hôpital de la Timone [CHU - APHM] (TIMONE), Service de génétique clinique, hôpital Sud, Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Institut NeuroMyoGène (INMG), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hospices Civils de Lyon (HCL), Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Université du Québec à Rimouski (UQAR), Physiopathologie du système nerveux., Université Louis Pasteur - Strasbourg I-IFR37-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Sciences Moléculaires de Marseille (ISM2), Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), AFM-16992, AFM-Téléthon, ANR-10-IDEX-0002-02, Agence Nationale de la Recherche, DBI20131228569, Fondation pour la Recherche Médicale, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Université de Strasbourg, ANR-10-INBS-09, Agence Nationale pour la Recherche, Fondation Maladies Rares, CREGEMES, Université de Toulouse (UT), Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Strasbourg, ANR-10-IDEX-0002,UNISTRA,Par-delà les frontières, l'Université de Strasbourg(2010), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-École Centrale de Marseille (ECM)-Institut de Chimie du CNRS (INC)
Subjects: 0301 basic medicine, Pathology, Severity of Illness Index, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Cohort Studies, 0302 clinical medicine, Respiratory function, Child, ComputingMilieux_MISCELLANEOUS, Congenital myopathy, Facial weakness, Middle Aged, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Protein Tyrosine Phosphatases, Non-Receptor, X-linked myotubular myopathy, 3. Good health, X inactivation, Phenotype, Child, Preschool, Female, medicine.symptom, Myopathies, Structural, Congenital, Adult, Weakness, medicine.medical_specialty, Heterozygote, MTM1, Adolescent, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Sciences du Vivant [q-bio]/Médecine humaine et pathologie, Pathology and Forensic Medicine, Diagnosis, Differential, 03 medical and health sciences, Cellular and Molecular Neuroscience, medicine, Humans, Centronuclear myopathy, Myopathy, Skewed X-inactivation, Aged, medicine.disease, 030104 developmental biology, Mutation, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neurology (clinical), 030217 neurology & neurosurgery
Abstract: Contains fulltext : 182328.pdf (Publisher’s version ) (Closed access) X-linked myotubular myopathy (XLMTM), a severe congenital myopathy, is caused by mutations in the MTM1 gene located on the X chromosome. A majority of affected males die in the early postnatal period, whereas female carriers are believed to be usually asymptomatic. Nevertheless, several affected females have been reported. To assess the phenotypic and pathological spectra of carrier females and to delineate diagnostic clues, we characterized 17 new unrelated affected females and performed a detailed comparison with previously reported cases at the clinical, muscle imaging, histological, ultrastructural and molecular levels. Taken together, the analysis of this large cohort of 43 cases highlights a wide spectrum of clinical severity ranging from severe neonatal and generalized weakness, similar to XLMTM male, to milder adult forms. Several females show a decline in respiratory function. Asymmetric weakness is a noteworthy frequent specific feature potentially correlated to an increased prevalence of highly skewed X inactivation. Asymmetry of growth was also noted. Other diagnostic clues include facial weakness, ptosis and ophthalmoplegia, skeletal and joint abnormalities, and histopathological signs that are hallmarks of centronuclear myopathy such as centralized nuclei and necklace fibers. The histopathological findings also demonstrate a general disorganization of muscle structure in addition to these specific hallmarks. Thus, MTM1 mutations in carrier females define a specific myopathy, which may be independent of the presence of an XLMTM male in the family. As several of the reported affected females carry large heterozygous MTM1 deletions not detectable by Sanger sequencing, and as milder phenotypes present as adult-onset limb-girdle myopathy, the prevalence of this myopathy is likely to be greatly underestimated. This report should aid diagnosis and thus the clinical management and genetic counseling of MTM1 carrier females. Furthermore, the clinical and pathological history of this cohort may be useful for therapeutic projects in males with XLMTM, as it illustrates the spectrum of possible evolution of the disease in patients surviving long term.
Published: 2017
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26. Longitudinal data of the European prospective natural history study of patients with type 2 and 3 spinal muscular atrophy

Author: Claude Cances, Jean-Marie Cuisset, Linda Lowes, Vincent Laugel, Laurent Servais, Teresa Gidaro, A. Chabanon, M. Annoussamy, Ulrike Schara, A. Daron, Omar Khwaja, Carole Vuillerot, Ricardo Hermosilla, J.Y. Hogrel, Andreea Mihaela Seferian, Nathalie Goemans, E. Gargaun, Yann Péréon, Pierre G. Carlier, and Christian Czech
Subjects: 0301 basic medicine, medicine.medical_specialty, Longitudinal data, business.industry, Medizin, Spinal muscular atrophy, medicine.disease, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Physical medicine and rehabilitation, Neurology, Pediatrics, Perinatology and Child Health, Physical therapy, medicine, Neurology (clinical), business, 030217 neurology & neurosurgery, Genetics (clinical), Natural history study
Published: 2017

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

Author: P. Baudin, Pierre G. Carlier, Paulo Loureiro de Sousa, Benjamin Marty, Eduard Snezhko, Dmitry Vlodavets, and Olivier Scheidegger
Subjects: Context (language use), 610 Medicine & health, Review, Biology, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Nuclear magnetic resonance, Outcome Assessment, Health Care, medicine, Humans, Muscle, Skeletal, Clinical Trials as Topic, medicine.diagnostic_test, Outcome measures, Skeletal muscle, Neuromuscular Diseases, Magnetic Resonance Imaging, Clinical trial, medicine.anatomical_structure, Neurology, Biomarker (medicine), Neurology (clinical), Intramuscular fat, Elastography, Perfusion, 030217 neurology & neurosurgery
Abstract: Recent years have seen tremendous progress towards therapy of many previously incurable neuromuscular diseases. This new context has acted as a driving force for the development of novel non-invasive outcome measures. These can be organized in three main categories: functional tools, fluid biomarkers and imagery. In the latest category, nuclear magnetic resonance imaging (NMRI) offers a considerable range of possibilities for the characterization of skeletal muscle composition, function and metabolism. Nowadays, three NMR outcome measures are frequently integrated in clinical research protocols. They are: 1/ the muscle cross sectional area or volume, 2/ the percentage of intramuscular fat and 3/ the muscle water T2, which quantity muscle trophicity, chronic fatty degenerative changes and oedema (or more broadly, "disease activity"), respectively. A fourth biomarker, the contractile tissue volume is easily derived from the first two ones. The fat fraction maps most often acquired with Dixon sequences have proven their capability to detect small changes in muscle composition and have repeatedly shown superior sensitivity over standard functional evaluation. This outcome measure will more than likely be the first of the series to be validated as an endpoint by regulatory agencies. The versatility of contrast generated by NMR has opened many additional possibilities for characterization of the skeletal muscle and will result in the proposal of more NMR biomarkers. Ultra-short TE (UTE) sequences, late gadolinium enhancement and NMR elastography are being investigated as candidates to evaluate skeletal muscle interstitial fibrosis. Many options exist to measure muscle perfusion and oxygenation by NMR. Diffusion NMR as well as texture analysis algorithms could generate complementary information on muscle organization at microscopic and mesoscopic scales, respectively. 31P NMR spectroscopy is the reference technique to assess muscle energetics non-invasively during and after exercise. In dystrophic muscle, 31P NMR spectrum at rest is profoundly perturbed, and several resonances inform on cell membrane integrity. Considerable efforts are being directed towards acceleration of image acquisitions using a variety of approaches, from the extraction of fat content and water T2 maps from one single acquisition to partial matrices acquisition schemes. Spectacular decreases in examination time are expected in the near future. They will reinforce the attractiveness of NMR outcome measures and will further facilitate their integration in clinical research trials.
Published: 2016
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28. Response

Author: Russell S. Richardson, Claire Wary, D. Walter Wray, Jan Hoff, Harry B. Rossiter, Gwenael Layec, and Pierre G. Carlier
Subjects: Magnetic Resonance Spectroscopy, Oxygen Consumption, Humans, Physical Therapy, Sports Therapy and Rehabilitation, Orthopedics and Sports Medicine, Muscle, Skeletal, Exercise, Article
Published: 2015

29. Adeno-associated virus vector (AAV) microdystrophin gene therapy prolongs survival and restores muscle function in the canine model of Duchenne muscular dystrophy (DMD)

Author: L. Servais, Takis Athanasopoulos, Oumeya Adjali, F Mingozzi, George Dickson, J.Y. Hogrel, Yan Cherel, Pierre G. Carlier, Marie Montus, Taeyoung Koo, T. Voit, Sophie Moullec, Fulvio Mavilio, Philippe Moullier, Bernard Gjata, F. Bodvael, C. Le Guiner, Carole Masurier, Généthon, UMR 1089, Atlantic Gene Therapies, Institut National de la Santé et de la Recherche Médicale (INSERM), Service of Clinical Trials and Databases, Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Neuromuscular Physiology and Evaluation Laboratory, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), AIM, Atlantic Gene Therapies, Royal Holloway [University of London] (RHUL), University of Wolverhampton, Physiopathologie Animale et bioThérapie du muscle et du système nerveux (PAnTher), Institut National de la Recherche Agronomique (INRA)-École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Paris Cité (UPCité), University of Florida [Gainesville] (UF), World Muscle Society (WMS). London, INT., Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Université de Paris (UP)
Subjects: 0303 health sciences, business.industry, Genetic enhancement, Duchenne muscular dystrophy, medicine.disease_cause, medicine.disease, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Neurology, 030220 oncology & carcinogenesis, Pediatrics, Perinatology and Child Health, medicine, Cancer research, Neurology (clinical), Vector (molecular biology), business, Adeno-associated virus, Canine model, Genetics (clinical), Function (biology), [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030304 developmental biology
Abstract: International audience; Duchenne muscular dystrophy (DMD) is an X-linked inherited muscle-wasting disease primarily affecting young boys with a prevalence of 1:5000. The disease is caused by loss-of-function mutations in the gene encoding for the Dystrophin protein and is characterised by systemic, progressive, irreversible and severe loss of muscle function. Among vector systems that allow efficient in vivo gene transfer, recombinant Adeno Associated Virus vectors (rAAV) hold great promise and result in particular in very efficient transduction of skeletal and cardiac muscles.
Published: 2015
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30. Structural and Functional Alterations of Skeletal Muscle Microvasculature in Dystrophin-Deficient mdx Mice

Author: Pierre G. Carlier, Claire Latroche, A.B. Martins-Bach, Claire Wary, David Briand, Fabrice Chrétien, B. Matot, Bénédicte Chazaud, Grégory Jouvion, Histopathologie humaine et Modèles animaux, Institut Pasteur [Paris] (IP), Laboratoire de Résonance Magnétique Nucléaire (LRMN), Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Structure et Réactivité des Systèmes Moléculaires Complexes (SRSMC), Institut de Chimie du CNRS (INC)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris], Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Résonance Magnétique Nucléaire ( LRMN ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Association française contre les myopathies ( AFM-Téléthon ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Association française contre les myopathies ( AFM-Téléthon ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Structure et Réactivité des Systèmes Moléculaires Complexes ( SRSMC ), Université de Lorraine ( UL ) -Centre National de la Recherche Scientifique ( CNRS ), and Latroche, Claire
Subjects: [SDV.MHEP.AHA] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Pathology, medicine.medical_specialty, [ SDV.MHEP.AHA ] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Duchenne muscular dystrophy, Biology, Pathology and Forensic Medicine, Phosphocreatine, Dystrophin, chemistry.chemical_compound, Fibrosis, medicine, [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Animals, Muscle, Skeletal, Microvessel, Skeletal muscle, medicine.disease, Magnetic Resonance Imaging, 3. Good health, Mice, Inbred C57BL, Muscular Dystrophy, Duchenne, Disease Models, Animal, medicine.anatomical_structure, chemistry, Microvessels, biology.protein, Mice, Inbred mdx, Perfusion, Blood vessel
Abstract: International audience; Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disease, caused by an absence of dystrophin, inevitably leading to death. Although muscle lesions are well characterized, blood vessel alterations that may have a major impact on muscle regeneration remain poorly understood. Our aim was to elucidate alterations of the vascular network organization, taking advantage of Flk1(GFP/+) crossed with mdx mice (model for human DMD where all blood vessels express green fluorescent protein) and functional repercussions using in vivo nuclear magnetic resonance, combining arterial spin-labeling imaging of perfusion, and (31)P-spectroscopy of phosphocreatine kinetics. For the first time, our study focused on old (12-month-old) mdx mice, displaying marked chronic muscle lesions, similar to the lesions observed in human DMD, in comparison to young-adult (3-month-old) mdx mice displaying only mild muscle lesions with no fibrosis. By using an original approach combining a specific animal model, state-of-the-art histology/morphometry techniques, and functional nuclear magnetic resonance, we demonstrated that the microvascular system is almost normal in young-adult in contrast to old mdx mice, displaying marked microvessel alterations, and the functional repercussions on muscle perfusion and bioenergetics after a hypoxic stress vary depending on stage of pathology. This original approach clarifies disease evolution and paves the way for setting up new diagnostic markers or therapeutic strategies.
Published: 2015
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31. Quantitative T2 combined with texture analysis of nuclear magnetic resonance images identify different degrees of muscle involvement in three mouse models of muscle dystrophy: mdx, Largemyd and mdx/Largemyd

Author: Paulo Loureiro de Sousa, Alberto Tannus, A.B. Martins-Bach, Mariz Vainzof, Pierre G. Carlier, B. Matot, P.C.M. Martins, Waldir Caldeira, Jackeline Moraes Malheiros, Alberto de Freitas Ribeiro, Noura Azzabou, and Camila F. Almeida
Subjects: Male, Pathology, medicine.medical_specialty, Necrosis, lcsh:Medicine, Inflammation, Biology, Mice, RESSONÂNCIA MAGNÉTICA NUCLEAR, Nuclear magnetic resonance, medicine, Animals, Cluster Analysis, Muscular dystrophy, Muscle, Skeletal, lcsh:Science, Multidisciplinary, medicine.diagnostic_test, Regeneration (biology), lcsh:R, Histology, Magnetic resonance imaging, Muscle dystrophy, Muscular Dystrophy, Animal, medicine.disease, Magnetic Resonance Imaging, Phenotype, Mice, Inbred C57BL, Radiography, Disease Models, Animal, Mice, Inbred mdx, Female, lcsh:Q, medicine.symptom, Research Article
Abstract: Quantitative nuclear magnetic resonance imaging (MRI) has been considered a promising non-invasive tool for monitoring therapeutic essays in small size mouse models of muscular dystrophies. Here, we combined MRI (anatomical images and transverse relaxation time constant—T2—measurements) to texture analyses in the study of four mouse strains covering a wide range of dystrophic phenotypes. Two still unexplored mouse models of muscular dystrophies were analyzed: The severely affected Largemyd mouse and the recently generated and worst double mutant mdx/Largemyd mouse, as compared to the mildly affected mdx and normal mice. The results were compared to histopathological findings. MRI showed increased intermuscular fat and higher muscle T2 in the three dystrophic mouse models when compared to the wild-type mice (T2: mdx/Largemyd: 37.6±2.8 ms; mdx: 35.2±4.5 ms; Largemyd: 36.6±4.0 ms; wild-type: 29.1±1.8 ms, p
Published: 2015

32. Quantitative Magnetic Resonance Imaging in Limb-Girdle Muscular Dystrophy 2I: A Multinational Cross-Sectional Study

Author: Tracey A Willis, Kieren G Hollingsworth, Anna Coombs, Marie-Louise Sveen, Soren Andersen, Tanya Stojkovic, Michelle Eagle, Anna Mayhew, Paulo Loureiro de Sousa, Liz Dewar, Jasper M Morrow, Christopher D J Sinclair, John S Thornton, Kate Bushby, Hanns Lochmuller, Michael G Hanna, Jean-Yves Hogrel, Pierre G Carlier, John Vissing, and Volker Straub
Subjects: Adult, Male, Adolescent, Clinical Research Design, Epidemiology, Adipose Tissue, White, lcsh:Medicine, Neuroimaging, Diagnostic Radiology, Sex Factors, Diagnostic Medicine, Pathology, Image Processing, Computer-Assisted, Humans, Pentosyltransferases, lcsh:Science, Muscle, Skeletal, lcsh:R, Proteins, Neuromuscular Diseases, Middle Aged, Magnetic Resonance Imaging, Europe, Biomarker Epidemiology, Cross-Sectional Studies, Neurology, Muscular Dystrophies, Limb-Girdle, Mutation, Medicine, lcsh:Q, Female, Radiology, Biomarkers, Research Article, General Pathology, Test Evaluation
Abstract: We conducted a prospective multinational study of muscle pathology using magnetic resonance imaging (MRI) in patients with limb-girdle muscular dystrophy 2I (LGMD2I). Thirty eight adult ambulant LGMD2I patients (19 male; 19 female) with genetically identical mutations (c.826C>A) in the fukutin-related protein (FKRP) gene were recruited. In each patient, T1-weighted (T1w) imaging was assessed by qualitative grading for 15 individual lower limb muscles and quantitative Dixon imaging was analysed on 14 individual lower limb muscles by region of interest analysis. We described the pattern and appearance of muscle pathology and gender differences, not previously reported for LGMD2I. Diffuse fat infiltration of the gastrocnemii muscles was demonstrated in females, whereas in males fat infiltration was more prominent in the medial than the lateral gastrocnemius (p = 0.05). In the anterior thigh of males, in contrast to females, median fat infiltration in the vastus medialis muscle (45.7%) exceeded that in the vastus lateralis muscle (11.2%) (p
Published: 2014

33. Medical Image Computing and Computer Assisted Intervention (MICCAI)

Author: Pierre-Yves Baudin, Danny Goodman, Puneet Kumar, Noura Azzabou, Pierre G. Carlier, Nikos Paragios, and M. Pawan Kumar
Published: 2013

34. Longitudinal in vivo muscle function analysis of the DMSXL mouse model of myotonic dystrophy type 1

Author: Geneviève Gourdon, Pierre G. Carlier, Bernard Gjata, Alban Vignaud, Isabelle Ledoux, B. Matot, Aline Huguet, Emilie Bertil, Valérie Decostre, Jean-Yves Hogrel, Immunologie moléculaire et biothérapies innovantes (IMBI), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Généthon, Biogéochimie et écologie des milieux continentaux (Bioemco), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut de Recherche pour le Développement (IRD)-Institut National de la Recherche Agronomique (INRA)-Université Pierre et Marie Curie - Paris 6 (UPMC)-AgroParisTech-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Photonique Quantique et Moléculaire (LPQM), École normale supérieure - Cachan (ENS Cachan)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), Institut de biologie et chimie des protéines [Lyon] (IBCP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Généthon, Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de physiologie et d'évaluation neuromusculaire, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Généthon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Évry-Val-d'Essonne (UEVE)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Recherche Agronomique (INRA)-Université Pierre et Marie Curie - Paris 6 (UPMC)-AgroParisTech-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU)
Subjects: Pathology, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Muscle Fibers, Skeletal, Mice, Transgenic, Muscle Strength Dynamometer, Protein Serine-Threonine Kinases, Myotonic dystrophy, Mice, 03 medical and health sciences, 0302 clinical medicine, In vivo, medicine, Animals, Humans, Myotonic Dystrophy, Longitudinal Studies, Muscle, Skeletal, Genetics (clinical), 030304 developmental biology, Analysis of Variance, 0303 health sciences, medicine.diagnostic_test, Muscle fatigue, business.industry, Body Weight, Age Factors, Skeletal muscle, Magnetic resonance imaging, Anatomy, medicine.disease, Myotonia, Magnetic Resonance Imaging, Hindlimb, Function analysis, Disease Models, Animal, medicine.anatomical_structure, Neurology, Pediatrics, Perinatology and Child Health, Neurology (clinical), Ankle, Trinucleotide Repeat Expansion, business, 030217 neurology & neurosurgery
Abstract: International audience; Myotonic dystrophy is the most common adult muscle dystrophy. In view of emerging therapies, which use animal models as a proof of principle, the development of reliable outcome measures for in vivo longitudinal study of mouse skeletal muscle function is becoming crucial. To satisfy this need, we have developed a device to measure ankle dorsi- and plantarflexion torque in rodents. We present an in vivo 8-month longitudinal study of the contractile properties of the skeletal muscles of the DMSXL mouse model of myotonic dystrophy type 1. Between 4 and 12months of age, we observed a reduction in muscle strength in the ankle dorsi- and plantarflexors of DMSXL compared to control mice although the strength per muscle cross-section was normal. Mild steady myotonia but no abnormal muscle fatigue was also observed in the DMSXL mice. Magnetic resonance imaging and histological analysis performed at the end of the study showed respectively reduced muscle cross-section area and smaller muscle fibre diameter in DMSXL mice. In conclusion, our study demonstrates the feasibility of carrying out longitudinal in vivo studies of muscle function over several months in a mouse model of myotonic dystrophy confirming the feasibility of this method to test preclinical therapeutics.
Published: 2013
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35. Quantitative Muscle MRI as an Assessment Tool for Monitoring Disease Progression in LGMD2I: A Multicentre Longitudinal Study

Author: Kate Bushby, Kieren G. Hollingsworth, Tracey Willis, L. Dewar, Pierre G. Carlier, Michelle Eagle, Jean-Yves Hogrel, Michael G. Hanna, Marie-Louise Sveen, Paulo Loureiro de Sousa, Christopher D. J. Sinclair, Hanns Lochmüller, John Vissing, Anna Mayhew, John S. Thornton, Søren Peter Andersen, Volker Straub, Anna Coombs, Tanya Stojkovic, and Jasper M. Morrow
Subjects: Male, Longitudinal study, Anatomy and Physiology, lcsh:Medicine, Adipose tissue, Muscular Dystrophies, 030218 nuclear medicine & medical imaging, Diagnostic Radiology, 0302 clinical medicine, Pathology, Longitudinal Studies, Young adult, Muscular dystrophy, lcsh:Science, Multidisciplinary, medicine.diagnostic_test, Muscles, Neuromuscular Diseases, Middle Aged, Magnetic Resonance Imaging, Neurology, Adipose Tissue, Cohort, Disease Progression, Medicine, Female, Radiology, Research Article, Adult, medicine.medical_specialty, Drugs and Devices, Drug Research and Development, Adolescent, 03 medical and health sciences, Young Adult, Diagnostic Medicine, Image Interpretation, Computer-Assisted, medicine, Genetics, Humans, Biology, Clinical Genetics, business.industry, lcsh:R, Disease progression, Magnetic resonance imaging, Human Genetics, medicine.disease, Clinical trial, Muscular Dystrophies, Limb-Girdle, Physical therapy, lcsh:Q, business, Physiological Processes, 030217 neurology & neurosurgery, Biomarkers, General Pathology, Follow-Up Studies
Abstract: Background: Outcome measures for clinical trials in neuromuscular diseases are typically based on physical assessments which are dependent on patient effort, combine the effort of different muscle groups, and may not be sensitive to progression over short trial periods in slow-progressing diseases. We hypothesised that quantitative fat imaging by MRI (Dixon technique) could provide more discriminating quantitative, patient-independent measurements of the progress of muscle fat replacement within individual muscle groups. Objective: To determine whether quantitative fat imaging could measure disease progression in a cohort of limb-girdle muscular dystrophy 2I (LGMD2I) patients over a 12 month period. Methods: 32 adult patients (17 male;15 female) from 4 European tertiary referral centres with the homozygous c.826C.A mutation in the fukutin-related protein gene (FKRP) completed baseline and follow up measurements 12 months later. Quantitative fat imaging was performed and muscle fat fraction change was compared with (i) muscle strength and function assessed using standardized physical tests and (ii) standard T1-weighted MRI graded on a 6 point scale. Results: There was a significant increase in muscle fat fraction in 9 of the 14 muscles analyzed using the quantitative MRI technique from baseline to 12 months follow up. Changes were not seen in the conventional longitudinal physical assessments or in qualitative scoring of the T1w images. Conclusions: Quantitative muscle MRI, using the Dixon technique, could be used as an important longitudinal outcome measure to assess muscle pathology and monitor therapeutic efficacy in patients with LGMD2I.
Published: 2013

36. British Machine Vision Conference (BMVC)

Author: Pierre-Yves Baudin, Noura Azzabou, Pierre G. Carlier, and Nikos Paragios
Published: 2012

37. Automatic skeletal muscle segmentation through random walks and graph-based seed placement

Author: Pierre G. Carlier, P-Y. Baudin, Noura Azzabou, N. Paragios, Centre de vision numérique (CVN), Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec, Organ Modeling through Extraction, Representation and Understanding of Medical Image Content (GALEN), Ecole Centrale Paris-Inria Saclay - Ile de France, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Institut de Myologie, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC), Service MIRCEN (MIRCEN), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Université Pierre et Marie Curie - Paris 6 (UPMC), imagine [Marne-la-Vallée], Laboratoire d'Informatique Gaspard-Monge (LIGM), Centre National de la Recherche Scientifique (CNRS)-Fédération de Recherche Bézout-ESIEE Paris-École des Ponts ParisTech (ENPC)-Université Paris-Est Marne-la-Vallée (UPEM)-Centre National de la Recherche Scientifique (CNRS)-Fédération de Recherche Bézout-ESIEE Paris-École des Ponts ParisTech (ENPC)-Université Paris-Est Marne-la-Vallée (UPEM)-Centre Scientifique et Technique du Bâtiment (CSTB), Centre National de la Recherche Scientifique (CNRS)-Fédération de Recherche Bézout-ESIEE Paris-École des Ponts ParisTech (ENPC)-Université Paris-Est Marne-la-Vallée (UPEM), Université Paris-Est Marne-la-Vallée (UPEM), École des Ponts ParisTech (ENPC), Mathématiques Appliquées aux Systèmes - EA 4037 (MAS), Ecole Centrale Paris, Inria Saclay - Ile de France, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Ecole Centrale Paris, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Paris-Est Marne-la-Vallée (UPEM)-École des Ponts ParisTech (ENPC)-ESIEE Paris-Fédération de Recherche Bézout-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Est Marne-la-Vallée (UPEM)-École des Ponts ParisTech (ENPC)-ESIEE Paris-Fédération de Recherche Bézout-Centre National de la Recherche Scientifique (CNRS)-Centre Scientifique et Technique du Bâtiment (CSTB), Université Paris-Est Marne-la-Vallée (UPEM)-École des Ponts ParisTech (ENPC)-ESIEE Paris-Fédération de Recherche Bézout-Centre National de la Recherche Scientifique (CNRS), Centre Scientifique et Technique du Bâtiment (CSTB)-École des Ponts ParisTech (ENPC)-Laboratoire d'Informatique Gaspard-Monge (LIGM), and Centre National de la Recherche Scientifique (CNRS)-Fédération de Recherche Bézout-ESIEE Paris-École des Ponts ParisTech (ENPC)-Université Paris-Est Marne-la-Vallée (UPEM)-Centre National de la Recherche Scientifique (CNRS)-Fédération de Recherche Bézout-ESIEE Paris-Université Paris-Est Marne-la-Vallée (UPEM)
Subjects: Markov random field, business.industry, muscle, [INFO.INFO-CV]Computer Science [cs]/Computer Vision and Pattern Recognition [cs.CV], Pattern recognition, Graph theory, 02 engineering and technology, Image segmentation, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Random walker algorithm, Discrete optimization, [INFO.INFO-TI]Computer Science [cs]/Image Processing [eess.IV], 0202 electrical engineering, electronic engineering, information engineering, graphical models, Graph (abstract data type), 020201 artificial intelligence & image processing, Segmentation, Artificial intelligence, Graphical model, business, image segmentation, Mathematics
Abstract: International audience; In this paper we propose a novel skeletal muscle segmentation method driven from discrete optimization. We introduce a graphical model that is able to automatically determine appropriate seed positions with respect to the different muscle classes. This is achieved by taking into account the expected local visual and geometric properties of the seeds through a pair-wise Markov Random Field. The outcome of this optimization process is fed to a powerful graphbased diffusion segmentation method (random walker) that is able to produce very promising results through a fully automated approach. Validation on challenging data sets demonstrates the potentials of our method.
Published: 2012
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38. pH as a biomarker of neurodegeneration in Huntington's disease: a translational rodent-human MRS study

Author: Emmanuel Brouillet, Philippe Remy, Celine Baligand, Amandine Rialland, Pierre Krystkowiak, Myriam M. Chaumeil, Christophe Verny, Vincent Lebon, Anne-Catherine Bachoud-Lévi, Philippe Damier, Véronique Gaura, Pierre G. Carlier, Philippe Hantraye, Julien Valette, and Gilles Bloch
Subjects: Adult, Male, Pathology, medicine.medical_specialty, Magnetic Resonance Spectroscopy, Intracellular pH, Disease, Striatum, Pharmacology, Translational Research, Biomedical, Neuroimaging, Huntington's disease, Medicine, Animals, Humans, Antihypertensive Agents, medicine.diagnostic_test, business.industry, Neurodegeneration, Feature Article, Magnetic resonance imaging, Hydrogen-Ion Concentration, Middle Aged, medicine.disease, Nitro Compounds, Magnetic Resonance Imaging, Corpus Striatum, Rats, Radiography, Huntington Disease, Neurology, Biomarker (medicine), Female, Neurology (clinical), Propionates, Cardiology and Cardiovascular Medicine, business, Biomarkers
Abstract: Early diagnosis and follow-up of neurodegenerative diseases are often hampered by the lack of reliable biomarkers. Neuroimaging techniques like magnetic resonance spectroscopy (MRS) offer promising tools to detect biochemical alterations at early stages of degeneration. Intracellular pH, which can be measured noninvasively by 31P-MRS, has shown variations in several brain diseases. Our purpose has been to evaluate the potential of MRS-measured pH as a relevant biomarker of early degeneration in Huntington's disease (HD). We used a translational approach starting with a preclinical validation of our hypothesis before adapting the method to HD patients. 31P-MRS-derived cerebral pH was first measured in rodents during chronic intoxication with 3-nitropropionic acid (3NP). A significant pH increase was observed early into the intoxication protocol (pH = 7.17 ± 0.02 after 3 days) as compared with preintoxication (pH = 7.08 ± 0.03). Furthermore, pH changes correlated with the 3NP-induced inhibition of succinate dehydrogenase and preceded striatum lesions. Using a similar MRS approach implemented on a clinical MRI, we then showed that cerebral pH was significantly higher in HD patients ( n = 7) than in healthy controls ( n = 6) (7.05 ± 0.03 versus 7.02 ± 0.01, respectively, P = 0.026). Altogether, both preclinical and human data strongly argue in favor of MRS-measured pH being a promising biomarker for diagnosis and follow-up of HD.
Published: 2012

39. IEEE International Syumposium on Biomedical Imaging (ISBI)

Author: Pierre-Yves Baudin, Noura Azzabou, and Pierre G. Carlier
Published: 2012

40. Whole-Body muscle MRI in a series of patients with congenital myopathy related to TPM2 gene mutations

Author: Adrien May, Anthony Behin, Robert-Yves Carlier, Pierre G. Carlier, Eugenio Mercuri, Nicole Monnier, Pascale Richard, Valérie Allamand, Mohamed Jarraya, Daniela Avila-Smirnov, Norma B. Romero, Brigitte Estournet, A. Barois, and Susana Quijano-Roy
Subjects: Adult, Male, Pathology, medicine.medical_specialty, Adolescent, Rectus femoris muscle, Tropomyosin, Biology, Gene mutation, TPM2, Young Adult, Nemaline myopathy, Settore MED/39 - NEUROPSICHIATRIA INFANTILE, Muscular Diseases, medicine, Humans, Whole Body Imaging, Child, Muscle, Skeletal, Genetics (clinical), Retrospective Studies, Soleus muscle, Arthrogryposis, Anatomy, Middle Aged, medicine.disease, Congenital myopathy, Magnetic Resonance Imaging, Masticatory force, Neurology, Pediatrics, Perinatology and Child Health, Mutation, Female, Neurology (clinical), medicine.symptom
Abstract: Beta-tropomyosin 2 ( TPM2 ) gene mutations are a rare cause of congenital myopathy with variable clinical and histological features. We describe muscle involvement using Whole-Body muscle Magnetic Resonance Imaging (WBMRI) in 8 individuals with genetically proven TPM2 mutations and different clinical and histological features (nemaline myopathy, ‘cap disease', Bethlem-like phenotype, arthrogryposis). Most patients shared a recognizable MRI pattern with the involvement of masticatory and distal lower leg muscles. The lower leg showed constant soleus muscle involvement, and often also involvement of peroneus, tibialis anterior, and toe flexor muscles. Pelvic and shoulder girdles, and upper limbs muscles were quite spared. Two adult subjects (a patient and a paucisymptomatic parent) had a more diffuse involvement with striking fat infiltration of the rectus femoris muscle. Two children showed variant findings: one presented with masseter involvement associated with severe axial fat infiltration, the second had masticatory and distal leg muscle involvement (soleus and gastrocnemius muscles). Our study suggests that, independently of the clinical and histological presentation, most patients with TPM2 mutations show a predominant involvement of masticatory and distal leg muscles with the other regions relatively spared. More spread involvement may be observed. This cephalic-distal MRI pattern is not frequent in other known myopathies.
Published: 2012

41. Manifold-enhanced Segmentation through Random Walks on Linear Subspace Priors

Author: Noura Azzabou, Nikos Paragios, P. Baudin, Pierre G. Carlier, Organ Modeling through Extraction, Representation and Understanding of Medical Image Content (GALEN), Ecole Centrale Paris-Inria Saclay - Ile de France, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Centre de vision numérique (CVN), Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec, Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service MIRCEN (MIRCEN), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Pierre et Marie Curie - Paris 6 (UPMC), imagine [Marne-la-Vallée], Laboratoire d'Informatique Gaspard-Monge (LIGM), Centre National de la Recherche Scientifique (CNRS)-Fédération de Recherche Bézout-ESIEE Paris-École des Ponts ParisTech (ENPC)-Université Paris-Est Marne-la-Vallée (UPEM)-Centre National de la Recherche Scientifique (CNRS)-Fédération de Recherche Bézout-ESIEE Paris-École des Ponts ParisTech (ENPC)-Université Paris-Est Marne-la-Vallée (UPEM)-Centre Scientifique et Technique du Bâtiment (CSTB), Centre National de la Recherche Scientifique (CNRS)-Fédération de Recherche Bézout-ESIEE Paris-École des Ponts ParisTech (ENPC)-Université Paris-Est Marne-la-Vallée (UPEM), Université Paris-Est Marne-la-Vallée (UPEM), École des Ponts ParisTech (ENPC), Mathématiques Appliquées aux Systèmes - EA 4037 (MAS), Ecole Centrale Paris, Inria Saclay - Ile de France, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Ecole Centrale Paris, Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Université Paris-Est Marne-la-Vallée (UPEM)-École des Ponts ParisTech (ENPC)-ESIEE Paris-Fédération de Recherche Bézout-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Est Marne-la-Vallée (UPEM)-École des Ponts ParisTech (ENPC)-ESIEE Paris-Fédération de Recherche Bézout-Centre National de la Recherche Scientifique (CNRS)-Centre Scientifique et Technique du Bâtiment (CSTB), Université Paris-Est Marne-la-Vallée (UPEM)-École des Ponts ParisTech (ENPC)-ESIEE Paris-Fédération de Recherche Bézout-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Centre Scientifique et Technique du Bâtiment (CSTB)-École des Ponts ParisTech (ENPC)-Laboratoire d'Informatique Gaspard-Monge (LIGM), Centre National de la Recherche Scientifique (CNRS)-Fédération de Recherche Bézout-ESIEE Paris-École des Ponts ParisTech (ENPC)-Université Paris-Est Marne-la-Vallée (UPEM)-Centre National de la Recherche Scientifique (CNRS)-Fédération de Recherche Bézout-ESIEE Paris-Université Paris-Est Marne-la-Vallée (UPEM), and Baudin, Pierre-Yves
Subjects: Quantitative Biology::Tissues and Organs, ComputingMethodologies_IMAGEPROCESSINGANDCOMPUTERVISION, Scale-space segmentation, 02 engineering and technology, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, [INFO.INFO-CV] Computer Science [cs]/Computer Vision and Pattern Recognition [cs.CV], 0302 clinical medicine, Prior probability, 0202 electrical engineering, electronic engineering, information engineering, Segmentation, Computer vision, Mathematics, Segmentation-based object categorization, business.industry, [INFO.INFO-CV]Computer Science [cs]/Computer Vision and Pattern Recognition [cs.CV], Pattern recognition, Image segmentation, Linear subspace, Manifold, [INFO.INFO-TI] Computer Science [cs]/Image Processing [eess.IV], Computer Science::Computer Vision and Pattern Recognition, [INFO.INFO-TI]Computer Science [cs]/Image Processing [eess.IV], Principal component analysis, 020201 artificial intelligence & image processing, Artificial intelligence, business
Abstract: International audience; In this paper we propose a novel method for knowledge-based segmentation. Our contribution lies on the introduction of linear sub-spaces constraints within the random-walk segmentation framework. Prior knowledge is obtained through principal component analysis that is then combined with conventional boundary constraints for image segmentation. The approach is validated on a challenging clinical setting that is multicomponent segmentation of the human upper leg skeletal muscle in Magnetic Resonance Imaging, where there is limited visual differentiation support between muscle classes.
Published: 2012

42. Early detection of contractile dysfunction in GRMD dogs by post-processing of standard cine FLASH-MRI

Author: Jean-Laurent Thibaud, Raymond Gilles, Marcel Toussaint, Stéphane Blot, and Pierre G. Carlier
Subjects: Medicine(all), musculoskeletal diseases, congenital, hereditary, and neonatal diseases and abnormalities, Pathology, medicine.medical_specialty, lcsh:Diseases of the circulatory (Cardiovascular) system, Radiological and Ultrasound Technology, biology, business.industry, Duchenne muscular dystrophy, Cardiomyopathy, Early detection, FLASH MRI, medicine.disease, lcsh:RC666-701, Heart failure, Poster Presentation, medicine, biology.protein, Radiology, Nuclear Medicine and imaging, Muscular dystrophy, Cardiology and Cardiovascular Medicine, Dystrophin, business, Angiology
Abstract: Duchenne muscular dystrophy (DMD) due to dystrophin deficiency leads to death by heart failure in nearly 30% of cases. An early detection of myocardial abnormalities in these patients would help in the optimization of their management. The GRMD is a canine model of DMD, that develops a severe cardiomyopathy.
Published: 2011

43. Discrepancies between the fate of myoblast xenograft in mouse leg muscle and NMR label persistency after loading with Gd-DTPA or SPIOs

Author: Karine Vauchez, Pierre G. Carlier, Jean-Thomas Vilquin, Marc Fiszman, Celine Baligand, Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en Myologie – U974 SU-INSERM, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)
Subjects: Gadolinium DTPA, Pathology, medicine.medical_specialty, Magnetic Resonance Spectroscopy, Time Factors, Cell Survival, Cell Transplantation, Gadolinium, Genetic enhancement, [SDV]Life Sciences [q-bio], Transplantation, Heterologous, Contrast Media, chemistry.chemical_element, Myoblasts, Cell therapy, Mice, Phagocytosis, Transplantation Immunology, In vivo, Genetics, medicine, Animals, Humans, Myocyte, Molecular Biology, Cells, Cultured, Cell Death, medicine.diagnostic_test, business.industry, Macrophages, Magnetic resonance imaging, Flow Cytometry, Ferrosoferric Oxide, Hindlimb, Mice, Inbred C57BL, Transplantation, Disease Models, Animal, chemistry, Nanoparticles, Molecular Medicine, Immunohistochemistry, business, Half-Life, Prussian Blue Reaction
Abstract: 1H-NMR (nuclear magnetic resonance) imaging is regularly proposed to non-invasively monitor cell therapy protocols. Prior to transplantation, cells must be loaded with an NMR contrast agent (CA). Most studies performed so far make use of superparamagnetic iron oxide particles (SPIOs), mainly for favorable detection sensitivity. However, in the case of labeled cell death, SPIO recapture by inflammatory cells might introduce severe bias. We investigated whether NMR signal changes induced by preloading with SPIOs or the low molecular weight gadolinium (Gd)-DTPA accurately monitored the outcome of transplanted cells in a murine model of acute immunologic rejection. CA-loaded human myoblasts were grafted in the tibialis anterior of C57BL/6 mice. NMR imaging was repeated regularly until 3 months post-transplantation. Label outcome was evaluated by the size of the labeled area and its relative contrast to surrounding tissue. In parallel, immunohistochemistry assessed the presence of human cells. Data analysis revealed that CA-induced signal changes did not strictly reflect the graft status. Gd-DTPA label disappeared rapidly yet with a 2-week delay compared with immunohistochemical evaluation. More problematically, SPIO label was still visible after 3 months, grossly overestimating cell survival (
Published: 2009
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44. Multiparametric NMR-Based Assessment of Skeletal Muscle Perfusion and Metabolism During Exercise in Elderly Persons: Preliminary Findings

Author: Aurélien Monnet, Russell S. Richardson, Steven K. Nishiyama, Claire Wary, Pierre G. Carlier, D. Walter Wray, and Sandrine Duteil
Subjects: Muscle tissue, Adult, medicine.medical_specialty, Aging, Magnetic Resonance Spectroscopy, Hemodynamics, Physical exercise, Microcirculation, Phosphocreatine, chemistry.chemical_compound, Internal medicine, medicine, Humans, Muscle, Skeletal, Exercise, Aged, business.industry, Skeletal muscle, Blood flow, Journal of Gerontology: Medical Sciences, Surgery, medicine.anatomical_structure, chemistry, Cardiology, Geriatrics and Gerontology, business, Perfusion
Abstract: THERE is accumulating experimental evidence that leg blood flow is attenuated in the elderly (1–7), a condition made worse during physical activity, when metabolic demand is increased and must be met by an appropriate rise in perfusion to the exercising tissue. Despite this well-known deficit, to our knowledge no studies have extended these whole-limb observations to the level of skeletal muscle microcirculation. This is an important distinction, as it is perfusion (ie, the movement of blood through muscle tissue), not bulk blood flow through large conduit vessels, which is the most relevant measure of O2 delivery to the muscle tissue itself. Using nuclear magnetic resonance (NMR) spectroscopy, previous work has found evidence both for (8–10) and against (11–13) a dysfunction in exercising skeletal muscle energetics with age. However, none of these prior studies evaluated skeletal muscle perfusion, leaving uncertainty as to whether altered metabolism, if present, could be related to vascular dysfunction in the elderly cohorts studied. The dynamic relationship between microcirculatory blood flow and oxidative metabolism during exercise thus remains virtually unknown. The recent approach of utilizing multiparametric NMR techniques may address this issue, as it offers the unique capability for near-simultaneous measurements of both muscle perfusion and metabolism in vivo (14–18). The interleaving of these imaging and spectroscopic modules provides the opportunity to determine skeletal muscle perfusion and metabolism kinetics during and following the stress of physical exercise. This NMR-based paradigm thus offers the promise of improving our understanding of the causal relationship between skeletal muscle hemodynamics and energetics in the elderly. Accordingly, we evaluated muscle perfusion (arterial spin labeling [ASL]) and metabolism (phosphocreatine [PCr] and inorganic phosphate [Pi]) during and following moderate-intensity (5W) dynamic plantar flexion exercise in younger and older adults. We hypothesized (1) that muscle perfusion would be attenuated during exercise in older participants compared with their younger counterparts (2), that metabolic demand would be similar between groups during exercise, and (3) that following the cessation of exercise, hyperemic decay would be accelerated and PCr recovery extended in older participants compared with young.
Published: 2009

45. Cardiac dyssynchrony in a Becker cohort: preliminary results

Author: Karim Wahbi, Marcel Toussaint, Pierre G. Carlier, Benjamin Marty, and Raymond Gilles
Subjects: Medicine(all), medicine.medical_specialty, Late enhancement, Radiological and Ultrasound Technology, business.industry, Early detection, Control subjects, Cardiac motion, Internal medicine, Cohort, Poster Presentation, Cardiology, Medicine, Radiology, Nuclear Medicine and imaging, Lateral segment, medicine.symptom, Cardiology and Cardiovascular Medicine, business, Myopathy, Angiology
Abstract: Background We previously reported the early detection of cardiac motion dyssynchrony in GRMD dogs (a model for Duchenne myopathy with cardiac involvement). In this new work, we applied the same dyssynchrony index in a cohort of 88 Becker patients of various age (38,7 ±13,6 years; range from 18 to 68) and disease burden (number of segment count with any Gd late enhancement : 4,37 ± 3,14 ; range from 0 to 12). We compared the data obtained to those in 10 control subjects.
Published: 2015

46. An automated image-processing strategy to analyze dynamic arterial spin labeling perfusion studies. Application to human skeletal muscle under stress

Author: David Lesage, Alain Herment, Pierre G. Carlier, Frédérique Frouin, Anne Leroy-Willig, Sandrine Duteil, Laboratoire d'Imagerie Fonctionnelle (LIF), Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-IFR49-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Saidi, Vanessa
Subjects: Adult, Male, Masking (art), Computer science, MESH: Factor Analysis, Statistical, Biomedical Engineering, Biophysics, Image processing, MESH: Algorithms, MESH: Magnetic Resonance Imaging, Automation, Region of interest, MESH: Automation, MESH: Analysis of Variance, MESH: Spin Labels, Image Processing, Computer-Assisted, Humans, Radiology, Nuclear Medicine and imaging, Segmentation, Computer vision, Muscle, Skeletal, Exercise, [SDV.IB] Life Sciences [q-bio]/Bioengineering, Analysis of Variance, Leg, MESH: Muscle, Skeletal, MESH: Humans, Pixel, business.industry, Dynamic data, MESH: Adult, Magnetic Resonance Imaging, MESH: Image Processing, Computer-Assisted, MESH: Male, Visualization, MESH: Leg, MESH: Exercise, Female, Spin Labels, [SDV.IB]Life Sciences [q-bio]/Bioengineering, Artificial intelligence, MESH: Sports, Factor Analysis, Statistical, business, Perfusion, MESH: Female, Algorithms, Sports, Biomedical engineering
Abstract: Arterial spin labeling (ASL) perfusion measurements allow the follow-up of muscle perfusion with high temporal resolution during a stress test. Automated image processing is proposed to estimate perfusion maps from ASL images. It is based on two successive analyses: at first, automated rejection of the image pairs between which a large displacement is detected is performed, followed by factor analysis of the dynamic data and cluster analysis to classify pixels with large signal variation characteristic of vessels. Then, after masking these "vascular" pixels, factor analysis and cluster analysis are further applied to separate the different muscles between low or high perfusion increase, yielding a functional map of the leg. Data from 10 subjects (five normal volunteers and five elite sportsmen) had been analyzed. Resulting time perfusion curves from a region of interest (ROI) in active muscles show a good accordance whether extracted with automated processing or with manual processing. This method of functional segmentation allows automated suppression of vessels and fast visualization of muscles with high, medium or low perfusion, without any a priori knowledge.
Published: 2006
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47. Skeletal muscle quantitative nuclear magnetic resonance imaging follow-up of adult Pompe patients

Author: Robert-Yves Carlier, Noura Azzabou, Pierre G. Carlier, Arnaud Hicks, Claire Wary, Paulo Loureiro de Sousa, Alexis Amadon, David Orlikowski, Jean-Marc Boisserie, and Pascal Laforêt
Subjects: Adult, Male, Pathology, medicine.medical_specialty, Glycogenoses, Biology, Young Adult, Internal medicine, Glycogen storage disease type II, medicine, Genetics, Humans, Enzyme Replacement Therapy, Genetics(clinical), Young adult, Muscle, Skeletal, Genetics (clinical), Aged, Retrospective Studies, medicine.diagnostic_test, Glycogen Storage Disease Type II, Dystrophy, Skeletal muscle, alpha-Glucosidases, Magnetic resonance imaging, Enzyme replacement therapy, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Endocrinology, medicine.anatomical_structure, Disease Progression, Female, Adductor muscles, Hamstring, Follow-Up Studies
Abstract: Adult late-onset Pompe disease is most often a slowly progressive limb-girdle and spine extensor muscle dystrophy, due to defective lysosomal acid maltase. With the exception of the few patients who present with a dramatically accelerated clinical course, standard diagnostic imaging fail to detect and evaluate disease progression between two successive visits. In muscle dystrophy of very rapid evolution, like the Duchenne disease, quantitative NMR imaging has successfully demonstrated its capacity to objectivate both disease activity and degenerative changes progression over short follow-up periods. The purpose of this retrospective monocentric open-label study was to investigate whether quantitative NMR imaging can monitor disease progression in adult Pompe patients despite its very slow nature. Quantitative imaging of Pompe patients succeeded in demonstrating that muscle fatty infiltration increased on average by 0.9 %/year, with the hamstring and adductor muscles showing the fastest degradation. Muscle water T2 mapping revealed that 32 % of all muscles had abnormally high T2 in at least one of two successive examinations. When muscle water T2 was abnormal, fatty degenerative changes were further increased by 0.61 %/year. Enzyme replacement therapy resulted in 0.68 %/year slowdown of the muscle fatty infiltration, in both muscles with normal and high T2s. Electronic supplementary material The online version of this article (doi:10.1007/s10545-015-9825-9) contains supplementary material, which is available to authorized users.
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48. Myocardial characterisation in Becker muscular dystrophy using T1 and T2 mapping

Author: Marcel Toussaint, Benjamin Marty, Raymond Gilles, Pierre G. Carlier, Karim Wahbi, and Andreas Greiser
Subjects: musculoskeletal diseases, Medicine(all), medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Extracellular volume fraction, Radiological and Ultrasound Technology, business.industry, T2 mapping, musculoskeletal, neural, and ocular physiology, Bioinformatics, medicine.disease, Control subjects, musculoskeletal system, Magnetic imaging, Poster Presentation, Late gadolinium enhancement, Medicine, Radiology, Nuclear Medicine and imaging, Muscular dystrophy, Cardiology and Cardiovascular Medicine, Nuclear medicine, business, Angiology
Abstract: Methods From April 2012 to May 2014, 84 consecutive patients (age=38,6 ± 13,6 years) with Becker muscular dystrophy (BMD) and 12 control subjects underwent cardiac magnetic imaging (MRI) on a 3-T clinical scanner (Magnetom Trio Tim, Siemens Healthcare). T1 maps and apparent extracellular volume fraction (appECV) preand post-GdDOTA injection was performed with a prototype modified Look-Locker sequence (MOLLI, 3, 3 and 5 image acquisitions). T2 maps were generated with a T2 prepared TrueFISP sequence acquired with 3 preparation times (0, 25 and 55 ms). Late Gadolinium enhancement (LGE), T1, T2, appECV were assessed according to the classification of the AHA segmentation.
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49. Letter to the editor.

Author: Didier Bertoldi and Pierre G. Carlier
Published: 2003
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50. BLOCH equations-based reconstruction of myocardium t1 maps from modified look-locker inversion recovery sequence.

Author: Benjamin Marty, Alexandre Vignaud, Andreas Greiser, Benjamin Robert, Paulo Loureiro de Sousa, and Pierre G Carlier
Subjects: Medicine, Science
Abstract: Modified Look-Locker Inversion recovery (MOLLI) sequence is increasingly performed for myocardial T1 mapping but is known to underestimate T1 values. The aim of the study was to quantitatively analyze several sources of errors when T1 maps are derived using standard post-processing of the sequence and to propose a reconstruction approach that takes into account inversion efficacy (η), T2 relaxation during balanced steady-state free-precession readouts and B1+ inhomogeneities. Contributions of the different sources of error were analyzed using Bloch equations simulations of MOLLI sequence. Bloch simulations were then combined with the acquisition of fast B1+ and T2 maps to derive more accurate T1 maps. This novel approach was evaluated on phantoms and on five healthy volunteers. Simulations show that T2 variations, B1+ heterogeneities and inversion efficiency represent major confounders for T1 mapping when MOLLI is processed with standard 3-parameters fitting. In vitro data indicate that T1 values are accurately derived with the simulation approach and in vivo data suggest that myocardium T1 are 15% underestimated when processed with the standard 3-parameters fitting. At the cost of additional acquisitions, this method might be suitable in clinical research protocols for precise tissue characterization as it decorrelates T1 and T2 effects on parametric maps provided by MOLLI sequence and avoids inaccuracies when B1+ is not homogenous throughout the myocardium.
Published: 2015
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