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Sherlock SP, McCrady A, Palmer J, Aghamolaey H, Ahlgren A, Widholm P, Dahlqvist Leinhard O, Karlsson M. Relationship Between Quantitative Magnetic Resonance Imaging Measures and Functional Changes in Patients With Duchenne Muscular Dystrophy. Muscle Nerve 2025; 71:343-352. [PMID: 39713935 PMCID: PMC11799397 DOI: 10.1002/mus.28321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 12/03/2024] [Accepted: 12/04/2024] [Indexed: 12/24/2024]
Abstract
INTRODUCTION/AIMS Improved methodologies to monitor the progression of Duchenne muscular dystrophy (DMD) are needed, especially in the context of clinical trials. We report changes in muscle magnetic resonance imaging (MRI) parameters in participants with DMD, including changes in lean muscle volume (LMV), muscle fat fraction (MFF), and muscle fat infiltration (MFI) and their relationship to changes in functional parameters. METHODS MRI data were obtained as part of a clinical study (NCT02310763) of domagrozumab, an antibody-targeting myostatin that negatively regulates skeletal muscle mass. This post hoc analysis evaluated participants with Dixon MRI data and corresponding functional data at baseline and weeks 49 and 97. Images were analyzed to evaluate changes in adductors, hamstrings, and quadriceps. RESULTS There was a positive correlation between increases in LMV and function. LMV changes in adductors (R = 0.51) and quadriceps (R = 0.54) showed a stronger correlation with function than LMV changes in hamstrings (R = 0.30). There was a negative correlation between MFF and MFI, respectively, and function in adductors (R = -0.57, R = -0.42), quadriceps (R = -0.59, R = -0.50), and hamstrings (R = -0.53, R = -048). Participants with preserved North Star Ambulatory Assessment scores had high total LMV (LMVtot) and low total MFI (MFItot). Low ratios of LMVtot to MFItot, or participants with small LMVtot and high MFItot, appeared to have a rapid decline in function and loss of ambulation. DISCUSSION These findings support the use of MRI biomarkers as potential surrogate endpoints in clinical trials of patients with DMD. TRIAL REGISTRATION ClinicalTrials.gov identifiers: NCT02310763.
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Affiliation(s)
| | - Allison McCrady
- Department of Biomedical EngineeringUniversity of VirginiaCharlottesvilleVirginiaUSA
| | | | - Haleh Aghamolaey
- Department of StatisticsQuanticate Clinical Research OrganizationOntarioCanada
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Yin K, Zhang C, Deng Z, Wei X, Xiang T, Yang C, Chen C, Chen Y, Luo F. FAPs orchestrate homeostasis of muscle physiology and pathophysiology. FASEB J 2024; 38:e70234. [PMID: 39676717 PMCID: PMC11647758 DOI: 10.1096/fj.202400381r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2024] [Revised: 10/26/2024] [Accepted: 11/26/2024] [Indexed: 12/17/2024]
Abstract
As a common clinical manifestation, muscle weakness is prevalent in people with mobility disorders. Further studies of muscle weakness have found that patients with muscle weakness present with persistent muscle inflammation, loss of muscle fibers, fat infiltration, and interstitial fibrosis. Therefore, we propose the concept of muscle microenvironment homeostasis, which explains the abnormal pathological changes in muscles through the imbalance of muscle microenvironment homeostasis. And we identified an interstitial progenitor cell FAP during the transition from normal muscle microenvironment homeostasis to muscle microenvironment imbalance caused by muscle damage diseases. As a kind of pluripotent stem cell, FAPs do not participate in myogenic differentiation, but can differentiate into fibroblasts, adipocytes, osteoblasts, and chondrocytes. As a kind of mesenchymal progenitor cell, it is involved in the generation of extracellular matrix, regulate muscle regeneration, and maintain neuromuscular junction. However, the muscle microenvironment is disrupted by the causative factors, and the abnormal activities of FAPs eventually contribute to the complex pathological changes in muscles. Targeting the mechanisms of these muscle pathological changes, we have identified appropriate signaling targets for FAPs to improve and even treat muscle damage diseases. In this review, we propose the construction of muscle microenvironmental homeostasis and find the key cells that cause pathological changes in muscle after homeostasis is broken. By studying the mechanism of abnormal differentiation and apoptosis of FAPs, we found a strategy to inhibit the abnormal pathological changes in muscle damage diseases and improve muscle regeneration.
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Affiliation(s)
- Kai Yin
- Department of OrthopedicsSouthwest Hospital, Third Military Medical University (Army Medical University)ChongqingPeople's Republic of China
| | - Chengmin Zhang
- Department of OrthopedicsSouthwest Hospital, Third Military Medical University (Army Medical University)ChongqingPeople's Republic of China
| | - Zihan Deng
- Department of OrthopedicsSouthwest Hospital, Third Military Medical University (Army Medical University)ChongqingPeople's Republic of China
| | - Xiaoyu Wei
- Department of OrthopedicsSouthwest Hospital, Third Military Medical University (Army Medical University)ChongqingPeople's Republic of China
| | - Tingwen Xiang
- Department of OrthopedicsSouthwest Hospital, Third Military Medical University (Army Medical University)ChongqingPeople's Republic of China
| | - Chuan Yang
- Department of Biomedical Materials ScienceThird Military Medical University (Army Medical University)ChongqingPeople's Republic of China
| | - Can Chen
- Department for Combat Casualty Care TrainingTraining Base for Army Health Care, Army Medical University (Third Military Medical University)ChongqingPeople's Republic of China
| | - Yueqi Chen
- Department of OrthopedicsSouthwest Hospital, Third Military Medical University (Army Medical University)ChongqingPeople's Republic of China
| | - Fei Luo
- Department of OrthopedicsSouthwest Hospital, Third Military Medical University (Army Medical University)ChongqingPeople's Republic of China
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Yoon DY, Daniels MJ, Willcocks RJ, Triplett WT, Morales JF, Walter GA, Rooney WD, Vandenborne K, Kim S. Five multivariate Duchenne muscular dystrophy progression models bridging six-minute walk distance and MRI relaxometry of leg muscles. J Pharmacokinet Pharmacodyn 2024; 51:671-683. [PMID: 38609673 PMCID: PMC11470134 DOI: 10.1007/s10928-024-09910-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Accepted: 02/15/2024] [Indexed: 04/14/2024]
Abstract
The study aimed to provide quantitative information on the utilization of MRI transverse relaxation time constant (MRI-T2) of leg muscles in DMD clinical trials by developing multivariate disease progression models of Duchenne muscular dystrophy (DMD) using 6-min walk distance (6MWD) and MRI-T2. Clinical data were collected from the prospective and longitudinal ImagingNMD study. Disease progression models were developed by a nonlinear mixed-effect modeling approach. Univariate models of 6MWD and MRI-T2 of five muscles were developed separately. Age at assessment was the time metric. Multivariate models were developed by estimating the correlation of 6MWD and MRI-T2 model variables. Full model estimation approach for covariate analysis and five-fold cross validation were conducted. Simulations were performed to compare the models and predict the covariate effects on the trajectories of 6MWD and MRI-T2. Sigmoid Imax and Emax models best captured the profiles of 6MWD and MRI-T2 over age. Steroid use, baseline 6MWD, and baseline MRI-T2 were significant covariates. The median age at which 6MWD is half of its maximum decrease in the five models was similar, while the median age at which MRI-T2 is half of its maximum increase varied depending on the type of muscle. The models connecting 6MWD and MRI-T2 successfully quantified how individual characteristics alter disease trajectories. The models demonstrate a plausible correlation between 6MWD and MRI-T2, supporting the use of MRI-T2. The developed models will guide drug developers in using the MRI-T2 to most efficient use in DMD clinical trials.
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Affiliation(s)
- Deok Yong Yoon
- Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida, Orlando, FL, USA
| | - Michael J Daniels
- Department of Statistics, University of Florida, Gainesville, FL, USA
| | | | - William T Triplett
- Department of Physical Therapy, University of Florida, Gainesville, FL, USA
| | - Juan Francisco Morales
- Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida, Orlando, FL, USA
| | - Glenn A Walter
- Department of Physiology and Aging, University of Florida, Gainesville, FL, USA
| | - William D Rooney
- Advanced Imaging Research Center, Oregon Health & Science University, Portland, OR, USA
| | - Krista Vandenborne
- Department of Physical Therapy, University of Florida, Gainesville, FL, USA
| | - Sarah Kim
- Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida, Orlando, FL, USA.
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Milot A, Raikova M, Huzar C, Thellier V, Hergibo N, Gauthier M, Billy-Lopez G, Durand C, Nugues F, Bourg V, Dieterich K. [Arthrogryposis Multiplex Congenita in pediatric age: Correlation between Muscle MRI and functional assessment]. Med Sci (Paris) 2024; 40 Hors série n° 1:26-29. [PMID: 39555873 DOI: 10.1051/medsci/2024131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2024] Open
Abstract
Arthrogryposis multiplex congenita (AMC) is a group of diseases with joint limitations at two or more distinct joint levels at birth. Joint limitations are not progressive, but the functional consequences have a lifelong impact on patients. In this article we will present the results of our study aimed at evaluating the correlation between muscle fat infiltration on MRI and activity deficiencies and limitations in children with AMC. Our study is one of the first in a pediatric population to establish the link between muscle imaging and functional aspects of AMC.
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Affiliation(s)
- Alicia Milot
- Université Grenoble Alpes, Inserm U1209, IAB, CHU Grenoble Alpes, Génétique Médicale, France - Médecine physique et réadaptation pédiatrique, CHU Grenoble Alpes, France - Centre de référence national des anomalies développementales, clinique multidisciplinaire AMC, CHU Grenoble Alpes, France
| | - Mariya Raikova
- Département d'Imagerie pédiatrique, CHU Grenoble Alpes, France
| | - Claire Huzar
- Médecine physique et réadaptation pédiatrique, CHU Grenoble Alpes, France - Centre de référence national des anomalies développementales, clinique multidisciplinaire AMC, CHU Grenoble Alpes, France
| | - Véronique Thellier
- Médecine physique et réadaptation pédiatrique, CHU Grenoble Alpes, France - Centre de référence national des anomalies développementales, clinique multidisciplinaire AMC, CHU Grenoble Alpes, France
| | - Nicolas Hergibo
- Département d'Imagerie pédiatrique, CHU Grenoble Alpes, France
| | - Marjolaine Gauthier
- Université Grenoble Alpes, Inserm U1209, IAB, CHU Grenoble Alpes, Génétique Médicale, France - Centre de référence national des anomalies développementales, clinique multidisciplinaire AMC, CHU Grenoble Alpes, France
| | - Gipsy Billy-Lopez
- Université Grenoble Alpes, Inserm U1209, IAB, CHU Grenoble Alpes, Génétique Médicale, France - Centre de référence national des anomalies développementales, clinique multidisciplinaire AMC, CHU Grenoble Alpes, France
| | - Chantal Durand
- Département d'Imagerie pédiatrique, CHU Grenoble Alpes, France
| | | | - Véronique Bourg
- Médecine physique et réadaptation pédiatrique, CHU Grenoble Alpes, France - Centre de référence national des anomalies développementales, clinique multidisciplinaire AMC, CHU Grenoble Alpes, France
| | - Klaus Dieterich
- Université Grenoble Alpes, Inserm U1209, IAB, CHU Grenoble Alpes, Génétique Médicale, France - Centre de référence national des anomalies développementales, clinique multidisciplinaire AMC, CHU Grenoble Alpes, France
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Jenkins BM, Dixon LD, Kokesh KJ, Zingariello CD, Vandenborne K, Walter GA, Barnard AM. Skeletal muscle symptoms and quantitative MRI in females with dystrophinopathy. Muscle Nerve 2024; 70:988-999. [PMID: 39221574 PMCID: PMC11493146 DOI: 10.1002/mus.28235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Revised: 08/04/2024] [Accepted: 08/06/2024] [Indexed: 09/04/2024]
Abstract
INTRODUCTION/AIMS The dystrophinopathies primarily affect males; however, female carriers of pathogenic dystrophin variants can develop skeletal muscle symptoms. This study aimed to evaluate muscle involvement and symptoms in females with dystrophinopathy using quantitative magnetic resonance imaging (MRI), functional assessments, and patient-reported outcomes. METHODS Controls and females with dystrophinopathy with muscle symptoms of pain, weakness, fatigue, or excessive tightness were enrolled in this cross-sectional study. Participants underwent lower extremity MRI to quantify muscle inflammation, replacement by fat, and disease asymmetry. Cardiac MRI, functional ability, muscle symptoms, and serum creatine kinase levels were also evaluated. RESULTS Six pediatric females with dystrophinopathy (mean age: 11.7 years), 11 adult females with dystrophinopathy (mean age: 41.3 years), and seven controls enrolled. The mean fat fraction was increased in females with dystrophinopathy compared to controls in the soleus (0.11 vs. 0.03, p = .0272) and vastus lateralis (0.16 vs. 0.03, p = .004). Magnetic resonance spectroscopy water T2, indicative of muscle inflammation, was elevated in the soleus and/or vastus lateralis in 11 of 17 individuals. North Star Ambulatory Assessment score was lower in the dystrophinopathy group compared to controls (29 vs. 34 points, p = .0428). From cardiac MRI, left ventricle T1 relaxation times were elevated in females with dystrophinopathy compared to controls (1311 ± 55 vs. 1263 ± 25 ms, p < .05), but ejection fraction and circumferential strain did not differ. DISCUSSION Symptomatic females with dystrophinopathy quantitatively demonstrate muscle replacement by fat and inflammation, along with impairments in functional ability and cardiac function. Additional research is needed to evaluate how symptoms and muscle involvement change longitudinally.
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Affiliation(s)
| | | | - Kevin J Kokesh
- Department of Pediatrics, Division of Pulmonology; University of Florida
| | - Carla D Zingariello
- Department of Pediatrics, Division of Pediatric Neurology; University of Florida
| | | | - Glenn A Walter
- Department of Physiology and Aging; University of Florida
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Gaeta M, Galletta K, Cavallaro M, Mormina E, Cannizzaro MT, Lanzafame LRM, D'Angelo T, Blandino A, Vinci SL, Granata F. T1 relaxation: Chemo-physical fundamentals of magnetic resonance imaging and clinical applications. Insights Imaging 2024; 15:200. [PMID: 39120775 PMCID: PMC11315875 DOI: 10.1186/s13244-024-01744-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2024] [Accepted: 06/07/2024] [Indexed: 08/10/2024] Open
Abstract
A knowledge of the complex phenomena that regulate T1 signal on Magnetic Resonance Imaging is essential in clinical practice for a more effective characterization of pathological processes. The authors review the physical basis of T1 Relaxation Time and the fundamental aspects of physics and chemistry that can influence this parameter. The main substances (water, fat, macromolecules, methemoglobin, melanin, Gadolinium, calcium) that influence T1 and the different MRI acquisition techniques that can be applied to enhance their presence in diagnostic images are then evaluated. An extensive case illustration of the different phenomena and techniques in the areas of CNS, abdomino-pelvic, and osteoarticular pathology is also proposed. CRITICAL RELEVANCE STATEMENT: T1 relaxation time is strongly influenced by numerous factors related to tissue characteristics and the presence in the context of the lesions of some specific substances. An examination of these phenomena with extensive MRI exemplification is reported. KEY POINTS: The purpose of the paper is to illustrate the chemical-physical basis of T1 Relaxation Time. MRI methods in accordance with the various clinical indications are listed. Several examples of clinical application in abdominopelvic and CNS pathology are reported.
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Affiliation(s)
- Michele Gaeta
- Radiology Unit - Biomorf Department, University of Messina, Messina, Italy
| | - Karol Galletta
- Neuroradiology Unit - Biomorf Department, University of Messina, Messina, Italy
| | - Marco Cavallaro
- Neuroradiology Unit - Biomorf Department, University of Messina, Messina, Italy
| | - Enricomaria Mormina
- Neuroradiology Unit - Biomorf Department, University of Messina, Messina, Italy
| | | | | | - Tommaso D'Angelo
- Radiology Unit - Biomorf Department, University of Messina, Messina, Italy.
- Department of Radiology and Nuclear Medicine, Erasmus MC, 3015 GD, Rotterdam, The Netherlands.
| | - Alfredo Blandino
- Radiology Unit - Biomorf Department, University of Messina, Messina, Italy
| | - Sergio Lucio Vinci
- Neuroradiology Unit - Biomorf Department, University of Messina, Messina, Italy
| | - Francesca Granata
- Neuroradiology Unit - Biomorf Department, University of Messina, Messina, Italy
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Mastropietro A, Casali N, Taccogna MG, D’Angelo MG, Rizzo G, Peruzzo D. Classification of Muscular Dystrophies from MR Images Improves Using the Swin Transformer Deep Learning Model. Bioengineering (Basel) 2024; 11:580. [PMID: 38927816 PMCID: PMC11200745 DOI: 10.3390/bioengineering11060580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 05/28/2024] [Accepted: 06/05/2024] [Indexed: 06/28/2024] Open
Abstract
Muscular dystrophies present diagnostic challenges, requiring accurate classification for effective diagnosis and treatment. This study investigates the efficacy of deep learning methodologies in classifying these disorders using skeletal muscle MRI scans. Specifically, we assess the performance of the Swin Transformer (SwinT) architecture against traditional convolutional neural networks (CNNs) in distinguishing between healthy individuals, Becker muscular dystrophy (BMD), and limb-girdle muscular Dystrophy type 2 (LGMD2) patients. Moreover, 3T MRI scans from a retrospective dataset of 75 scans (from 54 subjects) were utilized, with multiparametric protocols capturing various MRI contrasts, including T1-weighted and Dixon sequences. The dataset included 17 scans from healthy volunteers, 27 from BMD patients, and 31 from LGMD2 patients. SwinT and CNNs were trained and validated using a subset of the dataset, with the performance evaluated based on accuracy and F-score. Results indicate the superior accuracy of SwinT (0.96), particularly when employing fat fraction (FF) images as input; it served as a valuable parameter for enhancing classification accuracy. Despite limitations, including a modest cohort size, this study provides valuable insights into the application of AI-driven approaches for precise neuromuscular disorder classification, with potential implications for improving patient care.
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Affiliation(s)
- Alfonso Mastropietro
- Istituto di Sistemi e Tecnologie Industriali Intelligenti per il Manifatturiero Avanzato, Consiglio Nazionale delle Ricerche, 20133 Milan, Italy; (A.M.); (N.C.)
| | - Nicola Casali
- Istituto di Sistemi e Tecnologie Industriali Intelligenti per il Manifatturiero Avanzato, Consiglio Nazionale delle Ricerche, 20133 Milan, Italy; (A.M.); (N.C.)
- Dipartimento di Elettronica, Informazione e Bioingegneria, Politecnico di Milano, 20133 Milan, Italy
| | - Maria Giovanna Taccogna
- Istituto di Tecnologie Biomediche, Consiglio Nazionale delle Ricerche, 20054 Segrate, Milan, Italy;
| | - Maria Grazia D’Angelo
- Unit of Rehabilitation of Rare Diseases of the Central and Peripheral Nervous System, Scientific Institute IRCCS Eugenio Medea, 23842 Bosisio Parini, Lecco, Italy;
| | - Giovanna Rizzo
- Istituto di Sistemi e Tecnologie Industriali Intelligenti per il Manifatturiero Avanzato, Consiglio Nazionale delle Ricerche, 20133 Milan, Italy; (A.M.); (N.C.)
| | - Denis Peruzzo
- Neuroimaging Unit, Scientific Institute IRCCS Eugenio Medea, 23842 Bosisio Parini, Lecco, Italy
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Takatsu Y, Ohnishi H, Tateyama T, Miyati T. Usefulness of fat-containing agents: an initial study on estimating fat content for magnetic resonance imaging. Phys Eng Sci Med 2024; 47:339-350. [PMID: 38379016 DOI: 10.1007/s13246-023-01372-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Accepted: 12/11/2023] [Indexed: 02/22/2024]
Abstract
This initial study aimed at testing whether fat-containing agents can be used for the fat mass estimation methods using magnetic resonance imaging (MRI). As an example for clinical application, fat-containing agents (based on soybean oil, 10% and 20%), 100% soybean oil, and saline as reference substances were placed outside the proximal femurs obtained from 14 participants and analyzed by 0.3 T MRI. Fat content was the estimated fat fraction (FF) based on signal intensity (SIeFF, %). The SIeFF values of the femoral bone marrow, including the femoral head, neck, shaft, and trochanter area, were measured. MRI data were compared in terms of bone mineral content (BMC) and bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) in the proximal femur. Twelve pig femurs were also used to confirm the correlation between FF by the DIXON method and SIeFF. According to Pearson's correlation coefficient, the SIeFF and total BMC and BMD data revealed strong and moderate negative correlations in the femoral head (r < - 0.74) and other sites (r = - 0.66 to - 0.45). FF and SIeFF showed a strong correlation (r = 0.96). This study was an initial investigation of a method for estimating fat mass with fat-containing agents and showed the potential for use in MRI. SIeFF and FF showed a strong correlation, and SIeFF and BMD and BMC showed correlation; however, further studies are needed to use SIeFF as a substitute for DXA.
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Affiliation(s)
- Yasuo Takatsu
- Molecular Imaging, School of Medical Sciences, Fujita Health University, 1-98, Dengakugakubo, Kutsukake-Cho, Toyoake, Aichi, 470-1192, Japan.
- Division of Health Sciences, Graduate School of Medical Sciences, Kanazawa University, 5-11-80 Kodatsuno, Kanazawa, 920-0942, Japan.
| | - Hiroshi Ohnishi
- Department of Radiology, Geisei Ortho Clinic, 1495-1, Wajikikou, Geisei-Mura, Aki-Gun, Kochi, 781-5701, Japan
| | - Tomoko Tateyama
- Department of Intelligent Information Engineering, School of Medical Sciences, Fujita Health University, 1-98, Dengakugakubo, Kutsukake-Cho, Toyoake, Aichi, 470-1192, Japan
| | - Tosiaki Miyati
- Division of Health Sciences, Graduate School of Medical Sciences, Kanazawa University, 5-11-80 Kodatsuno, Kanazawa, 920-0942, Japan
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Timpani CA, Kourakis S, Debruin DA, Campelj DG, Pompeani N, Dargahi N, Bautista AP, Bagaric RM, Ritenis EJ, Sahakian L, Debrincat D, Stupka N, Hafner P, Arthur PG, Terrill JR, Apostolopoulos V, de Haan JB, Guven N, Fischer D, Rybalka E. Dimethyl fumarate modulates the dystrophic disease program following short-term treatment. JCI Insight 2023; 8:e165974. [PMID: 37751291 PMCID: PMC10721277 DOI: 10.1172/jci.insight.165974] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Accepted: 09/20/2023] [Indexed: 09/27/2023] Open
Abstract
New medicines are urgently required to treat the fatal neuromuscular disease Duchenne muscular dystrophy (DMD). Dimethyl fumarate (DMF) is a potent immunomodulatory small molecule nuclear erythroid 2-related factor 2 activator with current clinical utility in the treatment of multiple sclerosis and psoriasis that could be effective for DMD and rapidly translatable. Here, we tested 2 weeks of daily 100 mg/kg DMF versus 5 mg/kg standard-care prednisone (PRED) treatment in juvenile mdx mice with early symptomatic DMD. Both drugs modulated seed genes driving the DMD disease program and improved force production in fast-twitch muscle. However, only DMF showed pro-mitochondrial effects, protected contracting muscles from fatigue, improved histopathology, and augmented clinically compatible muscle function tests. DMF may be a more selective modulator of the DMD disease program than PRED, warranting follow-up longitudinal studies to evaluate disease-modifying impact.
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Affiliation(s)
- Cara A. Timpani
- Institute for Health and Sport (IHeS), Victoria University, Melbourne, Victoria, Australia
- Australian Institute for Musculoskeletal Science (AIMSS), St Albans, Victoria, Australia
- Department of Medicine – Western Health, Melbourne Medical School, The University of Melbourne, St Albans, Victoria, Australia
| | - Stephanie Kourakis
- Institute for Health and Sport (IHeS), Victoria University, Melbourne, Victoria, Australia
- Australian Institute for Musculoskeletal Science (AIMSS), St Albans, Victoria, Australia
| | - Danielle A. Debruin
- Institute for Health and Sport (IHeS), Victoria University, Melbourne, Victoria, Australia
- Australian Institute for Musculoskeletal Science (AIMSS), St Albans, Victoria, Australia
| | - Dean G. Campelj
- Institute for Health and Sport (IHeS), Victoria University, Melbourne, Victoria, Australia
| | - Nancy Pompeani
- Institute for Health and Sport (IHeS), Victoria University, Melbourne, Victoria, Australia
- Florey Institute of Neuroscience and Mental Health, Heidelberg, Victoria, Australia
| | - Narges Dargahi
- Institute for Health and Sport (IHeS), Victoria University, Melbourne, Victoria, Australia
| | - Angelo P. Bautista
- School of Molecular Sciences, The University of Western Australia, Perth, Western Australia, Australia
| | - Ryan M. Bagaric
- Institute for Health and Sport (IHeS), Victoria University, Melbourne, Victoria, Australia
- Australian Institute for Musculoskeletal Science (AIMSS), St Albans, Victoria, Australia
| | - Elya J. Ritenis
- College of Health and Biomedicine, Victoria University, Melbourne, Victoria, Australia
| | - Lauren Sahakian
- Institute for Health and Sport (IHeS), Victoria University, Melbourne, Victoria, Australia
- Department of Medicine – Western Health, Melbourne Medical School, The University of Melbourne, St Albans, Victoria, Australia
| | - Didier Debrincat
- College of Health and Biomedicine, Victoria University, Melbourne, Victoria, Australia
| | - Nicole Stupka
- Institute for Health and Sport (IHeS), Victoria University, Melbourne, Victoria, Australia
- Australian Institute for Musculoskeletal Science (AIMSS), St Albans, Victoria, Australia
- Department of Medicine – Western Health, Melbourne Medical School, The University of Melbourne, St Albans, Victoria, Australia
| | - Patricia Hafner
- Division of Neuropaediatrics and Developmental Medicine, University Children’s Hospital of Basel (UKBB), Basel, Switzerland
| | - Peter G. Arthur
- School of Molecular Sciences, The University of Western Australia, Perth, Western Australia, Australia
| | - Jessica R. Terrill
- School of Molecular Sciences, The University of Western Australia, Perth, Western Australia, Australia
| | - Vasso Apostolopoulos
- Institute for Health and Sport (IHeS), Victoria University, Melbourne, Victoria, Australia
- Australian Institute for Musculoskeletal Science (AIMSS), St Albans, Victoria, Australia
| | - Judy B. de Haan
- Basic Science Domain, Oxidative Stress Laboratory, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
- Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, Victoria, Australia
- Department of Physiology, Anatomy and Microbiology, La Trobe University, Melbourne, Victoria, Australia
- Faculty of Science, Engineering and Technology, Swinburne University, Melbourne, Victoria, Australia
- Baker Department of Cardiometabolic Health, University of Melbourne, Parkville, Victoria, Australia
| | - Nuri Guven
- Department of Medicine – Western Health, Melbourne Medical School, The University of Melbourne, St Albans, Victoria, Australia
| | - Dirk Fischer
- Division of Neuropaediatrics and Developmental Medicine, University Children’s Hospital of Basel (UKBB), Basel, Switzerland
| | - Emma Rybalka
- Institute for Health and Sport (IHeS), Victoria University, Melbourne, Victoria, Australia
- Australian Institute for Musculoskeletal Science (AIMSS), St Albans, Victoria, Australia
- Department of Medicine – Western Health, Melbourne Medical School, The University of Melbourne, St Albans, Victoria, Australia
- Division of Neuropaediatrics and Developmental Medicine, University Children’s Hospital of Basel (UKBB), Basel, Switzerland
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MME + fibro-adipogenic progenitors are the dominant adipogenic population during fatty infiltration in human skeletal muscle. Commun Biol 2023; 6:111. [PMID: 36707617 PMCID: PMC9883500 DOI: 10.1038/s42003-023-04504-y] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 01/18/2023] [Indexed: 01/29/2023] Open
Abstract
Fatty infiltration, the ectopic deposition of adipose tissue within skeletal muscle, is mediated via the adipogenic differentiation of fibro-adipogenic progenitors (FAPs). We used single-nuclei and single-cell RNA sequencing to characterize FAP heterogeneity in patients with fatty infiltration. We identified an MME+ FAP subpopulation which, based on ex vivo characterization as well as transplantation experiments, exhibits high adipogenic potential. MME+ FAPs are characterized by low activity of WNT, known to control adipogenic commitment, and are refractory to the inhibitory role of WNT activators. Using preclinical models for muscle damage versus fatty infiltration, we show that many MME+ FAPs undergo apoptosis during muscle regeneration and differentiate into adipocytes under pathological conditions, leading to a reduction in their abundance. Finally, we utilized the varying fat infiltration levels in human hip muscles and found less MME+ FAPs in fatty infiltrated human muscle. Altogether, we have identified the dominant adipogenic FAP subpopulation in skeletal muscle.
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11
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Kim YJ, Kim HS, Lee JH, Yoon YC, Choi BO. Magnetic resonance imaging-based lower limb muscle evaluation in Charcot-Marie-Tooth disease type 1A patients and its correlation with clinical data. Sci Rep 2022; 12:16622. [PMID: 36198750 PMCID: PMC9534835 DOI: 10.1038/s41598-022-21112-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Accepted: 09/22/2022] [Indexed: 11/25/2022] Open
Abstract
We aimed to derive comprehensive MRI parameters that reflect intramuscular fat infiltration severity for designated lower extremity levels, based on semiquantitative analyses in Charcot-Marie-Tooth disease type 1A (CMT1A) patients. We reviewed lower extremity MRIs of 116 CMT1A patients. Intramuscular fat infiltration grading using the Mercuri scale was performed for the non-dominant lower extremity at three levels (proximal, mid, and distal) for the thigh and at two levels (proximal and distal) for the lower leg. Based on MRI results, the following parameters were calculated for each level and for entire muscles: fat infiltration proportion (FIP), significant fat infiltration proportion (SigFIP), and severe fat infiltration proportion (SevFIP). The relationships between the MRI parameters and clinical data were evaluated using Spearman’s correlation analysis. FIP, SigFIP, and SevFIP measured for entire muscles significantly correlated with Charcot-Marie-Tooth Neuropathy Score (p < 0.001), functional disability scale (p < 0.001), 10-m walk test time (p = 0.0003, 0.0010, and 0.0011), and disease duration (p < 0.001). Similar correlations were demonstrated for FIP, SigFIP, and SevFIP acquired from the lower leg. Our MRI parameters obtained through semiquantitative analyses of muscles significantly correlated with clinical parameters in CMT1A patients, suggesting their potential applicability as imaging markers for clinical severity.
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Affiliation(s)
- Yeo Jin Kim
- Department of Radiology, Veterans Health Service Medical Center, Seoul, 05368, South Korea
| | - Hyun Su Kim
- Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, South Korea.
| | - Ji Hyun Lee
- Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, South Korea
| | - Young Cheol Yoon
- Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, South Korea
| | - Byung-Ok Choi
- Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, South Korea
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12
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Ran J, Dai B, Liu C, Zhang H, Li Y, Hou B, Li X. The diagnostic value of T2 map, diffusion tensor imaging, and diffusion kurtosis imaging in differentiating dermatomyositis from muscular dystrophy. Acta Radiol 2022; 63:467-473. [PMID: 33641450 DOI: 10.1177/0284185121999006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND Dermatomyositis (DM) and muscular dystrophy are clinically difficult to differentiate. PURPOSE To confirm the feasibility and assess the accuracy of conventional magnetic resonance imaging (MRI), T2 map, diffusion tensor imaging (DTI), and diffusion kurtosis imaging (DKI) in the differentiation of DM from muscular dystrophy. MATERIAL AND METHODS Forty-two patients with DM proven by diagnostic criteria were enrolled in the study along with 23 patients with muscular dystrophy. Conventional MR, T2 map, DTI, and DKI images were obtained in the thigh musculature for all patients. Intramuscular T2 value, apparent diffusion coefficient (ADC), fractional anisotropy (FA), mean diffusivity (MD), and mean kurtosis (MK) values were compared between the patients with DM and muscular dystrophy. Student's t-tests and receiver operating characteristic (ROC) curve analyses were performed for all parameters. P values < 0.05 were considered statistically significant. RESULTS The intramuscular T2, ADC, FA, MD, and MK values within muscles were statistically significantly different between the DM and muscular dystrophy groups (P<0.01). The MK value was statistically significantly different between the groups in comparison with T2 and FA value. As a supplement to conventional MRI, the parameters of MD and MK differentiated DM and muscular dystrophy may be valuable. The optimal cut-off value of ADC and MD values (with respective AUC, sensitivity, and specificity) between DM and muscular dystrophy were 1.698 ×10-3mm2/s (0.723, 54.1%, and 78.1%) and 1.80 ×10-3mm2/s (61.9% and 70.2%), respectively. CONCLUSION Thigh muscle ADC and MD parameters may be useful in differentiating patients with DM from those with muscular dystrophy.
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Affiliation(s)
- Jun Ran
- Department of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, PR China
| | - Bin Dai
- Department of Hepatobiliary Surgery, Wuhan No. 1 Hospital, Wuhan, Hubei Province, PR China
| | - Chanyuan Liu
- Department of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, PR China
| | - Huayue Zhang
- Department of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, PR China
| | - Yitong Li
- Department of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, PR China
| | - Bowen Hou
- Department of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, PR China
| | - Xiaoming Li
- Department of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, PR China
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13
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Yang Y, Qiu L, Gu X, Chen J, Chen S, Hu D, Hao Y, Shang X. Monitoring Rotator Cuff Muscle Fatty Infiltration Progression by Magnetic Resonance Imaging T1 Mapping: Correlation With Direct Evaluation Findings in Rats. Am J Sports Med 2022; 50:1078-1087. [PMID: 35099310 DOI: 10.1177/03635465211069976] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND Monitoring the fatty infiltration (FI) process in rotator cuff muscles is of value in establishing a treatment plan and predicting the postoperative prognosis. Quantitative T1 mapping shows promise for evaluating muscle degeneration, while its validity in monitoring rotator cuff muscle FI progression needs further investigation. PURPOSE To determine the validity of T1 mapping in monitoring FI progression of rotator cuff muscles. STUDY DESIGN Controlled laboratory study. METHODS Sprague-Dawley rats (N = 108) underwent left supraspinatus (SS) and infraspinatus (IS) tenotomy only (TT), suprascapular nerve transection only (NT), or SS and IS tenotomy plus suprascapular nerve transection (TT+NT). Sham surgery on the right shoulder served as the control. The magnetic resonance imaging examination included T1 mapping performed at 12, 16, and 20 weeks postoperation. SS and IS muscles were harvested to quantitatively evaluate FI via direct evaluation (triglyceride quantification assay and histological analysis) at the same predetermined intervals. The correlation of the imaging data with direct evaluation of rotator cuff muscles was analyzed. RESULTS T1 values were significantly lower in left SS and IS muscles at 12, 16, and 20 weeks postoperation as compared with those on the right side. T1 values of the left SS and IS muscles were continuously decreased in all groups. The TT+NT group had a greater decrease in T1 value than did the TT and NT groups. Triglyceride quantification assay and histological analysis demonstrated significant and progressive FI of the left SS and IS muscles in the 3 groups. The most serious FI changes were observed in the TT+NT group. T1 values were also well correlated with triglyceride contents and area fractions of fat. CONCLUSION T1 mapping can be an effective imaging modality for sensitive and quantitative monitoring of FI progression in rotator cuff muscles. CLINICAL RELEVANCE The findings of this study provide a tool for researchers to noninvasively and quantitatively monitor the process of muscle degeneration, contributing to the evaluation of surgical indication and postoperative prognosis.
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Affiliation(s)
- Yimeng Yang
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Longhua Qiu
- Department of Radiology, Huashan Hospital, Fudan University, Shanghai, China
| | - Xueping Gu
- Department of Orthopedics, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Jun Chen
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Shiyi Chen
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Dan Hu
- Department of Orthopedics, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Yuefeng Hao
- Department of Orthopedics, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Xiliang Shang
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, China
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14
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Acosta FM, Howland KK, Stojkova K, Hernandez E, Brey EM, Rathbone CR. Adipogenic Differentiation Alters Properties of Vascularized Tissue-Engineered Skeletal Muscle. Tissue Eng Part A 2022; 28:54-68. [PMID: 34102861 PMCID: PMC8812504 DOI: 10.1089/ten.tea.2021.0064] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Advances in the engineering of comprehensive skeletal muscle models in vitro will improve drug screening platforms and can lead to better therapeutic approaches for the treatment of skeletal muscle injuries. To this end, a vascularized tissue-engineered skeletal muscle (TE-SkM) model that includes adipocytes was developed to better emulate the intramuscular adipose tissue that is observed in skeletal muscles of patients with diseases such as diabetes. Muscle precursor cells cultured with and without microvessels derived from adipose tissue (microvascular fragments) were used to generate TE-SkM constructs, with and without a microvasculature, respectively. TE-SkM constructs were treated with adipogenic induction media to induce varying levels of adipogenesis. With a delayed addition of induction media to allow for angiogenesis, a robust microvasculature in conjunction with an increased content of adipocytes was achieved. The augmentation of vascularized TE-SkM constructs with adipocytes caused a reduction in maturation (compaction), mechanical integrity (Young's modulus), and myotube and vessel alignment. An increase in basal glucose uptake was observed in both levels of adipogenic induction, and a diminished insulin-stimulated glucose uptake was associated with the higher level of adipogenic differentiation and the greater number of adipocytes.
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Affiliation(s)
- Francisca M. Acosta
- Department of Biomedical Engineering and Chemical Engineering, University of Texas at San Antonio, San Antonio, Texas, USA.,UTSA-UTHSCSA Joint Graduate Program in Biomedical Engineering, San Antonio, Texas, USA
| | - Kennedy K. Howland
- Department of Biomedical Engineering and Chemical Engineering, University of Texas at San Antonio, San Antonio, Texas, USA
| | - Katerina Stojkova
- Department of Biomedical Engineering and Chemical Engineering, University of Texas at San Antonio, San Antonio, Texas, USA
| | - Elizabeth Hernandez
- Department of Biomedical Engineering and Chemical Engineering, University of Texas at San Antonio, San Antonio, Texas, USA
| | - Eric M. Brey
- Department of Biomedical Engineering and Chemical Engineering, University of Texas at San Antonio, San Antonio, Texas, USA
| | - Christopher R. Rathbone
- Department of Biomedical Engineering and Chemical Engineering, University of Texas at San Antonio, San Antonio, Texas, USA.,Address correspondence to: Christopher R. Rathbone, PhD, Department of Biomedical Engineering and Chemical Engineering, University of Texas at San Antonio, One UTSA Circle, San Antonio, TX 78249, USA
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15
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Muscular and Tendon Degeneration after Achilles Rupture: New Insights into Future Repair Strategies. Biomedicines 2021; 10:biomedicines10010019. [PMID: 35052699 PMCID: PMC8773411 DOI: 10.3390/biomedicines10010019] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 12/10/2021] [Accepted: 12/19/2021] [Indexed: 11/17/2022] Open
Abstract
Achilles tendon rupture is a frequent injury with an increasing incidence. After clinical surgical repair, aimed at suturing the tendon stumps back into their original position, the repaired Achilles tendon is often plastically deformed and mechanically less strong than the pre-injured tissue, with muscle fatty degeneration contributing to function loss. Despite clinical outcomes, pre-clinical research has mainly focused on tendon structural repair, with a lack of knowledge regarding injury progression from tendon to muscle and its consequences on muscle degenerative/regenerative processes and function. Here, we characterize the morphological changes in the tendon, the myotendinous junction and muscle belly in a mouse model of Achilles tendon complete rupture, finding cellular and fatty infiltration, fibrotic tissue accumulation, muscle stem cell decline and collagen fiber disorganization. We use novel imaging technologies to accurately relate structural alterations in tendon fibers to pathological changes, which further explain the loss of muscle mechanical function after tendon rupture. The treatment of tendon injuries remains a challenge for orthopedics. Thus, the main goal of this study is to bridge the gap between clinicians’ knowledge and research to address the underlying pathophysiology of ruptured Achilles tendon and its consequences in the gastrocnemius. Such studies are necessary if current practices in regenerative medicine for Achilles tendon ruptures are to be improved.
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16
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Gaeta M, Cavallaro M, Vinci SL, Mormina E, Blandino A, Marino MA, Granata F, Tessitore A, Galletta K, D'Angelo T, Visalli C. Magnetism of materials: theory and practice in magnetic resonance imaging. Insights Imaging 2021; 12:179. [PMID: 34862955 PMCID: PMC8643382 DOI: 10.1186/s13244-021-01125-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2021] [Accepted: 11/08/2021] [Indexed: 02/03/2023] Open
Abstract
All substances exert magnetic properties in some extent when placed in an external magnetic field. Magnetic susceptibility represents a measure of the magnitude of magnetization of a certain substance when the external magnetic field is applied. Depending on the tendency to be repelled or attracted by the magnetic field and in the latter case on the magnitude of this effect, materials can be classified as diamagnetic or paramagnetic, superparamagnetic and ferromagnetic, respectively. Knowledge of type and extent of susceptibility of common endogenous and exogenous substances and how their magnetic properties affect the conventional sequences used in magnetic resonance imaging (MRI) can help recognize them and exalt or minimize their presence in the acquired images, so as to improve diagnosis in a wide variety of benign and malignant diseases. Furthermore, in the context of diamagnetic susceptibility, chemical shift imaging enables to assess the intra-voxel ratio between water and fat content, analyzing the tissue composition of various organs and allowing a precise fat quantification. The following article reviews the fundamental physical principles of magnetic susceptibility and examines the magnetic properties of the principal endogenous and exogenous substances of interest in MRI, providing potential through representative cases for improved diagnosis in daily clinical routine.
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Affiliation(s)
- Michele Gaeta
- Department of Biomedical Sciences and Morphological and Functional Imaging, Policlinico Universitario G. Martino, University of Messina, Via Consolare Valeria 1, 98100, Messina, Italy
| | - Marco Cavallaro
- Department of Biomedical Sciences and Morphological and Functional Imaging, Policlinico Universitario G. Martino, University of Messina, Via Consolare Valeria 1, 98100, Messina, Italy
| | - Sergio Lucio Vinci
- Department of Biomedical Sciences and Morphological and Functional Imaging, Policlinico Universitario G. Martino, University of Messina, Via Consolare Valeria 1, 98100, Messina, Italy
| | - Enricomaria Mormina
- Department of Biomedical Sciences and Morphological and Functional Imaging, Policlinico Universitario G. Martino, University of Messina, Via Consolare Valeria 1, 98100, Messina, Italy.
| | - Alfredo Blandino
- Department of Biomedical Sciences and Morphological and Functional Imaging, Policlinico Universitario G. Martino, University of Messina, Via Consolare Valeria 1, 98100, Messina, Italy
| | - Maria Adele Marino
- Department of Biomedical Sciences and Morphological and Functional Imaging, Policlinico Universitario G. Martino, University of Messina, Via Consolare Valeria 1, 98100, Messina, Italy
| | - Francesca Granata
- Department of Biomedical Sciences and Morphological and Functional Imaging, Policlinico Universitario G. Martino, University of Messina, Via Consolare Valeria 1, 98100, Messina, Italy
| | - Agostino Tessitore
- Department of Biomedical Sciences and Morphological and Functional Imaging, Policlinico Universitario G. Martino, University of Messina, Via Consolare Valeria 1, 98100, Messina, Italy
| | - Karol Galletta
- Department of Biomedical Sciences and Morphological and Functional Imaging, Policlinico Universitario G. Martino, University of Messina, Via Consolare Valeria 1, 98100, Messina, Italy
| | - Tommaso D'Angelo
- Department of Biomedical Sciences and Morphological and Functional Imaging, Policlinico Universitario G. Martino, University of Messina, Via Consolare Valeria 1, 98100, Messina, Italy
| | - Carmela Visalli
- Department of Biomedical Sciences and Morphological and Functional Imaging, Policlinico Universitario G. Martino, University of Messina, Via Consolare Valeria 1, 98100, Messina, Italy
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17
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Molina T, Fabre P, Dumont NA. Fibro-adipogenic progenitors in skeletal muscle homeostasis, regeneration and diseases. Open Biol 2021; 11:210110. [PMID: 34875199 PMCID: PMC8651418 DOI: 10.1098/rsob.210110] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Skeletal muscle possesses a remarkable regenerative capacity that relies on the activity of muscle stem cells, also known as satellite cells. The presence of non-myogenic cells also plays a key role in the coordination of skeletal muscle regeneration. Particularly, fibro-adipogenic progenitors (FAPs) emerged as master regulators of muscle stem cell function and skeletal muscle regeneration. This population of muscle resident mesenchymal stromal cells has been initially characterized based on its bi-potent ability to differentiate into fibroblasts or adipocytes. New technologies such as single-cell RNAseq revealed the cellular heterogeneity of FAPs and their complex regulatory network during muscle regeneration. In acute injury, FAPs rapidly enter the cell cycle and secrete trophic factors that support the myogenic activity of muscle stem cells. Conversely, deregulation of FAP cell activity is associated with the accumulation of fibrofatty tissue in pathological conditions such as muscular dystrophies and ageing. Considering their central role in skeletal muscle pathophysiology, the regulatory mechanisms of FAPs and their cellular and molecular crosstalk with muscle stem cells are highly investigated in the field. In this review, we summarize the current knowledge on FAP cell characteristics, heterogeneity and the cellular crosstalk during skeletal muscle homeostasis and regeneration. We further describe their role in muscular disorders, as well as different therapeutic strategies targeting these cells to restore muscle regeneration.
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Affiliation(s)
- Thomas Molina
- CHU Sainte-Justine Research Center, Montreal, Quebec, Canada,Department of Pharmacology and Physiology, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada
| | - Paul Fabre
- CHU Sainte-Justine Research Center, Montreal, Quebec, Canada,Department of Pharmacology and Physiology, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada
| | - Nicolas A. Dumont
- CHU Sainte-Justine Research Center, Montreal, Quebec, Canada,School of Rehabilitation, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada
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18
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Brogna C, Cristiano L, Verdolotti T, Norcia G, Ficociello L, Ruiz R, Coratti G, Fanelli L, Forcina N, Petracca G, Chieppa F, Tartaglione T, Colosimo C, Pane M, Mercuri E. Longitudinal Motor Functional Outcomes and Magnetic Resonance Imaging Patterns of Muscle Involvement in Upper Limbs in Duchenne Muscular Dystrophy. Medicina (B Aires) 2021; 57:medicina57111267. [PMID: 34833484 PMCID: PMC8624281 DOI: 10.3390/medicina57111267] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Revised: 11/10/2021] [Accepted: 11/15/2021] [Indexed: 11/25/2022] Open
Abstract
Background and Objectives: The aim of this study was to evaluate longitudinal changes using both upper limb muscle Magnetic Resonance Imaging (MRI) at shoulder, arm and forearm levels and Performance of upper limb (PUL) in ambulant and non-ambulant Duchenne Muscular Dystrophy (DMD) patients. We also wished to define whether baseline muscle MRI could help to predict functional changes after one year. Materials and Methods: Twenty-seven patients had both baseline and 12month muscle MRI and PUL assessments one year later. Results: Ten were ambulant (age range 5–16 years), and 17 non ambulant (age range 10–30 years). Increased abnormalities equal or more than 1.5 point on muscle MRI at follow up were found on all domains: at shoulder level 12/27 patients (44%), at arm level 4/27 (15%) and at forearm level 6/27 (22%). Lower follow up PUL score were found in 8/27 patients (30%) at shoulder level, in 9/27 patients (33%) at mid-level whereas no functional changes were found at distal level. There was no constant association between baseline MRI scores and follow up PUL scores at arm and forearm levels but at shoulder level patients with moderate impairment on the baseline MRI scores between 16 and 34 had the highest risk of decreased function on PUL over a year. Conclusions: Our results confirmed that the integrated use of functional scales and imaging can help to monitor functional and MRI changes over time.
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Affiliation(s)
- Claudia Brogna
- Pediatric Neurology Unit, Fondazione Policlinico Universitario “A. Gemelli”, IRCCS, 00168 Rome, Italy;
- Nemo Clinical Centre, Fondazione Policlinico Universitario “A. Gemelli”, IRCCS, 00168 Rome, Italy; (G.N.); (G.C.); (L.F.); (N.F.); (M.P.)
| | - Lara Cristiano
- Pediatric Neurology, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (L.C.); (R.R.); (G.P.); (F.C.)
| | - Tommaso Verdolotti
- Institute of Radiology, Fondazione Policlinico Universitario “A. Gemelli”, IRCCS, 00168 Rome, Italy; (T.V.); (L.F.); (C.C.)
| | - Giulia Norcia
- Nemo Clinical Centre, Fondazione Policlinico Universitario “A. Gemelli”, IRCCS, 00168 Rome, Italy; (G.N.); (G.C.); (L.F.); (N.F.); (M.P.)
| | - Luana Ficociello
- Institute of Radiology, Fondazione Policlinico Universitario “A. Gemelli”, IRCCS, 00168 Rome, Italy; (T.V.); (L.F.); (C.C.)
| | - Roberta Ruiz
- Pediatric Neurology, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (L.C.); (R.R.); (G.P.); (F.C.)
| | - Giorgia Coratti
- Nemo Clinical Centre, Fondazione Policlinico Universitario “A. Gemelli”, IRCCS, 00168 Rome, Italy; (G.N.); (G.C.); (L.F.); (N.F.); (M.P.)
- Pediatric Neurology, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (L.C.); (R.R.); (G.P.); (F.C.)
| | - Lavinia Fanelli
- Nemo Clinical Centre, Fondazione Policlinico Universitario “A. Gemelli”, IRCCS, 00168 Rome, Italy; (G.N.); (G.C.); (L.F.); (N.F.); (M.P.)
| | - Nicola Forcina
- Nemo Clinical Centre, Fondazione Policlinico Universitario “A. Gemelli”, IRCCS, 00168 Rome, Italy; (G.N.); (G.C.); (L.F.); (N.F.); (M.P.)
| | - Giorgia Petracca
- Pediatric Neurology, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (L.C.); (R.R.); (G.P.); (F.C.)
| | - Fabrizia Chieppa
- Pediatric Neurology, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (L.C.); (R.R.); (G.P.); (F.C.)
| | - Tommaso Tartaglione
- Department of Radiology, Istituto Dermatologico Italiano, IRCCS, 00167 Rome, Italy;
| | - Cesare Colosimo
- Institute of Radiology, Fondazione Policlinico Universitario “A. Gemelli”, IRCCS, 00168 Rome, Italy; (T.V.); (L.F.); (C.C.)
- Institute of Radiology, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Marika Pane
- Nemo Clinical Centre, Fondazione Policlinico Universitario “A. Gemelli”, IRCCS, 00168 Rome, Italy; (G.N.); (G.C.); (L.F.); (N.F.); (M.P.)
- Pediatric Neurology, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (L.C.); (R.R.); (G.P.); (F.C.)
| | - Eugenio Mercuri
- Pediatric Neurology Unit, Fondazione Policlinico Universitario “A. Gemelli”, IRCCS, 00168 Rome, Italy;
- Nemo Clinical Centre, Fondazione Policlinico Universitario “A. Gemelli”, IRCCS, 00168 Rome, Italy; (G.N.); (G.C.); (L.F.); (N.F.); (M.P.)
- Pediatric Neurology, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (L.C.); (R.R.); (G.P.); (F.C.)
- Correspondence: ; Tel.: +39-06-30155340; Fax: +39-06-30154363
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Veeger TTJ, van Zwet EW, al Mohamad D, Naarding KJ, van de Velde NM, Hooijmans MT, Webb AG, Niks EH, de Groot JH, Kan HE. Muscle architecture is associated with muscle fat replacement in Duchenne and Becker muscular dystrophies. Muscle Nerve 2021; 64:576-584. [PMID: 34383334 PMCID: PMC9290788 DOI: 10.1002/mus.27399] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 08/02/2021] [Accepted: 08/07/2021] [Indexed: 12/21/2022]
Abstract
INTRODUCTION/AIMS Duchenne and Becker muscular dystrophies (DMD and BMD, respectively) are characterized by fat replacement of different skeletal muscles in a specific temporal order. Given the structural role of dystrophin in skeletal muscle mechanics, muscle architecture could be important in the progressive pathophysiology of muscle degeneration. Therefore, the aim of this study was to assess the role of muscle architecture in the progression of fat replacement in DMD and BMD. METHODS We assessed the association between literature-based leg muscle architectural characteristics and muscle fat fraction from 22 DMD and 24 BMD patients. Dixon-based magnetic resonance imaging estimates of fat fractions at baseline and 12 (only DMD) and 24 months were related to fiber length and physiological cross-sectional area (PCSA) using age-controlled linear mixed modeling. RESULTS DMD and BMD muscles with long fibers and BMD muscles with large PCSAs were associated with increased fat fraction. The effect of fiber length was stronger in muscles with larger PCSA. DISCUSSION Muscle architecture may explain the pathophysiology of muscle degeneration in dystrophinopathies, in which proximal muscles with a larger mass (fiber length × PCSA) are more susceptible, confirming the clinical observation of a temporal proximal-to-distal progression. These results give more insight into the mechanical role in the pathophysiology of muscular dystrophies. Ultimately, this new information can be used to help support the selection of current and the development of future therapies.
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Affiliation(s)
- Thom T. J. Veeger
- C.J. Gorter Center for High Field MRI, Department of RadiologyLeiden University Medical CenterLeidenThe Netherlands
| | - Erik W. van Zwet
- Department of BiostatisticsLeiden University Medical CenterLeidenThe Netherlands
| | - Diaa al Mohamad
- Department of BiostatisticsLeiden University Medical CenterLeidenThe Netherlands
| | - Karin J. Naarding
- Department of NeurologyLeiden University Medical CenterLeidenThe Netherlands
| | | | - Melissa T. Hooijmans
- Department of Radiology & Nuclear MedicineAmsterdam University Medical Centers, Location AMCAmsterdamThe Netherlands
| | - Andrew G. Webb
- C.J. Gorter Center for High Field MRI, Department of RadiologyLeiden University Medical CenterLeidenThe Netherlands
| | - Erik H. Niks
- Department of NeurologyLeiden University Medical CenterLeidenThe Netherlands
| | - Jurriaan H. de Groot
- Department of Rehabilitation MedicineLeiden University Medical CenterLeidenThe Netherlands
| | - Hermien E. Kan
- C.J. Gorter Center for High Field MRI, Department of RadiologyLeiden University Medical CenterLeidenThe Netherlands
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20
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Alonso-Jiménez A, Nuñez-Peralta C, Montesinos P, Alonso-Pérez J, García C, Montiel E, Belmonte I, Pedrosa I, Segovia S, Llauger J, Díaz-Manera J. Different Approaches to Analyze Muscle Fat Replacement With Dixon MRI in Pompe Disease. Front Neurol 2021; 12:675781. [PMID: 34305788 PMCID: PMC8298190 DOI: 10.3389/fneur.2021.675781] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Accepted: 06/08/2021] [Indexed: 12/13/2022] Open
Abstract
Quantitative MRI is an increasingly used method to monitor disease progression in muscular disorders due to its ability to measure changes in muscle fat content (reported as fat fraction) over a short period. Being able to objectively measure such changes is crucial for the development of new treatments in clinical trials. However, the analysis of the images involved continues to be a daunting task because of the time needed. Whether a more specific analysis selecting individual muscles or a global one analyzing the whole thigh or compartments could be a suitable alternative has only been marginally studied. In our study we compare three methods of analysis of 2-point-dixon images in a cohort of 34 patients with late onset Pompe disease followed over a period of one year. We measured fat fraction on MRIs obtained at baseline and at year 1, and we calculated the increment of fat fraction. We correlated the results obtained with the results of muscle function tests to investigate whether the three methods of analysis were equivalent or not. We observed significant differences between the three methods in the estimation of the fat fraction at both baseline and year 1, but no difference was found in the increment in fat fraction between baseline and year 1. When we correlated the fat fraction obtained with each method and the muscle function tests, we found a significant correlation with most tests in all three methods, although in most comparisons the highest correlation coefficient was found with the analysis of individual muscles. We conclude that the fastest strategy of analysis assessing compartments or the whole thigh could be reliable for certain cohorts of patients where the variable to study is the fat increment. In other sorts of studies, an individual muscle approach seems the most reliable technique.
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Affiliation(s)
- Alicia Alonso-Jiménez
- Neuromuscular Disorders Unit, Neurology Department, Departament de Medicina, Hospital de la Santa Creu I Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.,Neuromuscular Reference Center, Neurology Department, University Hospital of Antwerp, Edegem, Belgium
| | - Claudia Nuñez-Peralta
- Radiology Department, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
| | | | - Jorge Alonso-Pérez
- Neuromuscular Disorders Unit, Neurology Department, Departament de Medicina, Hospital de la Santa Creu I Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.,Biomedical Network Research Centre on Rare Diseases (CIBERER), Barcelona, Spain
| | - Carme García
- Rehabilitation and Physiotherapy Department, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Elena Montiel
- Rehabilitation and Physiotherapy Department, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Izaskun Belmonte
- Rehabilitation and Physiotherapy Department, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Irene Pedrosa
- Rehabilitation and Physiotherapy Department, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Sonia Segovia
- Neuromuscular Disorders Unit, Neurology Department, Departament de Medicina, Hospital de la Santa Creu I Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.,Biomedical Network Research Centre on Rare Diseases (CIBERER), Barcelona, Spain
| | - Jaume Llauger
- Radiology Department, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Jordi Díaz-Manera
- Neuromuscular Disorders Unit, Neurology Department, Departament de Medicina, Hospital de la Santa Creu I Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.,Biomedical Network Research Centre on Rare Diseases (CIBERER), Barcelona, Spain.,John Walton Muscular Dystrophy Research Centre, Newcastle University, International Centre for Life, Newcastle upon Tyne, United Kingdom
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21
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Abstract
Direct-type cavus foot deformities are most commonly encountered and are primarily sagittal plane deformities. Direct deformities should be delineated from rarer triplane pes cavovarus deformities. The lateral weight-bearing radiograph is the cornerstone of imaging evaluation of direct pes cavus foot deformity. The apex of Meary talo-first metatarsal angle on the lateral radiograph represents the pinnacle of the cavus deformity and assists in subclassification of the deformity. With routine application, ancillary radiographic imaging techniques, such as the modified Saltzman view or the modified Coleman block test, can give valuable insight into deformity assessment and surgical planning.
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Affiliation(s)
- Lawrence Osher
- Radiology, Division of Podiatric and General Medicine, Kent State University College of Podiatric Medicine, 6000 Rockside Woods Blvd. N, Independence, OH 44131, USA.
| | - Jeffrey E Shook
- Adjunct Faculty, St. Vincent Charity Medical Center, Cleveland, OH, USA
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22
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Musculoskeletal magnetic resonance imaging in the DE50-MD dog model of Duchenne muscular dystrophy. Neuromuscul Disord 2021; 31:736-751. [PMID: 34384671 PMCID: PMC8449064 DOI: 10.1016/j.nmd.2021.05.010] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 05/20/2021] [Accepted: 05/26/2021] [Indexed: 11/23/2022]
Abstract
Normalized muscle volumes distinguish between wild type and DE50-MD dogs. Global muscle T2 signal intensities discriminate between wild type and DE50-MD dogs. Musculoskeletal changes detected by MRI reflect those seen in human DMD patients. Musculoskeletal MRI in this model will be useful to assess treatment efficacy. The DE50-MD canine model of Duchenne muscular dystrophy (DMD) has a dystrophin gene splice site mutation causing deletion of exon 50, an out-of-frame transcript and absence of dystrophin expression in striated muscles. We hypothesized that the musculoskeletal phenotype of DE50-MD dogs could be detected using Magnetic Resonance Imaging (MRI), that it would progress with age and that it would reflect those in other canine models and DMD patients. 15 DE50-MD and 10 age-matched littermate wild type (WT) male dogs underwent MRI every 3 months from 3 to 18 months of age. Normalized muscle volumes, global muscle T2 and ratio of post- to pre-gadolinium T1-weighted SI were evaluated in 7 pelvic limb and 4 lumbar muscles bilaterally. DE50-MD dogs, compared to WT, had smaller volumes in all muscles, except the cranial sartorius; global muscle T2 was significantly higher in DE50-MD dogs compared to WT. Muscle volumes plateaued and global muscle T2 decreased with age. Normalized muscle volumes and global muscle T2 revealed significant differences between groups longitudinally and should be useful to determine efficacy of therapeutics in this model with suitable power and low sample sizes. Musculoskeletal changes reflect those of DMD patients and other dog models.
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23
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Ran J, Yin C, Liu C, Li Y, Hou B, Morelli JN, Dai B, Li X. The Diagnostic Value of MR IVIM and T2 Mapping in Differentiating Autoimmune Myositis From Muscular Dystrophy. Acad Radiol 2021; 28:e182-e188. [PMID: 32417032 DOI: 10.1016/j.acra.2020.04.022] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 04/11/2020] [Accepted: 04/12/2020] [Indexed: 01/15/2023]
Abstract
RATIONALE AND OBJECTIVES To confirm the feasibility and compare the accuracy of magnetic resonance imaging intravoxel incoherent motion (IVIM) and T2 mapping models for the differentiation of autoimmune myositis from muscular dystrophy. MATERIALS AND METHODS Fourty-two autoimmune myositis and 11 muscular dystrophy patients proven by diagnostic criteria were enrolled in the study. Conventional MR sequences, IVIM, and T2 mapping through the bilateral thighs were obtained as well as blood samples for all patients. IVIM and T2 mapping parameters as well as serum markers were compared between the autoimmune myositis and muscular dystrophy groups. Mann-Whitney U tests were performed for statistical analysis along with receiver operating characteristic curves. Spearman correlation coefficient models were constructed to analyze the correlation between IVIM and T2 mapping with serological parameters. RESULTS The intramuscular apparent diffusion coefficient, tissue diffusivity (D), perfusion fraction (fp), and T2 relaxation time values were statistically significantly different between the autoimmune myositis and muscular dystrophy groups (p < 0.05). Pseudo diffusivity (Dp) values showed no statistical difference between the groups (p > 0.05). D parameter of IVIM sequences differentiated autoimmune and muscular dystrophy with a higher specificity of 75.60%. T2 values within the thighs were correlated with serum creatine kinase and lactate dehydrogenase levels (p < 0.05). CONCLUSION Thigh muscle IVIM and T2 mapping parameters are useful in differentiating autoimmune myositis from muscular dystrophy, particularly the IVIM parameters.
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Affiliation(s)
- Jun Ran
- Department of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095, Jiefang Road, Wuhan 430030, Hubei Province, People's Republic of China
| | - Cuilin Yin
- Department of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095, Jiefang Road, Wuhan 430030, Hubei Province, People's Republic of China
| | - Chanyuan Liu
- Department of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095, Jiefang Road, Wuhan 430030, Hubei Province, People's Republic of China
| | - Yitong Li
- Department of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095, Jiefang Road, Wuhan 430030, Hubei Province, People's Republic of China
| | - Bowen Hou
- Department of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095, Jiefang Road, Wuhan 430030, Hubei Province, People's Republic of China
| | - John N Morelli
- Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Bin Dai
- Department of General Surgery, General Hospital of the Central Theater Command of the People's Liberation Army, Wuhan, People's Republic of China
| | - Xiaoming Li
- Department of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095, Jiefang Road, Wuhan 430030, Hubei Province, People's Republic of China.
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24
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Sherlock SP, Zhang Y, Binks M, Marraffino S. Quantitative muscle MRI biomarkers in Duchenne muscular dystrophy: cross-sectional correlations with age and functional tests. Biomark Med 2021; 15:761-773. [PMID: 34155911 PMCID: PMC8253163 DOI: 10.2217/bmm-2020-0801] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Accepted: 03/23/2021] [Indexed: 01/07/2023] Open
Abstract
Aim: Using baseline data from a clinical trial of domagrozumab in Duchenne muscular dystrophy, we evaluated the correlation between functional measures and quantitative MRI assessments of thigh muscle. Patients & methods: Analysis included timed functional tests, knee extension/strength and North Star Ambulatory Assessment. Patients (n = 120) underwent examinations of one thigh, with MRI sequences to enable measurements of muscle volume (MV), MV index, mean T2 relaxation time via T2-mapping and fat fraction. Results: MV was moderately correlated with strength assessments. MV index, fat fraction and T2-mapping measures had moderate correlations (r ∼ 0.5) to all functional tests, North Star Ambulatory Assessment and age. Conclusion: The moderate correlation between functional tests, age and baseline MRI measures supports MRI as a biomarker in Duchenne muscular dystrophy clinical trials. Trial registration: ClinicalTrials.gov, NCT02310763; registered 4 November 2014.
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Affiliation(s)
| | - Yao Zhang
- Pfizer Inc, Cambridge, MA 02139, USA
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25
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Greve T, Burian E, Zoffl A, Feuerriegel G, Schlaeger S, Dieckmeyer M, Sollmann N, Klupp E, Weidlich D, Inhuber S, Löffler M, Montagnese F, Deschauer M, Schoser B, Bublitz S, Zimmer C, Karampinos DC, Kirschke JS, Baum T. Regional variation of thigh muscle fat infiltration in patients with neuromuscular diseases compared to healthy controls. Quant Imaging Med Surg 2021; 11:2610-2621. [PMID: 34079727 DOI: 10.21037/qims-20-1098] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Background Chemical shift encoding-based water-fat magnetic resonance imaging (CSE-MRI) measures a quantitative biomarker: the proton density fat fraction (PDFF). The aim was to assess regional and proximo-distal PDFF variations at the thigh in patients with myotonic dystrophy type 2 (DM2), limb-girdle muscular dystrophy type 2A (LGMD2A), and late-onset Pompe disease (LOPD) as compared to healthy controls. Methods Seven patients (n=2 DM2, n=2 LGMD2A, n=3 LOPD) and 20 controls were recruited. A 3D-spoiled gradient echo sequence was used to scan the thigh musculature. Muscles were manually segmented to generate mean muscle PDFF. Results In all three disease entities, there was an increase in muscle fat replacement compared to healthy controls. However, within each disease group, there were patients with a shorter time since symptom onset that only showed mild PDFF elevation (range, 10% to 20%) compared to controls (P≤0.05), whereas patients with a longer period since symptom onset showed a more severe grade of fat replacement with a range of 50% to 70% (P<0.01). Increased PDFF of around 5% was observed for vastus medialis, semimembranosus and gracilis muscles in advanced compared to early DM2. LGMD2A_1 showed an early disease stage with predominantly mild PDFF elevations over all muscles and levels (10.9%±7.1%) compared to controls. The quadriceps, gracilis and biceps femoris muscles showed the highest difference between LGMD2A_1 with 5 years since symptom onset (average PDFF 11.1%±6.9%) compared to LGMD2A_2 with 32 years since symptom onset (average PDFF 66.3%±6.3%). For LOPD patients, overall PDFF elevations were observed in all major hip flexors and extensors (range, 25.8% to 30.8%) compared to controls (range, 1.7% to 2.3%, P<0.05). Proximal-to-distal PDFF highly varied within and between diseases and within controls. The intra-reader reliability was high (reproducibility coefficient ≤2.19%). Conclusions By quantitatively measuring muscle fat infiltration at the thigh, we identified candidate muscles for disease monitoring due to their gradual PDFF elevation with longer disease duration. Regional variation between proximal, central, and distal muscle PDFF was high and is important to consider when performing longitudinal MRI follow-ups in the clinical setting or in longitudinal studies.
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Affiliation(s)
- Tobias Greve
- Department of Diagnostic and Interventional Neuroradiology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.,Department of Neurosurgery, University Hospital, LMU Munich, Munich, Germany
| | - Egon Burian
- Department of Diagnostic and Interventional Neuroradiology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Agnes Zoffl
- Department of Diagnostic and Interventional Neuroradiology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Georg Feuerriegel
- Department of Diagnostic and Interventional Radiology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Sarah Schlaeger
- Department of Diagnostic and Interventional Neuroradiology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.,Department of Diagnostic and Interventional Radiology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Michael Dieckmeyer
- Department of Diagnostic and Interventional Neuroradiology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Nico Sollmann
- Department of Diagnostic and Interventional Neuroradiology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Elisabeth Klupp
- Department of Diagnostic and Interventional Neuroradiology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Dominik Weidlich
- Department of Diagnostic and Interventional Radiology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Stephanie Inhuber
- Department of Sports and Health Sciences, Technical University of Munich, Munich, Germany
| | - Maximilian Löffler
- Department of Diagnostic and Interventional Neuroradiology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Federica Montagnese
- Friedrich Baur Institute at the Department of Neurology, University Hospital, LMU Munich, Munich, Germany
| | - Marcus Deschauer
- Department of Neurology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Benedikt Schoser
- Friedrich Baur Institute at the Department of Neurology, University Hospital, LMU Munich, Munich, Germany
| | - Sarah Bublitz
- Department of Neurology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Claus Zimmer
- Department of Diagnostic and Interventional Neuroradiology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Dimitrios C Karampinos
- Department of Diagnostic and Interventional Radiology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Jan S Kirschke
- Department of Diagnostic and Interventional Neuroradiology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Thomas Baum
- Department of Diagnostic and Interventional Neuroradiology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
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26
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Alic L, Griffin JF, Eresen A, Kornegay JN, Ji JX. Using MRI to quantify skeletal muscle pathology in Duchenne muscular dystrophy: A systematic mapping review. Muscle Nerve 2021; 64:8-22. [PMID: 33269474 PMCID: PMC8247996 DOI: 10.1002/mus.27133] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Revised: 11/23/2020] [Accepted: 11/27/2020] [Indexed: 12/11/2022]
Abstract
There is a great demand for accurate non‐invasive measures to better define the natural history of disease progression or treatment outcome in Duchenne muscular dystrophy (DMD) and to facilitate the inclusion of a large range of participants in DMD clinical trials. This review aims to investigate which MRI sequences and analysis methods have been used and to identify future needs. Medline, Embase, Scopus, Web of Science, Inspec, and Compendex databases were searched up to 2 November 2019, using keywords “magnetic resonance imaging” and “Duchenne muscular dystrophy.” The review showed the trend of using T1w and T2w MRI images for semi‐qualitative inspection of structural alterations of DMD muscle using a diversity of grading scales, with increasing use of T2map, Dixon, and MR spectroscopy (MRS). High‐field (>3T) MRI dominated the studies with animal models. The quantitative MRI techniques have allowed a more precise estimation of local or generalized disease severity. Longitudinal studies assessing the effect of an intervention have also become more prominent, in both clinical and animal model subjects. Quality assessment of the included longitudinal studies was performed using the Newcastle‐Ottawa Quality Assessment Scale adapted to comprise bias in selection, comparability, exposure, and outcome. Additional large clinical trials are needed to consolidate research using MRI as a biomarker in DMD and to validate findings against established gold standards. This future work should use a multiparametric and quantitative MRI acquisition protocol, assess the repeatability of measurements, and correlate findings to histologic parameters.
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Affiliation(s)
- Lejla Alic
- Department of Electrical & Computer Engineering, Texas A&M University, Doha, Qatar.,Magnetic Detection and Imaging group, Technical Medical Centre, University of Twente, The Netherlands
| | - John F Griffin
- College of Vet. Med. & Biomedical Sciences, Texas A&M University, College Station, Texas, USA
| | - Aydin Eresen
- Department of Radiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.,Department of Electrical & Computer Engineering, Texas A&M University, College Station, Texas, USA
| | - Joe N Kornegay
- College of Vet. Med. & Biomedical Sciences, Texas A&M University, College Station, Texas, USA
| | - Jim X Ji
- Department of Electrical & Computer Engineering, Texas A&M University, Doha, Qatar.,Department of Electrical & Computer Engineering, Texas A&M University, College Station, Texas, USA
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27
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Shen X, Tang J, Ru W, Zhang X, Huang Y, Lei C, Cao H, Lan X, Chen H. CircINSR Regulates Fetal Bovine Muscle and Fat Development. Front Cell Dev Biol 2021; 8:615638. [PMID: 33490079 PMCID: PMC7815687 DOI: 10.3389/fcell.2020.615638] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Accepted: 12/07/2020] [Indexed: 01/22/2023] Open
Abstract
The level of muscle development in livestock directly affects the production efficiency of livestock, and the contents of intramuscular fat (IMF) is an important factor that affects meat quality. However, the molecular mechanisms through which circular RNA (circRNA) affects muscle and IMF development remains largely unknown. In this study, we isolated myoblasts and intramuscular preadipocytes from fetal bovine skeletal muscle. Oil Red O and BODIPY staining were used to identify lipid droplets in preadipocytes, and anti-myosin heavy chain (MyHC) immunofluorescence was used to identify myotubes differentiated from myoblasts. Bioinformatics, a dual-fluorescence reporter system, RNA pull-down, and RNA-binding protein immunoprecipitation were used to determine the interactions between circINSR and the micro RNA (miR)-15/16 family. Molecular and biochemical assays were used to confirm the roles played by circINSR in myoblasts and intramuscular preadipocytes. We found that isolated myoblasts and preadipocytes were able to differentiate normally. CircINSR was found to serve as a sponge for the miR-15/16 family, which targets CCND1 and Bcl-2. CircINSR overexpression significantly promoted myoblast and preadipocyte proliferation and inhibited cell apoptosis. In addition, circINSR inhibited preadipocyte adipogenesis by alleviating the inhibition of miR-15/16 against the target genes FOXO1 and EPT1. Taken together, our study demonstrated that circINSR serves as a regulator of embryonic muscle and IMF development.
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Affiliation(s)
- Xuemei Shen
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Jia Tang
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Wenxiu Ru
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Xiaoyan Zhang
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Yongzhen Huang
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Chuzhao Lei
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Hui Cao
- Shaanxi Kingbull Livestock Co., Ltd., Yangling, China
| | - Xianyong Lan
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Hong Chen
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, China
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28
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Global versus individual muscle segmentation to assess quantitative MRI-based fat fraction changes in neuromuscular diseases. Eur Radiol 2020; 31:4264-4276. [PMID: 33219846 DOI: 10.1007/s00330-020-07487-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 10/29/2020] [Accepted: 11/06/2020] [Indexed: 12/14/2022]
Abstract
OBJECTIVES Magnetic resonance imaging (MRI) constitutes a powerful outcome measure in neuromuscular disorders, yet there is a broad diversity of approaches in data acquisition and analysis. Since each neuromuscular disease presents a specific pattern of muscle involvement, the recommended analysis is assumed to be the muscle-by-muscle approach. We, therefore, performed a comparative analysis of different segmentation approaches, including global muscle segmentation, to determine the best strategy for evaluating disease progression. METHODS In 102 patients (21 immune-mediated necrotizing myopathy/IMNM, 21 inclusion body myositis/IBM, 10 GNE myopathy/GNEM, 19 Duchenne muscular dystrophy/DMD, 12 dysferlinopathy/DYSF, 7 limb-girdle muscular dystrophy/LGMD2I, 7 Pompe disease, 5 spinal muscular atrophy/SMA), two MRI scans were obtained at a 1-year interval in thighs and lower legs. Regions of interest (ROIs) were drawn in individual muscles, muscle groups, and the global muscle segment. Standardized response means (SRMs) were determined to assess sensitivity to change in fat fraction (ΔFat%) in individual muscles, muscle groups, weighted combinations of muscles and muscle groups, and in the global muscle segment. RESULTS Global muscle segmentation gave high SRMs for ΔFat% in thigh and lower leg for IMNM, DYSF, LGMD2I, DMD, SMA, and Pompe disease, and only in lower leg for GNEM and thigh for IBM. CONCLUSIONS Global muscle segment Fat% showed to be sensitive to change in most investigated neuromuscular disorders. As compared to individual muscle drawing, it is a faster and an easier approach to assess disease progression. The use of individual muscle ROIs, however, is still of interest for exploring selective muscle involvement. KEY POINTS • MRI-based evaluation of fatty replacement in muscles is used as an outcome measure in the assessment of 1-year disease progression in 8 different neuromuscular diseases. • Different segmentation approaches, including global muscle segmentation, were evaluated for determining 1-year fat fraction changes in lower limb skeletal muscles. • Global muscle segment fat fraction has shown to be sensitive to change in lower leg and thigh in most of the investigated neuromuscular diseases.
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29
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Liu CY, Yao J, Kovacs WC, Shrader JA, Joe G, Ouwerkerk R, Mankodi AK, Gahl WA, Summers RM, Carrillo N. Skeletal Muscle Magnetic Resonance Biomarkers in GNE Myopathy. Neurology 2020; 96:e798-e808. [PMID: 33219145 DOI: 10.1212/wnl.0000000000011231] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 09/30/2020] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVE To characterize muscle involvement and evaluate disease severity in patients with GNE myopathy using skeletal muscle MRI and proton magnetic resonance spectroscopy (1H-MRS). METHODS Skeletal muscle imaging of the lower extremities was performed in 31 patients with genetically confirmed GNE myopathy, including T1-weighted and short tau inversion recovery (STIR) images, T1 and T2 mapping, and 1H-MRS. Measures evaluated included longitudinal relaxation time (T1), transverse relaxation time (T2), and 1H-MRS fat fraction (FF). Thigh muscle volume was correlated with relevant measures of strength, function, and patient-reported outcomes. RESULTS The cohort was representative of a wide range of disease progression. Contractile thigh muscle volume ranged from 5.51% to 62.95% and correlated with thigh strength (r = 0.91), the 6-minute walk test (r = 0.82), the adult myopathy assessment tool (r = 0.83), the activities-specific balance confidence scale (r = 0.65), and the inclusion body myositis functional rating scale (r = 0.62). Four stages of muscle involvement were distinguished by qualitative (T1W and STIR images) and quantitative methods: stage I: unaffected muscle (T1 = 1,033 ± 74.2 ms, T2 = 40.0 ± 1.9 ms, FF = 7.4 ± 3.5%); stage II: STIR hyperintense muscle with minimal or no fat infiltration (T1 = 1,305 ± 147 ms, T2 = 50.2 ± 3.5 ms, FF = 27.6 ± 12.7%); stage III: fat infiltration and STIR hyperintensity (T1 = 1,209 ± 348 ms, T2 = 73.3 ± 12.6 ms, FF = 57.5 ± 10.6%); and stage IV: complete fat replacement (T1 = 318 ± 39.9 ms, T2 = 114 ± 21.2 ms, FF = 85.6 ± 4.2%). 1H-MRS showed a significant decrease in intramyocellular lipid and trimethylamines between stage I and II, suggesting altered muscle metabolism at early stages. CONCLUSION MRI biomarkers can monitor muscle involvement and determine disease severity noninvasively in patients with GNE myopathy. CLINICALTRIALSGOV IDENTIFIER NCT01417533.
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Affiliation(s)
- Chia-Ying Liu
- From Radiology and Imaging Sciences (C.-Y.L., J.Y., W.C.K., R.M.S.) and Rehabilitation Medicine Department (J.A.S., G.J.), Clinical Center, National Institute of Diabetes and Digestive and Kidney Diseases (R.O.), Neurogenetics Branch, National Institute of Neurological Disorders and Stroke (A.K.M.), and Medical Genetics Branch, National Human Genome Research Institute (W.A.G., N.C.), NIH, Bethesda, MD
| | - Jianhua Yao
- From Radiology and Imaging Sciences (C.-Y.L., J.Y., W.C.K., R.M.S.) and Rehabilitation Medicine Department (J.A.S., G.J.), Clinical Center, National Institute of Diabetes and Digestive and Kidney Diseases (R.O.), Neurogenetics Branch, National Institute of Neurological Disorders and Stroke (A.K.M.), and Medical Genetics Branch, National Human Genome Research Institute (W.A.G., N.C.), NIH, Bethesda, MD
| | - William C Kovacs
- From Radiology and Imaging Sciences (C.-Y.L., J.Y., W.C.K., R.M.S.) and Rehabilitation Medicine Department (J.A.S., G.J.), Clinical Center, National Institute of Diabetes and Digestive and Kidney Diseases (R.O.), Neurogenetics Branch, National Institute of Neurological Disorders and Stroke (A.K.M.), and Medical Genetics Branch, National Human Genome Research Institute (W.A.G., N.C.), NIH, Bethesda, MD
| | - Joseph A Shrader
- From Radiology and Imaging Sciences (C.-Y.L., J.Y., W.C.K., R.M.S.) and Rehabilitation Medicine Department (J.A.S., G.J.), Clinical Center, National Institute of Diabetes and Digestive and Kidney Diseases (R.O.), Neurogenetics Branch, National Institute of Neurological Disorders and Stroke (A.K.M.), and Medical Genetics Branch, National Human Genome Research Institute (W.A.G., N.C.), NIH, Bethesda, MD
| | - Galen Joe
- From Radiology and Imaging Sciences (C.-Y.L., J.Y., W.C.K., R.M.S.) and Rehabilitation Medicine Department (J.A.S., G.J.), Clinical Center, National Institute of Diabetes and Digestive and Kidney Diseases (R.O.), Neurogenetics Branch, National Institute of Neurological Disorders and Stroke (A.K.M.), and Medical Genetics Branch, National Human Genome Research Institute (W.A.G., N.C.), NIH, Bethesda, MD
| | - Ronald Ouwerkerk
- From Radiology and Imaging Sciences (C.-Y.L., J.Y., W.C.K., R.M.S.) and Rehabilitation Medicine Department (J.A.S., G.J.), Clinical Center, National Institute of Diabetes and Digestive and Kidney Diseases (R.O.), Neurogenetics Branch, National Institute of Neurological Disorders and Stroke (A.K.M.), and Medical Genetics Branch, National Human Genome Research Institute (W.A.G., N.C.), NIH, Bethesda, MD
| | - Ami K Mankodi
- From Radiology and Imaging Sciences (C.-Y.L., J.Y., W.C.K., R.M.S.) and Rehabilitation Medicine Department (J.A.S., G.J.), Clinical Center, National Institute of Diabetes and Digestive and Kidney Diseases (R.O.), Neurogenetics Branch, National Institute of Neurological Disorders and Stroke (A.K.M.), and Medical Genetics Branch, National Human Genome Research Institute (W.A.G., N.C.), NIH, Bethesda, MD
| | - William A Gahl
- From Radiology and Imaging Sciences (C.-Y.L., J.Y., W.C.K., R.M.S.) and Rehabilitation Medicine Department (J.A.S., G.J.), Clinical Center, National Institute of Diabetes and Digestive and Kidney Diseases (R.O.), Neurogenetics Branch, National Institute of Neurological Disorders and Stroke (A.K.M.), and Medical Genetics Branch, National Human Genome Research Institute (W.A.G., N.C.), NIH, Bethesda, MD
| | - Ronald M Summers
- From Radiology and Imaging Sciences (C.-Y.L., J.Y., W.C.K., R.M.S.) and Rehabilitation Medicine Department (J.A.S., G.J.), Clinical Center, National Institute of Diabetes and Digestive and Kidney Diseases (R.O.), Neurogenetics Branch, National Institute of Neurological Disorders and Stroke (A.K.M.), and Medical Genetics Branch, National Human Genome Research Institute (W.A.G., N.C.), NIH, Bethesda, MD
| | - Nuria Carrillo
- From Radiology and Imaging Sciences (C.-Y.L., J.Y., W.C.K., R.M.S.) and Rehabilitation Medicine Department (J.A.S., G.J.), Clinical Center, National Institute of Diabetes and Digestive and Kidney Diseases (R.O.), Neurogenetics Branch, National Institute of Neurological Disorders and Stroke (A.K.M.), and Medical Genetics Branch, National Human Genome Research Institute (W.A.G., N.C.), NIH, Bethesda, MD.
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Lee JH, Yoon YC, Kim HS, Kim JH, Choi BO. Texture analysis using T1-weighted images for muscles in Charcot-Marie-Tooth disease patients and volunteers. Eur Radiol 2020; 31:3508-3517. [PMID: 33125561 DOI: 10.1007/s00330-020-07435-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 09/08/2020] [Accepted: 10/15/2020] [Indexed: 01/30/2023]
Abstract
OBJECTIVES To explore whether texture features using T1-weighted images correlate with fat fraction, and whether they differ between Charcot-Marie-Tooth (CMT) disease patients and volunteers. METHODS The institutional review board approved this retrospective study, and the requirement for informed consent was waived; data of eighteen CMT patients and eighteen healthy volunteers from a previous study was used. Texture features of the muscles including mean, standard deviation (SD), skewness, kurtosis, and entropy of the signal intensity were derived from T1-weighted images. Spearman's correlation analysis was used to assess the relationship between texture features and fat fraction measured by 3D multiple gradient echo Dixon-based sequence. Mann-Whitney U test was used to compare the texture features between CMT patients and volunteers. Intraobserver and interobserver agreements for the texture features were assessed using the intraclass correlation coefficient. RESULTS The SD (ρ = 0.256, p < 0.001) and entropy (ρ = 0.263, p < 0.001) were significantly and positively correlated with fat fraction; skewness (ρ = - 0.110, p = 0.027) and kurtosis (ρ = - 0.149, p = 0.003) were significantly and inversely correlated with fat fraction. The CMT patients showed a significantly higher SD (63.45 vs. 49.26; p < 0.001), skewness (1.06 vs. 0.56; p < 0.001), kurtosis (4.00 vs. 1.81; p < 0.001), and entropy (3.20 vs. 3.02; p < 0.001) than did the volunteers. Intraobserver and interobserver agreements were almost perfect for mean, SD, and entropy. CONCLUSIONS Texture features using T1-weighted images correlated with fat fraction and differed between CMT patients and volunteers. KEY POINTS • Standard deviation and entropy of muscles derived from T1-weighted images were significantly and positively correlated with the muscle fat fraction. • Mean, standard deviation, and entropy were considered highly reliable in muscle analyses. • Texture features may have the potential to diagnose early stage of intramuscular fatty infiltration.
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Affiliation(s)
- Ji Hyun Lee
- Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Ilwon-Ro, Gangnam-gu, Seoul, 06351, South Korea
| | - Young Cheol Yoon
- Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Ilwon-Ro, Gangnam-gu, Seoul, 06351, South Korea.
| | - Hyun Su Kim
- Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Ilwon-Ro, Gangnam-gu, Seoul, 06351, South Korea
| | - Jae-Hun Kim
- Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Ilwon-Ro, Gangnam-gu, Seoul, 06351, South Korea
| | - Byung-Ok Choi
- Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Ilwon-Ro, Gangnam-gu, Seoul, 06351, South Korea
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31
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Liu Y, Wang J, Zhou X, Cao H, Zhang X, Huang K, Li X, Yang G, Shi X. miR-324-5p Inhibits C2C12 cell Differentiation and Promotes Intramuscular Lipid Deposition through lncDUM and PM20D1. MOLECULAR THERAPY-NUCLEIC ACIDS 2020; 22:722-732. [PMID: 33230469 PMCID: PMC7593507 DOI: 10.1016/j.omtn.2020.09.037] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/23/2020] [Accepted: 09/30/2020] [Indexed: 02/07/2023]
Abstract
Skeletal muscle is an important metabolic organ of the body, and impaired skeletal muscle differentiation can result in a wide range of metabolic diseases. It has been shown that microRNAs (miRNAs) play an important role in skeletal muscle differentiation. The aim of this study was to investigate the role of mmu-miR-324-5p in the differentiation of C2C12 myoblasts and lipid droplet deposition in myotubes for future targeted therapies. We found that mmu-miR-324-5p was highly expressed in mouse skeletal muscle. Overexpression of miR-324-5p significantly inhibited C2C12 myoblast differentiation while promoting oleate-induced lipid accumulation and β-oxidation in C2C12 myoblasts. Conversely, inhibition of mmu-miR-324-5p promoted C2C12 myoblast differentiation and inhibited lipid deposition in myotubes. Mechanistically, mmu-miR-324-5p negatively regulated the expression of long non-coding Dum (lncDum) and peptidase M20 domain containing 1 (Pm20d1) in C2C12 myoblasts. Reduced lncDum expression was associated with a significant decrease in the expression of myogenesis-related genes. Knockdown of mmu-miR-324-5p increased the levels of lncDum and myogenesis-related gene expression. Following oleate-induced lipid deposition in C2C12 myoblasts, overexpression of mmu-miR-324-5p decreased the expression of Pm20d1 while increasing the expression of mitochondrial β-oxidation and long-chain fatty acid synthesis-related genes. In conclusion, we provide evidence that miR-324-5p inhibits C2C12 myoblast differentiation and promotes intramuscular lipid deposition by targeting lncDum and Pm20d1, respectively.
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Affiliation(s)
- Yihao Liu
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, Laboratory of Animal Fat Deposition and Muscle Development, College of Animal Science and Technology, Northwest A&F University, Yangling 712100, Shaanxi, China
| | - Jie Wang
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, Laboratory of Animal Fat Deposition and Muscle Development, College of Animal Science and Technology, Northwest A&F University, Yangling 712100, Shaanxi, China
| | - Xiaomin Zhou
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, Laboratory of Animal Fat Deposition and Muscle Development, College of Animal Science and Technology, Northwest A&F University, Yangling 712100, Shaanxi, China
| | - Haigang Cao
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, Laboratory of Animal Fat Deposition and Muscle Development, College of Animal Science and Technology, Northwest A&F University, Yangling 712100, Shaanxi, China
| | - Xiaoyu Zhang
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, Laboratory of Animal Fat Deposition and Muscle Development, College of Animal Science and Technology, Northwest A&F University, Yangling 712100, Shaanxi, China
| | - Kuilong Huang
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, Laboratory of Animal Fat Deposition and Muscle Development, College of Animal Science and Technology, Northwest A&F University, Yangling 712100, Shaanxi, China
| | - Xiao Li
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, Laboratory of Animal Fat Deposition and Muscle Development, College of Animal Science and Technology, Northwest A&F University, Yangling 712100, Shaanxi, China
| | - Gongshe Yang
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, Laboratory of Animal Fat Deposition and Muscle Development, College of Animal Science and Technology, Northwest A&F University, Yangling 712100, Shaanxi, China
| | - Xin'e Shi
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, Laboratory of Animal Fat Deposition and Muscle Development, College of Animal Science and Technology, Northwest A&F University, Yangling 712100, Shaanxi, China
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Dahlqvist JR, Widholm P, Leinhard OD, Vissing J. MRI in Neuromuscular Diseases: An Emerging Diagnostic Tool and Biomarker for Prognosis and Efficacy. Ann Neurol 2020; 88:669-681. [PMID: 32495452 DOI: 10.1002/ana.25804] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2020] [Revised: 05/05/2020] [Accepted: 05/25/2020] [Indexed: 12/12/2022]
Abstract
There is an unmet need to identify biomarkers sensitive to change in rare, slowly progressive neuromuscular diseases. Quantitative magnetic resonance imaging (MRI) of muscle may offer this opportunity, as it is noninvasive and can be carried out almost independent of patient cooperation and disease severity. Muscle fat content correlates with muscle function in neuromuscular diseases, and changes in fat content precede changes in function, which suggests that muscle MRI is a strong biomarker candidate to predict prognosis and treatment efficacy. In this paper, we review the evidence suggesting that muscle MRI may be an important biomarker for diagnosis and to monitor change in disease severity. ANN NEUROL 2020;88:669-681.
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Affiliation(s)
- Julia R Dahlqvist
- Copenhagen Neuromuscular Center, Department of Neurology, Rigshospitalet, Copenhagen University, Copenhagen, Denmark
| | - Per Widholm
- Department of Medical and Health Sciences, Linköping University, Linköping, Sweden
- AMRA Medical AB, Linköping, Sweden
| | - Olof Dahlqvist Leinhard
- Department of Medical and Health Sciences, Linköping University, Linköping, Sweden
- AMRA Medical AB, Linköping, Sweden
| | - John Vissing
- Copenhagen Neuromuscular Center, Department of Neurology, Rigshospitalet, Copenhagen University, Copenhagen, Denmark
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33
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Senesac CR, Barnard AM, Lott DJ, Nair KS, Harrington AT, Willcocks RJ, Zilke KL, Rooney WD, Walter GA, Vandenborne K. Magnetic Resonance Imaging Studies in Duchenne Muscular Dystrophy: Linking Findings to the Physical Therapy Clinic. Phys Ther 2020; 100:2035-2048. [PMID: 32737968 PMCID: PMC7596892 DOI: 10.1093/ptj/pzaa140] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/30/2020] [Indexed: 12/31/2022]
Abstract
Duchenne muscular dystrophy (DMD) is a muscle degenerative disorder that manifests in early childhood and results in progressive muscle weakness. Physical therapists have long been an important component of the multidisciplinary team caring for people with DMD, providing expertise in areas of disease assessment, contracture management, assistive device prescription, and exercise prescription. Over the last decade, magnetic resonance imaging of muscles in people with DMD has led to an improved understanding of the muscle pathology underlying the clinical manifestations of DMD. Findings from magnetic resonance imaging (MRI) studies in DMD, paired with the clinical expertise of physical therapists, can help guide research that leads to improved physical therapist care for this unique patient population. The 2 main goals of this perspective article are to (1) summarize muscle pathology and disease progression findings from qualitative and quantitative muscle MRI studies in DMD and (2) link MRI findings of muscle pathology to the clinical manifestations observed by physical therapists with discussion of any potential implications of MRI findings on physical therapy management.
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Affiliation(s)
| | | | | | - Kavya S Nair
- Department of Physical Therapy, University of Florida
| | - Ann T Harrington
- Center for Rehabilitation, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania; and Department of Physical Therapy, Arcadia University, Glenside, Pennsylvania
| | | | - Kirsten L Zilke
- Oregon Health & Science University, Shriners Hospitals for Children, Portland, Oregon
| | - William D Rooney
- Advanced Imaging Research Center, Oregon Health & Science University
| | - Glenn A Walter
- Department of Physiology and Functional Genomics, University of Florida
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34
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Barnard AM, Willcocks RJ, Triplett WT, Forbes SC, Daniels MJ, Chakraborty S, Lott DJ, Senesac CR, Finanger EL, Harrington AT, Tennekoon G, Arora H, Wang DJ, Sweeney HL, Rooney WD, Walter GA, Vandenborne K. MR biomarkers predict clinical function in Duchenne muscular dystrophy. Neurology 2020; 94:e897-e909. [PMID: 32024675 PMCID: PMC7238941 DOI: 10.1212/wnl.0000000000009012] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Accepted: 08/29/2019] [Indexed: 12/17/2022] Open
Abstract
OBJECTIVE To investigate the potential of lower extremity magnetic resonance (MR) biomarkers to serve as endpoints in clinical trials of therapeutics for Duchenne muscular dystrophy (DMD) by characterizing the longitudinal progression of MR biomarkers over 48 months and assessing their relationship to changes in ambulatory clinical function. METHODS One hundred sixty participants with DMD were enrolled in this longitudinal, natural history study and underwent MR data acquisition of the lower extremity muscles to determine muscle fat fraction (FF) and MRI T2 biomarkers of disease progression. In addition, 4 tests of ambulatory function were performed. Participants returned for follow-up data collection at 12, 24, 36, and 48 months. RESULTS Longitudinal analysis of the MR biomarkers revealed that vastus lateralis FF, vastus lateralis MRI T2, and biceps femoris long head MRI T2 biomarkers were the fastest progressing biomarkers over time in this primarily ambulatory cohort. Biomarker values tended to demonstrate a nonlinear, sigmoidal trajectory over time. The lower extremity biomarkers predicted functional performance 12 and 24 months later, and the magnitude of change in an MR biomarker over time was related to the magnitude of change in function. Vastus lateralis FF, soleus FF, vastus lateralis MRI T2, and biceps femoris long head MRI T2 were the strongest predictors of future loss of function, including loss of ambulation. CONCLUSIONS This study supports the strong relationship between lower extremity MR biomarkers and measures of clinical function, as well as the ability of MR biomarkers, particularly those from proximal muscles, to predict future ambulatory function and important clinical milestones. CLINICALTRIALSGOV IDENTIFIER NCT01484678.
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Affiliation(s)
- Alison M Barnard
- From the Departments of Physical Therapy (A.M.B., R.J.W., W.T.T., S.C.F., D.J.L., C.R.S., H.A., K.V.), Statistics (M.J.D., S.C.), Pharmacology and Therapeutics (H.L.S.), and Physiology and Functional Genomics (G.A.W.), University of Florida, Gainesville; Departments of Pediatrics and Neurology (E.L.F., G.T., D.-J.W.) and Advanced Imaging Research Center (W.D.R.), Oregon Health & Science University, Portland; and Children's Hospital of Philadelphia (A.T.H.), PA
| | - Rebecca J Willcocks
- From the Departments of Physical Therapy (A.M.B., R.J.W., W.T.T., S.C.F., D.J.L., C.R.S., H.A., K.V.), Statistics (M.J.D., S.C.), Pharmacology and Therapeutics (H.L.S.), and Physiology and Functional Genomics (G.A.W.), University of Florida, Gainesville; Departments of Pediatrics and Neurology (E.L.F., G.T., D.-J.W.) and Advanced Imaging Research Center (W.D.R.), Oregon Health & Science University, Portland; and Children's Hospital of Philadelphia (A.T.H.), PA
| | - William T Triplett
- From the Departments of Physical Therapy (A.M.B., R.J.W., W.T.T., S.C.F., D.J.L., C.R.S., H.A., K.V.), Statistics (M.J.D., S.C.), Pharmacology and Therapeutics (H.L.S.), and Physiology and Functional Genomics (G.A.W.), University of Florida, Gainesville; Departments of Pediatrics and Neurology (E.L.F., G.T., D.-J.W.) and Advanced Imaging Research Center (W.D.R.), Oregon Health & Science University, Portland; and Children's Hospital of Philadelphia (A.T.H.), PA
| | - Sean C Forbes
- From the Departments of Physical Therapy (A.M.B., R.J.W., W.T.T., S.C.F., D.J.L., C.R.S., H.A., K.V.), Statistics (M.J.D., S.C.), Pharmacology and Therapeutics (H.L.S.), and Physiology and Functional Genomics (G.A.W.), University of Florida, Gainesville; Departments of Pediatrics and Neurology (E.L.F., G.T., D.-J.W.) and Advanced Imaging Research Center (W.D.R.), Oregon Health & Science University, Portland; and Children's Hospital of Philadelphia (A.T.H.), PA
| | - Michael J Daniels
- From the Departments of Physical Therapy (A.M.B., R.J.W., W.T.T., S.C.F., D.J.L., C.R.S., H.A., K.V.), Statistics (M.J.D., S.C.), Pharmacology and Therapeutics (H.L.S.), and Physiology and Functional Genomics (G.A.W.), University of Florida, Gainesville; Departments of Pediatrics and Neurology (E.L.F., G.T., D.-J.W.) and Advanced Imaging Research Center (W.D.R.), Oregon Health & Science University, Portland; and Children's Hospital of Philadelphia (A.T.H.), PA
| | - Saptarshi Chakraborty
- From the Departments of Physical Therapy (A.M.B., R.J.W., W.T.T., S.C.F., D.J.L., C.R.S., H.A., K.V.), Statistics (M.J.D., S.C.), Pharmacology and Therapeutics (H.L.S.), and Physiology and Functional Genomics (G.A.W.), University of Florida, Gainesville; Departments of Pediatrics and Neurology (E.L.F., G.T., D.-J.W.) and Advanced Imaging Research Center (W.D.R.), Oregon Health & Science University, Portland; and Children's Hospital of Philadelphia (A.T.H.), PA
| | - Donovan J Lott
- From the Departments of Physical Therapy (A.M.B., R.J.W., W.T.T., S.C.F., D.J.L., C.R.S., H.A., K.V.), Statistics (M.J.D., S.C.), Pharmacology and Therapeutics (H.L.S.), and Physiology and Functional Genomics (G.A.W.), University of Florida, Gainesville; Departments of Pediatrics and Neurology (E.L.F., G.T., D.-J.W.) and Advanced Imaging Research Center (W.D.R.), Oregon Health & Science University, Portland; and Children's Hospital of Philadelphia (A.T.H.), PA
| | - Claudia R Senesac
- From the Departments of Physical Therapy (A.M.B., R.J.W., W.T.T., S.C.F., D.J.L., C.R.S., H.A., K.V.), Statistics (M.J.D., S.C.), Pharmacology and Therapeutics (H.L.S.), and Physiology and Functional Genomics (G.A.W.), University of Florida, Gainesville; Departments of Pediatrics and Neurology (E.L.F., G.T., D.-J.W.) and Advanced Imaging Research Center (W.D.R.), Oregon Health & Science University, Portland; and Children's Hospital of Philadelphia (A.T.H.), PA
| | - Erika L Finanger
- From the Departments of Physical Therapy (A.M.B., R.J.W., W.T.T., S.C.F., D.J.L., C.R.S., H.A., K.V.), Statistics (M.J.D., S.C.), Pharmacology and Therapeutics (H.L.S.), and Physiology and Functional Genomics (G.A.W.), University of Florida, Gainesville; Departments of Pediatrics and Neurology (E.L.F., G.T., D.-J.W.) and Advanced Imaging Research Center (W.D.R.), Oregon Health & Science University, Portland; and Children's Hospital of Philadelphia (A.T.H.), PA
| | - Ann T Harrington
- From the Departments of Physical Therapy (A.M.B., R.J.W., W.T.T., S.C.F., D.J.L., C.R.S., H.A., K.V.), Statistics (M.J.D., S.C.), Pharmacology and Therapeutics (H.L.S.), and Physiology and Functional Genomics (G.A.W.), University of Florida, Gainesville; Departments of Pediatrics and Neurology (E.L.F., G.T., D.-J.W.) and Advanced Imaging Research Center (W.D.R.), Oregon Health & Science University, Portland; and Children's Hospital of Philadelphia (A.T.H.), PA
| | - Gihan Tennekoon
- From the Departments of Physical Therapy (A.M.B., R.J.W., W.T.T., S.C.F., D.J.L., C.R.S., H.A., K.V.), Statistics (M.J.D., S.C.), Pharmacology and Therapeutics (H.L.S.), and Physiology and Functional Genomics (G.A.W.), University of Florida, Gainesville; Departments of Pediatrics and Neurology (E.L.F., G.T., D.-J.W.) and Advanced Imaging Research Center (W.D.R.), Oregon Health & Science University, Portland; and Children's Hospital of Philadelphia (A.T.H.), PA
| | - Harneet Arora
- From the Departments of Physical Therapy (A.M.B., R.J.W., W.T.T., S.C.F., D.J.L., C.R.S., H.A., K.V.), Statistics (M.J.D., S.C.), Pharmacology and Therapeutics (H.L.S.), and Physiology and Functional Genomics (G.A.W.), University of Florida, Gainesville; Departments of Pediatrics and Neurology (E.L.F., G.T., D.-J.W.) and Advanced Imaging Research Center (W.D.R.), Oregon Health & Science University, Portland; and Children's Hospital of Philadelphia (A.T.H.), PA
| | - Dah-Jyuu Wang
- From the Departments of Physical Therapy (A.M.B., R.J.W., W.T.T., S.C.F., D.J.L., C.R.S., H.A., K.V.), Statistics (M.J.D., S.C.), Pharmacology and Therapeutics (H.L.S.), and Physiology and Functional Genomics (G.A.W.), University of Florida, Gainesville; Departments of Pediatrics and Neurology (E.L.F., G.T., D.-J.W.) and Advanced Imaging Research Center (W.D.R.), Oregon Health & Science University, Portland; and Children's Hospital of Philadelphia (A.T.H.), PA
| | - H Lee Sweeney
- From the Departments of Physical Therapy (A.M.B., R.J.W., W.T.T., S.C.F., D.J.L., C.R.S., H.A., K.V.), Statistics (M.J.D., S.C.), Pharmacology and Therapeutics (H.L.S.), and Physiology and Functional Genomics (G.A.W.), University of Florida, Gainesville; Departments of Pediatrics and Neurology (E.L.F., G.T., D.-J.W.) and Advanced Imaging Research Center (W.D.R.), Oregon Health & Science University, Portland; and Children's Hospital of Philadelphia (A.T.H.), PA
| | - William D Rooney
- From the Departments of Physical Therapy (A.M.B., R.J.W., W.T.T., S.C.F., D.J.L., C.R.S., H.A., K.V.), Statistics (M.J.D., S.C.), Pharmacology and Therapeutics (H.L.S.), and Physiology and Functional Genomics (G.A.W.), University of Florida, Gainesville; Departments of Pediatrics and Neurology (E.L.F., G.T., D.-J.W.) and Advanced Imaging Research Center (W.D.R.), Oregon Health & Science University, Portland; and Children's Hospital of Philadelphia (A.T.H.), PA
| | - Glenn A Walter
- From the Departments of Physical Therapy (A.M.B., R.J.W., W.T.T., S.C.F., D.J.L., C.R.S., H.A., K.V.), Statistics (M.J.D., S.C.), Pharmacology and Therapeutics (H.L.S.), and Physiology and Functional Genomics (G.A.W.), University of Florida, Gainesville; Departments of Pediatrics and Neurology (E.L.F., G.T., D.-J.W.) and Advanced Imaging Research Center (W.D.R.), Oregon Health & Science University, Portland; and Children's Hospital of Philadelphia (A.T.H.), PA
| | - Krista Vandenborne
- From the Departments of Physical Therapy (A.M.B., R.J.W., W.T.T., S.C.F., D.J.L., C.R.S., H.A., K.V.), Statistics (M.J.D., S.C.), Pharmacology and Therapeutics (H.L.S.), and Physiology and Functional Genomics (G.A.W.), University of Florida, Gainesville; Departments of Pediatrics and Neurology (E.L.F., G.T., D.-J.W.) and Advanced Imaging Research Center (W.D.R.), Oregon Health & Science University, Portland; and Children's Hospital of Philadelphia (A.T.H.), PA.
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Maggi L, Moscatelli M, Frangiamore R, Mazzi F, Verri M, De Luca A, Pasanisi MB, Baranello G, Tramacere I, Chiapparini L, Bruzzone MG, Mantegazza R, Aquino D. Quantitative Muscle MRI Protocol as Possible Biomarker in Becker Muscular Dystrophy. Clin Neuroradiol 2020; 31:257-266. [PMID: 31974637 DOI: 10.1007/s00062-019-00875-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Accepted: 12/30/2019] [Indexed: 12/16/2022]
Abstract
PURPOSE Aim of this study is to compare Quantitative Magnetic Resonance Imaging (qMRI) measures between Becker Muscular Dystrophy (BMD) and Healthy Subjects (HS) and to correlate these parameters with clinical scores. METHODS Ten BMD patients (mean age ±standard deviation: 38.7 ± 15.0 years) and ten age-matched HS, were investigated through magnetic resonance imaging (MRI) at thigh and calf levels, including: 1) a standard axial T1-weighted sequence; 2) a volumetric T2-weighted sequence; 3) a multiecho spin-echo sequence; 4) a 2-point Dixon sequence; 5) a Diffusion Tensor Imaging (DTI) sequence. RESULTS Mean Fat Fraction (FF), T2-relaxation time and Fractional Anisotropy (FA) DTI at thigh and calf levels were significantly higher in BMD patients than in HS (p-values < 0.01). FF at thigh and calf levels significantly correlated with North Star Ambulatory Assessment (NSAA) score (p-values < 0.01) and6 Minutes Walking Test (6MWT) (p-values < 0.01), whereas only calf muscle FF was significantly associated with time to get up from floor (p-value = 0.01). T2 significantly correlated with NSAA score (p-value < 0.01), 6MWT (p-value = 0.02) and time to get up from floor (p-value < 0.01) only at calf level. Among DTI values, only FA in thigh and calf muscles significantly correlated with NSAA score, 6MWT and 10-m walk (all p-values < 0.05); only FA in calf muscles significantly correlated with time to get up from floor (p = 0.01). CONCLUSIONS Muscle FF, T2-relaxometry and DTI, seem to be a promising biomarker to assess BMD disease severity, although further studies are needed to evaluate changes over the time.
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Affiliation(s)
- Lorenzo Maggi
- Neuroimmunology and Neuromuscular Diseases Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy. .,Neurology IV-Neuroimmunology and Neuromuscular Diseases Unit, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Via Celoria 11, 20133, Milan, Italy.
| | - Marco Moscatelli
- Neuroradiology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - Rita Frangiamore
- Neuroimmunology and Neuromuscular Diseases Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - Federica Mazzi
- Neuroradiology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - Mattia Verri
- Neuroradiology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - Alberto De Luca
- Image Sciences Institute, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Maria Barbara Pasanisi
- Neuroimmunology and Neuromuscular Diseases Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - Giovanni Baranello
- Developmental Neurology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - Irene Tramacere
- Department of Research and Clinical Development, Scientific Directorate, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - Luisa Chiapparini
- Neuroradiology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - Maria Grazia Bruzzone
- Neuroradiology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - Renato Mantegazza
- Neuroimmunology and Neuromuscular Diseases Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - Domenico Aquino
- Neuroradiology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
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Naarding KJ, Reyngoudt H, van Zwet EW, Hooijmans MT, Tian C, Rybalsky I, Shellenbarger KC, Le Louër J, Wong BL, Carlier PG, Kan HE, Niks EH. MRI vastus lateralis fat fraction predicts loss of ambulation in Duchenne muscular dystrophy. Neurology 2020; 94:e1386-e1394. [PMID: 31937624 PMCID: PMC7274919 DOI: 10.1212/wnl.0000000000008939] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Accepted: 10/08/2019] [Indexed: 02/04/2023] Open
Abstract
Objective We studied the potential of quantitative MRI (qMRI) as a surrogate endpoint in Duchenne muscular dystrophy by assessing the additive predictive value of vastus lateralis (VL) fat fraction (FF) to age on loss of ambulation (LoA). Methods VL FFs were determined on longitudinal Dixon MRI scans from 2 natural history studies in Leiden University Medical Center (LUMC) and Cincinnati Children's Hospital Medical Center (CCHMC). CCHMC included ambulant patients, while LUMC included a mixed ambulant and nonambulant population. We fitted longitudinal VL FF values to a sigmoidal curve using a mixed model with random slope to predict individual trajectories. The additive value of VL FF over age to predict LoA was calculated from a Cox model, yielding a hazard ratio. Results Eighty-nine MRIs of 19 LUMC and 15 CCHMC patients were included. At similar age, 6-minute walking test distances were smaller and VL FFs were correspondingly higher in LUMC compared to CCHMC patients. Hazard ratio of a percent-point increase in VL FF for the time to LoA was 1.15 for LUMC (95% confidence interval [CI] 1.05–1.26; p = 0.003) and 0.96 for CCHMC (95% CI 0.84–1.10; p = 0.569). Conclusions The hazard ratio of 1.15 corresponds to a 4.11-fold increase of the instantaneous risk of LoA in patients with a 10% higher VL FF at any age. Although results should be confirmed in a larger cohort with prospective determination of the clinical endpoint, this added predictive value of VL FF to age on LoA supports the use of qMRI FF as an endpoint or stratification tool in clinical trials.
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Affiliation(s)
- Karin J Naarding
- From the Department of Neurology (K.J.N., E.H.N.), Department of Biostatistics (E.W.v.Z), and C.J. Gorter Center for High Field MRI (M.T.H., H.E.K.), Department of Radiology, Leiden University Medical Center, Zuid-Holland; Duchenne Center Netherlands (K.J.N., H.E.K., E.H.N.); AIM and CEA NMR Laboratory (H.R., J.L.L., P.G.C.), Neuromuscular Investigation Center, Institute of Myology, Paris, France; and Department of Neurology (C.T., I.R., K.C.S., B.L.W.), Cincinnati Children's Hospital Medical Center, OH.
| | - Harmen Reyngoudt
- From the Department of Neurology (K.J.N., E.H.N.), Department of Biostatistics (E.W.v.Z), and C.J. Gorter Center for High Field MRI (M.T.H., H.E.K.), Department of Radiology, Leiden University Medical Center, Zuid-Holland; Duchenne Center Netherlands (K.J.N., H.E.K., E.H.N.); AIM and CEA NMR Laboratory (H.R., J.L.L., P.G.C.), Neuromuscular Investigation Center, Institute of Myology, Paris, France; and Department of Neurology (C.T., I.R., K.C.S., B.L.W.), Cincinnati Children's Hospital Medical Center, OH
| | - Erik W van Zwet
- From the Department of Neurology (K.J.N., E.H.N.), Department of Biostatistics (E.W.v.Z), and C.J. Gorter Center for High Field MRI (M.T.H., H.E.K.), Department of Radiology, Leiden University Medical Center, Zuid-Holland; Duchenne Center Netherlands (K.J.N., H.E.K., E.H.N.); AIM and CEA NMR Laboratory (H.R., J.L.L., P.G.C.), Neuromuscular Investigation Center, Institute of Myology, Paris, France; and Department of Neurology (C.T., I.R., K.C.S., B.L.W.), Cincinnati Children's Hospital Medical Center, OH
| | - Melissa T Hooijmans
- From the Department of Neurology (K.J.N., E.H.N.), Department of Biostatistics (E.W.v.Z), and C.J. Gorter Center for High Field MRI (M.T.H., H.E.K.), Department of Radiology, Leiden University Medical Center, Zuid-Holland; Duchenne Center Netherlands (K.J.N., H.E.K., E.H.N.); AIM and CEA NMR Laboratory (H.R., J.L.L., P.G.C.), Neuromuscular Investigation Center, Institute of Myology, Paris, France; and Department of Neurology (C.T., I.R., K.C.S., B.L.W.), Cincinnati Children's Hospital Medical Center, OH
| | - Cuixia Tian
- From the Department of Neurology (K.J.N., E.H.N.), Department of Biostatistics (E.W.v.Z), and C.J. Gorter Center for High Field MRI (M.T.H., H.E.K.), Department of Radiology, Leiden University Medical Center, Zuid-Holland; Duchenne Center Netherlands (K.J.N., H.E.K., E.H.N.); AIM and CEA NMR Laboratory (H.R., J.L.L., P.G.C.), Neuromuscular Investigation Center, Institute of Myology, Paris, France; and Department of Neurology (C.T., I.R., K.C.S., B.L.W.), Cincinnati Children's Hospital Medical Center, OH
| | - Irina Rybalsky
- From the Department of Neurology (K.J.N., E.H.N.), Department of Biostatistics (E.W.v.Z), and C.J. Gorter Center for High Field MRI (M.T.H., H.E.K.), Department of Radiology, Leiden University Medical Center, Zuid-Holland; Duchenne Center Netherlands (K.J.N., H.E.K., E.H.N.); AIM and CEA NMR Laboratory (H.R., J.L.L., P.G.C.), Neuromuscular Investigation Center, Institute of Myology, Paris, France; and Department of Neurology (C.T., I.R., K.C.S., B.L.W.), Cincinnati Children's Hospital Medical Center, OH
| | - Karen C Shellenbarger
- From the Department of Neurology (K.J.N., E.H.N.), Department of Biostatistics (E.W.v.Z), and C.J. Gorter Center for High Field MRI (M.T.H., H.E.K.), Department of Radiology, Leiden University Medical Center, Zuid-Holland; Duchenne Center Netherlands (K.J.N., H.E.K., E.H.N.); AIM and CEA NMR Laboratory (H.R., J.L.L., P.G.C.), Neuromuscular Investigation Center, Institute of Myology, Paris, France; and Department of Neurology (C.T., I.R., K.C.S., B.L.W.), Cincinnati Children's Hospital Medical Center, OH
| | - Julien Le Louër
- From the Department of Neurology (K.J.N., E.H.N.), Department of Biostatistics (E.W.v.Z), and C.J. Gorter Center for High Field MRI (M.T.H., H.E.K.), Department of Radiology, Leiden University Medical Center, Zuid-Holland; Duchenne Center Netherlands (K.J.N., H.E.K., E.H.N.); AIM and CEA NMR Laboratory (H.R., J.L.L., P.G.C.), Neuromuscular Investigation Center, Institute of Myology, Paris, France; and Department of Neurology (C.T., I.R., K.C.S., B.L.W.), Cincinnati Children's Hospital Medical Center, OH
| | - Brenda L Wong
- From the Department of Neurology (K.J.N., E.H.N.), Department of Biostatistics (E.W.v.Z), and C.J. Gorter Center for High Field MRI (M.T.H., H.E.K.), Department of Radiology, Leiden University Medical Center, Zuid-Holland; Duchenne Center Netherlands (K.J.N., H.E.K., E.H.N.); AIM and CEA NMR Laboratory (H.R., J.L.L., P.G.C.), Neuromuscular Investigation Center, Institute of Myology, Paris, France; and Department of Neurology (C.T., I.R., K.C.S., B.L.W.), Cincinnati Children's Hospital Medical Center, OH
| | - Pierre G Carlier
- From the Department of Neurology (K.J.N., E.H.N.), Department of Biostatistics (E.W.v.Z), and C.J. Gorter Center for High Field MRI (M.T.H., H.E.K.), Department of Radiology, Leiden University Medical Center, Zuid-Holland; Duchenne Center Netherlands (K.J.N., H.E.K., E.H.N.); AIM and CEA NMR Laboratory (H.R., J.L.L., P.G.C.), Neuromuscular Investigation Center, Institute of Myology, Paris, France; and Department of Neurology (C.T., I.R., K.C.S., B.L.W.), Cincinnati Children's Hospital Medical Center, OH
| | - Hermien E Kan
- From the Department of Neurology (K.J.N., E.H.N.), Department of Biostatistics (E.W.v.Z), and C.J. Gorter Center for High Field MRI (M.T.H., H.E.K.), Department of Radiology, Leiden University Medical Center, Zuid-Holland; Duchenne Center Netherlands (K.J.N., H.E.K., E.H.N.); AIM and CEA NMR Laboratory (H.R., J.L.L., P.G.C.), Neuromuscular Investigation Center, Institute of Myology, Paris, France; and Department of Neurology (C.T., I.R., K.C.S., B.L.W.), Cincinnati Children's Hospital Medical Center, OH
| | - Erik H Niks
- From the Department of Neurology (K.J.N., E.H.N.), Department of Biostatistics (E.W.v.Z), and C.J. Gorter Center for High Field MRI (M.T.H., H.E.K.), Department of Radiology, Leiden University Medical Center, Zuid-Holland; Duchenne Center Netherlands (K.J.N., H.E.K., E.H.N.); AIM and CEA NMR Laboratory (H.R., J.L.L., P.G.C.), Neuromuscular Investigation Center, Institute of Myology, Paris, France; and Department of Neurology (C.T., I.R., K.C.S., B.L.W.), Cincinnati Children's Hospital Medical Center, OH
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Strijkers GJ, Araujo EC, Azzabou N, Bendahan D, Blamire A, Burakiewicz J, Carlier PG, Damon B, Deligianni X, Froeling M, Heerschap A, Hollingsworth KG, Hooijmans MT, Karampinos DC, Loudos G, Madelin G, Marty B, Nagel AM, Nederveen AJ, Nelissen JL, Santini F, Scheidegger O, Schick F, Sinclair C, Sinkus R, de Sousa PL, Straub V, Walter G, Kan HE. Exploration of New Contrasts, Targets, and MR Imaging and Spectroscopy Techniques for Neuromuscular Disease - A Workshop Report of Working Group 3 of the Biomedicine and Molecular Biosciences COST Action BM1304 MYO-MRI. J Neuromuscul Dis 2020; 6:1-30. [PMID: 30714967 PMCID: PMC6398566 DOI: 10.3233/jnd-180333] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Neuromuscular diseases are characterized by progressive muscle degeneration and muscle weakness resulting in functional disabilities. While each of these diseases is individually rare, they are common as a group, and a large majority lacks effective treatment with fully market approved drugs. Magnetic resonance imaging and spectroscopy techniques (MRI and MRS) are showing increasing promise as an outcome measure in clinical trials for these diseases. In 2013, the European Union funded the COST (co-operation in science and technology) action BM1304 called MYO-MRI (www.myo-mri.eu), with the overall aim to advance novel MRI and MRS techniques for both diagnosis and quantitative monitoring of neuromuscular diseases through sharing of expertise and data, joint development of protocols, opportunities for young researchers and creation of an online atlas of muscle MRI and MRS. In this report, the topics that were discussed in the framework of working group 3, which had the objective to: Explore new contrasts, new targets and new imaging techniques for NMD are described. The report is written by the scientists who attended the meetings and presented their data. An overview is given on the different contrasts that MRI can generate and their application, clinical needs and desired readouts, and emerging methods.
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Affiliation(s)
| | - Ericky C.A. Araujo
- NMR Laboratory, Neuromuscular Investigation Center, Institute of Myology & NMR Laboratory, CEA/DRF/IBFJ/MIRCen, Paris, France
| | - Noura Azzabou
- NMR Laboratory, Neuromuscular Investigation Center, Institute of Myology & NMR Laboratory, CEA/DRF/IBFJ/MIRCen, Paris, France
| | | | - Andrew Blamire
- Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne, UK
| | - Jedrek Burakiewicz
- Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands
| | - Pierre G. Carlier
- NMR Laboratory, Neuromuscular Investigation Center, Institute of Myology & NMR Laboratory, CEA/DRF/IBFJ/MIRCen, Paris, France
| | - Bruce Damon
- Vanderbilt University Medical Center, Nashville, USA
| | - Xeni Deligianni
- Department of Radiology, Division of Radiological Physics, University Hospital Basel, Basel, Switzerland & Department of Biomedical Engineering, University of Basel, Basel, Switzerland
| | | | - Arend Heerschap
- Radboud University Medical Center, Nijmegen, the Netherlands
| | | | | | | | | | | | - Benjamin Marty
- NMR Laboratory, Neuromuscular Investigation Center, Institute of Myology & NMR Laboratory, CEA/DRF/IBFJ/MIRCen, Paris, France
| | - Armin M. Nagel
- Institute of Radiology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany & Division of Medical Physics in Radiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | | | | | - Francesco Santini
- Department of Radiology, Division of Radiological Physics, University Hospital Basel, Basel, Switzerland & Department of Biomedical Engineering, University of Basel, Basel, Switzerland
| | - Olivier Scheidegger
- Department of Neurology, Inselspital, Bern University Hospital, University of Bern, Switzerland
| | - Fritz Schick
- University of Tübingen, Section on Experimental Radiology, Tübingen, Germany
| | | | | | | | - Volker Straub
- Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne, UK
| | | | - Hermien E. Kan
- Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands
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Chrzanowski SM, Darras BT, Rutkove SB. The Value of Imaging and Composition-Based Biomarkers in Duchenne Muscular Dystrophy Clinical Trials. Neurotherapeutics 2020; 17:142-152. [PMID: 31879850 PMCID: PMC7007477 DOI: 10.1007/s13311-019-00825-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
As the drug development pipeline for Duchenne muscular dystrophy (DMD) rapidly advances, clinical trial outcomes need to be optimized. Effective assessment of disease burden, natural history progression, and response to therapy in clinical trials for Duchenne muscular dystrophy are critical factors for clinical trial success. By choosing optimal biomarkers to better assess therapeutic efficacy, study costs and sample size requirements can be reduced. Currently, functional measures continue to serve as the primary outcome for the majority of DMD clinical trials. Quantitative measures of muscle health, including magnetic resonance imaging and spectroscopy, electrical impedance myography, and ultrasound, sensitively identify diseased muscle, disease progression, and response to a therapeutic intervention. Furthermore, such non-invasive techniques have the potential to identify disease pathology prior to onset of clinical symptoms. Despite robust supportive evidence, non-invasive quantitative techniques are still not frequently utilized in clinical trials for Duchenne muscular dystrophy. Non-invasive quantitative techniques have demonstrated the ability to quantify disease progression and potential response to therapeutic intervention, and should be used as a supplement to current standard functional measures. Such methods have the potential to significantly accelerate the development and approval of therapies for DMD.
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Affiliation(s)
- Stephen M Chrzanowski
- Department of Medicine, Boston Children's Hospital, 300 Longwood Ave., Boston, MA, 02115, USA.
| | - Basil T Darras
- Department of Neurology, Boston Children's Hospital, Boston, MA, USA
| | - Seward B Rutkove
- Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA, USA
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Eresen A, Hafsa NE, Alic L, Birch SM, Griffin JF, Kornegay JN, Ji JX. Muscle percentage index as a marker of disease severity in golden retriever muscular dystrophy. Muscle Nerve 2019; 60:621-628. [PMID: 31397906 DOI: 10.1002/mus.26657] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Revised: 08/05/2019] [Accepted: 08/06/2019] [Indexed: 12/28/2022]
Abstract
INTRODUCTION Golden retriever muscular dystrophy (GRMD) is a spontaneous X-linked canine model of Duchenne muscular dystrophy that resembles the human condition. Muscle percentage index (MPI) is proposed as an imaging biomarker of disease severity in GRMD. METHODS To assess MPI, we used MRI data acquired from nine GRMD samples using a 4.7 T small-bore scanner. A machine learning approach was used with eight raw quantitative mapping of MRI data images (T1m, T2m, two Dixon maps, and four diffusion tensor imaging maps), three types of texture descriptors (local binary pattern, gray-level co-occurrence matrix, gray-level run-length matrix), and a gradient descriptor (histogram of oriented gradients). RESULTS The confusion matrix, averaged over all samples, showed 93.5% of muscle pixels classified correctly. The classification, optimized in a leave-one-out cross-validation, provided an average accuracy of 80% with a discrepancy in overestimation for young (8%) and old (20%) dogs. DISCUSSION MPI could be useful for quantifying GRMD severity, but careful interpretation is needed for severe cases.
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Affiliation(s)
- Aydin Eresen
- Department of Electrical and Computer Engineering, Texas A&M University, College Station, Texas
| | - Noor E Hafsa
- Department of Electrical and Computer Engineering, Texas A&M University, Doha, Qatar
| | - Lejla Alic
- Department of Electrical and Computer Engineering, Texas A&M University, Doha, Qatar.,Magnetic Detection & Imaging Group, Faculty of Science & Technology, University of Twente, Enschede, The Netherlands
| | - Sharla M Birch
- College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas
| | - John F Griffin
- College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas
| | - Joe N Kornegay
- College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas
| | - Jim X Ji
- Department of Electrical and Computer Engineering, Texas A&M University, College Station, Texas.,Department of Electrical and Computer Engineering, Texas A&M University, Doha, Qatar
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Pennati F, Arrigoni F, LoMauro A, Gandossini S, Russo A, D'Angelo MG, Aliverti A. Diaphragm Involvement in Duchenne Muscular Dystrophy (DMD): An MRI Study. J Magn Reson Imaging 2019; 51:461-471. [PMID: 31301202 DOI: 10.1002/jmri.26864] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Revised: 06/26/2019] [Accepted: 06/27/2019] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Duchenne muscular dystrophy (DMD) is characterized by progressive weakness and wasting of skeletal, cardiac, and respiratory muscles, with consequent cardiopulmonary failure as the main cause of death. Reliable outcome measures able to demonstrate specific trends over disease progression are essential. PURPOSE To investigate MRI as a noninvasive imaging modality to assess diaphragm impairment in DMD. In particular, we sought to correlate MRI measurement of diaphragm structure and function with pulmonary function tests and with the abdominal volumes (VAB ) measured by optoelectronic plethysmography, being an index of the action of the diaphragm. STUDY TYPE Cross-sectional study. POPULATION Twenty-six DMD patients (17.9 ± 6.2 years) and 12 age-matched controls (17.8 ± 5.9 years). FIELD STRENGTH/SEQUENCE 3-Point gradient echo Dixon sequence at 3T. ASSESSMENT Images were acquired in breath-hold at full-expiration (EXP) and full-inspiration (INSP). INSP and EXP lung volumes were segmented and the diaphragm surface was reconstructed as the bottom surface of the left and the right lung. The inspiratory and the expiratory diaphragm surfaces were aligned by a nonrigid iterative closest point algorithm. On MRI we measured: 1) craniocaudal diaphragmatic excursion; 2) diaphragm fatty infiltration. STATISTICAL TESTS Three-parameter sigmoid regression, one-way analysis of variance (ANOVA), Spearman's correlation. RESULTS In patients, diaphragm excursion decreased with age (r2 = 0.68, P < 0.0001) and fat fraction increased (r2 = 0.51, P = 0.0002). In healthy subjects, diaphragm excursion and fat fraction had no relationship with age. Diaphragm excursion decreased with decreasing FEV1 %pred (r = 0.78, P < 0.0001) and FVC %pred (r = 0.76, P < 0.0001) and correlated with VAB (r = 0.60, P = 0.0002). Fatty infiltration increased with decreasing FEV1 %pred (r = -0.88, P < 0.0001) and FVC %pred (r = -0.88, P < 0.0001). DATA CONCLUSION The progressive structural and functional diaphragm impairment is highly related to pulmonary function tests and to VAB . The results suggest that MRI might represent a new and noninvasive tool for the functional and structural assessment of the diaphragm. LEVEL OF EVIDENCE 2 Technical Efficacy: Stage 5 J. Magn. Reson. Imaging 2020;51:461-471.
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Affiliation(s)
- Francesca Pennati
- The Dipartimento di Elettronica, Informazione e Bioingegneria, Politecnico di Milano, Italy.,Scientific Institute, IRCCS E. Medea, Bosisio Parini, Italy
| | | | - Antonella LoMauro
- The Dipartimento di Elettronica, Informazione e Bioingegneria, Politecnico di Milano, Italy
| | | | | | | | - Andrea Aliverti
- The Dipartimento di Elettronica, Informazione e Bioingegneria, Politecnico di Milano, Italy
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Farrow M, Grainger AJ, Tan AL, Buch MH, Emery P, Ridgway JP, Feiweier T, Tanner SF, Biglands J. Normal values and test-retest variability of stimulated-echo diffusion tensor imaging and fat fraction measurements in the muscle. Br J Radiol 2019; 92:20190143. [PMID: 31298948 DOI: 10.1259/bjr.20190143] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
OBJECTIVES To assess the test-retest variability of both diffusion parameters and fat fraction (FF) estimates in normal muscle, and to assess differences in normal values between muscles in the thigh. METHODS 29 healthy volunteers (mean age 37 years, range 20-60 years, 17/29 males) completed the study. Magnetic resonance images of the mid-thigh were acquired using a stimulated echo acquisition mode-echoplanar imaging (STEAM-EPI) imaging sequence, to assess diffusion, and 2-point Dixon imaging, to assess FF. Imaging was repeated in 19 participants after a 30 min interval in order to assess test-retest variability of the measurements. RESULTS Intraclass correlation coefficients (ICCs) for test-retest variability were 0.99 [95% confidence interval, (CI): 0.98, 1] for FF, 0.94 (95% CI: 0.84, 0.97) for mean diffusivity and 0.89 (95% CI: 0.74, 0.96) for fractional anisotropy (FA). FF was higher in the hamstrings than the quadriceps by a mean difference of 1.81% (95% CI:1.63, 2.00)%, p < 0.001. Mean diffusivity was significantly lower in the hamstrings than the quadriceps (0.26 (0.13, 0.39) x10-3 mm2s-1, p < 0.001) whereas fractional anisotropy was significantly higher in the hamstrings relative to the quadriceps with a mean difference of 0.063 (0.05, 0.07), p < 0.001. CONCLUSIONS This study has shown excellent test-retest, variability in MR-based FF and diffusion measurements and demonstrated significant differences in these measures between hamstrings and quadriceps in the healthy thigh. ADVANCES IN KNOWLEDGE Test-retest variability is excellent for STEAM-EPI diffusion and 2-point Dixon-based FF measurements in the healthy muscle. Inter- and intraobserver variability were excellent for region of interest placement for STEAM-EPI diffusion and 2-point Dixon-based FF measurements in the healthy muscle. There are significant differences in FF and diffusion measurements between the hamstrings and quadriceps in the normal muscle.
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Affiliation(s)
- Matthew Farrow
- 1Leeds institute of Rheumatic and Musculoskeletal Medicine, Chapel Allerton Hospital, University of Leeds, United Kingdom.,2NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom
| | - Andrew J Grainger
- 1Leeds institute of Rheumatic and Musculoskeletal Medicine, Chapel Allerton Hospital, University of Leeds, United Kingdom.,2NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom
| | - Ai Lyn Tan
- 1Leeds institute of Rheumatic and Musculoskeletal Medicine, Chapel Allerton Hospital, University of Leeds, United Kingdom.,2NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom
| | - Maya H Buch
- 1Leeds institute of Rheumatic and Musculoskeletal Medicine, Chapel Allerton Hospital, University of Leeds, United Kingdom.,2NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom
| | - Paul Emery
- 1Leeds institute of Rheumatic and Musculoskeletal Medicine, Chapel Allerton Hospital, University of Leeds, United Kingdom.,2NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom
| | - John P Ridgway
- 2NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom.,3Medical Physics and Engineering, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom
| | | | - Steven F Tanner
- 2NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom.,3Medical Physics and Engineering, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom
| | - John Biglands
- 2NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom.,3Medical Physics and Engineering, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom
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42
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Marinkovic M, Fuoco C, Sacco F, Cerquone Perpetuini A, Giuliani G, Micarelli E, Pavlidou T, Petrilli LL, Reggio A, Riccio F, Spada F, Vumbaca S, Zuccotti A, Castagnoli L, Mann M, Gargioli C, Cesareni G. Fibro-adipogenic progenitors of dystrophic mice are insensitive to NOTCH regulation of adipogenesis. Life Sci Alliance 2019; 2:e201900437. [PMID: 31239312 PMCID: PMC6599969 DOI: 10.26508/lsa.201900437] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2019] [Accepted: 06/07/2019] [Indexed: 12/14/2022] Open
Abstract
Fibro-adipogenic progenitors (FAPs) promote satellite cell differentiation in adult skeletal muscle regeneration. However, in pathological conditions, FAPs are responsible for fibrosis and fatty infiltrations. Here we show that the NOTCH pathway negatively modulates FAP differentiation both in vitro and in vivo. However, FAPs isolated from young dystrophin-deficient mdx mice are insensitive to this control mechanism. An unbiased mass spectrometry-based proteomic analysis of FAPs from muscles of wild-type and mdx mice suggested that the synergistic cooperation between NOTCH and inflammatory signals controls FAP differentiation. Remarkably, we demonstrated that factors released by hematopoietic cells restore the sensitivity to NOTCH adipogenic inhibition in mdx FAPs. These results offer a basis for rationalizing pathological ectopic fat infiltrations in skeletal muscle and may suggest new therapeutic strategies to mitigate the detrimental effects of fat depositions in muscles of dystrophic patients.
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Affiliation(s)
| | - Claudia Fuoco
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
| | - Francesca Sacco
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
- Department of Proteomics and Signal Transduction, Max-Planck Institute of Biochemistry, Martinsried, Germany
| | | | - Giulio Giuliani
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
| | - Elisa Micarelli
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
| | | | | | - Alessio Reggio
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
| | - Federica Riccio
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
| | - Filomena Spada
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
| | - Simone Vumbaca
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
| | | | - Luisa Castagnoli
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
| | - Matthias Mann
- Department of Proteomics and Signal Transduction, Max-Planck Institute of Biochemistry, Martinsried, Germany
| | - Cesare Gargioli
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
| | - Gianni Cesareni
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
- Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione Santa Lucia, Rome, Italy
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43
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Effectiveness of High-Speed T2-Corrected Multiecho MR Spectroscopic Method for Quantifying Thigh Muscle Fat Content in Boys With Duchenne Muscular Dystrophy. AJR Am J Roentgenol 2019; 212:1354-1360. [PMID: 30860898 DOI: 10.2214/ajr.18.20354] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
OBJECTIVE. The purpose of this study was to investigate the potential of high-speed T2-corrected multiecho (HISTO) MR spectroscopy (MRS) for rapidly quantifying the fat content of thigh muscles in children with Duchenne muscular dystrophy (DMD). SUBJECTS AND METHODS. This study prospectively enrolled 58 boys with DMD (mean age, 7.5 years; range, 4-11 years) and 30 age-matched healthy boys (mean age, 7.2 years; range, 4-11 years) at one institution over a 1-year period. T1- and T2-weighted, multiecho Dixon, and HISTO sequences were performed on the right adductor magnus and vastus lateralis muscles. The fat fractions of these muscles were acquired from HISTO and multiecho Dixon images. An experienced radiologist graded the degree of fat infiltration of the adductor magnus and vastus lateralis muscles on axial T1-weighted images. The Bland-Altman method was used to assess the consistency and repeatability of the HISTO sequence. Pearson linear correlation analysis was used to determine the correlation coefficient relating HISTO fat fraction to multiecho Dixon fat fraction values. Spearman rank correlation analysis was used to assess the relation between the HISTO fat fraction values and T1-weighted image fat infiltration grades. The independent t test was used to compare the HISTO fat fraction values of the boys with DMD with those of the healthy control subjects. RESULTS. Bland-Altman analysis showed that 95.5% of the HISTO fat fraction values of the adductor magnus were within the 95% CI. HISTO fat fraction and multiecho Dixon fat fraction values of the adductor magnus and vastus lateralis muscles were highly positively correlated (adductor magnus, r = 0.983; vastus lateralis, r = 0.967; p < 0.0001). HISTO fat fraction values were also highly positively correlated with the grades of fat infiltration on T1-weighted images (adductor magnus, r = 0.911; vastus lateralis, r = 0.937; p < 0.0001). The HISTO fat fraction of the adductor magnus muscle was 33.3% ± 22.6% and of the vastus lateralis muscle was 25.6% ± 20.3% in patients with DMD. The corresponding values were 2.9% ± 2.1% and 2.3% ± 1.9% in the control group. The differences were statistically significant (p < 0.0001). CONCLUSION. The HISTO sequence is a rapid and feasible noninvasive MRS technique for quantifying the fat infiltration of thigh muscles in children with known or suspected DMD. It is useful for diagnosis and for assessment of disease activity and prognosis.
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44
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Weng WC, Lin CW, Shen HC, Chang CC, Tsui PH. Instantaneous frequency as a new approach for evaluating the clinical severity of Duchenne muscular dystrophy through ultrasound imaging. ULTRASONICS 2019; 94:235-241. [PMID: 30287072 DOI: 10.1016/j.ultras.2018.09.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Revised: 08/24/2018] [Accepted: 09/09/2018] [Indexed: 06/08/2023]
Abstract
Duchenne muscular dystrophy (DMD) results in loss of ambulation for the patients. Ultrasound attenuation correlates with fat content in muscles, resulting in changes in signal frequency. The Hilbert-Huang transform (HHT) allows time-frequency analysis with high time-frequency resolution. This study explored the feasibility of using the instantaneous frequency (IF) obtained from the HHT to diagnose the walking function of patients with DMD. Eighty-five participants (12 control and 73 patients with DMD) underwent a standard-care ultrasound examination of the gastrocnemius to acquire raw image data for ultrasound B-mode and IF calculations, which were compared with the DMD stage using Pearson correlation and receiver operating characteristic (ROC) curve analyses. With increasing DMD stage, the median IF decreased from 7.25 to 7.01 MHz (the correlation coefficient r = -0.73; the probability value p < 0.0001). The area under the ROC curve was 0.97 when using ultrasound IF to discriminate between ambulatory and nonambulatory patients (accuracy: 91.76%; sensitivity: 93.75%; and specificity: 90.57%). The study reveals that ultrasound IF has great potential in DMD evaluation and management.
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Affiliation(s)
- Wen-Chin Weng
- Department of Pediatrics, National Taiwan University Hospital, and College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Pediatrics, College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Pediatric Neurology, National Taiwan University Children's Hospital, Taipei, Taiwan
| | - Chia-Wei Lin
- Department of Physical Medicine and Rehabilitation, National Taiwan University Hospital Hsin-Chu Branch, Hsin-Chu, Taiwan
| | - Hui-Chung Shen
- Institute of Applied Mechanics, National Taiwan University, Taipei, Taiwan
| | - Chien-Cheng Chang
- Institute of Applied Mechanics, National Taiwan University, Taipei, Taiwan.
| | - Po-Hsiang Tsui
- Department of Medical Imaging and Radiological Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Medical Imaging Research Center, Institute for Radiological Research, Chang Gung University and Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Department of Medical Imaging and Intervention, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan.
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45
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Yin L, Xie ZY, Xu HY, Zheng SS, Wang ZX, Xiao JX, Yuan Y. T2 Mapping and Fat Quantification of Thigh Muscles in Children with Duchenne Muscular Dystrophy. Curr Med Sci 2019; 39:138-145. [PMID: 30868504 DOI: 10.1007/s11596-019-2012-8] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Revised: 12/12/2018] [Indexed: 11/24/2022]
Abstract
Quantitative magnetic resonance image (MRI) in individual muscles may be useful for monitoring disease progression in Duchenne muscular dystrophy (DMD). The purpose of this study was to measure T2 relaxation time of thigh muscles in children with DMD and healthy boys, and to correlate the T2 relaxation time of muscles with the fat fraction (FF) at quantitative magnetic resonance and results of clinical assessment. Thirty-two boys with DMD and 18 healthy boys were evaluated with T2 mapping and three-point Dixon MRI. Age, body mass index (BMI), muscle strength assessment, timed functional tests (time to walk or run 10 metres, rise from the floor and ascend four stairs), and the North Star Ambulatory Assessment (NSAA) were evaluated. Spearman's correlation was used to assess the relationships between FF and clinical assessments and T2 relaxation time. The mean T2 relaxation time of thigh muscles in DMD was significantly longer than that in the control group (P<0.05), except for the gracilis (P=0.952). The gracilis, sartorius and adductor longus were relatively spared by fatty infiltration in DMD patients. The T2 relaxation time was correlated significantly with the mean FF in all muscles. Age, BMI, total muscle strength score, timed functional tests and NSAA were significantly correlated with the overall mean T2 relaxation time. T2 mapping may prove clinically useful in monitoring muscle changes as a result of the disease process and in predicting the outcome of DMD patients.
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Affiliation(s)
- Liang Yin
- Department of Radiology, Peking University First Hospital, Beijing, 100034, China
| | - Zhi-Ying Xie
- Department of Neurology, Peking University First Hospital, Beijing, 100034, China
| | - Hai-Yan Xu
- Department of Radiology, Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China
| | - Sui-Sheng Zheng
- Department of Radiology, Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China
| | - Zhao-Xia Wang
- Department of Neurology, Peking University First Hospital, Beijing, 100034, China
| | - Jiang-Xi Xiao
- Department of Radiology, Peking University First Hospital, Beijing, 100034, China.
| | - Yun Yuan
- Department of Neurology, Peking University First Hospital, Beijing, 100034, China.
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Cai J, Xing F, Batra A, Liu F, Walter GA, Vandenborne K, Yang L. Texture Analysis for Muscular Dystrophy Classification in MRI with Improved Class Activation Mapping. PATTERN RECOGNITION 2019; 86:368-375. [PMID: 31105339 PMCID: PMC6521874 DOI: 10.1016/j.patcog.2018.08.012] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
The muscular dystrophies are made up of a diverse group of rare genetic diseases characterized by progressive loss of muscle strength and muscle damage. Since there is no cure for muscular dystrophy and clinical outcome measures are limited, it is critical to assess the progression of MD objectively. Imaging muscle replacement by fibrofatty tissue has been shown to be a robust biomarker to monitor disease progression in DMD. In magnetic resonance imaging (MRI) data, specific texture patterns are found to correlate to certain MD subtypes and thus present a potential way for automatic assessment. In this paper, we first apply state-of-the-art convolutional neural networks (CNNs) to perform accurate MD image classification and then propose an effective visualization method to highlight the important image textures. With a dystrophic MRI dataset, we found that the best CNN model delivers an 91.7% classification accuracy, which significantly outperforms non-deep learning methods, e.g., >40% improvement has been found over the traditional mean fat fraction (MFF) criterion for DMD and CMD classification. After investigating every single neuron at the top layer of CNN model, we found the superior classification ability of CNN can be explained by its 91 and 118 neurons were performing better than the MFF criterion under the measurements of Euclidean and Chi-square distance, respectively. In order to further interpret CNNs predictions, we tested an improved class activation mapping (ICAM) method to visualize the important regions in the MRI images. With this ICAM, CNNs are able to locate the most discriminative texture patterns of DMD in soleus, lateral gastrocnemius, and medial gastrocnemius; for CMD, the critical texture patterns are highlighted in soleus, tibialis posterior, and peroneus.
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Affiliation(s)
- Jinzheng Cai
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida
| | - Fuyong Xing
- Department of Biostatistics and Informatics, University of Colorado Denver
| | - Abhinandan Batra
- Department of Physiology and Functional Genomics, University of Florida
| | - Fujun Liu
- Department of Electrical and Computer Engineering, University of Florida
| | - Glenn A. Walter
- Department of Physiology and Functional Genomics, University of Florida
| | | | - Lin Yang
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida
- Department of Electrical and Computer Engineering, University of Florida
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47
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Monitoring skeletal muscle chronic fatty degenerations with fast T1-mapping. Eur Radiol 2018; 28:4662-4668. [PMID: 29713767 DOI: 10.1007/s00330-018-5433-z] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Revised: 03/05/2018] [Accepted: 03/16/2018] [Indexed: 10/17/2022]
Abstract
OBJECTIVES To develop a fast, high-resolution T1-mapping sequence dedicated to skeletal muscle imaging, and to evaluate the potential of T1 as a robust and sensitive biomarker for the monitoring of chronic fatty degenerations in a dystrophic disease. METHODS The magnetic resonance imaging sequence consisted of the acquisition of a 1,000-radial-spokes FLASH echo-train following magnetisation inversion, resulting in 10s scan time per slice. Temporal image series were reconstructed using compressed sensing and T1 maps were computed using Bloch simulations. Ten healthy volunteers and 30 patients suffering from Becker muscular dystrophy (BMD) participated in this prospective study, in order to evaluate the repeatability, the precision and the sensitivity of the proposed approach. Intramuscular fat fraction (FF) was also measured using a standard three-point Dixon method. The protocol was approved by a local ethics committee. RESULTS The mean T1 evaluated in the thighs muscles of healthy volunteers was 1,199 ± 45 ms, with a coefficient of reproducibility of 2.3%. Mean T1 values were statistically decreased in the thighs of BMD patients and were linearly correlated with intramuscular FF (R = -0.98). CONCLUSIONS T1-mapping is a good candidate for fast, sensitive and quantitative monitoring of fatty infiltrations in neuromuscular disorders. KEY POINTS • A T1 mapping sequence dedicated to skeletal muscle imaging was implemented. • The acquisition time was 10 s per slice. • Muscle T1 values were significantly decreased in dystrophic muscles compared to healthy muscles. • T1 values correlated with intramuscular fat fraction measured by three-point Dixon. • T1 represents an alternative biomarker for monitoring fatty infiltrations in neuromuscular disorders.
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48
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Jungbluth H. Myopathology in times of modern imaging. Neuropathol Appl Neurobiol 2018; 43:24-43. [PMID: 28111795 DOI: 10.1111/nan.12385] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2016] [Revised: 01/17/2017] [Accepted: 01/23/2017] [Indexed: 12/14/2022]
Abstract
Over the last two decades, muscle (magnetic resonance) imaging has become an important complementary tool in the diagnosis and differential diagnosis of inherited neuromuscular disorders, particularly in conditions where the pattern of selective muscle involvement is often more predictive of the underlying genetic background than associated clinical and histopathological features. Following an overview of different imaging modalities, the present review will give a concise introduction to systematic image analysis and interpretation in genetic neuromuscular disorders. The pattern of selective muscle involvement will be presented in detail in conditions such as the congenital or myofibrillar myopathies where muscle imaging is particularly useful to inform the (differential) diagnosis, and in disorders such as Duchenne or fascioscapulohumeral muscular dystrophy where the diagnosis is usually made on clinical grounds but where detailed knowledge of disease progression on the muscle imaging level may inform better understanding of the natural history. Utilizing the group of the congenital myopathies as an example, selected case studies will illustrate how muscle MRI can be used to inform the diagnostic process in the clinico-pathological context. Future developments, in particular, concerning the increasing use of whole-body MRI protocols and novel quantitative fat assessments techniques potentially relevant as an outcome measure, will be briefly outlined.
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Affiliation(s)
- H Jungbluth
- Department of Paediatric Neurology, Neuromuscular Service, Evelina's Children Hospital, Guy's & St. Thomas' Hospital NHS Foundation Trust, London, UK.,Randall Division of Cell and Molecular Biophysics, Muscle Signalling Section, London, UK.,Department of Clinical and Basic Neuroscience, IoPPN, King's College, London, UK
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49
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Barnard AM, Willcocks RJ, Finanger EL, Daniels MJ, Triplett WT, Rooney WD, Lott DJ, Forbes SC, Wang DJ, Senesac CR, Harrington AT, Finkel RS, Russman BS, Byrne BJ, Tennekoon GI, Walter GA, Sweeney HL, Vandenborne K. Skeletal muscle magnetic resonance biomarkers correlate with function and sentinel events in Duchenne muscular dystrophy. PLoS One 2018; 13:e0194283. [PMID: 29554116 PMCID: PMC5858773 DOI: 10.1371/journal.pone.0194283] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Accepted: 02/28/2018] [Indexed: 12/27/2022] Open
Abstract
OBJECTIVE To provide evidence for quantitative magnetic resonance (qMR) biomarkers in Duchenne muscular dystrophy by investigating the relationship between qMR measures of lower extremity muscle pathology and functional endpoints in a large ambulatory cohort using a multicenter study design. METHODS MR spectroscopy and quantitative imaging were implemented to measure intramuscular fat fraction and the transverse magnetization relaxation time constant (T2) in lower extremity muscles of 136 participants with Duchenne muscular dystrophy. Measures were collected at 554 visits over 48 months at one of three imaging sites. Fat fraction was measured in the soleus and vastus lateralis using MR spectroscopy, while T2 was assessed using MRI in eight lower extremity muscles. Ambulatory function was measured using the 10m walk/run, climb four stairs, supine to stand, and six minute walk tests. RESULTS Significant correlations were found between all qMR and functional measures. Vastus lateralis qMR measures correlated most strongly to functional endpoints (|ρ| = 0.68-0.78), although measures in other rapidly progressing muscles including the biceps femoris (|ρ| = 0.63-0.73) and peroneals (|ρ| = 0.59-0.72) also showed strong correlations. Quantitative MR biomarkers were excellent indicators of loss of functional ability and correlated with qualitative measures of function. A VL FF of 0.40 was an approximate lower threshold of muscle pathology associated with loss of ambulation. DISCUSSION Lower extremity qMR biomarkers have a robust relationship to clinically meaningful measures of ambulatory function in Duchenne muscular dystrophy. These results provide strong supporting evidence for qMR biomarkers and set the stage for their potential use as surrogate outcomes in clinical trials.
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Affiliation(s)
- Alison M. Barnard
- Department of Physical Therapy, University of Florida, Gainesville, FL, United States of America
| | - Rebecca J. Willcocks
- Department of Physical Therapy, University of Florida, Gainesville, FL, United States of America
| | - Erika L. Finanger
- Departments of Pediatrics and Neurology, Oregon Health & Science University, Portland, OR, United States of America
| | - Michael J. Daniels
- Department of Statistics, University of Florida, Gainesville, FL, United States of America
| | - William T. Triplett
- Department of Physical Therapy, University of Florida, Gainesville, FL, United States of America
| | - William D. Rooney
- Advanced Imaging Research Center, Oregon Health & Science University, Portland, OR, United States of America
| | - Donovan J. Lott
- Department of Physical Therapy, University of Florida, Gainesville, FL, United States of America
| | - Sean C. Forbes
- Department of Physical Therapy, University of Florida, Gainesville, FL, United States of America
| | - Dah-Jyuu Wang
- Department of Radiology, Division of Neurology, The Children’s Hospital of Philadelphia, Philadelphia, PA, United States of America
| | - Claudia R. Senesac
- Department of Physical Therapy, University of Florida, Gainesville, FL, United States of America
| | - Ann T. Harrington
- The Children’s Hospital of Philadelphia, Philadelphia, PA, United States of America
| | | | - Barry S. Russman
- Departments of Pediatrics and Neurology, Oregon Health & Science University, Portland, OR, United States of America
| | - Barry J. Byrne
- Department of Pediatrics and Molecular Genetics and Microbiology, Powell Gene Therapy Center, University of Florida, Gainesville, FL, United States of America
| | - Gihan I. Tennekoon
- The Children’s Hospital of Philadelphia, Philadelphia, PA, United States of America
| | - Glenn A. Walter
- Department of Physiology and Functional Genomics, University of Florida, Gainesville, FL, United States of America
| | - H. Lee Sweeney
- Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL, United States of America
| | - Krista Vandenborne
- Department of Physical Therapy, University of Florida, Gainesville, FL, United States of America
- * E-mail:
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50
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Carlier PG, Marty B, Scheidegger O, Loureiro de Sousa P, Baudin PY, Snezhko E, Vlodavets D. Skeletal Muscle Quantitative Nuclear Magnetic Resonance Imaging and Spectroscopy as an Outcome Measure for Clinical Trials. J Neuromuscul Dis 2018; 3:1-28. [PMID: 27854210 PMCID: PMC5271435 DOI: 10.3233/jnd-160145] [Citation(s) in RCA: 142] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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.
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Affiliation(s)
- Pierre G Carlier
- Institute of Myology, Pitie-Salpetriere University Hospital, Paris, France.,CEA, DSV, I2BM, MIRCen, NMR Laboratory, Paris, France.,National Academy of Sciences, United Institute for Informatics Problems, Minsk, Belarus
| | - Benjamin Marty
- Institute of Myology, Pitie-Salpetriere University Hospital, Paris, France.,CEA, DSV, I2BM, MIRCen, NMR Laboratory, Paris, France
| | - Olivier Scheidegger
- Institute of Myology, Pitie-Salpetriere University Hospital, Paris, France.,Support Center for Advanced Neuroimaging (SCAN), Institute of Diagnostic and Interventional Neuroradiology, Inselspital, Bern University Hospital, and University of Bern, Switzerland
| | | | | | - Eduard Snezhko
- National Academy of Sciences, United Institute for Informatics Problems, Minsk, Belarus
| | - Dmitry Vlodavets
- N.I. Prirogov Russian National Medical Research University, Clinical Research Institute of Pediatrics, Moscow, Russian Federation
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