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BACKGROUND: Improved characterization of healthy muscle aging is needed to establish early biomarkers in age-related diseases. PURPOSE: To quantify age-related changes on multiple MRI and clinical variables evaluated in the same cohort and identify correlations among them. STUDY TYPE: Prospective. POPULATION: 70 healthy subjects (30 men) from 20 to 81 years old. FIELD STRENGTH/SEQUENCE: 3T/water T2 (multiecho SE, multi-TE STEAM), water T1 (GRE MR Fingerprinting), fat-fraction (multiecho GRE, multi-TE STEAM), carnosine (PRESS), multicomponent water T2 (ISIS-CPMG SE train), and 31P pulse-acquire spectroscopy. ASSESSMENT: Age- and sex-related changes on: Imaging: fat-fraction (FFMRI), water T1 (T1-H2O), and T2 (T2-H2O-MRI) and their heterogeneities ΔT1-H2O and ΔT2-H2O-MRI in the posterior compartment (PC) and anterior compartment (AC) of the leg. 1H spectroscopy: Carnosine concentration, pH, water T2 components (T2-H2O-CPMG), fat-fraction (FFMRS), and water T2 (T2-H2O-MRS) in the gastrocnemius medialis. 31P spectroscopy: Phosphodiesters (PDE), phosphomonoesters, inorganic phosphates (Pi), and phosphocreatine (PCr) normalized to adenosine triphosphate (ATP) and pH in the calf. Clinical evaluation: Body-mass index (BMI), gait speed (GS), plantar flexion strength, handgrip strength (HS), HS normalized to wrist circumference (HSnorm), physical activity assessment. STATISTICAL TESTS: Multilinear regressions with sex and age as fixed factors. Spearman correlations calculated between variables. Benjamini-Hochberg procedure for false positives reduction (5% rate). A P < 0.05 significance level was used. RESULTS: Significant age-related increases were found for BMI (ρAge = 0.04), HSnorm (ρAge = -0.01), PDE/ATP (ρAge = 2.8 × 10-3), Pi/ATP (ρAge = 2.0 × 10-3), Pi/PCr (ρAge = 0.3 × 10-3), T2-H2O-MRS (ρAge = 0.051 msec), FFMRS (ρAge = 0.036) the intermediate T2-H2O-CPMG component time (ρAge = 0.112 msec), and fraction (ρAge = -0.3 × 10-3); and in both compartments for FFMRI (ρAge = 0.06, PC; ρAge = 0.06, AC), T2-H2O-MRI (ρAge = 0.05, PC; ρAge = 0.05, AC; msec), ΔT2-H2O-MRI (ρAge = 0.02, PC; ρAge = 0.02, AC; msec), T1-H2O (ρAge = 1.08, PC; ρAge = 1.06, AC; msec), and ΔT1-H2O (ρAge = 0.22, PC; ρAge = 0.37, AC; msec). The best age predictors, accounting for sex-related differences, were HSnorm (R2 = 0.52) and PDE/ATP (R2 = 0.44). In both leg compartments, the imaging measures and HSnorm were intercorrelated. In PC, T2-H2O-MRS and FFMRS also showed numerous correlations to the imaging measures. PDE/ATP correlated to T1-H2O, T2-H2O-MRI, ΔT2-H2O-MRI, FFMRI, FFMRS, the intermediate T2-H2O-CPMG, BMI, Pi/PCr, and HSnorm. DATA CONCLUSION: Our multiparametric MRI approach provided an integrative view of age-related changes in the leg and revealed multiple correlations between these parameters and the normalized HS. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 3.
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Background Quantitative MRI is increasingly proposed in clinical trials related to dystrophinopathies, including Becker muscular dystrophy (BMD). Purpose To establish the sensitivity of extracellular volume fraction (ECV) quantification using an MR fingerprinting sequence with water and fat separation as a quantitative imaging biomarker of skeletal muscle tissue alterations in BMD compared with fat fraction (FF) and water relaxation time quantification. Materials and Methods In this prospective study, study participants with BMD and healthy volunteers were included from April 2018 until October 2022 (ClinicalTrials.gov identifier NCT02020954). The MRI examination comprised FF mapping with the three-point Dixon method, water T2 mapping, and water T1 mapping before and after an intravenous injection of a gadolinium-based contrast agent by using MR fingerprinting, from which ECV was calculated. Functional status was measured with use of the Walton and Gardner-Medwin scale. This clinical evaluation tool stratifies disease severity from grade 0 (preclinical; elevated creatine phosphokinase; all activities normal) to grade 9 (unable to eat, drink, or sit without assistance). Mann-Whitney U tests, Kruskal-Wallis tests, and Spearman rank correlation tests were performed. Results Twenty-eight participants with BMD (median age, 42 years [IQR, 34-52 years]; 28 male) and 19 healthy volunteers (median age, 39 years [IQR, 33-55 years]; 19 male) were evaluated. ECV was higher in participants with dystrophy than in controls (median, 0.21 [IQR, 0.16-0.28] vs 0.07 [IQR, 0.07-0.08]; P < .001). In muscles of participants with BMD with normal FF, ECV was also higher than in muscles of healthy controls (median, 0.11 [IQR, 0.10-0.15] vs 0.07 [IQR, 0.07-0.08]; P = .02). ECV was correlated with FF (ρ = 0.56, P = .003), Walton and Gardner-Medwin scale score (ρ = 0.52, P = .006), and serum cardiac troponin T level (ρ = 0.60, P < .001). Conclusion Quantitative MR relaxometry with water and fat separation indicates a significant increase of skeletal muscle extracellular volume fraction in study participants with Becker muscular dystrophy. Clinical trial registration no. NCT02020954 Published under a CC BY 4.0 license. Supplemental material is available for this article.
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Distrofia Muscular de Duchenne , Adulto , Humanos , Masculino , Meios de Contraste , Imageamento por Ressonância Magnética/métodos , Músculo Esquelético , Estudos ProspectivosRESUMO
The objective of this work was to demonstrate the feasibility of measuring muscle O2 consumption (VËO2) noninvasively with a combination of functional nuclear magnetic resonance (NMR) imaging methods, and to verify that changes in muscle VËO2 can be detected with a temporal resolution compatible with physiological investigation and patient ease. T2-based oxymetry of arterial and venous blood was combined with the arterial-spin labeling (ASL)-based determination of muscle perfusion. These measurements were performed on 8 healthy volunteers under normoxic and hypoxic conditions in order to assess the sensitivity of measurements over a range of saturation values. Blood samples were drawn simultaneously and used to titrate blood T2 measurements versus hemoglobin O2 saturation (%HbO2) in vitro. The in vitro calibration curve of blood T2 fitted very well with the %HbO2 (r(2): 0.95). The in vivo venous T2 measurements agreed well with the in vitro measurements (intraclass correlation coefficient 0.82, 95% confidence interval 0.61-0.91). Oxygen extraction at rest decreased in the calf muscles subjected to hypoxia (p = 0.031). The combination of unaltered muscle perfusion and pinched arteriovenous O2 difference (p = 0.038) pointed towards a reduced calf muscle VËO2 during transient hypoxia (p = 0.018). The results of this pilot study confirmed that muscle O2 extraction and VËO2 can be estimated noninvasively using a combination of functional NMR techniques. Further studies are needed to confirm the usefulness in a larger sample of volunteers and patients.
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Imageamento por Ressonância Magnética , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/metabolismo , Oximetria , Consumo de Oxigênio , Oxigênio/sangue , Imagem de Perfusão/métodos , Adulto , Calibragem , Estudos de Viabilidade , Feminino , Voluntários Saudáveis , Humanos , Hipóxia/sangue , Hipóxia/fisiopatologia , Perna (Membro) , Imageamento por Ressonância Magnética/normas , Masculino , Modelos Biológicos , Oximetria/normas , Imagem de Perfusão/normas , Projetos Piloto , Valor Preditivo dos Testes , Padrões de Referência , Fluxo Sanguíneo Regional , Reprodutibilidade dos Testes , Fatores de TempoRESUMO
BACKGROUND: Finding sensitive clinical outcome measures has become crucial in natural history studies and therapeutic trials of neuromuscular disorders. Here, we focus on 1-year longitudinal data from quantitative magnetic resonance imaging (MRI) and phosphorus magnetic resonance spectroscopy (31P MRS) in a placebo-controlled study of sirolimus for inclusion body myositis (IBM), also examining their links to functional, strength, and clinical parameters in lower limb muscles. METHODS: Quantitative MRI and 31P MRS data were collected at 3 T from a single site, involving 44 patients (22 on placebo, 22 on sirolimus) at baseline and year-1, and 21 healthy controls. Assessments included fat fraction (FF), contractile cross-sectional area (cCSA), and water T2 in global leg and thigh segments, muscle groups, individual muscles, as well as 31P MRS indices in quadriceps or triceps surae. Analyses covered patient-control comparisons, annual change assessments via standard t-tests and linear mixed models, calculation of standardized response means (SRM), and exploration of correlations between MRI, 31P MRS, functional, strength, and clinical parameters. RESULTS: The quadriceps and gastrocnemius medialis muscles had the highest FF values, displaying notable heterogeneity and asymmetry, particularly in the quadriceps. In the placebo group, the median 1-year FF increase in the quadriceps was 3.2% (P < 0.001), whereas in the sirolimus group, it was 0.7% (P = 0.033). Both groups experienced a significant decrease in cCSA in the quadriceps after 1 year (P < 0.001), with median changes of 12.6% for the placebo group and 5.5% for the sirolimus group. Differences in FF and cCSA changes between the two groups were significant (P < 0.001). SRM values for FF and cCSA were 1.3 and 1.4 in the placebo group and 0.5 and 0.8 in the sirolimus group, respectively. Water T2 values were highest in the quadriceps muscles of both groups, significantly exceeding control values in both groups (P < 0.001) and were higher in the placebo group than in the sirolimus group. After treatment, water T2 increased significantly only in the sirolimus group's quadriceps (P < 0.01). Multiple 31P MRS indices were abnormal in patients compared to controls and remained unchanged after treatment. Significant correlations were identified between baseline water T2 and FF at baseline and the change in FF (P < 0.001). Additionally, significant correlations were observed between FF, cCSA, water T2, and functional and strength outcome measures. CONCLUSIONS: This study has demonstrated that quantitative MRI/31P MRS can discern measurable differences between placebo and sirolimus-treated IBM patients, offering promise for future therapeutic trials in idiopathic inflammatory myopathies such as IBM.
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Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Músculo Esquelético , Miosite de Corpos de Inclusão , Sirolimo , Humanos , Miosite de Corpos de Inclusão/tratamento farmacológico , Imageamento por Ressonância Magnética/métodos , Masculino , Feminino , Espectroscopia de Ressonância Magnética/métodos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/diagnóstico por imagem , Sirolimo/uso terapêutico , Sirolimo/farmacologia , Pessoa de Meia-Idade , Idoso , Imunossupressores/uso terapêutico , Imunossupressores/farmacologiaRESUMO
A fast and robust methodology for in vivo T(2) mapping is presented. The approach is based on the partially spoiled steady state free precession technique recently proposed by Bieri et al. (Magn Reson Med 2011). The accuracy of this method was demonstrated in simulations and phantom experiments. Variations in skeletal muscle T(2) relaxation time have been correlated with cell damage and inflammatory response. Nonetheless, the lack of easily implementable, fast, accurate and reproducible methods has hampered the adoption of T(2) measurement as a noninvasive tool for skeletal muscle characterization. The applicability of the partially spoiled steady state free precession method for tissue characterization in muscle disease is illustrated in this work by several examples. Quantitative MRI, in particular T(2) mapping based on partially spoiled steady state free precession acquisitions, might provide objective markers of muscle damage and degenerative changes, and an alternative to serial muscle biopsies.
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Artefatos , Aumento da Imagem/métodos , Interpretação de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Contração Muscular/fisiologia , Músculo Esquelético/anatomia & histologia , Músculo Esquelético/fisiologia , Humanos , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Water T2 (T2H2O ) mapping is increasingly being used in muscular dystrophies to assess active muscle damage. It has been suggested as a surrogate outcome measure for clinical trials. Here, we investigated the prognostic utility of T2H2O to identify changes in muscle function over time in limb girdle muscular dystrophies. METHODS: Patients with genetically confirmed dysferlinopathy were assessed as part of the Jain Foundation Clinical Outcomes Study in dysferlinopathy. The cohort included 18 patients from two sites, both equipped with 3-tesla magnetic resonance imaging (MRI) systems from the same vendor. T2H2O value was defined as higher or lower than the median in each muscle bilaterally. The degree of deterioration on four functional tests over 3 years was assessed in a linear model against covariates of high or low T2H2O at baseline, age, disease duration, and baseline function. RESULTS: A higher T2H2O at baseline significantly correlated with a greater decline on functional tests in 21 out of 35 muscles and was never associated with slower decline. Higher baseline T2H2O in adductor magnus, vastus intermedius, vastus lateralis, and vastus medialis were the most sensitive, being associated bilaterally with greater decline in multiple timed tests. Patients with a higher than median baseline T2H2O (>40.6 ms) in the right vastus medialis deteriorated 11 points more on the North Star Ambulatory Assessment for Dysferlinopathy and lost an additional 86 m on the 6-min walk than those with a lower T2H2O (<40.6 ms). Optimum sensitivity and specificity thresholds for predicting decline were 39.0 ms in adductor magnus and vastus intermedius, 40.0 ms in vastus medialis, and 40.5 ms in vastus lateralis from different sites equipped with different MRI systems. CONCLUSIONS: In dysferlinopathy, T2H2O did not correlate with current functional ability. However, T2H2O at baseline was higher in patients who worsened more rapidly on functional tests. This suggests that inter-patient differences in functional decline over time may be, in part, explained by different severities of the active muscle damage, assessed by T2H2O measure at baseline. Significant challenges remain in standardizing T2H2O values across sites to allow determining globally applicable thresholds. The results from the present work are encouraging and suggest that T2H2O could be used to improve prognostication, patient selection, and disease modelling for clinical trials.
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Distrofia Muscular do Cíngulo dos Membros , Distrofias Musculares , Humanos , Água , Distrofia Muscular do Cíngulo dos Membros/diagnóstico , Distrofia Muscular do Cíngulo dos Membros/patologia , Músculo Esquelético/patologia , Distrofias Musculares/patologiaRESUMO
BACKGROUND: Natural history studies in neuromuscular disorders are vital to understand the disease evolution and to find sensitive outcome measures. We performed a longitudinal assessment of quantitative magnetic resonance imaging (MRI) and phosphorus magnetic resonance spectroscopy (31 P MRS) outcome measures and evaluated their relationship with function in lower limb skeletal muscle of dysferlinopathy patients. METHODS: Quantitative MRI/31 P MRS data were obtained at 3 T in two different sites in 54 patients and 12 controls, at baseline, and three annual follow-up visits. Fat fraction (FF), contractile cross-sectional area (cCSA), and muscle water T2 in both global leg and thigh segments and individual muscles and 31 P MRS indices in the anterior leg compartment were assessed. Analysis included comparisons between patients and controls, assessments of annual changes using a linear mixed model, standardized response means (SRM), and correlations between MRI and 31 P MRS markers and functional markers. RESULTS: Posterior muscles in thigh and leg showed the highest FF values. FF at baseline was highly heterogeneous across patients. In ambulant patients, median annual increases in global thigh and leg segment FF values were 4.1% and 3.0%, respectively (P < 0.001). After 3 years, global thigh and leg FF increases were 9.6% and 8.4%, respectively (P < 0.001). SRM values for global thigh FF were over 0.8 for all years. Vastus lateralis muscle showed the highest SRM values across all time points. cCSA decreased significantly after 3 years with median values of 11.0% and 12.8% in global thigh and global leg, respectively (P < 0.001). Water T2 values in ambulant patients were significantly increased, as compared with control values (P < 0.001). The highest water T2 values were found in the anterior part of thigh and leg. Almost all 31 P MRS indices were significantly different in patients as compared with controls (P < 0.006), except for pHw , and remained, similar as to water T2 , abnormal for the whole study duration. Global thigh water T2 at baseline was significantly correlated to the change in FF after 3 years (ρ = 0.52, P < 0.001). There was also a significant relationship between the change in functional score and change in FF after 3 years in ambulant patients (ρ = -0.55, P = 0.010). CONCLUSIONS: This multi-centre study has shown that quantitative MRI/31 P MRS measurements in a heterogeneous group of dysferlinopathy patients can measure significant changes over the course of 3 years. These data can be used as reference values in view of future clinical trials in dysferlinopathy or comparisons with quantitative MRI/S data obtained in other limb-girdle muscular dystrophy subtypes.
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Distrofia Muscular do Cíngulo dos Membros , Fósforo , Humanos , Imageamento por Ressonância Magnética/métodos , Espectroscopia de Ressonância Magnética/métodos , Músculo Esquelético/patologia , Distrofia Muscular do Cíngulo dos Membros/diagnóstico por imagem , Distrofia Muscular do Cíngulo dos Membros/patologia , Coxa da Perna , ÁguaRESUMO
BACKGROUND: Quantitative nuclear magnetic resonance imaging (NMRI) is an objective and precise outcome measure for evaluating disease progression in neuromuscular disorders. We aimed to investigate predictive 'disease activity' NMR indices, including water T2 and 31P NMR spectroscopy (NMRS), and its relation to NMR markers of 'disease progression', such as the changes in fat fraction (ΔFat%) and contractile cross-sectional area (ΔcCSA), in GNE myopathy (GNEM) patients. METHODS: NMR was performed on a 3T clinical scanner, at baseline and at a 1-year interval, in 10 GNEM patients and 29 age-matched controls. Dixon-based fat-water imaging and water T2 mapping were acquired in legs and thighs, and in the dominant forearm. 31P NMRS was performed at the level of quadriceps and hamstring. Water T2 and 31P NMRS indices were determined for all muscle groups and visits. Correlations were performed with 'disease progression' indices ΔFat%, ΔcCSA and the muscle fat transformation rate (Rmuscle_transf). RESULTS: In quadriceps, known to be relatively preserved in GNEM, water T2 at baseline was significantly higher compared to controls, and correlated strongly with the one-year evolution of Fat% and cCSA and Rmuscle_transf. Various 31P NMRS indices showed significant differences in quadriceps and hamstring compared to controls and correlations existed between these indices and ΔFat%, ΔcCSA and Rmuscle_transf. CONCLUSIONS: This study demonstrates that disease activity indices such as water T2 and 31P NMRS may predict disease progression in skeletal muscles of GNEM patients, and suggests that these measures may be considered to be valuable surrogate endpoints in the assessment of GNEM disease progression.