Sodium quantification in skeletal muscle: comparison between Cartesian gradient-echo and radial ultra-short echo time 23Na MRI techniques.

BACKGROUND: Clinical magnetic resonance imaging (MRI) studies often use Cartesian gradient-echo (GRE) sequences with ~2-ms echo times (TEs) to monitor apparent total sodium concentration (aTSC). We compared Cartesian GRE and ultra-short echo time three-dimensional (3D) radial-readout sequences for measuring skeletal muscle aTSC. METHODS: We retrospectively evaluated 211 datasets from 112 volunteers aged 62.3 ± 12.1 years (mean ± standard deviation), acquired at 3 T from the lower leg. For 23Na MRI acquisitions, we used a two-dimensional Cartesian GRE sequence and a density-adapted 3D radial readout sequence with cuboid field-of-view (DA-3D-RAD-C). We calibrated the 23Na MR signal using reference tubes either with or without agarose and subsequently performed a relaxation correction. Additionally, we employed a six-echo 1H GRE sequence and a multi-echo spin-echo sequence to calculate proton density fat fraction (PDFF) and water T2. Paired Wilcoxon signed-rank test, Cohen dz for paired samples, and Spearman correlation were used. RESULTS: Relaxation correction effectively reduced the differences in muscle aTSC between the two acquisition and calibration methods (DA-3D-RAD-C using NaCl/agarose references: 20.05 versus 19.14 mM; dz = 0.395; Cartesian GRE using NaCl/agarose references: 19.50 versus 18.82 mM; dz = 0.427). Both aTSC of the DA-3D-RAD-C and Cartesian GRE acquisitions showed a small but significant correlation with PDFF as well as with water T2. CONCLUSIONS: Different 23Na MRI acquisition and calibration approaches affect aTSC values. Applying relaxation correction is advised to minimize the impact of sequence parameters on quantification, and considering additional fat correction is advisable for patients with increased fat fractions. RELEVANCE STATEMENT: This study highlights relaxation correction's role in improving sodium MRI accuracy, paving the way for better disease assessment and comparability of measured sodium signal in patients. KEY POINTS: • Differences in MRI acquisition methods hamper the comparability of sodium MRI measurements. • Measured sodium values depend on used MRI sequences and calibration method. • Relaxation correction during postprocessing mitigates these discrepancies. • Thus, relaxation correction enhances accuracy of sodium MRI, aiding its clinical use.

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

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.

Multiparametric Aging Study Across Adulthood in the Leg Through Quantitative MR Imaging, 1H Spectroscopy, and 31P Spectroscopy at 3T.

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.

Bi-component dictionary matching for MR fingerprinting for efficient quantification of fat fraction and water T1 in skeletal muscle.

PURPOSE: To propose an efficient bi-component MR fingerprinting (MRF) fitting method using a Variable Projection (VARPRO) strategy, applied to the quantification of fat fraction (FF) and water T1 ( T 1 H 2 0 $$ \mathrm{T}{1}_{{\mathrm{H}}_20} $$ ) in skeletal muscle tissues. METHODS: The MRF signals were analyzed in a two-step process by comparing them to the elements of separate water and fat dictionaries (bi-component dictionary matching). First, each pair of water and fat dictionary elements was fitted to the acquired signal to determine an optimal FF that was used to merge the fingerprints in a combined water/fat dictionary. Second, standard dictionary matching was applied to the combined dictionary for determining the remaining parameters. A clustering method was implemented to further accelerate the fitting. Accuracy, precision, and matching time of this approach were evaluated on both numerical and in vivo datasets, and compared to the reference dictionary-matching approach that includes FF as a dictionary parameter. RESULTS: In numerical phantoms, all MRF parameters showed high correlation with ground truth for the reference and the bi-component method (R2 > 0.98). In vivo, the estimated parameters from the proposed method were highly correlated with those from the reference approach (R2 > 0.997). The bi-component method achieved an acceleration factor of up to 360 compared to the reference dictionary matching. CONCLUSION: The proposed bi-component fitting approach enables a significant acceleration of the reconstruction of MRF parameter maps for fat-water imaging, while maintaining comparable precision and accuracy to the reference on FF and T 1 H 2 0 $$ \mathrm{T}{1}_{{\mathrm{H}}_20} $$ estimation.

New Insights into the Spread of MRS-Based Water T2 Values Observed in Highly Fatty Replaced Muscles.

BACKGROUND: The reference standard for assessing water T2 (T2,H2O ) at high fat fraction (FF) is 1 H MRS. T2,H2O (T2,H2O,MRS ) dependence on FF (FFMRS ) has recently been demonstrated in muscle at high FF (i.e. ≥60%). PURPOSE: To investigate the relationship between T2,H2O,MRS and FFMRS in the thigh/leg muscles of patients with neuromuscular diseases and to compare with quantitative MRI. STUDY TYPE: Retrospective case-control study. POPULATION: A total of 151 patients with neuromuscular disorders (mean age ± standard deviation = 52.5 ± 22.6 years, 54% male), 44 healthy volunteers (26.5 ± 13.0 years, 57% male). FIELD STRENGTH/SEQUENCE: A 3-T; single-voxel stimulated echo acquisition mode (STEAM) MRS, multispin echo (MSE) imaging (for T2 mapping, T2,H2O,MRI ), three-point Dixon imaging (for FFMRI and R 2 * mapping). ASSESSMENT: Mono-exponential and bi-exponential models were fitted to water T2 decay curves to extract T2,H2O,MRS and FFMRS . Water resonance full-width-at-half-maximum (FWHM) and B0 spread (∆B0 ) values were calculated. T2,H2O,MRI (mean), FFMRI (mean, kurtosis, and skewness), and R 2 * (mean) values were estimated in the MRS voxel. STATISTICAL TESTS: Mann-Whitney U tests, Kruskal-Wallis tests. A P-value <0.05 was considered statistically significant. RESULTS: Normal T2,H2O,MRS threshold was defined as the 90th percentile in healthy controls: 30.3 msec. T2,H2O,MRS was significantly higher in all patients with FFMRS < 60% compared to healthy controls. We discovered two subgroups in patients with FFMRS ≥ 60%: one with T2,H2O,MRS ≥ 30.3 msec and one with T2,H2O,MRS < 30.3 msec including abnormally low T2,H2O,MRS . The latter subgroup had significantly higher water resonance FWHM, ∆B0 , FFMRI kurtosis, and skewness values but nonsignificantly different R 2 * (P = 1.00) and long T2,H2O,MRS component and its fraction (P > 0.11) based on the bi-exponential analysis. DATA CONCLUSION: The findings suggest that the cause for (abnormally) T2,H2O,MRS at high FFMRS is biophysical, due to differences in susceptibility between muscle and fat (increased FWHM and ∆B0 ), rather than pathophysiological such as compartmentation changes, which would be reflected by the bi-exponential analysis. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 3.

Assessment of Extracellular Volume Fraction in Becker Muscular Dystrophy by Using MR Fingerprinting.

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.

Global versus individual muscle segmentation to assess quantitative MRI-based fat fraction changes in neuromuscular diseases.

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.

Multiexponential Analysis of the Water T2-Relaxation in the Skeletal Muscle Provides Distinct Markers of Disease Activity Between Inflammatory and Dystrophic Myopathies.

BACKGROUND: The monoexponential water T2 (T2-mono ) is a proven biomarker of disease activity in neuromuscular disorders (NMDs). However, it lacks specificity, being elevated in the presence of several pathological processes and pathomorphological alterations in the muscle tissue. PURPOSE: To investigate the multiexponential behavior of the water T2 -relaxation in the skeletal muscle of NMD patients, aiming to identify more sensitive and specific biomarkers of disease activity. STUDY TYPE: Retrospective case-control. POPULATION: Thirty Duchenne muscular dystrophy and 114 inclusion body myositis patients and 55 control subjects. FIELD STRENGTH/SEQUENCE: 3T/Single-voxel proton spectroscopy (1 H-MRS) and multispin-echo (MSE) imaging. ASSESSMENT: Water T2 -decay curves generated from 1 H-MRS data acquired at 14 echo-times were fitted to mono- and biexponential models and the adjusted R2 of each fit was computed. Additionally, T2 spectra were generated from a regularized inverse Laplace transform. For comparison, water T2 maps were generated from the MSE data. The performances of the different variables at identifying patients were assessed via receiver operating characteristic (ROC)-curve analysis. STATISTICAL TESTS: Chi-square, Kruskal-Wallis, and Mann-Whitney with Bonferroni correction for multiple comparisons. RESULTS: T2-mono was elevated in patients (P<0.05), but could not distinguish inclusion body myositis (IBM) from Duchenne muscular dystrophy (DMD). While 79% of IBM data presented a biexponential behavior, this was only 16% and 10% for DMD and control data, respectively (P<0.05). All T2 spectra presented an intermediate-T2 peak characterized by an elevated T2 in patients (P<0.05) and by a relative fraction that was abnormally smaller in IBM patients (P<0.05). Also, a long-T2 peak was exclusively observed in IBM patients. A combination of T2 -spectrum variables performed best at identifying patients. DATA CONCLUSION: T2 spectra not only provided more sensitive and specific markers of disease presence than the T2-mono , but also allowed distinguishing IBM from DMD patients. This must reflect distinct predominant pathological alterations between these diseases, suggesting that these markers provide additional pathophysiological/histopathological information that are missing from T2-mono . LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY STAGE: 3.

Relationship between markers of disease activity and progression in skeletal muscle of GNE myopathy patients using quantitative nuclear magnetic resonance imaging and 31P nuclear magnetic resonance spectroscopy.

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.

Quantitative nuclear magnetic resonance imaging detects subclinical changes over 1 year in skeletal muscle of GNE myopathy.

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

Prospective and longitudinal natural history study of patients with Type 2 and 3 spinal muscular atrophy: Baseline data NatHis-SMA study.

Spinal muscular atrophy (SMA) is a monogenic disorder caused by loss of function mutations in the survival motor neuron 1 gene, which results in a broad range of disease severity, from neonatal to adult onset. There is currently a concerted effort to define the natural history of the disease and develop outcome measures that accurately capture its complexity. As several therapeutic strategies are currently under investigation and both the FDA and EMA have recently approved the first medical treatment for SMA, there is a critical need to identify the right association of responsive outcome measures and biomarkers for individual patient follow-up. As an approved treatment becomes available, untreated patients will soon become rare, further intensifying the need for a rapid, prospective and longitudinal study of the natural history of SMA Type 2 and 3. Here we present the baseline assessments of 81 patients aged 2 to 30 years of which 19 are non-sitter SMA Type 2, 34 are sitter SMA Type 2, 9 non-ambulant SMA Type 3 and 19 ambulant SMA Type 3. Collecting these data at nine sites in France, Germany and Belgium established the feasibility of gathering consistent data from numerous and demanding assessments in a multicenter SMA study. Most assessments discriminated between the four groups well. This included the Motor Function Measure (MFM), pulmonary function testing, strength, electroneuromyography, muscle imaging and workspace volume. Additionally, all of the assessments showed good correlation with the MFM score. As the untreated patient population decreases, having reliable and valid multi-site data will be imperative for recruitment in clinical trials. The pending two-year study results will evaluate the sensitivity of the studied outcomes and biomarkers to disease progression. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02391831).

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

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.

Prospective exploratory muscle biopsy, imaging, and functional assessment in patients with late-onset Pompe disease treated with alglucosidase alfa: The EMBASSY Study.

BACKGROUND: Late-onset Pompe disease is characterized by progressive skeletal myopathy followed by respiratory muscle weakness, typically leading to loss of ambulation and respiratory failure. In this population, enzyme replacement therapy (ERT) with alglucosidase alfa has been shown to stabilize respiratory function and improve mobility and muscle strength. Muscle pathology and glycogen clearance from skeletal muscle in treatment-naïve adults after ERT have not been extensively examined. METHODS: This exploratory, open-label, multicenter study evaluated glycogen clearance in muscle tissue samples collected pre- and post- alglucosidase alfa treatment in treatment-naïve adults with late-onset Pompe disease. The primary endpoint was the quantitative reduction in percent tissue area occupied by glycogen in muscle biopsies from baseline to 6months. Secondary endpoints included qualitative histologic assessment of tissue glycogen distribution, secondary pathology changes, assessment of magnetic resonance images (MRIs) for intact muscle and fatty replacement, and functional assessments. RESULTS: Sixteen patients completed the study. After 6months of ERT, the percent tissue area occupied by glycogen in quadriceps and deltoid muscles decreased in 10 and 8 patients, respectively. No changes were detected on MRI from baseline to 6months. A majority of patients showed improvements on functional assessments after 6months of treatment. All treatment-related adverse events were mild or moderate. CONCLUSIONS: This exploratory study provides novel insights into the histopathologic effects of ERT in late-onset Pompe disease patients. Ultrastructural examination of muscle biopsies demonstrated reduced lysosomal glycogen after ERT. Findings are consistent with stabilization of disease by ERT in treatment-naïve patients with late-onset Pompe disease.

Simultaneous muscle water T2 and fat fraction mapping using transverse relaxometry with stimulated echo compensation.

Skeletal muscle inflammation/necrosis and fat infiltration are strong indicators of disease activity and progression in many neuromuscular disorders. They can be assessed by muscle T2 relaxometry and water-fat separation techniques, respectively. In the present work, we exploited differences between water and fat T1 and T2 relaxivities by applying a bi-component extended phase graph (EPG) fitting approach to simultaneously quantify the muscle water T2 and fat fraction from standard multi-slice multi-echo (MSME) acquisitions in the presence of stimulated echoes. Experimental decay curves were adjusted to the theoretical model using either an iterative non-negative least-squares (NNLS) procedure or a pattern recognition approach. Twenty-two patients (age, 49 ± 18 years) were selected to cover a large range of muscle fat infiltration. Four cases of chronic or subchronic juvenile dermatomyositis (age, 8 ± 3 years) were investigated before and 3 months following steroid treatment. For control, five healthy volunteers (age, 25 ± 2 years) were recruited. All subjects underwent the MSME sequence and EPG fitting procedure. The EPG fitting algorithm allowed a precise estimation of water T2 and fat fraction in diseased muscle, even in the presence of large B1(+) inhomogeneities. In the whole cohort of patients, there was no overall correlation between water T2 values obtained with the proposed method and the fat fraction estimated inside muscle tissues (R(2) = 0.02). In the patients with dermatomyositis, there was a significant decrease in water T2 (-4.09 ± 3.7 ms) consequent to steroid treatment. The pattern recognition approach resulted in a 20-fold decrease in processing time relative to the iterative NNLS procedure. The fat fraction derived from the EPG fitting approach correlated well with the fat fraction derived from a standard three-point Dixon method (≈1.5% bias). The bi-component EPG fitting analysis is a precise tool to monitor muscle tissue disease activity and is able to handle bias introduced by fat infiltration and B1(+) inhomogeneities.

Qualitative and quantitative evaluation of skeletal muscle fatty degenerative changes using whole-body Dixon nuclear magnetic resonance imaging for an important reduction of the acquisition time.

In recent years, MRI has proven its usefulness for the diagnostic workup of patients with musculo-skeletal diseases, and also shown great promise as a non-invasive, quantitative outcome measure in clinical studies. The characterization of patterns of fatty degenerative lesions, which now plays an important part in the diagnosis of some diseases, is typically performed by the radiologist on routine T1-weighted images. We propose to rationalize acquisitions and reduce patients' time in the scanner by allowing radiologists to perform the qualitative grading of the muscles on images derived from fat/water acquisitions. These maps are color-coded, where the different colors correspond to classes of fatty infiltration degree. This allows a quick visual assessment of the muscles, equivalent to the standard method. Using the weighted Kappa agreement test, the agreement between the proposed method and the traditional one, as well as the reproducibility of the results with two raters, was measured on twenty patients suffering from various neuromuscular pathologies. The presented comparisons show that the use of color coded fat fraction maps is statistically equivalent to using the traditional T1-weighted images when performing visual assessment of degenerative lesions with fatty infiltrations in patients with neuromuscular disorders.

Discriminative parameter estimation for random walks segmentation.

The Random Walks (RW) algorithm is one of the most efficient and easy-to-use probabilistic segmentation methods. By combining contrast terms with prior terms, it provides accurate segmentations of medical images in a fully automated manner. However, one of the main drawbacks of using the RW algorithm is that its parameters have to be hand-tuned. we propose a novel discriminative learning framework that estimates the parameters using a training dataset. The main challenge we face is that the training samples are not fully supervised. Specifically, they provide a hard segmentation of the images, instead of a probabilistic segmentation. We overcome this challenge by treating the optimal probabilistic segmentation that is compatible with the given hard segmentation as a latent variable. This allows us to employ the latent support vector machine formulation for parameter estimation. We show that our approach significantly outperforms the baseline methods on a challenging dataset consisting of real clinical 3D MRI volumes of skeletal muscles.