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Background Quantitative muscle MRI commonly evaluates disease activity and muscle wasting in Duchenne muscular dystrophy (DMD). Disturbances in ion homeostasis contribute to DMD pathophysiology, but their relationships with disease progression is unclear. 23Na MRI may provide insights into the disease course and treatment response. This longitudinal study assessed whether sodium levels are elevated in DMD patients regardless of fat fraction (FF) and whether baseline sodium levels influence FF changes over time. Additionally, we quantified the effect of slice selection on measured sodium values. Methods Thirteen DMD boys (age 7.8 ± 2.4 years) underwent MRI of lower leg muscles at 3T at three visits, spaced 6 months apart. We assessed FF for disease progression and water T2, pH, apparent tissue sodium concentration (aTSC), and intracellular‐weighted 23Na signal (ICwS) for disease activity. Fourteen healthy boys (age 9.5 ± 1.7 years) underwent the same MRI protocol once. Linear regression and mixed‐effect modelling were used to examine sodium level increases and their impact on FF changes. Results In DMD, muscles with FF < 10% exhibited significantly elevated aTSC (24.8 ± 4.6 mM vs. 14.5 ± 2.1 mM in controls, p < 0.001) and higher ICwS (23.6 ± 2.5 a.u. vs. 14.1 ± 2.1 a.u., p < 0.001). At Visit 1, FF values showed a significant negative association with aTSC (β = −17.30, p = 0.016) and ICwS (β = −21.02, p < 0.001). The first mixed‐effect model, which assessed aTSC alone, showed no significant effect on FF progression but indicated a weak trend (p = 0.098). The second, more comprehensive model—incorporating also ICwS and water T2—revealed that FF changes were positively associated with aTSC (p = 0.0023) and negatively associated with ICwS and wT2 (p < 0.001 and p = 0.025, respectively), with ICwS showing a significant interaction with time (p = 0.0033). Varying slice positioning and slice number demonstrated minimal impact on aTSC and ICwS, with low CV (2%–4%) in the mid‐belly region. Conclusions The study demonstrates significant MRI‐based changes related to dystrophic alterations in DMD. We identified early alterations in sodium homeostasis, independent of FF. Our findings suggest that the relationship between sodium levels and FF progression is complex and may not be fully explained by total sodium measurements alone. Given the small sample size, further validation in larger cohorts is needed. Combined 1H and 23Na‐MRI may offer deeper insights into how metabolic and ionic changes interact with FF progression and overall disease activity.

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.

Outcome measures for clinical trials in neuromuscular diseases are typically based on physical assessments which are dependent on patient effort, combine the effort of different muscle groups, and may not be sensitive to progression over short trial periods in slow-progressing diseases. We hypothesised that quantitative fat imaging by MRI (Dixon technique) could provide more discriminating quantitative, patient-independent measurements of the progress of muscle fat replacement within individual muscle groups. To determine whether quantitative fat imaging could measure disease progression in a cohort of limb-girdle muscular dystrophy 2I (LGMD2I) patients over a 12 month period. 32 adult patients (17 male;15 female) from 4 European tertiary referral centres with the homozygous c.826C>A mutation in the fukutin-related protein gene (FKRP) completed baseline and follow up measurements 12 months later. Quantitative fat imaging was performed and muscle fat fraction change was compared with (i) muscle strength and function assessed using standardized physical tests and (ii) standard T1-weighted MRI graded on a 6 point scale. There was a significant increase in muscle fat fraction in 9 of the 14 muscles analyzed using the quantitative MRI technique from baseline to 12 months follow up. Changes were not seen in the conventional longitudinal physical assessments or in qualitative scoring of the T₁w images. Quantitative muscle MRI, using the Dixon technique, could be used as an important longitudinal outcome measure to assess muscle pathology and monitor therapeutic efficacy in patients with LGMD2I.

We conducted a prospective multinational study of muscle pathology using magnetic resonance imaging (MRI) in patients with limb-girdle muscular dystrophy 2I (LGMD2I). Thirty eight adult ambulant LGMD2I patients (19 male; 19 female) with genetically identical mutations (c.826C>A) in the fukutin-related protein (FKRP) gene were recruited. In each patient, T1-weighted (T1w) imaging was assessed by qualitative grading for 15 individual lower limb muscles and quantitative Dixon imaging was analysed on 14 individual lower limb muscles by region of interest analysis. We described the pattern and appearance of muscle pathology and gender differences, not previously reported for LGMD2I. Diffuse fat infiltration of the gastrocnemii muscles was demonstrated in females, whereas in males fat infiltration was more prominent in the medial than the lateral gastrocnemius (p = 0.05). In the anterior thigh of males, in contrast to females, median fat infiltration in the vastus medialis muscle (45.7%) exceeded that in the vastus lateralis muscle (11.2%) (p<0.005). MRI is non-invasive, objective and does not rely on patient effort compared to clinical and physical measures that are currently employed. We demonstrated (i) that the quantitative Dixon technique is an objective quantitative marker of disease and (ii) new observations of gender specific patterns of muscle involvement in LGMD2I.

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.

Fibrosis is a key pathological feature in muscle disorders, but its quantification mainly relies on histological and biochemical assays. Muscle fibrosis most frequently is entangled with other pathological processes, as cell membrane lesions, inflammation, necrosis, regeneration, or fatty infiltration, making in vivo assessment difficult. Here, we (1) describe a novel mouse model with variable levels of induced skeletal muscle fibrosis displaying minimal inflammation and no fat infiltration, and (2) report how fibrosis affects non-invasive metrics derived from nuclear magnetic resonance (NMR) and ultrasound shear-wave elastography (SWE) associated with a passive biomechanical assay. Our findings show that collagen fraction correlates with multiple non-invasive metrics. Among them, muscle stiffness as measured by SWE, T 2 , and extracellular volume (ECV) as measured by NMR have the strongest correlations with histology. We also report that combining metrics in a multi-modality index allowed better discrimination between fibrotic and normal skeletal muscles. This study demonstrates that skeletal muscle fibrosis leads to alterations that can be assessed in vivo with multiple imaging parameters. Furthermore, combining NMR and SWE passive biomechanical assay improves the non-invasive evaluation of skeletal muscle fibrosis and may allow disentangling it from co-occurring pathological alterations in more complex scenarios, such as muscular dystrophies.

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

Background Natural history studies in neuromuscular disorders are vital to understand the disease evolution and to find sensitive outcome measures. We performed a longitudinal assessment of quantitative magnetic resonance imaging (MRI) and phosphorus magnetic resonance spectroscopy (31P MRS) outcome measures and evaluated their relationship with function in lower limb skeletal muscle of dysferlinopathy patients. Methods Quantitative MRI/31P MRS data were obtained at 3 T in two different sites in 54 patients and 12 controls, at baseline, and three annual follow‐up visits. Fat fraction (FF), contractile cross‐sectional area (cCSA), and muscle water T2 in both global leg and thigh segments and individual muscles and 31P MRS indices in the anterior leg compartment were assessed. Analysis included comparisons between patients and controls, assessments of annual changes using a linear mixed model, standardized response means (SRM), and correlations between MRI and 31P MRS markers and functional markers. Results Posterior muscles in thigh and leg showed the highest FF values. FF at baseline was highly heterogeneous across patients. In ambulant patients, median annual increases in global thigh and leg segment FF values were 4.1% and 3.0%, respectively (P < 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 31P 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/31P 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.

ObjectivesTo 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.MethodsThe 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.ResultsThe 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).ConclusionsT1-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.

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