Contractile Cross-sectional Area Research Articles

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

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. Quantitative MRI and 31P MRS data were collected at 3T 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. 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 1year (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. 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.

P124 A series of dysferlinopathy patients showing fluctuations in muscle fat fraction and contractile cross-sectional area values (cCSA) over a 3-year follow-up period

P124 A series of dysferlinopathy patients showing fluctuations in muscle fat fraction and contractile cross-sectional area values (cCSA) over a 3-year follow-up period

Exploring the peripheral mechanisms of lower limb immobilisation on muscle function using novel electrophysiological methods

ObjectiveTo explore the effects of short-term immobilisation and subsequent retraining on peripheral nervous system (PNS) measures using two novel electrophysiological methods, muscle velocity recovery cycles (MVRC) and MScanFit motor unit number estimation (MUNE) alongside lower limb muscle strength, muscle imaging and walking capacity. MethodsTwelve healthy participants underwent 1-week of ankle immobilisation and 2-weeks of retraining. Assessments before and after immobilisation, and after retraining, included MVRC [muscle membrane properties; muscle relative refractory period (MRRP), early and late supernormality], MScanFit, MRI-scans [muscle contractile cross-sectional area (cCSA)], isokinetic dynamometry [dorsal and plantar flexor muscle strength], and 2-minute maximal walk test [physical function]. ResultsAfter immobilisation, compound muscle action potential (CMAP) amplitude reduced (-1.35[-2.00;-0.69]mV); mean change [95%CI]) alongside reductions in plantar (but not dorsal) flexor muscle cCSA (-124[-246;3]mm2), dorsal flexor muscle strength (isometric −0.06[-0.10;-0.02]Nm/kg, dynamicslow −0.08[-0.11;-0.04]Nm/kg, dynamicfast no changes), plantar flexor muscle strength (isometric −0.20[-0.30;-0.10]Nm/kg, dynamicslow −0.19[-0.28;-0.09]Nm/kg, dynamicfast −0.12[-0.19;-0.05]Nm/kg) and walking capacity (-31[-39;–23]m). After retraining, all immobilisation-affected parameters returned to baseline levels. In contrast, neither MScanFit nor MVRC were affected apart from slightly prolonged MRRP in gastrocnemius. ConclusionsPNS do not contribute to the changes observed in muscle strength and walking capacity. SignificanceFurther studies should include both corticospinal and peripheral mechanisms.

Myostatin and follistatin as monitoring and prognostic biomarkers in dysferlinopathy

Myostatin is a myokine which acts upon skeletal muscle to inhibit growth and regeneration. Myostatin is endogenously antagonised by follistatin. This study assessed serum myostatin and follistatin concentrations as monitoring or prognostic biomarkers in dysferlinopathy, an autosomal recessively inherited muscular dystrophy. Myostatin was quantified twice with a three-year interval in 76 patients with dysferlinopathy and 38 controls. Follistatin was quantified in 62 of these patients at the same timepoints, and in 31 controls. Correlations with motor function, muscle fat fraction and contractile cross-sectional area were performed. A regression model was used to account for confounding variables. Baseline myostatin, but not follistatin, correlated with baseline function and MRI measures. However, in individual patients, three-year change in myostatin did not correlate with functional or MRI changes. Linear modelling demonstrated that function, serum creatine kinase and C-reactive protein, but not age, were independently related to myostatin concentration. Baseline myostatin concentration predicted loss of ambulation but not rate of change of functional or MRI measures, even when relative inhibition with follistatin was considered. With adjustment for extra-muscular causes of variation, myostatin could form a surrogate measure of functional ability or muscle mass, however myostatin inhibition does not form a promising treatment target in dysferlinopathy.

P.93 Effect of rapamycine on quantitative MRI outcome measures in inclusion body myositis

Quantitative magnetic resonance imaging (qMRI) outcome measures such as muscle fat fraction (FF) and contractile cross-sectional area (cCSA), reflecting disease progression, and water T2, reflecting disease activity (inflammation, edema), are used in the longitudinal studies of neuromuscular diseases, including inclusion body myositis (IBM). Here, we report qMRI results from the RAPAMI study (NCT02481453), obtained at 3 Tesla in the muscle of 45 patients (rapamycine vs. placebo) at baseline and year-1. Values for FF, cCSA and water T2 values were calculated in anterior and posterior (triceps surae) leg and anterior (quadriceps) and posterior (hamstring) thigh muscle groups. Functional assessments included the six-minute walking distance (6MWD). Student's t-tests and Pearson correlation analyses were performed (P<0.05). Standardized response means (SRM) values were calculated to assess the sensitivity to change for the different MRI outcome measures. No differences in demographic data existed between rapamycine and placebo groups (P>0.20). Overall, patients (20 female, 23 male) were 66±8 years old and had symptoms for 8±5 years. There was a significant left-right difference for FF and cCSA (P<0.001) but not for water T2 (P=0.89). Values of FF and cCSA at baseline were not significantly different between both patient groups for anterior and posterior leg and thigh muscle groups (P>0.11). FF increase after one year was significantly lower in the rapamycine group for the posterior (P<0.027) but not for the anterior muscle group (P>0.08). The one-year decrease in anterior thigh cCSA was slightly significantly higher in the placebo group (P=0.045). The SRM values for FF and cCSA changes were systematically higher in the placebo group with SRM>0.8 for FF in triceps surae and quadriceps and SRM>0.8 for cCSA in hamstring, only in the rapamycine group. Water T2 was significantly elevated in leg and anterior thigh muscle compared to control values (≈39ms) and a moderately strong relation between baseline water T2 and the FF change was observed in posterior thigh (R2=0.57, overall patients). The increase in anterior thigh FF associated with a decrease in 6MWD was particularly observed in the placebo group (R2=0.30). qMRI has demonstrated that small yet significant changes can be measured between non-treated and treated IBM patients, within specific muscle groups, and correlates to function measures.

Three-year quantitative magnetic resonance imaging and phosphorus magnetic resonance spectroscopy study in lower limb muscle in dysferlinopathy.

BackgroundNatural 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.MethodsQuantitative 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.ResultsPosterior 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).ConclusionsThis 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.

Selection Approach to Identify the Optimal Biomarker Using Quantitative Muscle MRI and Functional Assessments in Becker Muscular Dystrophy

ObjectiveTo identify the best quantitative fat–water MRI biomarker for disease progression of leg muscles in Becker muscular dystrophy (BMD) by applying a stepwise approach based on standardized response mean (SRM) over 24 months, correlations with baseline ambulatory tests, and reproducibility.MethodsDixon fat–water imaging was performed at baseline (n = 24) and 24 months (n = 20). Fat fractions (FF) were calculated for 3 center slices and the whole muscles for 19 muscles and 6 muscle groups. Contractile cross-sectional area (cCSA) was obtained from the center slice. Functional assessments included knee extension and flexion force and 3 ambulatory tests (North Star Ambulatory Assessment [NSAA], 10-meter run, 6-minute walking test). MRI measures were selected using SRM (≥0.8) and correlation with all ambulatory tests (ρ ≤ −0.8). Measures were evaluated based on intraclass correlation coefficient (ICC) and SD of the difference. Sample sizes were calculated assuming 50% reduction in disease progression over 24 months in a clinical trial with 1:1 randomization.ResultsMedian whole muscle FF increased between 0.2% and 2.6% without consistent cCSA changes. High SRMs and strong functional correlations were found for 8 FF but no cCSA measures. All measures showed excellent ICC (≥0.999) and similar SD of the interrater difference. Whole thigh 3 center slices FF was the best biomarker (SRM 1.04, correlations ρ ≤ −0.81, ICC 1.00, SD 0.23%, sample size 59) based on low SD and acquisition and analysis time.ConclusionIn BMD, median FF of all muscles increased over 24 months. Whole thigh 3 center slices FF reduced the sample size by approximately 40% compared to NSAA.

Function, structure and quality of striated muscles in the lower extremities in patients with late onset Pompe Disease-an MRI study.

BackgroundPompe Disease (PD) is a rare inherited metabolic myopathy, caused by lysosomal-α-glucosidase (GAA) deficiency, which leads to glycogen accumulation within the lysosomes, resulting in cellular and tissue damage. Due to the emergence of a disease modifying treatment with recombinant GAA there has been a large increase in studies of late onset Pompe Disease (LOPD) during the last decade.MethodsThe present study evaluates muscle quality in 10 patients with LOPD receiving treatment with enzyme replacement therapy and in 10 age and gender matched healthy controls applying T1-weighted Dixon MR imaging and isokinetic dynamometry. Muscle quality was determined by muscle strength in relation to muscle size (contractile cross-sectional area, CSA) and to muscle quality (fat fraction). A follow-up evaluation of the patients was performed after 8–12 months. Patient evaluations also included: six-minute walking test (6MWT), forced vital capacity, manual muscle testing and SF-36 questionnaire.ResultsFat fraction of knee flexors (0.15 vs 0.07, p < 0.05) and hip muscles (0.11 vs 0.07, p < 0.05) were higher in patients than controls. In patients, contractile CSA correlated with muscle strength (knee flexors: r = 0.86, knee extensors: r = 0.88, hip extensors: r = 0.83, p < 0.05). No correlation was found between fat fraction and muscle strength. The fat fraction of thigh muscles did not correlate with scores from the clinical tests nor did it correlate with the 6MWT. During follow-up, the contractile CSA of the knee extensors increased by 2%. No other statistically significant change was observed. Quantitative MRI reflects muscle function in patients with LOPD, but larger long-term studies are needed to evaluate its utility in detecting changes over time.

Isokinetic strength and degeneration of lower extremity muscles in patients with myotonic dystrophy; an MRI study

Our aim was to determine isokinetic strength and degeneration of lower extremity muscles in patients with Myotonic Dystrophy (DM1). In 19 patients with DM1 and 19 matched controls, strength measured by isokinetic dynamometry was expressed as percentage of expected strength (ePct), adjusted for age, height, weight and gender. MRI of the hip, thigh and calf muscles were obtained. Fat fraction (FF), mean contractile cross-sectional area (cCSA) and specific strength (Nm/cm2) were calculated. Patients’ ankle plantar flexors, knee flexors and extensors had higher FF (Δ: 0.08 – 0.42) and lower cCSA (Δ: 3.2 –17.1 cm2) compared to controls (p ≤ 0.005). EPct (Δ: 19.5 – 41.6%) and specific strength (Δ: 0.27 – 0.96 Nm/cm2) were lower in the majority of patients muscle groups (p˂0.05). Close correlations were found for patients when relating ePct to; FF for plantar flexors (R2=0.742, p<0.001) and knee extensors (R2=0.732, p<0.001), cCSA for plantar flexors (R2=0.696, p<0.001) and knee extensors (R2=0.633, p<0.001), and specific strength for dorsal flexors (ρ=0.855, p = 0.008). In conclusion, patients had weaker lower extremity muscles with higher FF, lower cCSA and specific strength compared to controls. Muscle degeneration determined by quantitative MRI strongly correlated to strength supporting its feasibility to quantify muscle dysfunction in DM1.

Multi-parametric MR in Becker muscular dystrophy patients.

Quantitative MRI and MRS of muscle are increasingly being used to measure individual pathophysiological processes in Becker muscular dystrophy (BMD). In particular, muscle fat fraction was shown to be highly associated with functional tests in BMD. However, the muscle strength per unit of contractile cross‐sectional area is lower in patients with BMD compared with healthy controls. This suggests that the quality of the non‐fat‐replaced (NFR) muscle tissue is lower than in healthy controls. Consequently, a measure that reflects changes in muscle tissue itself is needed. Here, we explore the potential of water T 2 relaxation times, diffusion parameters and phosphorus metabolic indices as early disease markers in patients with BMD. For this purpose, we examined these measures in fat‐replaced (FR) and NFR lower leg muscles in patients with BMD and compared these values with those in healthy controls. Quantitative proton MRI (three‐point Dixon, multi‐spin‐echo and diffusion‐weighted spin‐echo echo planar imaging) and 2D chemical shift imaging 31P MRS data were acquired in 24 patients with BMD (age 18.8‐66.2 years) and 13 healthy controls (age 21.3‐63.6 years). Muscle fat fractions, phosphorus metabolic indices, and averages and standard deviations (SDs) of the water T 2 relaxation times and diffusion tensor imaging (DTI) parameters were assessed in six individual leg muscles. Phosphodiester levels were increased in the NFR and FR tibialis anterior, FR peroneus and FR gastrocnemius lateralis muscles. No clear pattern was visible for the other metabolic indices. Increased T 2 SD was found in the majority of FR muscles compared with NFR and healthy control muscles. No differences in average water T 2 relaxation times or DTI indices were found between groups. Overall, our results indicate that primarily muscles that are further along in the disease process showed increases in T 2 heterogeneity and changes in some metabolic indices. No clear differences were found for the DTI indices between groups.

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.

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. 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). 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. 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.

Contractile properties are impaired in congenital myopathies

The ratio between muscle strength and muscle cross-sectional area is called the specific force. Fatty replacement of muscles is seen in many myopathies, affecting the specific force, without necessarily affecting the ability of the remaining muscle fibers to contract. This ability is called the contractility and is the ratio between muscle strength and the lean muscle cross-sectional area, i.e. the contractile cross-sectional area. We hypothesized that contractility is disrupted in patients with congenital myopathy, because of defects in contractile proteins of the sarcomere. Peak torque across ankle and knee joints was measured by isokinetic dynamometry in 16 patients with congenital myopathy and 13 healthy controls. Five patients only participated partially in the dynamometer measurements due to severe muscle weakness. Dixon MRI technique was used to quantify muscle fat fractions and calculate cross-sectional area. Patients with congenital myopathy had lower cross-sectional area in all muscle groups (P<0.01), higher fat fraction (P<0.01) and less strength (P<0.005) in all studied muscle groups. Their fat content was more than doubled and peak torque lower than half that in healthy controls. Muscle contractility was reduced (P<0.01) in three of four patient muscle groups. In conclusion, muscle contractility was reduced in patients with congenital myopathy, across different diagnoses, and was independent of the level of muscle fat fraction, suggesting that intrinsic defects of the myocyte are responsible for reduced contractility.

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

To identify the most responsive and sensitive clinical outcome measures in GNE myopathy. 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. 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. 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.

P.305MRI brachialis contractile cross-sectional area is correlated strongest to elbow flexion in non-ambulant Duchenne muscular dystrophy patients

P.305MRI brachialis contractile cross-sectional area is correlated strongest to elbow flexion in non-ambulant Duchenne muscular dystrophy patients

P.265Integrating clinical outcome measures, MRI and circulating biomarkers in subjects with Becker muscular dystrophy: a prospective longitudinal study

Becker muscular dystrophy (BMD) is caused by mutations in the dystrophin (DMD) gene. BMD is clinically characterized by a highly variable disease course ranging from mild symptoms to severe muscle weakness. Natural history studies in BMD subjects are required to prepare for clinical trials in this population as well as to understand what possible outcomes may be expected in pharmacological interventions aimed at restoring dystrophin expression in subjects affected by Duchenne MD. Until now, most studies have focused on a single or limited set of biomarkers. In the present study, we will present an approach that combines a large number of potential biomarkers to improve prognostic prediction in BMD. In this prospective study we obtained longitudinal and cross-sectional clinical, muscle MRI and serum biomarker data from 52 genetically confirmed BMD subjects with a follow-up of 2 to 8 years. Clinical tests included quantitative muscle assessment of the major muscle groups, the 6-Minute Walk Distance (6-MWD) test, Performance of the Upper Limb (PUL) and the North Star Ambulatory Assessment (NSAA). In a subgroup of 23 subjects, 3-point Dixon MRI scans were acquired and used to calculate weighted average fat fraction and contractile cross-sectional area of the middle of the quadriceps muscle. Serum samples were collected yearly to quantify a panel of biomarkers linked to the pathophysiology such as TGF-β factors, to the metabolic state of muscle such as creatine and creatinine, or to the mutation site (i.e. mutation affecting or not affecting the NOS binding site). Association and integration of the different readouts will be presented including testing on how MRI, clinical and circulating biomarker data can be integrated to improve the prognostic prediction of disease progression in BMD patients. Comparison with DMD patients will also be presented.

Free intramuscular Mg2+ concentration calculated using both 31P and 1H NMRS‐based pH in the skeletal muscle of Duchenne muscular dystrophy patients

Early studies have demonstrated that (total) magnesium was decreased in skeletal muscle of Duchenne muscular dystrophy (DMD) patients. Free intramuscular Mg2+ can be derived from 31 P NMRS measurements. The value of free intramuscular magnesium concentration ([Mg2+ ]) is highly dependent on precise knowledge of intracellular pH, which is abnormally alkaline in dystrophic muscle, possibly due to an expanded interstitial space, potentially causing an underestimation of [Mg2+ ]. We have recently shown that intracellular pH can be derived using 1 H NMRS of carnosine. Our aim was to determine whether 31 P NMRS-based [Mg2+ ] is, in fact, abnormally low in DMD patients, taking advantage of the 1 H NMRS-based pH. A comparative analysis was, therefore, made between [Mg2+ ] values calculated with both 1 H and 31 P NMRS-based approaches to determine pH in 25 DMD patients, on a 3-T clinical NMR scanner. [Mg2+ ] was also assessed with 31 P NMRS only in (forearm or leg) skeletal muscle of 60 DMD patients and 63 age-matched controls. Additionally, phosphodiester levels as well as quantitative NMRI indices including water T2 , fat fraction, contractile cross-sectional area and one-year changes were evaluated. The main finding was that the significant difference in [Mg2+ ] between DMD patients and controls was preserved even when the intracellular pH determined with 1 H NMRS was similar in both groups. Consequently, we observed that [Mg2+ ] is significantly lower in DMD patients compared with controls in the larger database where only 31 P NMRS data were obtained. Significant yet weak correlations existed between [Mg2+ ] and PDE, water T2 and fat fraction. We concluded that low [Mg2+ ] is an actual finding in DMD, whether intracellular pH is normal or alkaline, and that it is a likely consequence of membrane leakiness. The response of Mg2+ to therapeutic treatment remains to be investigated in neuromuscular disorders. Free [Mg2+ ] determination with 31 P NMRS is highly dependent on a precise knowledge of intracellular pH. The pH of Duchenne muscular dystrophy (DMD) patients, as determined by 31 P NMRS, is abnormally alkaline. We have recently shown that intracellular pH could be determined using 1 H NMRS of carnosine, and that intracellular pH was alkaline in a proportion of, but not all, DMD patients with a 31 P NMRS-based alkaline pH. Taking advantage of this 1 H NMRS-based intracellular pH, we found that free intramuscular [Mg2+ ] is in fact abnormally low in DMD patients.

SMA CLINICAL DATA, OUTCOME MEASURES AND REGISTRIES: P.88Associations between NMR, electrophysiological, strength and function variables in SMA type 2 and 3

NatHis-SMA is a prospective multicentre natural history study on spinal muscular atrophy (SMA) type 2 and 3 incorporating a combination of various measurements over 2 years. Among the 81 patients included, 43 patients were aged between 6 and 30 years. Twenty-four patients were SMA Type 2, 9 non-ambulant SMA Type 3 and 10 ambulant SMA Type 3. We present here the analyses on the relationships between skeletal muscle NMR imaging, electrophysiological, strength and function variables on this population of patients during a two-year follow-up. Measurements were performed in the forearm and hand muscles. Fat fraction, cross-sectional area (CSA) and contractile CSA values were determined for the forearm flexor muscles of 11 patients using manually segmented Dixon NMR imaging. Maximum motor response were induced in 38 patients on the anconeus and abductor digiti minimi muscles by maximal stimulation of the radial nerve and the ulnar nerve, respectively. Each compound muscle action potential (CMAP) was characterized by its amplitude and area. Grip and pinch strength were measured in 43 patients using the MyoGrip and MyoPinch dynamometers. Muscle function was assessed in 43 patients using the motor function measure (MFM) from which the dimension on distal motor function was deduced (MFM-D3). Spearman rho or Pearson correlation coefficients were computed between variables depending on monotonic or linear assumption on their relationship. All variables were moderately to strongly correlated to each other. Particularly, strength, CMAP amplitude and contractile CSA were closely associated. The poster will show the changes observed over two years in these variables in the patients. First analyses show that the patients are very slowly progressing. Interestingly, in this first analysis, some variables such as contractile cross-sectional area assessed by NMR or pinch strength are more sensitive to change. This will be confirmed in the subsequent analysis of the full dataset.

Muscle contractility of leg muscles in patients with mitochondrial myopathies

BackgroundThe primary disease mechanism underlying mitochondrial myopathies (MM) is impaired energy generation to support muscle endurance. Little is known about muscle contractility before energy becomes deficient during muscle contractions. We investigated muscle contractility in MM to uncover potentially fixed weakness aspects of the disorders. MethodsContractility of calf and thigh muscles was investigated by comparing strength with contractile cross-sectional area (CCSA) of the used muscles, as measured by stationary dynamometry and MRI, respectively. Results and discussionOur findings suggest reduced contractile properties in thigh and calf muscles of patients with MM.

P.192 - Muscle fiber dysfunction contributes to clinical muscle weakness in inclusion body myositis

Inclusion body myositis (IBM) is the most common acquired muscle disorder in adults over 50 years old. It is characterized by progressive muscle weakness and marked muscle atrophy, most prominent in the finger flexors and quadriceps muscle. In addition to atrophy, fatty replacement of muscle tissue contributes to clinical muscle weakness and functional decline. This study aims to investigate the contractile performance of residual muscle tissue. We included 8 participants with IBM and 12 healthy controls. We measured individual health related quality of life, functional performance and muscle strength. In all participants, muscle contractile capacity was measured both in vivo, using quantitative muscle testing and MRI imaging, and ex vivo, using single fiber studies of the vastus lateralis as well as tibialis anterior muscle biopsies. Quadriceps specific force was calculated by correcting the voluntary maximum force (N) for the contractile cross-sectional area (CCSA). CCSA was calculated by multiplying the total cross-sectional area by the muscle fraction on MRI. Voluntary maximum force generation of the quadriceps muscle was significantly reduced in IBM participants (216.9 ± 57.6 N vs. 572.1 ± 53.1 N, p < .001). Quadriceps specific force was reduced in IBM participants. Muscle fiber specific force was also reduced in IBM patients compared to healthy controls (type 1 fibers: 158.3 ± 4.1 mN/mm2 in IBM vs. 178.9 ± 3.4 in controls, type 2 fibers: 180.3 ± 7.2 mN/mm2 in IBM vs. 213.7 ± 4.2 in controls, p = .036). Reduced muscle fiber specific force was equally present in vastus lateralis and tibialis anterior muscles. Contractile performance of residual muscle tissue is impaired in IBM patients, both in vivo and ex vivo. We conclude that sarcomeric dysfunction contributes to clinical muscle weakness in IBM.

Quantitative Dixon MRI sequences to relate muscle atrophy and fatty degeneration with range of motion and muscle force in brachial plexus injury

BackgroundAssessment of muscle atrophy and fatty degeneration in brachial plexus injury (BPI) could yield valuable insight into pathophysiology and could be used to predict clinical outcome. The objective of this study was to quantify and relate fat percentage and cross-sectional area (CSA) of the biceps to range of motion and muscle force of traumatic brachial plexus injury (BPI) patients. MethodsT1-weighted TSE sequence and three-point Dixon images of the affected and non-affected biceps brachii were acquired on a 3 Tesla magnetic resonance scanner to determine the fat percentage, total and contractile CSA of 20 adult BPI patients. Regions of interest were drawn by two independent investigators to determine the inter-observer reliability. Paired Students' t-test and multivariate analysis were used to relate fat percentage, total and contractile CSA to active flexion and biceps muscle force. ResultsThe mean fat percentage 12±5.1% of affected biceps was higher than 6±1.0% of the non-affected biceps (p<0.001). The mean contractile CSA 8.1±5.1cm2 of the affected biceps was lower than 19.4±4.9cm2 of the non-affected biceps (p<0.001). The inter-observer reliability was excellent (ICC 0.82 to 0.96). The contractile CSA contributed most to the reduction in active flexion and muscle force. ConclusionQuantitative measurement of fat percentage, total and contractile CSA using three-point Dixon sequences provides an excellent reliability and relates with active flexion and muscle force in BPI.