The 6-minute walk test, motor function measure and quantitative thigh muscle MRI in Becker muscular dystrophy: A cross-sectional study.

Becker muscular dystrophy (BMD) has an incidence of 1 in 16 000 male births. This cross-sectional study investigated the relation between validated functional scores and quantitative MRI (qMRI) of thigh muscles in 20 ambulatory BMD patients, aged 18.3-60 years (mean 31.2; SD 11.1). Clinical assessments included the motor function measure (MFM) and its subscales, as well as timed function tests such as the 6-minute walk test (6MWT) and the timed 10-m run/walk test. Quantitative MRI of the thigh muscles included the mean fat fraction (MFF) using a 2-point Dixon (2-PD) technique, and transverse relaxation time (T2) measurements. The mean MFM value was 80.4%, SD 9.44 and the D1 subscore 54.5%, SD 19.9. The median 6MWT was 195m, IQR 160-330.2. The median 10-m run/walk test was 7.4 seconds, IQR 6.1-9.3. The mean fat fraction of the thigh muscles was 55.6%, SD 17.4%, mean T2 relaxation times of all muscles: 69.9 ms, SD 14.4. The flexors had the highest MFF and T2 relaxation times, followed by the extensors and the adductors. MFF and global T2 relaxation times were highly negatively correlated with the MFM total, D1-subscore and 6MWT, and positively correlated with the 10 m run/walk test time (p < 0.01). Age was not correlated with MFF, global T2 relaxation time or clinical assessments. Both MFF and T2 measures in the thigh muscle were well correlated with clinical function in BMD and may serve as a surrogate outcome measure in clinical trials.

Improved Muscle Function in Duchenne Muscular Dystrophy through L-Arginine and Metformin: An Investigator-Initiated, Open-Label, Single-Center, Proof-Of-Concept-Study.

UNLABELLED: Altered neuronal nitric oxide synthase function in Duchenne muscular dystrophy leads to impaired mitochondrial function which is thought to be one cause of muscle damage in this disease. The study tested if increased intramuscular nitric oxide concentration can improve mitochondrial energy metabolism in Duchenne muscular dystrophy using a novel therapeutic approach through the combination of L-arginine with metformin. Five ambulatory, genetically confirmed Duchenne muscular dystrophy patients aged between 7­10 years were treated with L-arginine (3 x 2.5 g/d) and metformin (2 x 250 mg/d) for 16 weeks. Treatment effects were assessed using mitochondrial protein expression analysis in muscular biopsies, indirect calorimetry, Dual-Energy X-Ray Absorptiometry, quantitative thigh muscle MRI, and clinical scores of muscle performance. There were no serious side effects and no patient dropped out. Muscle biopsy results showed pre-treatment a significantly reduced mitochondrial protein expression and increased oxidative stress in Duchenne muscular dystrophy patients compared to controls. Post-treatment a significant elevation of proteins of the mitochondrial electron transport chain was observed as well as a reduction in oxidative stress. Treatment also decreased resting energy expenditure rates and energy substrate use shifted from carbohydrates to fatty acids. These changes were associated with improved clinical scores. In conclusion pharmacological stimulation of the nitric oxide pathway leads to improved mitochondria function and clinically a slowing of disease progression in Duchenne muscular dystrophy. This study shall lead to further development of this novel therapeutic approach into a real alternative for Duchenne muscular dystrophy patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT02516085.

Quantitative muscle MRI: A powerful surrogate outcome measure in Duchenne muscular dystrophy.

In muscular dystrophies quantitative muscle MRI (qMRI) detects disease progression more sensitively than clinical scores. This prospective one year observational study compared qMRI with clinical scores in Duchenne muscular dystrophy (DMD) to investigate if qMRI can serve as a surrogate outcome measure in clinical trials. In 20 DMD patients the motor function measure (MFM) total and subscores (D1-D3) were done for physical examination, and the fat fraction (MFF) of thigh muscle qMRI was obtained using the two-point Dixon method. Effect sizes (ES) were calculated for all measures. Sample size estimation (SS) was done modelling assumed treatment effects. Ambulant patients <7 years at inclusion improved in the MFM total and D1 score (ES 1.1 and 1.0). Ambulant patients >7 years (highest ES in the MFM D1 subscore (1.2)), and non-ambulant patients (highest ES in the total MFM score (0.7)) worsened. In comparison the ES of QMRI was much larger, e.g. SS estimations for qMRI data were up to 17 fold smaller compared to the MFM total score and up to 7 fold to the D1 subscore, respectively. QMRI shows pathophysiological changes in DMD and might serve as a surrogate outcome measure in clinical trials.

Longitudinal 2-point dixon muscle magnetic resonance imaging in becker muscular dystrophy.

INTRODUCTION: Quantitative MRI techniques detect disease progression in myopathies more sensitively than muscle function measures or conventional MRI. To date, only conventional MRI data using visual rating scales are available for measurement of disease progression in Becker muscular dystrophy (BMD). METHODS: In 3 patients with BMD (mean age 36.8 years), the mean fat fraction (MFF) of the thigh muscles was assessed by MRI at baseline and at 1-year follow-up using a 2-point Dixon approach (2PD). The motor function measurement scale (MFM) was used for clinical assessment. RESULTS: The mean MFF of all muscles at baseline was 61.6% (SD 7.6). It increased by 3.7% to 65.3% (SD 4.7) at follow-up. The severity of muscle involvement varied between various muscle groups. CONCLUSIONS: As in other myopathies, 2PD can quantify fatty muscle degeneration in BMD and can detect disease progression in a small sample size and at relatively short imaging intervals.

Quantitative MRI and loss of free ambulation in Duchenne muscular dystrophy.

The purpose of this ethics approved trial was to correlate quantitative MRI with functional abilities in both ambulant and non-ambulant Duchenne muscular dystrophy (DMD). Twenty patients with genetically confirmed DMD were recruited. Physical assessment was performed using the motor function measurement (MFM) scale. Axial 3T MRI scans of the thighs were acquired using T1-weighted in- and opposed-phase images (TR = 20 ms, TE1 = 2.45 ms, TE2 = 3.68 ms, flip angle = 15°) to calculate the relative fat fraction according to the two-point Dixon method in the knee extensors, flexors, and adductor muscles. The average MFM was 65.3 % and correlated negatively to age (r (2) = 0.60). Overall mean fat fraction correlated positively to age (r (2) = 0.51-0.64). An average of 5 % increase in mean fat fraction per year was calculated. Mean fat fraction of the quadriceps showed a high negative correlation (r (2) = 0.93) to the D1 (standing position and transfers) component of the MFM. A cutoff for mean fat fraction of 50 % predicted loss of ambulation with a sensitivity of 100 % and a specificity of 91 %. Therefore, quantitative muscle MRI seems to be a promising endpoint for short clinical trials evaluating the effect of newer treatments on the time of loss of ambulation in DMD.