Relationship between markers of disease activity and progression in skeletal muscle of GNE myopathy patients using quantitative nuclear magnetic resonance imaging and (31)P 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 T(2) and (31)P 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 T(2) mapping were acquired in legs and thighs, and in the dominant forearm. (31)P NMRS was performed at the level of quadriceps and hamstring. Water T(2) and (31)P 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 (R(muscle_transf)). RESULTS: In quadriceps, known to be relatively preserved in GNEM, water T(2) at baseline was significantly higher compared to controls, and correlated strongly with the one-year evolution of Fat% and cCSA and R(muscle_transf). Various (31)P NMRS indices showed significant differences in quadriceps and hamstring compared to controls and correlations existed between these indices and ΔFat%, ΔcCSA and R(muscle_transf). CONCLUSIONS: This study demonstrates that disease activity indices such as water T(2) and (31)P 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

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

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 ( P MRS) outcome measures and evaluated their relationship with function in lower limb skeletal muscle of dysferlinopathy patients. METHODS: Quantitative MRI/ P MRS data were obtained at 3 T in two different sites in 54 patients and 12 controls, at baseline, and three annual follow-up visits. Fat fraction (FF), contractile cross-sectional area (cCSA), and muscle water T in both global leg and thigh segments and individual muscles and P MRS indices in the anterior leg compartment were assessed. Analysis included comparisons between patients and controls, assessments of annual changes using a linear mixed model, standardized response means (SRM), and correlations between MRI and P MRS markers and functional markers. RESULTS: Posterior muscles in thigh and leg showed the highest FF values. FF at baseline was highly heterogeneous across patients. In ambulant patients, median annual increases in global thigh and leg segment FF values were 4.1% and 3.0%, respectively (P \u3c 0.001). After 3 years, global thigh and leg FF increases were 9.6% and 8.4%, respectively (P \u3c 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 \u3c 0.001). Water T values in ambulant patients were significantly increased, as compared with control values (P \u3c 0.001). The highest water T values were found in the anterior part of thigh and leg. Almost all P MRS indices were significantly different in patients as compared with controls (P \u3c 0.006), except for pH , and remained, similar as to water T , abnormal for the whole study duration. Global thigh water T at baseline was significantly correlated to the change in FF after 3 years (ρ = 0.52, P \u3c 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/ P MRS measurements in a heterogeneous group of dysferlinopathy patients can measure significant changes over the course of 3 years. These data can be used as reference values in view of future clinical trials in dysferlinopathy or comparisons with quantitative MRI/S data obtained in other limb-girdle muscular dystrophy subtypes

Water T2 could predict functional decline in patients with dysferlinopathy

BACKGROUND: Water T2 (T2 ) mapping is increasingly being used in muscular dystrophies to assess active muscle damage. It has been suggested as a surrogate outcome measure for clinical trials. Here, we investigated the prognostic utility of T2 to identify changes in muscle function over time in limb girdle muscular dystrophies. METHODS: Patients with genetically confirmed dysferlinopathy were assessed as part of the Jain Foundation Clinical Outcomes Study in dysferlinopathy. The cohort included 18 patients from two sites, both equipped with 3-tesla magnetic resonance imaging (MRI) systems from the same vendor. T2 value was defined as higher or lower than the median in each muscle bilaterally. The degree of deterioration on four functional tests over 3 years was assessed in a linear model against covariates of high or low T2 at baseline, age, disease duration, and baseline function. RESULTS: A higher T2 at baseline significantly correlated with a greater decline on functional tests in 21 out of 35 muscles and was never associated with slower decline. Higher baseline T2 in adductor magnus, vastus intermedius, vastus lateralis, and vastus medialis were the most sensitive, being associated bilaterally with greater decline in multiple timed tests. Patients with a higher than median baseline T2 (\u3e40.6 ms) in the right vastus medialis deteriorated 11 points more on the North Star Ambulatory Assessment for Dysferlinopathy and lost an additional 86 m on the 6-min walk than those with a lower T2 (\u3c40.6 ms). Optimum sensitivity and specificity thresholds for predicting decline were 39.0 ms in adductor magnus and vastus intermedius, 40.0 ms in vastus medialis, and 40.5 ms in vastus lateralis from different sites equipped with different MRI systems. CONCLUSIONS: In dysferlinopathy, T2 did not correlate with current functional ability. However, T2 at baseline was higher in patients who worsened more rapidly on functional tests. This suggests that inter-patient differences in functional decline over time may be, in part, explained by different severities of the active muscle damage, assessed by T2 measure at baseline. Significant challenges remain in standardizing T2 values across sites to allow determining globally applicable thresholds. The results from the present work are encouraging and suggest that T2 could be used to improve prognostication, patient selection, and disease modelling for clinical trials