Background: Natural history data are essential for trial design in Duchenne (DMD) and Becker muscular dystrophy (BMD), but recruitment for observational studies can be challenging. Objective: We reviewed reasons why patients or caregivers declined participation, and compared characteristics of participants and non-participants to assess possible selection bias in four observational studies, three on DMD and one on BMD. Methods: Three pediatric DMD studies focused on cross-sectional cognitive function and brain MRI (DMDbrain, n = 35 and DMDperfusion, n = 12), and on longitudinal upper extremity function and muscle MRI (DMDarm, n = 22). One adult BMD study assessed longitudinal functioning (n = 36). Considerations for non-participation were retrospectively reviewed from screening logs. Age, travel-time, DMD gene mutations and age at loss of ambulation (DMDarm and BMD study only), of participants and non-participants were derived from the Dutch Dystrophinopathy Database and compared using nonparametric tests (p < 0.05). Results: The perceived burden of the protocol (38.2%), use of MRI (30.4%), and travel-time to the study site (19.1%) were the most frequently reported considerations for non-participation. Only few patients reported lack of personal gain (0.0– 5.9%). Overall, participating patients were representative for the studied sub-populations, except for a younger age of DMDarm study participants and a complete lack of participants with a mutation beyond exon 63. Conclusion: Optimizing patient involvement in protocol design, improving MRI experiences, and integrating research into clinics are important factors to decrease burden and facilitate participation. Nationwide registries are essential to compare participants and non-participants and ensure representative observational research. Specific effort is needed to include patients with distal mutations in cognitive studies.
Abstract Background Becker muscular dystrophy (BMD) is frequently characterized by myocardial involvement1 but little is known about the prevalence of left ventricular (LV) diastolic dysfunction (DD) in these patients, particularly when using more recently proposed measure of left atrial (LA) function. Purpose Purpose of our study was to assess LVDD in patients with BMD using the currently recommended echocardiographic multiparametric approach and adding LA reservoir strain as advanced measure of LVDD. Methods A total of 33 BMD patients (38±13 years) were analyzed including standard and advanced echocardiography at the time of their first visit and at 24 months follow-up. A control group consisted of 20 age- and gender-matched healthy subjects. Results 18% of BMD patients showed an e'lateral <10, 0% an E/e' >14, 22% a LAVI >34ml/m2 and 11% a tricuspid velocity >2.8m/s. When applying the currently recommended multiparametric approach, 83% of BMD patients showed normal DD and 17% showed indeterminate LV diastolic dysfunction (50% positive parameters); no BMD patient had >50% positive DD parameters for confirmed DD. LA reservoir strain was significantly lower in BMD patients as compared to controls (28±10% vs. 42±11%; p<0.001) (Figure), while LA indexed volume (LAVI) was not (26±19 ml/m2 vs. 21±6 ml/m2; p=0.142). When using the reported median value of LA reservoir strain (47%) for normal subjects with comparable age2, 31 (94%) BMD patients had impaired LA strain, but when using the cut-off value of <19% for increased LV filling pressure, 6 (18%) patients showed affected LA reservoir strain. Patients with more impaired six minute walk test (6MWT), defined as in the 1st tertile (1st tertile 0–309m; 2nd tertile 310–523m; 3rd tertile >523m) had significantly lower LA reservoir strain (1st tertile, 22±6% vs. 2nd tertile, 29±14% vs. 3rd tertile, 33±5%; p=0.022). LA reservoir strain tended to deteriorate at 1 year follow-up but not significantly (from 29±10% to 26±12%; p=0.200). Conclusions LVDD is not highly prevalent in BMD patients but LA dysfunction as assessed by LA reservoir strain is reduced and may improve detection of myocardial involvement in these patients, also over time. Funding Acknowledgement Type of funding sources: None.
In Becker muscular dystrophy evidence for neurocognitive and behavioral comorbidity is evolving. More insight into the extend of these problems is of great importance for early detection and remediation in clinical practice.In this study we aimed to describe the neurocognitive and behavioral features of a Dutch adult cohort of BMD patients, and to evaluate correlations to motor function outcomes.28 adult BMD patients were included. Intelligence, executive functioning, verbal memory and reaction times were assessed cross-sectionally. Additionally, patients completed questionnaires on behavioral and emotional symptoms, psychosocial and executive functions. Results were compared to normative data and correlated with disease severity as measured by the 10-meter run/walk test and Performance of the Upper Limb version 1.2.15 patients (53.6%) had a high educational level despite frequent grade repeating (48.3%) during primary or secondary school. Neuropsychological testing revealed that intellectual abilities, verbal memory, processing speed and executive functioning were statistically significant below average, but still within normal range. Regarding outcomes of the behavioral questionnaires, no significant differences were reported compared to the norm population. No relevant correlations with disease severity were found.This cohort of adult BMD patients exhibits minor cognitive impairments and no significant behavioral problems. The lower outcomes on processing speed and verbal memory, combined with the relatively high prevalence of grade repeating during primary and secondary school, implies that these minor impairments played a role in childhood. However, the on average high educational levels suggests that they grow out of their cognitive impairments with ageing.
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 31 P 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.
Duchenne Muscular Dystrophy (DMD) is a severe muscle disorder caused by lack of dystrophin. Predictive biomarkers able to anticipate response to the therapeutic treatments aiming at dystrophin re-expression are lacking. The objective of this study is to investigate Matrix Metalloproteinase-9 (MMP-9) as predictive biomarker for Duchenne. Two natural history cohorts were studied including 168 longitudinal samples belonging to 66 patients. We further studied 1536 samples obtained from 3 independent clinical trials with drisapersen, an antisense oligonucleotide targeting exon 51: an open label study including 12 patients; a phase 3 randomized, double blind, placebo controlled study involving 186 patients; an open label extension study performed after the phase 3. Analysis of natural history cohorts showed elevated MMP-9 levels in patients and a significant increase over time in longitudinal samples. MMP-9 decreased in parallel to clinical stabilization in the 12 patients involved in the open label study. The phase 3 study and subsequent extension study clarified that the decrease in MMP-9 levels was not predictive of treatment response. These data do not support the inclusion of serum MMP-9 as predictive biomarker for DMD patients.
Becker muscular dystrophy (BMD) is an X-linked disorder characterized by slow, progressive muscle damage and muscle weakness. Hallmarks include fibre-size variation and replacement of skeletal muscle with fibrous and adipose tissues, after repeated cycles of regeneration. Muscle histology can detect these features, but the required biopsies are invasive, are difficult to repeat and capture only small muscle volumes. Diffusion-tensor magnetic resonance imaging (DT-MRI) is a potential non-invasive alternative that can calculate muscle fibre diameters when applied with the novel random permeable barrier model (RPBM). In this study, we assessed muscle fibre diameters using DT-MRI in BMD patients and healthy controls and compared these with histology.We included 13 BMD patients and 9 age-matched controls, who underwent water-fat MRI and DT-MRI at multiple diffusion times, allowing RPBM parameter estimation in the lower leg muscles. Tibialis anterior muscle biopsies were taken from the contralateral leg in 6 BMD patients who underwent DT-MRI and from an additional 32 BMD patients and 15 healthy controls. Laminin and Sirius-red stainings were performed to evaluate muscle fibre morphology and fibrosis. Twelve ambulant patients from the MRI cohort underwent the North Star ambulatory assessment, and 6-min walk, rise-from-floor and 10-m run/walk functional tests.RPBM fibre diameter was significantly larger in BMD patients (P = 0.015): mean (SD) = 68.0 (25.3) μm versus 59.4 (19.2) μm in controls. Inter-muscle differences were also observed (P ≤ 0.002). Both inter- and intra-individual RPBM fibre diameter variability were similar between groups. Laminin staining agreed with the RPBM, showing larger median fibre diameters in patients than in controls: 72.5 (7.9) versus 63.2 (6.9) μm, P = 0.006. However, despite showing similar inter-individual variation, patients showed more intra-individual fibre diameter variability than controls-mean variance (SD) = 34.2 (7.9) versus 21.4 (6.9) μm, P < 0.001-and larger fibrosis areas: median (interquartile range) = 21.7 (5.6)% versus 14.9 (3.4)%, P < 0.001. Despite good overall agreement of RPBM and laminin fibre diameters, they were not associated in patients who underwent DT-MRI and muscle biopsy, perhaps due to lack of colocalization of DT-MRI with biopsy samples.DT-MRI RPBM metrics agree with histology and can quantify changes in muscle fibre size that are associated with regeneration without the need for biopsies. They therefore show promise as imaging biomarkers for muscular dystrophies.
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