Quantitative muscle MRI biomarkers in Duchenne muscular dystrophy: cross-sectional correlations with age and functional tests.
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ABSTRACT:
SUBMITTER: Sherlock SP
PROVIDER: S-EPMC8253163 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Duchenne muscular dystrophy (DMD) is a fatal inherited genetic disorder that results in progressive muscle weakness and ultimately loss of ambulation, respiratory failure and heart failure. Cardiac MRI (MRI) plays an increasingly important role in the diagnosis and clinical care of boys with DMD and associated cardiomyopathies. Conventional cardiac MRI biomarkers permit measurements of global cardiac function and presence of fibrosis, but changes in these measures are late manifestations. Emerging MRI biomarkers of myocardial function and structure include the estimation of rotational mechanics and regional strain using MRI tagging; T1-mapping; and T2-mapping, a marker of inflammation, edema and fat. These emerging biomarkers provide earlier insights into cardiac involvement in DMD, improving patient care and aiding the evaluation of emerging therapies.
| S-EPMC6462870 | biostudies-literature
Project description:ObjectiveThe aim of this study was to evaluate the usefulness of magnetic resonance imaging (MRI) in detecting the progression of Duchenne muscular dystrophy (DMD) by quantification of fat infiltration (FI) and muscle volume index (MVI, a residual-to-total muscle volume ratio).MethodsTwenty-six patients (baseline age: 5-12 years) with genetically proven DMD were longitudinally analyzed with lower limb 3T MRI, force measurements, and functional tests (Gowers, 10-m time, North Star Ambulatory Assessment, 6-min walking test). Five age-matched controls were also examined, with a total of 85 MRI studies. Semiquantitative (scores) and quantitative MRI (qMRI) analyses (signal intensity ratio - SIR, lower limb MVI, and individual muscle MVI) were carried out. Permutation and regression analyses according to both age and functional test-outcomes were calculated. Age-related quantitative reference curves of SIRs and MVIs were generated.ResultsFI was present on glutei and adductor magnus in all patients since the age of 5, with a proximal-to-distal progression and selective sparing of sartorius and gracilis. Patients' qMRI measures were significantly different from controls' and among age classes. qMRI were more sensitive than force measurements and functional tests in assessing disease progression, allowing quantification also after loss of ambulation. Age-related curves with percentile values were calculated for SIRs and MVIs, to provide a reference background for future experimental therapy trials. SIRs and MVIs significantly correlated with all clinical measures, and could reliably predict functional outcomes and loss of ambulation.InterpretationsqMRI-based indexes are sensitive measures that can track the progression of DMD and represent a valuable tool for follow-up and clinical studies.
| S-EPMC4999593 | biostudies-literature
Project description:We assessed changes in quantitative muscle ultrasound data in boys with Duchenne muscular dystrophy (DMD) and healthy controls to determine whether ultrasound can serve as a biomarker of disease progression. Two approaches were used: gray scale level (GSL), measured from the ultrasound image, and quantitative backscatter analysis (QBA), measured directly from the received echoes.GSL and QBA were obtained from 6 unilateral arm/leg muscles in 36 boys with DMD and 28 healthy boys (age?=?2-14 years) for up to 2 years. We used a linear mixed effects model with random intercept and slope terms to compare trajectories of GSL, QBA, and functional assessments. We analyzed separately a subset of boys who initiated corticosteroids.Compared to healthy boys, increasing GSL in DMD boys >7.0 years old was first identified at 6 months (eg, anterior forearm slope difference of 1.16 arbitrary units/mo, p?=?0.004, 95% confidence interval [CI]?=?0.38-1.94); in boys???7 years old, differences in GSL first appeared at 12 months (0.82 arbitrary units/mo, p?=?0.04, 95% CI?=?0.075-1.565, in rectus femoris). QBA performed similarly to GSL (eg, DMD boys?>?7 years old: 0.41dB/mo, p?=?0.01, 95% CI?=?0.096-0.72, in anterior forearm at 6 months). Ultrasound identified differences earlier than functional measures including 6-minute walk and supine-to-stand tests. However, neither QBA nor GSL showed an effect of corticosteroid initiation.QBA performs similarly to GSL, and both appear more sensitive than functional assessments for detecting muscle deterioration in DMD. Additional studies will be required to determine whether quantitative muscle ultrasound can detect therapeutic efficacy. Ann Neurol 2017;81:633-640.
| S-EPMC5444989 | biostudies-literature
Project description:Skeletal muscle has an extraordinary capacity to regenerate after injury and trauma. The muscle repair mechanism is a complex process orchestrated by multiple steps. In neuromuscular disorders such as Duchenne muscular dystrophy (DMD), the pathological consequences of the lack of dystrophin and the loss of the dystrophin-associated protein complex are dramatic, with a progressive cascade of events, such as continual influx of inflammation, repeated cycles of degeneration and impaired regeneration. Thus, muscle regeneration is a hallmark of the disease and careful monitoring of regenerative processes with robust markers should provide useful information to the field. Since decades, several indices of regeneration such as centronucleation and fibre size have been commonly used. In the present review, we discuss the impaired regenerative process in DMD, the common and new indices of regeneration and their associated methodologies. We notably highlight the regenerative marker embryonic myosin as a robust indicator of muscle regeneration. We also describe new quantitative methodologies offering the possibility of using a panel of translational regenerative biomarkers to obtain a more complete view of the regeneration processes. Upregulation of utrophin, an autosomal and functional paralogue of dystrophin, is one of the most promising therapeutic strategies as it targets the primary cause of the disease and is applicable to all DMD patients regardless their genetic defects. As utrophin is a regeneration associated protein increased in dystrophic muscle, we discuss the correlation of utrophin levels after drug treatment with regeneration markers. The recent advances in technologies and complementary markers of muscle regeneration described in this review, provide an unprecedented opportunity to develop more robust utrophin DMD based strategies for all DMD patients.
| S-EPMC6524502 | biostudies-literature
Project description:Numerous biomarkers have been unveiled in the rapidly evolving biomarker discovery field, with an aim to improve the clinical management of disorders. In rare diseases, such as Duchenne muscular dystrophy, this endeavor has created a wealth of knowledge that, if effectively exploited, will benefit affected individuals, with respect to health care, therapy, improved quality of life and increased life expectancy. The most promising findings and molecular biomarkers are inspected in this review, with an aim to provide an overview of currently known biomarkers and the technological developments used. Biomarkers as cells, genetic variations, miRNAs, proteins, lipids and/or metabolites indicative of disease severity, progression and treatment response have the potential to improve development and approval of therapies, clinical management of DMD and patients' life quality. We highlight the complexity of translating research results to clinical use, emphasizing the need for biomarkers, fit for purpose and describe the challenges associated with qualifying biomarkers for clinical applications.
| S-EPMC6053903 | biostudies-literature
Project description:In Duchenne muscular dystrophy (DMD), abnormal cardiac function is typically preceded by a decade of skeletal muscle disease. Molecular reasons for differences in onset and progression of these muscle groups are unknown. Human biomarkers are lacking.We analyzed cardiac and skeletal muscle microarrays from normal and golden retriever muscular dystrophy (GRMD) dogs (ages 6, 12, or 47+ mo) to gain insight into muscle dysfunction and to identify putative DMD biomarkers. These biomarkers were then measured using human DMD blood samples.We identified GRMD candidate genes that might contribute to the disparity between cardiac and skeletal muscle disease, focusing on brain-derived neurotropic factor (BDNF) and osteopontin (OPN/SPP1, hereafter indicated as SPP1). BDNF was elevated in cardiac muscle of younger GRMD but was unaltered in skeletal muscle, while SPP1 was increased only in GRMD skeletal muscle. In human DMD, circulating levels of BDNF were inversely correlated with ventricular function and fibrosis, while SPP1 levels correlated with skeletal muscle function.These results highlight gene expression patterns that could account for differences in cardiac and skeletal disease in GRMD. Most notably, animal model-derived data were translated to DMD and support use of BDNF and SPP1 as biomarkers for cardiac and skeletal muscle involvement, respectively.
| S-EPMC4837049 | biostudies-literature
Project description:Dystrophin absence in Duchenne muscular dystrophy (DMD) causes severe muscle degeneration. We describe that, as consequence of fibre damage, specific muscle-miRNAs are released in to the bloodstream of DMD patients and their levels correlate with the severity of the disease. The same miRNAs are abundant also in the blood of mdx mice and recover to wild-type levels in animals 'cured' through exon skipping. Even though creatine kinase (CK) blood levels have been utilized as diagnostic markers of several neuromuscular diseases, including DMD, we demonstrate that they correlate less well with the disease severity. Although the analysis of a larger number of patients should allow to obtain more refined correlations with the different stages of disease progression, we propose that miR-1, miR-133, and miR-206 are new and valuable biomarkers for the diagnosis of DMD and possibly also for monitoring the outcomes of therapeutic interventions in humans. Despite many different DMD therapeutic approaches are now entering clinical trials, a unifying method for assessing the benefit of different treatments is still lacking.
| S-EPMC3112257 | biostudies-literature
Project description:Duchenne muscular dystrophy (DMD) is a progressive muscle disease involving complex skeletal muscle pathogenesis. The pathogenesis is triggered by sarcolemma instability due to the lack of dystrophin protein expression, leading to Ca2+ influx, muscle fiber apoptosis, inflammation, muscle necrosis, and fibrosis. Our lab recently used two high-throughput multiplexing techniques (e.g., SomaScan® aptamer assay and tandem mass tag-(TMT) approach) and identified a series of serum protein biomarkers tied to different pathobiochemical pathways. In this study, we focused on validating the circulating levels of three proinflammatory chemokines (CCL2, CXCL10, and CCL18) that are believed to be involved in an early stage of muscle pathogenesis. We used highly specific and reproducible MSD ELISA assays and examined the association of these chemokines with DMD pathogenesis, age, disease severity, and response to glucocorticoid treatment. As expected, we confirmed that these three chemokines were significantly elevated in serum and muscle samples of DMD patients relative to age-matched healthy controls (p-value < 0.05, CCL18 was not significantly altered in muscle samples). These three chemokines were not significantly elevated in Becker muscular dystrophy (BMD) patients, a milder form of dystrophinopathy, when compared in a one-way ANOVA to a control group but remained significantly elevated in the age-matched DMD group (p < 0.05). CCL2 and CCL18 but not CXCL10 declined with age in DMD patients, whereas all three chemokines remained unchanged with age in BMD and controls. Only CCL2 showed significant association with time to climb four steps in the DMD group (r = 0.48, p = 0.038) and neared significant association with patients' reported outcome in the BMD group (r = 0.39, p = 0.058). Furthermore, CCL2 was found to be elevated in a serum of the mdx mouse model of DMD, relative to wild-type mouse model. This study suggests that CCL2 might be a suitable candidate biomarker for follow-up studies to demonstrate its physiological significance and clinical utility in DMD.
| S-EPMC8401931 | biostudies-literature
Project description:Recent studies have revealed the contribution of fibro-adipogenic progenitors (FAPs) to the pathogenesis and progression of Duchenne Muscular Dystrophy (DMD). While FAPs direct compensatory regeneration at early stages of disease, as the disease progresses they contribute to the progressive replacement of contractile myofibers with fibrotic scars and fatty infiltration. Using the mouse model of DMD - the mdx mice - we have recently reported that FAPs mediate the ability of HDAC inhibitors (HDACi) to promote muscle regeneration and prevent fibro-adipogenic degeneration at early stages of disease. This effect is mediated by the induction of myomiRs that, in turn, target the SWI/SNF components BAF60A and B, thereby favoring the formation of BAF60C-based SWI/SNF complex, which directs the switch from the fibro-adipogenic to the myogenic lineage. Here we show direct evidence of induction of miR-206 and BAF60C, and reduction of BAF60A, in FAPs isolated from mdx muscles exposed to the HDACi Trichostatin A (TSA). We also discuss how increased expression of myomiRs in dystrophic muscles can be integrated with circulating myomiRs to provide accurate biomarkers of disease progression and response to treatment.
| S-EPMC4755242 | biostudies-other
Project description:The aim of the study was to evaluate the spectrum of upper limb functional activities and imaging finding in a cohort of patients affected by Duchenne muscular dystrophy. Thirty-one patients of age between 5 and 29 years were included in the study (17 ambulant and 14 non-ambulant). They were all assessed using the Performance of Upper Limb (PUL) test and muscle MRI of shoulder, arm and forearm in order to establish if the functional scores obtained at shoulder, mid and distal level related to specific patterns of involvement in each upper limb segment on muscle MRI. At shoulder level, latissimus dorsi, serratus anterior, infraspinatus and subscapularis were always involved, even in patients with full functional scores at shoulder level. Diffuse and severe involvement of all muscles was found in the patients with a PUL shoulder functional score of ? 5. At arm level biceps brachii, brachialis and triceps were generally concordantly involved or spared. Some degree of involvement could already be detected in patients with reduced scores on the PUL mid domain. They were generally severely involved in patients with functional scores less than 6 at mid-level. At distal level supinator and pronator muscles were often involved, followed by brachioradialis and, less frequently, by the muscles of the flexor compartment. The extensor muscles were generally completely spared. A diffuse and severe involvement was found only in patients who had very low scores (8 or below) on the PUL distal domain. The integrated use of functional scales and imaging allowed to establish patterns of involvement at each level, and the functional scores that were more frequently associated with diffuse and severe involvement.
| S-EPMC6010282 | biostudies-literature