Magnetic resonance imaging and spectroscopy biomarkers for facioscapulohumeral muscular dystrophy

 描述(由申请者提供)：面肩肱骨肌营养不良症(FSHD)是一种遗传性肌肉疾病，大约每20,000人中就有1人受到影响。尽管在阐明FSHD的发病机制方面取得了进展，但由于有关疾病自然病史的信息有限和缺乏适当的疾病生物标志物，这些知识转化为有效的治疗方法受到阻碍。MRI是一种很有前途的评估骨骼肌亚临床疾病的工具，我们假设它比目前用于肌肉营养不良研究的结果指标更能预测疾病严重程度的变化。这项拟议研究的3个具体目标将使用非侵入性MRI技术来前瞻性地研究FSHD的疾病进展，并为未来的临床研究开发基于成像的生物标记物。具体目的1：应用形态全身MRI前瞻性评价FSHD的放射学进展。这项纵向队列研究的前瞻性设计将使我们能够检验我们的假设，即全身T1加权和短tau反转恢复MRI序列将在两年内检测FSHD受试者个别肌肉的临床和亚临床疾病进展。具体目标2：使用新的代谢成像技术来表征青少年和年轻成人FSHD受试者正常外观肌肉的早期疾病相关变化。我们假设，我们将能够使用扩散加权成像和磁共振波谱来检测在传统MRI序列上看起来正常的肌肉内的代谢异常。这一目的在利用儿科FSHD人群方面是独一无二的，这将为研究症状出现时发生的病理过程提供有价值的见解。具体目标3：比较基于MRI的生物标记物和肌营养不良症的临床结果。由于肌营养不良研究中最广泛使用的结果指标是临床结果指标(强度和定时功能测试)，我们将在大样本FSHD患者中比较使用全身MRI获得的基于成像的生物标记物和临床结果指标。我们期望MRI能更好、更客观地预测FSHD患者的功能。我们建议的研究将利用肌肉特异性磁共振成像方案来详细描述纵向变化 在FSHD的放射学表型中。这些信息将被用来开发肌肉疾病临床试验和观察研究所需的定量、非侵入性结果衡量标准。我们预计，代谢和形态MRI序列的结合不仅将成为有价值的疾病生物标记物，而且将为验证未来FSHD的遗传和表观遗传学疾病生物标记物提供新的金标准。

 DESCRIPTION (provided by applicant): Facioscapulohumeral muscular dystrophy (FSHD) is a hereditary muscle disorder that affects approximately 1 in 20,000 individuals. Although there has been progress in elucidating the mechanisms of disease in FSHD, the translation of this knowledge into effective therapies is impeded by limited information on the natural history of disease and a lack of appropriate disease biomarkers. MRI is a promising tool in the assessment of subclinical disease in skeletal muscle, and we hypothesize that it is a better predictor of changes in disease severity than the current outcome measures used in studies of muscular dystrophy. The 3 specific aims of the proposed research will use non-invasive MRI techniques to prospectively study the progression of disease in FSHD and develop imaging-based biomarkers for future clinical research. Specific Aim 1: To prospectively evaluate the radiographic progression of disease in FSHD using morphologic whole-body MRI. The prospective design of this longitudinal cohort study will allow us to test our hypothesis that whole-body T1-weighted and short-tau inversion recovery MRI sequences will detect clinical and subclinical disease progression in individual muscles over 2 years in subjects with FSHD. Specific Aim 2: To characterize early disease-related changes in normal-appearing muscle using novel metabolic imaging techniques in adolescent and young adult subjects with FSHD. We hypothesize that we will be able to detect metabolic abnormalities within muscles that appear normal on traditional MRI sequences using diffusion-weighted imaging and magnetic resonance spectroscopy. This aim is unique in its utilization of the pediatric FSHD population, which will provide valuable insight into the pathological processes that occur at the time of symptom onset. Specific Aim 3: To compare MRI-based biomarkers to clinical outcome measures in muscular dystrophy. As the most widely-used outcome measures in muscular dystrophy research are clinical outcome measures (strength and timed function tests), we will compare imaging-based biomarkers obtained using whole-body MRI to clinical outcome measures in a large cross-sectional sample of subjects with FSHD. We anticipate that MRI will prove to be a superior and more objective predictor of function in FSHD. Our proposed research will utilize a muscle-specific MRI protocol to characterize in detail longitudinal changes in the radiographic phenotype of FSHD. This information will be used to develop quantitative, non- invasive outcome measures that are needed for clinical trials and observational studies in muscle disease. We anticipate that the combination of metabolic and morphologic MRI sequences will not only become valuable disease biomarkers, but will provide a new gold standard for the validation of future genetic and epigenetic biomarkers of disease in FSHD.