Magnetic resonance imaging and spectroscopy biomarkers for facioscapulohumeral muscular dystrophy

 描述（由申请人提供）：面肩肱型肌营养不良症（FSHD）是一种遗传性肌肉疾病，大约每20，000人中就有1人患病。虽然在阐明FSHD的疾病机制方面取得了进展，但由于疾病自然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是评估骨骼肌亚临床疾病的一种很有前途的工具，我们假设它是一个更好的预测疾病严重程度的变化比目前的肌营养不良症研究中使用的结果措施。拟议研究的3个具体目标将使用非侵入性MRI技术前瞻性研究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志物。具体目的1：使用形态学全身MRI前瞻性评价FSHD疾病的放射学进展。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2年内检测FSHD受试者个体肌肉的临床和亚临床疾病进展。具体目标二：在青少年和年轻成人FSHD受试者中使用新型代谢成像技术表征外观正常的肌肉的早期疾病相关变化。我们假设，我们将能够检测到肌肉内的代谢异常，似乎正常的传统MRI序列使用扩散加权成像和磁共振波谱。这一目标在儿科FSHD人群中的应用是独一无二的，这将为症状发作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的生物标志物与肌营养不良症的临床结局指标。由于肌营养不良症研究中最广泛使用的结局指标是临床结局指标（力量和定时功能测试），我们将在FSHD受试者的大型横断面样本中比较使用全身MRI获得的基于成像的生物标志物与临床结局指标。我们预计MRI将被证明是一个上级和更客观的预测功能FSHD。 我们提出的研究将利用肌肉特异性MRI协议来详细描述纵向变化 FSHD的放射学表型。这些信息将用于制定肌肉疾病临床试验和观察性研究所需的定量、非侵入性结局指标。我们预计，代谢和形态MRI序列的组合不仅将成为有价值的疾病生物标志物，而且将为FSHD疾病的未来遗传和表观遗传生物标志物的验证提供新的金标准。

 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.