MRI Biomarkers of Disease Progression in Inherited Neuropathies

项目摘要 该提案的总体目标是推进候选磁共振的临床试验准备 Charcot-Marie-Tooth（CMT）疾病1A型（CMT 1A）疾病进展的MRI（MRI）生物标志物， 伴有继发性轴突缺失的髓鞘形成障碍遗传性神经病。虽然有希望的治疗CMT 1A 即将到来，人类试验中的治疗评估受到缺乏响应性生物标志物的阻碍， 由于CMT 1A的缓慢进展性质，这是关键的。CMT神经病变评分（CMTNS）是一种 复合残疾评分被提议作为CMT的生物标志物;然而， CMTNS每年都需要非常大的样本量用于CMT临床研究。最近，在- 肌肉脂肪百分比（通过脂肪-水MRI）已被提议作为更敏感的生物标志物。很不幸- 事实上，脂肪替代代表CMT 1A的慢性终点;因此，可能难以评估治疗效果。 馅饼，减缓或停止（而不是逆转）已经失去神经支配的肌肉的进展， measure.基于我们开发的神经MRI方法，我们假设直接成像的病理， 对神经本身的兴趣可以提供补充信息，并提高我们监测 CMT 1A患者的疾病进展。我们实验室公布的结果表明坐骨神经肥大- 髓鞘化转移率（MTR），对脱髓鞘/髓鞘化障碍引起的髓鞘含量变化敏感， 轴突缺失与CMT亚型残疾有关，另外的初步数据表明， MTR对疾病进展有反应。最近的初步和发表的数据表明，MRI- 基于神经直径的估计可能是CMT 1A的特异性生物标志物。这些结果表明， 神经MRI可能产生可行的CMT生物标志物;然而，问题仍然存在：i）相对反应， 基于神经MRI（MTR和直径）和肌肉MRI（肌内脂肪）的潜在生物标志物的有效性; ii）这些候选生物标志物与功能（CMTNS，测力法）、电生理学和免疫学之间的关系。 同一队列中的病理学（神经传导研究，NCS）、病理学（皮肤活检）和生活质量;以及iii） 神经/肌肉的成像生物标志物是否在各研究中心和供应商之间产生可靠的结果，以供将来使用 审判我们的目标是通过以下目标来解决这些差距：1）确定MRI衍生的响应性 神经MTR、神经直径和肌内脂肪百分比值与疾病进展的关系 CMT 1A和2）确定神经MTR、神经 直径和肌内脂肪百分比值。这项建议是以各小组现有的专门知识为基础， 韦恩州立大学和巴罗神经学研究所，并设计为每个目标平行进行 通过各站点的协调工作。如果成功的话，这些研究将提供反应性的成像生物标志物， 未来试验的CMT 1A进展，这是至关重要的，因为反应性之间的反比关系 以及在这种罕见的神经系统疾病中进行临床试验所需的样本量。

PROJECT SUMMARY The overarching goal of this proposal is to advance the clinical trial readiness of candidate magnetic resonance imaging (MRI) biomarkers of disease progression in Charcot-Marie-Tooth (CMT) disease type 1A (CMT1A), a dysmyelinating inherited neuropathy with secondary axonal loss. Although promising treatments for CMT1A are on the horizon, the evaluation of therapies in human trails is hindered by a lack of responsive biomarkers, which is critical due to the slowly progressive nature of CMT1A. The CMT neuropathy score (CMTNS) is a composite disability score proposed as a biomarker of CMT; however, the limited responsiveness of the CMTNS annually demands a formidably large sample size for use in CMT clinical studies. More recently, in- tramuscular fat percentage (via fat-water MRI) has been proposed as a more sensitive biomarker. Unfortunate- ly, fat replacement represents the chronic endpoint of CMT1A; therefore, it may be difficult to evaluate thera- pies that slow or halt (rather than reverse) progression in muscles that are already denervated using this measure. Based on our developed nerve MRI methods, we hypothesize that directly imaging the pathology of interest within nerves themselves may offer complementary information and improve our ability to monitor disease progression in patients with CMT1A. Published results from our labs indicate that sciatic nerve mag- netization transfer ratios (MTR), which are sensitive to myelin content changes from de/dysmyelination and axonal loss, relate to disability across CMT subtypes, and additional preliminary data indicate that nerve MTRs are responsive to disease progression. More recent preliminary and published data indicate that MRI- based nerve diameter estimates may be a specific biomarker of CMT1A. Together, these results indicate that nerve MRI may yield viable biomarkers of CMT; however, questions remain regarding: i) the relative respon- siveness of potential biomarkers based on nerve MRI (MTR and diameter) and muscle MRI (intramuscular fat); ii) the relationships between these candidate biomarkers and function (CMTNS, dynamometry), electrophysi- ology (nerve conduction studies, NCS), pathology (skin biopsy), and quality-of-life in the same cohort; and iii) whether imaging biomarkers of nerve/muscle yield reliable results across sites and vendors for use in future trials. We aim to address these gaps via the following aims: 1) determine the responsiveness of MRI-derived nerve MTR, nerve diameter, and intramuscular fat percentage values to disease progression in patients with CMT1A and 2) determine the inter-site and inter-vendor reproducibility and repeatability of nerve MTR, nerve diameter, and intramuscular fat percentage values. This proposal builds upon existing expertise of the teams at Wayne State and the Barrow Neurological Institute and is designed for each aim to be undertaken in parallel with coordinated effort across sites. If successful, these studies will provide responsive imaging biomarkers of CMT1A progression for future trials, which is critical due to the inverse relationship between responsiveness and the sample size needed to power clinical trials in this rare neurological disorder.