MRI Biomarkers of Disease Progression in Inherited Neuropathies

项目总结 这项建议的首要目标是推进候选磁共振的临床试验准备情况 Charcot-Marie-Tooth(CMT)病1A型(CMT1a)的影像(MRI)生物标志物 髓鞘障碍遗传性神经病伴继发性轴突丧失。尽管CMT1A的治疗前景看好 人类试验的治疗评估因缺乏反应灵敏的生物标记物而受阻， 由于CMT1a进展缓慢，这一点至关重要。CMT神经病变评分(CMTNS)是 综合残疾评分被认为是CMT的生物标志物；然而， CMTNS每年都需要巨大的样本量用于CMT临床研究。最近，在- 肌间脂肪百分比(通过脂肪-水MRI)已被认为是一个更敏感的生物标志物。不幸的是- Ly，脂肪替代代表CMT1a的慢性终点；因此，可能很难评估Thera- 延缓或停止(而不是逆转)已经失去神经的肌肉的进展的馅饼 测量。基于我们开发的神经核磁共振方法，我们假设直接成像的病理 神经本身的兴趣可能会提供补充信息，并提高我们的监控能力 CMT1a患者的疾病进展。我们实验室发表的结果表明，坐骨神经- 髓鞘转移率(MTR)，它对脱/脱髓鞘和髓鞘脱失引起的髓鞘含量变化敏感 与CMT各亚型残疾有关的轴突损失，以及其他初步数据表明神经 MTR对疾病进展做出反应。最新的初步和公布的数据表明，磁共振成像- 基于神经直径的估计可能是CMT1A的一个特异性生物标志物。总而言之，这些结果表明 神经MRI可能提供CMT的有效生物标志物；然而，关于以下问题仍然存在：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敏感性； Ii)这些候选生物标志物与功能(CMTNS、测功术)、电物理- 同一队列中的生物学(神经传导研究，NCS)、病理学(皮肤活检)和生活质量； 神经/肌肉的成像生物标记物是否在不同地点和供应商之间产生可靠的结果，以供未来使用 审判。我们旨在通过以下目标来解决这些差距：1)确定磁共振成像的响应性 神经MTR、神经直径和肌内脂肪百分比值对疾病进展的影响 CMT1a和2)确定神经MTR的站点间和供应商间的重复性和重复性 直径和肌内脂肪百分比值。这项建议建立在以下团队现有专业知识的基础上 韦恩州立大学和巴罗神经学研究所，旨在为每个目标并行进行 通过跨站点的协调努力。如果成功，这些研究将提供响应的成像生物标记物 未来试验的CMT1a进展，这是至关重要的，因为反应性之间存在反向关系 以及为这种罕见的神经疾病的临床试验提供动力所需的样本量。

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.