Clinical Research in ALS & Related Disorders for Therapeutic Development (CReATe) - Project Core #3

项目概要/摘要 尽管经过了数十年的研究和数十次试验，针对肌萎缩侧索硬化症的有效疾病缓解治疗方法仍然有效。 侧索硬化症（ALS）和其他神经退行性疾病仍然困扰着我们。一连串的主要来源 阴性试验是越来越多的人认识到实验性治疗经常实施得太晚 在疾病过程中，在已经发生不可逆的神经元损失之后。这些延误部分源于 事实上，ALS 的退行性过程在明显的临床疾病之前就开始了，部分原因是延迟 诊断（症状出现后约 12 个月）以及发病与临床试验之间的延迟 入组（大约 17 个月的干预延迟）。该项目的总体目标是解决 ALS 药物开发面临的挑战是疾病进程的相对晚期阶段 做出诊断并将患者纳入临床试验。目前对症状前疾病的研究 仅可能（但也最相关）那些具有 ALS 遗传形式的人，最常见的原因是 SOD1 基因突变或 C9orf72 重复扩增。但症状性疾病的早期诊断是 与所有形式的 ALS（遗传性和非遗传性）患者相关。在这个项目中，我们概述了两个 应对这些挑战的策略，以便为未来的临床试验做好准备 患者处于病程的早期阶段。在该项目的目标 1 中，我们建议使用 多模态神经影像（MRI、DTI 和灌注 MRI）结合伪纵向、探索性 纵向和多元网络统计技术来表征解剖分布和 症状前 C9orf72 和 SOD1 突变携带者结构和功能变化的时间过程。 我们假设这种方法将帮助我们更好地了解解剖变化如何以及何时发生 相对于年龄匹配的非 ALS（或 FTD）风险的症状前个体的成年衰老过程 突变控制。我们还假设网络和多元方法将有助于提高我们的 对 C9orf72 和 SOD1 的生物学理解，以及家族性 ALS 的这些不同病因如何可能 彼此不同。在该项目的目标 2 中，我们将使用“队列”方法来评估诊断 血清和脑脊液测量的准确性（敏感性、特异性和阳性/阴性预测值） 轻神经丝 (NfL) 和重磷酸化神经丝 (pNfH) 用于 ALS 的早期诊断。这个 该方法将填补当前文献中有关神经丝诊断用途的关键空白，并且 尤其是在 ALS 的早期阶段。由于目前可用的证据基于病例对照研究 （即对已知患有 ALS 的患者与已知患有其他疾病的患者进行比较 疾病），目前对敏感性、特异性和阳性/阴性预测值的估计可能会被夸大，并且 需要重新定义截止点。总之，通过识别神经退行性变的最早的解剖位点和 使用队列而不是病例对照设计重新校准生物流体生物标志物，我们将促进关键的 需要早期干预以确保紧急临床试验的成功。

PROJECT SUMMARY/ABSTRACT Despite decades of research and dozens of trials, effective disease-modifying treatments for amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders still elude us. A primary source of the litany of negative trials is the increasing recognition that experimental therapeutics are frequently administered too late in the course of disease, after irreversible neuronal loss has already occurred. These delays stem in part from the fact that the degenerative processes in ALS begins prior to overt clinical disease, and in part from delays in diagnosis (approximately 12 months from symptom onset) and delays between onset and clinical trial enrollment (approximately 17 months interventional delay). The overall goal of this project is to address the challenge to ALS drug development that is posed by the relatively late stage in the course of disease when diagnosis is made and patients are enrolled in clinical trials. The study of pre-symptomatic disease is currently only possible in (but also most relevant to) those with the genetic forms of ALS, most commonly due to point mutations in the SOD1 gene or a repeat expansion in C9orf72. But earlier diagnosis of symptomatic disease is relevant to patients with all forms of ALS (both genetic and non-genetic). In this project, we outline two strategies for addressing these challenges, with a view to preparing for a future of clinical trials that enroll patients at significantly earlier stages in the course of their disease. In Aim 1 of this project we propose to use multimodal neuroimaging (MRI, DTI, and perfusion MRI) combined with pseudo-longitudinal, exploratory longitudinal, and multivariate network statistical techniques to characterize the anatomic distribution and temporal course of structural and functional changes in pre-symptomatic C9orf72 and SOD1 mutation carriers. We hypothesize that this approach will help us better understand how and when anatomic changes occur across adult aging in pre-symptomatic individuals at risk for ALS (or FTD) relative to age-matched non- mutation controls. We also hypothesize that network and multivariate approaches will help increase our biological understanding of C9orf72 and SOD1, as well as how these distinct etiologies of familial ALS may differ from one another. In Aim 2 of this project we will use a “cohort” approach to evaluate the diagnostic accuracy (sensitivity, specificity and positive/negative predictive value) of serum and CSF measurement of neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) for the early diagnosis of ALS. This approach will fill a critical gap in the current literature about the utility of neurofilaments for the diagnosis, and particularly in earlier stages of ALS. Since the currently available evidence is based on case-control studies (i.e. a comparison of patients already known to have ALS vs. patients already known to have some other disease), current estimates of sensitivity, specificity and positive/negative predictive value may be inflated and cut-offs need to be redefined. Together, by identifying the earliest anatomic loci of neurodegeneration and recalibrating biofluid biomarkers using a cohort rather than case-control design, we will facilitate the critical need for earlier interventions to ensure the success of emergent clinical trials.