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

项目总结/摘要 尽管经过数十年的研究和数十次试验， 侧索硬化症（ALS）和其他神经变性疾病仍然困扰着我们。一个主要的来源， 消极的试验是越来越多的人认识到，实验性治疗往往是管理太晚 在疾病过程中，在不可逆的神经元损失已经发生之后。这些延迟部分源于 事实上，ALS中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 诊断（症状发作后约12个月）和发作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过程中的相对晚期阶段， 做出诊断并将患者纳入临床试验。症状前疾病的研究目前 只有在那些有ALS遗传形式的人中才有可能（但也是最相关的），最常见的原因是 SOD1基因突变或C9orf72重复扩增。但早期诊断出有症状的疾病， 与所有形式的ALS（遗传和非遗传）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，以期为未来的临床试验做好准备， 患者在疾病的早期阶段。在本项目的目标1中，我们建议使用 多模式神经成像（MRI、DTI和灌注MRI）结合伪纵向、探索性 纵向和多变量网络统计技术来表征解剖分布， 症状前C9orf72和SOD1突变携带者结构和功能变化的时间进程 我们假设这种方法将帮助我们更好地了解解剖学变化如何以及何时发生 在有ALS（或FTD）风险的症状前个体中， 突变控制我们还假设网络和多元方法将有助于增加我们的 对C9orf72和SOD 1的生物学理解，以及这些家族性ALS的不同病因如何可能 彼此不同。在本项目的目标2中，我们将使用"队列"方法来评估诊断 血清和CSF测量的准确性（灵敏度、特异性和阳性/阴性预测值） 神经丝轻蛋白（NfL）和磷酸化神经丝重蛋白（pNfH）用于ALS的早期诊断。这 这种方法将填补目前文献中关于神经丝用于诊断的重要空白， 特别是在ALS的早期阶段。由于现有的证据是基于病例对照研究 (i.e.已经知道患有ALS的患者与已经知道患有其他疾病的患者的比较 疾病），灵敏度、特异性和阳性/阴性预测值的当前估计可能被夸大， 需要重新界定界限。总之，通过识别神经变性的最早解剖位点， 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.