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

项目摘要/摘要 尽管进行了数十年的研究和数十次试验，但对肌营养不良患者进行有效的疾病修正治疗 侧索硬化症(ALS)和其他神经退行性疾病仍然困扰着我们。长篇大论的主要来源 阴性试验是越来越多的人认识到，实验疗法往往实施得太晚了 在病程中，后脑已经发生不可逆转的神经元丢失。这些延误的部分原因是 肌萎缩侧索硬化症的退变过程在明显的临床疾病之前就开始了，部分原因是 诊断(从症状出现起约12个月)以及发病和临床试验之间的延迟 招生(大约17个月的干预延迟)。该项目的总体目标是解决 在疾病过程中处于相对较晚的阶段对ALS药物开发构成的挑战 做出诊断，并将患者纳入临床试验。对有症状前疾病的研究目前正在进行 只有那些具有ALS基因形式的人才有可能(但也是最相关的)，最常见的原因是 SOD1基因突变或C9orf72的重复扩增。但症状性疾病的早期诊断是 与所有形式的肌萎缩侧索硬化症(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 应对这些挑战的战略，以期为未来登记的临床试验做准备 患者的病程明显处于早期。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)与伪纵、探查相结合 纵向和多变量网络统计技术，以表征解剖分布和 症状前C9orf72和SOD1突变携带者结构和功能变化的时间进程 我们假设这种方法将帮助我们更好地理解解剖变化是如何以及何时发生的。 与年龄匹配的非匹配人群相比，有ALS(或FTD)风险的症状前个体的成年年龄 突变控制。我们还假设，网络和多变量方法将有助于增加我们的 对C9orf72和SOD1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 血清和脑脊液检测的准确性(敏感性、特异性和阳性/阴性预测值) 神经丝轻(NFL)和磷酸化神经丝重(PNfH)在ALS早期诊断中的价值这 该方法将填补目前文献中关于神经细丝用于诊断的一个关键空白，以及 尤其在肌萎缩侧索硬化症的早期阶段。由于目前可用的证据是基于病例对照研究 (即已知患有肌萎缩侧索硬化症的患者与已知患有其他疾病的患者的比较 疾病)，目前对敏感性、特异性和阳性/阴性预测值的估计可能被夸大， 分界线需要重新定义。通过确定神经退行性变的最早解剖位置和 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.