Defining trajectories of dynamic biomarkers for C9ORF72 repeat expansion carriers

项目总结/摘要 2011年，发现C9 ORF 72中的六核苷酸扩增是最常见的遗传原因， 额颞叶痴呆（FTD）和肌萎缩侧索硬化症（ALS），揭示了一个共同的机制， 这两种致命的疾病无法治愈从那时起，对C9 ORF 72的深入研究达到了高潮， 其可能的病理生理机制的鉴定和令人兴奋的是，新的药物治疗。有前途 靶向重复扩增效应的药物减少C9 ORF 72小鼠模型的病理变化 和源自患者的细胞模型。虽然这些药物现在已经准备好进行人体临床试验，但缺乏 用于检测疾病和监测治疗的生物标志物是成功的主要障碍。 这些审判。因此，该提议旨在通过以下方式来推进C9 ORF 72扩增携带者的诊断和护理： 分析在C9 ORF 72寿命的整个自然历史中有希望的生物标志物的轨迹。我们 将研究120名C9 ORF 72扩增携带者（60名症状前患者，60名症状性患者）和60名基因阴性非 携带者家族成员的3个纵向时间点。所有受试者数据将来自NIH资助的两名家长 额颞叶变性的研究项目：1）家族性额颞叶痴呆的纵向评估 受试者（LEFFTDS，1U 01 AG 045390）和2）推进额颞叶的研究和治疗 变性（ARTFL，U 54 NS 092089）。LEFFTDS和ARTFL采用完全统一的数据协议， 在16个中心收集全面的纵向临床、成像和生物标本数据。我们将模型 C9 ORF 72疾病轨迹通过分析多模态神经成像测量和流体生物标志物， 确定C9 ORF 72中最早的疾病表现以及它们如何追踪疾病的自然史。目的 1将确定C9 ORF 72携带者脑结构和神经网络功能障碍的纵向变化。目的 2将对候选流体生物标志物的轨迹进行建模。目标3将确定流体之间的关联 生物标志物和大脑结构和功能。本研究将创新性地作为一个综合性、纵向 分析有希望的生物标志物以捕获C9 ORF 72疾病轨迹。在完成这项研究后，我们 希望为生物标志物的综合框架奠定基础，以监测治疗反应， 在生化水平和大脑系统水平。

PROJECT SUMMARY/ABSTRACT In 2011, the discovery that a hexanucleotide expansion in C9ORF72 is the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), revealed a common mechanism for these two fatal diseases that have no cure. Since then, intensive research on C9ORF72 has culminated in the identification of its possible pathophysiological mechanisms and excitingly, new drug treatments. Promising drugs that target the effects of the repeat expansion reduce pathological changes in C9ORF72 mouse models and patient-derived cell models. Although these drugs are now ready for human clinical trials, the absence of established biomarkers for detecting disease and monitoring treatment is a major obstacle to the success of these trials. Thus, this proposal aims to advance the diagnosis and care of C9ORF72 expansion carriers by analyzing the trajectories of promising biomarkers throughout the natural history of the C9ORF72 lifespan. We will study 120 C9ORF72 expansion carriers (60 presymptomatic, 60 symptomatic) and 60 gene negative non- carrier family members for 3 longitudinal time points. All subject data will come from two NIH-funded parent projects for frontotemporal lobar degeneration: 1) Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS, 1U01AG045390) and 2) Advancing the Research and Treatment of Frontotemporal Lobar Degeneration (ARTFL, U54NS092089). LEFFTDS and ARTFL employ fully harmonized data protocols to collect comprehensive longitudinal clinical, imaging and biospecimen data across 16 centers. We will model C9ORF72 disease trajectories by analyzing multimodal neuroimaging measures and fluid biomarkers to identify the earliest disease manifestations in C9ORF72 and how they track the natural history of disease. Aim 1 will identify longitudinal changes in brain structure and neural network dysfunction in C9ORF72 carriers. Aim 2 will model trajectories of candidate fluid biomarkers. Aim 3 will determine associations between fluid biomarkers and brain structure and function. This study will be innovative as a comprehensive, longitudinal analysis of promising biomarkers to capture C9ORF72 disease trajectories. Upon completion of this study, we expect to lay the foundation for an integrated framework of biomarkers to monitor treatment response both at the biochemical level and at the brain-systems level.