Defining trajectories of dynamic biomarkers for C9ORF72 repeat expansion carriers

项目摘要/摘要 2011年，发现C9ORF72中的六核苷酸扩展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 这两种无法治愈的致命疾病。从那时起，对C9ORF72的密集研究达到了顶峰 确定其可能的病理生理机制，令人兴奋的是，新的药物治疗。前景看好 靶向重复扩增作用的药物可减轻C9ORF72小鼠模型的病理改变 以及患者来源的细胞模型。尽管这些药物现在已经准备好进行人体临床试验，但缺乏 已建立的用于检测疾病和监测治疗的生物标记物是成功的主要障碍 这些审判。因此，这项建议旨在通过以下方式推进C9ORF72扩展载体的诊断和护理 分析C9ORF72使用寿命的整个自然历史中有前景的生物标志物的轨迹。我们 将研究120名C9ORF72扩张型携带者(60名症状前，60名症状)和60名基因阴性的非 3个纵向时间点的承运人家庭成员。所有研究对象的数据将来自NIH资助的两位家长 额颞叶变性方案：1)家族性额颞叶痴呆的纵向评估 主题(LEFFTDS，1U01AG045390)和2)推进额颞叶的研究和治疗 变性(ARTFL，U54NS092089)。LEFFTDS和ARTFL采用完全协调的数据协议来 在16个中心收集全面的纵向临床、影像和生物成像数据。我们会做模特 C9ORF72疾病轨迹通过分析多模式神经成像措施和液体生物标志物 确定C9ORF72中最早的疾病表现，以及它们如何跟踪疾病的自然历史。目标 1将确定C9ORF72携带者大脑结构和神经网络功能障碍的纵向变化。目标 2将对候选流体生物标志物的轨迹进行建模。目标3将确定流体和液体之间的联系 生物标志物与大脑结构和功能。这项研究将具有创新性，作为一个全面的、纵向的 分析有希望捕捉C9ORF72疾病轨迹的生物标记物。在完成这项研究后，我们 期望为生物标志物的综合框架奠定基础，以监测治疗反应 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.