Project 1

摘要-- ARTFL LEFFTDS纵向FTLD：项目1 额颞叶退行性变（FTLD）是一组破坏性神经退行性变的总称。 对患者及其家属的生活有深远影响的疾病。FTLD的研究正在进入 这是一个令人兴奋的时期，因为正在开发潜在的改善疾病的药物。一种极具吸引力的方法 强迫疗法是在症状出现之前开始治疗。然而，FTLD目前几乎总是被诊断 在症状已经开始很久之后，当疾病已经对大脑产生了深远的影响时。关于 20%的FTLD是由常染色体显性突变引起的，最常见的是在MAPT、GRN或 C9 orf 72基因（家族性或f-FTLD）。突变携带者可在痴呆发作前被鉴定， 因此对于试图延迟或预防症状的研究是关键的。对f-FTLD的干预研究将 需要独特的方法来跟踪治疗效果。首先，它们必须选择 证明干预可产生临床获益，即使是在很少（如果有的话）发生这种情况的患者中 症状第二，他们必须证明治疗可以预防或延迟症状的发作。然而，在这方面， 在f-FTLD中突变携带者发生痴呆的年龄差异很大，并且没有可靠的 预测发病年龄的标志物。如果没有这样的预测工具，就不可能针对那些 接近症状发作，并计算需要多少人进行症状研究 预防本项目的总体目标是通过开发更好的F-FTLD基因，为F-FTLD的临床试验做准备。 选择参与者和跟踪疾病负担以证明治疗效果的方法。的 该项目将追求以下具体目标：1）确定最佳的临床和影像学跟踪措施 无症状（FTLD-CDR=0）或轻度症状（FTLD-CDR=0）突变携带者的疾病负担 CDR=0.5），2）开发多模式风险评分，以预测无症状或轻度 使用基线临床、遗传学、蛋白质生物标志物和成像数据的症状性突变携带者，以及3） 量化一年内皮质体积的跟踪变化对预测未来恶化的价值 无症状或轻度症状突变携带者的症状。

ABSTRACT – ARTFL LEFFTDS Longitudinal FTLD: Project 1 Frontotemporal lobar degeneration (FTLD) is the overall term for a group of devastating neurodegenerative disorders that have a profound effect on the lives of patients and their families. Research in FTLD is entering an exciting period as potential disease-modifying drugs are being developed. One highly attractive approach for therapy is to start treatment before symptoms occur. However, FTLD is currently almost always diagnosed long after symptoms have begun, when the disease has already had profound effects on the brain. About twenty percent of FTLD is due to autosomal dominant mutations, most commonly in the MAPT, GRN, or C9orf72 genes (familial, or f-FTLD). Mutation carriers can be identified before the onset of dementia, and are therefore critical for studies that would seek to delay or prevent symptoms. Intervention studies in f-FTLD will require unique approaches for tracking the effects of treatment. First, they must choose measures that demonstrate that an intervention is resulting in clinical benefit, even in people who are experiencing few if any symptoms. Second, they must show that the treatment prevents or delays the onset of symptoms. However, the age when a mutation carrier will develop dementia varies dramatically in f-FTLD, and there are no reliable markers for predicting age of onset. Without such predictive tools, it is impossible to target patients who are approaching symptom onset and calculate how many people would be needed for a study of symptom prevention. The overall goal of this project is to prepare for clinical trials in f-FTLD by developing better methods for selecting participants and for tracking disease burden to demonstrate treatment effects. The project will pursue the following specific aims: 1) To identify the best clinical and imaging measures for tracking disease burden in mutation carriers who are asymptomatic (FTLD-CDR=0), or mildly symptomatic (FTLD- CDR=0.5), 2) To develop a multimodal risk score to predict worsening symptoms in asymptomatic or mildly symptomatic mutation carriers using baseline clinical, genetic, protein biomarker and imaging data, and 3) To quantify the value of tracking change in cortical volume over one year for predicting future worsening of symptoms in asymptomatic or mildly symptomatic mutation carriers.