Project 1

摘要-ARTFL LEFFTDS纵向FTLD：项目1 额颞叶变性(FTLD)是一组破坏性神经退行性疾病的总称 对患者及其家人的生活有深远影响的疾病。FTLD的研究正在进入 随着潜在的疾病修改药物的开发，这是一个令人兴奋的时期。一种极具吸引力的方法 治疗的关键是在症状出现之前就开始治疗。然而，FTLD目前几乎总是被诊断为 在症状开始很久之后，当疾病已经对大脑产生深远影响的时候。关于 20%的FTLD是由常染色体显性突变引起的，最常见的是MAPT、GRN或 C9ORF72基因(家族性或f-FTLD)。突变携带者可以在痴呆症发作之前被识别出来，并且是 因此，对于寻求延缓或预防症状的研究来说至关重要。F-FTLD的干预研究将 需要独特的方法来跟踪治疗的效果。首先，他们必须选择以下措施 证明一种干预措施正在产生临床益处，即使是在经历过很少甚至没有经历过的人中也是如此 症状。其次，他们必须证明治疗可以预防或推迟症状的出现。然而， 在f-FTLD中，突变携带者患痴呆症的年龄差异很大，而且没有可靠的 预测发病年龄的标记物。如果没有这样的预测工具，就不可能瞄准那些 接近症状出现，并计算进行症状研究需要多少人 预防。这个项目的总体目标是通过开发更好的方法来为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。这个 该项目将追求以下具体目标：1)确定用于跟踪的最佳临床和成像措施 无症状突变携带者的疾病负担(FTLD-CDR=0)或轻微症状(FTLD-CDR=0) CDR=0.5)，2)开发多模式风险评分以预测无症状或轻度患者的症状恶化 症状突变携带者使用基线临床、遗传、蛋白质生物标记物和成像数据，以及3) 量化一年内皮质体积变化的跟踪价值，以预测未来病情恶化 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.