Project 1

项目1

基本信息

批准号：
10208708
负责人：
HOWARD J ROSEN
金额：
$ 37.72万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-15 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10208708
关键词：
Address Age Age of Onset Biological Biological Markers Brain Brain imaging C9ORF72 Cerebrum Clinical Clinical Markers Clinical Trials Clinical assessments Data Dementia Deterioration Development Diagnosis Disease Enrollment Family Frontotemporal Lobar Degenerations Future Genes Genetic Genetic Markers Genetic Polymorphism Goals Image Individual Intervention Intervention Studies Light Liquid substance Logistics Maps Measurement Measures Medical Genetics Methods Neurodegenerative Disorders Neurons Neuropsychology Participant Patients Pharmaceutical Preparations Plasma Prevention Publishing Research Risk Sample Size Severities Sum Symptoms System Time United States National Institutes of Health Work autosomal dominant mutation brain volume burden of illness executive function experience functional decline imaging biomarker improved multimodality mutation carrier neurofilament novel predictive marker predictive tools prevent protein biomarkers rate of change treatment choice treatment effect

项目摘要

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.

摘要 - Artfl Lefftds纵向FTLD：项目1 额颞叶变性（FTLD）是一组毁灭性神经退行性的总术语对患者及其家人的生活产生深远影响的疾病。 FTLD的研究正在进入由于正在开发潜在的改良疾病药物，因此一个令人兴奋的时期。一种高度吸引力的方法因为治疗是在症状发生之前开始治疗。但是，FTLD目前几乎总是被诊断出症状开始很久以后，这种疾病已经对大脑产生了深远的影响。关于 FTLD的20％是由于常染色体显性突变，最常见于MAPT，GRN或 C9orf72基因（家族性或F-FTLD）。突变载体可以在痴呆发作之前鉴定出来，并且是因此，对于试图延迟或预防症状的研究至关重要。 F-FTLD的干预研究将需要独特的方法来跟踪治疗的影响。首先，他们必须选择措施证明干预措施会导致临床利益症状。其次，他们必须表明治疗可以预防或延迟症状的发作。然而，突变载体会在F-FTLD中显着发展各种痴呆的年龄，并且没有可靠的预测发病年龄的标记。没有这样的预测工具，就不可能针对接近症状发作并计算症状研究需要多少人预防。该项目的总体目标是通过更好地发展F-FTLD的临床试验准备选择参与者和跟踪疾病伯恩以证明治疗效果的方法。这项目将追求以下特定目的：1）确定跟踪的最佳临床和成像措施渐近疾病（FTLD-CDR = 0）的突变携带者中疾病燃烧，或有症状（FTLD- CDR = 0.5），2）建立多模式风险评分，以预测无症状或轻度的症状使用基线临床，遗传，蛋白质生物标志物和成像数据的有症状突变载体，以及3）量化一年来跟踪皮质体积变化的价值，以预测未来的担忧无症状或轻度症状突变载体的症状。