JPND - Defining measures of proximity to symptom onset in the GENetic Frontotemporal dementia Initiative

额颞叶痴呆（FTD）是一种高度遗传性的神经退行性疾病，其大部分遗传性是由三个基因的常染色体显性突变引起的：前颗粒蛋白（GRN）、微管相关蛋白tau （MAPT）和9号染色体开放阅读框72 （C9orf72）。遗传FTD倡议（GENFI）是一项欧洲和加拿大多中心的遗传FTD自然历史研究，对症状前和症状突变携带者进行了详细的表型分析。在缺乏可以延缓或预防遗传性FTD发病或进展的治疗方法的情况下，GENFI的目的是为未来的试验确定可靠的生物标志物。然而，随着临床试验的临近，识别接近症状发作的生物标志物，在个体基础上识别那些在未来5到10年内可能进展为临床FTD的人，将是至关重要的。因此，本研究的目的是表征遗传性FTD的前驱期，建立认知、成像和液体生物标志物测量方法，以允许i)将个体症状前携带者分层到症状发作的近端阶段，以及ii)测量该近端期间的后续疾病进展。特别是，这项工作将扩展先前GENFI研究中在群体基础上发现的结果，以确定个体基础上的措施和变化模式，从而为针对FTD的精准医学方法铺平道路。它将利用目前GENFI研究中至少950名参与者的数据，这些数据是纵向获得的生物标志物数据（到目前为止访问了2000次）。它将重点关注那些可能接近症状发作的人，对500名参与者进行长期随访，对参与者进行认知、神经成像和液体生物标志物评估，以及基因组、蛋白质组学和转录组学分析。这些方法的整合将允许对遗传性FTD进行分层，描绘出一种个性化的疾病概况，以确定那些接近症状发作及其随后的进展。这将是未来几年涉及无症状参与者的合理试验设计的基础——没有这一点，此类试验将不可能进行。

Frontotemporal dementia (FTD) is a highly heritable neurodegenerative disorder with the majority of that heritability accounted for by autosomal dominant mutations in three genes: progranulin (GRN), microtubule-associated protein tau (MAPT) and chromosome 9 open reading frame 72 (C9orf72). The Genetic FTD Initiative (GENFI) is a European and Canadian multicentre natural history study of genetic FTD with detailed phenotyping of both presymptomatic and symptomatic mutation carriers. In the absence of treatments that can delay the onset or prevent the progression of genetic FTD, the aim of GENFI has been to identify robust biomarkers for future trials. However, with trials imminent, it will be critically important to identify biomarkers of proximity to symptom onset, identifying on an individual basis those who are likely to progress to clinical FTD over the next 5 to 10 years. The aim of this study is therefore to characterize the prodromal period of genetic FTD, establishing cognitive, imaging and fluid biomarker measures that allow i) stratification of individual presymptomatic carriers into a stage proximal to symptom onset, and ii) measurement of subsequent disease progression during that proximal period. In particular, the work will extend the results found on a group basis in the prior GENFI studies to identify measures and patterns of change on an individual basis, thus paving the way for a precision medicine approach to FTD. It will make use of data from at least 950 participants already in the current GENFI studies with biomarker data acquired longitudinally (>2000 visits so far). It will focus on those likely to be in proximity to symptom onset, following 500 participants over time, with cognitive, neuroimaging, and fluid biomarker assessment as well as genomic, proteomic and transcriptomic profiling of participants. Integration of these approaches will allow stratification of genetic FTD, delineating an individualized disease profile that identifies those in proximity to symptom onset and their subsequent progression. This will be fundamental to rational trial design involving presymptomatic participants over the next few years - such trials will not be possible without this.