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

额颞叶痴呆（FTD）是一种高度遗传性神经退行性疾病，大部分遗传性由三种基因的常染色体显性突变引起：颗粒蛋白前体（GRN）、微管相关蛋白tau（MAPT）和9号染色体开放阅读框72（C9 orf 72）。遗传FTD计划（GENFI）是一项欧洲和加拿大的多中心遗传FTD自然史研究，对症状前和症状性突变携带者进行了详细的表型分析。在缺乏可延迟遗传性FTD发作或阻止其进展的治疗的情况下，GENFI的目的是为未来试验确定稳健的生物标志物。然而，随着试验的临近，确定接近症状发作的生物标志物，在个体基础上确定可能在未来5 - 10年内进展为临床FTD的患者将至关重要。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，以允许i）将个体症状前携带者分层至症状发作近端阶段，和ii）测量该近端阶段的后续疾病进展。特别是，这项工作将扩展在先前的GENFI研究中以组为基础发现的结果，以确定个体基础上的变化措施和模式，从而为FTD的精确医学方法铺平道路。它将利用目前GENFI研究中至少950名参与者的数据，并纵向采集生物标志物数据（迄今为止超过2000次访问）。它将重点关注那些可能接近症状发作的人，随着时间的推移，对500名参与者进行认知，神经成像和液体生物标志物评估以及参与者的基因组，蛋白质组和转录组分析。这些方法的整合将允许对遗传FTD进行分层，描绘个体化疾病特征，以识别接近症状发作及其后续进展的疾病。这将是未来几年涉及症状前受试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.