Improving Prediction of Prognosis in Frontotemporal Dementia Using Epigenetic and Genetic Markers of Biological Aging and Disease

项目摘要 额颞叶痴呆（FTD）是一种严重的神经退行性疾病， 基础病理学、遗传学、临床表现和病程。没有治疗方案可供选择， 治愈FTD或减缓其疾病进展，FTD最终具有致死性，病程范围为 2至>20年。目前，可靠的预后预测因素有限，这在以下方面至关重要： 患者管理，而且还妨碍了对潜在的疾病改善治疗的评价。遗传和 表观遗传标记物似乎是有希望的预后标记物，但它们的效用尚未在FTD中检验。 本研究的总体目的是改善FTD的预后预测。为此，我们将（一） 检查FTD疾病状态的表观遗传特征，（ii）评估表观遗传年龄预测因子的贡献， FTD疾病状态的遗传风险特征，和（iii）对可用的遗传， 分子和临床数据，以确定其对FTD疾病进展和结局的预测价值。 我们将使用一个独特的队列，包括深表型FTD患者和对照，包括广泛的 神经心理学信息，遗传数据（即，突变携带者状态，测序数据），生物流体（例如， 脑脊髓液（CSF）），以及一些患者的死后组织和数据。我们将选择最 疾病进展的相关临床特征，包括常规结局（即，发病年龄 持续时间）和FTD特异性测量，如纵向神经影像学测量，（社会）认知， 行为和个性。现在已经确定，表观遗传标记与衰老有关， mortality.因此，我们将测量从基因组DNA中提取的全基因组DNA甲基化水平， 全血，以检查FTD的老化和疾病进展。此外，我们将确定是否遗传 风险特征也可预测FTD进展和结局。简而言之，我们的项目将提高 预测FTD患者的进展率，这对患者及其护理人员至关重要， 用于未来FTD临床试验的患者分层。 这是一个高风险、高回报的项目，使用的是一个非常明确的患者和对照组队列 来自荷兰阿姆斯特丹的一个生物库如果FTD疾病和疾病进展的生物标志物 可以在这个相对同质的样本中确定，大规模的研究将随后验证研究结果， 来自美国和地球仪不同遗传背景的临床样本。

PROJECT SUMMARY Frontotemporal dementia (FTD) is a severe neurodegenerative disorder with marked heterogeneity in underlying pathology, genetics, clinical presentation and disease course. No treatment options are available to cure FTD or to slow its disease progression, and FTD is eventually fatal with a disease duration ranging between 2 and >20 years. Currently, reliable predictors of prognosis are limited, which is crucial in terms of patient management but also hampers the evaluation of potential disease modifying treatments. Genetic and epigenetic markers seem to be promising prognostic markers, but their utility have not been examined in FTD. The overall aim of the proposed study is to improve prediction of prognosis in FTD. To this end, we will (i) examine epigenetic profiles of FTD disease status, (ii) assess the contribution of epigenetic age predictors and genetic risk profiles to FTD disease status, and (iii) perform an integrated analysis of available genetic, molecular, and clinical data to establish its predictive value of FTD disease progression and outcome. We will make use of a unique cohort of deeply phenotyped FTD patients and controls, including extensive neuropsychological information, genetic data (i.e., mutation carrier-status, sequencing data), biofluid (e.g., cerebrospinal fluid (CSF)) and, for some patients, post-mortem tissue and data. We will select the most relevant clinical features of disease progression, including conventional outcomes (i.e., age of onset, disease duration) and FTD-specific measures, such as longitudinal neuroimaging measures, (social) cognition, behavior and personality. It is now firmly established that epigenetic markers are associated with aging and mortality. We will therefore measure genome-wide DNA methylation levels from genomic DNA extracted from whole blood, to examine aging and disease progression in FTD. Moreover, we will establish whether genetic risk profiles are also predictive of FTD progression and outcome. In short, our project will increase the ability to predict the rate of progression in FTD patients, which is imperative for patients and their caregivers, as well as for patient stratification in future clinical trials in FTD. This is a high-risk, high-reward project using an extremely well-characterized cohort of patients and controls from a biobank in Amsterdam, The Netherlands. If biological markers for FTD disease and disease progression can be identified in this relatively homogenous sample, large-scale studies will ensue to validate the findings in clinical samples of diverse genetic backgrounds across the United States and the globe.