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

项目总结 额颞叶痴呆(FTD)是一种严重的神经退行性疾病，具有明显的异质性。 潜在的病理学、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最终是致命的，病程不等 在2年至20年之间。目前，预测预后的可靠指标有限，这在以下方面至关重要 患者管理，但也阻碍了对可能的疾病修改治疗的评估。遗传和 表观遗传标记物似乎是很有前途的预后标记物，但它们在FTD中的应用尚未得到检验。 拟议研究的总体目标是改善对FTD预后的预测。为此，我们将(一) 检查FTD疾病状态的表观遗传学概况，(Ii)评估表观遗传年龄预测因子和 对FTD疾病状态的遗传风险描述，以及(Iii)对可用的遗传、 分子和临床数据，以建立其对FTD疾病进展和结果的预测价值。 我们将利用一组独特的深表型FTD患者和对照组，包括广泛的 神经心理信息、遗传数据(即，突变携带者状态、测序数据)、生物流体(例如， 脑脊液(CSF))，对于一些患者，还包括尸检组织和数据。我们将选择最多的 疾病进展的相关临床特征，包括常规结果(即发病年龄、疾病 持续时间)和特定于FTD的测量，例如纵向神经成像测量、(社会)认知、 行为和个性。现在已经确定，表观遗传标记与衰老和 死亡率。因此，我们将从提取的基因组DNA中测量全基因组DNA甲基化水平 全血，以检查FTD的衰老和疾病进展。此外，我们将确定基因是否 风险特征也可以预测FTD的进展和结果。简而言之，我们的项目将增加 预测FTD患者的进展速度，这对患者及其照顾者以及 在未来的FTD临床试验中用于患者分层。 这是一个高风险、高回报的项目，使用了一组非常有特点的患者和对照组。 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，随后将进行大规模研究，以验证 美国和全球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.