KBASE2: Korean Brain Aging Study, Longitudinal Endophenotypes and Systems Biology

项目概要/摘要 韩国AD早期诊断和预测脑老化研究（KBASE）是一项全面的 2014年在首尔国立大学（SNU）启动的一项前瞻性队列研究，采用了类似的设计， 北美阿尔茨海默病神经影像学倡议（ADNI）。KBASE队列 由特征良好的参与者组成，包括认知正常（CN）的对照组，年龄范围很广（20 至90岁）、轻度认知障碍（MCI）和AD痴呆（AD）。KBASE的一个独特之处在于 系统纵向收集综合临床、认知和生活方式数据，多模式 神经影像学（MRI/MRA、DTI、rsfMRI、淀粉样蛋白、tau蛋白和FDG PET），以及前五年在韩国的生物标本 年（“KBASE 1”）。一些KBASE数据已被分析和报告，但大部分广泛的KBASE数据 这组和样品有待全面分析。拟议的项目（“KBASE 2”）是一项合作， NIA阿尔茨海默病测序项目（ADSP）和合作伙伴印第安纳州大学（ADNI 遗传学核心，印第安纳州国家免疫局指定的ADRC，和IU网络科学研究所），KBASE团队在SNU在 韩国、南加州大学（USC）和宾夕法尼亚大学。超过1000个全基因组 韩国参与者的序列（WGS）将被贡献给ADSP，以及广泛的ADSP多种族 将对数据集进行分析。WGS数据将由NIA AD遗传学和基因组学中心协调 （GCAD），并通过NIA遗传学AD数据存储网站（NIAGADS）共享。神经影像学实验室 （LONI）将支持MRI和PET以及相关内在表型的共享，就像它对ADNI所做的那样。KBASE2 将继续纵向数据和样本收集，并提供高通量WGS和RNA-Seq，以及 数据协调和共享（目标1），对纵向淀粉样蛋白进行密集的基于脑网络的分析， tau、神经变性和血管（A/T/N/V）成像生物标志物与临床数据的关系（目的2），采用 整合系统生物学和功能基因组学方法来分析多组学数据， AD的A/T/N/V生物标志物，并为AD生物标志物相关的失调基因模块提供新的见解， 路径（目标3）。推动这一多学科国际合作项目的总体概念是 1）开发AD和相关疾病（ADRD）的精准医学需要系统的多模式 在疾病的早期风险阶段期间在不同群组中收集生物标志物以鉴定稳健的诊断， 预后和治疗目标和2）复杂的分析策略，解决多个复杂的， 分层多模式数据和异质和多样化的参与者群体是必不可少的。我们假设 对遗传和组学网络与结构和功能脑网络的综合纵向分析将 产生与A/T/N/V和其他衰老相关途径相关的新的诊断和治疗相关见解。 这种合作和数据共享的结果将促进ADSP结果的翻译， 国家阿尔茨海默病项目法案的目标是到2025年预防和治疗AD。

Project Summary/Abstract The Korean Brain Aging Study for the Early Diagnosis and Prediction of AD (KBASE) is a comprehensive prospective cohort study launched at Seoul National University (SNU) in 2014 using a similar design and methods as the North American Alzheimer’s Disease Neuroimaging Initiative (ADNI). The KBASE cohort consists of well-characterized participants including cognitively normal (CN) controls with a wide age range (20 to 90 years), mild cognitive impairment (MCI) and AD dementia (AD). A unique aspect of KBASE is the systematic longitudinal collection of comprehensive clinical, cognitive and lifestyle data, multimodal neuroimaging (MRI/MRA, DTI, rsfMRI, amyloid, tau and FDG PET), and bio-specimens in Korea for the first five years (“KBASE1”). Some KBASE data have been analyzed and reported but much of the extensive KBASE data set and samples await comprehensive analysis. The proposed project (“KBASE2”) represents a collaboration between the NIA Alzheimer’s Disease Sequencing Project (ADSP) and partners, Indiana University (ADNI Genetics Core, Indiana NIA-designated ADRC, and IU Network Science Institute), the KBASE team at SNU in Korea, University of Southern California (USC), and the University of Pennsylvania. Over 1000 whole genome sequences (WGS) of Korean participants will be contributed to the ADSP, and the extensive ADSP multi-ethnic data set will be analyzed. WGS data will be harmonized by the NIA Genetics and Genomics Center for AD (GCAD) and shared via the NIA Genetics of AD Data Storage Site (NIAGADS). The Laboratory of Neuroimaging (LONI) at USC will support sharing of MRI and PET and related endophenotypes, as it does for ADNI. KBASE2 will continue longitudinal data and sample collection and provide high throughput WGS and RNA-Seq as well as data harmonization and sharing (Aim 1), perform intensive brain network-based analyses of longitudinal amyloid, tau, neurodegeneration and vascular (A/T/N/V) imaging biomarkers in relation to clinical data (Aim 2), employ integrative systems biology and functional genomics methods to analyze multi-omics data for association with A/T/N/V biomarkers for AD, and provide new insight into AD biomarker-related dysregulated gene modules and pathways (Aim 3). The overarching concepts driving this multidisciplinary international collaborative project are that 1) development of precision medicine for AD and related disorders (ADRD) requires systematic multi-modal biomarker collection in diverse cohorts during early at-risk stages of disease to identify robust diagnostic, prognostic and therapeutic targets and 2) sophisticated analytic strategies that address the complexity of multi- layer multimodal data and heterogeneous and diverse participant cohorts are essential. We hypothesize that integrative longitudinal analysis of genetic and -omics networks with structural and functional brain networks will yield new diagnostic and treatment-relevant insights related to A/T/N/V and other aging related pathways. Results of this collaboration and data sharing will facilitate translation of ADSP findings for therapeutic development in support of the National Alzheimer's Project Act goal of prevention and treatment of AD by 2025.