ENIGMA World Aging Center

ENIGMA世界老龄化中心

基本信息

批准号：
10576402
负责人：
PAUL M THOMPSON
金额：
$ 64.94万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-15 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10576402
关键词：
Acceleration Address Affect Age Age-associated memory impairment Aging Alzheimer&apos s Disease Alzheimer&apos s disease risk Alzheimer’s disease biomarker Amyloid Atrophic Biological Blood Brain Capital Chronology Clinical Clinical Data Cost of Illness Country Cytosine DNA Data Data Collection Data Set Dementia Diffusion Diffusion Magnetic Resonance Imaging Educational Status Epigenetic Process Functional Magnetic Resonance Imaging Funding Genetic Genetic Carriers Genetic Risk Genetic study Genome Genome Mappings Genomics Goals Grant Guanine Haplotypes Health Priorities Hippocampus Image Infrastructure Institution International Libraries Life Longevity Magnetic Resonance Imaging Maps Measures Mental disorders Methods Nature Nerve Degeneration Nomograms Pattern Persons Pilot Projects Population Population Heterogeneity Predisposition Productivity Proxy Publications Publishing Pythons Qualifying Reproducibility Research Rest Risk Risk Factors Role Science Site Structure Testing Tissues Variant Woman Work age related aged aging brain apolipoprotein E-4 brain tissue brain tract cerebral atrophy clinical predictors cognitive performance cohort cost disorder risk economic cost empowerment epigenetic marker epigenome epigenome-wide association studies epigenomics executive function fluorodeoxyglucose positron emission tomography functional decline genome wide methylation genome-wide genomic locus global health hazard human old age (65+)imaging genetics indexing inorganic phosphate longitudinal analysis machine learning algorithm men mortality multimodality nervous system disorder neural tract neuroimaging neuroimaging marker novel physical conditioning polygenic risk score processing speed prototype sex

项目摘要

ABSTRACT One in three seniors dies with Alzheimer’s disease (AD) or another dementia - diseases that cost the nation $259 billion, to rise to $1.1 trillion by 2050 (Alzheimer’s Association, 2017). Despite the vast personal and economic cost of these diseases, two major barriers stall efforts to discover key biological mechanisms that influence brain aging. First, the sheer cost of data collection means that most national initiatives have limited power to detect factors that affect brain aging. Even in datasets of N=1,000+ people (e.g., ADNI) – the power to discover modulators of brain aging is limited and may not generalize worldwide. Second, with the crisis of reproducibility, we do not always know if a finding will replicate; and if not, if this is due to true population heterogeneity or problems with methods. ENIGMA offers a coordinated global approach to solve these problems. ENIGMA’s World Aging Center is a global brain aging study that builds on our vast and highly productive ENIGMA consortium - a global network of 340 institutions in 45 countries. ENIGMA published the largest-ever genetic studies of the brain (Nature 2017; Science 2020), and the largest neuroimaging studies of 5 major psychiatric disorders. ENIGMA’s World Aging Center is a concerted global effort to pool all available data, methods, expertise and capital infrastructure to discover factors that affect brain aging. Our long-term goal is to identify personalized biological predictors of brain structural and functional decline and assess how they generalize globally. We have 4 aims: Aim 1: ENIGMA-Lifespan. Develop Lifespan Charts for Brain and Neural Tract Aging in 20,000 people. We will create charts showing how MRI brain measures change throughout life in 20,000 people, aged 1-92. We will compute a composite brain aging score, ‘Brain Age’, from available MRI, DTI, rsFMRI data, that measures how much the brain deviates from expected values, for a person’s age and sex. Aim 2: ENIGMA-Epigenetics. Relate genome-wide methylation levels to brain metrics in 10,000+ people, to discover epigenetic markers of accelerated brain aging. We discovered 2 epigenetic loci promoting brain aging in pilot studies. We will compute a “epigenetic clock” and test if it predicts brain metrics better than simple biological age. Aim 3: ENIGMA-Plasticity. Discover genomic loci that promote or mitigate brain tissue loss, in > 37 worldwide cohorts with longitudinal MRI. Aim 4: ENIGMA-Alzheimer’s Disease (New Aim). Meta-analyze the role of APOE, AD polygenic risk, and a new risk score for accelerated atrophy on neuroimaging biomarkers in aging and AD, including amyloid and FDG PET. These aims seek to analyze worldwide imaging, epigenetic, and clinical data with harmonized methods. We aim to create new aging “clocks” and reveal targetable risk factors and modifiers of brain aging in the genome and epigenome, test how and when they shift AD biomarkers, and test their generalizability worldwide.

抽象的三分之一的老年人死于阿尔茨海默病 (AD) 或其他痴呆症，这种疾病给国家造成的损失为 2,590 亿美元，到 2050 年将增加到 1.1 万亿美元（阿尔茨海默病协会，2017 年），尽管这些疾病给个人和经济造成巨大损失，但两种主要疾病造成的损失将高达 2,590 亿美元。首先，数据收集的巨大成本意味着大多数国家计划检测影响大脑衰老因素的能力有限。 N=1,000+ 人（例如 ADNI）——发现大脑衰老调节剂的能力是有限的，可能无法在全球范围内推广。其次，由于存在可重复性危机，我们并不总是知道某个发现是否会重复；如果这是由于真正的人口异质性或方法问题造成的，ENIGMA 提供了一种协调的全球方法来解决这些问题。 ENIGMA 联盟 - 由 45 个国家的 340 个机构组成的全球网络，ENIGMA 发表了有史以来最大规模的大脑遗传学研究（《自然》杂志，2017 年；《科学》杂志，2020 年），以及针对 5 种主要精神疾病的最大的神经影像学研究。全球努力汇集所有可用的数据、方法、专业知识和资本基础设施，以发现影响大脑衰老的因素。我们的长期目标是确定大脑的个性化生物预测因素。我们有 4 个目标：目标 1：开发 20,000 人的大脑和神经束衰老寿命图表。我们将根据可用的 MRI、DTI、rsFMRI 数据计算综合大脑老化评分“大脑年龄”。目标 2：ENIGMA-表观遗传学将 10,000 多人的全基因组甲基化水平与大脑指标联系起来，以发现加速大脑老化的表观遗传标记。试点研究中的 2 个促进大脑衰老的表观遗传基因座我们将计算一个“表观遗传时钟”，并测试它是否比简单的生物年龄更好地预测大脑指标。 ENIGMA-可塑性。在超过 37 个全球队列中发现促进或减轻脑组织损失的基因座。目标 4：ENIGMA-阿尔茨海默病（新目标）对 APOE、AD 多基因风险和 a 的作用进行荟萃分析。衰老和 AD 中神经影像生物标志物（包括淀粉样蛋白和 FDG PET）加速萎缩的新风险评分这些目标旨在分析全球影像、表观遗传学和临床。我们的目标是创建新的衰老“时钟”，揭示基因组和表观基因组中大脑衰老的可针对性风险因素和修饰因素，测试它们如何以及何时改变 AD 生物标志物，并测试它们在全球范围内的普遍性。