ENIGMA World Aging Center

ENIGMA世界老龄化中心

• 批准号: 10328963
• 负责人: PAUL M THOMPSON
• 金额: $ 64.96万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 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/10328963
• 关键词: Address; Affect; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Alzheimer' 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; Genomics; Goals; Grant; Guanine; Haplotypes; Health Priorities; Hippocampus (Brain); 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; Problem Solving; Proxy; Publications; Publishing; Pythons; Reproducibility; Research; Rest; Risk; Risk Factors; Role; Science; Site; Structure; Testing; Tissues; Variant; Weight; Woman; Work; age related; aged; aging brain; base; brain magnetic resonance imaging; brain tissue; brain tract; cerebral atrophy; clinical predictors; cognitive performance; cohort; cost; disorder risk; economic cost; 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

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，但两大障碍阻碍了发现影响大脑衰老的关键生物机制的努力。首先，数据收集的巨大成本意味着大多数国家举措检测影响大脑衰老因素的能力有限。即使在 N=1,000 多人的数据集中（例如 ADNI），发现大脑衰老调节因子的能力也是有限的，可能无法在全世界范围内推广。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；如果不是，这是否是由于真正的群体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 世界老龄化中心是一项全球脑衰老研究，建立在我们庞大且高效的 ENIGMA 联盟的基础上，ENIGMA 联盟是一个由 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》，2020 年），以及针对 5 种主要精神疾病的最大规模的神经影像学研究。 ENIGMA 的世界老龄化中心是一项全球性的共同努力，旨在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结构和功能衰退的个性化生物预测因素，并评估它们如何在全球范围内推广。我们有 4 个目标： 目标 1：ENIGMA-Lifespan。绘制 20,000 人大脑和神经束老化的寿命图表。我们将创建图表，显示 MRI 如何测量 20,000 名 1-92 岁的人一生中的大脑变化。我们将根据现有的 MRI、DTI、rsFMRI 数据计算出大脑老化综合评分“脑年龄”，该评分可衡量一个人的年龄和性别的大脑与预期值的偏差程度。目标 2：ENIGMA-表观遗传学。将全基因组甲基化水平与 10,000 多人的大脑指标联系起来，以发现加速大脑老化的表观遗传标记。我们在试点研究中发现了 2 个促进大脑衰老的表观遗传位点。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。目标 3：ENIGMA-可塑性。通过纵向 MRI 在全球超过 37 个队列中发现促进或减轻脑组织损失的基因组位点。目标 4：ENIGMA-阿尔茨海默病（新目标）。荟萃分析 APOE、AD 多基因风险以及加速萎缩的新风险评分对衰老和 AD 中神经影像生物标志物（包括淀粉样蛋白和 FDG PET）的作用。这些目标旨在利用统一的方法分析全球成像、表观遗传学和临床数据。我们的目标是创造新的衰老“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。