Preclinical AD: Correlates of Amyloid, Tau PET and fcMRI in Framingham Gen 3 Young Adults

临床前 AD：弗雷明汉第 3 代年轻人中淀粉样蛋白、Tau PET 和 fcMRI 的相关性

• 批准号: 9222693
• 负责人: Sudha Seshadri
• 金额: $ 62.07万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-15 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9222693
• 关键词: Accelerometer; Adult; Age; Alzheimer disease prevention; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Amyloidosis; Area; Autopsy; Biological; Biological Markers; Blood; Blood Vessels; Brain; Cerebrovascular Trauma; ChIP-seq; Child; Clinical; Cognition; Cognitive; Collaborations; Communities; Data; Data Set; Dementia; Diabetes Mellitus; Diet; Diffusion Magnetic Resonance Imaging; Disease; Disease Pathway; Epigenetic Process; Family; Functional disorder; Funding; Genes; Genetic; Genetic Markers; Genetic study; Growth Factor; Heterogeneity; Hip region structure; Hippocampus (Brain); Hypertension; Image; Inflammatory; Inherited; Injury; International; Late Onset Alzheimer Disease; Lead; Life Style; Lipids; Magnetic Resonance Imaging; Measures; Memory; Metabolic; Moods; Parents; Participant; Pathology; Pathway interactions; Pattern; Performance; Persons; Pharmaceutical Preparations; Phase; Physical activity; Positron-Emission Tomography; Prevalence; Prevention; Prevention strategy; Preventive Intervention; Process; Public Health; Registries; Rest; Risk; Risk Factors; Risk stratification; Sampling; Symptoms; Testing; Thick; adipokines; aged; aging brain; base; circulating biomarkers; clinically relevant; cognitive change; cognitive function; cognitive performance; cognitive testing; cohort; endophenotype; epigenetic marker; executive function; exome; experience; functional outcomes; genome wide association study; grandparent; imaging biomarker; improved; inflammatory marker; interest; methylome; middle age; neural recruitment; novel; offspring; pre-clinical; prevent; public health relevance; sulfated glycoprotein 2; tau Proteins; young adult

 DESCRIPTION (provided by applicant): The pathology of Alzheimer's disease (AD) starts >2-4 decades prior to onset of clinical dementia. Therefore it is critical to identify persons with preclinical AD, who may be most responsive to preventive interventions, and also risk factors and biomarkers for preclinical AD which may lead to new, effective AD prevention strategies. We propose to study, in a community-based cohort, heterogeneity of cognitive change at mean age 45, and (in a subset) 3 markers of preclinical AD: amyloid (PIB)-PET, resting state functional connectivity MRI, and tau (F18T807) PET at age 45-65. Such data are not currently available. Framingham Gen 3 participants are grandchildren of the Original cohort (followed since 1948) and children of the Offspring (Gen 2, followed since 1971). Omni 1 & 2 are multiethnic cohorts corresponding to Gen 2 & 3. All cohorts have genetic/epigenetic (GWAS, exome chip and sequencing, blood expression, methylome), lifestyle (diet, mood, hip accelerometry, etc.), vascular/metabolic risk factor and circulating biomarker (e.g., beta-amyloid, clusterin, inflammatory, lipids, adipokines, growth factors) data, verified clinical dementia statu, structural brain MRI (including diffusion tensor imaging [DTI]) and detailed cognitive assessments. Gen 3/Omni 2 (n=4200) participants have already been examined twice (2002-2005 and 2008-2011). These exams included 2 brief cognitive tests (of memory [CERAD word list], and of executive function [Victoria Stroop]) and a brain MRI. We have previously shown that hypertension and diabetes have a greater adverse impact in younger Gen 3 than in Gen 2 participants (2 & 6 years of brain aging in Gen 2, versus 7 & 23 years in Gen 3, respectively). We now propose the following Specific Aims: Aim 1: Obtain a brief subjective (AD8) and objective (Montreal Cognitive Assessment [MOCA], repeat Stroop and CERAD word list) cognitive assessment in all Gen 3/Omni 2 (N~3800) at exam 3 (2015-2018) and assess each person's change from 6-7 years earlier. We hypothesize that persons with a high vascular burden and/or high genetic burden of AD will experience the greatest decline in cognition. Aim 2: Obtain amyloid & tau PET and brain structural and fcMRI in 200 persons, aged 45-65 years, with prior MRI, and carefully selected to represent the entire spectrum of vascular risk. We will: assess (2-i) prevalence of amyloid, tau and fcMRI abnormalities at this age and their correlation with cognition, both directly and via an interaction with vascular brain injury; (2-ii) risk factorand circulating biomarker associations with these preclinical imaging markers of AD; also extend/validate the risk factor & biomarker associations with PET/ fcMRI (noted in Gen 3) in subjects >65 yrs with PET/ fcMRI via 4 international collaborations (N~2500). Aim 3: Examine genes, risk factors and biomarkers that we find are associated with PET/ fcMRI for additional association with: (3-i) structural MRI and cognitive measures already available in Gen 1, 2 & 3, e.g., hippocampal volumes, cortical thickness, logical memory (N=4,700); and (3-ii) with risk of developing clinical AD in Gen 1 & 2 participants (up to 1300 AD cases, 750 incident in >7500 persons).

 描述（由申请人提供）：阿尔茨海默病（AD）的病理学在临床痴呆发作前>2- 40年开始。因此，识别可能对预防性干预最敏感的临床前AD患者以及可能导致新的有效AD预防策略的临床前AD的风险因素和生物标志物至关重要。我们建议在基于社区的队列中研究平均年龄45岁时认知变化的异质性，以及（在一个子集中）临床前AD的3种标志物：淀粉样蛋白（PIB）-PET、静息状态功能连接MRI和45-65岁时的tau（F18 T807）PET。目前没有这方面的数据。第三代参与者是原始队列的孙子（自1948年以来）和后代（第二代，自1971年以来）的子女。Omni 1和Omni 2是对应于Gen 2和Gen 3的多种族队列。所有队列具有遗传/表观遗传（GWAS、外显子组芯片和测序、血液表达、甲基化组）、生活方式（饮食、情绪、髋关节加速度计等），血管/代谢危险因素和循环生物标志物（例如，β-淀粉样蛋白， clusterin、炎症、脂质、脂肪因子、生长因子）数据、验证的临床痴呆状态、结构脑MRI（包括扩散张量成像[DTI]）和详细的认知评估。Gen 3/Omni 2（n=4200）参与者已经接受了两次检查（2002-2005年和2008-2011年）。这些检查包括2项简短的认知测试（记忆[CERAD单词列表]和执行功能[维多利亚Stroop]）和脑MRI。我们之前已经表明，高血压和糖尿病对年轻的第三代参与者的不利影响比第二代参与者更大（第二代大脑老化2年和6年，第三代分别为7年和23年）。我们现在提出以下具体目标：目标1：在第3次考试（2015-2018年）中获得所有Gen 3/Omni 2（N~3800）的简短主观（AD 8）和客观（蒙特利尔认知评估[莫卡]，重复Stroop和CERAD单词列表）认知评估，并评估每个人从6-7年前的变化。我们假设，AD的高血管负担和/或高遗传负担的人将经历认知能力的最大下降。目标二：在200名年龄在45-65岁之间的人中获得淀粉样蛋白和tau PET以及脑结构和fcMRI，先前进行MRI，并仔细选择以代表整个血管风险谱。我们将：评估（2-i）在该年龄的淀粉样蛋白、tau和fcMRI异常的患病率及其与认知的相关性，直接地和通过与血管性脑损伤的相互作用;（2-ii）与AD的这些临床前成像标志物相关的风险因素和循环生物标志物;还扩展/验证了风险因素和生物标志物与PET/ fcMRI的相关性（第3代中指出）通过4项国际合作（N~2500）对65岁以上的受试者进行PET/ fcMRI。目标3：检查我们发现与PET/ fcMRI相关的基因、风险因素和生物标志物，以确定与以下方面的额外关联：（3-i）结构MRI和认知测量已经在Gen 1、2和3中可用，例如，海马体积、皮质厚度、逻辑记忆（N= 4，700）;和（3-ii）在第1代和第2代参与者中具有发展临床AD的风险（多达1300个AD病例，在>7500人中750个事件）。