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（由适用提供）：在临床痴呆发作之前，阿尔茨海默氏病（AD）的病理> 2-4年。因此，确定具有临床前广告的人，他们可能对预防干预措施最有反应，以及临床前广告的危险因素和生物标志物，这可能会导致新的，有效的AD预防策略。我们建议在基于社区的队列中研究平均年龄在45岁时认知变化的异质性，以及（在一个子集中）3临床前AD标记：淀粉样蛋白（PIB）-PET，静止状态功能连接性MRI和TAU（F18T807）PET（F18T807）PET，年龄45-65岁。此类数据当前尚不可用。 Framingham Gen 3参与者是原始队列的孙子（随后是1948年）和后代的孩子（Gen 2，随后，自1971年以来）。 Omni 1和2是对应于Gen 2＆3的多民族人群。所有队列均具有遗传/表观遗传学（GWAS，Exome芯片和测序，血液表达，甲基甲基），生活方式（饮食，情绪，情绪，髋关节加速度计量等），血管/代谢风险因素和循环生物群（E.G.G. G.，BETA-AMYYYID） 簇蛋白，炎症，脂质，脂肪因子，生长因子）数据，经过验证的临床痴呆型Statu，结构性脑MRI（包括扩散张量张量成像[DTI]）和详细的认知评估。 Gen 3/Omni 2（n = 4200）参与者已经两次检查（2002-2005和2008-2011）。这些考试包括2个简短的认知测试（记忆[Cerad Word列表]，执行功能[Victoria] Stroop]）和一个大脑MRI。我们先前已经表明，高血压和糖尿病在年轻的Gen 3中比Gen 2参与者具有更大的不利影响（Gen 2的大脑衰老2和6年，分别为Gen 3中的7和23年）。现在，我们提出以下具体目的：目标1：在所有Gen 3/Omni 2（N〜3800）中，在考试3（2015-2018）中获得简短的主观（AD8）和客观（Montreal认知评估[MOCA]，重复Stroop和Cerad Word列表），并在6-7岁以前的每个人的变化中进行评估。我们假设患有高血管燃烧和/或广告遗传燃烧的人会经历认知的最大下降。 AIM 2：获得200人，年龄在45-65岁的人中，获得淀粉样蛋白和tau PET和大脑结构和FCMRI，并具有先验的MRI，并精心挑选以代表整个血管风险。我们将：评估（2-i）在这个年龄的淀粉样蛋白，tau和FCMRI异常的流行及其与认知的相关性直接直接通过与血管脑损伤的相互作用； （2-II）与AD的这些临床前成像标记的危险因素和循环生物标志物关联；还可以通过4年International Collaborations（N〜2500）扩展/验证与PET/ FCMRI的PET/ FCMRI（Gen 3中的注释）的风险因素和生物标志物关联（Gen 3中的注释）。 AIM 3：检查我们发现的基因，危险因素和生物标志物与PET/ FCMRI有关，以与以下相关性：（3-i）结构MRI和Gen 1、2和3中已经可用的认知度量（3-ii）在第1和2世纪参与者中有临床广告的风险（最多1300例AD病例，> 7500人中的750例事件）。