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)的病理在临床痴呆症发病前2-40年开始。因此，关键是要确定对预防干预最敏感的临床前AD患者，以及临床前AD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。我们建议在一个以社区为基础的队列中，研究平均年龄为45岁的认知改变的异质性，以及(在一个子集中)临床前AD的3个标记物：淀粉样蛋白(PIB)-PET、静息状态功能连接性MRI和Tau(F18T807)PET。目前还没有这样的数据。弗雷明翰第三代参与者是原始队列(自1948年以来一直遵循)的孙辈和后代(第二代，自1971年以来一直遵循)的子女。OMNI 1和OMNI 2是对应于Gen 2和Gen 3的多民族队列。所有队列都有遗传/表观遗传(GWAS、外显子组芯片和测序、血液表达、甲基组)、生活方式(饮食、情绪、髋关节加速测量等)、血管/代谢危险因素和循环生物标记物(例如，β-淀粉样蛋白， 数据(包括凝集素、炎症、脂质、脂肪因子、生长因子)、经过验证的临床痴呆状态、结构性脑MRI(包括弥散张量成像[DTI])和详细的认知评估。第三代/OMNI 2(n=4200)参与者已经接受了两次检查(2002-2005年和2008-2011年)。这些检查包括两个简短的认知测试(记忆[CERAD词表]和执行功能[Victoria Stroop])和大脑核磁共振。我们之前已经证明，高血压和糖尿病在年轻的第三代参与者中比第二代参与者有更大的不良影响(第二代参与者的大脑老化时间分别为2年和6年，而第三代参与者分别为7年和23年)。我们现在提出以下具体目标：目标1：在考试3(2015-2018)中对所有Gen 3/OMNI 2(N~3800)进行简短的主观(AD8)和客观(蒙特利尔认知评估[MOCA]，重复Stroop和CERAD词表)认知评估，并评估每个人与6-7年前的变化。我们假设，具有高血管负担和/或高遗传负担的人将经历最大的认知下降。目的2：对200名年龄在45-65岁之间的人进行淀粉样蛋白-tau PET、脑结构和功能磁共振成像，并仔细选择代表血管风险的全谱。我们将：评估(2-i)淀粉样蛋白、tau和fcMRI异常在这个年龄段的患病率及其与认知的相关性，包括直接和通过与血管脑损伤的相互作用；(2-ii)风险因素和循环生物标记物与这些AD的临床前成像标记物的关联；还通过4个国际合作(N~2500)在研究对象中扩展/验证风险因素和生物标记物与PET/fcMRI的关联(在第3代中提到)。目的3：检查我们发现的与PET/fcMRI相关的基因、危险因素和生物标记物，以寻找额外的关联：(3-I)结构MRI和Gen 1、2和3已有的认知测量，例如，海马体体积、皮质厚度、逻辑记忆(N=4,700)；以及(3-II)Gen 1和2参与者发展为临床AD的风险(多达1300例AD病例，750例GT；7500人)。