Molecular and structural imaging in atypical Alzheimer's disease: a longitudinal study

非典型阿尔茨海默病的分子和结构成像：一项纵向研究

• 批准号: 10372031
• 负责人: Jennifer Louise Whitwell
• 金额: $ 79.3万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10372031
• 关键词: Address; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease patient; American; Amyloid beta-Protein; Aphasia; Apolipoproteins; Area; Automobile Driving; Behavior; Biological; Biological Models; Biology; Blood; Blood specimen; Brain; Clinical; Cognitive; Data; Deposition; Development; Disease; Functional Magnetic Resonance Imaging; Future; Genetic; Genotype; Goals; Grant; Heterogeneity; Image; Imaging Techniques; Individual; Intervention; Iron; Knowledge; Language; Lead; Link; Longitudinal Studies; Magnetic Resonance Imaging; Measures; Memory Loss; Modeling; Molecular; Multimodal Imaging; Nerve Degeneration; Neurologic; Neuropsychological Tests; Other Genetics; Pathology; Patients; Pattern; Persons; Phenotype; Pittsburgh Compound-B; Positron-Emission Tomography; Predisposition; Proteins; Public Health; Research; Rest; Risk Estimate; Route; Syndrome; Techniques; Variant; Visuospatial; Work; abeta deposition; age difference; age related; base; cerebral atrophy; cohort; genetic analysis; genetic risk factor; genetic variant; genome sequencing; improved; in vivo; neuroimaging; novel; programs; recruit; serial imaging; skills; spatial relationship; tau Proteins; uptake; whole genome

PROJECT SUMMARY Alzheimer’s disease (AD) is a major public health problem affecting over 5 million people in the US. Patients with AD have beta-amyloid (Aβ) and tau pathology and typically present with memory loss. However, approximately 25% of AD subjects do not present with early memory loss and instead present with other cognitive complaints, and are referred to as atypical AD. The most common atypical AD syndromes include logopenic aphasia (LPA), a syndrome affecting language syndrome, and posterior cortical atrophy (PCA), a syndrome affecting visuospatial/perceptual skills. In the 1st cycle of this R01 we used positron emission tomography (PET) to assess Aβ and tau deposition across atypical and typical variants of AD, and we found a large degree of heterogeneity both cross-sectionally and longitudinally that was associated with syndrome and age. The goal of the 2nd cycle of the R01 is to investigate the degree to which other biological mechanisms are related to the heterogeneity we observed in tau and Aβ. In aim 1, we will assess how both functional connectivity, measured using resting state fMRI, and iron deposition, measured using quantitative susceptibility mapping, are related to cross-sectional and longitudinal heterogeneity in tau and Aβ in AD. In aim 2, we will assess how genetic risk factors are related to heterogeneity in tau and Aβ. We will assess the relationship between apolipoprotein (APOE) ε4 and tau and Aβ, and we will also perform a whole genome sequencing analysis to identify genetic variants associated with heterogeneity in tau and Aβ in AD. In aim 3, we will model the system of genetic and multi-modal imaging mechanisms in order to determine inter- relationships and independent contributions of each of our disease mechanisms to the heterogeneity of tau and Aβ. We plan to recruit a cohort of 100 subjects (33 LPA, 33 PCA, 34 typical AD) into the 2nd cycle of the R01. Each subject will undergo two serial assessments 12 months apart that will include neurological and neuropsychological testing, 3T MRI that includes resting state fMRI and quantitative susceptibility mapping, Aβ PET using Pittsburgh Compound B and tau-PET using [18F]flortaucipir. All subjects will also undergo a blood draw for genetic analysis. These 100 subjects will be used to address aims 1 and 3. For aim 2, we will utilize the 100 subjects from the 2nd cycle plus the 70 subjects recruited into the 1st cycle that underwent Aβ and tau PET and provided a blood sample (total=170 subjects), and we will replicate our whole genome sequencing analyses in the AD Neuroimaging Initiative (ADNI) cohort. Our R01 will have a major impact on public health since atypical AD effects ~1,000,000 Americans. Our research will increase understanding of biological mechanisms underlying phenotypical and age differences in AD and mechanisms that may determine routes of protein spread through the brain. This knowledge will be useful to aid in the future development of mechanistically based treatments and interventions for AD.

项目总结 阿尔茨海默病(AD)是影响美国500多万人的主要公共卫生问题。病人 患有AD的患者有β-淀粉样蛋白(A-β)和tau病理，通常表现为记忆力丧失。然而， 大约25%的AD受试者没有出现早期记忆丧失，而是出现了其他 认知主诉，称为非典型阿尔茨海默病。最常见的非典型AD综合征包括 对数失语症(LPA)是一种影响语言综合征的综合征，后脑皮质萎缩(PCA)是一种 影响视觉空间/知觉技能的综合症。在R01的第一个周期中，我们使用了正电子发射 断层扫描评估Aβ和tau在非典型和典型AD变异体中的沉积，我们发现 在横向和纵向上都存在高度的异质性，这与综合征和 年龄。R01的第二个周期的目标是调查其他生物机制在多大程度上 与我们在tau和Aβ中观察到的异质性有关。在目标1中，我们将评估两者如何发挥作用 连接性，使用静息状态功能磁共振测量，以及铁沉积，使用定量测量 易感性定位与AD患者tau和Aβ的横断面和纵向不均一性有关。在AIM 2，我们将评估遗传风险因素与tau和Aβ异质性的关系。我们将评估 载脂蛋白ε4与tau和Aβ的关系以及我们还将进行全基因组 测序分析以确定与AD中tau和Aβ异质性相关的遗传变异。在《目标3》中， 我们将对遗传和多模式成像机制的系统进行建模，以确定 我们的每一种疾病机制对tau异质性的关系和独立贡献 还有一辆β。我们计划招募100名受试者(33名LPA，33名PCA，34名典型AD)进入第二个周期 R01。每名受试者将在12个月内接受两次系列评估，包括神经学和 神经心理测试，3T磁共振，包括静息状态功能磁共振和定量易感性映射，Aβ 使用匹兹堡化合物B的PET和使用[18F]氟他西平的tau-PET。所有受试者还将接受抽血 抽签进行基因分析。这100个主题将用于解决目标1和3。对于目标2，我们将利用 第二个周期的100名受试者加上70名受试者被招募到第一个周期接受Aβ和Tau检查 PET，并提供了血液样本(总共=170名受试者)，我们将复制我们的全基因组测序 在AD神经成像倡议(ADNI)队列中的分析。我们的R01将对公众健康产生重大影响 由于非典型的AD影响了大约100万美国人。我们的研究将增加对生物学的理解 阿尔茨海默病表型和年龄差异的潜在机制以及可能决定AD发病途径的机制 蛋白质在大脑中传播。这些知识将有助于未来的发展。 AD的机械性治疗和干预。