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.

项目摘要 阿尔茨海默氏病（AD）是影响美国超过500万人的主要公共卫生问题。患者 AD具有β-淀粉样蛋白（Aβ）和TAU病理学，通常存在记忆丧失。然而， 大约25％ 认知投诉，被称为非典型广告。最常见的非典型广告综合症包括 徽标失语症（LPA），一种影响语言综合征的综合征和后皮质萎缩（PCA），一个 影响视觉/感知技能的综合征。在此R01的第一个周期中，我们使用了正电子发射 层析成像（PET）评估AD的非典型和典型变体的Aβ和TAU沉积，我们发现了一个 在横截面和纵向上，都与综合征和 年龄。 R01第二周期的目的是研究其他生物学机制的程度 与我们在Tau和Aβ中观察到的异质性有关。在AIM 1中，我们将评估两个功能 使用静息状态fMRI和铁沉积测量的连通性，使用定量测量 易感映射与AD中的Tau和Aβ中的横截面和纵向异质性有关。 2，我们将评估遗传危险因素与TAU和Aβ中异质性的关系。我们将评估 载脂蛋白（APOE）ε4和Tau和Aβ之间的关系，我们还将执行整个基因组 测序分析以鉴定与AD中tau和Aβ中异质性相关的遗传变异。在AIM 3中， 我们将对遗传和多模式成像机制的系统进行建模，以确定间 我们每种疾病机制对TAU异质性的关系和独立贡献 和Aβ。我们计划招募100名受试者（33 LPA，33个PCA，34典型AD）的队列， R01。每个受试者将进行两次连续评估，相隔12个月，其中包括神经系统和 神经心理学测试，3T MRI，包括静止状态fMRI和定量敏感性映射，Aβ 使用匹兹堡化合物B和tau-pet使用[18F] Flortaucipir。所有受试者也会遭受血液 绘制遗传分析。这100个受试者将用于解决目标1和3。对于AIM 2，我们将使用 第二个周期的100名受试者加上70名受试者招募到Aβ和TAU的第一个周期 PET并提供了一个血液样本（总计= 170名受试者），我们将复制整个基因组测序 AD神经影像倡议（ADNI）队列中的分析。我们的R01将对公共卫生产生重大影响 由于非典型广告影响约100万美国人。我们的研究将增加对生物学的理解 AD的表型和年龄差异的机制以及可能决定的路线的机制 蛋白质通过大脑传播。这些知识将有助于帮助未来的发展 基于机械的AD治疗和干预措施。