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

项目摘要 阿尔茨海默病（AD）是影响美国超过500万人的主要公共卫生问题。患者 患有AD的患者具有β-淀粉样蛋白（Aβ）和tau病理学，并且通常表现为记忆丧失。然而，在这方面， 大约25%的AD受试者不存在早期记忆丧失，而是存在其他记忆丧失。 认知主诉，并被称为非典型AD。最常见的非典型AD综合征包括 语言缺乏性失语（LPA），一种影响语言综合征的综合征，和后皮质萎缩（PCA），一种 影响视觉空间/知觉技能的综合征。在R 01的第一个循环中，我们使用了正电子发射 我们使用正电子断层扫描（PET）来评估非典型和典型AD变体中的Aβ和tau沉积，我们发现 与综合征相关的横截面和纵向的高度异质性， 年龄R 01的第二个周期的目标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。在目标1中，我们将评估两者的功能 连接，使用静息状态fMRI测量，铁沉积，使用定量 与AD中tau和Aβ的横截面和纵向异质性相关。在aim中 2，我们将评估遗传风险因素如何与tau和Aβ的异质性相关。我们将评估 载脂蛋白（APOE）ε4与tau和Aβ之间的关系，我们还将进行全基因组 测序分析以鉴定与AD中tau和Aβ的异质性相关的遗传变异。在目标3中， 我们将对遗传和多模态成像机制的系统进行建模，以确定内部- 我们的每种疾病机制对tau蛋白异质性的关系和独立贡献 Aβ。我们计划招募100名受试者（33名LPA，33名PCA，34名典型AD）进入第二周期的研究。 R01。每名受试者将接受两次连续评估，间隔12个月，包括神经和 神经心理学测试，3 T MRI，包括静息状态fMRI和定量易感性绘图，Aβ 使用匹兹堡化合物B的PET和使用[18 F]flortaucipir的tau-PET。所有受试者还将接受血液检查。 进行基因分析。这100个主题将用于实现目标1和3。对于目标2，我们将利用 第2个周期的100例受试者加上第1个周期招募的70例接受Aβ和tau的受试者 PET并提供血液样本（总共=170名受试者），我们将复制我们的全基因组测序 AD Neuroimaging Initiative（ADNI）队列中的分析。我们的R 01将对公众健康产生重大影响 因为非典型AD影响约100万美国人。我们的研究将增加对生物学的理解， AD中表型和年龄差异的潜在机制以及可能决定 蛋白质在大脑中扩散这些知识将有助于未来的发展， 基于机制的治疗和干预AD。

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.