High Resolution Neuroimaging Biomarkers for Preclinical Alzheimer's Disease

项目1：临床前阿尔茨海默病的高分辨率神经成像生物标志物（Yassa） 项目摘要 今天，超过500万美国人患有阿尔茨海默病（AD）。生物医学研究的一个关键目标是 在临床前阶段建立AD的指标（即生物标志物），允许早期诊断， 干预目前，A病理学和神经影像学/认知测量之间的关系， 临床前阶段还没有得到很好的理解。我们的项目结合了新的高分辨率磁共振技术 成像（MRI）工具，对海马记忆特别敏感的新型认知测试，以及对 β-淀粉样蛋白（A β）病理在脑脊液（CSF）或florbetapir（18F）PET扫描，以获得更好的 了解临床前AD的神经基础，并确定临床前AD的新机制生物标志物， AD使用非侵入性技术。该项目的目标是（1）提高我们的能力， 认知能力下降，（2）增强标准神经影像生物标志物对临床前AD的敏感性，以及 利用超高分辨率神经成像技术开发和验证新的生物标志物，（3）测试有效性 作为早期易感性模型（唐氏综合征DS）的两个特殊队列中的生物标志物候选物， 晚期抵抗（非痴呆90+），以及（4）提供概念验证高分辨率多模态神经成像 ADRC平台，以建立建立高分辨率神经成像所需的基础设施 核心我们将招募和测试总共90名参与者：（a）纵向队列：30名健康的非痴呆患者 参与者（15名A�+和15名A�-）和15名A�+遗忘型MCI参与者，年龄在65岁至85岁之间;（B） 唐氏综合征队列：15名年龄在45至65岁之间的A+非痴呆个体;（c）90+队列：30名 非痴呆90+参与者（15 A+和15 A-）。A状态将通过以下方式确定纵向队列 CSF（通过ADRC Path Core）和DS/90+通过florbetapir PET（通过Dr. Kawas和Lott博士）。在目标1中，我们将使用一组新开发的模式分离认知测试。 这些测试在对象、空间和时间域上改变记忆干扰。在目标2中，我们收集 高分辨率结构MRI（0.55 mm各向同性）、静息状态fMRI（1.5 mm各向同性）和DTI（0.66 mm in- 平面）来检验关于与病理状态（例如，内嗅的 皮质厚度、穿通通路完整性、内嗅皮质与 海马）。在目标3中，我们将把目标1和2中的技术应用于唐氏综合征和90多名参与者 来探索这个大脑网络对病理的抵抗力和脆弱性。在目标4中，我们将研究 我们的生物标志物和ADRC数据库中已有的指标之间的关系，如遗传学， 血液/血清标志物和其他CSF病理（例如磷酸化tau）。在目标5中，我们将建立基础设施 存档和整理所有新的成像数据，以便分发给ADRC调查人员， ADRC未来神经成像核心的概念。总之，这个项目的目标将使我们能够更好地 了解临床前AD的状况，并开发可用于未来预防试验的生物标志物。

Project 1: High-Resolution Neuroimaging Biomarkers for Preclinical Alzheimer's Disease (Yassa) Project Summary Over five million Americans have Alzheimer's disease (AD) today. A critical goal of biomedical research is establishing indicators of AD during the preclinical stage (i.e. biomarkers) allowing for early diagnosis and intervention. Currently, the relationship between A� pathology and neuroimaging/cognitive measures during the preclinical stage is not well understood. Our project combines novel high-resolution magnetic resonance imaging (MRI) tools, novel cognitive testing particularly sensitive to hippocampal memory, and assessments of beta-amyloid (A�) pathology in cerebrospinal fluid (CSF) or florbetapir (18F) PET scans to gain a better understanding of the neural basis of preclinical AD and to identify novel mechanistic biomarkers for preclinical AD using non-invasive techniques. The goals of the project are to (1) improve our ability to detect subtle cognitive decline, (2) enhance the sensitivity of standard neuroimaging biomarkers for preclinical AD as well as develop and validate novel biomarkers using ultrahigh-resolution neuroimaging techniques, (3) test the validity of biomarker candidates in two special cohorts as models of early susceptibility (Down syndrome DS) and late resistance (nondemented 90+), and (4) deliver a proof of concept high-resolution multimodal neuroimaging platform for the ADRC to build the infrastructure necessary for establishing a high-resolution neuroimaging core. We will recruit and test a total of 90 participants: (a) Longitudinal cohort: 30 healthy nondemented participants (15 A�+ and 15 A�-) and 15 A�+ amnestic MCI participants between the ages of 65 and 85; (b) Down syndrome cohort: 15 A�+ nondemented individuals between the ages of 45 and 65; (c) 90+ cohort: 30 nondemented 90+ participants (15 A�+ and 15 A�-). A� status will be determined for longitudinal cohort via CSF (through ADRC Path Core) and for DS/90+ via florbetapir PET (through synergistic NIH R01's by Dr. Kawas and Dr. Lott). In Aim 1, we will use a set of newly developed cognitive tests of pattern separation. These tests vary mnemonic interference in the object, spatial and temporal domains. In Aim 2, we will collect high resolution structural MRI (0.55 mm isotropic), resting state fMRI (1.5 mm isotropic) and DTI (0.66 mm in- plane) to test hypotheses about changes in neural features related to pathological status (e.g. entorhinal cortical thickness, perforant path integrity, resting state connectivity between the entorhinal cortex and the hippocampus). In Aim 3, we will apply the techniques in Aims 1 and 2 to Down syndrome and 90+ participants to explore resistance and vulnerability to pathology in this brain network. In Aim 4, we will examine relationships between our biomarkers and pre-existing measures in the ADRC database such as genetics, blood/serum markers, and other CSF pathologies (e.g. phospho-tau). In Aim 5, we will build the infrastructure to archive and curate all new imaging data for dissemination to ADRC investigators to provide a proof of concept for a future neuroimaging core at the ADRC. Together, the Aims of this project will allow us to better understand the condition of preclinical AD and develop biomarkers that can be used in future prevention trials.