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记物(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重要目标是 在临床前阶段建立阿尔茨海默病的指标(即生物标志物)，以便早期诊断和 干预。目前，A�的病理与神经影像/认知测量的关系 临床前阶段还不是很清楚。我们的项目结合了新的高分辨率磁共振 成像(MRI)工具，对海马体记忆特别敏感的新认知测试，以及对 脑脊液中的β-淀粉样蛋白(A-�)或氟倍他平(18F)正电子发射计算机断层扫描以获得更好的 认识临床前阿尔茨海默病的神经基础并寻找新的临床前机械性生物标志物 广告使用非侵入性技术。该项目的目标是(1)提高我们发现细微之处的能力 认知功能下降，(2)提高标准神经影像生物标记物对临床前AD的敏感性 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 在两个特殊队列中作为早期易感性模型(唐氏综合征DS)和 晚期阻力(非痴呆90+)，以及(4)提供概念验证高分辨率多模式神经成像 为ADRC建立建立高分辨率神经成像所需的基础设施的平台 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 年龄在65至85岁之间的参与者(15 A�+和15 A�-)和15 A�+遗忘型MCI参与者；(B) 唐氏综合征队列：15名45岁至65岁的�+非痴呆者；(C)90+队列：30人 90多名非痴呆者(15名A�+和15名A�-)。将通过以下方式确定纵向队列的�状态 脑脊液(通过ADRC路径核心)和DS/90+通过florbetapir PET(通过协作型NIH R01‘S博士)。 卡瓦斯和洛特博士)。在目标1中，我们将使用一套新开发的模式分离认知测试。 这些测试在物体、空间和时间域上有不同的助记干扰。在《目标2》中，我们将收集 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)以测试与病理状态(例如内嗅觉)相关的神经特征变化的假说 皮质厚度、穿支路径完整性、内嗅觉皮质和 海马体)。在目标3中，我们将把目标1和目标2中的技术应用于唐氏综合症和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 我们的生物标记物与ADRC数据库中预先存在的指标之间的关系，如遗传学、 血液/血清标记物和其他脑脊液病理(如磷酸-tau)。在目标5中，我们将建设基础设施 存档和整理所有新的成像数据，以便分发给ADRC调查人员，以提供 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 了解临床前阿尔茨海默病的情况，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.