Characterizing the Evolution of Amyloid Deposition in Normal Elderly

正常老年人淀粉样蛋白沉积演变的特征

• 批准号: 8318676
• 负责人: Keith A. Johnson
• 金额: $ 63.93万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8318676
• 关键词: Age; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Amyloid deposition; Anatomy; Applications Grants; Asses; Autopsy; Binding; Brain; Brain scan; CH3OCF2CH(CF3)OCH2F; Clinical; Clinical Data; Cognitive; Data; Deposition; Detection; Diagnosis; Disease; Early Diagnosis; Elderly; Enrollment; Evaluation; Evolution; Functional Imaging; Functional Magnetic Resonance Imaging; Functional disorder; Glucose; Head; Image; Impaired cognition; Impairment; Individual; Lateral; Link; Magnetic Resonance Imaging; Measures; Memory; Memory impairment; Methodology; Methods; Parietal; Pathologic; Patients; Pattern; Performance; Pittsburgh Compound-B; Play; Positron-Emission Tomography; Price; Public Health; Research; Research Personnel; Rest; Risk; Role; Sampling; Series; Signal Transduction; Staging; Structure; Symptoms; Testing; Time; amyloid imaging; amyloid pathology; cognitive reserve; cohort; design; endophenotype; executive function; fluorodeoxyglucose positron emission tomography; follow-up; hippocampal atrophy; imaging modality; improved; in vivo; neuropsychological; novel; pre-clinical; public health relevance

DESCRIPTION (provided by applicant): The deposition of amyloid-beta (Ass) deposition is thought to begin many years prior to the onset of clinical Alzheimer's disease, but until recently it was not possible to track the longitudinal accumulation of Ass in vivo. Cross-sectional autopsy series and recent PET studies using 11CPittsburgh Compound B (PiB) suggest that a large fraction of cognitively normal older individuals harbor amyloid pathology. Our preliminary cross-sectional PiB imaging data in 100 cognitively normal (CN) older individuals have demonstrated significant variability in the level and anatomic distribution of amyloid deposition. It remains unknown whether there is a specific threshold of amyloid pathology in these CN that will predict 1) further amyloid accumulation, 2) the emergence of abnormalities on structural and functional imaging consistent with preclinical AD, and 3) subsequent cognitive decline. This project will acquire longitudinal PiB imaging, FDG-PET, resting fMRI, and detailed neuropsychological assessments in 80 CN subjects every 2 years to investigate the temporal course and anatomic pattern of amyloid accumulation (Aim 1). We will also utilize a recently developed, high-sensitivity PET camera to determine if there is a gradual accumulation of amyloid deposition that is not currently detectable with existing standard cameras (Aim 2). Finally, we will relate longitudinal amyloid accumulation to other indicators of prodromal AD, including regional FDG hypometabolism, functional MRI default network disruption, hippocampal atrophy, cortical thinning, and cognitive decline (Aim 3). This study will capitalize on an existing cohort of well-characterized clinically normal older subjects, a strong multi-disciplinary team of investigators, and state-of-the-art imaging methodology to probe the link between amyloid accumulation and the earliest brain changes associated with preclinical AD. PUBLIC HEALTH RELEVANCE: The symptoms of Alzheimer's disease, a major threat to public health, are preceded by a period of brain amyloid accumulation of at least 10 years duration. The overall aim of this grant proposal is to improve our ability during the presymptomatic period to detect amyloid, to trace its accumulation at low levels, and to assess its impact on the brain, so that treatments may begin at an earlier stage of disease when damage is more limited. To accomplish this, we propose to re-enroll a group of older adults who have already participated in our amyloid research, to now undergo a set of follow-up brain scans and cognitive tests every two years. We propose to measure the buildup of amyloid over time with PiB PET and assess the impact on brain structure with MRI and function with FDG PET. We will also test a powerful new, high-sensitivity PET scanner that we predict will improve our detection of amyloid and permit us to better study it's earliest consequences.

描述（由申请人提供）：β淀粉样蛋白（Ass）沉积被认为在临床阿尔茨海默氏病发病前许多年就开始了，但直到最近还不可能追踪As在体内的纵向积累。横断面尸检系列和最近使用 11CPittsburgh 化合物 B (PiB) 进行的 PET 研究表明，很大一部分认知正常的老年人存在淀粉样蛋白病理。我们对 100 名认知正常 (CN) 老年人的初步横断面 PiB 成像数据表明，淀粉样蛋白沉积的水平和解剖分布存在显着差异。目前尚不清楚这些 CN 中是否存在特定的淀粉样蛋白病理阈值，该阈值将预测 1）进一步的淀粉样蛋白积累，2）与临床前 AD 一致的结构和功能成像异常的出现，以及 3）随后的认知能力下降。该项目将每两年对 80 名 CN 受试者进行纵向 PiB 成像、FDG-PET、静息功能磁共振成像和详细的神经心理学评估，以研究淀粉样蛋白积累的时间过程和解剖模式（目标 1）。我们还将利用最近开发的高灵敏度 PET 相机来确定是否存在目前现有标准相机无法检测到的淀粉样蛋白沉积的逐渐积累（目标 2）。最后，我们将纵向淀粉样蛋白积累与 AD 前驱期的其他指标联系起来，包括区域 FDG 代谢低下、功能性 MRI 默认网络破坏、海马萎缩、皮质变薄和认知能力下降（目标 3）。这项研究将利用现有的一组临床正常的老年受试者、强大的多学科研究团队以及最先进的成像方法来探讨淀粉样蛋白积累与与淀粉样蛋白相关的最早大脑变化之间的联系。临床前AD。 公共健康相关性：阿尔茨海默病是公共健康的一个主要威胁，其症状出现之前会经历一段持续至少 10 年的大脑淀粉样蛋白积累期。该拨款提案的总体目标是提高我们在症状前阶段检测淀粉样蛋白的能力，追踪其低水平积累，并评估其对大脑的影响，以便在疾病受损时在疾病的早期阶段开始治疗。是比较有限的。为了实现这一目标，我们建议重新招募一组已经参与我们淀粉样蛋白研究的老年人，现在每两年接受一系列后续脑部扫描和认知测试。我们建议使用 PiB PET 测量淀粉样蛋白随时间的积累，并使用 MRI 评估其对大脑结构的影响，并使用 FDG PET 评估其对功能的影响。我们还将测试一种功能强大的新型高灵敏度 PET 扫描仪，我们预测该扫描仪将改善我们对淀粉样蛋白的检测，并使我们能够更好地研究其最早的后果。