Characterizing the Evolution of Amyloid Deposition in Normal Elderly

描述(申请人提供)：淀粉样β蛋白(Ass)的沉积被认为是在临床阿尔茨海默病发病前多年开始的，但直到最近才有可能追踪Ass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)的PET研究表明，很大一部分认知正常的老年人患有淀粉样蛋白病理。我们对100名认知正常(CN)老年人的初步PIB横断面成像数据显示，淀粉样蛋白沉积的水平和解剖分布存在显著差异。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)淀粉样蛋白的进一步堆积，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。该项目将每两年获取80名CN患者的纵向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聚的时间进程和解剖模式(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用现有标准相机无法检测到的淀粉样蛋白沉积的逐渐积累(AIM 2)。最后，我们将把纵向淀粉样蛋白堆积与前驱AD的其他指标联系起来，包括局部FDG代谢低下、功能MRI缺省网络中断、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具有良好特征的临床正常老年受试者队列、强大的多学科研究团队和最先进的成像方法来探索淀粉样蛋白积累与与临床前AD相关的最早大脑变化之间的联系。 公共卫生相关性：阿尔茨海默病的症状是对公共健康的主要威胁，在此之前，大脑淀粉样蛋白积累期至少持续10年。这项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，追踪其在低水平的积累，并评估其对大脑的影响，以便在损害更有限的疾病早期阶段开始治疗。为了实现这一目标，我们建议重新招募一组已经参与我们的淀粉样蛋白研究的老年人，现在每两年接受一系列后续的脑扫描和认知测试。我们建议用PIB PET测量随着时间推移淀粉样蛋白的堆积，并用MRI和FDG PET评估对大脑结构和功能的影响。我们还将测试一种功能强大的新型高灵敏度PET扫描仪，预计它将改进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。

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.