AMYLOID PATHOLOGY AND COGNITION IN NORMAL ELDERLY

在这个项目的前五年，我们开始了使用PIB-PET淀粉样蛋白成像和认知成像的工作 评估以解决以下三个基本问题：1)淀粉样蛋白沉积在 临床未受损的老年人；2)临床未受损的老年人认知能力的变异性较大 老年人(与年轻人相比)由淀粉样蛋白沉积的存在或不存在所解释；以及3)将 有淀粉样蛋白沉积证据的临床未受损的老年人总是进展到临床 在一段合理的时间内诊断出轻度认知障碍(MCI)或阿尔茨海默病？一如既往 在最初的申请中强调，所有这些问题，最明显的第三个问题，将需要更多 五年多的时间才能令人满意地解决。我们的目标是开始这一重要进程，并召集一批 临床上没有受损的老年人，我们预计其中一些人会表现出淀粉样沉积的证据，所以我们 可以开始提供关于前两个问题的初步数据，并组织一个队列来跟踪 十年或更长时间来解决第三个问题。我们现在有56人(这个数字还在增长) 临床上未受损的老年人和~25%的人表现出淀粉样蛋白沉积的客观证据。对于 本次功勋奖的延期，我们建议延续原有的具体目标，但增加 根据前314年学习到的新数据对该项目进行了改进。它们包括：a) 从现有心血管健康研究-认知研究中招募年龄最大(85岁以上)的队列 (CHS-CS)；b)增加脑代谢成像数据的详细相关分析(FDG-PET) 基于最近发现的PIB-PET数据表明，这些措施的组合可能 提供有关认知状态即将发生变化的更准确信息；c)增加休息- 状态和激活功能磁共振(FMRI)研究，以进一步淀粉样蛋白-代谢相关性和 确定默认模式网络在调节大脑效应中的作用和代偿性变化 淀粉样蛋白沉积；以及d)收集脑脊液中Ap42和p-tau181 志愿者进行腰椎穿刺术，以开始确定PIB阳性与 “脑脊液异常”。应该强调的是，研究方向没有重大变化，因为 这是原提案中所描述的。上述四项新增内容反映了 正常衰老与认知功能障碍混合的脑成像和生物标志物研究 从MCI到AD。这将使原来的项目在正常老化的情况下保持在成像研究的前沿 并允许它带头进行其他类似的研究，并与世界各地进行的其他类似研究相衔接。 相关性(见说明)； 这些问题的答案将有助于我们理解淀粉样蛋白沉积在非脑血管疾病中的意义。 精神错乱的人。随着抗淀粉样蛋白疗法的出现，这一理解将变得重要。 如果临床前淀粉样蛋白沉积明显进展为高频率的临床阿尔茨海默病，那么它 对于识别和治疗非痴呆症、淀粉样蛋白阳性的个体将变得重要。它还处于早期阶段。 抗淀粉样蛋白疗法可能是最有效的，甚至可能它们在这方面是唯一有效的。 舞台。也是在这个阶段，治疗实际上可以在临床症状发生之前预防。

In the first five years of this project, we initiated work using PiB-PET amyloid imaging along with cognitive evaluations to address the following three fundamental questions: 1) how common is amyloid deposition in clinically unimpaired elderly; 2) is the greater variability of cognitive performance in the clinically unimpaired elderly (compared to the young) explained by the presence or absence of amyloid deposition; and 3) will clinically unimpaired elderly who have evidence of amyloid deposition invariably progress to a clinical diagnosis of mild cognitive impairment (MCI) or AD within some reasonable amount of time? As was emphasized in that original application, all of these questions, and most clearly the third, will require more than five years to satisfactorily address. Our goal was to begin this important process and gather a cohort of clinically unimpaired elderly, some of whom we expected to show evidence of amyloid deposition, so we could begin to provide preliminary data on the first two questions and assemble a cohort to follow for a decade or more to address the third question. We now have a cohort of 56 (this number is still growing) clinically unimpaired elderly and ~25% of them show objective evidence of amyloid deposition. For the extension of this MERIT Award, we are proposing to continue the original specific aims, but add enhancements to the project based on new data learned during the first 314 years. They include: a) recruitment ofthe oldest-old (85+) cohort from the existing Cardiovascular Health Study-Cognition Study (CHS-CS); b) addition of a detailed correlational analysis ofthe brain metabolic Imaging data (FDG-PET) with the PiB-PET data based on recent findings that suggest the combination of these measures may provide more precise information regarding impending changes in cognitive status; c) addition of resting- state and activation functional MRI (fMRI) studies to further the amyloid-metabolic correlations and determine the role of the default-mode network and compensatory changes in modulating the effects of brain amyloid deposition; and d) collection of CSF for Ap42 and p-tau181 on a subset of subjects who will volunteer for a lumbar puncture to begin to determine the temporal relationship between PiB-positivity and "abnormal CSF". It should be stressed that there are no major changes to the direction of the research as described in the original proposal. The four additions described above reflect the current state-of-the-art in brain imaging and biomarker studies of normal aging as it blends with the spectrum of cognitive impairment from MCI to AD. This will keep the original project on the cutting edge of imaging research in normal aging and allow it to lead the way for and dovetail with other similar studies being conducted around the world. RELEVANCE (See instructions); Answers to these questions will help us to understand the significance of amyloid deposition in non- demented individuals. This understanding will become important as anti-amyloid therapies become available. If it becomes clear that pre-clinical amyloid deposition progresses to clinical AD with high frequency, then it will become important to identify and treat non-demented, amyloid-positive individuals. It is at this early stage that anti-amyloid therapies will likely be most effective, or it may even be that they are onlv effective at this stage. It also is at this stage when treatment could actually prevent clinical symptoms before they occur.