AMYLOID PATHOLOGY AND COGNITION IN NORMAL ELDERLY

在这个项目的前五年，我们开始使用PiB-PET淀粉样蛋白成像沿着认知功能， 评估以解决以下三个基本问题：1）淀粉样蛋白沉积在 临床上未受损的老年人; 2）临床上未受损的老年人中认知表现的变异性更大 老年人（与年轻人相比）通过淀粉样蛋白沉积的存在或不存在来解释;以及3）将 有淀粉样蛋白沉积证据的临床上未受损的老年人总是进展为临床 在合理的时间内诊断出轻度认知障碍（MCI）或AD？正如 在最初的申请中强调，所有这些问题，最明显的是第三个问题，将需要更多的 五年以上才能圆满解决。我们的目标是开始这一重要进程， 临床上未受损的老年人，我们预计其中一些人会显示淀粉样蛋白沉积的证据，所以我们 可以开始提供前两个问题的初步数据，并组建一个队列， 十年或更长时间来解决第三个问题。我们现在有56个队列（这个数字还在增长） 临床上未受损的老年人，其中约25%显示淀粉样蛋白沉积的客观证据。为 延长这一优异奖，我们建议继续原来的具体目标，但增加 根据前314年的新数据对项目进行了改进。这些措施包括： 从现有的心血管健康研究-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（FDG-PET）的详细相关性分析 根据最近的研究结果，PiB-PET数据表明，这些措施的组合可能 提供关于认知状态即将发生的变化的更精确的信息; c）增加休息- 状态和激活功能性MRI（fMRI）研究，以进一步研究淀粉样蛋白代谢的相关性， 确定默认模式网络和补偿性变化在调节大脑效应中的作用 淀粉样蛋白沉积;和d）在受试者亚组上收集CSF的Ap 42和p-tau 181，所述受试者亚组将 志愿者进行腰椎穿刺，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， 在最初的建议中。上述四项增加反映了目前的最新技术水平， 大脑成像和生物标志物研究的正常老化，因为它与认知障碍的频谱混合 从MCI到AD这将使原来的项目保持在正常衰老的成像研究的前沿 并使其能够引领世界各地正在进行的其他类似研究并与之相吻合。 相关性（参见说明）; 这些问题的答案将有助于我们理解淀粉样蛋白沉积在非免疫性疾病中的意义。 精神错乱的人。随着抗淀粉样蛋白疗法的出现，这种理解将变得重要。 如果临床前淀粉样蛋白沉积进展为临床AD的频率很高， 将成为重要的识别和治疗非痴呆症，淀粉样蛋白阳性的个人。在这个早期阶段 抗淀粉样蛋白治疗可能是最有效的，或者甚至可能是他们只在这个方面有效。 阶段也正是在这个阶段，治疗实际上可以在临床症状发生之前预防它们。

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.