Neural and Biochemical Mechanisms of Cognitive Aging

项目总结/摘要 这个项目的重点是在正常衰老和衰老之间的边界上改变记忆功能的基础。 最近被描述为临床前阿尔茨海默病（AD）。衰老和AD都是 其特征在于聚集的蛋白质tau和β-淀粉样蛋白（Aβ）。在该项目的基础模型中， 内侧颞叶（MTL）被假设为与轻度年龄相关性下降相关的主要因素， 情节记忆和海马功能的破坏。然而，在临床前AD中， 发生在后扣带回（PCC）和压后皮质（RSC）;当这种Aβ积聚发生时，tau 在MTL外发现累积，并且海马与新皮质的连接性（PCC/RSC）是 被打乱了这些影响严重破坏记忆功能，也影响其他认知过程。我们计划 通过招募年龄在20岁到90岁之间的健康人来测试这个模型。前一 本研究的第一阶段招募了157名老年受试者，所有受试者都将接受大约6年的纵向研究。 跟进所有参与者将使用新型配体[18F]AV-1451进行tau成像，使用 [11 C]PIB、结构MRI扫描和静息状态MRI扫描。招募60岁以上的人将是 按PIB状态（PIB+/PIB-）平衡。所有受试者还将使用基于任务的功能性MRI（fMRI）进行研究 同时他们使用模式分离范式执行情景记忆任务。在这项任务中，受试者必须 区分与先前观看的刺激相似但不相同的视觉刺激。识别 这些类似的刺激作为“旧”的证据是模式完成和记忆处理失败;这有 特征性地与海马过度激活相关，这可能是有害的。我们预计 增加MTL tau将使受试者偏向模式完成，tau积累和Aβ- 相关的海马分离将与海马过度激活相关。其他关键假设包括 （1）年龄将与MTL tau增加相关，而Aβ将与新皮质中的tau相关， (2)情景记忆功能将与MTL tau相关，而整体认知将与Aβ和 新皮质tau蛋白该项目的最终目标是确定年龄、tau蛋白和Aβ之间的关系， 表明衰老和临床前AD中记忆障碍的潜在机制涉及质的不同， Aβ和tau蛋白对行为、海马连接和海马功能的影响。区分正常 通过研究这些影响，将对AD的早期发现、AD的选择和AD的治疗具有重要意义。 受试者进行临床试验，并开发非AD年龄相关的诊断和治疗方法， 认知能力下降

PROJECT SUMMARY/ABSTRACT This project is focused on the basis of altered memory function at the boundary between normal aging and what has recently been described as preclinical Alzheimer's disease (AD). Both aging and AD are characterized by the aggregated proteins tau and β-amyloid (Aβ). In the model that underlies the project, tau in the medial temporal lobe (MTL) is hypothesized as a major factor associated with mild age-related decline in episodic memory and disruption of hippocampal function. In preclinical AD, however, early Aβ accumulation occurs in the posterior cingulate (PCC) and retrosplenial cortex (RSC); as this Aβ accumulation occurs, tau accumulation is found outside the MTL and connectivity of the hippocampus to neocortex (PCC/RSC) is disrupted. These effects severely disrupt memory function and also affect other cognitive processes. We plan to test this model by recruiting a lifespan cohort of healthy people ranging in age from 20 to 90. The previous phase of this study recruited 157 older subjects, all of whom will have approximately 6 years of longitudinal follow up. All participants will undergo tau imaging using the novel ligand [18F]AV-1451, amyloid imaging using [11C]PIB, structural MRI scanning, and resting state MRI scanning. Recruitment of those over 60 will be balanced by PIB status (PIB+/PIB-). All subjects will also be studied using task-based functional MRI (fMRI) while they perform an episodic memory task using a pattern separation paradigm. In this task subjects must discriminate between visual stimuli that are similar, but not identical, to previously viewed stimuli. Identification of these similar stimuli as “old” is evidence of pattern completion and failure of memory processing; this has characteristically been associated with hippocampal hyperactivation which is likely detrimental. We anticipate that increasing MTL tau will bias subjects towards pattern completion, and that tau accumulation, and Aβ- related hippocampal disconnection will be related to hippocampal hyperactivation. Other key hypotheses are that (1) age will be associated with increased MTL tau, while Aβ will be associated with tau in neocortex and (2) episodic memory function will be related to MTL tau while global cognition will be related to both Aβ and neocortical tau. The ultimate goal of the project is to define relationships between age, tau, and Aβ and to show that the mechanisms underlying memory failure in aging and preclinical AD involve qualitatively different effects of Aβ and tau on behavior, hippocampal connectivity and hippocampal function. Differentiating normal cognitive aging from AD by studying these effects will be important for early detection of AD, selection of subjects for clinical trials, and developing diagnostic and therapeutic approaches to non-AD age-related cognitive decline.