Neural and Biochemical Mechanisms of Cognitive Aging

项目摘要/摘要 这个项目的重点是在正常衰老和衰老之间改变记忆功能的基础上 最近被描述为临床前阿尔茨海默病(AD)的疾病。衰老和AD都是 以聚集蛋白tau和β-淀粉样蛋白(Aβ)为特征。在作为项目基础的模型中，tau in 内侧颞叶(MTL)被认为是与年龄相关性轻度下降有关的一个主要因素 情节记忆和海马体功能障碍。然而，在临床前AD中，早期Aβ积聚 发生在后扣带回和脾后皮质；当这种β积聚发生时，tau 在MTL外发现蓄积，海马区与新皮质的连接(PCC/RSC)是 打乱了。这些影响严重扰乱了记忆功能，也影响了其他认知过程。我们计划 通过招募年龄从20岁到90岁的健康人群来测试这一模型。上一次 这一阶段的研究招募了157名年长的受试者，他们都将有大约6年的纵向 继续跟进。所有参与者都将接受使用新型配体[18F]AV-1451的tau成像，使用 [11C]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。所有受试者也将使用基于任务的功能磁共振成像(FMRI)进行研究。 而他们使用模式分离范例执行情节记忆任务。在这项任务中，被试必须 区分与先前观察到的刺激相似但不完全相同的视觉刺激。鉴定 这些与“旧”类似的刺激是模式完成和记忆处理失败的证据； 特点是与海马区过度激活有关，这可能是有害的。我们期待着 增加MTLtau将使受试者偏向模式完成，tau累积，以及Aβ- 相关的海马区连接中断将与海马区过度激活有关。其他关键假设包括 这(1)年龄将与增加的MTLtau有关，而Aβ将与tau在新皮质和 (2)情景记忆功能与MTL tau有关，而全局认知与Aβ和Tau有关 新皮质tau。该项目的最终目标是定义年龄、tau和Aβ之间的关系，并 显示衰老和临床前阿尔茨海默病记忆衰竭的潜在机制有本质上的不同 Aβ和tau对行为学、海马区连接性和海马区功能的影响区分正常 通过研究这些影响来研究AD的认知老化对于AD的早期发现、选择 临床试验的对象，以及开发非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.