Modulators of Medial Temporal Lobe Subregion Structure and Function in Normal and Pathological Aging

项目摘要 阿尔茨海默病(AD)是我们这个时代的主要公共卫生危机。基于治疗的基本原理 在重大认知障碍发生之前更有可能有效，人们越来越关注 在临床前期或前驱症状早期进行干预。在这些人群中进行临床试验的一个主要挑战是 开发工具以确定这些干预措施是否有效。作为最早的神经退行性变 AD的改变被认为与内侧颞叶(MTL)内的病理发展有关， 对这一区域的情景记忆和成像的测量可能在作为一种手段发挥关键作用 疾病监测。然而，“正常”衰老也与结构和功能改变有关。 情节记忆是与年龄相关的认知最显著的领域之一 拒绝。这项建议的主要目标是确定与MTL相关的特征，以区分正常衰老和 临床前AD，以及影响这些差异的因素。 根据正常衰老和临床前AD的结构、功能和认知重叠，更细粒度的 为了更好地区分这些情况，有必要进行检查。这样做对于有效的疾病是必不可少的。 将年龄效应与进化中的阿尔茨海默病分离的监测。至关重要的是，MTL由多个 与记忆的不同方面相关联的相互关联的子区域，并且可以选择性地 与临床前AD相比，易受衰老的影响。然而，尽管几十年的工作主要集中在认知上 随着年龄的增长记忆丧失的神经科学，这是对发生的具体变化的更细粒度的理解 MTL内部和相关网络缺乏，文献相互冲突。 我们将用以前的文献解决一些方法论问题，这些问题可能会解释这一点 前后不一致。首先，我们将利用我们在开发MTL结构方法方面的丰富经验 和功能测量，并利用7特斯拉(T)MRI成像的更高分辨率 更标准的临床或研究核磁共振扫描。其次，我们将获得淀粉样蛋白成像来确定 临床前阿尔茨海默病的存在，使我们能够独立地隔离衰老的影响。三是综合核算 对于其他可能影响MTL变化的因素，包括脑血管疾病(CVD)， 神经原纤维缠结(NFT)病理独立于临床前AD和遗传因素。我们将获得 7T磁共振心脑血管疾病的敏感标记物，Tau PET成像的NFT负荷，以及与AD风险相关的SNPs。 第四，我们将通过实验记忆测量来检验这些变化对认知的影响。 我们预计，对年龄对MTL结构和功能的影响的详细了解将使 明确临床前AD的监测指标，显著提高我们对AD的认识 与年龄相关的记忆衰退的潜在机制。

Project Summary Alzheimer's Disease (AD) is the major public health crisis of our time. Based on the rationale that treatments are more likely to be effective before significant cognitive impairment has accrued, there is increased focus on intervening in preclinical or early prodromal stages. A major challenge for clinical trials in these populations is development of tools to determine if these interventions are effective. As the earliest neurodegenerative changes of AD are thought linked to the development of pathology within the medial temporal lobe (MTL), measures of episodic memory and imaging of this region may play a critical role in serving as a means for disease monitoring. However, “normal” aging is also associated with both structural and functional alterations of the MTL, and episodic memory is one of the domains most saliently implicated in age-associated cognitive decline. The major goal of this proposal is to identify MTL-related features that distinguish normal aging from preclinical AD, as well as the factors that influence these differences. In light of structural, functional, and cognitive overlap in normal aging and preclinical AD, a more granular examination is necessary to better distinguish these conditions. Doing so is essential for effective disease monitoring that dissociates age-effects from those of evolving AD. Critically, the MTL consists of a number of inter-related subregions that have been associated with different aspects of memory and may be selectively vulnerable to aging versus preclinical AD. However, despite decades of work focused on the cognitive neuroscience of memory loss with aging, this more granular understanding of specific changes that occur within the MTL and related networks is lacking and the literature conflicting. We will address a number of methodologic issues with the prior literature that may account for this inconsistency. First, we will leverage our extensive experience in development of methods for MTL structural and functional measurement and take advantage of the improved resolution of 7 Tesla (T) MRI imaging over more standard clinical or research MRI scans. Second, we will obtain amyloid imaging to determine the presence preclinical AD, allowing us to isolate aging effects on its own. Third, we will comprehensively account for other factors that may influence MTL changes, including cerebrovascular disease (CVD), presence of neurofibrillary tangle (NFT) pathology independent of preclinical AD, and genetic factors. We will obtain sensitive markers of CVD with 7T MRI, NFT burden with Tau PET imaging, and SNPs associated with AD risk. Fourth, we will examine the cognitive effects of these changes with experimental memory measures. We anticipate that the detailed understanding of the effect of age on MTL structure and function will allow for definition of monitoring targets of preclinical AD and significantly enhance our understanding of mechanisms underlying age-associated memory decline.