Memory network dysfunction as an early marker of preclinical Alzheimer's Disease

描述(申请人提供)：寻找治疗阿尔茨海默病(AD)的疾病修正疗法是我们这一代人面临的最大挑战之一。科学界的共识是，治疗阿尔茨海默病的成功关键是在发生重大脑损伤之前尽早开始治疗。因此，确定临床前生物标记物和早期检测范例是至关重要的，这是我工作的重点。大脑区域的分布网络，包括海马体，内侧颞叶邻近的皮质区域，以及其他大脑区域，次级服务于记忆功能。依赖于这个网络的配对联想记忆任务已经被证明对AD临床前阶段的细微缺陷很敏感。我建议在我以前对常染色体显性AD的研究的基础上，建立概念框架，并与晚发型散发性AD进行比较，重点是分析记忆网络中断作为临床前AD的早期标志。为此，我将利用我对两个非常丰富的临床前AD组的访问，1)具有早老素1 E280A(Glu280Ala)突变的哥伦比亚家族，估计有1,500个突变携带者，以及2)一组没有症状的老年人，他们是麻省理工学院哈佛老龄化脑研究(HABS)的参与者，并且被认为是(通过分子病理学成像)发展为晚发性散发性AD的高危人群。这一应用的主要目的是：(I)研究联想记忆过程的异常作为临床前AD的可能认知标志；(Ii)研究脑高活动/高连接作为早期AD病理的标志；以及(Iii)研究tau和淀粉样蛋白聚集在记忆网络功能障碍中的作用。在这项申请中提出的研究将使用认知测量、功能磁共振成像和PET成像来检验记忆网络功能障碍发生在阿尔茨海默病临床前早期阶段的假设。这项研究将为认知和大脑的相互作用提供洞察力 临床前阿尔茨海默病的功能生物标志物。特别是，这项工作将为淀粉样蛋白和tau病理如何在疾病过程的早期影响记忆功能，以及它们在随后的神经元死亡和认知下降中的作用提供新的理解。

DESCRIPTION (provided by applicant): Finding a disease-modifying treatment for Alzheimer's disease (AD) is one of the greatest challenges of our generation. There is a consensus in the scientific community that the key to success in treating AD is to begin therapies as early as possible before significant brain damage occurs. Thus characterizing preclinical biomarkers and early detection paradigms, which is the focus of my work, is paramount. A distributed network of brain regions, including the hippocampus, adjacent cortical regions in the medial temporal lobe, and other brain regions sub-serve memory function. Paired associative memory tasks that rely on this network have been shown to be sensitive to subtle deficits in the preclinical stages of AD. I propose to build upon my previous research with autosomal dominant AD to establish conceptual frameworks and comparisons with late-onset sporadic AD with an emphasis on the analysis of memory network disruption as an early marker of preclinical AD. To this end, I will leverage my access to two extraordinarily rich preclinical AD groups, 1) the Colombian kindred with Presenilin 1 E280A (Glu280Ala) mutation, estimated to have 1,500 mutation carriers, and 2) a group of asymptomatic older individuals who are participants in the Harvard Aging Brain Study (HABS) at MGH and are considered at high risk (by molecular pathology imaging) to develop late- onset sporadic AD. The primary goals of this application are to: (i) investigate abnormalities of associative-memory processes as a possible cognitive marker of preclinical AD; (ii) investigate brain hyper-activity/hyper- connectivity as a marker of early AD pathology; and, (iii) examine the role of tau and amyloid aggregation in memory network dysfunction. The research proposed in this application will use cognitive measures, fMRI and PET imaging to examine the hypothesis that memory network dysfunction occurs in early preclinical stages of Alzheimer's disease. This research will provide insight into the interaction of cognitive and brain function biomarkers in preclinical AD. In particular, this work will provide new understanding of how amyloid and tau pathology impact memory function very early in the disease process, and their role in subsequent neuronal death and cognitive decline.