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

记忆网络功能障碍是临床前阿尔茨海默病的早期标志

• 批准号: 9349386
• 负责人: Yakeel T. Quiroz
• 金额: $ 51.74万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-19 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9349386
• 关键词: Alzheimer' s Disease; Amyloid; Amyloid deposition; Binding; Biological Markers; Brain; Brain Injuries; Brain region; Cognition; Cognitive; Collection; Colombian; Color; Communities; Consensus; Data; Dementia; Diagnosis; Disease; Early Diagnosis; Elderly; Evaluation; Face; Family member; Functional Magnetic Resonance Imaging; Functional disorder; Generations; Goals; Hippocampus (Brain); Hyperactive behavior; Image; Impaired cognition; Individual; Inherited; Investigation; Measures; Medial; Memory; Mutation; Names; Neuropsychology; Parietal; Participant; Pathology; Pattern; Performance; Pharmaceutical Preparations; Pilot Projects; Positron-Emission Tomography; Predisposition; Presenile Alzheimer Dementia; Process; Research; Rest; Risk; Role; Sampling; Sampling Studies; Shapes; Temporal Lobe; Testing; Time; Validation; Work; abeta accumulation; aging brain; amyloid pathology; candidate marker; cognitive performance; cohort; comparative; disease diagnosis; disease-causing mutation; familial Alzheimer disease; high risk; improved; in vivo; insight; kindred; memory process; molecular pathology; mutation carrier; network dysfunction; neuron loss; novel marker; outcome forecast; pre-clinical; presenilin-1; prevention clinical trial; public health relevance; success; support network; tau Proteins; tau aggregation

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.

描述（由申请人提供）：为阿尔茨海默氏病（AD）寻找修改疾病的治疗方法是我们这一代人的最大挑战之一。科学界达成了共识，即成功治疗广告的关键是在发生重大脑损伤之前尽早开始治疗。因此，表征我工作的重点是临床前生物标志物和早期检测范例，这是至关重要的。大脑区域的分布式网络，包括海马，内侧颞叶中的相邻皮质区域以及其他大脑区域的子囊记忆功能。依靠该网络的配对联想内存任务已被证明对AD的临床前阶段中的细微缺陷很敏感。我建议以常染色体显性广告的研究为基础，以建立概念框架和与晚发的零星广告的比较，重点是将记忆网络中断的分析作为临床前AD的早期标志。为此，我将利用我进入两个非常丰富的临床前广告小组，1）哥伦比亚人伴随着老龄蛋白1 E280A（GLU280ALA）突变，估计有1,500个突变载体和2）较高的人在哈佛大学（Harbad Aging Brain Parter）（Hard Hard Agg Agg Aging Parter）（HAREC）（HAB）（HAB）（HAB）（HAB）（HAB）（HAB）（HABS）（HAB）（HABS）（HAB）（HAB）（HAB）（HAB）（HAB）（HABS）有1,500个突变携带者和2）发作零星广告。该应用的主要目标是：（i）研究关联记忆过程的异常，作为临床前AD的认知标记； （ii）研究大脑过度活跃/超连通性作为早期AD病理学的标志； （iii）检查tau和淀粉样蛋白聚集在记忆网络功能障碍中的作用。本应用程序中提出的研究将使用认知措施，fMRI和PET成像，以研究记忆网络功能障碍发生在阿尔茨海默氏病的早期临床前阶段。这项研究将洞悉认知和大脑的相互作用 临床前广告中的功能生物标志物。特别是，这项工作将提供对淀粉样蛋白和TAU病理学在疾病过程中如何影响记忆的新了解，以及它们在随后的神经元死亡和认知下降中的作用。