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）：寻找阿尔茨海默病（AD）的疾病缓解疗法是我们这一代人面临的最大挑战之一。科学界达成共识，成功治疗 AD 的关键是在严重脑损伤发生之前尽早开始治疗。因此，表征临床前生物标志物和早期检测范例是我工作的重点，这一点至关重要。大脑区域的分布式网络，包括海马体、内侧颞叶的邻近皮质区域和其他大脑区域，有助于记忆功能。依赖于该网络的配对联想记忆任务已被证明对 AD 临床前阶段的细微缺陷很敏感。我建议以我之前对常染色体显性 AD 的研究为基础，建立概念框架并与晚发散发性 AD 进行比较，重点分析记忆网络破坏作为临床前 AD 的早期标志。为此，我将利用我接触到的两个极其丰富的临床前 AD 群体，1) 患有早老素 1 E280A (Glu280Ala) 突变的哥伦比亚亲属，估计有 1,500 名突变携带者，以及 2) 一群无症状的老年人，他们是麻省总医院哈佛大脑老化研究 (HABS) 的参与者，并且被认为处于晚期发展的高风险（通过分子病理学成像）。 AD 发病散发。该应用程序的主要目标是：(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) 研究大脑过度活跃/过度连接作为早期 AD 病理学的标志； (iii) 检查 tau 蛋白和淀粉样蛋白聚集在记忆网络功能障碍中的作用。本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早期临床前阶段的假设。这项研究将深入了解认知和大脑的相互作用 临床前 AD 中的功能生物标志物。特别是，这项工作将为了解淀粉样蛋白和 tau 蛋白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能力下降中的作用提供新的认识。