Role of age, dopamine, and tau related network disruption in setting a context for progression toward Alzheimer's disease

年龄、多巴胺和 tau 相关网络破坏在阿尔茨海默病进展背景中的作用

• 批准号: 9816387
• 负责人: Julius C Hedden
• 金额: $ 84.47万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9816387
• 关键词: Age; Aging; Alzheimer' s Disease; Amyloid; Amyloidosis; Brain; Clinical; Cognition; Cognitive; Cognitive aging; Cross-Sectional Studies; Data; Dementia; Development; Diagnosis; Diagnostic; Differential Diagnosis; Disease; Dopamine; Elderly; Etiology; Exhibits; Functional disorder; Goals; Human; Impaired cognition; Impairment; Individual; Intervention; Laboratories; Lead; Link; Magnetic Resonance Imaging; Measures; Medial; Mediation; Memory; Methods; Modeling; Nature; Neurobehavioral Manifestations; Neurofibrillary Tangles; Neurotransmitters; Outcome; Pathologic; Pathology; Pathway interactions; Patients; Performance; Play; Positron-Emission Tomography; Prevention trial; Public Health; Raclopride; Research; Role; Sampling; Series; Severities; System; Tauopathies; Temporal Lobe; Testing; Time; Work; age related; aged; brain dysfunction; cognitive ability; cognitive change; cognitive performance; dopamine system; executive function; experimental study; human old age (65+); imaging biomarker; improved; mild cognitive impairment; molecular marker; neuropsychiatric symptom; non-demented; normal aging; older patient; population based; prevent; relating to nervous system; serial imaging; tau Proteins; tool

PROJECT SUMMARY The heterogeneous, multifactorial nature of Alzheimer's disease and the overlap of its temporal course with changes attributable to typical aging has been a critical barrier to the development of diagnostic tools and interventions targeting the direct effects of the disease on brain function and cognition. A major challenge is to understand how multiple age-related cascades combine in an individual to create vulnerabilities to cognitive decline during the progression of Alzheimer's disease. One prominent age-related cascade involves disruption of the dopaminergic system. While the dopamine system is not generally understood to be a direct contributor to Alzheimer's disease, patients with Alzheimer's disease exhibit impairments in the mesolimbic dopamine pathway and dopamine may play a role in the severity of neuropsychiatric and cognitive symptoms of Alzheimer's disease. This application proposes a disconnection model in which parallel pathways lead from neuropathological alterations to impaired brain network integrity and cognition. These parallel pathways are proposed to have direct and indirect points of interaction by which age-linked dopaminergic changes induce vulnerabilities to tauopathy and amyloidosis. That is, this is a “dual hit” model where individuals with pre- existing age-related dopaminergic disruption are proposed to be more likely to exhibit declines in network integrity and cognition in the presence of tauopathy and amyloidosis. The overall goal is to test whether the pathways proposed by this model induce vulnerabilities during the progression of Alzheimer's disease. Each aim tests a different set of pathways in the model. First, the project tests an Alzheimer's disease cascade whereby tauopathy and amyloidosis impact integrity of a network known as the default network, leading to change in memory performance. Second, the project tests an age-related cascade whereby dopaminergic function impacts integrity of a frontoparietal control network, leading to change in executive function. Third, the project tests whether increased vulnerability to the Alzheimer's disease cascade is a function of network alterations from the age-related dopaminergic cascade. To test these aims, the project applies simultaneous magnetic resonance imaging and positron emission tomography data to acquire multiple measures of brain function and pathology. A sample of cognitively normal older adults and patients with mild cognitive impairment is tested and followed over time to cover the early spectrum of progression toward Alzheimer's disease. Successful completion will aid differential diagnosis, provide a model for vulnerability to Alzheimer's disease that could be extended to other age-related cascades, and provide alternative targets for bolstering neural integrity to delay or prevent vulnerability during the progression of early Alzheimer's disease.

项目摘要 阿尔茨海默氏病的异质性，多因素性质及其临时过程的重叠 构成典型衰老的变化一直是开发诊断工具和的关键障碍 针对疾病直接影响脑功能和认知的干预措施。一个主要挑战是 了解多个与年龄相关的级联反应如何在一个个体中结合在一起以创造认知脆弱性 阿尔茨海默氏病进展过程中的下降。一个突出的与年龄相关的级联反应涉及中断 多巴胺能系统。虽然通常不认为多巴胺系统是直接贡献者 在阿尔茨海默氏病中，中唇多巴胺的阿尔茨海默氏病患者展示了障碍 途径和多巴胺可能在神经精神病和认知症状的严重程度中起作用 阿尔茨海默氏病。该应用程序提出了一个断开模型，在该模型中，并行途径从 神经病理学改变了脑网络完整性和认知受损。这些平行路径是 提议具有直接和间接的相互作用点，而年龄相关的多巴胺能影响 tauopathy和淀粉样变性的脆弱性。也就是说，这是一个“双重命中”模型 有人认为现有与年龄相关的多巴胺能破坏更有可能退出网络下降 在有青霉病和淀粉样变性的情况下的完整性和认知。总体目标是测试是否 该模型提出的途径在阿尔茨海默氏病进展过程中引起了脆弱性。每个 AIM测试模型中的一组不同的途径。 首先，该项目测试了阿尔茨海默氏病级联 被称为默认网络的网络的完整性，导致内存性能的变化。第二， 项目测试与年龄相关的级联 网络，导致执行功能变化。第三，该项目测试是否增加了对 阿尔茨海默氏病级联反应是与年龄相关的多巴胺能级联反应的网络改变的函数。 为了测试这些目标，该项目应用了简单的磁共振成像和正电子发射 断层扫描数据以获取大脑功能和病理的多种测量。认知正常样本 测试了老年人和轻度认知障碍患者 向阿尔茨海默氏病进展的范围。成功完成将有助于鉴别诊断， 提供一个模型，以使其易受到阿尔茨海默氏病的脆弱性，可以扩展到其他与年龄相关的级联 并为加强神经完整性提供替代目标，以延迟或防止脆弱性 阿尔茨海默氏病早期的进展。