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.

项目概要 阿尔茨海默病的异质性、多因素性质及其时间过程与其他疾病的重叠 典型衰老引起的变化一直是诊断工具和技术开发的关键障碍 针对疾病对大脑功能和认知的直接影响，一个主要挑战是： 了解多个与年龄相关的级联如何在个体中结合起来造成认知脆弱性 阿尔茨海默病进展过程中的一个重要的与年龄相关的级联反应涉及破坏。 虽然多巴胺系统通常不被理解为直接贡献者。 对于阿尔茨海默氏病，阿尔茨海默氏病患者表现出中脑边缘多巴胺受损 通路和多巴胺可能在神经精神和认知症状的严重程度中发挥作用 该申请提出了一种断开模型，其中平行通路来自于。 这些平行途径会导致大脑网络完整性和认知功能的神经病理学改变。 提出有直接和间接的相互作用点，通过这些相互作用点，年龄相关的多巴胺能变化会引起 也就是说，这是一个“双重打击”模型，其中患有前期疾病的个体。 现有的与年龄相关的多巴胺能破坏更有可能表现出网络下降 总体目标是测试存在 tau 蛋白病和淀粉样变性时的完整性和认知能力。 该模型提出的途径在阿尔茨海默病的进展过程中会导致脆弱性。 目标测试模型中的一组不同的路径。 首先，该项目测试了阿尔茨海默氏病级联反应，其中 tau 蛋白病和淀粉样变性影响 一个被称为默认网络的完整性，导致内存性能的变化。 该项目测试了与年龄相关的级联，多巴胺能功能影响额顶叶控制的完整性 第三，该项目测试是否增加了漏洞。 阿尔茨海默病级联是与年龄相关的多巴胺能级联网络改变的函数。 为了测试这些目标，该项目应用同步磁共振成像和正电子发射 断层扫描数据获取大脑功能和病理学的多种测量数据 认知正常的样本。 对老年人和患有轻度认知障碍的患者进行测试并随时间推移进行随访，以涵盖早期认知障碍 成功完成阿尔茨海默病的进展谱将有助于鉴别诊断， 提供了一个易受阿尔茨海默病影响的模型，可以扩展到其他与年龄相关的级联反应， 并提供增强神经完整性的替代目标，以延迟或防止脆弱性 早期阿尔茨海默病的进展。