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

项目总结 阿尔茨海默病的异质性、多因素特性及其时间病程与 可归因于典型老化的变化一直是诊断工具和 针对疾病对大脑功能和认知的直接影响的干预措施。一个主要的挑战是 了解多个与年龄相关的级联反应如何在一个个体中组合在一起，从而造成认知缺陷 在阿尔茨海默病的发展过程中。一个突出的与年龄相关的级联涉及到中断 多巴胺能系统。虽然多巴胺系统通常不被理解为直接贡献者 对于阿尔茨海默病，阿尔茨海默病患者表现出中脑边缘多巴胺的损害 通路和多巴胺可能在神经精神和认知症状的严重程度中起作用 阿尔茨海默氏症。此应用程序提出了一种断开模型，在该模型中，并行路径从 大脑网络完整性和认知受损的神经病理改变。这些平行的路径是 被认为具有直接和间接的相互作用点，年龄相关的多巴胺能变化通过这些相互作用点引起 易患肌萎缩症和淀粉样变性。也就是说，这是一种“双重打击”的模式，在这种模式下，有前科的个体 现有的与年龄相关的多巴胺能干扰被认为更有可能在网络中表现出下降 在存在直肠畸形和淀粉样变性时的完整性和认知力。总体目标是测试 该模型提出的通路在阿尔茨海默病的发展过程中会导致脆弱性。每个人 AIM在模型中测试了一组不同的路径。 首先，该项目测试了阿尔茨海默氏症的级联反应，即牛磺酸和淀粉样变性对 称为默认网络的网络的完整性，会导致内存性能发生变化。第二， 该项目测试了与年龄相关的级联反应，多巴胺能功能由此影响额顶控制的完整性 网络，导致执行职能的变化。第三，该项目测试是否增加了对 阿尔茨海默氏病的级联是年龄相关的多巴胺能级联网络改变的功能。 为了测试这些目标，该项目使用了同时的磁共振成像和正电子发射 断层扫描数据，以获取脑功能和病理的多个测量。一个认知正常的样本 对老年人和轻度认知障碍患者进行测试，并随着时间的推移进行跟踪，以涵盖早期 发展为阿尔茨海默病的谱系。成功完成将有助于鉴别诊断， 为阿尔茨海默病的易感性提供了一个模型，可以扩展到其他与年龄相关的级联反应中， 并提供支持神经完整性的替代目标，以延迟或防止在 早期阿尔茨海默病的进展。

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.