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

项目摘要 阿尔茨海默病的异质性、多因素性及其时间进程与阿尔茨海默病的重叠 典型老化引起的变化一直是诊断工具开发的关键障碍， 针对疾病对大脑功能和认知的直接影响的干预措施。一项重大的挑战是 了解多个与年龄相关的级联反应如何在个体中联合收割机，以产生认知脆弱性 在阿尔茨海默病的发展过程中下降。一个突出的与年龄相关的级联涉及破坏 多巴胺能系统。虽然多巴胺系统通常不被认为是直接贡献者， 与阿尔茨海默病相比，阿尔茨海默病患者的中脑边缘多巴胺 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。 老年痴呆症本申请提出了一种断开模型，其中平行通路从 神经病理学改变导致脑网络完整性和认知受损。这些平行的路径是 提出有直接和间接的相互作用点，通过这些相互作用点，与年龄相关的多巴胺能变化诱导 易患tau蛋白病和淀粉样变性。也就是说，这是一个“双重打击”模型，其中具有前 现有的与年龄相关的多巴胺能障碍更有可能表现出网络功能的下降， 在tau蛋白病和淀粉样变性的存在下的完整性和认知。总体目标是测试 该模型提出的通路在阿尔茨海默病的进展过程中诱导脆弱性。每个 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病级联反应，其中tau蛋白病和淀粉样变性影响 称为默认网络的网络的完整性，导致内存性能发生变化。二是 一个项目测试了与年龄相关的级联反应，多巴胺能功能影响额顶叶控制的完整性 网络，导致执行功能的改变。第三，该项目测试是否增加脆弱性， 阿尔茨海默氏病级联是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，该项目同时应用磁共振成像和正电子发射技术， 断层扫描数据，以获取脑功能和病理学的多个测量。一个认知正常的样本 老年人和轻度认知障碍患者进行测试，并随时间推移进行随访，以涵盖早期 阿尔茨海默病的发展谱。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， 并提供了支持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。

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.