Environmental Enrichment and Cognitive Survival: Role of ABeta and Metabolism

描述（由申请人提供）：尸检研究表明，在25-50%的认知正常老年对照受试者中存在脑淀粉样蛋白斑块，最近的匹兹堡化合物-B（PiB）PET研究表明，在认知正常的老年人中存在类似的发现。在一些对照中的PiB保留可以与在阿尔茨海默病（AD）中观察到的一样高。这些发现的一个首要问题是，为什么面对大量的淀粉样蛋白负担，有些人会患上AD，而另一些人则保持正常。据报道，丰富的环境和生活方式可以抵抗痴呆症的发展（人类）和A2的影响（动物模型）。据推测，富集的影响与病理变化的减少或对该病理影响的脆弱性的降低有关。然而，尽管老年人经常被建议丰富他们的环境，但几乎没有数据可以知道环境丰富是否会在生命后期产生影响，或者是否必须在生命早期开始。使用翻译的方法，这个建议将提供一个研究计划的基础，致力于了解环境富集的作用（和富集的时间）赋予抵抗神经退行性过程。迄今为止，我的培训为我提供了动物模型和人类神经影像学方面的强大背景，以分别探索涉及神经退行性疾病（如AD）的研究问题。目前的职业发展计划旨在扩展我以前的培训和经验，使我具备建立一个研究计划所需的技能，该计划利用更全面的转化方法，结合针对相同潜在问题的动物和人类研究。为此，在这个应用程序中，我试图探索丰富的环境中的影响“平行”研究的人类和动物模型的AD。这里提出的研究计划将建立在行为方法的基础上，包括认知和生活方式的测量，辅以成像技术，包括A2和大脑代谢的测量。只要有可能，将比较动物模型和人类受试者之间的相关措施。拟议的职业发展计划反映了这些目标，并包括在人类和动物的认知，A2和代谢的评估培训。该提案解决了关于生活方式活动对几个因素的影响的重要问题，包括人类和AD小鼠模型中的淀粉样蛋白沉积和葡萄糖代谢。这些问题的答案将有助于我们了解生活方式活动（以及这些活动的时间）对AD风险的重要性。

DESCRIPTION (provided by applicant): Postmortem studies have shown that brain amyloid plaques are present in 25-50% of cognitively normal elderly control subjects and recent Pittsburgh Compound-B (PiB) PET studies have shown similar findings in living cognitively normal elderly. PiB retention in some controls can be as high as that observed in Alzheimer's disease (AD). An overarching question from these findings is why, in the face of substantial amyloid burden, some people develop AD and others remain normal. Enriched environments and lifestyle have been reported to confer resistance to development of dementia (in humans) and to the effects of A2 (in animal models). The effects of enrichment are hypothesized to be related either to a decrease in pathological changes or a decrease in vulnerability to the effects of that pathology. However, although older individuals are often advised to enrich their environment, there is little data to know if environmental enrichment can have an impact late in life, or whether it must begin much earlier in life. Using a translational approach, this proposal will provide the foundation for a research program dedicated to understanding the role of environmental enrichment (and the timing of that enrichment) in conferring resistance to neurodegenerative processes. To date, my training has provided me with a strong background in animal models and human neuroimaging to separately explore research questions involving neurodegenerative diseases, such as AD. The present career development proposal seeks to extend my previous training and experience to give me the skills necessary to establish a research program that utilizes a more comprehensive translational approach that combines both animal and human studies directed at the same underlying questions. To that end, in this application I seek to explore the effects of enriched environments in "parallel" studies of both humans and animal models of AD. The research program proposed here will be built on behavioral approaches, including measurements of cognition and lifestyle, complimented by imaging techniques, including measures of A2 and metabolism in brain. Whenever possible, will to compare related measures between animal models and human subjects. The proposed career development plan reflects these goals and includes training in evaluation of cognition, A2, and metabolism in both humans and animals. This proposal addresses important questions regarding the impact of lifestyle activities on several factors including; amyloid deposition and glucose metabolism in humans and a mouse model of AD. Answers to these questions will help us to understand the significance of lifestyle activities (and the timing of those activities) on the risk for developing AD.