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%认知正常的老年对照受试者中存在脑淀粉样斑块，最近匹兹堡化合物- b (PiB) PET研究在认知正常的老年人中也显示了类似的发现。在一些对照组中，PiB保留率可以与阿尔茨海默病（AD）中观察到的一样高。从这些发现中得出的一个首要问题是，为什么面对大量淀粉样蛋白负担，有些人会患上阿尔茨海默病，而另一些人却保持正常。据报道，丰富的环境和生活方式赋予对痴呆症发展（人类）和A2影响（动物模型）的抵抗力。据推测，富集的影响要么与病理变化的减少有关，要么与易受病理影响的减少有关。然而，尽管老年人经常被建议丰富他们的环境，但很少有数据表明环境丰富是否会在晚年产生影响，或者是否必须在生命的早期开始。使用翻译的方法，该提案将为一个致力于理解环境富集（和富集时间）在赋予神经退行性过程抗性中的作用的研究项目提供基础。到目前为止，我的训练为我提供了强大的动物模型和人类神经影像学背景，可以分别探索涉及神经退行性疾病（如AD）的研究问题。目前的职业发展建议旨在扩展我以前的培训和经验，使我具备建立研究项目所需的技能，该研究项目利用更全面的转化方法，将动物和人类研究结合起来，针对相同的潜在问题。为此，在本应用程序中，我试图在人类和动物AD模型的“平行”研究中探索丰富环境的影响。这里提出的研究计划将建立在行为方法上，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。在可能的情况下，将动物模型与人类受试者的相关措施进行比较。拟议的职业发展计划反映了这些目标，包括人类和动物的认知、A2和代谢评估方面的培训。该建议解决了有关生活方式活动对以下几个因素的影响的重要问题：淀粉样蛋白沉积和葡萄糖代谢在人和AD小鼠模型中的作用这些问题的答案将帮助我们了解生活方式活动（以及这些活动的时间）对患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.