Environmental Enrichment and Cognitive Survival: Role of ABeta and Metabolism

描述(由申请人提供)：尸检研究表明，在认知正常的老年对照组受试者中，25%-50%的人存在大脑淀粉样斑块，最近匹兹堡化合物-B(PIB)PET研究显示，在生活在认知正常的老年人中也有类似的发现。在一些对照组中，PIB滞留的程度可能与阿尔茨海默病(AD)的观察结果一样高。这些发现的一个关键问题是，为什么在淀粉样蛋白负担巨大的情况下，一些人会患上阿尔茨海默病，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(在人类中)和A2的影响(在动物模型中)。浓缩的影响被假设为与病理变化的减少或对这种病理影响的脆弱性的减少有关。然而，尽管老年人经常被建议丰富他们的环境，但几乎没有数据可以知道环境丰富是否会在晚年产生影响，或者是否必须在生命更早的时候就开始影响。使用转化的方法，这项提议将为一个致力于了解环境丰富(以及丰富的时机)在抵抗神经退化过程中的作用的研究计划提供基础。到目前为止，我的培训为我提供了一个在动物模型和人类神经成像方面的强大背景，以单独探索涉及神经退行性疾病的研究问题，如阿尔茨海默病。目前的职业发展建议旨在扩展我以前的培训和经验，使我获得必要的技能，以建立一个研究计划，利用更全面的翻译方法，将针对相同基本问题的动物和人类研究结合起来。为此，在本申请中，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的基础上，包括对认知和生活方式的测量，并辅之以成像技术，包括测量A2和大脑的新陈代谢。只要有可能，就会比较动物模型和人类受试者之间的相关测量。拟议的职业发展计划反映了这些目标，并包括评估人类和动物的认知、A2和新陈代谢方面的培训。这项建议解决了生活方式活动对几个因素的影响的重要问题，包括人类和阿尔茨海默病小鼠模型中的淀粉样蛋白沉积和葡萄糖代谢。对这些问题的回答将帮助我们理解生活方式活动(以及这些活动的时机)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.