Cognitive and Neural Correlates of Inflammation in Healthy Older Adults

描述（由申请人提供）：这是加州大学旧金山记忆与衰老中心（MAC）神经心理学研究员Brianne Bettcher博士的K23奖申请。作为一名年轻的研究人员，贝彻博士正在开展以患者为导向的临床研究，研究炎症在认知衰老中的作用。K23奖将为Bettcher博士提供必要的支持，以实现以下目标：(1)获得衰老认知神经科学方面的专业知识；2)通过翻译基础科学的创新发现，推进免疫学对健康和病理性衰老的贡献；(3)熟练掌握结构和扩散神经影像学；（四）熟练掌握先进的统计方法；(5)发展独立的研究事业。为了实现这些目标，贝彻博士组建了一个指导团队，其中包括一位主要导师：克莱默博士（临床神经心理学家，衰老认知神经科学领域的国际领军人物）；三位共同导师：博士；Kristine Yaffe（免疫学生物标志物和生物统计学专业的神经学家），Maria Luisa Gorno-Tempini（结构MRI专业的神经学家，特别是扩散张量成像分析）和Bruce Miller（行为神经病学和临床研究专业的神经学家）；还有一位顾问：托尼·威斯-科雷（Tony Wyss-Coray）博士（免疫学家，具有炎症方面的基础科学专业知识）。提出的研究重点是健康老年人炎症的认知和神经相关。Bettcher博士将使用炎症的实验室指数来评估炎症与认知功能之间的关系，特别是记忆巩固、执行功能和处理速度（目的1）。Bettcher博士将使用结构和扩散神经成像数据来解释炎症的神经相关性，并进一步确定这些神经系统是否介导炎症和认知之间的关系（目的2）。为了分离免疫功能障碍的新机制，Bettcher博士还将研究炎症的上游调节剂（即前颗粒蛋白）在认知功能中的作用及其与大脑结构的关联（Aim 3）。拟议的研究将利用MAC现有的基础设施来调查这个新的研究项目。公共卫生相关性：本研究的结果将为健康老年人炎症、认知和大脑结构之间的关系提供完整的信息，并为健康与病理性衰老的认知神经科学提供信息。Bettcher博士的K23培训将为她进行认知衰老的多模态研究做好准备，并实施未来的纵向研究，调查认知能力下降的可改变风险因素。

DESCRIPTION (provided by applicant): This is an application for a K23 award for Dr. Brianne Bettcher, a neuropsychology fellow at the University of California, San Francisco Memory and Aging Center (MAC). Dr. Bettcher is establishing herself as a young investigator who conducts patient-oriented clinical research on the role of inflammation in cognitive aging. This K23 award will provide Dr. Bettcher with the support necessary to accomplish the following goals: (1) to garner expertise in the cognitive neuroscience of aging; 2) to advance her knowledge of the immunological contributions to healthy and pathological aging by translating innovative findings from basic science; (3) to acquire proficiency in structural and diffusion neuroimaging; (4) to develop proficiency in advanced statistical methods; and (5) to develop an independent research career. To achieve these goals, Dr. Bettcher has assembled a mentoring team that includes one primary mentor: Dr. Kramer (a clinical neuropsychologist and international leader in the cognitive neuroscience of aging); three co-mentors: Drs. Kristine Yaffe (a neurologist with expertise in immunological biomarkers and biostatistics), Maria Luisa Gorno-Tempini (a neurologist with expertise in structural MRI, specifically diffusion tensor imaging analyses), and Bruce Miller (a neurologist with expertise in behavioral neurology and clinical research); and one consultant: Dr. Tony Wyss-Coray (an immunologist with basic science expertise in inflammation). The proposed research study focuses on the cognitive and neural correlates of inflammation in healthy older adults. Dr. Bettcher will use laboratory indices of inflammation to assess the association between inflammation and cognitive functions, specifically memory consolidation, executive functions, and processing speed (Aim 1). Dr. Bettcher will employ structural and diffusion neuroimaging data to explicate the neural correlates of inflammation, and further identify whether these neural systems mediate the relation between inflammation and cognition (Aim 2). In order to isolate a novel mechanism of immune dysfunction, Dr. Bettcher will also examine the role of an upstream regulator of inflammation (i.e. progranulin) in cognitive functions and its association with brain structure (Aim 3). The proposed research will utilize the existing infrastructure of the MAC to investigate this new program of study. Public health relevance: The results from this study will provide integral information regarding the relationship between inflammation, cognition and brain structure in healthy older adults, and inform the cognitive neuroscience of healthy versus pathological aging. Dr. Bettcher's K23 training will prepare her to conduct multimodal studies of cognitive aging and implement future longitudinal studies that investigate modifiable risk factors for cognitive decline. PUBLIC HEALTH RELEVANCE: Recent evidence indicates that inflammation may confer risk for accelerated aging and may precede early stages of neurodegenerative disease; yet, strikingly little is known about the relationship between inflammation, cognition, and brain structure in healthy older adults. Results gleaned from this project will inform the cognitive neuroscience of healthy versus pathological aging, identify potential mechanisms of inflammation- associated alterations in brain structure and cognition, and provide a platform for identification of individuals at risk for cognitive decline. This work will also translate basic science studies of inflammation and aging to humans and will utilize a cutting edge marker of inflammation to pinpoint a potential mechanism of immune dysfunction.