Cognitive and Neural Correlates of Inflammation in Healthy Older Adults

描述（由申请人提供）：这是加州大学弗朗西斯科记忆与衰老中心（MAC）神经心理学研究员Brianne Bettcher博士的K23奖申请。Bettcher博士将自己定位为一名年轻的研究者，她对炎症在认知老化中的作用进行了以患者为导向的临床研究。这个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，提高她对健康和病理衰老的免疫学贡献的认识;（3）熟练掌握结构和扩散神经成像;（4）熟练掌握先进的统计方法;（5）发展独立的研究生涯。为了实现这些目标，Bettcher博士组建了一个指导团队，其中包括一位主要导师：克雷默博士（临床神经心理学家和老龄化认知神经科学的国际领导者）;三位共同导师：Kristine Yaffe博士（具有免疫学生物标志物和生物统计学专业知识的神经学家），Maria Luisa Gorno-Tempini（一位在结构MRI，特别是弥散张量成像分析方面具有专长的神经学家）和布鲁斯米勒（一位在行为神经学和临床研究方面具有专长的神经学家）;和一位顾问：Tony Wyss-Coray博士（一位在炎症方面具有基础科学专长的免疫学家）。 拟议的研究重点是健康老年人炎症的认知和神经相关性。Bettcher博士将使用炎症的实验室指标来评估炎症与认知功能之间的关联，特别是记忆巩固，执行功能和处理速度（目标1）。Bettcher博士将采用结构和弥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（目标2）。为了分离免疫功能障碍的新机制，Bettcher博士还将研究炎症上游调节因子（即颗粒蛋白原）在认知功能中的作用及其与大脑结构的关系（目标3）。拟议的研究将利用MAC的现有基础设施来调查这一新的研究计划。公共卫生相关性：这项研究的结果将提供有关健康老年人炎症，认知和大脑结构之间关系的完整信息，并为健康与病理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老化的多模态研究做好准备，并实施未来的纵向研究，调查认知衰退的可改变风险因素。 公共卫生相关性：最近的证据表明，炎症可能会带来加速衰老的风险，并且可能先于神经退行性疾病的早期阶段;然而，人们对健康老年人的炎症、认知和大脑结构之间的关系知之甚少。从该项目中收集的结果将为健康与病理性衰老的认知神经科学提供信息，确定炎症相关的脑结构和认知改变的潜在机制，并为识别有认知能力下降风险的个体提供平台。这项工作还将把炎症和衰老的基础科学研究转化为人类，并将利用炎症的尖端标志物来确定免疫功能障碍的潜在机制。

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.