Can Behavior Shape Neural Health? Identifying Modifiable Factors to Prevent Cognitive Decline in Age

项目摘要/摘要 在这个K23职业发展奖中，凯特琳·卡萨莱托博士将开发针对生物的培训 预防年龄相关性认知衰退的生活方式策略。卡萨莱托博士是印度的博士后研究员 临床神经心理学将过渡到加州大学旧金山分校的教员 记忆和衰老中心(MAC)。她的长期目标是成为一名领先的临床衰老研究人员 开发基于行为的干预措施，以促进大脑健康，并随着年龄的增长改善患者的预后。 通过K23的支持和丰富的跨学科培训环境和资源 卡萨莱托博士的目标是完成以下培训目标：1)获得神经生物学方面的专业知识 老化，重点是环境可改变的途径；2)发展对血浆和 用于临床研究的脑脊液生物标记物分析平台；3)在随机试验中拓展技能 设计；4)将K23培训和结果转化为R01，制定行为干预措施，以防止 年龄相关性神经退行性变。为了实现这些目标，卡萨莱托博士汇集了一个模范 导师团队，包括她的主要导师，乔尔·克莱默博士，一位有数十年研究经验的神经心理学家 致力于老年行为和认知的测量；共同导师，克里斯汀·亚菲博士， 神经学、精神病学和流行病学，在确定生活方式预防因素方面处于领先地位 合作者，Lennart Mucke博士，一位神经生物学家，研究并指导加州大学旧金山分校的一个研究所 描述神经退行性疾病的机制；合作者Henrik Zetterberg博士， 神经化学家，开发了本K23中提出的脑脊液生物标记物；合作者Adam Gazzaley博士， 神经学家，领导研究中心开发优化大脑功能的技术； 合作者John Neuhaus博士是一位生物统计学家，在生物医学数据的高级建模方面拥有专业知识。 这项拟议的研究的主要目标是描述生活方式和生活方式之间的关系 衰老和阿尔茨海默病患者认知和身体行为及神经健康的蛋白质组学标志物。中环 理论基础是，神经可塑性发生在整个成年期，在阿尔茨海默病中是不受调节的，可以通过 行为。尽管据估计，可改变的生活方式因素导致了全球900万例AD病例， 行为预防策略并不是神经生物学的目标，这限制了它们的效力。首先，我们将 确定日常认知和身体行为与神经蛋白质标记物的关系 阿尔茨海默病高危人群和阿尔茨海默病患者的血浆和脑脊液功能。这些模型将在 独立样本。其次，我们将通过随机训练来操纵认知和身体行为 实验并确定对神经蛋白浓度的方向性影响。这个翻译项目将 确定可以用来在衰老过程中改善神经健康的日常活动，并最终利用这些活动 制定以行为为基础的干预措施以预防AD。

PROJECT SUMMARY/ABSTRACT In this K23 career development award, Dr. Kaitlin Casaletto will develop training in biologically-targeted lifestyle strategies for the prevention of age-related cognitive decline. Dr. Casaletto is a postdoctoral fellow in clinical neuropsychology who will be transitioning to faculty at the University of California, San Francisco Memory and Aging Center (MAC). Her longer term goal is to become a leading clinical aging researcher developing behaviorally-based interventions to promote brain health and improve patient outcomes with age. Through the support of this K23 and the enriched transdisciplinary training environment and resources at the MAC, Dr. Casaletto aims to accomplish the following training goals: 1) gain expertise in the neurobiology of aging with a focus on environmentally modifiable pathways; 2) develop specialized proficiency in plasma and cerebrospinal fluid (CSF) biomarker analytic platforms for clinical research; 3) expand skills in randomized trial design; 4) translate the K23 training and findings into an R01 developing a behavioral intervention to prevent age-related neurodegeneration. To achieve these goals, Dr. Casaletto has assembled an exemplary mentorship team, including her primary mentor, Dr. Joel Kramer, a neuropsychologist with decades of research dedicated to the measurement of behavior and cognition in aging; co-mentor, Dr. Kristine Yaffe, a professor of neurology, psychiatry, and epidemiology who is a leader in the identification of lifestyle prevention factors in AD; collaborator, Dr. Lennart Mucke, a neurobiologist who investigates and directs a UCSF-affiliated institute characterizing the mechanisms of neurodegenerative diseases; collaborator, Dr. Henrik Zetterberg, a neurochemist who developed the CSF biomarkers proposed in this K23; collaborator, Dr. Adam Gazzaley, a neuroscientist who directs a research center developing technologies to optimize brain function; and collaborator, Dr. John Neuhaus, a biostatistician with expertise in advanced modeling of biomedical data. The overarching goal of the proposed study is to characterize the relationship between lifestyle cognitive and physical behaviors and proteomic markers of neural health in aging and AD. The central rationale is that neural plasticity occurs throughout adulthood, is dysregulated in AD, and can be induced with behaviors. Though modifiable lifestyle factors are estimated to account for >9 million AD cases worldwide, behavioral prevention strategies have not been neurobiologically-targeted, limiting their potency. First, we will determine the relationship between daily cognitive and physical behaviors and protein markers of neural function in plasma and CSF in adults at-risk for and with AD. These models will be replicated in an independent sample. Second, we will manipulate cognitive and physical behaviors using a randomized training experiment and determine the directional impact on neural protein concentrations. This translational project will identify daily activities that can be used to improve neural health in aging and, ultimately, be leveraged to develop behavior-based interventions to prevent AD.