Neurophysiological Assessments of Network Dysfunction in Alzheimer's Disease

项目摘要 这是K 08指导临床科学家研究职业发展奖的申请，以促进 候选人作为临床神经科学独立研究人员的发展，重点是 了解阿尔茨海默病（AD）的神经生理学异常，并最终在其他疾病中 痴呆综合征Ranasinghe博士的长期职业目标是开发一个深入的大脑知识库- 与神经退行性疾病中特定病理生理过程相关的行为关系。 目前的研究项目提出了一个多模式，纵向脑成像研究，整合 脑磁图成像（MEGI）与正电子发射断层扫描（PET），并与渐进 AD患者神经退行性过程的轨迹。AIM-1检查了网络的不同模式 使用MEGI的AD患者的同步缺陷，及其与PET衍生的 淀粉样蛋白β和tau的分子标记物。AIM-2对网络缺陷进行纵向MEGI评估 结合认知和体积测量，每年随访两年。结果将 揭示人类AD中异常神经元功能的神经生理学特征， 对转化研究和临床试验的重要意义。K 08将为拉纳辛哈博士提供 为实现以下目标提供必要的支持：（1）多模式应用和分析培训 神经影像学技术;（2）患者评估和纵向随访的临床培训;（3）获得 更深入地了解AD的机制;（4）在临床中进行高级生物统计分析的培训 研究;（5）在拨款写作，职业发展和研究道德的培训。为了实现这些目标，博士。 Ranasinghe组建了一个指导团队，其中包括她的主要导师：凯瑟琳兰金博士（a 具有神经退行性疾病专业知识的神经心理学家）;和两位共同导师：Gil Rabinovici博士（a 行为神经学家，具有分子成像方面的专业知识）和Srikantan Nagarajan（神经科学家， 脑磁图（magnetoencephalography）Ranasingh博士项目的合作者包括Maria Luisa博士 Gorno-Tempini（一位在神经成像方面有专长的行为神经学家），Joel克雷默（一位神经心理学家 具有认知老化方面的专业知识），莱亚格林伯格（具有AD神经生物学专业知识的神经病理学家），以及 Maria Gaviour（生物统计学家）。候选人是一位对职业有强烈承诺的医生科学家 神经退行性痴呆症的研究加州大学旧金山分校弗朗西斯科记忆与衰老 该中心是一个理想的环境，为拟议的培训，是一个顶级的痴呆症研究机构在全国 与世界领先的临床和转化研究专家接触。研究和培训 本建议书中描述的经验将使候选人能够实现发展强大的独立性的目标。 在神经退行性疾病的神经生理学评估领域的研究生涯。

PROJECT SUMMARY This is an application for a K08 Mentored Clinical Scientist Research Career Development Award to promote the candidate's development as an independent researcher in clinical neuroscience, with a focus on understanding the neurophysiological abnormalities in Alzheimer's disease (AD), and eventually, in other dementia syndromes. Dr. Ranasinghe's long-term career goal is to develop a deep knowledge base on brain- behavior relationships associated with specific pathophysiological processes in neurodegenerative diseases. The current research project proposes a multimodal, longitudinal brain imaging study, integrating magnetoencephalographic imaging (MEGI) with positron emission tomography (PET), and with progressive trajectories of neurodegenerative processes, in AD patients. AIM-1 examines the distinct patterns of network synchronization deficits in patients with AD using MEGI, and their specific associations to PET-derived molecular markers of amyloid beta and tau. AIM-2 conducts longitudinal MEGI assessments of network deficits combined with cognitive and volumetric measures with annual follow-ups for two years. The results will uncover neurophysiological signatures of aberrant neuronal functions in AD, in humans, and will have important implications for translational research and clinical trials. This K08 will provide Dr. Ranasinghe with the support necessary to accomplish the following goals: (1) Training in application and analysis of multimodal neuroimaging techniques; (2) Clinical training in patient evaluations and longitudinal follow-up; (3) Gaining greater depth of knowledge in mechanisms of AD; (4) Training in advanced biostatistical analyses in clinical research; (5) Training in grant writing, career development, and research ethics. To achieve these goals, Dr. Ranasinghe has assembled a mentoring team including her primary mentor: Dr. Katherine Rankin (a neuropsychologist with expertise in neurodegenerative diseases); and two co-mentors: Drs. Gil Rabinovici (a behavioral neurologist with expertise in molecular imaging), and Srikantan Nagarajan (a neuroscientist with expertise in magnetoencephalography). The collaborators of Dr. Ranasingh'e project include Drs. Maria Luisa Gorno-Tempini (a behavioral neurologist with expertise in neuroimaging), Joel Kramer (a neuropsychologist with expertise in cognitive ageing), Lea Grinberg (a neuropathologist with expertise in neurobiology of AD), and Maria Glymour (a biostatistician). The candidate is a physician-scientist with a strong commitment to a career in neurodegenerative dementia research. The University of California San Francisco Memory and Aging Center is an ideal environment for the proposed training, being a top dementia research institute in the nation with access to world leading experts in clinical and translational research. The research and training experience described in this proposal will enable the candidate's goal of developing a strong independent research career in the field of neurophysiological assessments in neurodegenerative diseases.