Mechanisms of Spatial Cognitive Impairment in Neurodegenerative Disease

描述(由申请人提供)：这是为加州大学旧金山记忆和衰老中心(MAC)的神经心理学家Katherine Possin博士申请K23奖项。在面向患者的神经退行性疾病空间认知临床研究中，波辛博士确立了自己作为年轻研究员的地位。这一K23奖项将为Possin博士提供必要的支持，以实现以下目标：(1)成为神经退行性疾病的行为神经学专家；(2)通过采用认知神经科学的创新方法，对神经退行性疾病的空间认知进行临床调查；(3)熟练掌握先进的多模式神经成像分析；以及(4)发展独立的临床研究事业。为了实现这些目标，Possin博士组建了一个指导团队，成员包括：首席导师Bruce Miller博士，MAC主任，负责神经退行性疾病的临床研究；PI on a Program Project Grant(额颞叶痴呆项目拨款)和阿尔茨海默病研究中心(ADRC)；以及三位共同导师：神经心理学家Joel Kramer博士，神经心理测试开发的国际领先者；Maria Luisa Gorno Tempini博士，在结构磁共振成像(包括扩散张量成像)方面的专业知识；以及William Seeley博士，神经病学家在静息状态功能连接MRI方面的专业知识。空间认知障碍通常是神经退行性疾病的最早症状之一，然而目前痴呆评估中使用的空间功能测试缺乏区分阿尔茨海默病(AD)、帕金森病(PD)伴认知障碍和行为变异额颞叶痴呆(BvFTD)等痴呆的病理原因的解剖学特异性。早期诊断不仅仅是学术上的兴趣，因为帕金森病的神经抗精神病药物是禁忌症，而且有望在地平线上进行分子特异性治疗。波辛博士的研究将使用在认知神经科学框架内开发和验证的严格评估方法，包括虚拟现实导航测试(目标1)，剖析每种疾病所针对的空间功能的特定组成部分，她的研究将利用结构和扩散张量成像分析阐明空间表现的神经相关性(目标2)。此外，她的研究将确定与空间处理的重要方面相关的功能神经网络，这些方面在这些疾病中受到干扰(目标3)。这项拟议的研究将利用PPG和ADRC的现有基础设施，招募31名早期AD患者、31名PD患者、31名bvFTD患者和31名神经学健康对照。通过母项目，Possin博士将获得丰富的数据集，用于分析空间认知数据，其中包括多模式神经成像、一般神经心理测试、神经学检查和功能评估数据。公共卫生相关性这项研究的结果将为痴呆评估中的空间评估提供解剖学上的具体方法，并将提供关于空间认知的神经基础的有价值的信息。 公共卫生相关性：空间认知缺陷通常是神经退行性疾病的最早症状之一，但目前痴呆症评估中使用的空间功能测试缺乏区分神经退行性疾病的解剖学特异性。通过这一研究计划开发的工具将改善痴呆症的早期鉴别诊断，为临床试验提供敏感的空间评估方法，帮助临床医生进行治疗监测，并预测真实世界的空间功能，如驾驶技能。此外，这项工作将有助于将空间认知的基础科学研究与临床联系起来，并将提供关于空间认知的神经基础的有价值的信息。

DESCRIPTION (provided by applicant): This is an application for a K23 award for Dr. Katherine Possin, a neuropsychologist at the University of California, San Francisco Memory and Aging Center (MAC). Dr. Possin is establishing herself as a young investigator in patient-oriented clinical research of spatial cognition in neurodegenerative disease. This K23 award will provide Dr. Possin with the support necessary to accomplish the following goals: (1) to become an expert in the behavioral neurology of neurodegenerative disease; (2) to conduct clinical investigations of spatial cognition in neurodegenerative disease by adapting innovative methods from cognitive neuroscience; (3) to develop proficiency in advanced multimodal neuroimaging analyses; and (4) to develop an independent clinical research career. To achieve these goals, Dr. Possin has assembled a mentoring team comprised of a primary mentor, Dr. Bruce Miller, Director of the MAC, who conducts clinical investigations in neurodegenerative disease as the PI on a Program Project Grant (PPG) on Frontotemporal Dementia and an Alzheimer's Disease Research Center (ADRC); and three co-mentors: Dr. Joel Kramer, a neuropsychologist who is an international leader in the development of neuropsychological tests; Dr. Maria Luisa Gorno Tempini, a neurologist with expertise in structural MRI including diffusion tensor imaging; and Dr. William Seeley, a neurologist with expertise in resting state functional connectivity MRI. Spatial cognitive deficits are often among the earliest symptoms of neurodegenerative disease, yet spatial function tests used in current dementia evaluations lack the anatomic specificity to differentiate between pathologic causes of dementia including Alzheimer's disease (AD), Parkinson's disease (PD) with cognitive impairment, and behavioral variant Frontotemporal dementia (bvFTD). Early diagnosis is more than merely of academic interest due to the contraindication of neuroleptic drugs in PD and the promise of molecule-specific treatments on the horizon. Dr. Possin's research will dissect the specific components of spatial function targeted by each disease using rigorous assessment methods developed and validated within a cognitive neuroscience framework, including virtual reality navigation tests (Aim 1), and her research will elucidate the neural correlates of spatial performance using structural and diffusion tensor imaging analyses (Aim 2). In addition, her research will identify the functional neural networks related to important aspects of spatial processing that are disrupted in these diseases (Aim 3). The proposed research will use the existing infrastructure of the PPG and the ADRC to enroll 31 patients with early AD, 31 patients with PD, 31 patients with bvFTD, and 31 neurologically healthy controls. Via the parent projects, a rich dataset will be made available to Dr. Possin for analysis with the spatial cognitive data that includes multimodal neuroimaging, general neuropsychological testing, neurological exam, and functional evaluation data. Public health relevance the results from this study will inform anatomically-specific methods for spatial assessment in dementia evaluations, and will provide valuable information about the neural substrates of spatial cognition. PUBLIC HEALTH RELEVANCE: Spatial cognitive deficits are often among the earliest symptoms of neurodegenerative disease, yet spatial function tests used in current dementia evaluations lack the anatomic specificity to differentiate between neurodegenerative disorders. Tools developed through this research program will improve the early differential diagnosis of dementia, inform sensitive methods of spatial assessment for clinical trials, assist clinicians in treatment monitoring, and predict real-world spatial functioning such as driving skills. Additionally, this work will help to link basic science studies of spatial cognition to the clinic and will provide valuable information about the neural substrates of spatial cognition.