Mechanisms of Spatial Cognitive Impairment in Neurodegenerative Disease

描述（由申请人提供）：这是一份K23奖的申请，申请对象是加利福尼亚大学旧金山记忆与衰老中心（MAC）的神经心理学家凯瑟琳·普萨辛博士。posin博士在以患者为导向的神经退行性疾病的空间认知临床研究方面是一名年轻的研究者。该K23奖将为posin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行为神经学方面的专家；(2)应用认知神经科学的创新方法开展神经退行性疾病的空间认知临床研究；(3)熟练掌握先进的多模态神经成像分析；(4)发展独立的临床研究事业。为了实现这些目标，posin博士组建了一个由主要导师Bruce Miller博士组成的指导团队，Bruce Miller博士是MAC主任，他在额颞叶痴呆和阿尔茨海默病研究中心（ADRC）的项目项目资助（PPG）中作为PI进行神经退行性疾病的临床研究；以及三位共同导师：神经心理学家乔尔·克莱默博士（Joel Kramer），他是神经心理学测试开发领域的国际领军人物；Maria Luisa Gorno Tempini博士，在结构MRI（包括弥散张量成像）方面具有专长的神经学家；以及在静息状态功能连接核磁共振方面具有专长的神经学家威廉·西利博士。空间认知缺陷通常是神经退行性疾病的早期症状之一，但目前用于痴呆症评估的空间功能测试缺乏解剖学特异性，无法区分痴呆症的病理原因，包括阿尔茨海默病（AD）、伴有认知障碍的帕金森病（PD）和行为变异性额颞叶痴呆（bvFTD）。由于PD患者使用抗精神病药物的禁忌症以及分子特异性治疗的前景，早期诊断不仅仅是学术上的兴趣。posin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），剖析每种疾病针对的空间功能的具体组成部分，她的研究将使用结构和扩散张量成像分析（目标2）阐明空间表现的神经相关性。此外，她的研究将确定与这些疾病中中断的空间处理重要方面相关的功能性神经网络（目标3）。拟议的研究将利用PPG和ADRC现有的基础设施，招募31名早期AD患者、31名PD患者、31名bvFTD患者和31名神经健康对照。通过母项目，一个丰富的数据集将提供给posin博士分析空间认知数据，包括多模态神经成像、一般神经心理学测试、神经学检查和功能评估数据。本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，并将提供有关空间认知的神经基质的宝贵信息。

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.