Neurodevelopmental Trajectories Towards Neurodegenerative Disease

 描述(由申请人提供)：这是Zachary A.Miller博士的K23奖项申请，他是加州大学旧金山记忆和衰老中心(MAC)的行为神经学家，在以患者为导向的临床研究中确立了年轻研究员的地位，专注于神经退行性疾病的语言处理。这一K23奖项将为米勒博士提供必要的支持，以实现以下目标：(1)获得神经退行性疾病和语言处理的认知神经科学方面的专业知识；(2)熟练使用和分析结构和功能神经成像；(3)获得评估神经退行性疾病患者的神经发育和遗传因素的经验；(4)增进他的生物统计学知识；(5)获得语言障碍的神经病理学方面的接触和培训；以及(6)发展独立的临床研究事业。为了实现这些目标，他组建了一个多学科导师团队，包括两位主要导师：Maria Luisa Gorno-Tempini博士(擅长语言障碍和先进神经成像技术的神经病学家)和Bruce Miller博士(擅长行为、神经退行性疾病和临床研究)；共同导师：Srikantan Nagarajan博士(擅长脑磁图的生物工程师)；和三位顾问：Matt State博士(擅长神经发育障碍和遗传学)、William Seeley博士(擅长神经病理学和功能成像的神经病学家)和John Neuhaus博士(擅长多元分析的生物统计学家)。这项拟议的研究调查了与语言障碍和临床表现相关的发病前个体特征对神经退行性疾病的影响。中心假设是，神经发育因素与语言网络对疾病的易感性增加有关，导致特定的语言表现、成像变化和疾病进展。我们将研究PPA和FTD基因携带者，以检验语言学习障碍和手的偏好对临床、认知和神经成像表型的影响。我们将收集标准化的神经发育史、详细的认知评估和成像数据，以确定有和没有语言学习障碍病史的PPA患者在陈述时的表型差异(目标1)。我们将利用脑磁图在PPA和健康对照组受试者中建立手部偏爱和语言偏侧化模式，并将它们与大脑结构对称性的测量相关联(目标2)。我们将收集PPA和FTD基因携带者的纵向认知和神经成像数据，并比较有和没有语言学习障碍的受试者的进展模式(目标3)。这项研究将增加对PPA临床异质性的发病前因素的了解，指导未来对早期诊断和治疗策略的研究，并提供新的神经发育和影像测量作为PPA表征和诊断的新工具。这项K23培训将使米勒博士能够将选择性神经发育脆弱性的概念应用于理解其他神经退行性疾病。]

 DESCRIPTION (provided by applicant): This is a K23 award application for Dr. Zachary A. Miller, a behavioral neurologist at the University of California, San Francisco Memory and Aging Center (MAC) who is establishing himself as a young investigator in patient-oriented clinical research focusing on language processing in neurodegenerative disease. This K23 award will provide Dr. Miller with the necessary support to accomplish the following: (1) gain expertise in neurodegenerative disease and the cognitive neuroscience of language processing; (2) develop proficiency in the use and analysis of structural and functional neuroimaging; (3) gain experience in evaluating neurodevelopmental and genetic factors in neurodegenerative patients; (4) advance his knowledge of biostatistics; (5) gain exposure and training in the neuropathology of language disorders; and (6) develop an independent clinical research career. To achieve these goals, he assembled a multidisciplinary mentoring team with two primary mentors: Dr. Maria Luisa Gorno-Tempini (a neurologist with expertise in language disorders and advanced neuroimaging techniques) and Dr. Bruce Miller (a neurologist with expertise in behavior, neurodegenerative disease, and clinical research); a co-mentor: Dr. Srikantan Nagarajan (a bioengineer with expertise in magnetoencephalography); and three advisors: Dr. Matt State (a psychiatrist with expertise in neurodevelopmental disorders and genetics), Dr. William Seeley (a neurologist with expertise in neuropathology and functional imaging), and Dr. John Neuhaus (a biostatistician with expertise in multivariate analyses). The proposed research investigates the effect of pre-morbid, individual characteristics related to language disabilities and clinical presentation in neurodegenerative diseases. The central hypothesis is that neurodevelopmental factors are associated with increased vulnerability of the language networks to disease, leading to specific language presentations, imaging changes, and disease progression. We will study PPA and FTD gene carriers to examine the consequences of language learning disability and hand preference on clinical, cognitive, and neuroimaging phenotype. We will collect a standardized neurodevelopmental history, detailed cognitive assessment, and imaging data to determine phenotypic differences between PPA patients with and without a history of language-learning disabilities at presentation (Aim 1). We will establish hand preference and language lateralization patterns using magnetoencephalography in PPA and healthy control subjects and correlate them with measures of structural brain symmetry (Aim 2). We will collect longitudinal cognitive and neuroimaging data on PPA and FTD gene carriers and compare patterns of progression in subjects with and without language learning disabilities (Aim 3). This research will increase understanding of pre-morbid factors on clinical heterogeneity in PPA, direct future studies into early diagnostic and treatment strategies, and offer novel neurodevelopmental and imaging measures as new tools for PPA characterization and diagnosis. This K23 training will enable Dr. Miller to apply concepts of selective neurodevelopmental vulnerability to the understanding of other neurodegenerative diseases.]