Primary Progressive Aphasia: Beyond the Clinical Variants

项目概要/摘要 这是一份K23职业发展奖的申请，申请者是杰西卡·德里昂博士，一位行为科学家。 她是一名神经科医生，目前正在加州大学旧金山分校弗朗西斯科担任初级研究员 （UCSF）。她的长期目标是成为一名独立的临床研究人员，专注于原发性进行性 失语症（PPA）和言语/语言障碍在不同的患者群体。在K23的支持下， 和最佳的，多学科的培训环境和资源，在加州大学旧金山分校，博士。 以下培训目标：1）提高她在多模态神经成像和PPA的神经基础方面的知识; 2)发展研究设计和生物统计学技能; 3）获得神经语言学和双语能力的专业知识; 4） 将神经遗传学和神经病理学应用于PPA中的语音和语言网络;以及5）实施她的K23 培训和研究结果纳入R 01，重点是改善言语/语言的诊断和治疗 PPA和其他语言障碍的症状。为了实现这些目标，德里昂博士召集了一个 导师团队包括主要导师Maria Luisa Gorno-Tempini博士，行为神经学家和世界 PPA和多模态神经成像的领导者;共同导师Nina Dronkers博士，神经心理学家和专家， 神经语言学和双语;霍华德罗森博士，行为神经学家，专注于家庭 额颞叶痴呆和神经影像学;莱亚格林伯格博士，神经病理学家，专门研究 神经退行性疾病;伊莎贝尔Elaine艾伦博士，具有研究设计和 统计分析; Manuel Carreiras博士，一位在双语方面发表了大量文章的心理学家; 王培宁，一位神经科医生，在评估说普通话的PPA患者方面有着丰富的知识。 PPA是一种使人衰弱的神经退行性疾病，可导致言语和语言的逐渐丧失 能力.由于其疾病发作和进展的异质性，它可能被误诊和诊断不足， 言语/语言症状和神经影像学发现。这种异质性对以下方面具有重要意义： 准确的治疗和临床试验。在这项提案中，Deleon博士将研究三个候选因素 （神经病理学，遗传学和口头语言）通过发展一种 全面的、多语种的语音/语言组合，并利用多模态神经成像技术 （基于体素的形态测量、扩散张量成像和分子PET成像）。她将应用这些 方法对530名历史和新招募的患者进行为期2年（3个时间点）的横断面和纵向研究 PPA患者。Deleon医生将识别言语/语言症状和神经成像特征， 基础神经病理学（目标1），并研究遗传因素（目标2）和语言因素（目标3） 通过它们对神经网络的影响来影响PPA异质性。该提案将提供新的 知识，以检测PPA，完善PPA诊断，并为改善个人治疗铺平道路， 与PPA和相关神经退行性疾病相关的言语和语言症状。

PROJECT SUMMARY/ABSTRACT This is an application for a K23 career development award for Dr. Jessica Deleon, a behavioral neurologist who is establishing herself as a junior investigator at the University of California, San Francisco (UCSF). Her long-term goal is to become an independent clinical researcher focused on primary progressive aphasia (PPA) and speech/ language disorders in diverse patient populations. Through the support of this K23 and the optimal, multidisciplinary training environment and resources at UCSF, Dr. Deleon aims to achieve the following training goals: 1) advance her knowledge in multi-modal neuroimaging and the neural basis of PPA; 2) develop skills in study design and biostatistics; 3) gain expertise in neurolinguistics and bilingualism; 4) apply neurogenetics and neuropathology to speech and language networks in PPA; and 5) implement her K23 training and findings into an R01 that focuses on improved diagnosis and treatment of speech/language symptoms in PPA and other language disorders. To achieve these goals, Dr. Deleon has assembled a mentorship team including primary mentor Dr. Maria Luisa Gorno-Tempini, a behavioral neurologist and world leader in PPA and multi-modal neuroimaging; co-mentor Dr. Nina Dronkers, a neuropsychologist and expert in neurolinguistics and bilingualism; Dr. Howard Rosen, a behavioral neurologist focusing on familial frontotemporal dementia and neuroimaging; Dr. Lea Grinberg, a neuropathologist specializing in neurodegenerative disease; Dr. Isabel Elaine Allen, a biostatistician with expertise in study design and statistical analysis; Dr. Manuel Carreiras, a psychologist who has published extensively in bilingualism; and Dr. Pei-Ning Wang, a neurologist with immense knowledge in the evaluation of Mandarin-speaking PPA patients. PPA is a debilitating neurodegenerative disorder that causes progressive loss of speech and language abilities. It can be mis- and underdiagnosed due to heterogeneity in its disease onset and progression, speech/language symptoms and neuroimaging findings. This heterogeneity has significant implications for accurate treatment and clinical trials. In this proposal, Dr. Deleon will investigate how three candidate factors (neuropathology, genetics and spoken languages) influence PPA heterogeneity by developing a comprehensive, multilingual speech/language battery and by utilizing multi-modal neuroimaging techniques (voxel-based morphometry, diffusion tensor imaging and molecular PET imaging). She will apply these methods in a 2-year (3 time-point) cross-sectional and longitudinal study of 530 historical and newly recruited PPA patients. Dr. Deleon will identify speech/language symptoms and neuroimaging signatures that predict underlying neuropathology (Aim 1) and investigate how genetic factors (Aim 2) and language factors (Aim 3) influence PPA heterogeneity through their effects on neural networks. This proposal will provide new knowledge to detect PPA, refine PPA diagnosis and pave the way for improved treatments for individuals with speech and language symptoms related to PPA and related neurodegenerative disorders.