Primary Progressive Aphasia: Beyond the Clinical Variants

项目摘要/摘要 这是为Jessica Deleon博士申请K23职业发展奖的申请表，她是一名行为主义者 一位神经病学家，她正成为加州大学旧金山分校的初级研究员 (加州大学旧金山分校)她的长期目标是成为一名专注于初级进展的独立临床研究人员 不同患者群体中的失语症(PPA)和言语/语言障碍。通过这个K23的支持 以及加州大学旧金山分校最佳的多学科培训环境和资源，Deleon博士的目标是实现 培训目标：1)提高多模式神经影像知识和PPA的神经基础； 2)培养研究设计和生物统计学方面的技能；3)获得神经语言学和双语方面的专业知识；4) 将神经遗传学和神经病理学应用于PPA的语音和语言网络；以及5)实施HER K23 R01中的培训和发现，重点是改善语音/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，德伦博士组建了一个 导师团队包括主要导师Maria Luisa Gorno-Tempini博士，一位行为神经学家和世界 PPA和多模式神经成像领域的领导者；联合导师Nina Dronkers博士，一位神经心理学家和 神经语言学和双语；霍华德·罗森博士，专注于家庭语言的行为神经学家 额颞叶痴呆症和神经成像；Lea Grinberg博士，专门研究 神经退行性疾病；伊莎贝尔·伊莱恩·艾伦博士，生物统计学家，在研究设计和 统计分析；曼努埃尔·卡雷拉斯博士，一位发表了大量双语著作的心理学家； 王培宁，一位在评估说普通话的PPA患者方面拥有丰富知识的神经科医生。 PPA是一种衰弱的神经退行性疾病，会导致言语和语言的进行性丧失 超能力。由于疾病发生和发展的异质性，它可能被误诊和低估， 言语/语言症状和神经影像表现。这种异质性对以下方面有重要影响 精准治疗和临床试验。在这项提案中，德伦博士将研究三个候选因素 (神经病理学、遗传学和口语)通过形成一种 全面的多语言语音/语言电池，并利用多模式神经成像技术 (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名既往和新兵进行为期2年(3个时间点)的横断面和纵向研究 PPA患者。Deleon博士将识别语音/语言症状和神经成像特征，这些特征可以预测 基础神经病理学(目标1)和研究遗传因素(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的异质性。这项提议将提供新的 了解检测PPA、完善PPA诊断并为改善对患有PPA的患者的治疗铺平道路 与PPA和相关的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.