Primary Progressive Aphasia: Beyond the Clinical Variants

原发性进行性失语：超越临床变异

• 批准号: 10380055
• 负责人: Jessica Anne Deleon
• 金额: $ 19.91万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10380055
• 关键词: Address; Age; Age of Onset; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease pathology; American; Amyloid; Aphasia; Atrophic; Autopsy; Behavioral; Biometry; California; Classification; Clinical; Clinical Trials; Cognitive; Cross-Sectional Studies; Data; Deposition; Detection; Deterioration; Diagnosis; Diagnostic; Diffusion Magnetic Resonance Imaging; Disease Progression; Environment; Evaluation; Frontotemporal Dementia; Frontotemporal Lobar Degenerations; Genes; Genetic; Goals; Heterogeneity; Imaging Techniques; Individual; K-Series Research Career Programs; Knowledge; Language; Language Disorders; Life; Linguistics; Longitudinal Studies; Measures; Memory; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Methods; Molecular; Multilingualism; Multimodal Imaging; Mutation; Neurobehavioral Manifestations; Neurodegenerative Disorders; Neurologist; Onset of illness; Pathologic; Pathology; Patients; Pattern; Phenotype; Population; Population Heterogeneity; Positioning Attribute; Positron-Emission Tomography; Primary Progressive Aphasia; Production; Progressive Aphasias; Psychologist; Publishing; Research; Research Design; Research Personnel; Resources; Role; San Francisco; Scientist; Severity of illness; Speech; Statistical Data Interpretation; Symptoms; Syndrome; Techniques; Therapeutic; Time; Training; Typology; Universities; Variant; accurate diagnosis; base; bilingualism; career; carrier status; clinical phenotype; cognitive reserve; cognitive testing; cohort; diagnostic criteria; genetic risk factor; gray matter; improved; in vivo; language impairment; molecular pathology; morphometry; multidisciplinary; multimodal neuroimaging; neural network; neurogenetics; neuroimaging; neuropathology; novel; patient population; predictive signature; recruit; relating to nervous system; risk variant; skills; success; syntax; treatment trial; white matter

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.

项目摘要/摘要 这是为行为的杰西卡·德莱昂（Jessica DeLeon）博士颁发的K23职业发展奖的申请 在加利福尼亚大学旧金山大学建立初级调查员的神经科医生 （UCSF）。她的长期目标是成为一名专注于主要进步的独立临床研究人员 不同患者人群中的失语（PPA）和语音/语言障碍。通过此K23的支持 以及UCSF的最佳，多学科的培训环境和资源，DeLeon博士旨在实现 遵循培训目标：1）提高她在多模式神经影像学和PPA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主义方面的专业知识； 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； 5）实施她的K23 培训和发现为R01，重点是改进语音/语言的诊断和处理 PPA和其他语言疾病的症状。为了实现这些目标，DeLeon博士聚集了 指导团队包括主要导师玛丽亚·路易莎·戈尔诺·泰米（Maria Luisa Gorno-Tempini），行为神经科医生和世界 PPA和多模式神经影像学的领导者；神经心理学家兼专家Nina Dronkers博士 神经语言学和双语主义；霍华德·罗森（Howard Rosen）博士，专注于家族的行为神经科医生 额颞痴呆和神经影像学； Lea Grinberg博士，专门研究的神经病理学家 神经退行性疾病；伊莎贝尔·伊莱恩·艾伦（Isabel Elaine Allen）博士，生物统计学家，具有研究设计专业知识 统计分析；心理学家曼努埃尔·卡雷拉斯（Manuel Carreiras）博士在双语中广泛发表；和博士 Peining Wang是一名神经科医生，在评估普通话PPA患者时拥有巨大的知识。 PPA是一种令人衰弱的神经退行性障碍，会导致语音和语言逐渐丧失 能力。由于其疾病发作和进展中的异质性，它可能被误导和诊断不足， 语音/语言症状和神经影像学发现。这种异质性对 准确的治疗和临床试验。在此提案中，DeLeon博士将调查如何三个候选因素 （神经病理学，遗传学和口语）通过开发一种 全面，多语言/语言电池，并利用多模式神经影像学技术 （基于体素的形态计量学，扩散张量成像和分子PET成像）。她会应用这些 在2年（3个时间点）的横截面和纵向研究中，有530个历史和新招募的方法 PPA患者。 Deleon博士将确定言语/语言症状和神经影像学签名 神经病理学（目标1）并研究遗传因素（目标2）和语言因素如何（目标3） 通过对神经网络的影响影响PPA异质性。该建议将提供新的 知识以检测PPA，完善PPA诊断并为改善患有患者的治疗方法铺平了道路 与PPA和相关神经退行性疾病有关的语音和语言症状。