Primary Progressive Aphasia: Beyond the Clinical Variants

原发性进行性失语：超越临床变异

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

项目摘要

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.

项目概要/摘要这是 Jessica Deleon 博士的 K23 职业发展奖申请，她是一名行为学博士。神经学家，正在将自己定位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原发性进展性疾病的独立临床研究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 UCSF 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如下： 1) 提高多模态神经影像学和 PPA 神经基础方面的知识； 2）培养研究设计和生物统计学的技能； 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 中的语音和语言网络； 5) 实施她的 K23 R01 的培训和研究结果，重点是改进言语/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，Deleon 博士组建了一个导师团队包括主要导师 Maria Luisa Gorno-Tempini 博士，她是一位行为神经学家和世界 PPA 和多模式神经影像领域的领导者；共同导师 Nina Dronkers 博士是一位神经心理学家和专家神经语言学和双语；霍华德·罗森 (Howard Rosen) 博士，一位专注于家庭研究的行为神经学家额颞叶痴呆和神经影像学； Lea Grinberg 博士，一位神经病理学家，专门从事神经退行性疾病； Isabel Elaine Allen 博士是一位生物统计学家，在研究设计和统计分析；曼努埃尔·卡雷拉斯 (Manuel Carreiras) 博士，一位心理学家，在双语领域发表了大量著作；和博士。王培宁是一位神经科医生，在评估说普通话的 PPA 患者方面拥有丰富的知识。 PPA 是一种使人衰弱的神经退行性疾病，会导致言语和语言进行性丧失能力。由于疾病发作和进展的异质性，它可能会被误诊和漏诊，言语/语言症状和神经影像学结果。这种异质性对于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如何（神经病理学、遗传学和口语）通过开发全面的多语言语音/语言电池并利用多模式神经影像技术（基于体素的形态测量、扩散张量成像和分子 PET 成像）。她将应用这些对 530 名历史人员和新招募人员进行为期 2 年（3 个时间点）的横断面和纵向研究的方法 PPA 患者。 Deleon 博士将识别言语/语言症状和神经影像学特征来预测潜在的神经病理学（目标 1）并研究遗传因素（目标 2）和语言因素（目标 3）如何影响通过对神经网络的影响来影响 PPA 异质性。该提案将提供新的检测 PPA 的知识、完善 PPA 诊断并为改善患有 PPA 的个体的治疗铺平道路与 PPA 和相关神经退行性疾病相关的言语和语言症状。