Digital biomarkers in narrative and conversational speech in Frontotemporal Dementia

额颞叶痴呆叙事和会话言语中的数字生物标志物

• 批准号: 10284370
• 负责人: Naomi Nevler
• 金额: $ 12.95万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10284370
• 关键词: Acoustics; Address; Algorithms; Anatomy; Anterior; Aphasia; Atrophic; Autopsy; Behavior; Biological Markers; Caregivers; Caring; Clinical; Clinical Trials; Clinical Trials Design; Code; Cognitive; Communication; Complex; Computational Linguistics; Consumption; Cross-Sectional Studies; Data; Databases; Dementia; Development; Disease; Disease Marker; Ensure; Family; Foundations; Frontotemporal Dementia; Frontotemporal Lobar Degenerations; Funding; Goals; Gold; Grant; Human; Image; Impairment; Inferior; Knowledge; Language; Leadership; Life; Linguistics; Link; Longitudinal Studies; Magnetic Resonance Imaging; Manuals; Measures; Mentors; Methods; Military Personnel; Modeling; Monitor; Mutation; Natural Language Processing; Nerve Degeneration; Neurobiology; Neurology; Neuropsychology; Non-aphasic; Pathogenicity; Pathologic; Pathology; Pathway interactions; Patients; Pattern; Personal Satisfaction; Phase; Phenotype; Postdoctoral Fellow; Procedures; Production; Regional Disease; Reproducibility; Research; Sampling; Speech; Speech Acoustics; Thick; Thinness; Time; Training; Translational Research; United States National Institutes of Health; Update; Variant; Work; Writing; automated algorithm; automated analysis; automated speech recognition; career; design; digital; endophenotype; experience; frontal lobe; frontotemporal degeneration; impression; improved; in vivo; in vivo Model; lexical; meetings; minimally invasive; mutation carrier; neuroimaging; neuropathology; novel; novel marker; post-doctoral training; programs; responsible research conduct; screening; skills; social communication; tau Proteins; tool; translational scientist; treatment trial

Today clinical criteria are the gold standard to identify variants of Frontotemporal Dementia (FTD). Though well established and useful clinically, these criteria rely on lengthy procedures that are expensive and invasive. There is urgent need for reliable, objective, and valid measures to screen for likely pathology and monitor disease longitudinally in disease-modifying treatment trials. While preparing the PI to become an independent translational researcher, this research program addresses clinical objectives to develop novel, reproducible, inexpensive, non-invasive, validated biomarkers derived from automated analyses of digitized speech in patients with Frontotemporal Lobar Degeneration (FTLD) pathology. This program is also designed with the scientific objectives to enrich neurobiologic models of language with essential but missing speech components and to improve our pathophysiologic understanding of spreading pathology. In Aim 1 of the K99 mentored phase, the PI will identify informative digitized acoustic and lexical markers in antemortem speech and relate these directly to regional pathologic burden in FTLD-Tau and FTLD-TDP, and uniquely study these speech markers and associated MRI cortical thinning in presymptomatic and symptomatic mutation carriers. In Aim 2, she will examine acoustic and lexical markers longitudinally in FTLD-Tau and FTLD-TDP and in mutation carriers. The PI’s preliminary data show that automated algorithms such as automated speech recognition (ASR) and natural language processing (NLP) tools extract novel digital markers from speech that are sensitive and specific to FTD phenotypes, are associated with imaging and biofluid markers of underlying FTLD pathology, and are related directly to regional pathologic burden in cross-sectional and longitudinal studies of autopsied FTLD-Tau and FTLD-TDP as well as carriers of mutations related to FTLD. During the R00 independent phase, Aim 3 will discover novel markers in the highly elusive domain of natural conversational speech, the most common form of human-to-human communication, and relate these to biomarkers of FTD. The PI will accomplish these aims with the guidance of a world-class mentoring team (Drs. Murray Grossman, Mark Liberman, James Gee, and David Irwin) who have expertise in computational linguistics, neuroimaging, and experimental neuropathology. The PI has available a unique database of 1500 digitized speech samples in deeply endophenotyped autopsied cases and mutation carriers. The mentoring team has a very strong track record of training postdoctoral fellows for independent research careers. A detailed training plan includes regular one-on-one meetings, seminars, coursework, grant writing, and responsible conduct of research. The new skills acquired during this period, combined with the PI’s prior expertise in cognitive neurology and leadership experience as a Major in the military, will ensure a strong foundation to launch an independent translational research career that will synergistically address vital scientific and clinical issues.

今天，临床标准是识别额颞叶痴呆（FTD）变体的金标准。虽然好 这些标准在临床上已经建立并有用，但依赖于昂贵且侵入性的冗长程序。 迫切需要可靠、客观和有效的措施来筛查可能的病理和监测 在改变疾病的治疗试验中纵向观察疾病。在准备PI成为独立的 翻译研究员，这项研究计划解决临床目标，开发新的，可重复的， 廉价的，非侵入性的，有效的生物标志物来自数字化语音的自动分析， 额颞叶变性（FTLD）病理学患者。此程序还使用 科学目标是丰富语言的神经生物学模型，其中包含重要但缺失的语音成分 并提高我们对传播病理学的病理生理学理解。在K99的目标1中， 阶段，PI将识别死前语音中信息丰富的数字化声学和词汇标记， 这些直接与FTLD-Tau和FTLD-TDP中的区域病理负荷相关，并且独特地研究这些语音 症状前和症状性突变携带者的标记物和相关MRI皮质变薄。在目标2中， 她将纵向研究FTLD-Tau和FTLD-TDP中的声学和词汇标记， 载波PI的初步数据显示，自动语音识别等自动算法 (ASR)和自然语言处理（NLP）工具从语音中提取新的数字标记， 对FTD表型敏感和特异，与基础免疫缺陷的成像和生物流体标志物相关。 FTLD病理，并直接相关的区域病理负担的横截面和纵向 尸体解剖的FTLD-Tau和FTLD-TDP以及与FTLD相关的突变携带者的研究。期间 R 00独立阶段，Aim 3将在高度难以捉摸的天然结构域中发现新的标记物。 会话语音，人与人之间最常见的沟通形式，并将这些与 FTD的生物标志物。PI将在世界级指导团队的指导下实现这些目标。 Murray Grossman，Mark Liberman，James Gee和大卫欧文），他们在计算领域具有专业知识， 语言学、神经影像学和实验神经病理学。PI有一个独特的数据库， 数字化语音样本在深度内表型尸检病例和突变携带者。辅导 团队有一个非常强大的跟踪记录培训博士后研究员的独立研究生涯。一 详细的培训计划包括定期的一对一会议，研讨会，课程作业，赠款写作， 负责任地进行研究。在此期间获得的新技能，结合PI的先前 在认知神经学的专业知识和领导经验，作为一个主要的军事，将确保一个强大的 基金会推出一个独立的翻译研究事业，将协同解决至关重要的 科学和临床问题。