Digital biomarkers in narrative and conversational speech in Frontotemporal Dementia

今天，临床标准是识别额颞部痴呆(FTD)变种的金标准。虽然很好 这些标准已经确立并在临床上有用，依赖于昂贵和侵入性的冗长程序。 迫切需要可靠、客观和有效的措施来筛选可能的病理和监测 疾病改变治疗试验中的纵向疾病。在准备让PI成为独立的 翻译研究人员，这项研究计划致力于临床目标，以开发新的，可重复的， 来自数字化语音自动分析的廉价、非侵入性、经过验证的生物标记物 额颞叶变性(FTLD)病理患者。这个程序也是用 用基本但缺失的语音成分丰富语言神经生物学模型的科学目标 并提高我们对传播病理学的病理生理学理解。在K99导师的目标1中 在这一阶段，PI将识别死前语音中的信息数字化声学和词汇标记，并与 这些都直接给FTLD-Tau和FTLD-TDP带来了区域病理负担，并对这些语音进行了独特的研究 症状前和症状性突变携带者的标志物和相关的MRI皮质变薄。在目标2中， 她将纵向检查FTLD-Tau和FTLD-TDP以及突变中的声学和词汇标记 承运人。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，与潜在的影像和生物流体标志物相关 FTLD病理，并与横断面和纵向的局部病理负担直接相关 尸检FTLD-Tau和FTLD-TDP以及FTLD相关突变携带者的研究在.期间 R00独立阶段，目标3将在高度难以捉摸的自然领域发现新的标记 对话语言，人与人之间最常见的交流形式，并将其与 FTD的生物标志物。PI将在一支世界级的指导团队(Dr. Murray Grossman、Mark Liberman、James Gee和David Irwin)，他们拥有计算方面的专业知识 语言学、神经成像和实验神经病理学。PI有一个独特的数据库，有1500个 深度内表型尸检病例和突变携带者的数字化语音样本。指导工作 团队在培训博士后研究员从事独立研究方面有着非常出色的记录。一个 详细的培训计划包括定期的一对一会议、研讨会、课程安排、拨款申请和 负责任的研究行为。在此期间获得的新技能，与PI之前的 认知神经学方面的专业知识和在军队中担任少校的领导经验，将确保 基金会将启动独立的翻译研究事业，将协同解决至关重要的问题 科学和临床问题。

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.