Primary Progressive Aphasia: Cognition, Anatomy and Progression

摘要 原发性进行性失语（PPA）是一种临床综合征，其特征是孤立的、进行性的失语症。 言语和语言能力。PPA发生时，神经变性选择性地针对语言网络 在大脑里。它最常由额颞叶典型的分子和病理变化引起 痴呆症（FTLD）或阿尔茨海默病（AD）。在这个项目的过去12年里，我们研究了一个 队列的300个良好的特点PPA患者，并获得了前所未有的数量的尸检 样品我们已经发表了130多篇论文，并取得了重要的发现， 描述PPA临床变异并定义主要临床解剖表现： 非流利/语法（nfvPPA）、语义（svPPA）和逻辑开放（lvPPA）变体，每个变体与一个 潜在的分子原因的不同概率。 尽管取得了这一重大进展，但许多关于认知表现、临床病程和 生物学基础仍然没有答案。在这个项目中，我们将应用新的神经成像和认知 神经科学技术研究临床症状，体内tau沉积，纵向进展， 预测PPA的病理和分子变化。我们提出了一个五年的横截面和 对200多名新招募人员的认知、解剖和生物学特征进行了纵向研究 个人PPA特别地，在目标1中，我们将研究白色物质、灰色物质和白色物质的差异贡献。 问题，和功能的变化，在大脑中的PPA症状的发展，并使用新的任务， 研究语义、语法和拼写功能。在目标2中，我们将应用新的正电子 发射断层扫描[18F] AV 1451 tau配体研究体内分子脑变化如何与临床 和认知因素。最后，在目标3中，我们将研究PPA级数，以及 神经变性的网络传播理论，通过将患者的纵向神经影像学变化与 健康的连接结构。此外，我们将对组合的 最大、最全面的PPA数据集中的临床、神经影像、遗传和病理数据 以确定分子诊断是否可以在体内预测。 该项目将为语言的神经基础提供新的证据，并为语言学提供关键数据。 在早期阶段诊断神经退行性疾病，此时治疗可能最有效。

ABSTRACT Primary progressive aphasia (PPA) is a clinical syndrome characterized by isolated, progressive loss of speech and language abilities. PPA occurs when neurodegeneration selectively targets the language networks in the brain. It is most often caused by molecular and pathological changes typical of Frontotemporal lobar degeneration (FTLD) or Alzheimer’s disease (AD). Over the past 12 years of this project, we have studied a cohort of 300 well-characterized PPA patients, and have obtained an unprecedented number of post-mortem samples. We have published more than 130 papers, and have made discoveries that were essential in characterizing the PPA clinical variants and in defining the main clinico-anatomical presentations: the nonfluent/agrammatic (nfvPPA), semantic (svPPA) and logopenic (lvPPA) variants, each associated with a different probability of underlying molecular causes. Despite this significant progress, many questions regarding cognitive presentation, clinical course and biological basis remain unanswered. In this project, we will apply novel neuroimaging and cognitive neuroscience techniques to study clinical symptoms, in-vivo tau deposition, longitudinal progression, and prediction of pathological and molecular changes in PPA. We propose a five-year cross-sectional and longitudinal study of the cognitive, anatomical and biological features of more than 200 newly recruited individuals with PPA. In particular, in Aim 1, we will study the differential contribution of white matter, gray matter, and functional changes in the brain to the development of PPA symptoms, and use new tasks to investigate semantic, grammatical, and orthographic functions. In Aim 2, we will apply the novel positron emission tomography [18F]AV1451 tau ligand to study how in-vivo molecular brain changes relate to clinical and cognitive factors in lvPPA and nfvPPA. Finally, in Aim 3, we will study PPA progression, and the validity of the network-spread theory of neurodegeneration, by relating longitudinal neuroimaging changes in patients to the healthy connective architecture. Furthermore, we will perform multivariate analyses on the combined clinical, neuroimaging, genetic, and pathological data, in the largest and most comprehensive PPA dataset ever examined to determine whether molecular diagnosis can be predicted in-vivo. This project will provide novel evidence on the neural basis of language, and provide crucial data for the diagnosis of neurodegenerative diseases in their early stages, when treatment can be most effective.