Primary Progressive Aphasia: Cognition, Anatomy and Progression

摘要 原发性进行性失语(PPA)是一种以孤立性进行性失语为特征的临床综合征 口语和语言能力。当神经退行性变选择性地以语言网络为目标时，就会发生PPA 在大脑里。它最常见的原因是额颞叶典型的分子和病理改变。 变性(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 300名特征良好的PPA患者的队列，并获得了前所未有的数量的尸检 样本。我们已经发表了130多篇论文，并取得了在 PPA临床变异的特征和主要的临床解剖学表现： 非流畅/无语法(NfvPPA)、语义(SvPPA)和对数(LvPPA)变体，每个变体都与 潜在分子原因的不同概率。 尽管取得了这一重大进展，但关于认知表现、临床病程和 生物学基础仍未得到回答。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、纵向进展和 预测PPA的病理和分子变化。我们提议一项为期五年的横截面和 200多名新兵认知、解剖和生物学特征的纵向研究 患有PPA的个体。特别是，在目标1中，我们将研究白质、灰质 物质，以及大脑功能的变化来发展PPA的症状，并使用新的任务来 调查语义、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]AV1451 tau配体研究体内分子脑变化与临床的关系 LvPPA和nfvPPA中的认知因素。最后，在目标3中，我们将研究PPA级数，以及PPA级数的有效性 神经退行性变的网络传播理论，通过将患者的纵向神经影像变化与 健康的连接架构。此外，我们将对合并后的 临床、神经影像、遗传和病理数据，在最大和最全面的PPA数据集中 进行过检查，以确定是否可以在体内预测分子诊断。 该项目将为语言的神经基础提供新的证据，并为 神经退行性疾病的早期诊断，此时的治疗最有效。

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.