Primary Progressive Aphasia: Cognition, Anatomy and Progression

摘要 原发性进行性失语(PPA)是一种以相对孤立的衰退为特征的临床解剖学综合征 在言语和语言能力方面。PPA发生在额颞叶的病理和分子变化 变性tau(FTLD-tau)、FTLD-TDP或阿尔茨海默病(AD)选择性地损害大脑网络 维持言语和语言功能。自2004年R01计划开始以来，我们对 超过400名PPA参与者，收集临床和认知评估、详细的言语和语言 特征，结构和功能核磁共振，在大多数情况下，生物标志物，遗传和病理数据。 这一史无前例的数据集的结果导致了160多篇同行评议的论文，包括当前 国际临床标准，为PPA个人的临床护理和基础科学提供了新的见解。 尽管取得了重大进展，但关键问题仍有待解决。的药理试验 引起PPA的神经退行性疾病已经开始，PPA患者往往因为缺乏 量化、客观的临床结果工具。此外，最近的研究表明，非语言症状， 例如视觉空间和执行困难可能发生在PPA中，导致临床异质性和诊断 挑战。最后，虽然现在知道PPA的发生是因为特定的网络容易受到疾病的影响， 这种脆弱性的结构、功能和分子机制仍然难以捉摸。在这个新的周期中，我们 将研究成果转化为可扩展的临床工具，我们将继续研究认知和神经 根据PPA症状改善诊断和治疗，并探索这一独特的人群以告知 神经科学研究。我们汇聚了一支强大的合作者团队，进行创新、 多学科项目，将利用尖端技术、理论神经科学方法和 创新科学方法。结果将提高和简化鉴别诊断，可靠地监测症状 进展，并改善PPA的认知和神经生物学模型。在目标1中，我们将应用自动化 声学和语言技术，以促进对PPA变种的诊断并跟踪疾病进展； 目标2，我们将考察数学认知、社会情绪语义和数学认知的神经认知基础 对语言的执行控制，以提高对PPA症状和鉴别诊断的理解； 目的3.应用MRI技术对PPA神经网络进行活体解剖研究，并结合组织病理学进行研究 以及对死后脑组织的转录组学分析。在这次更新中，我们将检查150个新的队列 PPA患者纵向采用混合的面对面和远程评估模式。到今年R01的第23年，我们的 队列将包括550多名PPA患者。这项研究将改善临床护理，通知治疗，并 提高语言神经基础的知识。

ABSTRACT Primary progressive aphasia (PPA) is a clinico-anatomical syndrome characterized by relatively isolated decline in speech and language abilities. PPA occurs when pathological and molecular changes of frontotemporal lobar degeneration tau (FTLD-tau), FTLD-TDP, or Alzheimer's disease (AD) selectively damage brain network that sustain speech and language functions. Since the beginning of this R01 program in 2004, we evaluated more than 400 PPA participants, collecting clinical and cognitive evaluations, detailed speech and language characterization, structural and functional MRI, and in most cases biomarkers, genetic and pathological data. Results from this unprecedented dataset led to more than 160 peer-reviewed papers, including current international clinical criteria, providing new insights into the clinical care and basic science of PPA individuals. Despite significant progress, crucial questions remain to be resolved. Pharmacological trials for neurodegenerative diseases causing PPA have started, and PPA patients are often excluded due to lack of quantitative, objective clinical outcome tools. Furthermore, recent studies show that non-linguistic symptoms, such as visuospatial and executive difficulties can occur in PPA, causing clinical heterogeneity and diagnostic challenges. Finally, while it is now known that PPA occurs because specific networks are vulnerable to disease, the structural, functional and molecular mechanisms of such vulnerability remain elusive. In this new cycle, we will translate research findings into scalable clinical tools, we will continue to investigate the cognitive and neural basis of PPA symptoms to improve diagnosis and treatment and probe this unique population to inform neuroscience research. We have assembled a strong team of collaborators to conduct an innovative, multidisciplinary project that will leverage cutting-edge technologies, theoretical neuroscience approaches, and innovative scientific methods. Results will advance and simplify differential diagnosis, reliably monitor symptom progression, and improve cognitive and neurobiological models of PPA. In Aim 1, we will apply automated acoustic and linguistic techniques to facilitate diagnosis across PPA variants and track disease progression; in Aim 2, we will investigate the neurocognitive basis of mathematical cognition, socio-emotional semantics and executive control of language to improve understanding of PPA symptoms and differential diagnosis; and in Aim 3, we will study neuroanatomy of PPA networks with MRI technology in vivo, and with histopathological and transcriptomics analyses of post-mortem brain tissue. In this renewal, we will examine a new cohort of 150 PPA patients longitudinally with a hybrid in-person and remote evaluation model. By year 23 of this R01, our cohort will include more than 550 PPA patients. This study will improve clinical care, inform treatment, and advance knowledge of the neural bases of language.