Primary Progressive Aphasia: Cognition, Anatomy and Progression

描述（由申请人提供）：言语和语言缺陷通常是神经退行性疾病的最初症状，如额颞叶变性、皮质基底变性和阿尔茨海默病。当言语和语言缺陷孤立存在至少两年时，称为“原发性进行性失语症”（PPA）。在这种疾病的初始阶段，语言障碍的特征可以为早期鉴别诊断提供关键信息。然而，言语和语言功能很少在痴呆症诊所的环境中进行评估，并且经常失去机会。此外，PPA的大规模纵向临床和神经影像学研究数据无法指导临床医生做出诊断、预后和治疗决策。我们建议对200多名原发性进行性失语症患者的语言、解剖和病理特征进行一项详细的、为期四年的纵向研究。由于加州大学旧金山分校的记忆和衰老中心是美国国立卫生研究院资助的非典型和早发性痴呆研究项目的所在地，这个大型队列的积累将成为可能。该计划还将提供一般神经心理学，神经学，神经病理学和大多数神经影像学数据。在目标1中，我们将把详细语言测试的分数与区域灰质体积联系起来；在目标2中，扩散张量成像和功能MRI将用于研究PPA语言网络中结构和功能连接的改变；在目标3中，我们将把死后组织病理学和体内皮层淀粉样蛋白发现与纵向临床，认知和解剖学数据联系起来，以发现每种神经退行性疾病的典型进展模式。从这项研究中收集的证据将增加我们对言语和语言功能的神经基础的认识，并为早期治疗最有效的神经退行性疾病的诊断提供关键数据。公共卫生相关性研究的重点是语言和语言症状，这是致命的神经退行性疾病的第一表现。我们将使用最现代的认知和神经成像技术研究这些早期缺陷及其神经相关性，以提高这些破坏性疾病的早期鉴别诊断和最终治疗的目标。这项研究的结果也将进一步加深我们对语言的神经基础的认识。

DESCRIPTION (provided by applicant): Speech and language deficits are often the very first symptoms of neurodegenerative diseases, such as frontotemporal lobar degeneration, corticobasal degeneration and Alzheimer's disease. When speech and language deficits remain isolated for at least two years, the term "primary progressive aphasia" (PPA) applies. Characterization of the linguistic impairments in this initial stage of the disease can provide critical information for early differential diagnosis. However, speech and language functions are rarely assessed in the setting of dementia clinics and the opportunity is often lost. Moreover, data from large-scale longitudinal clinical and neuroimaging studies of PPA are not available to guide clinicians in making diagnostic, prognostic and therapeutic decisions. We propose a detailed, four-year longitudinal study of the linguistic, anatomical and pathological features of over 200 patients with primary progressive aphasia. The accrual of this large cohort will be possible because the UCSF Memory and Aging Center is the site of an NIH-funded research program in atypical and early-onset dementias. This program will also provide general neuropsychological, neurological, neuropathological and most neuroimaging data. In aim 1 we will correlate scores in detailed language tests and regional gray matter volumes; in aim 2 diffusion tensor imaging and functional MRI will be used to investigate alteration in structural and functional connectivity in the language network in PPA; and in aim 3 we will associate post-mortem histopathological and in-vivo cortical amyloid findings with longitudinal clinical, cognitive and anatomical data to find patterns of progression typical of each neurodegenerative disease. Evidence gathered from this research will increase our knowledge about the neural basis of speech and language functions and provide crucial data for the diagnosis of neurodegenerative diseases in their early stages, when treatment can be most effective. PUBLIC HEALTH RELEVANCE The research focuses on speech and language symptoms that are the first manifestation of fatal neurodegenerative diseases. We will study these early deficits and their neural correlates using the most modern cognitive and neuroimaging techniques, with the goal of improving early differential diagnosis and ultimately treatment of these devastating disorders. Results form this study will also further our knowledge regarding the neural basis of language.