Primary Progressive Aphasia: Cognition, Anatomy and Progression

描述(申请人提供)：言语和语言障碍通常是神经退行性疾病的首发症状，如额颞叶变性、皮质基底膜变性和阿尔茨海默病。当言语和语言缺陷保持隔离状态至少两年时，术语“原发进行性失语”(PPA)适用。在疾病的初始阶段，语言障碍的特征可以为早期鉴别诊断提供关键信息。然而，在痴呆症诊所的环境中，很少对言语和语言功能进行评估，而且经常失去机会。此外，来自PPA的大规模纵向临床和神经影像研究的数据无法指导临床医生做出诊断、预后和治疗决策。我们提议对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为期四年的详细纵向研究。这一大规模队列的累积是可能的，因为加州大学旧金山分校的记忆和衰老中心是NIH资助的非典型和早发性痴呆研究项目的所在地。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成像数据。在目标1中，我们将详细的语言测试的分数与区域灰质体积相关联；在目标2中，将使用扩散张量成像和功能磁共振来研究PPA中语言网络的结构和功能连接的变化；在目标3中，我们将把死后组织病理学和体内皮质淀粉样蛋白的发现与纵向的临床、认知和解剖学数据相关联，以找出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了解，并为神经退行性疾病的早期诊断提供关键数据，届时治疗可能是最有效的。公共卫生相关性这项研究的重点是言语和语言症状，这些症状是致命的神经退行性疾病的第一个表现。我们将使用最现代的认知和神经成像技术来研究这些早期缺陷及其神经相关性，目的是改善这些破坏性疾病的早期鉴别诊断和最终治疗。这项研究的结果也将进一步加深我们对语言神经基础的了解。

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.