Primary Progressive Aphasia: Cognition, Anatomy and Progression

描述(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，如额颞叶退行性疾病和阿尔茨海默病。当语言和语言缺陷在疾病的初始阶段仍然是孤立的时，术语“原发进行性失语”(PPA)适用。语言障碍的特征可以提供对早期鉴别诊断至关重要的信息，但在痴呆症诊所的设置中很少评估言语和语言功能。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、预后或治疗决定。我们建议对300多名PPA患者的语言、解剖学和生物学特征进行为期五年的详细纵向研究，从而扩展我们从2004年开始的工作。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项目的所在地。这里提出的研究项目将利用加州大学旧金山分校提供的基础设施，并将通过将特定的语言和神经成像专业知识引入PPA潜在的临床、认知和神经机制的研究来补充该计划。在目标1中，我们将把新语言领域的分数与区域脑体积相关联；在目标2中，将使用Q-ball轨迹图、静息状态和激活功能磁共振来研究PPA语言网络结构和功能连接的变化，并将它们与语言缺陷相关联；在目标3中，我们将应用多元统计方法来研究PPA的进展，并将纵向多学科数据与临床结果或尸检病理结果相关联。我们将确定每种PPA变异的典型进展模式，并探索综合纵向评估的结果是否可以在体内预测病理亚型。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语言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的神经基础的了解。

DESCRIPTION (provided by applicant): Speech and language deficits are often the very first symptoms of neurodegenerative diseases, such as frontotemporal lobar degeneration and Alzheimer's disease. When speech and language deficits remain isolated for the initial phases of the disease, the term "primary progressive aphasia" (PPA) applies. Characterization of the linguistic impairments can provide information critical for early differential diagnosis, but speec and language functions are rarely assessed in the setting of dementia clinics. Moreover, data from large-scale longitudinal clinical and neuroimaging studies of PPA are not available to guide clinicians in making diagnostic, prognostic or therapeutic decisions. We propose a detailed, five-year longitudinal study of the linguistic, anatomical and biological features of over 300 patients with PPA, thus extending the work we began in 2004. The accrual of this large cohort is possible because the UCSF Memory and Aging Center is the site of an NIH-funded program in atypical and early-age-of-onset dementias. The research project proposed here will take advantage of the infrastructure offered at UCSF and will complement the program by bringing specific linguistic and neuroimaging expertise to the study of the clinical, cognitive and neural mechanisms underlying PPA. In Aim 1 we will correlate scores in novel language domains with regional brain volumes; in Aim 2 Q-ball tractography, resting state and activation functional MRI will be used to investigate alterations in structural and functional connectivity in the language networks in PPA and correlate them with linguistic deficits; and in Aim 3 we will apply multivariate statistical methods to study the progression of PPA and associate longitudinal multidisciplinary data with clinical outcomes or post-mortem pathological findings. We will identify patterns of progression typical of each PPA variant and explore whether results from a comprehensive longitudinal assessment can predict pathological subtypes, in-vivo. 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 manifestation of fatal neurodegenerative diseases. We will study these linguistic 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 from this study will also further our knowledge regarding the neural basis of language.