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，如额颞叶变性和阿尔茨海默病。当言语和语言缺陷在疾病的初始阶段仍然孤立时，术语“原发性进行性失语症”（PPA）适用。语言障碍的特征可以提供早期鉴别诊断的关键信息，但言语和语言功能很少在痴呆症诊所进行评估。此外，PPA的大规模纵向临床和神经影像学研究的数据无法指导临床医生做出诊断，预后或治疗决策。我们提出了一个详细的，为期五年的纵向研究的语言，解剖和生物学特征的300多名患者与PPA，从而延长我们在2004年开始的工作。这一大型队列的累积是可能的，因为UCSF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UCSF提供的基础设施，并将通过将特定的语言和神经影像学专业知识引入PPA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得分与局部脑容量相关联;在目标2中，将使用Q球纤维束成像、静息状态和激活功能MRI来研究PPA中语言网络的结构和功能连接的改变，并将它们与语言缺陷相关联;在目标3中，我们将应用多变量统计方法来研究PPA的进展，并将纵向多学科数据与临床结局或术后结局相关联。尸检病理结果。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预测体内病理亚型。从这项研究中收集的证据将增加我们对语音和语言功能的神经基础的了解，并为早期神经退行性疾病的诊断提供关键数据，此时治疗可能最有效。 公共卫生相关性：研究重点是致命神经退行性疾病的表现形式-言语和语言症状。我们将使用最现代的认知和神经成像技术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 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.