Project 2: Susceptibility Factors for Primary Progressive Aphasia

项目2--摘要 摘要原发性进行性失语(PPA)是以渐进性、选择性为特征的临床症状的集合。 言语和语言功能衰退。它是由大脑中持续存在的区域的神经退化引起的 语言。PPA是一种毁灭性的疾病，影响正值壮年的成年人，剥夺他们 在社会中进行沟通和发挥作用。在过去的十年里，PPA的认知和神经基础是 经过深入研究，已描述了该病的三种临床解剖学变异。重要的是，每个 变异型的特点是潜在的额颞叶变性(FTLD)或 阿尔茨海默病(AD)病理学。最近的初步数据表明，不同的神经发育和 生物因素与每一种主要的PPA变种有关。在这个项目中，我们将进一步发展这一点 研究路线，调查可能决定的发育、遗传和分子因素 语言网络对每个PPA亚型的敏感度。我们将招募125名新的PPA患者和 将数据与我们现有的大型队列的数据结合起来，以实现以下主要目标：(1)确定存在 以语言为基础的学习障碍，如诵读困难，并确定它们对认知和 解剖表型。我们假设，基于语言的学习障碍将最常出现在 对数变异的PPA和将预测更早的发病年龄和更大的语音障碍。(2) 测量大脑半球语言功能的偏侧化并评估大脑对称性 脑磁图和结构磁共振成像。我们预测svPPA患者将表现出异常 语言激活的偏侧化和特定的齿周语言区域的不对称性降低。(3) 评估APOE等位基因状态、炎症基因表达模式和血浆细胞因子水平。我们预计 发现对数型学习障碍患者中APOE4等位基因的发生率低于那些 寻找指示svPPA免疫反应改变的生物标记物。这项研究将 增加我们对PPA的发病机制和语言的神经生物学的了解。此外， 研究结果可作为制定早期干预策略和个性化风险评估的基础 用于预测神经退行性疾病。

PROJECT 2 - ABSTRACT Primary progressive aphasia (PPA) is a collection of clinical syndromes characterized by gradual, selective decline in speech and language functions. It is caused by neurodegeneration in the brain regions that sustain language. PPA is a devastating disease affecting adults in the prime of their life, depriving them of the ability to communicate and function in society. In the last decade, the cognitive and neural bases of PPA have been studied thoroughly, and three clinic-anatomical variants of the disease have been described. Importantly, each variant is characterized by a different probability of underlying frontotemporal lobar degeneration (FTLD) or Alzheimer's disease (AD) pathology. Recent preliminary data suggest that different neurodevelopmental and biological factors are associated with each of the main PPA variants. In this project, we will further develop this line of research and investigate developmental, genetic and molecular factors that might determine susceptibility of the language network to each PPA subtype. We will recruit 125 new PPA patients and combine data with that of our large existing cohort to realize the following main goals: (1) Identify the presence of language-based learning disabilities, such as dyslexia, and determine their effect on cognitive and anatomical phenotypes. We hypothesize that language-based learning disabilities will be present most often in the logopenic variant PPA and will predict earlier age at onset and greater phonological impairment. (2) Measure hemispheric lateralization of language function an asses brain symmetry using magnetoencephalography and structural MRI. We predict that svPPA patients will show anomalous lateralization of language activation and decreased asymmetry of specific perisylvian language regions. (3) evaluate APOE allele status, inflammatory gene expression patterns and plasma cytokines levels. We expect to find a lower incidence of the APOE4 allele among logopenic patients with learning disabilities than those without, and to find biomarkers indicative of an altered immunological response in svPPA. This research will increase our knowledge about the pathogenesis of PPA and the neurobiology of language. Moreover, the results might serve as the foundation to develop early intervention strategies and personalized risk assessment for the prediction of neurodegenerative disease.