Project 2: Susceptibility Factors for Primary Progressive Aphasia

项目2 -摘要 原发性进行性失语症（PPA）是一组临床综合征，其特征是渐进性、选择性、 言语和语言功能下降。它是由维持大脑活动的大脑区域的神经退化引起的。 语言PPA是一种毁灭性的疾病，影响着壮年的成年人，剥夺了他们的能力， 在社会中沟通和发挥作用。在过去的十年中，PPA的认知和神经基础已经被 研究彻底，并已描述了该疾病的三种临床解剖变异。重要的是，每个 变异的特征在于潜在的额颞叶变性（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 生物学因素与每种主要PPA变体相关。在这个项目中，我们将进一步发展这一点， 一系列的研究和调查的发展，遗传和分子因素，可能决定 语言网络对每个PPA亚型的易感性。我们将招募125名新的PPA患者， 将联合收割机数据与我们现有的大型队列数据相结合，以实现以下主要目标：（1）识别 语言学习障碍，如阅读障碍，并确定其对认知和 解剖表型我们假设，语言学习障碍将最常见于 逻辑缺失变体PPA，并将预测早期发病年龄和更大的语音障碍。（二） 测量语言功能的大脑半球偏侧化， 脑磁图和结构MRI。我们预测svPPA患者将表现出异常的 语言激活的偏侧化和特定大脑外侧裂语言区域的不对称性降低。（三） 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APOE 4等位基因在学习障碍的逻辑缺失患者中的发生率低于那些 没有，并找到生物标志物指示改变免疫反应svPPA。这项研究将 增加我们对PPA发病机制和语言神经生物学的认识。而且 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.