The neurobiology of two distinct subtypes of neurodegenerative apraxia of speech: phenotypes of Alzheimer disease related 4-repeat tauopathies

项目摘要 进行性言语失用症（PAOS）是一种破坏性的神经退行性综合征， 这种疾病通常是由于阿尔茨海默病相关疾病（ADRD）四重复tau蛋白病（four-repeat tauopathy）。 九年前，我们描述了两种不同的PAOS亚型：语音PAOS，主要特征是 发音失真和韵律PAOS，主要表现为语速缓慢和异常 韵律学在第一个周期中，我们证明了言语，语言和神经功能在不同的人之间存在差异。 PAOS亚型，有助于验证这些亚型是不同的。我们进行了横断面的 分析包括结构MRI的基于体素的形态测量、扩散张量成像和18F- 氟脱氧葡萄糖PET（FDG-PET），并发现了更多的皮质参与语音PAOS的证据。 利用尸检数据，我们还证明了PAOS亚型与特定的4-重复序列相关， tau蛋白病（语音与皮质基底节变性和韵律与PSP），并在不同的神经元损失 皮质-纹状体和苍白球-黑质-路易体-小脑区。然而，在知识方面仍然存在许多差距。 关于进展以及PAOS患者的纵向临床进展率是否不同，我们知之甚少。 亚型，无论解剖和代谢率不同，都可以通过先进的神经影像学检测到 技术，以及铁的遗传和组织病理学特征，阿尔茨海默病神经病理学 变化或其他共病在PAOS亚型中起任何作用。在第二个周期，我们将继续在新的 使用从120例PAOS患者中收集的数据，指导解决这些知识差距和局限性 包括第一周期的47例患者。在目标1中，我们将确定言语和语言能力的下降率是否 其他通信特征，包括从新的速率调制任务导出的声学特性，或者 临床结局的发展时间与亚型相关。这一目标对援助至关重要 疾病进展的诊断和证实。在目标2中，我们将确定是否先进和 新的神经成像技术可以检测区域纵向差异， 与PAOS亚型间随时间推移的临床变化差异相关。我们会分析核磁共振结构， FDG-PET和定量磁敏感性成像（QSM）评估体积、代谢和铁沉积。 这一目标将提高对这些区域的不同参与与PAOS亚型之间关系的理解 并提供用于诊断和疾病追踪的特异性神经成像生物标志物， 临床试验在目标3中，我们将确定tau蛋白和阿尔茨海默病相关遗传因子之间的关系。 风险等位基因、局部铁负荷、阿尔茨海默病神经病理学变化和其他共病，以及 PAOS亚型。这一目标的结果将提高我们对PAOS亚型神经生物学的理解。 实现第二周期的目标将对每一位语言病理学家具有重要的临床意义 和神经科医生，诊断和护理言语和语言障碍患者。

PROJECT SUMMARY Progressive apraxia of speech (PAOS) is a devastating neurodegenerative syndrome that ultimately shortens lifespan and is most commonly due to an Alzheimer’s disease related disorders (ADRD) four-repeat tauopathy. Nine years ago, we described two distinct subtypes of PAOS: phonetic PAOS characterized predominantly by articulatory distortions and prosodic PAOS characterized predominantly by slow speech rate and abnormal prosody. In the 1st cycle we demonstrated that speech, language, and neurological features differ across PAOS subtypes which helped to validate these subtypes as being distinct. We performed cross-sectional analyses including voxel-based morphometry of structural MRI, diffusion tensor imaging and 18F- fluorodeoxyglucose PET (FDG-PET) and found evidence for greater cortical involvement in phonetic PAOS. Leveraging autopsy data, we also demonstrated that the PAOS subtypes are associated with specific 4-repeat tauopathies (phonetic with corticobasal degeneration and prosodic with PSP) and have neuronal loss in distinct cortico-striatal and pallido-nigro-luysial-cerebellar regions. However, there are still many gaps in knowledge. Little is known about progression, and whether longitudinal rates of clinical progression differ in PAOS subtypes, whether anatomic and metabolic rates differ and can be detected with advanced neuroimaging techniques, and whether genetic and histopathologic features of iron, Alzheimer disease neuropathologic changes or other co-pathologies play any role in PAOS subtypes. In the 2nd cycle we will proceed in new directions to address these knowledge gaps and limitations using data collected from 120 PAOS patients including 47 patients from the 1st cycle. In Aim 1, we will determine whether rates of decline in speech and other communication features, including acoustic characteristics derived from a novel rate modulation task, or time to the development of clinical outcomes, are associated with subtype. This aim will be critical to aid diagnosis and prognostication of disease progression. In Aim 2, we will determine whether advanced and novel neuroimaging techniques can detect regional longitudinal differences and whether imaging differences correlate with differences in clinical change over time, across PAOS subtypes. We will analyze structural MRI, FDG-PET and quantitative susceptibility mapping (QSM) to assess volume, metabolism, and iron deposition. This aim will improve understanding of how differential involvement of these regions relate to PAOS subtypes and provide specific neuroimaging biomarkers for diagnosis and disease tracking which is also important for clinical trials. In Aim 3, we will determine the relationship between tau- and Alzheimer disease related genetic risk alleles, regional iron burden, Alzheimer disease neuropathologic changes, and other co-pathologies, and PAOS subtype. Results from this aim will improve our understanding of the neurobiology of PAOS subtype. Achieving the aims of the 2nd cycle will have significant clinical relevance to every speech-language pathologist and neurologist who diagnose and care for patients with speech and language disorders.