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

神经退行性言语失用症两种不同亚型的神经生物学：阿尔茨海默病相关 4 重复 tau蛋白病的表型

• 批准号: 10654129
• 负责人: Keith A Josephs
• 金额: $ 65.18万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10654129
• 关键词: Acoustics; Address; Alzheimer' s Disease; Alzheimer' s disease related dementia; Anatomy; Aphasia; Apraxias; Atrophic; Autopsy; Biological; Brain; Brain Injuries; Brain Stem; Brain scan; Cerebellum; Characteristics; Clinical; Clinical Trials; Collection; Communication; Corpus striatum structure; Cross-Sectional Studies; Data; Data Collection; Deposition; Development; Diagnosis; Differential Diagnosis; Diffusion Magnetic Resonance Imaging; Disease; Disease Progression; Dysarthria; Evolution; Frequencies; Functional Magnetic Resonance Imaging; Future; Genetic; Genetic Risk; Grant; Haplotypes; Image; Intervention; Iron; Knowledge; Language; Language Disorders; Language Therapy; Longevity; Magnetic Resonance Imaging; Maps; Measures; Metabolism; Methods; Mutism; Nerve Degeneration; Neurobiology; Neurologic; Neurologist; Outcome; Parkinson Disease; Pathologic; Pathologist; Pathology; Patient Care; Patients; Phenotype; Phonetics; Play; Predisposition; Reporting; Role; Severities; Speech; Speech Disorders; Structure; Syndrome; Tauopathies; Techniques; Time; brain volume; clinical development; clinically relevant; corticobasal degeneration; cost; disease prognosis; experience; fluorodeoxyglucose positron emission tomography; genetic risk factor; improved; indexing; metabolic rate; morphometry; neuroimaging; neuroimaging marker; neuron loss; neuropathology; novel; prognostic; prospective; response; risk variant; tau Proteins

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.

项目概要 进行性言语失用症 (PAOS) 是一种毁灭性的神经退行性综合征，最终会缩短言语能力 寿命缩短，最常见的原因是阿尔茨海默病相关疾病 (ADRD) 四重复 tau 蛋白病。 九年前，我们描述了 PAOS 的两种不同亚型：语音 PAOS，其主要特征是 发音扭曲和韵律 PAOS 主要表现为语速缓慢和异常 韵律。在第一个周期中，我们证明了语音、语言和神经特征在不同人群中存在差异。 PAOS 亚型有助于验证这些亚型是不同的。我们进行了横截面 分析包括基于体素的结构 MRI 形态测量、扩散张量成像和 18F- 氟脱氧葡萄糖 PET (FDG-PET) 并发现了语音 PAOS 中更多皮质参与的证据。 利用尸检数据，我们还证明 PAOS 亚型与特定的 4 次重复相关 tau蛋白病（语音伴皮质基底节变性，韵律伴PSP），并有明显的神经元损失 皮质-纹状体和苍白球-黑质-卢西尔-小脑区域。然而，在知识方面仍然存在许多空白。 对于 PAOS 的进展以及临床进展的纵向速率是否存在差异，我们知之甚少 亚型，解剖学和代谢率是否不同并且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是否与阿尔茨海默病神经病理学有关 变化或其他共同病理在 PAOS 亚型中发挥着重要作用。在第二个周期中，我们将继续进行新的 使用从 120 名 PAOS 患者收集的数据来解决这些知识差距和局限性的指导 包括第一个周期的 47 名患者。在目标 1 中，我们将确定言语下降率和 其他通信特征，包括源自新颖速率调制任务的声学特征，或 临床结果发展的时间与亚型相关。这一目标对于援助至关重要 疾病进展的诊断和预测。在目标 2 中，我们将确定是否先进和 新颖的神经影像技术可以检测区域纵向差异以及影像学差异是否存在 与不同 PAOS 亚型随时间的临床变化差异相关。我们将分析结构 MRI， FDG-PET 和定量磁化率图 (QSM) 用于评估体积、代谢和铁沉积。 这一目标将增进对这些区域的差异参与与 PAOS 亚型之间的关系的理解 并提供用于诊断和疾病追踪的特定神经影像生物标志物，这对于 临床试验。在目标 3 中，我们将确定 tau 蛋白与阿尔茨海默病相关遗传之间的关系 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同病理学，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位言语病理学家具有重要的临床意义 以及诊断和护理言语和语言障碍患者的神经科医生。