The neurobiology of two distinct types of progressive apraxia of speech

两种不同类型的进行性言语失用的神经生物学

• 批准号: 10224718
• 负责人: Keith A Josephs
• 金额: $ 47.1万
• 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 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10224718
• 关键词: Acoustics; Acute; Address; Affect; Aggressive course; Aphasia; Apraxias; Area; Atrophic; Autopsy; Behavioral; Biological; Brain; Brain Diseases; Brain Stem; Brain region; Brain scan; Characteristics; Chronic; Classification; Clinical; Clinical Data; Clinical assessments; Cognitive; Consensus; Corpus striatum structure; Data; Deposition; Development; Diagnosis; Diffusion; Diffusion Magnetic Resonance Imaging; Disease; Disease Progression; Dopamine; Dopamine Receptor; Dysarthria; Equipment; Functional Magnetic Resonance Imaging; Goals; Grant; Histologic; Image; Individual; Language; Language Tests; Longevity; Longitudinal Studies; Magnetic Resonance Imaging; Measurement; Measures; Mediating; Molecular; Morbidity - disease rate; Motor; Neocortex; Nerve Degeneration; Neurobiology; Neurodegenerative Disorders; Neurologic; Neuropsychology; Pathologic; Pathology; Patients; Pattern; Prognosis; Progressive Supranuclear Palsy; Proteins; Protocols documentation; Reporting; Research Project Grants; Rest; Scanning; Societies; Speech; Speech Disorders; Stroke; Structure; Syndrome; Testing; Time; Work; base; clinical phenotype; clinically relevant; cohort; corticobasal degeneration; demographics; dopamine transporter; gray matter; improved; loved ones; neurocognitive test; neuroimaging; neuropathology; novel; prognostic; recruit; single photon emission computed tomography; sound; spasticity; tau Proteins; therapy development; uptake; white matter

The primary goal of this R01 is to improve understanding of the neurobiology and clinical utility of recognizing two distinct types of primary progressive apraxia of speech (PAOS). Phonetic PAOS is characterized predominantly by distorted sound substitutions and additions, whereas Prosodic PAOS is characterized predominantly by slow, prosodically segmented speech (previously referred to as type 1 and 2, respectively; a third type is characterized by a relatively equal combination of the Phonetic and Prosodic characteristics). Little is known about these PAOS types; however, pilot data suggest biological and clinically meaningful differences between PAOS types. Specifically, Phonetic PAOS seems to be related to degeneration of neocortex, while Prosodic PAOS appears to be more subcortically and brainstem mediated. Pathological underpinnings may also differ across PAOS types. There is some evidence that Prosodic, and not Phonetic, PAOS is associated with the development of a devastating extrapyramidal syndrome and shortened survival. Our approach to the understanding of PAOS types will involve a comprehensive longitudinal assessment of clinical, neuroanatomical, functional, molecular and histopathological data for these patients. By the end of the R01, we expect to have collected and analyzed clinical data - including demographic, speech and language (perceptual and acoustic), neurological, and neuropsychological variables - for 80 PAOS patients. Of these 80, 33 have already been recruited and 47 will be recruited via this R01 mechanism. All 47 new patients will complete the identical volumetric brain MRI protocol which will allow us to assess grey matter atrophy on structural MRI, white matter tract degeneration on diffusion tensor imaging, and functional network disruption on task free fMRI. All new patients to be recruited via this R01 mechanism will also complete a dopamine transporter SPECT scan to assess for striatal dopamine receptor integrity. All tests will be completed annually. Postmortem brain examinations and additional histological analyses of specific brain regions will also be performed on the PAOS patients who are expected to die during this R01. This will be the first study to systematically investigate PAOS types, as well as follow the course of disease longitudinally, and hence is highly novel. The PI of this grant, Dr. Josephs, will be working with a team of experts in AOS (Drs. Duffy and Utianski), structural neuroimaging (Dr. Whitwell), functional neuroimaging (Dr. Jones), molecular neuroimaging (Dr. Lowe), neuropsychology (Drs. Machulda and Butts), and neuropathology (Dr. Dickson) who will work among state of the art facilities and equipment to collectively to reach the aims. At the completion of the R01, we will 1) better understand the neurobiology of PAOS and 2) validate the clinical validity and utility of PAOS types through perceptual consensus, acoustic correlates, and data driven analysis to support prognostication and the development of targeted treatments.

R01 的主要目标是提高对神经生物学的理解和识别的临床实用性 两种不同类型的原发性进行性言语失用症（PAOS）。语音 PAOS 的特点 主要是通过扭曲的声音替换和添加，而 Prosodic PAOS 的特点是 主要是缓慢的、韵律分段的语音（以前分别称为类型 1 和类型 2； 第三种类型的特点是语音和韵律特征的相对平等的组合）。小的 了解这些 PAOS 类型；然而，试点数据表明生物学和临床上有意义的差异 PAOS 类型之间。具体来说，Phonetic PAOS 似乎与新皮质退化有关，而 韵律 PAOS 似乎更多是皮质下和脑干介导的。病理基础可能 不同 PAOS 类型也有所不同。有一些证据表明 PAOS 与韵律相关，而不是语音相关 随着毁灭性锥体外系综合征的发展和生存期的缩短。我们的方法 对 PAOS 类型的了解将涉及对临床、 这些患者的神经解剖学、功能、分子和组织病理学数据。到 R01 结束时，我们 期望收集和分析临床数据 - 包括人口统计、言语和语言（感知 和声学）、神经学和神经心理学变量——针对 80 名 PAOS 患者。这 80 人中，有 33 人 已经招募了 47 名，将通过 R01 机制招募 47 名。所有 47 名新患者都将完成 相同的体积脑 MRI 协议，这将使我们能够评估结构 MRI 上的灰质萎缩， 扩散张量成像中的白质束变性，以及无任务中的功能网络中断 功能磁共振成像。通过该 R01 机制招募的所有新患者也将完成多巴胺转运蛋白 SPECT 扫描评估纹状体多巴胺受体的完整性。所有测试将每年完成。 死后大脑检查和特定大脑区域的额外组织学分析也将进行 对预计在 R01 期间死亡的 PAOS 患者进行了治疗。这将是第一项研究 系统地研究 PAOS 类型，并纵向追踪病程，因此 非常新颖。此项资助的 PI Josephs 博士将与 AOS 专家团队（Duffy 博士和 Utianski）、结构神经影像学（Whitwell 博士）、功能神经影像学（Jones 博士）、分子神经影像学 （Lowe 博士）、神经心理学（Machulda 和 Butts 博士）和神经病理学（Dickson 博士）谁将工作 最先进的设施和设备，共同实现目标。 R01完成后， 我们将 1) 更好地了解 PAOS 的神经生物学，2) 验证 PAOS 的临床有效性和实用性 通过感知共识、声学关联和数据驱动分析来支持预测的类型 以及针对性治疗的开发。