The neurobiology of two distinct types of progressive apraxia of speech

这本R01的主要目标是提高对神经生物学的理解和识别的临床效用 两种不同类型的原发进行性言语失用症(PAO)。拼音PAO的特点是 主要是通过扭曲的声音替换和添加，而韵律PAO的特点是 主要是通过缓慢、韵律分段的语音(以前分别称为类型1和类型2；a 第三类的特征是语音和韵律特征的相对相等的组合)。一点儿 已知这些PAO类型；然而，试点数据表明生物学和临床上有意义的差异 在PAO类型之间。具体地说，语音PAO似乎与新皮质的退化有关，而 韵律PAO似乎更多地是皮质下和脑干介导的。病理性基础可能 不同的PAO类型也有所不同。有一些证据表明，韵律的，而不是语音的，与PAO有关 随着毁灭性的锥体外系综合征的发展和生存时间的缩短。我们的方法是 对PAOS类型的理解将涉及对临床、 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 预期已收集和分析临床数据--包括人口统计、语言和语言(知觉 以及声学)、神经学和神经心理学变量--针对80名PAOS患者。在这80人中，有33人拥有 已经征聘了47人，将通过这一R01机制征聘47人。所有47名新患者将完成 相同的体积脑MRI方案，使我们能够在结构MRI上评估灰质萎缩， 扩散张量成像上白质束变性，无任务时功能网络破坏 功能磁共振成像。所有通过R01机制招募的新患者也将完成多巴胺转运体 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一次。 还将对特定脑区进行尸检和额外的组织学分析 对预计将在今年R01期间死亡的PAO患者进行了检查。这将是第一项研究 系统地研究PAO的类型，以及纵向跟踪疾病的过程，因此 非常新奇。这笔赠款的PI Josephs博士将与一个AOS专家团队(Dr.Duffy和 结构神经成像(惠特韦尔博士)、功能神经成像(琼斯博士)、分子神经成像 (洛威博士)，神经心理学(马库尔达博士和巴茨博士)，和神经病理学(迪克森博士)，谁将工作 跻身于最先进的设施和设备之中，共同达到目标。在R01完工时， 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支持预测的类型 以及靶向治疗的发展。

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.