Longitudinal multi-modality imaging in non-fluent/agrammatic primary progressive aphasia

不流利/语法障碍的原发性进行性失语症的纵向多模态成像

• 批准号: 10665296
• 负责人: Jennifer Louise Whitwell
• 金额: $ 69.94万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10665296
• 关键词: Address; Aphasia; Apraxias; Area; Atrophic; Autopsy; Biological; Biological Markers; Biological Process; Biology; Blood specimen; Brain; Broca' s area; Chitinase; Clinical; Clinical Trials; Cognitive; Data; Deposition; Diffusion; Diffusion Magnetic Resonance Imaging; Disease; Disease Progression; Functional Magnetic Resonance Imaging; Future; Generations; Glial Fibrillary Acidic Protein; Grant; Inflammation; Injury; Knowledge; Language; Ligand Binding; Ligands; Light; MRI Scans; Magnetic Resonance Imaging; Measures; Mediating; Modeling; Motor; Motor Cortex; Multimodal Imaging; Nerve Degeneration; Neurodegenerative Disorders; Neurologic; Participant; Pathologic Processes; Patients; Pattern; Plasma; Play; Positron-Emission Tomography; Primary Progressive Aphasia; Process Measure; Prognostic Marker; Proteins; Rest; Role; Severities; Severity of illness; Signal Transduction; Speech; Structure; Tauopathies; Techniques; Time; Variant; Visit; Work; astrogliosis; blood-based biomarker; brain abnormalities; comparison control; improved; in vivo; inflammatory marker; multimodality; neurofilament; neuroimaging; neuroinflammation; novel; prognosis biomarker; recruit; research study; tau Proteins; tau aggregation; tractography; uptake; white matter

PROJECT SUMMARY The non-fluent/agrammatic variant of primary progressive aphasia (nfvPPA) is a neurodegenerative disorder defined by the presence of agrammatic aphasia and/or apraxia of speech that commonly results from a 4- repeat tauopathy. During the previous 2 cycles of the R01 we used neuroimaging to characterize the patterns of neurodegeneration and structural and functional breakdowns in connectivity associated with nfvPPA. However, little is known about how these brain changes are related to, or driven by, underlying biological processes. Two important biological mechanisms relevant to nfvPPA are deposition of the protein tau and neuroinflammation. In the 2nd cycle of the R01 we assessed tau deposition in vivo using PET. In the 3rd cycle we will focus on assessing the role of neuroinflammation and other biological processes. The first aim of the grant is to characterize the patterns of neuroinflammation in the brain using PET imaging with the 3rd generation ligand 11C-ER176 and determine whether neuroinflammation changes over time and is associated with clinical disease severity. The second aim is to determine whether biomarkers of pathological processes measured from blood plasma, including neurofilament light chain, plasma glial fibrillary acidic protein, tau, and inflammation biomarkers, are abnormal in nfvPPA. We will also assess whether these biomarkers change over time and are associated with clinical disease severity. These first two aims will determine whether neuroinflammation PET and blood plasma biomarkers are useful disease biomarkers in nfvPPA, and we will determine whether these measures could be useful prognostic markers of future clinical decline. Our third objective is to build upon knowledge gained from the first 2 cycles and determine how structural and functional abnormalities in the brain, measured using structural MRI, diffusion tractography and resting state fMRI, are related to neuroinflammation PET and blood plasma biomarkers. This aim will help model the degree to which these biological processes relate to other more established breakdowns in brain structure and function. To accomplish these aims we will recruit 50 patients with nfvPPA, and each participant will undergo three serial assessments one year apart. At each assessment, patients will have a neurological and speech-language assessment, 11C-ER176 neuroinflammation PET and a 3T magnetic resonance imaging scan that will include resting-state functional MRI and diffusion tensor imaging sequences. A blood sample will be collected from all patients at both visits. Blood samples were also collected in the 2nd cycle of the R01 and hence blood plasma biomarkers will be measured in 100 nfvPPA patients. We will also recruit 50 cognitively normal healthy controls who will undergo identical neuroimaging and provide a blood sample. This renewal is highly significant as results gained will be critical to understand the biology of nfvPPA and mechanisms of disease spread. Furthermore, this work may also help provide potential mechanistic treatment targets for nfvPPA and establish disease biomarkers for prognosis and for future research studies and clinical trials in patients with nfvPPA.

项目摘要 主要进行性失语症（NFVPPA）的非氟/农业变体是神经退行性疾病 由语言失语症和/或语言的存在定义，通常是由4-造成的 重复tauopathy。在R01的前两个循环中，我们使用神经影像来表征图案 与NFVPPA相关的连通性中的神经变性以及结构和功能分解的。 但是，对于这些大脑变化与潜在生物学的关系或驱动的方式知之甚少 过程。与NFVPPA相关的两种重要生物学机制是蛋白质tau的沉积和 神经炎症。在R01的第二个周期中，我们使用PET评估了Tau在体内的沉积。在第三周期 我们将专注于评估神经炎症和其他生物学过程的作用。第一个目标 赠款的是用第三次使用PET成像来表征大脑中神经炎症的模式 一代配体11C-ER176并确定神经炎症是否随着时间而变化，并且与之相关 患有临床疾病的严重程度。第二个目的是确定病理过程的生物标志物是否 从血浆中测量的，包括神经丝轻链，血浆神经胶质原纤维酸性蛋白，tau和 炎症生物标志物在NFVPPA中异常。我们还将评估这些生物标志物是否改变 时间并与临床疾病严重程度有关。前两个目标将决定是否 神经炎症宠物和血浆生物标志物是NFVPPA中有用的疾病生物标志物，我们将 确定这些措施是否可能是未来临床下降的有用预后标志物。我们的第三个 目的是建立在前两个周期中获得的知识，并确定结构和功能 使用结构MRI，扩散片段和静止状态fMRI测量的大脑异常是 与神经炎症宠物和血浆生物标志物有关。这个目标将有助于建模 这些生物学过程与大脑结构和功能中其他更确定的细分有关。到 完成这些目标，我们将招募50名NFVPPA患者，每个参与者将经历三个系列 评估相距一年。在每个评估中，患者将具有神经系统和语音语言 评估，11C-ER176神经炎症宠物和3T磁共振成像扫描将包括 静止状态功能性MRI和扩散张量成像序列。将收集所有的血液样本 两次访问的患者。还在R01的第二周期中收集了血液样本，因此还收集了血浆 生物标志物将在100名NFVPPA患者中进行测量。我们还将招募50个认知正常的健康对照 谁将接受相同的神经影像学并提供血液样本。这种更新非常重要，因为 获得的结果对于了解NFVPPA的生物学和疾病传播机制至关重要。 此外，这项工作还可能有助于为NFVPPA提供潜在的机械治疗目标并建立 用于NFVPPA患者的预后以及未来研究和临床试验的疾病生物标志物。

项目成果

In Vivo Imaging and Autoradiography in a Case of Autopsy-Confirmed Pick Disease.

一例尸检确诊的皮克病病例的体内成像和放射自显影。

• DOI: 10.1212/cpj.0000000000000755
• 发表时间: 2021
• 期刊: Neurology. Clinical practice
• 作者: Utianski,ReneL;Schwarz,ChristopherG;Murray,MelissaE;Tranovich,JessicaF;Scott,NancyE;Lowe,ValJ;Whitwell,JenniferL;Josephs,KeithA
• 通讯作者: Josephs,KeithA

Assessing Change in Communication Limitations in Primary Progressive Apraxia of Speech and Aphasia: A 1-Year Follow-Up Study.

评估原发性进行性言语失用和失语症的沟通限制变化：一项为期一年的随访研究。

• DOI: 10.1044/2021_ajslp-20-00402
• 发表时间: 2021
• 期刊: American journal of speech-language pathology
• 影响因子: 2.6
• 作者: Utianski,ReneL;Martin,PeterR;Duffy,JosephR;Botha,Hugo;Clark,HeatherM;Josephs,KeithA
• 通讯作者: Josephs,KeithA

Diffusion tensor imaging-based multi-fiber tracking reconstructions can regionally differentiate phonetic versus prosodic subtypes of progressive apraxia of speech.

基于扩散张量成像的多纤维跟踪重建可以在区域上区分进行性言语失用的语音亚型和韵律亚型。

• DOI: 10.1016/j.cortex.2023.08.019
• 发表时间: 2024
• 期刊: Cortex; a journal devoted to the study of the nervous system and behavior
• 作者: Gatto,RodolfoG;Martin,PeterR;Utianski,ReneL;Duffy,JosephR;Clark,HeatherM;Botha,Hugo;Machulda,MaryM;Josephs,KeithA;Whitwell,JenniferL
• 通讯作者: Whitwell,JenniferL

Communication Limitations in Patients With Progressive Apraxia of Speech and Aphasia.

进行性言语失用和失语症患者的沟通限制。

• DOI: 10.1044/2020_ajslp-20-00012
• 发表时间: 2020
• 期刊: American journal of speech-language pathology
• 影响因子: 2.6
• 作者: Utianski,ReneL;Clark,HeatherM;Duffy,JosephR;Botha,Hugo;Whitwell,JenniferL;Josephs,KeithA
• 通讯作者: Josephs,KeithA

Electroencephalography in Primary Progressive Aphasia and Apraxia of Speech.

原发性进行性失语症和言语失用症的脑电图。

• DOI: 10.1080/02687038.2018.1545991
• 发表时间: 2019
• 期刊: Aphasiology
• 影响因子: 2
• 作者: Utianski,ReneL;Caviness,JohnN;Worrell,GregoryA;Duffy,JosephR;Clark,HeatherM;Machulda,MaryM;Whitwell,JenniferL;Josephs,KeithA
• 通讯作者: Josephs,KeithA