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

项目总结 非流利/无语法变异的原发性进行性失语(NfvPPA)是一种神经退行性疾病 由失语性失语症和/或言语失用症的存在定义，通常由4- 重复推拿疗法。在R01的前两个周期中，我们使用神经成像来表征这些模式 神经退行性变以及与nfvPPA相关的连接结构和功能崩溃。 然而，关于这些大脑变化如何与潜在的生物学相关或由其驱动，我们知之甚少。 流程。与nfvPPA相关的两个重要生物学机制是tau蛋白的沉积和 神经炎。在R01的第二个周期中，我们使用PET评估了tau在体内的沉积。在第三个周期 我们将重点评估神经炎症和其他生物过程的作用。第一个目标 这项资助的目的是用PET成像来表征大脑中神经炎症的模式 生成配体11C-ER176，并确定神经炎症是否随时间变化并与 与临床疾病严重程度有关。第二个目标是确定病理过程的生物标志物 从血浆中测量，包括神经丝轻链、血浆胶质纤维酸性蛋白、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会发生变化 并与临床疾病的严重程度相关。这前两个目标将决定是否 神经炎症PET和血浆生物标记物是nfvPPA有用的疾病生物标记物，我们将 确定这些指标是否可以作为未来临床下降的有用的预后标志物。我们的第三个 目标是在前两个周期中获得的知识基础上，确定结构和功能如何 使用结构磁共振成像、扩散束成像和静息功能磁共振成像测量的大脑异常是 与神经炎、PET和血浆生物标记物有关。这一目标将有助于在多大程度上模拟 这些生物过程与大脑结构和功能的其他更确定的故障有关。至 为了达到这些目标，我们将招募50名nfvPPA患者，每个参与者将经历三个系列 每隔一年评估一次。在每一次评估中，患者都将进行神经和语言方面的检查 评估，11C-ER176神经炎症PET和3T磁共振成像扫描，将包括 静息状态功能磁共振成像和扩散张量成像序列。将从所有人身上采集血液样本 患者在两次探视中。在R01的第二个周期中也采集了血液样本，因此血浆 将对100例nfvPPA患者进行生物标志物检测。我们还将招募50名认知正常的健康对照 他将接受相同的神经成像，并提供血样。此次续签具有重要意义，因为 所获得的结果将对理解nfvPPA的生物学和疾病传播机制至关重要。 此外，这项工作还有助于为nfvPPA提供潜在的机械性治疗靶点，并建立 NfvPPA患者预后和未来研究和临床试验的疾病生物标志物。

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.