Diffusion Basis Spectrum Imaging for Measurement of Neuroinflammation in Parkinson Disease

项目摘要/摘要 帕金森病(PD)是一种与年龄相关的神经退行性疾病，影响着大量美国退伍军人 这会导致明显的运动症状，如运动缓慢和震颤，以及非运动症状 比如认知能力下降和痴呆症。延缓帕金森病进展的治疗方法的开发需要验证 预测疾病进展的病理过程的生物标记物。大脑的炎症反应越来越多 被认为是帕金森病的重要病理来源，帕金森病患者神经炎症的影像生物标志物 需要的。提出了一种新的磁共振成像技术--扩散基谱成像 对大脑微结构的混合变化敏感，并有能力测量 大量组织中的炎性细胞，并将该成分与神经退行性病变区分开来 或解剖变异。DBSI核磁共振成像最近被证明可以量化多发性硬化症的神经炎症 和阿尔茨海默氏症。在这里，我们将在PD中开发和验证这一措施。我们将决定如何 已经收集的神经炎症的DBSI测量与定量免疫组织化学的比较 帕金森病患者的生前MRI数据和相应的死后固定脑组织(目标1)。 前瞻性地，在PD和对照组参与者中，我们将比较DBSI措施和正电子发射 神经炎症的断层扫描(PET)标志物PBR28(AIM 2)和血液中T细胞的激活谱 和脑脊液(目标3)。我们将横断面和纵向DBSI测量与临床相关联 运动和认知疾病进展的特征(目标4)。通过这种方式，我们将发展出强大的 从机制上理解炎症的神经影像和T细胞生物标记物的变化，以及如何 这些都与帕金森病患者的运动和认知能力下降有关。该项目对识别和验证具有很大的前景 神经炎生物标志物用于预测帕金森病进展、患者分层试验和评估 针对帕金森病患者免疫系统的新疗法。因为DBSI MRI只需要符合以下条件的序列 已经得到食品和药物管理局的批准，并在现有的临床核磁共振扫描仪上使用，它可能是 迅速扩展到临床应用和临床试验。

Project Summary/Abstract Parkinson disease (PD) is an age-related neurodegenerative disease affecting a large number of U.S. veterans that causes significant motor symptoms such as slow movement and tremor, as well as non-motor symptoms such as cognitive decline and dementia. Development of therapies to slow PD progression requires validated biomarkers of pathologic processes that predict progression. The brain’s inflammatory response is increasingly recognized as an important source of pathology in PD, and imaging biomarkers of neuroinflammation in PD are needed. A novel Magnetic Resonance Imaging (MRI) technique, Diffusion Basis Spectrum Imaging (DBSI), is sensitive to intermingled changes in brain microstructure, and has the capacity to measure the component of inflammatory cells within a volume of tissue, and distinguish this component from neurodegenerative pathology or anatomic variation. DBSI MRI has been recently shown to quantify neuroinflammation in multiple sclerosis and Alzheimer’s disease. Here, we will develop and validate this measure in PD. We will determine how the DBSI measure of neuroinflammation compares to quantitative immunohistochemistry in already-collected antemortem MRI data with corresponding postmortem fixed brain tissues from people with PD (Aim 1). Prospectively, in PD and control participants we will compare DBSI measures to the positron emission tomography (PET) marker of neuroinflammation, PBR28 (Aim 2), and to the activation profile of T cells in blood and cerebrospinal fluid (Aim 3). We will correlate cross-sectional and longitudinal DBSI measures with clinical features of motor and cognitive disease progression (Aim 4). In this manner, we will develop a strong mechanistic understanding of changes in both neuroimaging and T cell biomarkers of inflammation, and how these relate to motor and cognitive decline in PD. This project holds great promise for identifying and validating biomarkers of neuroinflammation for prediction of PD progression, patient stratification for trials, and evaluation of new treatments targeting the immune system in PD. Because DBSI MRI only requires sequences that are already Food and Drug Administration approved and available on existing clinical MRI scanners, it could be quickly scaled to clinical applications and clinical trials.