Diffusion Basis Spectrum Imaging for Measurement of Neuroinflammation in Parkinson Disease

项目总结/摘要 帕金森病（PD）是一种与年龄相关的神经退行性疾病，影响了大量的美国退伍军人 引起明显的运动症状，如运动缓慢和震颤，以及非运动症状 例如认知能力下降和痴呆症。开发减缓PD进展的疗法需要经过验证 预测疾病进展的病理过程的生物标志物。大脑的炎症反应 被认为是PD病理学的重要来源，PD中神经炎症的成像生物标志物是 needed.一种新的磁共振成像（MRI）技术，扩散基频谱成像（DBSI）， 对大脑微观结构的混合变化敏感，并有能力测量 组织体积内的炎性细胞，并将该组分与神经退行性病理学区分开来 或解剖变异。DBSI MRI最近被证明可以量化多发性硬化症的神经炎症 和老年痴呆症在这里，我们将在PD中开发和验证此措施。我们将决定如何 神经炎症的DBSI测量与已收集的 死前MRI数据与来自PD患者的相应死后固定脑组织（目的1）。 因此，在PD和对照参与者中，我们将比较DBSI测量与正电子发射 神经炎症的断层扫描（PET）标记物PBR28（Aim 2）以及血液中T细胞的活化谱 和脑脊液（目标3）。我们将把横截面和纵向DBSI测量与临床 运动和认知疾病进展的特征（目标4）。通过这种方式，我们将建立一个强大的 对炎症的神经影像学和T细胞生物标志物变化的机制理解，以及如何 这些与PD中的运动和认知下降有关。这个项目对于识别和验证 用于预测PD进展的神经炎症生物标志物、试验患者分层和评价 针对帕金森病免疫系统的新疗法。因为DBSI MRI只需要 食品和药物管理局已经批准并可用于现有的临床MRI扫描仪， 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.