The Role of Brain Glial Activation in knee Ostoarthritis

 描述（由申请人提供）：膝关节骨关节炎（KOA）是疼痛和残疾的最常见原因之一，随着老年人和肥胖人群的增长，其发病率持续增加。虽然大多数KOA患者报告在全膝关节置换术（TKA）后疼痛减轻和功能改善，但其中约20%的患者甚至在TKA后数年仍持续经历显著的疼痛和残疾。TKA术后疼痛易感性个体间差异的潜在因素在很大程度上是未知的。在这个项目中，我们将测量接受TKA的患者大脑中转运蛋白（TSPO）的水平，TSPO是一种在活化的胶质细胞中上调的蛋白质，并评估TSPO在TKA后疼痛中的作用。TSPO的功能是限制神经胶质介导的炎症反应的程度，从而促进恢复到损伤前状态和从疼痛中恢复。因此，TSPO表达的个体间差异可能解释了为什么一小部分但相当大比例的OA患者在TKA后不能完全愈合。我们将对110名KOA患者（术前、TKA后1-2周，以及TKA后12个月的患者子集）和25名健康志愿者（一次）进行脑部扫描。所有患者还将在TKA术后1年接受临床评价。将使用集成正电子发射断层扫描/磁共振（PET/MR）成像和最近开发的与TSPO结合的[11 C] PBR 28放射性配体进行脑部扫描。与PET数据同时收集的MR数据将允许我们对PET数据执行基于MR的运动校正（一种显著提高PT数据的保真度、灵敏度和特异性的新程序）。首先，我们将检验术前KOA患者的[11 C] PBR 28脑结合率高于健康对照的假设，这将是KOA相关神经胶质激活的证据。然后，我们将评估TKA本身导致额外增加的假设。 [11 C] PBR 28脑结合，这将是TKA相关神经胶质激活的证据。我们还假设，在TKA术后1年，[11 C] PBR 28结合在仍经历显著疼痛和残疾的患者中仍将升高，而在康复患者中将降低至对照受试者的水平。最后，我们将检验以下假设：术前和围手术期[11 C] PBR 28结合可预测TKA术后1年长期术后疼痛的发生。特别是，考虑到TSPO的抗炎和疼痛保护作用，我们将检验以下假设：术前/围手术期TSPO水平低将预测发生TKA术后疼痛的可能性较高。 识别胶质细胞及其调节在TKA后持续性疼痛和疼痛相关残疾的发展和维持中的作用，将对术后疼痛的管理以及开发专注于胶质细胞调节的量身定制的预防性干预措施具有重要的实际意义。

 DESCRIPTION (provided by applicant): Knee osteoarthritis (KOA) is one of the most prevalent causes of pain and disability, and its incidence continues to increase as the elderly and obese populations grow. While most KOA patients report reduced pain and improved function after Total Knee Arthroplasty (TKA), approximately 20% of them continue to experience significant pain and disability even years post-TKA. The factors underlying inter-individual differences in susceptibility to post-TKA pain are largely unknown. In this project, we will measure levels of the translocator protein (TSPO), a protein upregulated in activated glia, in the brains of patients undergoing TKA and evaluate TSPO's role in post-TKA pain. TSPO functions to limit the magnitude of glia-mediated inflammatory responses, thereby promoting the return to pre-injury status and recovery from pain. Thus, interindividual differences in TSPO expression may explain why a small but substantial percentage of OA patients do not fully heal following TKA. We will perform brain scans in 110 KOA patients (pre-surgically, 1-to-2 weeks post-TKA and, in a subset of patients also 12 months post-TKA), and in 25 healthy volunteers (once). All patients will be also evaluated clinically 1 year post-TKA. Brain scans will be performed using integrated Positron Emission Tomography / Magnetic Resonance (PET/MR) imaging and the recently developed [11C]PBR28 radioligand, which binds to TSPO. MR data collected simultaneously to PET data will allow us to perform an MR-based motion correction of the PET data (a novel procedure that significantly improves the fidelity, sensitivity, and specificity of PT data). First, we will test the hypothesis that pre-surgically KOA patients will demonstrate higher [11C]PBR28 brain binding than healthy controls, which will be evidence of KOA-related glial activation. Then we will evaluate the hypothesis that TKA itself leads to an additional increase of [11C]PBR28 brain binding, which will be evidence of TKA-related glial activation. We also hypothesize that at 1-year post-TKA, [11C]PBR28 binding will still be elevated in patients still experiencing significant pain and disability, whereas it will be reduced to the levels of the contrl subjects in recovered patients. Finally, we will test the hypothesis that [11C]PBR28 binding pre- and peri-surgically will predict occurrence of long-term postsurgical pain 1 year after TKA. In particular, given the proposed anti-inflammatory and pain-protective role of TSPO, we will test the hypothesis that low pre-surgical / peri-surgical TSPO levels will predict higher likelihood of developing post-TKA pain. The identification of a role of glia and its modulation in the development and maintenance of persistent pain and pain-related disability following TKA will have important practical implications for the management of post-operative pain, and the development of tailored preventive interventions focused on glial modulation.