The Role of Brain Glial Activation in knee Ostoarthritis

 描述(申请人提供)：膝骨性关节炎(KOA)是导致疼痛和残疾的最常见原因之一，随着老年和肥胖人口的增长，其发病率持续上升。虽然大多数膝关节骨性关节炎患者报告全膝关节置换术(TKA)后疼痛减轻，功能改善，但其中约20%的患者即使在TKA后数年仍有明显的疼痛和残疾。TKA术后疼痛易感性的个体间差异的因素在很大程度上是未知的。在这个项目中，我们将测量TKA患者大脑中转位蛋白(TSPO)的水平，TSPO是一种在激活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的作用是限制神经胶质细胞介导的炎症反应的大小，从而促进损伤前状态的恢复和疼痛的恢复。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骨性关节炎患者在全膝关节置换术后没有完全愈合。我们将对110名膝关节骨性关节炎患者(术前、术后1至2周以及部分患者术后12个月)和25名健康志愿者(ONCE)进行脑部扫描。所有患者还将在全膝关节置换术后1年进行临床评估。脑扫描将使用集成的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[11C]PBR28放射性配体。与PET数据同步收集的MR数据将允许我们对PET数据执行基于MR的运动校正(这是一种显著提高PT数据保真度、敏感度和特异度的新程序)。首先，我们将检验这一假设，即手术前KOA患者将表现出比健康对照组更高的[11C]PBR28脑结合，这将是KOA相关胶质细胞激活的证据。然后，我们将评估TKA本身会导致额外增加 [11C]PBR28脑结合，这将是TKA相关胶质细胞激活的证据。我们还假设，在TKA术后1年，仍有明显疼痛和残疾的患者的[11C]PBR28结合量仍将升高，而康复患者的[11C]PBR28结合量将降至对照组的水平。最后，我们将检验这一假设，即手术前和围手术期结合[11C]PBR28将预测TKA术后1年长期疼痛的发生。特别是，考虑到TSPO的抗炎和疼痛保护作用，我们将检验这样一个假设，即术前/围手术期TSPO水平低将预测发生TKA后疼痛的可能性更高。明确神经胶质细胞在全膝关节置换术后持续性疼痛和疼痛相关功能障碍的发生和维持中的作用，将对术后疼痛的治疗和针对神经胶质细胞调节的针对性预防性干预的发展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.