Feasibility of Using PET Imaging for Detection of Treatment-Induced Changes in Chronic Neuroinflammation Following TBI

摘要 本研究的目的是测试开发临床前平台用于研究TBI诱导的 慢性神经炎症，使用PET成像检测和监测炎症。此外，本发明还提供了一种方法， 这些研究将测试药物治疗（哌甲酯）上调中枢神经系统的假定功效。 去甲肾上腺素能和多巴胺能神经支配。该提案解决了一个临床问题，（慢性 神经炎症），其已知是继发性脑损伤和TBI诱导的脑损伤恶化的主要因素。 残疾。这些研究将使用已知的重量下降冲击加速度闭头TBI（chTBI）大鼠模型， 捕捉由福尔斯、交通事故、训练和运动损伤引起的TBI的显著特征 对平民和军人来说。我们以前的工作表明，该模型产生了显着的， 脑干区域是去甲肾上腺素能神经细胞和投射纤维的宿主， 多巴胺能系统这些损伤与人体中发生的峰值剪切力损伤相关。 脑干撞击加速度创伤我们假设chTBI诱导的慢性炎症持续存在， 神经炎症部分是由于这些NA和DA投射的损伤，这些投射通常起着重要的作用。 在调节大脑先天免疫系统中的作用。我们之前的工作量化了长期认知 和焦虑障碍，这些将在目前的研究中发挥重要作用，以评估安全性 MP治疗对这些行为的疗效作为TBI残疾的慢性结局指标。*FDG-18 PET MRI将用于对脑干喙部和两个功能特异性区域（海马（认知））进行成像。 杏仁核的中央核（焦虑功能）。为期三周的每日治疗将 受伤后两个月开始。PET MRI、认知和焦虑评估将进行三个月 受伤后。为确保适当的安全性指标，将使用正常、正常 治疗组、假手术组、假手术治疗组、TBI组和TBI治疗组。认知功能将使用每日四次的 在莫里斯水迷宫中进行连续学习。焦虑行为将在高架加迷宫中进行测试。 在行为研究之后，将处死动物并进行常规免疫组织化学检测。 神经炎症和小胶质细胞、去甲肾上腺素能细胞和纤维以及多巴胺能细胞和纤维的测量， 将被执行。假设：*FDG-18 PET/MRI成像将揭示慢性小胶质细胞激活模式， 将与活化的小胶质细胞的常规免疫组织化学（IHC）标记物（CD 68，IBA-4）相关， 在来自时间匹配的TBI动物的组织中的慢性神经炎症（NFkB）的伴随标志物。TBI 动物在认知和焦虑功能测试中会显示出明显的残疾。与未治疗的 在动物中，MP处理的TBI动物将显示降低的认知和焦虑障碍。较 在未处理的TBI动物中，MP处理的TBI动物将显示减少的慢性小胶质细胞活化模式， *PET/MRI成像和激活的小胶质细胞和伴随的神经炎症的IHC标记物。 意义总的来说，这些数据旨在提供伴随 *FDG-18 PET / MRI成像， 行为障碍评估，以及NA和DA的常规IHC评估，小胶质细胞增殖， 以及神经炎症标志物的表达。这些数据将提供一个机会， 测试关于TBI诱导神经炎症和MP治疗对神经炎症的影响的假设。 神经炎症、小胶质细胞增殖和TBI诱导残疾的长期结局评估。它 将为脑损伤的脑震荡模型中的慢性炎症提供急需的研究， 替补演员哌醋甲酯目前被广泛使用，这项研究可以提供重要的新的安全性数据 关于它的使用。*FDG-18 PET广泛可用，可获得，并增强了临床应用的潜力。 翻译发现。

Abstract The purpose of this study is to test the feasibility of developing a preclinical platform for the study of TBI-induced chronic neuroinflammation using PET imaging for the detection and surveillance of inflammation. In addition, these studies will test the putative efficacy of pharmacologic treatment (methylphenidate) to upregulate central noradrenergic and dopaminergic innervation. This proposal addresses a clinical problem, (chronic neuroinflammation) that is known to be a major factor in secondary brain injury and the worsening of TBI-induced disabilities. The studies will use a weight drop impact acceleration close-head TBI (chTBI) rat model that is known to capture significant features of TBIs produced by falls, vehicular accidents, training, and sports injuries common to the civilian and military population. Our previous work has shown that the model produces significant and enduring injuries to the brainstem region that hosts the cells and projection fibers of noradrenergic and dopaminergic systems. These injuries correlate with the injuries from peak shear forces that occur in the human brainstem following impact acceleration TBI. We hypothesize that the persistence of chTBI-induced chronic neuroinflammation is, in part, due to the injury of these NA and DA projections that normally play a significant role in the regulation of the brain’s innate immune system. Our previous work has quantitated long- term cognitive and anxiety disabilities, and these will serve an important purpose in the present studies to evaluate the safety and efficacy of MP treatments on these behaviors as chronic outcome measures of TBI disabilities. *FDG-18 PET MRI will be used to image the rostral brainstem and two functions-specific regions (hippocampus (cognitive function) and the central nucleus of the amygdala (anxiety function). Three weeks of daily treatments will be initiated two months following injury. PET MRI, cognitive, and anxiety assessment will be performed three months following injury. To ensure appropriate measures of safety, the studies will be performed using Normal, Normal treated, Sham, Sham treated, TBI, and TBI treated groups. Cognitive function will be assessed using four-daily sessions of serial learning in a Morris Water Maze. Anxiety behavior will be tested in an Elevated Plus Maze. Following the behavioral studies, the animals will be sacrificed and immunohistochemistry for conventional measures of neuroinflammation and microglia, noradrenergic cells and fibers, and dopaminergic cells and fibers, will be performed. Hypotheses: *FDG-18 PET/MRI imaging will reveal chronic microglial activation patterns that will correlate with conventional immunohistochemical (IHC) markers for activated microglia (CD68, IBA-4) and accompanying markers for chronic neuroinflammation (NFkB) in tissues from time-matched TBI animals. TBI animals will reveal significant disabilities in tests of cognitive and anxiety functions. Compared with untreated animals, MP-treated TBI animals will reveal decreased cognitive and anxiety disabilities. Compared with untreated TBI animals, MP-treated TBI animals will reveal decreased chronic microglial activation patterns in both *PET/MRI imaging and IHC markers for activated microglia and accompanying neuroinflammation. Significance. Collectively, these data are designed to provide companion *FDG-18 PET / MRI imaging, behavioral disability assessments, and conventional IHC assessments of NA and DA, microglial proliferation, and the expression of neuroinflammation markers. These data will provide an opportunity to comprehensively test the hypotheses regarding TBI-induction of neuroinflammation and the impact of MP treatment on neuroinflammation, microglial proliferation, and long-term outcome assessments of TBI-induced disabilities. It will provide much need research on chronic inflammation in this concussion model of brain injury which is greatly understudied. Methylphenidate is currently widely used and this study could provide important new safety data in regard to its use. *FDG-18 PET is widely available, accessible, and enhances the potential for clinical translation of findings.