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

使用 PET 成像检测 TBI 后治疗引起的慢性神经炎症变化的可行性

• 批准号: 10703823
• 负责人: FLOYD J. THOMPSON
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10703823
• 关键词: Acceleration; Acute; Address; Amygdaloid structure; Animals; Anxiety; Area; Athletic Injuries; Attention deficit hyperactivity disorder; Behavior; Behavioral; Brain; Brain Concussion; Brain Injuries; Brain Stem; Catecholamines; Cd68; Cell Nucleus; Cells; Chronic; Clinic; Clinical; Cognitive; Companions; Data; Detection; Disparity; Dopamine; Dopaminergic Cell; Down-Regulation; Drops; Drug usage; Ensure; Fiber; Glial Fibrillary Acidic Protein; Glucose Transporter; Goals; Head; Heterogeneity; Hippocampus; Human; Image; Immunohistochemistry; Inflammation; Inflammatory; Injury; Innate Immune System; Interleukin-1 beta; Interruption; Investigational Therapies; Laboratories; Magnetic Resonance Imaging; Measures; Metabolic; Methods; Microglia; Military Personnel; Modeling; NF-kappa B; Non-Invasive Detection; Norepinephrine; Outcome; Outcome Assessment; Outcome Measure; Pathogenicity; Pattern; Pharmacological Treatment; Play; Positron-Emission Tomography; Process; Proliferating; Prosencephalon; Rattus; Recovery; Regulation; Rehabilitation therapy; Reporting; Research; Ritalin; Role; Safety; Secondary to; Serial Learning; Signal Transduction; Source; Stream; System; TLR4 gene; TNF gene; Testing; Therapeutic; Time; Tissues; Training; Translating; Translations; Up-Regulation; Veterans; Weight; Work; behavioral study; clinical translation; cognitive function; cognitive testing; design; detection method; disability; effective therapy; falls; feasibility testing; fiber cell; glial activation; head impact; imaging approach; imaging biomarker; imaging detection; immunohistochemical markers; inflammatory marker; magnetic resonance imaging biomarker; metabolic rate; morris water maze; nerve supply; neuroinflammation; neuron loss; noradrenergic; pharmacologic; pre-clinical; reuptake; success; vehicular accident

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.

抽象的 本研究的目的是测试开发用于研究 TBI 诱发的临床前平台的可行性 使用 PET 成像检测和监测慢性神经炎症。 这些研究将测试药物治疗（哌醋甲酯）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），这是继发性脑损伤和 TBI 引起的恶化的主要因素 这些研究将使用已知的体重下降冲击加速近头脑损伤 (chTBI) 大鼠模型。 捕捉常见的跌倒、交通事故、训练和运动损伤所产生的 TBI 的重要特征 我们之前的工作表明，该模型对平民和军人产生了显着的影响。 脑干区域遭受持久性损伤，该区域承载着去甲肾上腺素能和投射纤维的细胞和投射纤维 这些损伤与人体中发生的峰值剪切力损伤相关。 冲击加速 TBI 后的脑干，我们发现 chTBI 诱发的慢性脑干持续存在。 神经炎症的部分原因是这些 NA 和 DA 投射的损伤，这些投射通常起着重要的作用 我们之前的工作量化了长期认知能力。 和焦虑障碍，这些将在本研究中评估安全性方面发挥重要作用 MP 治疗对这些行为的疗效，作为 TBI 残疾的慢性结果衡量标准 *FDG-18。 PET MRI 将用于对脑干头端和两个特定功能区域（海马体（认知 功能）和杏仁核中央核（焦虑功能）将进行三周的每日治疗。 受伤后两个月开始进行 PET MRI、认知和焦虑评估，三个月后进行。 为了确保采取适当的安全措施，研究将使用“正常”、“正常”进行。 治疗组、假治疗组、假治疗组、TBI 组和 TBI 治疗组将使用四天评估认知功能。 莫里斯水迷宫中的连续学习课程将在高架加迷宫中进行测试。 行为研究后，将处死动物并进行常规免疫组织化学分析 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， 将进行假设：*FDG-18 PET/MRI 成像将揭示慢性小胶质细胞激活模式。 将与激活小胶质细胞的传统免疫组织化学 (IHC) 标记物（CD68、IBA-4）相关联， 时间匹配的 TBI 动物组织中慢性神经炎症 (NFkB) 的伴随标记。 与未经治疗的动物相比，它们在认知和焦虑功能测试中会表现出明显的残疾。 与动物相比，经 MP 治疗的 TBI 动物会表现出认知和焦虑障碍减少。 未经治疗的 TBI 动物、MP 治疗的 TBI 动物将显示慢性小胶质细胞激活模式减少 *PET/MRI 成像和 IHC 标记物可检测激活的小胶质细胞和伴随的神经炎症。 总的来说，这些数据旨在提供配套的*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、 这些数据将为全面分析神经炎症标记物的表达提供机会。 检验有关 TBI 诱发神经炎症的假设以及 MP 治疗对 神经炎症、小胶质细胞增殖和 TBI 引起的残疾的长期结果评估。 将为这种脑损伤脑震荡模型中的慢性炎症提供大量需要的研究，这极大地 哌醋甲酯目前被广泛使用，这项研究可以提供重要的新安全数据。 *FDG-18 PET 广泛可用、易于使用，并增强了临床潜力。 调查结果的翻译。