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 这项研究的目的是测试开发用于研究TBI诱导的临床前平台的可行性 使用PET成像进行慢性神经炎症来检测和监测炎症。此外， 这些研究将测试药物治疗（哌醋甲酯）的假定效率上调中央 去甲肾上腺素能和多巴胺能神经。该建议解决了一个临床问题，（慢性） 神经炎症）已知是继发性脑损伤的主要因素和TBI诱导的担心 残疾。研究将使用已知的重量下降撞击加速度闭合TBI（CHTBI）大鼠模型 捕获瀑布产生的TBI的重要特征，车祸，训练和运动伤害常见 对平民和军事人口。我们以前的工作表明，该模型产生了重要的 对脑干区域的持久损伤，该区域容纳了甲肾上腺素能的细胞和投影纤维和投射纤维 多巴胺能系统。这些伤害与人类发生的峰值剪力力的伤害相关 影响加速度TBI的脑干。我们假设CHTBI引起的慢性 神经炎症的部分原因是这些NA和DA项目的受伤通常是重要的 在调节大脑先天免疫系统中的作用。我们以前的工作已经量化了长期认知 和焦虑障碍，这些将在本研究中起一个重要目的来评估安全性 MP治疗对这些行为的有效性是TBI疾病的慢性结果指标。 *FDG-18 PET MRI将用于成像鼻脑干和两个功能特异性区域（Hippocampus（认知） 功能）和杏仁核的中央核（焦虑函数）。每天三周的治疗将是 受伤后两个月开始。 PET MRI，认知和动画评估将三个月进行 受伤后。为了确保适当的安全措施，将使用正常的正常进行研究 经过处理，假，假治疗，TBI和TBI治疗组。认知功能将使用四天进行评估 莫里斯水迷宫中连续学习的会议。焦虑行为将在高高的迷宫中测试。 遵循行为研究，将牺牲动物并进行免疫组织化学 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度量， 将执行。假设： *FDG-18 PET/MRI成像将显示慢性小胶质激活模式 将与激活的小胶质细胞（CD68，IBA-4）和 参与时间匹配的TBI动物的组织中慢性神经炎症（NFKB）的标记。 TBI 动物将在认知和动画功能的测试中揭示重要的障碍。与未经处理的相比 动物，经MP处理的TBI动物将揭示认知和动画障碍的改善。与 未经治疗的TBI动物，经MP处理的TBI动物将揭示改善的慢性小胶质细胞激活模式 *PET/MRI成像和IHC标记，用于激活的小胶质细胞和参与神经炎症。 意义。总的来说，这些数据旨在提供伴侣 *FDG-18 PET / MRI成像， 行为障碍评估以及NA和DA的常规IHC评估，小胶质增殖， 以及神经炎症标记的表达。这些数据将为全面提供机会 测试有关TBI诱导神经炎症的假设以及MP治疗对 神经炎症，小胶质细胞增殖和对TBI诱发的疾病的长期结局评估。它 将在这种脑损伤的咨询模型中提供有关慢性感染的急需研究，这很棒 研究了。目前广泛使用哌醋甲酯，这项研究可以提供重要的新安全数据 *FDG-18 PET广泛可用，可访问并增强了临床的潜力 调查结果的翻译。