In vivo metabolic imaging of neuroinflammation after TBI

 描述（由申请人提供）：创伤性脑损伤（TBI）是多种神经退行性疾病（包括阿尔茨海默病（AD）和痴呆）发展的主要风险因素。TBI后最显著的反应之一是诱导与神经炎症相关的多种信号传导介质，这始终归因于先天免疫系统的激活。TBI诱导的单核吞噬细胞（小胶质细胞/巨噬细胞，MP）的慢性激活已被证明在人类和动物模型中的初始损伤后持续多年。活化的MP是脑中炎症过程的关键效应物，可以在TBI的病理生理学中发挥双重和决定性的作用，促进炎症（M1-极化）或诱导修复（M2-极化）。多项研究表明，MP经历代谢重编程，其极化状态截然不同。类似于在肿瘤细胞中观察到的瓦尔堡效应，M1极化的MP增加乳酸释放，而M2极化的MP主要利用氧化代谢。更确切地说，最近的证据表明，丙酮酸代谢是一个关键的球员在差异激活的MP。 我们发表的数据表明，在TBI后的急性，亚急性和慢性时间点，M1先于M2反应的强烈和永久诱导。我们证明，改变这种反应可以挽救长期的认知缺陷。因此，体内M1/M2巨噬细胞的非侵入性评估对于靶向TBI依赖性认知缺陷的治疗策略的开发和验证将是重要的。然而，迄今为止，没有非放射性成像技术可以直接无创地评估神经炎症，更不用说区分M1和M2巨噬细胞。 为了解决这个具体问题，本研究的目标是验证，据我们所知，第一次在TBI，一种新的技术，即超极化（HP）[1- 13 C]丙酮酸的13 C磁共振光谱成像，以监测M1/M2神经炎症在体内的大脑。 目的1：应用HPpyruvate的13 C MRSI无创检测脑外伤后MPs的极化状态。我们将验证HP [1- 13 C]丙酮酸盐的13 C MRSI作为一种方法，用于在啮齿动物轻度/中度和中度TBI后的急性、亚急性和慢性时间点非侵入性地确定体内MP极化状态。 目标二：评估体内代谢成像以监测对M1/M2极化修饰治疗的反应：我们将使用我们的代谢成像方法监测对影响M1/M2极化和挽救长期认知结果的临床相关治疗的反应。 该项目将验证一种新的强大的和临床上可翻译的代谢成像方法，允许无创评估MP激活和对TBI治疗的反应。此外，在临床转化后，该提案中开发的方法可以改善TBI进展的诊断和预后，帮助完善治疗方案，并最终导致更好的临床结果和患者生活质量。

 DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is a major risk factor for the development of multiple neurodegenerative diseases, including Alzheimer's disease (AD) and dementia. One of the most pronounced responses following TBI is the induction of multiple signaling mediators associated with neuroinflammation, consistently attributed to the activation of the innate immune system. TBI-induced chronic activation of mononuclear phagocytes (microglia/macrophages, MPs) has been shown to persist for many years following the initial insult in humans and animal models. Activated MPs, the key effectors of inflammatory processes in the brain, can play a dual and decisive role in the pathophysiology of TBI, promoting inflammation (M1-polarized) or inducing repair (M2- polarized). Multiple studies have shown that MPs undergo metabolic reprogramming that differs drastically upon their polarization status. Similar to the Warburg effect observed in tumor cells, M1-polarized MPs increase lactate release, whereas M2-polarized MPs mainly employ oxidative metabolism. More precisely, recent evidences suggest that pyruvate metabolism is a key player in the differential activation of MPs. Our published data demonstrate a strong and permanent induction of the M1 preceded M2 response at acute, sub-acute and chronic time points after TBI. We demonstrated that modifying this response can rescue long term cognitive deficits. Therefore, non-invasive assessment of M1/M2 macrophages in vivo would be important for the development and validation of treatment strategies targeting TBI-dependent cognitive deficits. However, to date, no non-radioactive imaging technique can non-invasively assess neuroinflammation directly, even less distinguish between M1 and M2 macrophages. To solve this specific problem, the goal of this study is to validate, to our knowledge for the first time in TBI, a new technique, namely 13C Magnetic Resonance Spectroscopic Imaging of hyperpolarized (HP) [1-13C] pyruvate, to monitor M1/M2 neuroinflammation in vivo in the brain. Aim 1: Validate 13C MRSI of HP pyruvate to non-invasively measure MPs polarization status in vivo after TBI. We will validate 13C MRSI of HP [1-13C] pyruvate as a method to non-invasively determine MPs polarization status in vivo at acute, sub acute and chronic time points after mild/moderate and moderate TBI in rodents. Aim 2: Evaluate in vivo metabolic imaging to monitor response to an M1/M2 polarization modifying therapy: We will use our metabolic imaging approach to monitor response to a clinically relevant therapy that affect M1/M2 polarization and rescue long term cognitive outcome. This project will validate a new robust and clinically translatable metabolic imaging approach allowing for non-invasive assessment of MPs activation and response to therapy in TBI. Additionally, upon clinical translation, the method developed in this proposal could improve diagnosis and prognosis for TBI progression, help refine therapeutic regimens and, ultimately, lead to better clinical outcome and patient quality of life.