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.
The proposed research will identify and validate a new magnetic resonance metabolic imaging approach that will enhance current imaging methods and help monitor Traumatic Brain Injury (TBI) progression and response to therapy in a personalized way. The developed method will serve to improve noninvasive, personalized imaging of response to current and emerging therapies, resulting in improved care and life quality for TBI patients.
|Guglielmetti, Caroline; Chou, Austin; Krukowski, Karen et al. (2017) In vivo metabolic imaging of Traumatic Brain Injury. Sci Rep 7:17525|