Can Metabolic Imaging of Inflammatory Brain Disorders Aid Diagnosis and Prognosis?

Lay Summary

Can metabolic imaging of inflammatory brain disorders aid diagnosis and prognosis?

A new type of molecular imaging being used in cancer diagnosis and treatment evaluation also may be applicable to early diagnosis and therapeutic assessment in inflammatory degenerative brain disorders such as traumatic brain injury (TBI), multiple sclerosis (MS) and Alzheimer’s disease (AD). Since inflammation initiates or contributes to disease processes before symptoms are apparent, molecular imaging that has the potential to identify early brain inflammation holds promise for identifying neurodegeneration before too much damage has been done. The molecular imaging also holds promise for determining whether treatments to halt neurodegeneration are working. The investigators will validate accuracy of this new molecular imaging method, called “hyperpolarized (HP) 13C Magnetic Resonance spectroscopic metabolic imaging,” in animal models of TBI and MS.

The molecular imaging method works by following the actions of two types of immune “macrophages” called ‘M1” and “M2” that reside in the brain. When activated, M1 macrophages release chemicals that initiate inflammatory processes and recruit immune T cells to the brain to attack the inflamed tissue. In contrast, activated M2 macrophages release a chemical that acts to reduce T cell activity in the brain and to promote brain tissue repair. The investigators hypothesize that the metabolic imaging technique can detect the status of each type of macrophage in mouse models of TBI and MS, and by doing so can monitor each disorder’s progression and response to clinically used therapies. Successful animal studies would lead to human clinical testing following the grant period.

Significance: This new molecular imaging method has the potential to improve the diagnoses of neuroinflammatory diseases, to monitor their progression and responses to therapy, and ultimately to lead to better clinical outcomes.

Abstract

Can metabolic imaging of inflammatory brain disorders aid diagnosis and prognosis?

HYPOTHESIS: Hyperpolarized 13C Magnetic Resonance Spectroscopic Imaging (HP 13C MRSI), a metabolic imaging method that has revolutionized the field of cancer, can detect inflammation in neurological diseases, thus improving monitoring of early progression and therapy response. AIMS: Neuroinflammation is linked to early pathogenesis in most neurodegenerative diseases. Imaging methods capable of detecting neuroinflammatory processes in vivo are thus critically needed. Such methods would provide surrogate measures of early disease existence and progression, and could improve patient management, prediction of outcome and individualized therapeutic approaches. Activated mononuclear phagocytes (MPs, macrophages/microglia) are often the most abundant immune cells in the brain parenchyma, driving neuroinflammation. Activated MPs can present a classical M1 pro-inflammatory or an alternative M2-polarized neuroprotective phenotype, with multiple shades of activation in between. From a metabolic perspective, reports have shown that, upon activation, MPs undergo a fundamental metabolic reprogramming. Similar to the Warburg effect observed in tumor cells, activated M1/M2 MPs increase glycolysis and lactate release. Furthermore, M2-polarized MPs excrete high levels of arginase, an enzyme that, by converting arginine to urea, inhibits T cells function through depletion of the arginine pool. Altogether, these considerations are of utmost importance as they open the door to using metabolic imaging to monitor neuroinflammation. HP 13C MRSI is a safe method that detects metabolic reactions in vivo post injection of HP probes. Over the last decade, HP 13C MRSI has revolutionized the field of diagnostic oncology and detected early metabolic alterations in preclinical and clinical cancer studies. However, to date, this approach has never been applied to neurological disorders. Here, we propose to validate HP 13C MRSI for detection and monitoring of neuroinflammatory processes in vivo for the first time using two HP probes: HP [6-13C, 6-15N3]-arginine, a unique and new probe; and HP [1-13C] pyruvate, the most clinically translatable probe to date. Models of Traumatic Brain Injury (TBI) and Multiple Sclerosis (MS) will be used for validation, but it is important to note that this method could be applied to any neurological disease presenting an inflammatory component. Aim 1. Detect neuroprotective M2 MPs using in vivo 13C MRSI of HP arginine. Given the fact that only M2 neuroprotective MPs express arginase, we hypothesize that conversion of HP [6-13C, 6-15N3]-arginine, the arginase substrate, to HP urea can be used to specifically detect M2 MPs in vivo in MS and TBI models. Aim 1. Validate 13C MRSI of HP pyruvate as an imaging method to monitor activated MPs in vivo. Because lactate levels increase upon MPs activation through PDK1 upregulation, we hypothesize that this imaging method can detect activated MPs through increased HP lactate production in models of MS and TBI. Aim 3. Evaluate in vivo MR metabolic imaging to monitor response to therapies. We will combine 13C MRSI of HP [1-13C] pyruvate and HP [6-13C, 6-15N3]-arginine and hypothesize that this multiprobe metabolic imaging approach will improve monitoring of response to therapy in preclinical models of MS and TBI. METHODS: We will first validate a unique MR metabolic neuroimaging method, namely 13C MRSI of HP [6-13C, 6-15N3] arginine, to detect MPs M2 polarization through detection of HP arginine to urea (Aim 1). We will also validate 13C MRSI of HP [1-13C] pyruvate, a clinically available probe, to monitor MPs activation through monitoring of HP pyruvate to lactate conversion (Aim 2). MR acquisitions will be performed on a mouse-dedicated 3 Tesla Biospec system equipped with powerful imaging gradients (Bruker) and a dedicated brain 1H/13C coil. Note that the use of a clinically-relevant field of 3 Tesla will facilitate clinical translation of our findings. The modulation of HP urea and HP lactate levels with disease progression will be evaluated in well-characterized models of two highly prevalent disorders, namely the cuprizone (CPZ) induced model (±IL-13) for Multiple Sclerosis (MS) and the Controlled Cortical Impact (CCI) model for Traumatic Brain Injury (TBI). Both models have well characterized M1/M2 pathogenesis. Animals will be imaged longitudinally (Weeks W0/4/6/12 CPZ, 0/24h/7/28days TBI). The HP methods will then be used to evaluate response to two therapies that have an effect on outcome and MPs metabolism, i.e. dimethylfumarate DMF (MS) and Scriptaid (TBI) (Aim 3). Throughout the aims, comparison of the metabolic imaging approaches with established MR methods will be performed to establish the specificity, sensitivity and diagnostic/monitoring accuracy of our approaches. Biochemical assays and immunofluorescence (IF) staining will be performed to validate the metabolic mechanisms and the localization of the signal.