Symposium



Hyperpolarized 13C MRSI can detect neuroinflammation in vivo in a Multiple Sclerosis murine model


Presenting Author Senior Author
Name: Caroline Guglielmetti Name: Myriam Chaumeil
Email: caroline.guglielmetti@ucsf.edu Email: myriam.chaumeil@ucsf.edu
Presenting Author’s RIG/SRG: Neurodegenerative Diseases MRI/MRS  
Presenting Author's Lab Location: Mission Bay   

Abstract Information
Imaging Modality: MR
Disease Application: Neurodegenerative Diseases Multiple sclerosis
Complete author list: Caroline Guglielmetti, Chloe Najac, Annemie Van der Linden, Sabrina M. Ronen, Myriam M. Chaumeil
Abstract highlights: This study demonstrates that 13C MRS of hyperpolarized pyruvate can be used to detect increased lactate production from pro-inflammatory macrophages, mechanism mediated by PDK1 upregulation, in a preclinical model of Multiple Sclerosis, hence providing a novel tool for in-vivo detection of neuroinflammation.
 
Introduction
Activated mononuclear phagocytes (MPs, macrophages/microglia) are key players in the progression of Multiple Sclerosis (MS). Interestingly, recent evidences show that, upon activation, MPs undergo metabolic reprogramming, more precisely increase their glycolysis and lactate production1,2. Looking at MPs activation from the metabolic perspective of metabolism, an emerging field dubbed immunometabolism, opens the door to innovative approaches to image neuroinflammation. In this context, the goal of this study was to validate hyperpolarized 13C Magnetic Resonance Spectroscopic Imaging (HP 13C MRSI) of pyruvate, a non-invasive safe imaging approach3, to assess increased glycolysis linked to MPs activation during MS progression in the toxin-induced cuprizone (CPZ) mouse model for MS4.
 
Methods
C57BL/6J mice (n=5) received a 0.2% CPZ diet for 6 weeks to induce demyelination and inflammation. Mice were imaged prior (W0) and after 4 and 6 weeks of CPZ (W4 CPZ, W6 CPZ). T2-weighted images were acquired (TE/TR=20/1200ms, thickness=0.5mm, NA=2, matrix= 256x256, FOV=30x30mm²). For 13C MRS, 24μL of [1-13C] pyruvate preparation was hyperpolarized for one hour3. After dissolution, HP pyruvate was injected iv over 12sec and 2D dynamic CSI 13C data were acquired on a 14.1T MR system using: TE/TR=1.2/60ms; SW 2500Hz; 128 points; 4 sec resolution; FA 10deg; FOV 24x24; 5mm thickness. HP lactate and HP pyruvate levels were calculated as the sum of integrals over time (Fig.A). Inflammation was assessed by immunofluorescence (IF) against MPs (Iba1), and pyruvate dehydrogenase kinase 1 (PDK1).
 
Results
At W4 CPZ, HP lactate produced from HP pyruvate was largely increased in the corpus callosum (CC) region, as seen on the HP 13C spectra and heatmaps (B). IF confirmed that this increase was associated with a massive influx of MPs and upregulation of PDK1 in the CC. In contrast, at W6 CPZ, HP lactate levels decreased, in line with decreased MPs and decreased PDK1 as seen by IF. In all animals, the HP lactate/pyruvate ratio significantly increased by 72±29% at W4 CPZ and significantly differ from the control ratios (p=0.002; C, D), then decreased by 20±14% at W6 CPZ (C, E), in line with the IF, while the control ratios (C) remained stable.
 
Conclusions
All together, these results demonstrate that 13C MRSI of HP pyruvate can detect increased glycolysis in vivo in a preclinical MS model, and that this increase is linked to the presence of activated MPs that upregulate PDK1 as recently demonstrated in vitro5. Importantly, this study is the first to report the use of a metabolic imaging method to monitor neuroinflammation. Because HP 13C MRSI is clinically translatable and expanding rapidly, this study is of high significance for future clinical trials not only on MS, but also all neurological diseases presenting an inflammatory component. Such method would enhance diagnosis and help refine therapeutic regimen, which will ultimately improve clinical outcome and patient care. FUNDING IWT-Vlaanderen PhD grant; NMSS_PP3395; Cal-BRAIN349087; UCSF_RAP7500634; UCSF Department of Radiology seed grants #14-04 & #14-05 REFERENCES [1] Galvan-Pena, Front. Immunol.(2014) [2] Tannahill, Front. Immunol.(2015) [3] Kurhanewicz, Neoplasia (2011) [4] Kipp, Acta Neuropathol. (2009) [5] Tan, J. Immunol (2015)