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INTRODUCTION Hyperpolarized carbon-13 (HP-13C) MR enables rapid dynamic imaging of metabolic pathways in the human brain using non-toxic, non-radioactive metabolites as tracers. This study presents our unique experience on the benefit of using [1-13C]pyruvate and [2-13C]pyruvate MR for evaluating patients with glioma. METHODS 132 scans (71 using an integrated 13C /1H coil) including steady-state 1H-MRSI (~10 min) and dynamic HP-13C imaging (60 sec) following injection of HP [1-13C]pyruvate (N=125) or [2-13C]pyruvate (N=7) were acquired from 46 patients with glioma (18F/28M; 15 IDH-mutant, 27 IDH-wildtype, 4 IDH-status-unknown). Maps of temporally-summed 13C-metabolite signals, ratios, and kinetic rate constants were calculated for contrast-enhancing, nonenhancing, and normal-appearing-white-matter (NAWM) regions and compared to steady-state metabolic metrics. RESULTS The only adverse event, in a single patient, was a burning sensation after the injection that resolved after saline flush. The mean time-to-injection of HP probes was 58.6±14.0 sec. Signal-to-noise ratios of [1-13C]lactate and [13C]bicarbonate within the NAWM from the HP [1-13C]pyruvate data were 53±39 and 13±6, respectively. The SD/mean of repeated injections (N=3) for lactate/pyruvate and pyruvate-to-lactate conversion rates were 3.8±3.1% and 6.5±3.1% in the NAWM, respectively. Patients with progressive GBM had significantly higher lactate/pyruvate and lower bicarbonate/lactate (p< 0.05) in contrast- and non-enhancing lesions compared to NAWM. Significantly elevated lactate/pyruvate and reduced bicarbonate/lactate (p< 0.01) were found in contrast-enhancing compared to nonenhancing regions, whereas choline/NAA and steady-state 1H-lactate levels were similar. HP [2-13C]pyruvate data showed reduced glutamate/pyruvate and pyruvate-to-glutamate conversion rates in T2 lesions compared to contralateral normal-appearing brain in IDH-mutant gliomas, consistent with known metabolic reprogramming. CONCLUSION This study demonstrates the potential benefit of dynamic HP-13C MRI for evaluating patients with glioma, which provides unique and spatially distinct contrast compared to steady-state metabolic imaging. Ongoing studies will further characterize dynamic metabolism in specific glioma subtypes and provide biomarkers for evaluating responses to treatment.

Purpose With the initiation of human hyperpolarized 13 C (HP-13 C) trials at multiple sites and the development of improved acquisition methods, there is an imminent need to maximally extract diagnostic information to facilitate clinical interpretation. This study aims to improve human HP-13 C MR spectroscopic imaging through means of Tensor Rank truncation-Image enhancement (TRI) and optimal receiver combination (ORC). Methods A data-driven processing framework for dynamic HP 13 C MR spectroscopic imaging (MRSI) was developed. Using patient data sets acquired with both multichannel arrays and single-element receivers from the brain, abdomen, and pelvis, we examined the theory and application of TRI, as well as 2 ORC techniques: whitened singular value decomposition (WSVD) and first-point phasing. Optimal conditions for TRI were derived based on bias-variance trade-off. Results TRI and ORC techniques together provided a 63-fold mean apparent signal-to-noise ratio (aSNR) gain for receiver arrays and a 31-fold gain for single-element configurations, which particularly improved quantification of the lower-SNR-[13 C]bicarbonate and [1-13 C]alanine signals that were otherwise not detectable in many cases. Substantial SNR enhancements were observed for data sets that were acquired even with suboptimal experimental conditions, including delayed (114 s) injection (8× aSNR gain solely by TRI), or from challenging anatomy or geometry, as in the case of a pediatric patient with brainstem tumor (597× using combined TRI and WSVD). Improved correlation between elevated pyruvate-to-lactate conversion, biopsy-confirmed cancer, and mp-MRI lesions demonstrated that TRI recovered quantitative diagnostic information. Conclusion Overall, this combined approach was effective across imaging targets and receiver configurations and could greatly benefit ongoing and future HP 13 C MRI research through major aSNR improvements.

INTRODUCTION Mutations in isocitrate dehydrogenase (IDH) have been investigated as a prognostic biomarker in glioma. The presence of the IDH mutation (IDHm) is associated with 2-hydroxyglutarate (2HG) production and inhibition of glutamate synthesis (McBrayer, Cell 2018). Hyperpolarized carbon-13 (HP-13C) MRI enables dynamic measurements of in-vivo metabolism using a [2-13C]pyruvate labeled probe that undergoes conversion to [2-13C]lactate and [5-13C]glutamate. Here, we present HP [2-13C]pyruvate data from healthy volunteers and patients with IDHm diffuse glioma. Due to its intrinsic low signal-to-noise ratio (SNR), we demonstrate the ability of post-processing denoising to improve its utility and aid in detection of metabolic changes associated with IDHm. METHODS Dynamic HP 13C data were acquired following intravenous injection of [2-13C]pyruvate from five healthy volunteers and one patient with IDHm grade III astrocytoma. A novel multi-resolution frequency specific multislice EPI sequence was used to obtain [2-13C]pyruvate, [5-13C]glutamate, and downfield and upfield [2-13C]lactate signals (3s temporal resolution, pyruvate/lactate/glutamate spatial resolutions = 0.75x0.75cm2/ 2.25x2.25cm2/ 2.25x2.25cm2, 5 slices 3cm thick). Following phase correction, patch-based tensor decomposition denoising was applied to metabolite images. Metabolite differences between normal-appearing white matter (NAWM) and T2 lesion were examined for the patient data. RESULTS HP [2-13C]pyruvate imaging is able to simultaneously probe glycolytic ([2-13C]lactate) and oxidative ([5-13C]glutamate) metabolism. Denoised pyruvate/lactate/glutamate signals achieved a 4-9/3-6/3-7 fold increase in SNR. T2 lesion exhibited decreased glutamate-to-pyruvate and glutamate-to-lactate AUC ratios versus contralateral NAWM (p< 0.018, p < 1.5e-5), consistent with IDH mutant status. CONCLUSION We successfully demonstrated the feasibility of applying variable resolution HP [2-13C]pyruvate metabolic imaging to detect IDHm specific metabolism. This technique addresses a major hurdle in HP 13C MRI by improving SNR while permitting robust metabolism quantification. Future studies will optimize methods for acquiring and processing data to evaluate further data acquired from IDHm glioma patients. Supported by NIH T32 CA151022, P01 CA118816, and NICO.

PURPOSE: To improve hyperpolarized (13)C (HP-(13)C) MRI by image denoising with a new approach, patch-based higher-order singular value decomposition (HOSVD). METHODS: The benefit of using a patch-based HOSVD method to denoise dynamic HP-(13)C MR imaging data was investigated. Image quality and the accuracy of quantitative analyses following denoising were evaluated first using simulated data of [1-(13)C]pyruvate and its metabolic product, [1-(13)C]lactate, and compared the results to a global HOSVD method. The patch-based HOSVD method was then applied to healthy volunteer HP [1-(13)C]pyruvate echo-planar imaging (EPI) studies. Voxel-wise kinetic modeling was performed on both non-denoised and denoised data to compare the number of voxels quantifiable based on SNR criteria and fitting error. RESULTS: Simulation results demonstrated an 8-fold increase in the calculated signal-to-noise ratio (SNR) of [1-(13)C]pyruvate and [1-(13)C]lactate with the patch-based HOSVD denoising. The voxel-wise quantification of k(PL) (pyruvate-to-lactate conversion rate) showed a 9-fold decrease in standard errors for the fitted k(PL) after denoising. The patch-based denoising performed superior to the global denoising in recovering k(PL) information. In volunteer datasets, [1-(13)C]lactate and [(13)C]bicarbonate signals became distinguishable from noise across captured timepoints with over a 5-fold apparent SNR gain. This resulted in >3-fold increase in the number of voxels quantifiable for mapping k(PB) (pyruvate-to-bicarbonate conversion rate) and whole brain coverage for mapping k(PL). CONCLUSIONS: Sensitivity enhancement provided by this denoising significantly improved quantification of metabolite dynamics and could benefit future studies by improving image quality, enabling higher spatial resolution, and facilitating the extraction of metabolic information for clinical research.

Effective coil combination methods for human hyperpolarized 13C spectroscopy multi-channel data had been relatively unexplored. This study implemented and tested several coil combination methods, including (1) the sum-of-squares (SOS), (2) singular value decomposition (SVD), (3) Roemer method by using reference peak area as a sensitivity map (RefPeak), and (4) Roemer method by using ESPIRiT-derived sensitivity map (ESPIRiT). These methods were evaluated by numerical simulation, thermal phantom experiments, and human cancer patient studies. Overall, the SVD, RefPeak, and ESPIRiT methods demonstrated better accuracy and robustness than the SOS method. Extracting complex pyruvate signal provides an easy and excellent approximation of the coil sensitivity map while maintaining valuable phase information of the coil-combined data.

PURPOSE To compare the performance of an 8-channel surface coil/clamshell transmitter and 32-channel head array coil/birdcage transmitter for hyperpolarized 13 C brain metabolic imaging. METHODS To determine the field homogeneity of the radiofrequency transmitters, B1 + mapping was performed on an ethylene glycol head phantom and evaluated by means of the double angle method. Using a 3D echo-planar imaging sequence, coil sensitivity and noise-only phantom data were acquired with the 8- and 32-channel receiver arrays, and compared against data from the birdcage in transceiver mode. Multislice frequency-specific 13 C dynamic echo-planar imaging was performed on a patient with a brain tumor for each hardware configuration following injection of hyperpolarized [1-13 C]pyruvate. Signal-to-noise ratio (SNR) was evaluated from pre-whitened phantom and temporally summed patient data after coil combination based on optimal weights. RESULTS The birdcage transmitter produced more uniform B1 + compared with the clamshell: 0.07 versus 0.12 (fractional error). Phantom experiments conducted with matched lateral housing separation demonstrated 8- versus 32-channel mean transceiver-normalized SNR performance: 0.91 versus 0.97 at the head center; 6.67 versus 2.08 on the sides; 0.66 versus 2.73 at the anterior; and 0.67 versus 3.17 on the posterior aspect. While the 8-channel receiver array showed SNR benefits along lateral aspects, the 32-channel array exhibited greater coverage and a more uniform coil-combined profile. Temporally summed, parameter-normalized patient data showed SNRmean,slice ratios (8-channel/32-channel) ranging 0.5-2.00 from apical to central brain. White matter lactate-to-pyruvate ratios were conserved across hardware: 0.45 ± 0.12 (8-channel) versus 0.43 ± 0.14 (32-channel). CONCLUSION The 8- and 32-channel hardware configurations each have advantages in particular brain anatomy.

INTRODUCTION Mutations in isocitrate dehydrogenase (IDH1/2) genes are both diagnostic and prognostic biomarkers for lower grade gliomas, which can be noninvasively evaluated via MRS detection of 2-hydroxyglutarate (2HG). A high percentage of lower grade gliomas harbor IDH mutations that have a major impact on tumor biology. METHODS Forty IDH-mutant lower grade glioma patients were recruited and scanned using 2HG-optimized 97ms PRESS spectroscopy prior to surgical resection, whereupon image-guided tissue samples were acquired and analyzed via histopathology. Spectra were processed and quantified using LCModel. Wilcoxon ranksum tests were used to compare the difference in metabolic parameters between patient subgroups. Cox proportional hazard models were used to evaluate the influence of metabolic parameters on progression free survival (PFS). Pearson and Kendall Tau rank correlations were used for metabolites and histopathology parameters. RESULTS Levels of 2HG were quantifiable in 37/40 (92.5%) IDH+ patients, yielding a detection rate of 92.5%. A significant difference in myoinositol/total choline was found between astrocytoma and oligodendroglioma in the newly diagnosed grade II population (N=10/13, p=0.042) and also in the overall population (N=25/15, p=0.022). 2HG/creatine was the only significant prognostic indicator on PFS in newly diagnosed patients (p=0.036, HR=4.435; N=33), who had a median PFS of 1472 days [95%CI 994 1950 days] (15 censored). Significantly decreased glutamate/creatine and increased (2HG+GABA)/creatine (p< 0.0001) were found in the T2 lesion compared to those in the normal appearing white matter. At the location where the biopsy samples were taken, there was a significant relationship between 2HG/creatine and glycine/creatine (0.93±0.01; mean±SD Tau; p=0.0005) as well as 2HG/creatine and glutathione/creatine (0.96±0.02; mean±SD Tau; p=0.001) but no significance between the metabolites and pathology parameters were found. CONCLUSIONS The non-invasive detection of 2HG can provide clinically relevant information for patient management and our study demonstrated both the feasibility of 2HG detection and its relationship with PFS.

Based on the expanding set of applications for hyperpolarized carbon-13 (HP-13 C) MRI, this work aims to communicate standardized methodology implemented at the University of California, San Francisco, as a primer for conducting reproducible metabolic imaging studies of the prostate and brain. Current state-of-the-art HP-13 C acquisition, data processing/reconstruction and kinetic modeling approaches utilized in patient studies are presented together with the rationale underpinning their usage. Organized around spectroscopic and imaging-based methods, this guide provides an extensible framework for handling a variety of HP-13 C applications, which derives from two examples with dynamic acquisitions: 3D echo-planar spectroscopic imaging of the human prostate and frequency-specific 2D multislice echo-planar imaging of the human brain. Details of sequence-specific parameters and processing techniques contained in these examples should enable investigators to effectively tailor studies around individual-use cases. Given the importance of clinical integration in improving the utility of HP exams, practical aspects of standardizing data formats for reconstruction, analysis and visualization are also addressed alongside open-source software packages that enhance institutional interoperability and validation of methodology. To facilitate the adoption and further development of this methodology, example datasets and analysis pipelines have been made available in the supporting information.

Graphical abstract, Highlights • Serial HP 13C MRI was evaluated for data consistency and abnormal metabolism. • Metabolism of [1-13C]pyruvate to lactate and bicarbonate was kinetically modeled. • Conversion rates within NAWM were consistent in healthy volunteer and patient scans • Progressed tumor lesions showed higher relative conversion rates to [1-13C]lactate. • Globally elevated rate constants were observed with anti-angiogenic treatment., Background Hyperpolarized carbon-13 (HP-13C) MRI is a non-invasive imaging technique for probing brain metabolism, which may improve clinical cancer surveillance. This work aimed to characterize the consistency of serial HP-13C imaging in patients undergoing treatment for brain tumors and determine whether there is evidence of aberrant metabolism in the tumor lesion compared to normal-appearing tissue. Methods Serial dynamic HP [1-13C]pyruvate MRI was performed on 3 healthy volunteers (6 total examinations) and 5 patients (21 total examinations) with diffuse infiltrating glioma during their course of treatment, using a frequency-selective echo-planar imaging (EPI) sequence. HP-13C imaging at routine clinical timepoints overlapped treatment, including radiotherapy (RT), temozolomide (TMZ) chemotherapy, and anti-angiogenic/investigational agents. Apparent rate constants for [1-13C]pyruvate conversion to [1-13C]lactate (kPL) and [13C]bicarbonate (kPB) were simultaneously quantified based on an inputless kinetic model within normal-appearing white matter (NAWM) and anatomic lesions defined from 1H MRI. The inter/intra-subject consistency of kPL-NAWM and kPB-NAWM was measured in terms of the coefficient of variation (CV). Results When excluding scans following anti-angiogenic therapy, patient values of kPL-NAWM and kPB-NAWM were 0.020 s−1 ± 23.8% and 0.0058 s−1 ± 27.7% (mean ± CV) across 17 HP-13C MRIs, with intra-patient serial kPL-NAWM/kPB-NAWM CVs ranging 6.8–16.6%/10.6–40.7%. In 4/5 patients, these values (0.018 s−1 ± 13.4% and 0.0058 s−1 ± 24.4%; n = 13) were more similar to those from healthy volunteers (0.018 s−1 ± 5.0% and 0.0043 s−1 ± 12.6%; n = 6) (mean ± CV). The anti-angiogenic agent bevacizumab was associated with global elevations in apparent rate constants, with maximum kPL-NAWM in 2 patients reaching 0.047 ± 0.001 and 0.047 ± 0.003 s−1 (±model error). In 3 patients with progressive disease, anatomic lesions showed elevated kPL relative to kPL-NAWM of 0.024 ± 0.001 s−1 (±model error) in the absence of gadolinium enhancement, and 0.032 ± 0.008, 0.040 ± 0.003 and 0.041 ± 0.009 s−1 with gadolinium enhancement. The lesion kPB in patients was reduced to unquantifiable values compared to kPB-NAWM. Conclusion Serial measures of HP [1-13C]pyruvate metabolism displayed consistency in the NAWM of healthy volunteers and patients. Both kPL and kPB were globally elevated following bevacizumab treatment, while progressive disease demonstrated elevated kPL in gadolinium-enhancing and non-enhancing lesions. Larger prospective studies with homogeneous patient populations are planned to evaluate metabolic changes following treatment.

INTRODUCTION Hyperpolarized (HP) 13C MRI is a novel metabolic imaging that allows for real time in vivo probing of pathway-specific metabolic processes relevant to gliomas. The first human brain application reports were published recently. In this study, we characterized longitudinal dynamic and static brain metabolism changes from serial HP 13C and 1H metabolic imaging in a patient with multiply recurrent glioma. METHODS Eight dynamic HP 13C imaging, 1H MRI and MRSI examinations were acquired over a period of 15 months in a patient with multiply recurrent glioma that underwent malignant transformation. The patient was imaged after initial tumor debulking, after chemoradiotherapy, at first recurrence, after re-irradiation and anti-angiogentic therapy, and at second recurrence. Ratios of pyruvate-to-lactate and pyruvate-to-bicarbonate were calculated from HP 13C imaging and choline-to-NAA index (CNI) was derived from 1H MRSI. RESULTS/ DISCUSSION Successful therapies are usually associated with a drop in pyruvate-to-lactate conversion, mediated by different mechanisms from various treatments. We identified three key findings over repeat HP 13C MRIs: 1) a marked response to therapy with a reduction in pyruvate-to-lactate conversion corresponding to associated imaging response to therapy at the primary site of disease. Following chemoradiotherapy, the volume of T2 hyperintensity decreased from 28.21cc to 15.29 cc, and the volume of metabolic abnormality (CNI >3) decreased from 27.84 cc to 10.36 cc. 2) increasing pyruvate-to-lactate conversion in a region of recurrence before morphologic signal abnormality, and 3) a reduction in pyruvate-to-lactate conversion in a recurrent lesion following anti-angiogenic therapy. CONCLUSION Here we show that one can reliably image glioma patients using HP 13C MRI alongside standard of care morphologic and physiologic MRI including diffusion, perfusion, and 1H MRSI. Serial HP 13C MRI can be performed in the neuro-oncologic clinical setting and pyruvate-to-lactate metabolism may be useful to monitor treatment response.

INTRODUCTION The goal of this study was to characterize progressive and pseudoprogressive GBM using multi-parametric hyperpolarized (HP)-13C / 1H MRI. METHODS Dynamic HP-13C MRI was acquired from 13 patients with progressive GBM [patients (scans): 2(3) IDH-mutant; 11(13) IDH-wildtype] and 2 IDH-wildtype patients (3 scans) demonstrating pseudo-progression following intravenous injection of HP [1-13C]pyruvate. Frequency-selective echo-planar imaging (3s temporal resolution, 3.38 cm3 spatial resolution) captured [1-13C]pyruvate metabolism to [1-13C]lactate and 13C-bicarbonate in the brain. Dynamic 13C data were kinetically modeled to obtain the pyruvate-to-lactate conversion rate constant k PL and temporally summed to calculate 13C-metabolite percentiles and ratios (linearly interpolated 2x in-plane). 1H imaging included T2, post-Gd T1, perfusion (nCBV, %recovery), diffusion (ADC), and lactate-edited spectroscopy (CNI, choline-to-NAA index; 1H-lactate). The normal-appearing white matter (NAWM), non-enhancing lesion (NEL), and contrast-enhancing lesion (CEL) were segmented from 1H images. 13C-resolution masks were iteratively applied on a voxel-wise basis to evaluate 1H imaging parameters within each ROI and multi-parametric data were collectively evaluated using a mixed effects model in R. RESULTS Progressive IDH-mutant GBM compared to wildtype counterparts displayed increased perfusion %recovery (p < 0.001) and k PL (p < 0.01), together with reduced 1H-lactate (p < 0.001) and pyruvate percentile (p < 0.01), in the T2 lesion. Among IDH-wildtype progressive GBM, the CEL was distinguished from NEL/NAWM by increased nCBV (p < 0.05/0.001), 1H-lactate (p < 0.05/0.001); and decreased bicarbonate / lactate (p < 0.05/0.001). The CEL and NEL were collectively distinguished from NAWM by elevated CNI (p < 0.001/0.001), ADC (p < 0.05/0.001), pyruvate percentile (p < 0.001/0.001), lactate percentile (p < 0.001/0.001), and relative lactate / pyruvate (p < 0.001/0.05). Psuedo-progressive IDH-wildtype GBM displayed lower k PL (T2 Lesion; p < 0.01) and nCBV (CEL; p < 0.01) compared to progressive GBM. CONCLUSION HP-13C parameters can potentially augment proton imaging and demonstrated Warburg-associated metabolic alterations.

Treatment-related changes often mimic or mask tumor on standard anatomic imaging, making it difficult to monitor disease recurrence. Hyperpolarized (HP) carbon-13 MR imaging allows for real-time non-invasive measurement of metabolism, which may improve patient surveillance. Here, we focused on characterizing serial HP scans in patients undergoing treatment compared to healthy controls. Serial dynamic HP C-13 MRI scans were performed on 5 patients with recurrent glioma (22 total) and 3 healthy controls (4 total) using an echo-planar imaging sequence (2.88-8cm3 spatial resolution, 3s temporal resolution, 60s), following injection of 0.43mL/kg of 250mM HP [1-13C]pyruvate. Apparent rate constants were modeled for enzymatic conversion of pyruvate-to-lactate (kPL) via cytosolic lactate dehydrogenase and pyruvate-to-bicarbonate (kPB) via mitochondrial pyruvate dehydrogenase and carbonic anhydrase. Regions of interest included normal-appearing white matter (NAWM) and T2-hyperintense lesions (T2L), which were segmented from H-1 MR images and then aligned to the HP data. Carbon voxels containing >30% of NAWM or T2L were included in the analysis. Healthy controls demonstrated consistent kPL and kPB values over 4 scans in NAWM with SD/Mean of 5% and 12%, respectively. Compared to the median kPL-NAWM of 0.022s-1 in controls, the 5 patients had median serial kPL-NAWM values of 0.023, 0.023, 0.023, 0.029, and 0.015s-1, and mean serial ratios of kPL between T2L and NAWM (kPL-T2L/kPL-NAWM) of 1.22, 1.27, 1.05, 1.32, and 1.37s-1, indicating higher values in putative tumor. Median kPB-NAWM in controls was 0.004s-1 and ranged in patients 0.003-0.006s-1. Two patients with >4 serial scans, showed consistent kPL-NAWM over standard-of-care treatment and elevated kPL-T2L within new lesions, but up to 85% increase in kPL-NAWM with bevacizumab, which may be attributed to reduced BBB permeability. Stable patients generally demonstrated consistent kPL-T2L values that were lower compared to progressive patients. Future studies will include multi-parametric 1H imaging analysis in a larger patient population.

Kinetic modeling of the in vivo pyruvate-to-lactate conversion is crucial to investigating aberrant cancer metabolism that demonstrates Warburg effect modifications. Non-invasive detection of alterations to metabolic flux might offer prognostic value and improve the monitoring of response to treatment. In this clinical research project, hyperpolarized [1–13C] pyruvate was intravenously injected in a total of 10 brain tumor patients to measure its rate of conversion to lactate ( ${k}_{{\textit {PL}}}$ ) and bicarbonate ( ${k}_{{\textit {PB}}}$ ) via echo-planar imaging. Our aim was to investigate new methods to provide ${k}_{{\textit {PL}}}$ and ${k}_{{\textit {PB}}}$ maps with whole-brain coverage. The approach was data-driven and addressed two main issues: selecting the optimal model for fitting our data and determining an appropriate goodness-of-fit metric. The statistical analysis suggested that an input-less model had the best agreement with the data. It was also found that selecting voxels based on post-fitting error criteria provided improved precision and wider spatial coverage compared to using signal-to-noise cutoffs alone.

Proton magnetic resonance spectroscopic imaging (1H MRSI) is a powerful noninvasive method for assessing the spatial extent and properties of abnormal metabolism in patients with glioma. Hyperpolarized 13C metabolic imaging is a new molecular imaging modality that can be used to assess real-time changes in metabolism and has been shown to be safe and feasible in patients with glioma. In this study, both 3D 1H lactate-edited MRSI and hyperpolarized [1-13C]pyruvate imaging data were obtained and compared in thirteen patients with glioma to assess steady state versus dynamic brain metabolism. FLAIR images from the 1H examination were registered to the FSE images from the 13C examination for each subject. The corresponding transformation matrix was then applied to spectra and metabolite maps from the excitation volume of the 1H MRSI data. The volumes of the anatomic and metabolic lesions varied between patients, and using a multi-slice frequency specific EPI sequence allowed improved coverage of the lesion of interest compared to a 2D dynamic EPSI sequence. The choline-to-NAA index values and levels of steady state lactate peak heights from the 1H MRSI data were elevated in the lesion, while 13C bicarbonate levels were reduced and 13C lactate levels were similar or lower compared with normal appearing brain. The initial results indicated that there was a negative association between estimates of hyperpolarized 13C lactate/pyruvate and steady state normalized lactate peak heights, and a positive association between hyperpolarized 13C lactate/pyruvate and Cho/NAA in the T2 lesion. For one patient who received repeated examinations within 2 months and was assessed as having stable disease after treatment, the 13C lactate-to-pyruvate ratio in the T2 lesion was 0.65 vs. 0.35 and 0.43 vs. 0.43 in normal appearing brain. Future studies will evaluate a larger patient population to see whether these relationships hold up.

Purpose To develop and translate a metabolite-specific imaging sequence using a symmetric echo planar readout for clinical hyperpolarized (HP) Carbon-13 (13 C) applications. Methods Initial data were acquired from patients with prostate cancer (N = 3) and high-grade brain tumors (N = 3) on a 3T scanner. Samples of [1-13 C]pyruvate were polarized for at least 2 h using a 5T SPINlab system operating at 0.8 K. Following injection of the HP substrate, pyruvate, lactate, and bicarbonate (for brain studies) were sequentially excited with a singleband spectral-spatial RF pulse and signal was rapidly encoded with a single-shot echo planar readout on a slice-by-slice basis. Data were acquired dynamically with a temporal resolution of 2 s for prostate studies and 3 s for brain studies. Results High pyruvate signal was seen throughout the prostate and brain, with conversion to lactate being shown across studies, whereas bicarbonate production was also detected in the brain. No Nyquist ghost artifacts or obvious geometric distortion from the echo planar readout were observed. The average error in center frequency was 1.2 ± 17.0 and 4.5 ± 1.4 Hz for prostate and brain studies, respectively, below the threshold for spatial shift because of bulk off-resonance. Conclusion This study demonstrated the feasibility of symmetric EPI to acquire HP 13 C metabolite maps in a clinical setting. As an advance over prior single-slice dynamic or single time point volumetric spectroscopic imaging approaches, this metabolite-specific EPI acquisition provided robust whole-organ coverage for brain and prostate studies while retaining high SNR, spatial resolution, and dynamic temporal resolution.

We developed methods for the preparation of hyperpolarized (HP) sterile [2-13C]pyruvate to test its feasibility in first-ever human NMR studies following FDA-IND & IRB approval. Spectral results using this MR stable-isotope imaging approach demonstrated the feasibility of investigating human cerebral energy metabolism by measuring the dynamic conversion of HP [2-13C]pyruvate to [2-13C]lactate and [5-13C]glutamate in the brain of four healthy volunteers. Metabolite kinetics, signal-to-noise (SNR) and area-under-curve (AUC) ratios, and calculated [2-13C]pyruvate to [2-13C]lactate conversion rates (kPL) were measured and showed similar but not identical inter-subject values. The kPL measurements were equivalent with prior human HP [1-13C]pyruvate measurements.

Objective. The purpose of this study was to demonstrate the feasibility of using hyperpolarized carbon-13 (13C) metabolic imaging with [1-13C]-labeled pyruvate for evaluating real-time in vivo metabolism of orthotopic diffuse intrinsic pontine glioma (DIPG) xenografts. Materials and Methods. 3D 13C magnetic resonance spectroscopic imaging (MRSI) data were acquired on a 3T scanner from 8 rats that had been implanted with human-derived DIPG cells in the brainstem and 5 healthy controls, following injection of 2.5 mL (100 mM) hyperpolarized [1-13C]-pyruvate. Results. Anatomical images from DIPG-bearing rats characteristically exhibited T2-hyperintensity throughout the cerebellum and pons that was not accompanied by contrast enhancement. Evaluation of real-time in vivo13C spectroscopic data revealed ratios of lactate-to-pyruvate (p<0.002), lactate-to-total carbon (p<0.002), and normalized lactate (p<0.002) that were significantly higher in T2 lesions harboring tumor relative to corresponding values of healthy normal brain. Elevated levels of lactate in lesions demonstrated a distinct metabolic profile that was associated with infiltrative, viable tumor recapitulating the histopathology of pediatric DIPG. Conclusions. Results from this study characterized pyruvate and lactate metabolism in orthotopic DIPG xenografts and suggest that hyperpolarized 13C MRSI may serve as a noninvasive imaging technique for in vivo monitoring of biochemical processes in patients with DIPG.

BACKGROUND: Although the contrast-enhancing (CE) lesion on T 1 -weighted MR images is widely used as a surrogate for glioblastoma (GBM), there are also non-enhancing regions of infiltrative tumor within the T 2 -weighted lesion, which elude radiologic detection. Because non-enhancing GBM (Enh−) challenges clinical patient management as latent disease, this study sought to characterize ex vivo metabolic profiles from Enh− and CE GBM (Enh+) samples, alongside histological and in vivo MR parameters, to assist in defining criteria for estimating total tumor burden. Methods: Fifty-six patients with newly diagnosed GBM received a multi-parametric pre-surgical MR examination. Targets for obtaining image-guided tissue samples were defined based on in vivo parameters that were suspicious for tumor. The actual location from where tissue samples were obtained was recorded, and half of each sample was analyzed for histopathology while the other half was scanned using HR-MAS spectroscopy. Results: The Enh+ and Enh− tumor samples demonstrated comparable mitotic activity, but also significant heterogeneity in microvascular morphology. Ex vivo spectroscopic parameters indicated similar levels of total choline and N -acetylaspartate between these contrast-based radiographic subtypes of GBM, and characteristic differences in the levels of myo-inositol, creatine/phosphocreatine, and phosphoethanolamine. Analysis of in vivo parameters at the sample locations were consistent with histological and ex vivo metabolic data. CONCLUSIONS: The similarity between ex vivo levels of choline and NAA, and between in vivo levels of choline, NAA and nADC in Enh+ and Enh− tumor, indicate that these parameters can be used in defining non-invasive metrics of total tumor burden for patients with GBM.

Infiltrating gliomas are primary brain tumors that express significant biological and clinical heterogeneity in adults, which complicates their treatment and prognosis. Characterization of tumor subtypes using spectroscopic analysis may assist in predicting malignant transformation and quantification of response to therapy. To implement an automated algorithm for classification of metabolomic profiles for the classification of glioma pathological grades and the prediction of malignant progression using spectra obtained by high-resolution magic angle spinning (HR-MAS) spectroscopy of patient-derived tissue samples. 237 image-guided tissue samples were obtained from 152 patients who underwent surgery for newly diagnosed or recurrent glioma and analyzed via HR-MAS spectroscopy. Orthogonal projection to latent structures discriminant analysis was used as a classifier and the variable-influence-on-projection values were evaluated to identify signature spectral regions. The accuracy of classifiers developed for discriminating glioma subtypes was 68% for newly diagnosed grade II versus III samples; 86 and 92% for new and recurrent grade III versus IV, respectively; 95% for newly diagnosed grade II versus IV; and 88% for recurrent grade II versus IV lesions. Classifiers distinguished between samples from newly diagnosed vs. recurrent lesions with an accuracy of 78% for grade III and 99% for grade IV glioma. Classifying metabolomic profiles for new and recurrent glioma without prior assumptions regarding spectral components identified candidate in vivo biomarkers for use in assessing changes that are likely to impact treatment decisions.

As a non-invasive method for probing in vivo metabolism, hyperpolarized carbon-13 metabolic imaging may enhance the diagnostic assessment of response-to-treatment in patients with glioma. Having demonstrated the feasibility of applying this technique to human glioma (Park et al. 2017), the current study seeks to evaluate the reproducibility of carbon data by measuring serial metabolic changes in white matter. In total, 4 radiologically stable patients (2 male, 2 female) who were treated with radiation and TMZ for heterogeneous diagnoses (GBM, grade III oligo, gliosarcoma, secondary GBM) received either 2 (n=1) or 3 (n=3) serial exams. Following injection of hyperpolarized [1-(13)C]pyruvate, dynamic echo-planar imaging was acquired with a 3s temporal resolution and 2–8 cm(3) spatial resolution. Dynamic data were summed together and the ratio of metabolically-produced lactate relative to pyruvate substrate (lac/pyr) was evaluated in segmented normal-appearing white matter (NAWM, >50% voxel). Median and SD of lac/pyr values in NAWM are reported for serial scans, along with %change per interval: P1-male [0.32 ± 0.14, 0.28 ± 0.11 (-12.5%), 0.33 ± 0.10 (+17.9%)]; P2-male [0.32 ± 0.10, 0.28 ± 0.10 (-12.5%)]; P3-female [0.37 ± 0.09, 0.45 ± 0.14 (+21.6%), 0.59 ± 0.19 (+31.1%)]; and P4-female [0.49 ± 0.14, 0.43 ± 0.12 (-12.2%), 0.44 ± 0.10 (2.3%)]. These results show an average absolute change of 15.7% in lac/pyr within NAWM over the entire population, with considerable overlap of the variance. Patient P3, who was treated with adjuvant agent pembrolizumab, also notably showed a serial increase in lac/pyr. When separating the population according to gender, females demonstrated a higher average lac/pyr value of 0.46, compared to 0.31 in males. In summary, our initial experience with serial hyperpolarized carbon data indicates that the range of lactate-to-pyruvate ratios is relatively consistent across patient scans, but may differ according to gender and adjuvant treatment. Future studies will evaluate changes in the T2 lesion relative to NAWM over the course of treatment.

In primary central nervous system lymphoma (PCNSL), L265P mutation of the myeloid differentiation 88 (MYD88) protein is the most common, and induces a constitutive activation of IRAK4 kinase, IRAK1 phosphorylation and increased NF-kB signaling, offering a unique window for therapeutic development. We previously show that AZ1495, a potent inhibitor of IRAK4, significantly delayed progression and improved OS in L265P-mutated PCNSL models [ASH 2016], highlighting the clinical potential of IRAK inhibition. In the clinic however, early monitoring of such targeted therapies remains challenging using conventional imaging, as treatment often results in non-readily detectable anatomical changes. Here, we questioned the potential of a new neuroimaging method, hyperpolarized 13C magnetic resonance spectroscopic imaging (HP-13C MRSI), to non-invasively monitor IRAK inhibition in PCNSL for the first time. Two PCNSL patient-derived xenografts models were studied: one harboring the L265P MYD88 mutation (MYD88mut), and the other, wild type for this protein (MYD88wt). Using HP-13C MRSI, a high production of HP [1-13C] lactate was detected in both MYD88wt and MYD88mut (0.5 ± 0.04, n=2 MYD88wt; 0.61 ± 0.2, n=4 MYD88mut), indicating PCNSL presence throughout the brain. At day 2 and 4 of AZ1495 treatment, the HP [1-13C] lactate-to-pyruvate ratio remains unchanged in MYD88wt animals at all treatment time points (p=0.29 and p=0.29 at day 2 and 4 when compared to baseline, respectively) On the other hand, this ratio significantly decreased in MYD88mut animals at all time points (36.6% at day 2, p=0.07 and 56.3% at day 4, p=0.0006), in line with the previously reported effect of AZ1495 treatment on MYD88mut PCNSL only. To conlude, we showed that HP-13C MRSI can detect MYD88-mutation-specific modulations of HP lactate production following IRAK inhibition. Because HP-13C MRSI is clinically translatable and expanding rapidly, this study is of high significance for future clinical trials, to enhance monitoring of PCNSL progression and response of targeted therapies.