Search

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.

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.

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.

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.

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.