Dynamic 13 C MR spectroscopy as an alternative to imaging for assessing cerebral metabolism using hyperpolarized pyruvate in humans.

PURPOSE: This study is to investigate time-resolved 13 C MR spectroscopy (MRS) as an alternative to imaging for assessing pyruvate metabolism using hyperpolarized (HP) [1-13 C]pyruvate in the human brain. METHODS: Time-resolved 13 C spectra were acquired from four axial brain slices of healthy human participants (n = 4) after a bolus injection of HP [1-13 C]pyruvate. 13 C MRS with low flip-angle excitations and a multichannel 13 C/1 H dual-frequency radiofrequency (RF) coil were exploited for reliable and unperturbed assessment of HP pyruvate metabolism. Slice-wise areas under the curve (AUCs) of 13 C-metabolites were measured and kinetic analysis was performed to estimate the production rates of lactate and HCO3- . Linear regression analysis between brain volumes and HP signals was performed. Region-focused pyruvate metabolism was estimated using coil-wise 13 C reconstruction. Reproducibility of HP pyruvate exams was presented by performing two consecutive injections with a 45-minutes interval. RESULTS: [1-13 C]Lactate relative to the total 13 C signal (tC) was 0.21-0.24 in all slices. [13 C] HCO3- /tC was 0.065-0.091. Apparent conversion rate constants from pyruvate to lactate and HCO3- were calculated as 0.014-0.018 s-1 and 0.0043-0.0056 s-1 , respectively. Pyruvate/tC and lactate/tC were in moderate linear relationships with fractional gray matter volume within each slice. White matter presented poor linear regression fit with HP signals, and moderate correlations of the fractional cerebrospinal fluid volume with pyruvate/tC and lactate/tC were measured. Measured HP signals were comparable between two consecutive exams with HP [1-13 C]pyruvate. CONCLUSIONS: Dynamic MRS in combination with multichannel RF coils is an affordable and reliable alternative to imaging methods in investigating cerebral metabolism using HP [1-13 C]pyruvate.

Clinical translation of hyperpolarized 13 C pyruvate and urea MRI for simultaneous metabolic and perfusion imaging.

PURPOSE: The combined hyperpolarized (HP) 13 C pyruvate and urea MRI has provided a simultaneous assessment of glycolytic metabolism and tissue perfusion for improved cancer diagnosis and therapeutic evaluation in preclinical studies. This work aims to translate this dual-probe HP imaging technique to clinical research. METHODS: A co-polarization system was developed where [1-13 C]pyruvic acid (PA) and [13 C, 15 N2 ]urea in water solution were homogeneously mixed and polarized on a 5T SPINlab system. Physical and chemical characterizations and toxicology studies of the combined probe were performed. Simultaneous metabolic and perfusion imaging was performed on a 3T clinical MR scanner by alternatively applying a multi-slice 2D spiral sequence for [1-13 C]pyruvate and its downstream metabolites and a 3D balanced steady-state free precession (bSSFP) sequence for [13 C, 15 N2 ]urea. RESULTS: The combined PA/urea probe has a glass-formation ability similar to neat PA and can generate nearly 40% liquid-state 13 C polarization for both pyruvate and urea in 3-4 h. A standard operating procedure for routine on-site production was developed and validated to produce 40 mL injection product of approximately 150 mM pyruvate and 35 mM urea. The toxicology study demonstrated the safety profile of the combined probe. Dynamic metabolite-specific imaging of [1-13 C]pyruvate, [1-13 C]lactate, [1-13 C]alanine, and [13 C, 15 N2 ]urea was achieved with adequate spatial (2.6 mm × 2.6 mm) and temporal resolution (4.2 s), and urea images showed reduced off-resonance artifacts due to the JCN coupling. CONCLUSION: The reported technical development and translational studies will lead to the first-in-human dual-agent HP MRI study and mark the clinical translation of the first HP 13 C MRI probe after pyruvate.

Multi-band echo-planar spectroscopic imaging of hyperpolarized 13 C probes in a compact preclinical PET/MR scanner.

PURPOSE: Hyperpolarized (HP) 13 C MRI has enabled real-time imaging of specific enzyme-catalyzed metabolic reactions, but advanced pulse sequences are necessary to capture the dynamic, localized metabolic information. Herein we describe the design, implementation, and testing of a rapid and efficient HP 13 C pulse sequence strategy on a cryogen-free simultaneous positron emission tomography/MR molecular imaging platform with compact footprint. METHODS: We developed an echo planar spectroscopic imaging pulse sequence incorporating multi-band spectral-spatial radiofrequency (SSRF) pulses for spatially coregistered excitation of 13 C metabolites with differential individual flip angles. Excitation profiles were measured in phantoms, and the SSRF-echo planar spectroscopic imaging sequence was tested in rats in vivo and compared to conventional echo planar spectroscopic imaging. The new sequence was applied for 2D dynamic metabolic imaging of HP [1-13 C]pyruvate and its molecular analog [1-13 C] α -ketobutyrate at a spatial resolution of 5 mm × 5 mm × 20 mm and temporal resolution of 4 s. We also obtained simultaneous 18 F-fluorodeoxyglucose positron emission tomography data for comparison with HP [1-13 C]pyruvate data acquired during the same scan session. RESULTS: Measured SSRF excitation profiles corresponded well to Bloch simulations. Multi-band SSRF excitation facilitated efficient sampling of the multi-spectral kinetics of [1-13 C]pyruvate and [1-13 C] α - ketobutyrate . Whereas high pyruvate to lactate conversion was observed in liver, corresponding reduction of α -ketobutyrate to [1-13 C] α -hydroxybutyrate ( α HB) was largely restricted to the kidneys and heart, consistent with the known expression pattern of lactate dehydrogenase B. CONCLUSION: Advanced 13 C SSRF imaging approaches are feasible on our compact positron emission tomography/MR platform, maximizing the potential of HP 13 C technology and facilitating direct comparison with positron emission tomography.

Metabolite-Specific Echo-Planar Imaging of Hyperpolarized [1-13C]Pyruvate at 4.7 T.

Although hyperpolarization (HP) greatly increases the sensitivity of 13C MR, the usefulness of HP in vivo is limited by the short lifetime of HP agents. To address this limitation, we developed an echo-planar (EPI) sequence with spectral-spatial radiofrequency (SSRF) pulses for fast and efficient metabolite-specific imaging of HP [1-13C]pyruvate and [1-13C]lactate at 4.7 T. The spatial and spectral selectivity of each SSRF pulse was verified using simulations and phantom testing. EPI and CSI imaging of the rat abdomen were compared in the same rat after injecting HP [1-13C]pyruvate. A procedure was also developed to automatically set the SSRF excitation pulse frequencies based on real-time scanner feedback. The most significant results of this study are the demonstration that a greater spatial and temporal resolution is attainable by metabolite-specific EPI as compared with CSI, and the enhanced lifetime of the HP signal in EPI, which is attributable to the independent flip angle control between metabolites. Real-time center frequency adjustment was also highly effective for minimizing off-resonance effects. To the best of our knowledge, this is the first demonstration of metabolite-specific HP 13C EPI at 4.7 T. In conclusion, metabolite-specific EPI using SSRF pulses is an effective way to image HP [1-13C]pyruvate and [1-13C]lactate at 4.7 T.

Preoperative imaging of glioblastoma patients using hyperpolarized 13C pyruvate: Potential role in clinical decision making.

BACKGROUND: Glioblastoma remains incurable despite treatment with surgery, radiation therapy, and cytotoxic chemotherapy, prompting the search for a metabolic pathway unique to glioblastoma cells.13C MR spectroscopic imaging with hyperpolarized pyruvate can demonstrate alterations in pyruvate metabolism in these tumors. METHODS: Three patients with diagnostic MRI suggestive of a glioblastoma were scanned at 3 T 1-2 days prior to tumor resection using a 13C/1H dual-frequency RF coil and a 13C/1H-integrated MR protocol, which consists of a series of 1H MR sequences (T2 FLAIR, arterial spin labeling and contrast-enhanced [CE] T1) and 13C spectroscopic imaging with hyperpolarized [1-13C]pyruvate. Dynamic spiral chemical shift imaging was used for 13C data acquisition. Surgical navigation was used to correlate the locations of tissue samples submitted for histology with the changes seen on the diagnostic MR scans and the 13C spectroscopic images. RESULTS: Each tumor was histologically confirmed to be a WHO grade IV glioblastoma with isocitrate dehydrogenase wild type. Total hyperpolarized 13C signals detected near the tumor mass reflected altered tissue perfusion near the tumor. For each tumor, a hyperintense [1-13C]lactate signal was detected both within CE and T2-FLAIR regions on the 1H diagnostic images (P = .008). [13C]bicarbonate signal was maintained or decreased in the lesion but the observation was not significant (P = .3). CONCLUSIONS: Prior to surgical resection, 13C MR spectroscopic imaging with hyperpolarized pyruvate reveals increased lactate production in regions of histologically confirmed glioblastoma.

The effect of transmit B1 inhomogeneity on hyperpolarized [1-13 C]-pyruvate metabolic MR imaging biomarkers.

PURPOSE: A specialized Helmholtz-style 13 C volume transmit "clamshell" coil is currently being utilized for 13 C excitation in pre-clinical and clinical hyperpolarized 13 C MRI studies aimed at probing the metabolic activity of tumors in various target anatomy. Due to the widespread use of this 13 C clamshell coil design, it is important that the effects of the 13 C clamshell coil B1 + profile on HP signal evolution and quantification are well understood. The goal of this study was to characterize the B1 + field of the 13 C clamshell coil and assess the impact of inhomogeneities on semi-quantitative and quantitative hyperpolarized MR imaging biomarkers of metabolism. METHODS: The B1 + field of the 13 C clamshell coil was mapped by hand using a network analyzer equipped with an S-parameter test set. Pharmacokinetic models were used to simulate signal evolution as a function of position-dependent local excitation angles, for various nominal excitation angles, which were assumed to be accurately calibrated at the isocenter. These signals were then quantified according to the normalized lactate ratio (nLac) and the apparent rate constant for the conversion of pyruvate to lactate (kPL ). The percent difference between these metabolic imaging biomarker maps and the reference value observed at the isocenter of the clamshell coil was calculated to estimate the potential for error due to position within the clamshell coil. Finally, regions were identified within the clamshell coil where deviations in B1 + field inhomogeneity or imaging biomarker errors imparted by the B1 + field were within ±10% of the value at the isocenter. RESULTS: The B1 + field maps show that a limited volume encompassed by a region measuring approximately 12.9 × 11.5 × 13.4 cm (X-direction, Y-direction, Z-direction) centered in the 13 C clamshell coil will produce deviations in the B1 + field within ±10% of that at the isocenter. For the metabolic imaging biomarkers that we evaluated, the case when the pyruvate excitation angle (θP ) and lactate excitation angle (θL ) were equal to 10° produced the largest volumetric region with deviations within ±10% of the value at the isocenter. Higher excitation angles yielded higher signal and SNR, but the size of the region in which uniform measurements could be collected near the isocenter of the coil was reduced at higher excitation angles. The tradeoff between the size of the homogenous region at the isocenter and signal intensity must be weighed carefully depending on the particular imaging application. CONCLUSION: This work identifies regions and optimal excitation angles (θP and θL ) within the 13 C clamshell coil where deviations in B1 + field inhomogeneity or imaging biomarker errors imparted by the B1 + field were within ±10% of the respective value at the isocenter, and thus where excitation angles are reproducible and well-calibrated. Semi-quantitative and quantitative metabolic imaging biomarkers can vary with position in the clamshell coil as a result of B1 + field inhomogeneity, necessitating care in patient positioning and the selection of an excitation angle set that balances reproducibility and SNR performance over the target imaging volume.

Hyperpolarized 13C MR Spectroscopy Depicts in Vivo Effect of Exercise on Pyruvate Metabolism in Human Skeletal Muscle.

Background Pyruvate dehydrogenase (PDH) and lactate dehydrogenase are essential for adenosine triphosphate production in skeletal muscle. At the onset of exercise, oxidation of glucose and glycogen is quickly enabled by dephosphorylation of PDH. However, direct measurement of PDH flux in exercising human muscle is daunting, and the net effect of covalent modification and other control mechanisms on PDH flux has not been assessed. Purpose To demonstrate the feasibility of assessing PDH activation and changes in pyruvate metabolism in human skeletal muscle after the onset of exercise using carbon 13 (13C) MRI with hyperpolarized (HP) [1-13C]-pyruvate. Materials and Methods For this prospective study, sedentary adults in good general health (mean age, 42 years ± 18 [standard deviation]; six men) were recruited from August 2019 to September 2020. Subgroups of the participants were injected with HP [1-13C]-pyruvate at resting, during plantar flexion exercise, or 5 minutes after exercise during recovery. In parallel, hydrogen 1 arterial spin labeling MRI was performed to estimate muscle tissue perfusion. An unpaired t test was used for comparing 13C data among the states. Results At rest, HP [1-13C]-lactate and [1-13C]-alanine were detected in calf muscle, but [13C]-bicarbonate was negligible. During moderate flexion-extension exercise, total HP 13C signals (tC) increased 2.8-fold because of increased muscle perfusion (P = .005), and HP [1-13C]-lactate-to-tC ratio increased 1.7-fold (P = .04). HP [13C]-bicarbonate-to-tC ratio increased 8.4-fold (P = .002) and returned to the resting level 5 minutes after exercise, whereas the lactate-to-tC ratio continued to increase to 2.3-fold as compared with resting (P = .008). Conclusion Lactate and bicarbonate production from hyperpolarized (HP) [1-carbon 13 {13C}]-pyruvate in skeletal muscle rapidly reflected the onset and the termination of exercise. These results demonstrate the feasibility of imaging skeletal muscle metabolism using HP [1-13C]-pyruvate MRI and the sensitivity of in vivo pyruvate metabolism to exercise states. © RSNA, 2021 Online supplemental material is available for this article.

Cardiac T2∗ measurement of hyperpolarized 13 C metabolites using metabolite-selective multi-echo spiral imaging.

PURPOSE: Noninvasive imaging with hyperpolarized (HP) pyruvate can capture in vivo cardiac metabolism. For proper quantification of the metabolites and optimization of imaging parameters, understanding MR characteristics such as T2∗ s of the HP signals is critical. This study is to measure in vivo cardiac T2∗ s of HP [1-13 C]pyruvate and the products in rodents and humans. METHODS: A dynamic 13 C multi-echo spiral imaging sequence that acquires [13 C]bicarbonate, [1-13 C]lactate, and [1-13 C]pyruvate images in an interleaved manner was implemented for a clinical 3 Tesla system. T2∗ of each metabolite was calculated from the multi-echo images by fitting the signal decay of each region of interest mono-exponentially. The performance of measuring T2∗ using the sequence was first validated using a 13 C phantom and then with rodents following a bolus injection of HP [1-13 C]pyruvate. In humans, T2∗ of each metabolite was calculated for left ventricle, right ventricle, and myocardium. RESULTS: Cardiac T2∗ s of HP [1-13 C]pyruvate, [1-13 C]lactate, and [13 C]bicarbonate in rodents were measured as 24.9 ± 5.0, 16.4 ± 4.7, and 16.9 ± 3.4 ms, respectively. In humans, T2∗ of [1-13 C]pyruvate was 108.7 ± 22.6 ms in left ventricle and 129.4 ± 8.9 ms in right ventricle. T2∗ of [1-13 C]lactate was 40.9 ± 8.3, 44.2 ± 5.5, and 43.7 ± 9.0 ms in left ventricle, right ventricle, and myocardium, respectively. T2∗ of [13 C]bicarbonate in myocardium was 64.4 ± 2.5 ms. The measurements were reproducible and consistent over time after the pyruvate injection. CONCLUSION: The proposed metabolite-selective multi-echo spiral imaging sequence reliably measures in vivo cardiac T2∗ s of HP [1-13 C]pyruvate and products.

Characterization and compensation of f0 inhomogeneity artifact in spiral hyperpolarized 13 C imaging of the human heart.

PURPOSE: This study aimed to investigate the role of regional f0 inhomogeneity in spiral hyperpolarized 13 C image quality and to develop measures to alleviate these effects. METHODS: Field map correction of hyperpolarized 13 C cardiac imaging using spiral readouts was evaluated in healthy subjects. Spiral readouts with differing duration (26 and 45 ms) but similar resolution were compared with respect to off-resonance performance and image quality. An f0 map-based image correction based on the multifrequency interpolation (MFI) method was implemented and compared to correction using a global frequency shift alone. Estimation of an unknown frequency shift was performed by maximizing a sharpness objective based on the Sobel variance. The apparent full width half at maximum (FWHM) of the myocardial wall on [13 C]bicarbonate was used to estimate blur. RESULTS: Mean myocardial wall FWHM measurements were unchanged with the short readout pre-correction (14.1 ± 2.9 mm) and post-MFI correction (14.1 ± 3.4 mm), but significantly decreased in the long waveform (20.6 ± 6.6 mm uncorrected, 17.7 ± 7.0 corrected, P = .007). Bicarbonate signal-to-noise ratio (SNR) of the images acquired with the long waveform were increased by 1.4 ± 0.3 compared to those acquired with the short waveform (predicted 1.32). Improvement of image quality was observed for all metabolites with f0 correction. CONCLUSIONS: f0 -map correction reduced blur and recovered signal from dropouts, particularly along the posterior myocardial wall. The low image SNR of [13 C]bicarbonate can be compensated with longer duration readouts but at the expense of increased f0 artifacts, which can be partially corrected for with the proposed methods.

Hyperpolarized Carbon (13C) MRI of the Kidneys: Basic Concept.

Existing clinical markers for renal disease are limited. Hyperpolarized (HP) 13C MRI is based on the technology of dissolution dynamic nuclear polarization (DNP) and provides new avenues for imaging kidney structure, function, and most notably, renal metabolism, addressing some of these prior limitations. Changes in kidney structure and function associated with kidney disease can be evaluated using [13C]urea, a metabolically inert tracer. Metabolic changes can be assessed using [1-13C]pyruvate and a range of other rapidly metabolized small molecules, which mainly probe central carbon metabolism. Results from numerous preclinical studies using a variety of these probes demonstrated that this approach holds great potential for monitoring renal disease, although more work is needed to bridge intelligently into clinical studies. Here we introduce the general concept of HP 13C MRI and review the most relevant probes and applications to renal disease, including kidney cancer, diabetic nephropathy and ischemic kidney injury.This chapter is based upon work from the PARENCHIMA COST Action, a community-driven network funded by the European Cooperation in Science and Technology (COST) program of the European Union, which aims to improve the reproducibility and standardization of renal MRI biomarkers. This introduction chapter is complemented by two separate chapters describing the experimental procedure and data analysis.

Hyperpolarized Carbon (13C) MRI of the Kidney: Experimental Protocol.

Alterations in renal metabolism are associated with both physiological and pathophysiologic events. The existing noninvasive analytic tools including medical imaging have limited capability for investigating these processes, which potentially limits current understanding of kidney disease and the precision of its clinical diagnosis. Hyperpolarized 13C MRI is a new medical imaging modality that can capture changes in the metabolic processing of certain rapidly metabolized substrates, as well as changes in kidney function. Here we describe experimental protocols for renal metabolic [1-13C]pyruvate and functional 13C-urea imaging step-by-step. These methods and protocols are useful for investigating renal blood flow and function as well as the renal metabolic status of rodents in vivo under various experimental (patho)physiological conditions.This chapter is based upon work from the COST Action PARENCHIMA, a community-driven network funded by the European Cooperation in Science and Technology (COST) program of the European Union, which aims to improve the reproducibility and standardization of renal MRI biomarkers. This experimental protocol is complemented by two separate chapters describing the basic concept and data analysis.

Analysis Methods for Hyperpolarized Carbon (13C) MRI of the Kidney.

Hyperpolarized 13C MR is a novel medical imaging modality with substantially different signal dynamics as compared to conventional 1H MR, thus requiring new methods for processing the data in order to access and quantify the embedded metabolic and functional information. Here we describe step-by-step analysis protocols for functional renal hyperpolarized 13C imaging. These methods are useful for investigating renal blood flow and function as well as metabolic status of rodents in vivo under various experimental physiological conditions.This chapter is based upon work from the COST Action PARENCHIMA, a community-driven network funded by the European Cooperation in Science and Technology (COST) program of the European Union, which aims to improve the reproducibility and standardization of renal MRI biomarkers. This analysis protocol chapter is complemented by two separate chapters describing the basic concept and experimental procedure.

Comparison of hyperpolarized 13 C and non-hyperpolarized deuterium MRI approaches for imaging cerebral glucose metabolism at 4.7 T.

PURPOSE: The purpose of this study was to directly compare two isotopic metabolic imaging approaches, hyperpolarized (HP) 13 C MRI and deuterium metabolic imaging (DMI), for imaging specific closely related segments of cerebral glucose metabolism at 4.7 T. METHODS: Comparative HP-13 C and DMI neuroimaging experiments were conducted consecutively in normal rats during the same scanning session. Localized conversions of [1-13 C]pyruvate and [6,6-2 H2 ]glucose to their respective downstream metabolic products were measured by spectroscopic imaging, using an identical 2D-CSI sequence with parameters optimized for the respective experiments. To facilitate direct comparison, a pair of substantially equivalent 2.5-cm double-tuned X/1 H RF surface coils was developed. For improved results, multidimensional low-rank reconstruction was applied to denoise the raw DMI data. RESULTS: Localized conversion of HP [1-13 C]pyruvate to [1-13 C]lactate, and [6,6-2 H2 ]glucose to [3,3-2 H2 ]lactate and Glx-d (glutamate and glutamine), was detected in rat brain by spectroscopic imaging at 4.7 T. The SNR and spatial resolution of HP-13 C MRI was superior to DMI but limited to a short time window, whereas the lengthy DMI acquisition yielded maps of not only lactate, but also Glx production, albeit with relatively poor spectral discrimination between metabolites at this field strength. Across the individual rats, there was an apparent inverse correlation between cerebral production of HP [1-13 C]lactate and Glx-d, along with a trend toward increased [3,3-2 H2 ]lactate. CONCLUSION: The HP-13 C MRI and DMI methods are both feasible at 4.7 T and have significant potential for metabolic imaging of specific segments of glucose metabolism.

15 N-carnitine, a novel endogenous hyperpolarized MRI probe with long signal lifetime.

PURPOSE: The purpose of this study was to investigate hyperpolarization and in vivo imaging of [15 N]carnitine, a novel endogenous MRI probe with long signal lifetime. METHODS: L-[15 N]carnitine-d9 was hyperpolarized by the method of dynamic nuclear polarization followed by rapid dissolution. The T1 signal lifetimes were estimated in aqueous solution and in vivo following intravenous injection in rats, using a custom-built dual-tuned 15 N/1 H RF coil at 4.7 T. 15 N chemical shift imaging and 15 N fast spin-echo images of rat abdomen were acquired 3 minutes after [15 N]carnitine injection. RESULTS: Estimated T1 times of [15 N]carnitine at 4.7 T were 210 seconds (in H2 O) and 160 seconds (in vivo), with an estimated polarization level of 10%. Remarkably, the [15 N]carnitine coherence was detectable in rat abdomen for 5 minutes after injection for the nonlocalized acquisition. No downstream metabolites were detected on localized or nonlocalized 15 N spectra. Diffuse liver enhancement was detected on 15 N fast spin-echo imaging 3 minutes after injection, with mean hepatic SNR of 18 ± 5 at a spatial resolution of 4 × 4 mm. CONCLUSION: This study showed the feasibility of hyperpolarizing and imaging the biodistribution of HP [15 N]carnitine.

Imaging Acute Metabolic Changes in Patients with Mild Traumatic Brain Injury Using Hyperpolarized [1-13C]Pyruvate.

Traumatic brain injury (TBI) involves complex secondary injury processes following the primary injury. The secondary injury is often associated with rapid metabolic shifts and impaired brain function immediately after the initial tissue damage. Magnetic resonance spectroscopic imaging (MRSI) coupled with hyperpolarization of 13C-labeled substrates provides a unique opportunity to map the metabolic changes in the brain after traumatic injury in real-time without invasive procedures. In this report, we investigated two patients with acute mild TBI (Glasgow coma scale 15) but no anatomical brain injury or hemorrhage. Patients were imaged with hyperpolarized [1-13C]pyruvate MRSI 1 or 6 days after head trauma. Both patients showed significantly reduced bicarbonate (HCO3 -) production, and one showed hyperintense lactate production at the injured sites. This study reports the feasibility of imaging altered metabolism using hyperpolarized pyruvate in patients with TBI, demonstrating the translatability and sensitivity of the technology to cerebral metabolic changes after mild TBI.

Tensor image enhancement and optimal multichannel receiver combination analyses for human hyperpolarized 13 C MRSI.

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.

Simultaneous T1 and T2 mapping of hyperpolarized 13C compounds using the bSSFP sequence.

As in conventional 1H MRI, T1 and T2 relaxation times of hyperpolarized (HP) 13C nuclei can provide important biomedical information. Two new approaches were developed for simultaneous T1 and T2 mapping of HP 13C probes based on balanced steady state free precession (bSSFP) acquisitions: a method based on sequential T1 and T2 mapping modules, and a model-based joint T1/T2 approach analogous to MR fingerprinting. These new methods were tested in simulations, HP 13C phantoms, and in vivo in normal Sprague-Dawley rats. Non-localized T1 values, low flip angle EPI T1 maps, bSSFP T2 maps, and Bloch-Siegert B1 maps were also acquired for comparison. T1 and T2 maps acquired using both approaches were in good agreement with both literature values and data from comparative acquisitions. Multiple HP 13C compounds were successfully mapped, with their relaxation time parameters measured within heart, liver, kidneys, and vasculature in one acquisition for the first time.

A metabolite-specific 3D stack-of-spiral bSSFP sequence for improved lactate imaging in hyperpolarized [1-13 C]pyruvate studies on a 3T clinical scanner.

PURPOSE: The balanced steady-state free precession sequence has been previously explored to improve the efficient use of nonrecoverable hyperpolarized 13C magnetization, but suffers from poor spectral selectivity and long acquisition time. The purpose of this study was to develop a novel metabolite-specific 3D bSSFP ("MS-3DSSFP") sequence with stack-of-spiral readouts for improved lactate imaging in hyperpolarized [1-13 C]pyruvate studies on a clinical 3T scanner. METHODS: Simulations were performed to evaluate the spectral response of the MS-3DSSFP sequence. Thermal 13C phantom experiments were performed to validate the MS-3DSSFP sequence. In vivo hyperpolarized [1-13 C], pyruvate studies were performed to compare the MS-3DSSFP sequence with metabolite-specific gradient echo ("MS-GRE") sequences for lactate imaging. RESULTS: Simulations, phantom, and in vivo studies demonstrate that the MS-3DSSFP sequence achieved spectrally selective excitation on lactate while minimally perturbing other metabolites. Compared with MS-GRE sequences, the MS-3DSSFP sequence showed approximately a 2.5-fold SNR improvement for lactate imaging in rat kidneys, prostate tumors in a mouse model, and human kidneys. CONCLUSIONS: Improved lactate imaging using the MS-3DSSFP sequence in hyperpolarized [1-13 C]pyruvate studies was demonstrated in animals and humans. The MS-3DSSFP sequence could be applied for other clinical applications such as in the brain or adapted for imaging other metabolites such as pyruvate and bicarbonate.

Imaging of glucose metabolism by 13C-MRI distinguishes pancreatic cancer subtypes in mice.

Metabolic differences among and within tumors can be an important determinant in cancer treatment outcome. However, methods for determining these differences non-invasively in vivo is lacking. Using pancreatic ductal adenocarcinoma as a model, we demonstrate that tumor xenografts with a similar genetic background can be distinguished by their differing rates of the metabolism of 13C labeled glucose tracers, which can be imaged without hyperpolarization by using newly developed techniques for noise suppression. Using this method, cancer subtypes that appeared to have similar metabolic profiles based on steady state metabolic measurement can be distinguished from each other. The metabolic maps from 13C-glucose imaging localized lactate production and overall glucose metabolism to different regions of some tumors. Such tumor heterogeneity would not be not detectable in FDG-PET.