Deuterium metabolic imaging for 3D mapping of glucose metabolism in humans with central nervous system lesions at 3T.

PURPOSE: To explore the potential of 3T deuterium metabolic imaging (DMI) using a birdcage 2 H radiofrequency (RF) coil in both healthy volunteers and patients with central nervous system (CNS) lesions. METHODS: A modified gradient filter, home-built 2 H volume RF coil, and spherical k-space sampling were employed in a three-dimensional chemical shift imaging acquisition to obtain high-quality whole-brain metabolic images of 2 H-labeled water and glucose metabolic products. These images were acquired in a healthy volunteer and three subjects with CNS lesions of varying pathologies. Hardware and pulse sequence experiments were also conducted to improve the signal-to-noise ratio of DMI at 3T. RESULTS: The ability to quantify local glucose metabolism in correspondence to anatomical landmarks across patients with varying CNS lesions is demonstrated, and increased lactate is observed in one patient with the most active disease. CONCLUSION: DMI offers the potential to examine metabolic activity in human subjects with CNS lesions with DMI at 3T, promising for the potential of the future clinical translation of this metabolic imaging technique.

Investigating the origin of the 13 C lactate signal in the anesthetized healthy rat brain in vivo after hyperpolarized [1-13 C]pyruvate injection.

The goal of this study was to investigate the origin of brain lactate (Lac) signal in the healthy anesthetized rat after injection of hyperpolarized (HP) [1-13 C]pyruvate (Pyr). Dynamic two-dimensional spiral chemical shift imaging with flow-sensitizing gradients revealed reduction in both vascular and brain Pyr, while no significant dependence on the level of flow suppression was detected for Lac. These results support the hypothesis that the HP metabolites predominantly reside in different compartments in the brain (i.e., Pyr in the blood and Lac in the parenchyma). Data from high-resolution metabolic imaging of [1-13 C]Pyr further demonstrated that Lac detected in the brain was not from contributions of vascular signal attributable to partial volume effects. Additionally, metabolite distributions and kinetics measured with dynamic imaging after injection of HP [1-13 C]Lac were similar to Pyr data when Pyr was used as the substrate. These data do not support the hypothesis that Lac observed in the brain after Pyr injection was generated in other organs and then transported across the blood-brain barrier (BBB). Together, the presented results provide further evidence that even in healthy anesthetized rats, the transport of HP Pyr across the BBB is sufficiently fast to permit detection of its metabolic conversion to Lac within the brain.

Critical Degree of Orbital Floor Displacement Drives Operative Repair of Zygomaticomaxillary Complex Fractures: Findings from a 10-Year Retrospective Study.

Among zygomaticomaxillary complex (ZMC) fractures presenting to a tertiary urban academic center, the authors hypothesized the presence of both clinical and radiographic predictors of operative management. The investigators conducted a retrospective cohort study of 1,914 patients with facial fractures managed at an academic medical center in New York City between 2008 and 2017. The predictor variables were based on both clinical data and features of pertinent imaging studies, and the outcome variable was an operative intervention. Descriptive and bivariate statistics were computed and the p-value was set at 0.05. In total, 196 patients sustained ZMC fractures (5.0%) and 121 (61.7%) ZMC fractures were treated surgically. All patients who presented with globe injury, blindness, retrobulbar injury, restricted gaze, or enophthalmos and a concurrent ZMC fracture were managed surgically. The most common surgical approach was the gingivobuccal corridor (31.9% of all approaches), and there were no significant immediate postoperative complications. Younger patients (38.9 ± 18 years vs. 56.1 ± 23.5 years, p < 0.0001) and patients with greater than or equal to 4 mm of orbital floor displacement were more likely to receive surgical treatment than observation (82 vs. 56%, p = 0.045), as were patients with comminuted orbital floor fractures (52 vs. 26%, p = 0.011). In this cohort, patients more likely to undergo surgical reduction were young patients with ophthalmologic symptoms on presentation and at least 4 mm displacement of the orbital floor. Low kinetic energy ZMC fractures may warrant surgical management as often as high-energy ZMC fractures. While orbital floor comminution has been shown to be a predictor for operative reduction, in this study we also demonstrated a difference in the rate of reduction based on the severity of orbital floor displacement. This may have significant implications in both the triage and selection of patients most suitable for operative repair.

Proton magnetic resonance spectroscopy assessment of neonatal brain metabolism during cardiopulmonary bypass surgery.

Here, we report on the development and performance of a robust 3-T single-voxel proton magnetic resonance spectroscopy (1 H MRS) experimental protocol and data analysis pipeline for quantifying brain metabolism during cardiopulmonary bypass (CPB) surgery in a neonatal porcine model, with the overall goal of elucidating primary mechanisms of brain injury associated with these procedures. The specific aims were to assess which metabolic processes can be reliably interrogated by 1 H MRS on a 3-T clinical scanner and to provide an initial assessment of brain metabolism during deep hypothermia cardiac arrest (DHCA) surgery and recovery. Fourteen neonatal pigs underwent CPB surgery while placed in a 3-T MRI scanner for 18, 28, and 37°C DHCA studies under hyperglycemic, euglycemic, and hypoglycemic conditions. Total imaging times, including baseline measurements, circulatory arrest (CA), and recovery averaged 3 h/animal, during which 30-40 single-voxel 1 H MRS spectra (sLASER pulse sequence, TR/TE = 2000/30 ms, 64 or 128 averages) were acquired from a 2.2-cc right midbrain voxel. 1 H MRS at 3 T was able to reliably quantify (1) anaerobic metabolism via depletion of brain glucose and the associated build-up of lactate during CA, (2) phosphocreatine (PCr) to creatine (Cr) conversion during CA and subsequent recovery upon reperfusion, (3) a robust increase in the glutamine-to-glutamate (Gln/Glu) ratio during the post-CA recovery period, and (4) a broadening of the water peak during CA. In vivo 1 H MRS at 3 T can reliably quantify subtle metabolic brain changes previously deemed challenging to interrogate, including brain glucose concentrations even under hypoglycemic conditions, ATP usage via the conversion of PCr to Cr, and differential changes in Glu and Gln. Observed metabolic changes during CPB surgery of a neonatal porcine model provide new insights into possible mechanisms for prevention of neuronal injury.

Thalamic and prefrontal GABA concentrations but not GABAA receptor densities are altered in high-functioning adults with autism spectrum disorder.

The gamma aminobutyric acid (GABA) neurotransmission system has been implicated in autism spectrum disorder (ASD). Molecular neuroimaging studies incorporating simultaneous acquisitions of GABA concentrations and GABAA receptor densities can identify objective molecular markers in ASD. We measured both total GABAA receptor densities by using [18F]flumazenil positron emission tomography ([18F]FMZ-PET) and GABA concentrations by using proton magnetic resonance spectroscopy (1H-MRS) in 28 adults with ASD and 29 age-matched typically developing (TD) individuals. Focusing on the bilateral thalami and the left dorsolateral prefrontal cortex (DLPFC) as our regions of interest, we found no differences in GABAA receptor densities between ASD and TD groups. However, 1H-MRS measurements revealed significantly higher GABA/Water (GABA normalized by water signal) in the left DLPFC of individuals with ASD than that of TD controls. Furthermore, a significant gender effect was observed in the thalami, with higher GABA/Water in males than in females. Hypothesizing that thalamic GABA correlates with ASD symptom severity in gender-specific ways, we stratified by diagnosis and investigated the interaction between gender and thalamic GABA/Water in predicting Autism-Spectrum Quotient (AQ) and Ritvo Autism Asperger's Diagnostic Scale-Revised (RAADS-R) total scores. We found that gender is a significant effect modifier of thalamic GABA/Water's relationship with AQ and RAADS-R scores for individuals with ASD, but not for TD controls. When we separated the ASD participants by gender, a negative correlation between thalamic GABA/Water and AQ was observed in male ASD participants. Remarkably, in female ASD participants, a positive correlation between thalamic GABA/Water and AQ was found.

Benign bony tumors of the paranasal sinuses, orbit, and skull base.

Benign bony tumors of the skull base and paranasal sinuses are uncommon entities, with an overall higher incidence in males. Benign bony tumors may lead to local expansion with resultant mass effect of potentially critical structures. Some benign bony tumors may undergo malignant transformation. This article reviews the presentation and management of benign bone tumors of the skull base and paranasal sinuses with special consideration to involvement of the adjacent orbit, intracranial and critical neurovascular structures. This review covers tumor incidence, location, gross and histologic appearance as well as radiographic findings, treatment, and recurrence rates. Tumors discussed in this article include osteochondromas, osteomas, osteoid osteomas, aneurysmal bone cysts, fibrous dysplasia, giant cell tumors, cemento-ossifying fibroma, ameloblastic fibro-odontoma, ecchordosis physaliphora, chondromyxoid fibroma, primary chronic osteomyelitis, primary chronic osteomyelitis, osteochondromyxoma, and dense bone islands.

Hyperpolarized NMR study of the impact of pyruvate dehydrogenase kinase inhibition on the pyruvate dehydrogenase and TCA flux in type 2 diabetic rat muscle.

The role of pyruvate dehydrogenase in mediating lipid-induced insulin resistance stands as a central question in the pathogenesis of type 2 diabetes mellitus. Many researchers have invoked the Randle hypothesis to explain the reduced glucose disposal in skeletal muscle by envisioning an elevated acetyl CoA pool arising from increased oxidation of fatty acids. Over the years, in vivo NMR studies have challenged that monolithic view. The advent of the dissolution dynamic nuclear polarization NMR technique and a unique type 2 diabetic rat model provides an opportunity to clarify. Dynamic nuclear polarization enhances dramatically the NMR signal sensitivity and allows the measurement of metabolic kinetics in vivo. Diabetic muscle has much lower pyruvate dehydrogenase activity than control muscle, as evidenced in the conversion of [1-13C]lactate and [2-13C]pyruvate to HCO3- and acetyl carnitine. The pyruvate dehydrogenase kinase inhibitor, dichloroacetate, restores rapidly the diabetic pyruvate dehydrogenase activity to control level. However, diabetic muscle has a much larger dynamic change in pyruvate dehydrogenase flux than control. The dichloroacetate-induced surge in pyruvate dehydrogenase activity produces a differential amount of acetyl carnitine but does not affect the tricarboxylic acid flux. Further studies can now proceed with the dynamic nuclear polarization approach and a unique rat model to interrogate closely the biochemical mechanism interfacing oxidative metabolism with insulin resistance and metabolic inflexibility.

MRI of [2-13 C]Lactate without J-coupling artifacts.

PURPOSE: Imaging of [2-13 C]lactate, a metabolic product of [2-13 C]pyruvate, is over considerable interest in hyperpolarized 13 C studies. However, artifact-free imaging of a J-coupled nuclear spin species can be challenging due to the peak-splitting induced by the spin-spin interactions. In this work, two new techniques resolving these J-modulated artifacts are presented. THEORY AND METHODS: The Product Operator Formalism (POF) of density matrix theory is used to both numerically and analytically derive the coherences arising during radiofrequency excitation and readout of a J-coupled spin system. A combination of computer simulations and experiments with [2-13 C]lactate and 13 C-formate phantoms are then used to verify the performance of two imaging methods. In the first approach, a quadrature imaging technique is used to eliminate scalar coupling artifacts via the combination of in-phase and quadrature images acquired at echo times differing by 1/2J with an echoplanar readout. The second approach employs a highly narrowband RF excitation pulse to image a single peak from the J-coupled doublet. RESULTS: Simulations using a numerical Shepp-Logan phantom, in vitro experiments using thermally polarized [2-13 C]lactate, thermally and hyperpolarized 13 C-formate phantoms, and in vivo imaging of [2-13 C]lactate produced in rat brain following injection of hyperpolarized [2-13 C]pyruvate show artifact-free images and demonstrate potential utility of these methods. CONCLUSION: The quadrature imaging and the narrowband excitation techniques resolve the J-coupling induced ghosting and blurring artifacts present with conventional MRI of J-coupled signals such as [2-13 C]lactate.

Water and lipid suppression techniques for advanced 1 H MRS and MRSI of the human brain: Experts' consensus recommendations.

The neurochemical information provided by proton magnetic resonance spectroscopy (MRS) or MR spectroscopic imaging (MRSI) can be severely compromised if strong signals originating from brain water and extracranial lipids are not properly suppressed. The authors of this paper present an overview of advanced water/lipid-suppression techniques and describe their advantages and disadvantages. Moreover, they provide recommendations for choosing the most appropriate techniques for proper use. Methods of water signal handling are primarily focused on the VAPOR technique and on MRS without water suppression (metabolite cycling). The section on lipid-suppression methods in MRSI is divided into three parts. First, lipid-suppression techniques that can be implemented on most clinical MR scanners (volume preselection, outer-volume suppression, selective lipid suppression) are described. Second, lipid-suppression techniques utilizing the combination of k-space filtering, high spatial resolutions and lipid regularization are presented. Finally, three promising new lipid-suppression techniques, which require special hardware (a multi-channel transmit system for dynamic B1+ shimming, a dedicated second-order gradient system or an outer volume crusher coil) are introduced.

Office-Based Sinus Surgery for Cystic Fibrosis Chronic Rhinosinusitis.

OBJECTIVE: Chronic rhinosinusitis (CRS) is nearly ubiquitous in the cystic fibrosis (CF) population, and many patients require multiple endoscopic sinus surgeries throughout their lifetime. Recent studies have demonstrated the profound pulmonary and systemic health benefits of comprehensive CRS treatment. Both endotracheal intubation with mechanical ventilation and inpatient hospital care represent significant risks for CF patients. The goal of this study is to evaluate the safety and feasibility of performing revision endoscopic sinus surgery for CF patients in the outpatient office setting using only local anesthesia to decrease the need for mechanical ventilation and inpatient hospitalization. METHODS: This is a prospective cohort study conducted at a tertiary care academic medical center with a CF Foundation-accredited care center. Patients with CF and refractory CRS despite prior surgery and medical therapy were eligible for inclusion. Comprehensive revision ESS was performed in the office using only local anesthesia. RESULTS: Five patients were enrolled and underwent revision endoscopic sinus surgery without complication. The average preoperative Sinonasal-Outcome Test-22 score was 52.0 ± 12.1 and the average preoperative Lund-Mackay score was 15.2 ± 3.8. No patients requested aborting the procedure early due to pain, discomfort, or any other reason. No subjects required prolonged observation or postoperative hospital admission. CONCLUSION: This prospective pilot study is the first to demonstrate the safety and feasibility of performing comprehensive revision endoscopic sinus surgery for CF patients in the outpatient office setting using only local anesthesia.

Frontal Sinus Fractures: 10-Year Contemporary Experience at a Level 1 Urban Trauma Center.

ABSTRACT: Frontal sinus fractures account for 5% to 15% of all facial fractures, and have traditionally been associated with high kinetic energy blunt injury. Surgical management is largely focused on minimizing potentially serious sequelae including frontal sinus dysfunction, CSF leak, and significant cosmetic deformity. An institutional database of 1944 patients presenting with maxillofacial fractures over a 10-year period was queried. Demographics, mechanism of injury, yearly trends, surgical approaches, and follow-up data were examined. A total of 160 (8.3%) patients presented with at least 1 fracture of the frontal sinus anterior table, posterior table, or frontal sinus outflow tract during the study period. The average annual number of cases was 15.9 ±â€Š5.7 per year with a peak of 21.5 ±â€Š4.0 cases during the 2014 to 2015 period and a decline to 8.5 ±â€Š1.5 cases/year from 2016 to 2017. Among those patients with falls, 61.5% (n = 40) were a result of tripping or fainting at a height of <6 ft. 55.6% of fracture types were isolated to the anterior table, but fracture location was not significantly associated with operative intervention. Cases of operative fracture type had a higher rate of both displacement and comminution compared to nonoperative fractures (P < 0.00001). Of all patients presenting with frontal sinus fractures, 75% of cases were managed nonoperatively. However, many patients presented with falls and other seemingly low energy injuries which are not traditionally associated with frontal sinus trauma. These results highlight the need for continued follow-up even in otherwise low-risk urban populations in order to avoid long term sinus dysfunction.

Injury Patterns in Pediatric Facial Fractures Unique to an Urban Environment.

This study aimed to define better the clinical presentation, fracture patterns, and features predictive of associated injuries and need for surgery in pediatric facial trauma patients in an urban setting. Charts of patients 18 years or younger with International Classification of Disease 9th and 10th revision (ICD-9/ICD-10) codes specific for facial fractures (excluding isolated nasal fractures) at NY-Presbyterian/Weill Cornell Medical Center between 2008 and 2017 were retrospectively reviewed. Of 204 patients, most were referred to the emergency department by a physician's office or self-presented. Children (age 0-6 years) were most likely to have been injured by falls, while more patients 7 to 12 years and 13 to 18 years were injured during sporting activities (p < 0.0001). Roughly half (50.5%) of the patients had a single fracture, and the likelihood of surgery increased with greater numbers of fractures. Older patients with either orbital or mandibular fractures were more likely to undergo surgery than younger ones (p = 0.0048 and p = 0.0053, respectively). Cranial bone fractures, CSF leaks, and intracranial injuries were more common in younger patients (p < 0.0001) than older patients and were more likely after high energy injuries; however, 16.2% of patients sustaining low energy injuries also sustained cranial bone, CSF leak, or intracranial injury. In an urban environment, significant pediatric facial fractures and associated injuries may occur after nonclassic low kinetic energy traumatic events. The age of the patient impacts both the injuries sustained and the treatment rendered. It is essential to maintain a high index of suspicion for associated injuries in all pediatric facial trauma patients.

The Nasoseptal Chondromucosal Flap: A Rigid Reconstructive Technique for Skull Base and Orbital Defects.

INTRODUCTION: The pedicled mucoperichondrial nasoseptal flap serves as the predominant reconstructive option for anterior skull base defects. Its use has also been described for repair of the lamina papyracea following orbital tumor removal. Large skull base or orbital defects may benefit from a more rigid reconstruction to reduce the risk of herniation of orbital or intracranial contents into the sinonasal cavity, which could result in enophthalmos, diplopia, or an encephalocele. OBJECTIVE: This study aims to test the feasibility of using a vascularized rigid composite nasoseptal chondromucosal flap for increased structural support in repairing skull base or orbital defects. METHODS: The study was conducted in a cadaver model in a surgical skills laboratory. RESULTS: We demonstrate a novel technique for harvesting and insetting a pedicled vascularized autologous rigid composite nasoseptal chondromucosal flap to repair both orbital and anterior skull base defects. The graft is harvested with intact mucosa, cartilage, and bilateral perichondrium to preserve a contiguous vascular supply. Confirmation of successful reconstruction is achieved via transcranial and transorbital access to visualize the graft from above. CONCLUSION: The cartilaginous support with associated perichondrium adds to the structural integrity of the reconstruction and may serve as an alternative to devascularized autologous grafts or synthetic materials, which may be particularly advantageous in patients with large defects or those requiring adjuvant radiation.

GABA editing with macromolecule suppression using an improved MEGA-SPECIAL sequence.

PURPOSE: The most common γ-aminobutyric-acid (GABA) editing approach, MEGA-PRESS, uses J-editing to measure GABA distinct from larger overlapping metabolites, but suffers contamination from coedited macromolecules (MMs) comprising 40 to 60% of the observed signal. MEGA-SPECIAL is an alternative method with better MM suppression, but is not widely used primarily because of its relatively poor spatial localization. Our goal was to develop an improved MM-suppressed GABA editing sequence at 3 Tesla. METHODS: We modified a single-voxel MEGA-SPECIAL sequence with an oscillating readout gradient for improved spatial localization, and used very selective 30-ms editing pulses for improved suppression of coedited MMs. RESULTS: Simulation and in vivo experiments confirmed excellent MM suppression, insensitive to the range of B0 frequency drifts typically encountered in vivo. Both intersubject and intrasubject studies showed that MMs, when suppressed by the improved MEGA-SPECIAL method, contributed approximately 40% to the corresponding MEGA-PRESS measurements. From the intersubject study, the coefficient of variation for GABA+/Cre (MEGA-PRESS) was 11.2% versus 7% for GABA/Cre (improved MEGA-SPECIAL), demonstrating significantly reduced variance (P = 0.005), likely coming from coedited MMs. CONCLUSIONS: This improved MEGA-SPECIAL sequence provides unbiased GABA measurements with reduced variance as compared with conventional MEGA-PRESS. This approach is also relatively insensitive to the range of B0 drifts typically observed in in vivo human studies. Magn Reson Med 79:41-47, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Hyperpolarized Sodium [1-13C]-Glycerate as a Probe for Assessing Glycolysis In Vivo.

Hyperpolarized 13C magnetic resonance spectroscopy (MRS) provides unprecedented opportunities to obtain clinical diagnostic information through in vivo monitoring of metabolic pathways. The continuing advancement of this field relies on the identification of molecular probes that can effectively interrogate pathways critical to disease. In this report, we describe the synthesis, development, and in vivo application of sodium [1-13C]-glycerate ([13C]-Glyc) as a novel probe for evaluating glycolysis using hyperpolarized 13C MRS. This agent was prepared by a concise synthetic route and formulated for dynamic nuclear polarization. [13C]-Glyc displayed a high level of polarization and long spin-lattice relaxation time-both of which are necessary for future clinical investigations. In vivo spectroscopic studies with hyperpolarized [13C]-Glyc in rat liver furnished metabolic products, [13C]-labeled pyruvate and lactate, originating from glycolysis. The levels of production and relative intensities of these metabolites were directly correlated with the induced glycolytic state (fasted versus fed groups). This work establishes hyperpolarized [13C]-Glyc as a novel agent for clinically relevant 13C MRS studies of energy metabolism and further provides opportunities for evaluating intracellular redox states in biochemical investigations.

In vivo assessment of intracellular redox state in rat liver using hyperpolarized [1-13 C]Alanine.

PURPOSE: The intracellular lactate to pyruvate concentration ratio is a commonly used tissue assay biomarker of redox, being proportional to free cytosolic [NADH]/[NAD+ ]. In this study, we assessed the use of hyperpolarized [1-13 C]alanine and the subsequent detection of the intracellular products of [1-13 C]pyruvate and [1-13 C]lactate as a useful substrate for assessing redox levels in the liver in vivo. METHODS: Animal experiments were conducted to measure in vivo metabolism at baseline and after ethanol infusion. A solution of 80-mM hyperpolarized [1-13 C]alanine was injected intravenously at baseline (n = 8) and 45 min after ethanol infusion (n = 4), immediately followed by the dynamic acquisition of 13 C MRS spectra. RESULTS: In vivo rat liver spectra showed peaks from [1-13 C] alanine and the products of [1-13 C]lactate, [1-13 C]pyruvate, and 13 C-bicarbonate. A significantly increased 13 C-lactate/13 C-pyruvate ratio was observed after ethanol infusion (8.46 ± 0.58 at baseline versus 13.58 ± 0.69 after ethanol infusion; P < 0.001) consistent with the increased NADH produced by liver metabolism of ethanol to acetaldehyde and then acetate. A decrease in 13 C-bicarbonate production was also noted, potentially reflecting ethanol-induced mitochondrial redox changes. CONCLUSION: A method to measure in vivo tissue redox using hyperpolarized [1-13 C]alanine is presented, with the validity of the proposed 13 C-pyruvate/13 C-lactate metric tested using an ethanol challenge to alter liver redox state. Magn Reson Med 77:1741-1748, 2017. © 2017 International Society for Magnetic Resonance in Medicine.

Doublet asymmetry for estimating polarization in hyperpolarized 13 C-pyruvate studies.

Hyperpolarized 13 C MRS allows in vivo interrogation of key metabolic pathways, with pyruvate (Pyr) the substrate of choice for current clinical studies. Knowledge of the liquid-state polarization is needed for full quantitation, and asymmetry of the C2 doublet, arising from 1% naturally abundant [1,2-13 C]Pyr in any hyperpolarized [1-13 C]Pyr sample, has been suggested as a direct measure of in vivo C1 polarization via the use of an in vitro calibration curve. Here we show that different polarization levels can yield the same C2 -doublet asymmetry, thus limiting the utility of this metric for quantitation. Furthermore, although the time evolution of doublet asymmetry is poorly modeled using the expected dominant relaxation mechanisms of carbon-proton dipolar coupling and chemical shift anisotropy, the inclusion of a C-C dipolar coupling term can explain the observed initial evolution of the C2 doublet asymmetry beyond its expected thermal equilibrium value.

A Metabolic Therapy for Malignant Glioma Requires a Clinical Measure.

Cancers are "reprogrammed" to use a much higher rate of glycolysis (GLY) relative to oxidative phosphorylation (OXPHOS), even in the presence of adequate amounts of oxygenation. Originally identified by Nobel Laureate Otto Warburg, this hallmark of cancer has recently been termed metabolic reprogramming and represents a way for the cancer tissue to divert carbon skeletons to produce biomass. Understanding the mechanisms that underlie this metabolic shift should lead to better strategies for cancer treatments. Malignant gliomas, cancers that are very resistant to conventional treatments, are highly glycolytic and seem particularly suited to approaches that can subvert this phenotype.

Volumetric spiral chemical shift imaging of hyperpolarized [2-(13) c]pyruvate in a rat c6 glioma model.

PURPOSE: MRS of hyperpolarized [2-(13)C]pyruvate can be used to assess multiple metabolic pathways within mitochondria as the (13)C label is not lost with the conversion of pyruvate to acetyl-CoA. This study presents the first MR spectroscopic imaging of hyperpolarized [2-(13)C]pyruvate in glioma-bearing brain. METHODS: Spiral chemical shift imaging with spectrally undersampling scheme (1042 Hz) and a hard-pulse excitation was exploited to simultaneously image [2-(13)C]pyruvate, [2-(13)C]lactate, and [5-(13)C]glutamate, the metabolites known to be produced in brain after an injection of hyperpolarized [2-(13)C]pyruvate, without chemical shift displacement artifacts. A separate undersampling scheme (890 Hz) was also used to image [1-(13)C]acetyl-carnitine. Healthy and C6 glioma-implanted rat brains were imaged at baseline and after dichloroacetate administration, a drug that modulates pyruvate dehydrogenase kinase activity. RESULTS: The baseline metabolite maps showed higher lactate and lower glutamate in tumor as compared to normal-appearing brain. Dichloroacetate led to an increase in glutamate in both tumor and normal-appearing brain. Dichloroacetate-induced %-decrease of lactate/glutamate was comparable to the lactate/bicarbonate decrease from hyperpolarized [1-(13)C]pyruvate studies. Acetyl-carnitine was observed in the muscle/fat tissue surrounding the brain. CONCLUSION: Robust volumetric imaging with hyperpolarized [2-(13)C]pyruvate and downstream products was performed in glioma-bearing rat brains, demonstrating changes in mitochondrial metabolism with dichloroacetate.

Hyperpolarized (13)C-lactate to (13)C-bicarbonate ratio as a biomarker for monitoring the acute response of anti-vascular endothelial growth factor (anti-VEGF) treatment.

Hyperpolarized [1-(13)C]pyruvate MRS provides a unique imaging opportunity to study the reaction kinetics and enzyme activities of in vivo metabolism because of its favorable imaging characteristics and critical position in the cellular metabolic pathway, where it can either be reduced to lactate (reflecting glycolysis) or converted to acetyl-coenzyme A and bicarbonate (reflecting oxidative phosphorylation). Cancer tissue metabolism is altered in such a way as to result in a relative preponderance of glycolysis relative to oxidative phosphorylation (i.e. Warburg effect). Although there is a strong theoretical basis for presuming that readjustment of the metabolic balance towards normal could alter tumor growth, a robust noninvasive in vivo tool with which to measure the balance between these two metabolic processes has yet to be developed. Until recently, hyperpolarized (13)C-pyruvate imaging studies had focused solely on [1-(13)C]lactate production because of its strong signal. However, without a concomitant measure of pyruvate entry into the mitochondria, the lactate signal provides no information on the balance between the glycolytic and oxidative metabolic pathways. Consistent measurement of (13)C-bicarbonate in cancer tissue, which does provide such information, has proven difficult, however. In this study, we report the reliable measurement of (13)C-bicarbonate production in both the healthy brain and a highly glycolytic experimental glioblastoma model using an optimized (13)C MRS imaging protocol. With the capacity to obtain signal in all tumors, we also confirm for the first time that the ratio of (13)C-lactate to (13)C-bicarbonate provides a more robust metric relative to (13)C-lactate for the assessment of the metabolic effects of anti-angiogenic therapy. Our data suggest a potential application of this ratio as an early biomarker to assess therapeutic effectiveness. Furthermore, although further study is needed, the results suggest that anti-angiogenic treatment results in a rapid normalization in the relative tissue utilization of glycolytic and oxidative phosphorylation by tumor tissue.