Deuterium MR spectroscopy: potential applications in oncology research.

Metabolic imaging in clinical practice has long relied on PET with fluorodeoxyglucose (FDG), a radioactive tracer. However, this conventional method presents inherent limitations such as exposure to ionizing radiation and potential diagnostic uncertainties, particularly in organs with heightened glucose uptake like the brain. This review underscores the transformative potential of traditional deuterium MR spectroscopy (MRS) when integrated with gradient techniques, culminating in an advanced metabolic imaging modality known as deuterium MRI (DMRI). While recent advancements in hyperpolarized MRS hold promise for metabolic analysis, their widespread clinical usage is hindered by cost constraints and the availability of hyperpolarizer devices or facilities. DMRI, also denoted as deuterium metabolic imaging (DMI), represents a pioneering, single-shot, and noninvasive paradigm that fuses conventional MRS with nonradioactive deuterium-labelled substrates. Extensively tested in animal models and patient cohorts, particularly in cases of brain tumours, DMI's standout feature lies in its seamless integration into standard clinical MRI scanners, necessitating only minor adjustments such as radiofrequency coil tuning to the deuterium frequency. DMRI emerges as a versatile tool for quantifying crucial metabolites in clinical oncology, including glucose, lactate, glutamate, glutamine, and characterizing IDH mutations. Its potential applications in this domain are broad, spanning diagnostic profiling, treatment response monitoring, and the identification of novel therapeutic targets across diverse cancer subtypes.

Human Brain Deuterium Metabolic Imaging at 7 T: Impact of Different [6,6'-2H2]Glucose Doses.

BACKGROUND: Deuterium metabolic imaging (DMI) is an innovative, noninvasive metabolic MR imaging method conducted after administration of 2H-labeled substrates. DMI after [6,6'-2H2]glucose consumption has been used to investigate brain metabolic processes, but the impact of different [6,6'-2H2]glucose doses on DMI brain data is not well known. PURPOSE: To investigate three different [6,6'-2H2]glucose doses for DMI in the human brain at 7 T. STUDY TYPE: Prospective. POPULATION: Six healthy participants (age: 28 ± 8 years, male/female: 3/3). FIELD STRENGTH/SEQUENCE: 7 T, 3D 2H free-induction-decay (FID)-magnetic resonance spectroscopic imaging (MRSI) sequence. ASSESSMENT: Three subjects received two different doses (0.25 g/kg, 0.50 g/kg or 0.75 g/kg body weight) of [6,6'-2H2]glucose on two occasions and underwent consecutive 2H-MRSI scans for 120 minutes. Blood was sampled every 10 minutes during the scan, to determine plasma glucose levels and plasma 2H-Glucose atom percent excess (APE) (part-1). Three subjects underwent the same protocol once after receiving 0.50 g/kg [6,6'-2H2]glucose (part-2). STATISTICAL TEST: Mean plasma 2H-Glucose APE and glucose plasma concentrations were compared using one-way ANOVA. Brain 2H-Glc and brain 2H-Glx (part-1) were analyzed with a two-level Linear Mixed Model. In part-2, a General Linear Model was used to compare brain metabolite signals. Statistical significance was set at P < 0.05. RESULTS: Between 60 and 100 minutes after ingesting [6,6'-2H2]glucose, plasma 2H-Glc APE did not differ between 0.50 g/kg and 0.75 g/kg doses (P = 0.961), but was significantly lower for 0.25 g/kg. Time and doses significantly affected brain 2H-Glucose levels (estimate ± standard error [SE]: 0.89 ± 0.01, 1.09 ± 0.01, and 1.27 ± 0.01, for 0.25 g/kg, 0.50 g/kg, and 0.75 g/kg, respectively) and brain 2H-Glutamate/Glutamine levels (estimate ± SE: 1.91 ± 0.03, 2.27 ± 0.03, and 2.46 ± 0.03, for 0.25 g/kg, 0.50 g/kg, and 0.75 g/kg, respectively). Plasma 2H-Glc APE, brain 2H-Glc, and brain 2H-Glx levels were comparable among subjects receiving 0.50 g/kg [6,6'-2H2]glucose. DATA CONCLUSION: Brain 2H-Glucose and brain 2H-Glutamate/Glutamine showed to be [6,6'-2H2]glucose dose dependent. A dose of 0.50 g/kg demonstrated comparable, and well-detectable, 2H-Glucose and 2H-Glutamate/Glutamine signals in the brain. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 2.

Evaluation of Hepatic Glucose and Palmitic Acid Metabolism in Rodents on High-Fat Diet Using Deuterium Metabolic Imaging.

BACKGROUND: One of the main features of several metabolic disorders is dysregulation of hepatic glucose and lipid metabolism. Deuterium metabolic imaging (DMI) allows for assessing the uptake and breakdown of 2H-labeled substrates, giving specific insight into nutrient processing in healthy and diseased organs. Thus, DMI could be a useful approach for analyzing the differences in liver metabolism of healthy and diseased subjects to gain a deeper understanding of the alterations related to metabolic disorders. PURPOSE: Evaluating the feasibility of DMI as a tool for the assessment of metabolic differences in rodents with healthy and fatty livers (FLs). STUDY TYPE: Animal Model. POPULATION: 18 male Sprague Dawley rats on standard (SD, n = 9, healthy) and high-fat diet (HFD, n = 9, FL disease). FIELD STRENGTH/SEQUENCE: Phase-encoded 1D pulse-acquire sequence and anatomy co-registered phase-encoded 3D pulse-acquire chemical shift imaging for 2H at 9.4T. ASSESSMENT: Localized and nonlocalized liver spectroscopy was applied at eight time points over 104 minutes post injection. The obtained spectra were preprocessed and quantified using jMRUI (v7.0) and the resulting amplitudes translated to absolute concentration (mM) according to the 2H natural abundance water peak. STATISTICAL TESTS: Two-way repeated measures ANOVA were employed to assess between-group differences, with statistical significance at P < 0.05. RESULTS: DMI measurements demonstrated no significant difference (P = 0.98) in the uptake of [6,6'-2H2]glucose between healthy and impaired animals (AUCSD = 1966.0 ± 151.5 mM - minutes vs. AUCHFD = 2027.0 ± 167.6 mM·minutes). In the diseased group, the intrahepatic uptake of palmitic acid d-31 was higher (AUCHFD = 57.4 ± 17.0 mM·minutes, AUCSD = 33.3 ± 10.5 mM·minutes), but without statistical significance owing to substantial in-group variation (P = 0.73). DATA CONCLUSION: DMI revealed higher concentrations of palmitic acid in rats with FL disease and no difference in hepatic glucose concentration between healthy and impaired animals. Thus, DMI appears to be a useful tool for evaluating metabolism in rodents with FL disease. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 3.

Whole-brain deuterium metabolic imaging via concentric ring trajectory readout enables assessment of regional variations in neuronal glucose metabolism.

Deuterium metabolic imaging (DMI) is an emerging magnetic resonance technique, for non-invasive mapping of human brain glucose metabolism following oral or intravenous administration of deuterium-labeled glucose. Regional differences in glucose metabolism can be observed in various brain pathologies, such as Alzheimer's disease, cancer, epilepsy or schizophrenia, but the achievable spatial resolution of conventional phase-encoded DMI methods is limited due to prolonged acquisition times rendering submilliliter isotropic spatial resolution for dynamic whole brain DMI not feasible. The purpose of this study was to implement non-Cartesian spatial-spectral sampling schemes for whole-brain 2H FID-MR Spectroscopic Imaging to assess time-resolved metabolic maps with sufficient spatial resolution to reliably detect metabolic differences between healthy gray and white matter regions. Results were compared with lower-resolution DMI maps, conventionally acquired within the same session. Six healthy volunteers (4 m/2 f) were scanned for ~90 min after administration of 0.8 g/kg oral [6,6']-2H glucose. Time-resolved whole brain 2H FID-DMI maps of glucose (Glc) and glutamate + glutamine (Glx) were acquired with 0.75 and 2 mL isotropic spatial resolution using density-weighted concentric ring trajectory (CRT) and conventional phase encoding (PE) readout, respectively, at 7 T. To minimize the effect of decreased signal-to-noise ratios associated with smaller voxels, low-rank denoising of the spatiotemporal data was performed during reconstruction. Sixty-three minutes after oral tracer uptake three-dimensional (3D) CRT-DMI maps featured 19% higher (p = .006) deuterium-labeled Glc concentrations in GM (1.98 ± 0.43 mM) compared with WM (1.66 ± 0.36 mM) dominated regions, across all volunteers. Similarly, 48% higher (p = .01) 2H-Glx concentrations were observed in GM (2.21 ± 0.44 mM) compared with WM (1.49 ± 0.20 mM). Low-resolution PE-DMI maps acquired 70 min after tracer uptake featured smaller regional differences between GM- and WM-dominated areas for 2H-Glc concentrations with 2.00 ± 0.35 mM and 1.71 ± 0.31 mM, respectively (+16%; p = .045), while no regional differences were observed for 2H-Glx concentrations. In this study, we successfully implemented 3D FID-MRSI with fast CRT encoding for dynamic whole-brain DMI at 7 T with 2.5-fold increased spatial resolution compared with conventional whole-brain phase encoded (PE) DMI to visualize regional metabolic differences. The faster metabolic activity represented by 48% higher Glx concentrations was observed in GM- compared with WM-dominated regions, which could not be reproduced using whole-brain DMI with the low spatial resolution protocol. Improved assessment of regional pathologic alterations using a fully non-invasive imaging method is of high clinical relevance and could push DMI one step toward clinical applications.

Interleaved trinuclear MRS for single-session investigation of carbohydrate and lipid metabolism in human liver at 7T.

The liver plays a central role in metabolic homeostasis, as exemplified by a variety of clinical disorders with hepatic and systemic metabolic disarrays. Of particular interest are the complex interactions between lipid and carbohydrate metabolism in highly prevalent conditions such as obesity, diabetes, and fatty liver disease. Limited accessibility and the need for invasive procedures challenge direct investigations in humans. Hence, noninvasive dynamic evaluations of glycolytic flux and steady-state assessments of lipid levels and composition are crucial for basic understanding and may open new avenues toward novel therapeutic targets. Here, three different MR spectroscopy (MRS) techniques that have been combined in a single interleaved examination in a 7T MR scanner are evaluated. 1H-MRS and 13C-MRS probe endogenous metabolites, while deuterium metabolic imaging (DMI) relies on administration of deuterated tracers, currently 2H-labelled glucose, to map the spatial and temporal evolution of their metabolic fate. All three techniques have been optimized for a robust single-session clinical investigation and applied in a preliminary study of healthy subjects. The use of a triple-channel 1H/2H/13C RF coil enables interleaved examinations with no need for repositioning. Short-echo-time STEAM spectroscopy provides well resolved spectra to quantify lipid content and composition. The relative benefits of using water saturation versus metabolite cycling and types of respiratory synchronization were evaluated. 2H-MR spectroscopic imaging allowed for registration of time- and space-resolved glucose levels following oral ingestion of 2H-glucose, while natural abundance 13C-MRS of glycogen provides a dynamic measure of hepatic glucose storage. For DMI and 13C-MRS, the measurement precision of the method was estimated to be about 0.2 and about 16 mM, respectively, for 5 min scanning periods. Excellent results were shown for the determination of dynamic uptake of glucose with DMI and lipid profiles with 1H-MRS, while the determination of changes in glycogen levels by 13C-MRS is also feasible but somewhat more limited by signal-to-noise ratio.

Deuterium Magnetic Resonance Spectroscopy Quantifies Tumor Fraction in a Mouse Model of a Mixed Radiation Necrosis / GL261-Glioblastoma Lesion.

PURPOSE: Distinguishing recurrent brain tumor from treatment effects, including late time-to-onset radiation necrosis (RN), presents an on-going challenge in post-treatment imaging of neuro-oncology patients. Experiments were performed in a novel mouse model that recapitulates the relevant clinical histologic features of recurrent glioblastoma growing in a RN environment, the mixed tumor/RN model. The goal of this work was to apply single-voxel deuterium (2H) magnetic resonance spectroscopy (MRS), in concert with administration of deuterated glucose, to determine if the metabolic signature of aerobic glycolysis (Warburg effect: glucose → lactate in the presence of O2), a distinguishing characteristic of proliferating tumor, provides a quantitative readout of the tumor fraction (percent) in a mixed tumor/RN lesion. PROCEDURES: 2H MRS employed the SPin-ECho full-Intensity Acquired Localized (SPECIAL) MRS pulse sequence and outer volume suppression at 11.74 T. For each subject, a single 2H MRS voxel was placed over the mixed lesion as defined by contrast enhanced (CE) 1H T1-weighted MRI. Following intravenous administration of [6,6-2H2]glucose (Glc), 2H MRS monitored the glycolytic conversion to [3,3-2H2]lactate (Lac) and glutamate + glutamine (Glu + Gln = Glx). RESULTS: Based on previous work, the tumor fraction of the mixed lesion was quantified as the ratio of tumor volume, defined by 1H magnetization transfer experiments, vs. the total mixed-lesion volume. Metabolite 2H MR spectral-amplitude values were converted to metabolite concentrations using the natural-abundance semi-heavy water (1HO2H) resonance as an internal concentration standard. The 2H MR-determined [Lac] / [Glx] ratio was strongly linearly correlated with tumor fraction in the mixed lesion (n = 9), Pearson's r = 0.87, and 77% of the variation in the [Lac] / [Glx] ratio was due to tumor percent r2 = 0.77. CONCLUSIONS: This preclinical study supports the proposal that 2H MR could occupy a well-defined secondary role when standard-of-care 1H imaging is non-diagnostic regarding tumor presence and/or response to therapy.

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.

Application and development of Deuterium Metabolic Imaging in tumor glucose metabolism: visualization of different metabolic pathways.

Cancer metabolism has emerged as a pivotal area of research recently. The ability to visualize and comprehend the metabolic processes of cancer holds immense clinical value, particularly in the diagnosis of malignant tumors and the assessment of treatment responses. Deuterium Metabolic Imaging (DMI), as a robust, simple, and versatile MR spectroscopic imaging tool, demonstrates promise in tumor diagnosis and treatment efficacy assessment. This review explored the latest developments and applications of DMI in oncology across various tumor metabolic axes, with a specific emphasis on its potential for clinical translation. DMI offers invaluable insights into tumor biology, treatment responses, and prognostic outcomes. Notably, DMI can identify early responses to immunotherapy, a prominent area of current research interest. In conclusion, DMI harbors the potential to evolve into a convenient and efficient imaging technique in clinical practice, thereby advancing precision medicine and improving the diagnosis and evaluation of cancer treatments.

Reproducibility of 3D MRSI for imaging human brain glucose metabolism using direct (2H) and indirect (1H) detection of deuterium labeled compounds at 7T and clinical 3T.

INTRODUCTION: Deuterium metabolic imaging (DMI) and quantitative exchange label turnover (QELT) are novel MR spectroscopy techniques for non-invasive imaging of human brain glucose and neurotransmitter metabolism with high clinical potential. Following oral or intravenous administration of non-ionizing [6,6'-2H2]-glucose, its uptake and synthesis of downstream metabolites can be mapped via direct or indirect detection of deuterium resonances using 2H MRSI (DMI) and 1H MRSI (QELT), respectively. The purpose of this study was to compare the dynamics of spatially resolved brain glucose metabolism, i.e., estimated concentration enrichment of deuterium labeled Glx (glutamate+glutamine) and Glc (glucose) acquired repeatedly in the same cohort of subjects using DMI at 7T and QELT at clinical 3T. METHODS: Five volunteers (4 m/1f) were scanned in repeated sessions for 60 min after overnight fasting and 0.8 g/kg oral [6,6'-2H2]-glucose administration using time-resolved 3D 2H FID-MRSI with elliptical phase encoding at 7T and 3D 1H FID-MRSI with a non-Cartesian concentric ring trajectory readout at clinical 3T. RESULTS: One hour after oral tracer administration regionally averaged deuterium labeled Glx4 concentrations and the dynamics were not significantly different over all participants between 7T 2H DMI and 3T 1H QELT data for GM (1.29±0.15 vs. 1.38±0.26 mM, p=0.65 & 21±3 vs. 26±3 µM/min, p=0.22) and WM (1.10±0.13 vs. 0.91±0.24 mM, p=0.34 & 19±2 vs. 17±3 µM/min, p=0.48). Also, the observed time constants of dynamic Glc6 data in GM (24±14 vs. 19±7 min, p=0.65) and WM (28±19 vs. 18±9 min, p=0.43) dominated regions showed no significant differences. Between individual 2H and 1H data points a weak to moderate negative correlation was observed for Glx4 concentrations in GM (r=-0.52, p<0.001), and WM (r=-0.3, p<0.001) dominated regions, while a strong negative correlation was observed for Glc6 data GM (r=-0.61, p<0.001) and WM (r=-0.70, p<0.001). CONCLUSION: This study demonstrates that indirect detection of deuterium labeled compounds using 1H QELT MRSI at widely available clinical 3T without additional hardware is able to reproduce absolute concentration estimates of downstream glucose metabolites and the dynamics of glucose uptake compared to 2H DMI data acquired at 7T. This suggests significant potential for widespread application in clinical settings especially in environments with limited access to ultra-high field scanners and dedicated RF hardware.

Deuterium imaging of the Warburg effect at sub-millimolar concentrations by joint processing of the kinetic and spectral dimensions.

Deuterium metabolic imaging (DMI) is a promising molecular MRI approach, which follows the administration of deuterated substrates and their metabolization. [6,6'-2 H2 ]-glucose for instance is preferentially converted in tumors to [3,3'-2 H2 ]-lactate as a result of the Warburg effect, providing a distinct resonance whose mapping using time-resolved spectroscopic imaging can diagnose cancer. The MR detection of low-concentration metabolites such as lactate, however, is challenging. It has been recently shown that multi-echo balanced steady-state free precession (ME-bSSFP) increases the signal-to-noise ratio (SNR) of these experiments approximately threefold over regular chemical shift imaging; the present study examines how DMI's sensitivity can be increased further by advanced processing methods. Some of these, such as compressed sensing multiplicative denoising and block-matching/3D filtering, can be applied to any spectroscopic/imaging methods. Sensitivity-enhancing approaches were also specifically tailored to ME-bSSFP DMI, by relying on priors related to the resonances' positions and to features of the metabolic kinetics. Two new methods are thus proposed that use these constraints for enhancing the sensitivity of both the spectral images and the metabolic kinetics. The ability of these methods to improve DMI is evidenced in pancreatic cancer studies carried at 15.2 T, where suitable implementations of the proposals imparted eightfold or more SNR improvement over the original ME-bSSFP data, at no informational cost. Comparisons with other propositions in the literature are briefly discussed.

Deuterium body array for the simultaneous measurement of hepatic and renal glucose metabolism and gastric emptying with dynamic 3D deuterium metabolic imaging at 7 T.

Deuterium metabolic imaging (DMI) is a novel noninvasive method to assess tissue metabolism and organ (patho)physiology in vivo using deuterated substrates, such as [6,6'-2 H2 ]-glucose. The liver and kidneys play a central role in whole-body glucose homeostasis, and in type 2 diabetes, both hepatic and renal glucose metabolism are dysregulated. Diabetes is also associated with gastric emptying abnormalities. In this study, we developed a four-channel 2 H transmit/receive body array coil for DMI in the human abdomen at 7 T and assessed its performance. In addition, the feasibility of simultaneously measuring gastric emptying, and hepatic and renal glucose uptake and metabolism with dynamic 3D DMI upon administration of deuterated glucose, was investigated. Simulated and measured B1 + patterns were in good agreement. The intrasession variability of the natural abundance deuterated water signal in the liver and right kidney, measured in nine healthy volunteers, was 5.6% ± 0.9% and 4.9% ± 0.7%, respectively. Dynamic 3D DMI scans with oral administration of [6,6'-2 H2 ]-glucose showed similar kinetics of deuterated glucose appearance and disappearance in the liver and kidney. The measured gastric emptying half time was 80 ± 10 min, which is in good agreement with scintigraphy measurements. In conclusion, DMI with oral administration of [6,6'-2 H2 ]-glucose enables simultaneous assessment of gastric emptying and liver and kidney glucose uptake and metabolism. When applied in patients with diabetes, this approach may advance our understanding of the interplay between disturbances in liver and kidney glucose uptake and metabolism and gastric emptying, at a detail that cannot be achieved by any other method.

In vivo imaging of cerebral glucose metabolism informs on subacute to chronic post-stroke tissue status - A pilot study combining PET and deuterium metabolic imaging.

Recanalization therapy after acute ischemic stroke enables restoration of cerebral perfusion. However, a significant subset of patients has poor outcome, which may be caused by disruption of cerebral energy metabolism. To assess changes in glucose metabolism subacutely and chronically after recanalization, we applied two complementary imaging techniques, fluorodeoxyglucose (FDG) positron emission tomography (PET) and deuterium (2H) metabolic imaging (DMI), after 60-minute transient middle cerebral artery occlusion (tMCAO) in C57BL/6 mice. Glucose uptake, measured with FDG PET, was reduced at 48 hours after tMCAO and returned to baseline value after 11 days. DMI revealed effective glucose supply as well as elevated lactate production and reduced glutamate/glutamine synthesis in the lesion area at 48 hours post-tMCAO, of which the extent was dependent on stroke severity. A further decrease in oxidative metabolism was evident after 11 days. Immunohistochemistry revealed significant glial activation in and around the lesion, which may play a role in the observed metabolic profiles. Our findings indicate that imaging (altered) active glucose metabolism in and around reperfused stroke lesions can provide substantial information on (secondary) pathophysiological changes in post-ischemic brain tissue.

Deuterium metabolic imaging of the human brain in vivo at 7 T.

PURPOSE: To explore the potential of deuterium metabolic imaging (DMI) in the human brain in vivo at 7 T, using a multi-element deuterium (2 H) RF coil for 3D volume coverage. METHODS: 1 H-MR images and localized 2 H MR spectra were acquired in vivo in the human brain of 3 healthy subjects to generate DMI maps of 2 H-labeled water, glucose, and glutamate/glutamine (Glx). In addition, non-localized 2 H-MR spectra were acquired both in vivo and in vitro to determine T1 and T2 relaxation times of deuterated metabolites at 7 T. The performance of the 2 H coil was assessed through numeric simulations and experimentally acquired B1 + maps. RESULTS: 3D DMI maps covering the entire human brain in vivo were obtained from well-resolved deuterated (2 H) metabolite resonances of water, glucose, and Glx. The T1 and T2 relaxation times were consistent with those reported at adjacent field strengths. Experimental B1 + maps were in good agreement with simulations, indicating efficient and homogeneous B1 + transmission and low RF power deposition for 2 H, consistent with a similar array coil design reported at 9.4 T. CONCLUSION: Here, we have demonstrated the successful implementation of 3D DMI in the human brain in vivo at 7 T. The spatial and temporal nominal resolutions achieved at 7 T (i.e., 2.7 mL in 28 min, respectively) were close to those achieved at 9.4 T and greatly outperformed DMI at lower magnetic fields. DMI at 7 T and beyond has clear potential in applications dealing with small brain lesions.

Interleaved fluid-attenuated inversion recovery (FLAIR) MRI and deuterium metabolic imaging (DMI) on human brain in vivo.

PURPOSE: To integrate deuterium metabolic imaging (DMI) with clinical MRI through an interleaved MRI and DMI acquisition workflow. Interleaved MRI-DMI was enabled with hardware and pulse sequence modifications, and the performance was demonstrated using fluid-attenuated inversion recovery (FLAIR) MRI as an example. METHODS: Interleaved FLAIR-DMI was developed by interleaving the 2 H excitation and acquisition time windows into the intrinsic delay periods presented in the FLAIR method. All 2 H MR signals were up-converted to the 1 H Larmor frequency using a custom-built hardware unit, which also achieved frequency and phase locking of the output signal in real-time. The interleaved measurements were compared with direct measurements both in phantom and in the human brain in vivo. RESULTS: The interleaved MRI-DMI acquisition strategy allowed simultaneous detection of FLAIR MRI and DMI in the same scan time as a FLAIR-only MRI acquisition. Both phantom and in vivo data showed that the MR image quality, DMI sensitivity as well as information content were preserved using interleaved MRI-DMI. CONCLUSION: The interleaved MRI-DMI technology can be used to extend clinical MRI protocols with DMI, thereby offering a metabolic component to the MR imaging contrasts without a penalty on patient comfort or scan time.

Deuterium magnetic resonance spectroscopy enables noninvasive metabolic imaging of tumor burden and response to therapy in low-grade gliomas.

BACKGROUND: The alternative lengthening of telomeres (ALT) pathway is essential for tumor proliferation in astrocytomas. The goal of this study was to identify metabolic alterations linked to the ALT pathway that can be exploited for noninvasive magnetic resonance spectroscopy (MRS)-based imaging of astrocytomas in vivo. METHODS: Genetic and pharmacological methods were used to dissect the association between the ALT pathway and glucose metabolism in genetically engineered and patient-derived astrocytoma models. 2H-MRS was used for noninvasive imaging of ALT-linked modulation of glycolytic flux in mice bearing orthotopic astrocytomas in vivo. RESULTS: The ALT pathway was associated with higher activity of the rate-limiting glycolytic enzyme phosphofructokinase-1 and concomitantly elevated flux of glucose to lactate in astrocytoma cells. Silencing the ALT pathway or treating with the poly(ADP-ribose) polymerase inhibitor niraparib that induces telomeric fusion in ALT-dependent astrocytoma cells abrogated glycolytic flux. Importantly, this metabolic reprogramming could be non-invasively visualized by 2H-MRS. Lactate production from [6,6'-2H]-glucose was higher in ALT-dependent astrocytoma tumors relative to the normal brain in vivo. Furthermore, treatment of orthotopic astrocytoma-bearing mice with niraparib reduced lactate production from [6,6'-2H]-glucose at early timepoints when alterations in tumor volume could not be detected by anatomical imaging, pointing to the ability of [6,6'-2H]-glucose to report on pseudoprogression in vivo. CONCLUSIONS: We have mechanistically linked the ALT pathway to elevated glycolytic flux and demonstrated the ability of [6,6'-2H]-glucose to non-invasively assess tumor burden and response to therapy in astrocytomas. Our findings point to a novel, clinically translatable method for metabolic imaging of astrocytoma patients.

Residual quadrupolar couplings observed in 7 Tesla deuterium MR spectra of skeletal muscle.

PURPOSE: Deuterium metabolic imaging could potentially be used to investigate metabolism in skeletal muscle noninvasively. However, skeletal muscle is a tissue with a high degree of spatial organization. In this study, we investigated the effect of incomplete motional averaging on the naturally abundant deuterated water signal in 7 Tesla deuterium spectra of the lower leg muscles and the dependence on the angle between the muscle fibers and the main magnetic field B0 , as determined by DTI. METHODS: Natural abundance deuterium MRSI measurements of the right lower leg muscles were performed at 7 Tesla. Three subjects were scanned in a supine position, with the right leg parallel with the B0 field. One subject was scanned twice; during the second scan, the subject was laying on his right side and the right knee was bent such that the angle between the right lower leg and B0 was approximately 45°. DTI was performed in the same subjects in the same positions at 3 Tesla to determine muscle fiber angles. RESULTS: We observed splittings in the natural abundance deuterated water signal. The size of the splittings varied between different muscles in the lower leg but were mostly similar among subjects for each muscle. The splittings depended on the orientation of the muscle fibers with respect to the main magnetic field B0 . CONCLUSION: Partial molecular alignment in skeletal muscle leads to residual deuteron quadrupolar couplings in deuterated water, the size of which depends on the angle between the muscle fibers and B0 .

Simultaneous Recording of the Uptake and Conversion of Glucose and Choline in Tumors by Deuterium Metabolic Imaging.

Increased glucose and choline uptake are hallmarks of cancer. We investigated whether the uptake and conversion of [2H9]choline alone and together with that of [6,6'-2H2]glucose can be assessed in tumors via deuterium metabolic imaging (DMI) after administering these compounds. Therefore, tumors with human renal carcinoma cells were grown subcutaneously in mice. Isoflurane anesthetized mice were IV infused in the MR magnet for ~20 s with ~0.2 mL solutions containing either [2H9]choline (0.05 g/kg) alone or together with [6,6'-2H2]glucose (1.3 g/kg). 2H MR was performed on a 11.7T MR system with a home-built 2H/1H coil using a 90° excitation pulse and 400 ms repetition time. 3D DMI was recorded at high resolution (2 × 2 × 2 mm) in 37 min or at low resolution (3.7 × 3.7 × 3.7 mm) in 2:24 min. Absolute tissue concentrations were calculated assuming natural deuterated water [HOD] = 13.7 mM. Within 5 min after [2H9]choline infusion, its signal appeared in tumor spectra representing a concentration increase to 0.3-1.2 mM, which then slowly decreased or remained constant over 100 min. In plasma, [2H9]choline disappeared within 15 min post-infusion, implying that its signal arises from tumor tissue and not from blood. After infusing a mixture of [2H9]choline and [6,6'-2H2]glucose, their signals were observed separately in tumor 2H spectra. Over time, the [2H9]choline signal broadened, possibly due to conversion to other choline compounds, [[6,6'-2H2]glucose] declined, [HOD] increased and a lactate signal appeared, reflecting glycolysis. Metabolic maps of 2H compounds, reconstructed from high resolution DMIs, showed their spatial tumor accumulation. As choline infusion and glucose DMI is feasible in patients, their simultaneous detection has clinical potential for tumor characterization.

Deuterium Magnetic Resonance Imaging and the Discrimination of Fetoplacental Metabolism in Normal and L-NAME-Induced Preeclamptic Mice.

Recent magnetic resonance studies in healthy and cancerous organs have concluded that deuterated metabolites possess highly desirable properties for mapping non-invasively and, as they happen, characterizing glycolysis and other biochemical processes in animals and humans. A promising avenue of this deuterium metabolic imaging (DMI) approach involves looking at the fate of externally administered 2H6,6'-glucose, as it is taken up and metabolized into different products as a function of time. This study employs deuterium magnetic resonance to follow the metabolism of wildtype and preeclamptic pregnant mice models, focusing on maternal and fetoplacental organs over ≈2 h post-injection. 2H6,6'-glucose uptake was observed in the placenta and in specific downstream organs such as the fetal heart and liver. Main metabolic products included 2H3,3'-lactate and 2H-water, which were produced in individual fetoplacental organs with distinct time traces. Glucose uptake in the organs of most preeclamptic animals appeared more elevated than in the control mice (p = 0.02); also higher was the production of 2H-water arising from this glucose. However, the most notable differences arose in the 2H3,3'-lactate concentration, which was ca. two-fold more abundant in the placenta (p = 0.005) and in the fetal (p = 0.01) organs of preeclamptic-like animals, than in control mice. This is consistent with literature reports about hypoxic conditions arising in preeclamptic and growth-restricted pregnancies, which could lead to an enhancement in anaerobic glycolysis. Overall, the present measurements suggest that DMI, a minimally invasive approach, may offer new ways of studying and characterizing health and disease in mammalian pregnancies, including humans.

Improving deuterium metabolic imaging (DMI) signal-to-noise ratio by spectroscopic multi-echo bSSFP: A pancreatic cancer investigation.

PURPOSE: Deuterium metabolic imaging (DMI) maps the uptake of deuterated precursors and their conversion into lactate and other markers of tumor metabolism. Even after leveraging 2 H's short T1 s, DMI's signal-to-noise ratio (SNR) is limited. We hypothesize that a multi-echo balanced steady-state free precession (ME-bSSFP) approach would increase SNR compared to chemical shift imaging (CSI), while achieving spectral isolation of the metabolic precursors and products. METHODS: Suitably tuned 2 H ME-bSSFP (five echo times [TEs], ΔTE = 2.2 ms, repetition time [TR]/flip-angle = 12 ms/60°) was implemented at 15.2T and compared to CSI (TR/flip-angle = 95 ms/90°) regarding SNR and spectral isolation, in simulations, in deuterated phantoms and for the in vivo diagnosis of a mouse tumor model of pancreatic adenocarcinoma (N = 10). RESULTS: Simulations predicted an SNR increase vs. CSI of 3-5, and that the peaks of 2 H-water, 2 H6,6' -glucose, and 2 H3,3' -lactate can be well isolated by ME-bSSFP; phantoms confirmed this. In vivo, at equal spatial resolution (1.25 × 1.25 mm2 ) and scan time (10 min), 2 H6,6' -glucose's and 2 H3,3' -lactate's SNR were indeed higher for bSSFP than for CSI, three-fold for glucose (57 ± 30 vs. 19 ± 11, P < .001), doubled for water (13 ± 5 vs. 7 ± 3, P = .005). The time courses and overall localization of all metabolites agreed well, comparing CSI against ME-bSSFP. However, a clearer localization of glucose in kidneys and bladder, the detection of glucose-avid rims in certain tumors, and a heterogeneous pattern of intra-tumor lactate production could only be observed using ME-bSSFP's higher resolution. CONCLUSIONS: ME-bSSFP provides greater SNR per unit time than CSI, providing for higher spatial resolution mapping of glucose uptake and lactate production in tumors.