Keywords: Hyperpolarized MR (Non-Gas), Hyperpolarized MR (Non-Gas)

Motivation: Hyperpolarized MR (HP-MR) ¹³C pyruvate is a valuable probe for evaluating glycolytic flux, but it remains unknown which cells contribute to the HP-MR signals in the brain.

Goal(s): To verify whether astrocyte metabolism is involved in the signal of HP-MR ¹³C pyruvate in the brain.

Approach: We perturbed Gq-GPCR/calcium (Ca²⁺) signaling in astrocytes using the hM3Dq DREADD system and examined the fluctuations of the HP-MR pyruvate signals in awake mice.

Results: In HP-MR experiments conducted 30 minutes after the elevation of astrocyte Ca²⁺, the lactate/pyruvate ratio decreased compared to the control, and the bicarbonate/pyruvate ratio also decreased.
 

Impact: Investigating the involvement of astrocyte metabolism in brain hyperpolarized MR(HP-MR) ¹³C pyruvate signals, astrocyte GPCR/Ca²⁺ signaling was perturbed using DREADD, revealing a decrease in lactate/pyruvate and bicarbonate/pyruvate ratios in HP-MR experiments, suggesting metabolic alterations in response to astrocyte GPCR/Ca²⁺ modulation.

Keywords: Hyperpolarized MR (Non-Gas), Molecular Imaging, Molecular design

Motivation: Detection of aminopeptidase (AP) activities related to renin-angiotensin system (RAS) can lead to diagnosis of various diseases. Magnetic resonance imaging utilizing suitable hyperpolarized molecular probes can non-invasively detect in vivo AP activities. However, there have been no hyperpolarized molecular probes for APA, APB, and leucine AP.

Goal(s): We aimed to design and develop new hyperpolarized molecular probes for the detection and imaging of RAS related AP activities in vivo.

Approach:  Based on the previously reported APN probe scaffold, three new hyperpolarized probes were designed.

Results: Using the developed probes, target AP activities were successfully detected and visualized in vivo.

Impact: This study exhibits a framework that artificially designed hyperpolarized molecular probes can detect in vivo aminopeptidase activities, which is assumed impossible with isotope labeled natural substrates and broadens the possibility of hyperpolarized MR diagnosis based on AP activities.

Keywords: Hyperpolarized MR (Non-Gas), Contrast Agent

Motivation: Isocitrate dehydrogenase (IDH) mutational status is crucial for accurate diagnosis and prognosis of malignant gliomas. However, the current clinical assessment of IDH mutation requires an invasive brain biopsy for pathological testing.

Goal(s): We aimed to perform first in-human MR studies using hyperpolarized [1-¹³C]alpha-ketoglutarate as a new probe of IDH mutational status via cancer metabolic reprogramming, along with cerebral bioenergetics.

Approach: We acquired ¹³C MRS data from healthy brain volunteers (N=6) and glioma patients (N=6) who received hyperpolarized aKG.

Results: Feasibility and safety were demonstrated in these 12 studies, with signals observed from [1-¹³C]alpha-ketoglutarate and its metabolite glutamate in the obtained ¹³C MRS data.

Impact: MR molecular imaging with the new probe hyperpolarized [1-¹³C]alpha-ketoglutarate provided novel measurements of aKG metabolism and can investigate glioma IDH mutational status by detecting glutamate or the oncometabolite, 2-hydroxyglutarate.

Keywords: Hyperpolarized MR (Non-Gas), Metabolism

Motivation: Fructose intake has increased 80-times over the past century, although the effect of this increase in the body remains unclear.

Goal(s): To assess the metabolic flux of fructose at different metabolic states (fed vs fasted) for future human studies.

Approach: Fed or fasted mice were injected with hyperpolarized fructose to observe metabolic flux.

Results: Fed mice showed the formation of glucose (gluconeogenesis) by F1P, while fasted mice metabolized the fructose to obtain energy.

Impact: The results pressented have significant implications for the understanding of fructoylsis and provides a translational metabolic imaging strategy for future human studies.

Keywords: Hyperpolarized MR (Non-Gas), Metabolism, Cancer, Brain

Motivation: The metabolic profile of normal appearing brain tissue in patients with brain metastases may be related to the course of disease.   

Goal(s): To test whether patients with brain metastases exhibit differential metabolism in normal appearing brain parenchyma compared to healthy control participants.

Approach: Hyperpolarized [1-¹³C]-pyruvate and T1w MRI were used to compare the metabolism and volumes of normal appearing brain regions in patients and healthy control participants.

Results: The lactate-to-bicarbonate (p=0.0004) and lactate-to-pyruvate (p=0.04) ratios were significantly increased in the normal appearing brain parenchyma of patients compared to controls.

Impact: The metabolic profile of normal appearing brain parenchyma in patients with brain metastases exhibits significantly increased glycolytic metabolism compared to healthy control brains when imaged using hyperpolarized [1-¹³C]-pyruvate MRI and may be related to the course of disease.

Keywords: Probes & Targets, Hyperpolarized MR (Non-Gas), pyruvate, hyperpolarization, hepatic gluconeogenesis, liver

Motivation: Assessing gluconeogenesis using hyperpolarized [1-¹³C]pyruvate is technically challenging because [¹³C]bicarbonate can be produced from both oxidative and gluconeogenic pathways and spectrally resolving the gluconeogenic products from large, neighboring peaks is non-trivial at 3T.

Goal(s): This study examines the utility of deuterated hyperpolarized [2-¹³C]pyruvate in assessing gluconeogenesis.

Approach: Sodium [2-¹³C]pyruvate-d₃ was synthesized to prolong the T₁. Hepatic metabolism was investigated using hyperpolarized [2-¹³C]pyruvate-d₃with D₂O dissolution under normal fed and fasted conditions.

Results: The T₁ of [2-¹³C]pyruvate-d₃ was ~80 s when dissolved with D₂O. Gluconeogenic products such as [2-¹³C]oxaloacetate and [2-¹³C]phosphoenolpyruvate were observed from fasted rats only, highlighting clear advantages over [1-¹³C]pyruvate in investigating gluconeogenesis.

Impact: Hyperpolarization technology is rapidly being translated to humans. With the proven safety and feasibility, hyperpolarized [2-¹³C]pyruvate-d₃ will facilitate its utilization in underexplored liver and kidney metabolism, illuminating mechanistic understanding for several disorders that are believed to depend on altered gluconeogenesis.

Keywords: Hyperpolarized MR (Non-Gas), Hyperpolarized MR (Non-Gas)

Motivation: Human hyperpolarized metabolic imaging relies upon unstable exogenous radicals like the trityl radical EPA, necessitating clean rooms, pharmacy staff, and filters. 

Goal(s): We wished to avoid EPA by using an ultrahigh-dose-rate 6 MeV electron accelerator, generating endogenous [1-¹³C]alanine radicals for DNP. 

Approach: We studied irradiated samples up to 100 kGy at two polariser field-strengths (3.35/6.7T), characterised radical species formed by EPR, X-ray diffraction, and numerical quantum-mechanical simulations. 

Results: Radicals from biologically sterilising doses were stable for months when stored anhydrously, quenching rapidly with dissolution. Comparable nuclear polarisation to pyruvate at 6.7T was observed in a partially-ordered glycerol/alanine mix, potentially via a cross-effect mechanism. 

Impact: This has several novel impacts – it: (1) makes centralised manufacturing & storage possible with dual-purpose irradiation sterilising a sealed fluid-path; (2) demonstrates electron irradiation feasible for DNP; and (3) highlights how molecular environments could be partially controlled for polarisation optimisation.

Keywords: Hyperpolarized MR (Non-Gas), Hyperpolarized MR (Non-Gas), NMR spectroscopy, imaging agents, parahydrogen, 13C pyruvate, SABRE, perfluorinated compounds

Motivation: Signal Amplification by Reversible Exchange (SABRE) recent progresses include hyperpolarizing [1-13C]pyruvate in aqueous solutions. However, overcoming the challenge of iridium toxicity in hyperpolarized mixtures is essential for broader biocompatible SABRE applications.

Goal(s): The removal of Ir metal from hyperpolarized SABRE mixtures is an unmet need with substantial clinical significance.

Approach: A perfluorinated SABRE catalyst was developed to counter iridium contamination in hyperpolarized aqueous solutions by exploiting its high hydrophobicity for straightforward separation.

Results: The residual Ir was found to be only 177 ppb, representing a 8130-fold reduction in Ir concentration and the lowest and safest level reported to date for a SABRE-hyperpolarized solution.

Impact: Hyperpolarizing [1-13C]pyruvate using a perfluorinated SABRE catalyst reduced the residual iridium levels to safe levels for human injection. Future development along with solvent removal could make SABRE-SHEATH a faster and cost-effective alternative for biocompatible hyperpolarized agents in next-generation molecular imaging.

Keywords: Hyperpolarized MR (Non-Gas), Non-Proton, Fumarate, Necrosis, Treatment Response

Motivation: Clinical translation of hyperpolarized ¹³C-fumarate has the potential to enable early, non-invasive assessment of treatment response in cancer.

Goal(s): To advance a novel hyperpolarized probe from the laboratory to the clinic.

Approach: Translation involved optimizing clinical scale hyperpolarization, establishing an imaging protocol at clinical field strength (3T), preclinical toxicology and first in-human injections.

Results: ¹³C-fumarate showed good hyperpolarization properties and the imaging protocol achieved sufficient spectral separation of peaks and spatial separation of phantoms respectively. Toxicological assessment demonstrated the safety of ¹³C-fumarate, no adverse events observed in rodents and humans have so far been observed.

Impact: While promising preclinical molecules exist, clinical hyperpolarized ¹³C MRI lacks probe versatility due to a complex, unclear translation process. This study on fumarate narrows the gap between preclinical and clinical utility and fosters transparent clinical translation pipelines for the field.

Keywords: Hyperpolarized MR (Non-Gas), Hyperpolarized MR (Non-Gas), whole-abdomen imaging, hyperpolarized [1-13C]pyruvate, deuterium oxide (D2O), pancreatic ductal adenocarcinoma (PDAC)

Motivation: Whole-abdomen imaging with hyperpolarized [1-¹³C]pyruvate holds promise to diagnose metabolic diseases. D₂O solvation could extend the ¹³C T₁ lifetime, resulting in enhanced image SNR.

Goal(s): Establish the safety and feasibility of utilizing D₂O to administer hyperpolarized [1-¹³C]pyruvate in whole-abdomen imaging, and present the first application of whole-abdomen hyperpolarized [1-¹³C]pyruvate MRI in a PDAC patient.

Approach: We quantified the metabolic characteristics of organs in healthy and diseased subjects.

Results: The use of D₂O is safe and feasible. It has no significant impact on organ metabolism and delivery of the pyruvate bolus. This technique demonstrates potential for application in cancer patients.

Impact: The safety and feasibility of employing D₂O for hyperpolarized ¹³C whole-abdomen MRI sets the stage for translational studies. The first application of hyperpolarized whole-abdomen [1-¹³C]pyruvate MRI to a PDAC patient provides essential support for its future exploration in oncology.

Keywords: Deuterium, Deuterium, Glucose Metabolic Rates

Motivation: Cerebral glucose metabolism via non-oxidative and oxidative pathways is critical for brain function, however, methods capable of quantitatively imaging metabolic rates are lacking. 

Goal(s): To develop a quantitative dynamic deuterium (²H) MRSI (DMRSI) method capable of mapping human brain glucose metabolic rates. 

Approach: Combining novel hardware and advanced post-processing method with kinetic models, we established a high-resolution, high-quality dynamic DMRSI capable of quantifying and imaging three metabolic rates of glucose consumption (CMR_Glc), lactate generation (CMR_Lac) and TCA cycle (V_TCA) in human brain at 7T.

Results: We demonstrate consistent whole-brain maps of CMR_Glc, CMR_Lac, V_TCA in health subjects.

Impact: We developed a novel DMRSI platform on an FDA-approved clinical 7T scanner that enables simultaneous high-resolution imaging of CMR_Glc, CMR_Lac and V_TCA  of entire human brain for the first time. This novel technology has potential for brain research and translation.

Keywords: Deuterium, Deuterium

Motivation: Formate overflow linked to mitochondrial oxidative serine catabolism has been observed in various forms of cancer, and there is evidence that elevated formate concentrations promote cell infiltration. 

Goal(s): Our goal was to monitor serine catabolism using deuterium metabolic imaging. 

Approach: Cell experiments were conducted using a 14.1 T high-resolution NMR spectrometer and ²H experiments on tumors in vivo using a 7.0 T horizontal bore magnet.  

Results: [2,3,3-²H₂]serine catabolism can be monitored directly from measurements of ²H-formate production and indirectly from ²H-labeling of water.

Impact: Monitoring [2,3,3-²H₂]serine metabolism holds huge potential when assessing novel cancer treatments that target the one-carbon pathway to inhibit tumor cell proliferation. 

Keywords: Deuterium, Deuterium, bSSFP, DMI, ultra high field, brain, metabolism, cancer

Motivation: Deuterium metabolic imaging could significantly impact the field of neuro-oncology by providing clinical quantitative metabolic information.

Goal(s): To improve the spatial resolution of human deuterium metabolic imaging at 9.4 T.

Approach: We performed phantom and in vivo experiments with oral intake of deuterated glucose using multi-echo phase-cycled bSSFP acquisitions. The results were compared with a standard 3D spectroscopy sequence.

Results: We achieved higher spatial resolution compared to a 3D spectroscopy sequence. Phase cycling improved the reliability of the metabolite quantification especially in the large off-resonance and low SNR regimes.

Impact: We present an improved whole-brain dynamic deuterium metabolic imaging strategy at 9.4 T using bSSFP with multiple echoes and phase cycling. The efficacy of this method is validated with phantom and in vivo experiments along with standard spectroscopy measurements.

Keywords: Tumors (Post-Treatment), Deuterium

Motivation: The oxidative subtype of glioblastoma (GB) has potential mitochondrial therapeutic vulnerabilities that can be targeted for treatment. 

Goal(s): To detect early response to a mitochondrial complex 1 inhibitor, IACS-010759, using deuterium metabolic imaging (DMI). 

Approach: Measurements of oxygen consumption, extracellular acidification rate and ²H-labelled lactate production in GB cell suspensions in vitro and ²H-labelled lactate and Glx production from [6,6’-²H₂]glucose in GB xenografts in vivo, pre- and post-treatment.

Results: DMI detects an in vivo response to treatment with IACS-010759 from measurements of decreased ²H-labeled Glx production and increased ²H-labeled lactate production.

Impact: Deuterium metabolic imaging can be used to detect the early response of a glioblastoma model to treatment with a mitochondrial complex 1 inhibitor.

Keywords: Biology, Models, Methods, Deuterium, Deuterium metabolic imaging; Intracerebral hemorrhage; Lactate

Motivation: Lactate, as an important metabolism product after intracerebral hemorrhage (ICH), plays a crucial role in the pathophysiology and prognosis. Deuterium metabolic imaging (DMI), as a potentially transformative technique, can localize abnormal metabolism associated with lactate.

Goal(s): Optimize deuterium coils and sequences to improve the signal-to-noise ratio of DMI, and quantitatively analyze lactate changes after ICH with optimized techniques.

Approach: Propose the active decoupling 2H/1H dual-tuned transceiver coil and CSI-bSSFP sequence for DMI and measure the dynamical lactate metabolism in three groups of rats before and after ICH.

Results: DMI can measure the lactate metabolic changes at different time points after ICH.

Impact: This study presents a non-invasive technique for monitoring the lactate metabolic changes after ICH, which holds clinical potential in determining the time of onset, treatment plan, and real-time response evaluation.

Keywords: Deuterium, Deuterium, Spectroscopy

Motivation: During heavy water loading, deuterium is incorporated into newly synthesised lipids; measurement of deuterium content thus provides a measure of lipid turnover.  Currently this involves in vitro analysis of biopsy samples. 

Goal(s): We investigated whether deuterium magnetic resonance can detect increased deuteration of subcutaneous fat following heavy water loading. 

Approach: Deuterium signals from calf and abdomen from three participants were monitored during/after a 28-day period of loading with heavy water to ~100x natural abundance.

Results: Fat signal was increased relative to natural abundance in 5 of the 6 measurements (average at times > 50 days), reaching statistical significance (P<0.05) in three measurements. 

Impact: A non-invasive technique for monitoring lipid turnover anywhere in the human body would be a powerful tool, allowing investigation of fat metabolism in health and disease. Deuterium magnetic resonance during heavy water loading could form this tool.

Keywords: Hyperpolarized MR (Gas), Contrast Agent, Dynamic Imaging of Respiratory Function

Motivation: The study aims to refine lung disease diagnosis through dynamic imaging, surpassing conventional breath-hold MRI limitations.

Goal(s): This research aims to confirm the efficacy of a new 4D dynamic HXe MRI method for real-time lung function imaging, enhancing our grasp of diseases like COPD.

Approach: Our method employs synchronized 4D dynamic MRI to differentiate lung function in healthy individuals, COPD sufferers, and a smoker, revealing subtle health variations.

Results: Dynamic imaging revealed consistent ventilation in healthy lungs but identified irregularities and a novel reversed RBC:Gas ratio pattern in COPD, indicating significant alterations in gas exchange dynamics.

Impact: This study enhances understanding of COPD and could shift diagnostic and treatment practices, paving the way for targeted therapies and improved patient outcomes.

Keywords: Hyperpolarized MR (Gas), Image Reconstruction

Motivation: Cardiogenic oscillations in dissolved ¹²⁹Xe red blood cell (RBC) signal are sensitive to cardiopulmonary disease. Current methods to map the amplitude of these oscillations do not consider oscillation phase, leading to physiologically unrealistic amplitude values.

Goal(s): To map the amplitude and phase of ¹²⁹Xe RBC oscillations in the lung vasculature.

Approach: Multiple phases of the cardiac cycle were reconstructed from multi-echo dissolved ¹²⁹Xe spectroscopic imaging data using a sliding window keyhole method, to map both oscillation amplitude and phase in healthy volunteers and post-COVID-19 patients.

Results: Both oscillation amplitude and phase were mapped regionally. Phase-adjustment improved oscillation amplitude inter-scan repeatability in healthy volunteers.

Impact: Sliding-window keyhole ¹²⁹Xe RBC oscillation amplitude and phase mapping corrects for physiologically unrealistic negative amplitudes. This approach allows regional mapping of RBC oscillation phase, which may represent the cardiac pulse wave in the pulmonary microvasculature, and its alteration in disease.

Keywords: Visualization, Hyperpolarized MR (Gas), 129Xe MRI, Lung cancer, immunotherapy, ferroptosis

Motivation: The evaluation of lung cancer immunotherapy progress using non-invasive methods is challenging. Also, multiple scans of CT during the treatment period expose patients to more radiation.

Goal(s): To confirm ¹²⁹Xe MRI is a potentially robust technology for monitoring immunotherapy effects.

Approach: Fe₃O₄-based nanoprobe that could induce ferroptosis of tumor cells was prepared for immunotherapy of lung metastatic cancer combined with α-PD-L1, finally the immunotherapy effect was evaluated via ¹²⁹Xe MRI.

Results: The ¹²⁹Xe MRI displayed a complete ventilatory image of the lung in the probe plus α-PD-L1 group while severe ventilation deficiency was observed in the control group.

Impact: The ¹²⁹Xe MRI results of the lung showed significant differences in ventilation defects among different treatment groups, revealing the excellent tumor immunotherapy efficiency of nanoprobe-mediated immunotherapy, which represents a potential protocol for the evaluation of immunotherapy against tumors.

Keywords: Hyperpolarized MR (Gas), Hyperpolarized MR (Gas)

Motivation: Improving the diagnosis and monitoring of chronic lung allograft dysfunction (CLAD) post-lung transplantation may lead to improved long-term patient outcomes.

Goal(s): To identify hyperpolarized xenon-129 imaging markers for more comprehensively evaluating lung function in transplant recipients.

Approach: A multi-breath xenon-polarization transfer contrast (XTC) technique was used to quantify ventilation and gas exchange longitudinally in lung transplant patients.

Results: Correlations between the derived imaging metrics and current clinical standards for assessing lung function provided additional insight into the functional changes associated with post-transplant recovery or decline.

Impact: Hyperpolarized xenon-129 MRI enables more comprehensive assessments of the functional and physiological changes associated with recovery and/or deterioration after lung transplantation, potentially leading to earlier CLAD diagnosis and improved long-term outcomes.