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18 pages, 3070 KiB

Open AccessArticle

Radial Flow Perfusion Enables Real-Time Profiling of Cellular Metabolism at Low Oxygen Levels with Hyperpolarized ¹³C NMR Spectroscopy

by Anthony Mancuso, Mehrdad Pourfathi, Ryan M. Kiefer, Michael C. Noji, Sarmad Siddiqui, Enri Profka, Charles N. Weber, Austin Pantel, Stephen J. Kadlecek, Rahim Rizi and Terence P. F. Gade

Metabolites 2021, 11(9), 576; https://doi.org/10.3390/metabo11090576 - 26 Aug 2021

Viewed by 2324

Abstract

In this study, we describe new methods for studying cancer cell metabolism with hyperpolarized ¹³C magnetic resonance spectroscopy (HP ¹³C MRS) that will enable quantitative studies at low oxygen concentrations. Cultured hepatocellular carcinoma cells were grown on the surfaces of non-porous [...] Read more.

In this study, we describe new methods for studying cancer cell metabolism with hyperpolarized ¹³C magnetic resonance spectroscopy (HP ¹³C MRS) that will enable quantitative studies at low oxygen concentrations. Cultured hepatocellular carcinoma cells were grown on the surfaces of non-porous microcarriers inside an NMR spectrometer. They were perfused radially from a central distributer in a modified NMR tube (bioreactor). The oxygen level of the perfusate was continuously monitored and controlled externally. Hyperpolarized substrates were injected continuously into the perfusate stream with a newly designed system that prevented oxygen and temperature perturbations in the bioreactor. Computational and experimental results demonstrated that cell mass oxygen profiles with radial flow were much more uniform than with conventional axial flow. Further, the metabolism of HP [1-¹³C]pyruvate was markedly different between the two flow configurations, demonstrating the importance of avoiding large oxygen gradients in cell perfusion experiments. Full article

(This article belongs to the Special Issue Applications of Magnetic Resonance (MR)-Based Metabolic Imaging in Medicine)

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12 pages, 2492 KiB

Open AccessArticle

Characterization of Distinctive In Vivo Metabolism between Enhancing and Non-Enhancing Gliomas Using Hyperpolarized Carbon-13 MRI

by Seunggwi Park, Hashizume Rintaro, Seul Kee Kim and Ilwoo Park

Metabolites 2021, 11(8), 504; https://doi.org/10.3390/metabo11080504 - 31 Jul 2021

Cited by 3 | Viewed by 1923

Abstract

The development of hyperpolarized carbon-13 (¹³C) metabolic MRI has enabled the sensitive and noninvasive assessment of real-time in vivo metabolism in tumors. Although several studies have explored the feasibility of using hyperpolarized ¹³C metabolic imaging for neuro-oncology applications, most of [...] Read more.

The development of hyperpolarized carbon-13 (¹³C) metabolic MRI has enabled the sensitive and noninvasive assessment of real-time in vivo metabolism in tumors. Although several studies have explored the feasibility of using hyperpolarized ¹³C metabolic imaging for neuro-oncology applications, most of these studies utilized high-grade enhancing tumors, and little is known about hyperpolarized ¹³C metabolic features of a non-enhancing tumor. In this study, ¹³C MR spectroscopic imaging with hyperpolarized [1-¹³C]pyruvate was applied for the differential characterization of metabolic profiles between enhancing and non-enhancing gliomas using rodent models of glioblastoma and a diffuse midline glioma. Distinct metabolic profiles were found between the enhancing and non-enhancing tumors, as well as their contralateral normal-appearing brain tissues. The preliminary results from this study suggest that the characterization of metabolic patterns from hyperpolarized ¹³C imaging between non-enhancing and enhancing tumors may be beneficial not only for understanding distinct metabolic features between the two lesions, but also for providing a basis for understanding ¹³C metabolic processes in ongoing clinical trials with neuro-oncology patients using this technology. Full article

(This article belongs to the Special Issue Applications of Magnetic Resonance (MR)-Based Metabolic Imaging in Medicine)

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12 pages, 1516 KiB

Open AccessFeature PaperArticle

Hyperpolarized Dihydroxyacetone Is a Sensitive Probe of Hepatic Gluconeogenic State

by Mukundan Ragavan, Marc A. McLeod, Anthony G. Giacalone and Matthew E. Merritt

Metabolites 2021, 11(7), 441; https://doi.org/10.3390/metabo11070441 - 05 Jul 2021

Cited by 8 | Viewed by 2497

Abstract

Type II diabetes and pre-diabetes are widely prevalent among adults. Elevated serum glucose levels are commonly treated by targeting hepatic gluconeogenesis for downregulation. However, direct measurement of hepatic gluconeogenic capacity is accomplished only via tracer metabolism approaches that rely on multiple assumptions, and [...] Read more.

Type II diabetes and pre-diabetes are widely prevalent among adults. Elevated serum glucose levels are commonly treated by targeting hepatic gluconeogenesis for downregulation. However, direct measurement of hepatic gluconeogenic capacity is accomplished only via tracer metabolism approaches that rely on multiple assumptions, and are clinically intractable due to expense and time needed for the studies. We previously introduced hyperpolarized (HP) [2-¹³C]dihydroxyacetone (DHA) as a sensitive detector of gluconeogenic potential, and showed that feeding and fasting produced robust changes in the ratio of detected hexoses (6C) to trioses (3C) in the perfused liver. To confirm that this ratio is robust in the setting of treatment and hormonal control, we used ex vivo perfused mouse livers from BLKS mice (glucagon treated and metformin treated), and db/db mice. We confirm that the ratio of signal intensities of 6C to 3C in ¹³C nuclear magnetic resonance spectra post HP DHA administration is sensitive to hepatic gluconeogenic state. This method is directly applicable in vivo and can be implemented with existing technologies without the need for substantial modifications. Full article

(This article belongs to the Special Issue Applications of Magnetic Resonance (MR)-Based Metabolic Imaging in Medicine)

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18 pages, 2367 KiB

Open AccessFeature PaperArticle

Measuring Glycolytic Activity with Hyperpolarized [²H₇, U-¹³C₆] D-Glucose in the Naive Mouse Brain under Different Anesthetic Conditions

by Emmanuelle Flatt, Bernard Lanz, Yves Pilloud, Andrea Capozzi, Mathilde Hauge Lerche, Rolf Gruetter and Mor Mishkovsky

Metabolites 2021, 11(7), 413; https://doi.org/10.3390/metabo11070413 - 23 Jun 2021

Cited by 7 | Viewed by 3050

Abstract

Glucose is the primary fuel for the brain; its metabolism is linked with cerebral function. Different magnetic resonance spectroscopy (MRS) techniques are available to assess glucose metabolism, providing complementary information. Our first aim was to investigate the difference between hyperpolarized ¹³C-glucose MRS [...] Read more.

Glucose is the primary fuel for the brain; its metabolism is linked with cerebral function. Different magnetic resonance spectroscopy (MRS) techniques are available to assess glucose metabolism, providing complementary information. Our first aim was to investigate the difference between hyperpolarized ¹³C-glucose MRS and non-hyperpolarized ²H-glucose MRS to interrogate cerebral glycolysis. Isoflurane anesthesia is commonly employed in preclinical MRS, but it affects cerebral hemodynamics and functional connectivity. A combination of low doses of isoflurane and medetomidine is routinely used in rodent functional magnetic resonance imaging (fMRI) and shows similar functional connectivity, as in awake animals. As glucose metabolism is tightly linked to neuronal activity, our second aim was to assess the impact of these two anesthetic conditions on the cerebral metabolism of glucose. Brain metabolism of hyperpolarized ¹³C-glucose and non-hyperpolaized ²H-glucose was monitored in two groups of mice in a 9.4 T MRI system. We found that the very different duration and temporal resolution of the two techniques enable highlighting the different aspects in glucose metabolism. We demonstrate (by numerical simulations) that hyperpolarized ¹³C-glucose reports on de novo lactate synthesis and is sensitive to cerebral metabolic rate of glucose (CMR_Glc). We show that variations in cerebral glucose metabolism, under different anesthesia, are reflected differently in hyperpolarized and non-hyperpolarized X-nuclei glucose MRS. Full article

(This article belongs to the Special Issue Applications of Magnetic Resonance (MR)-Based Metabolic Imaging in Medicine)

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15 pages, 3048 KiB

Open AccessArticle

Non-Invasive Differentiation of M1 and M2 Activation in Macrophages Using Hyperpolarized ¹³C MRS of Pyruvate and DHA at 1.47 Tesla

by Kai Qiao, Lydia M. Le Page and Myriam M. Chaumeil

Metabolites 2021, 11(7), 410; https://doi.org/10.3390/metabo11070410 - 22 Jun 2021

Cited by 5 | Viewed by 2650

Abstract

Macrophage activation, first generalized to the M1/M2 dichotomy, is a complex and central process of the innate immune response. Simply, M1 describes the classical proinflammatory activation, leading to tissue damage, and M2 the alternative activation promoting tissue repair. Given the central role of [...] Read more.

Macrophage activation, first generalized to the M1/M2 dichotomy, is a complex and central process of the innate immune response. Simply, M1 describes the classical proinflammatory activation, leading to tissue damage, and M2 the alternative activation promoting tissue repair. Given the central role of macrophages in multiple diseases, the ability to noninvasively differentiate between M1 and M2 activation states would be highly valuable for monitoring disease progression and therapeutic responses. Since M1/M2 activation patterns are associated with differential metabolic reprogramming, we hypothesized that hyperpolarized ¹³C magnetic resonance spectroscopy (HP ¹³C MRS), an innovative metabolic imaging approach, could distinguish between macrophage activation states noninvasively. The metabolic conversions of HP [1-¹³C]pyruvate to HP [1-¹³C]lactate, and HP [1-¹³C]dehydroascorbic acid to HP [1-¹³C]ascorbic acid were monitored in live M1 and M2 activated J774a.1 macrophages noninvasively by HP ¹³C MRS on a 1.47 Tesla NMR system. Our results show that both metabolic conversions were significantly increased in M1 macrophages compared to M2 and nonactivated cells. Biochemical assays and high resolution ¹H MRS were also performed to investigate the underlying changes in enzymatic activities and metabolite levels linked to M1/M2 activation. Altogether, our results demonstrate the potential of HP ¹³C MRS for monitoring macrophage activation states noninvasively. Full article

(This article belongs to the Special Issue Applications of Magnetic Resonance (MR)-Based Metabolic Imaging in Medicine)

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18 pages, 6495 KiB

Open AccessArticle

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

by Stefan Markovic, Tangi Roussel, Michal Neeman and Lucio Frydman

Metabolites 2021, 11(6), 376; https://doi.org/10.3390/metabo11060376 - 10 Jun 2021

Cited by 12 | Viewed by 2963

Abstract

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 [...] Read more.

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 ²H_6,6′-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. ²H_6,6′-glucose uptake was observed in the placenta and in specific downstream organs such as the fetal heart and liver. Main metabolic products included ²H_3,3′-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 ²H_3,3′-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. Full article

(This article belongs to the Special Issue Applications of Magnetic Resonance (MR)-Based Metabolic Imaging in Medicine)

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15 pages, 2989 KiB

Open AccessArticle

Alterations of Striato-Thalamic Metabolism in Normal Aging Human Brain—An MR Metabolic Imaging Study

by Mareike Ahlswede, Patrick Nösel, Andrew A. Maudsley, Sulaiman Sheriff, Nima Mahmoudi, Paul Bronzlik, Heinrich Lanfermann and Xiao-Qi Ding

Metabolites 2021, 11(6), 371; https://doi.org/10.3390/metabo11060371 - 09 Jun 2021

Cited by 1 | Viewed by 2254

Abstract

Aging effects on striato-thalamic metabolism in healthy human brains were studied in vivo using short-TE whole brain ¹H-MR spectroscopic imaging (wbMRSI) on eighty healthy subjects aged evenly between 20 to 70 years at 3T. Relative concentrations of N-acetyl-aspartate (NAA), choline, total creatine [...] Read more.

Aging effects on striato-thalamic metabolism in healthy human brains were studied in vivo using short-TE whole brain ¹H-MR spectroscopic imaging (wbMRSI) on eighty healthy subjects aged evenly between 20 to 70 years at 3T. Relative concentrations of N-acetyl-aspartate (NAA), choline, total creatine (tCr), myo-inositol (mI), glutamate, and glutamine in bilateral caudate nucleus, putamen, pallidum, and thalamus were determined using signal normalization relative to brain tissue water. Linear regression analysis was used to analyze the age-dependence of the metabolite concentrations. The metabolite concentrations revealed spatial inhomogeneity across brain regions and metabolites. With age, NAA decreased significantly in bilateral caudate nucleus and putamen, left pallidum, and left thalamus, tCr decreased in left putamen and bilateral pallidum, mI increased in bilateral caudate nucleus and right thalamus, and spectral linewidth increased in left putamen and right thalamus. In conclusion, normal aging of striato-thalamic metabolism in healthy human is associated with regional specific decreases of NAA and tCr and increases of mI, which may reflect the individual role of each brain structure within brain functionality. Full article

(This article belongs to the Special Issue Applications of Magnetic Resonance (MR)-Based Metabolic Imaging in Medicine)

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15 pages, 1773 KiB

Open AccessArticle

Metabolic Response of Pancreatic Carcinoma Cells under Treatment with Dichloroacetate

by Benedikt Feuerecker, Philipp Biechl, Christian Veltkamp, Dieter Saur and Wolfgang Eisenreich

Metabolites 2021, 11(6), 350; https://doi.org/10.3390/metabo11060350 - 30 May 2021

Cited by 2 | Viewed by 2730

Abstract

In modern oncology, the analysis and evaluation of treatment response are still challenging. Hence, we used a ¹³C-guided approach to study the impacts of the small molecule dichloroacetate (DCA) upon the metabolic response of pancreatic cancer cells. Two different oncogenic PI3K-driven pancreatic [...] Read more.

In modern oncology, the analysis and evaluation of treatment response are still challenging. Hence, we used a ¹³C-guided approach to study the impacts of the small molecule dichloroacetate (DCA) upon the metabolic response of pancreatic cancer cells. Two different oncogenic PI3K-driven pancreatic cancer cell lines, 9580 and 10,158, respectively, were treated with 75 mM DCA for 18 h. In the presence of [U-¹³C₆]glucose, the effects of DCA treatment in the core carbon metabolism were analyzed in these cells using gas chromatography–mass spectrometry (GC/MS). ¹³C-enrichments and isotopologue profiles of key amino acids revealed considerable effects of the DCA treatment upon glucose metabolism. The DCA treatment of the two pancreatic cell lines resulted in a significantly decreased incorporation of [U-¹³C₆]glucose into the amino acids alanine, aspartate, glutamate, glycine, proline and serine in treated, but not in untreated, cancer cells. For both cell lines, the data indicated some activation of pyruvate dehydrogenase with increased carbon flux via the TCA cycle, but also massive inhibition of glycolytic flux and amino acid biosynthesis presumably by inhibition of the PI3K/Akt/mTORC axis. Together, it appears worthwhile to study the early treatment response in DCA-guided or accompanied cancer therapy in more detail, since it could open new avenues for improved diagnosis and therapeutic protocols of cancer. Full article

(This article belongs to the Special Issue Applications of Magnetic Resonance (MR)-Based Metabolic Imaging in Medicine)

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10 pages, 1582 KiB

Open AccessArticle

Enhancing Metabolic Imaging of Energy Metabolism in Traumatic Brain Injury Using Hyperpolarized [1-¹³C]Pyruvate and Dichloroacetate

by Stephen J. DeVience, Xin Lu, Julie L. Proctor, Parisa Rangghran, Juliana A. Medina, Elias R. Melhem, Rao P. Gullapalli, Gary Fiskum and Dirk Mayer

Metabolites 2021, 11(6), 335; https://doi.org/10.3390/metabo11060335 - 24 May 2021

Cited by 5 | Viewed by 2187

Abstract

Hyperpolarized magnetic resonance spectroscopic imaging (MRSI) of [1-¹³C]pyruvate metabolism has previously been used to assess the effects of traumatic brain injury (TBI) in rats. Here, we show that MRSI can be used in conjunction with dichloroacetate to measure the phosphorylation state [...] Read more.

Hyperpolarized magnetic resonance spectroscopic imaging (MRSI) of [1-¹³C]pyruvate metabolism has previously been used to assess the effects of traumatic brain injury (TBI) in rats. Here, we show that MRSI can be used in conjunction with dichloroacetate to measure the phosphorylation state of pyruvate dehydrogenase (PDH) following mild-to-moderate TBI, and that measurements can be repeated in a longitudinal study to monitor the course of injury progression and recovery. We found that the level of ¹³C-bicarbonate and the bicarbonate-to-lactate ratio decreased on the injured side of the brain four hours after injury and continued to decrease through day 7. Levels recovered to normal by day 28. Measurements following dichloroacetate administration showed that PDH was inhibited equally by PDH kinase (PDK) on both sides of the brain. Therefore, the decrease in aerobic metabolism is not due to inhibition by PDK. Full article

(This article belongs to the Special Issue Applications of Magnetic Resonance (MR)-Based Metabolic Imaging in Medicine)

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18 pages, 3808 KiB

Open AccessArticle

Hyperpolarized ¹³C Magnetic Resonance Spectroscopic Imaging of Pyruvate Metabolism in Murine Breast Cancer Models of Different Metastatic Potential

by Erin B. Macdonald, Paul Begovatz, Gregory P. Barton, Sarah Erickson-Bhatt, David R. Inman, Benjamin L. Cox, Kevin W. Eliceiri, Roberta M. Strigel, Suzanne M. Ponik and Sean B. Fain

Metabolites 2021, 11(5), 274; https://doi.org/10.3390/metabo11050274 - 27 Apr 2021

Cited by 8 | Viewed by 2181

Abstract

This study uses dynamic hyperpolarized [1-¹³C]pyruvate magnetic resonance spectroscopic imaging (MRSI) to estimate differences in glycolytic metabolism between highly metastatic (4T1, n = 7) and metastatically dormant (4T07, n = 7) murine breast cancer models. The apparent conversion rate of pyruvate-to-lactate [...] Read more.

This study uses dynamic hyperpolarized [1-¹³C]pyruvate magnetic resonance spectroscopic imaging (MRSI) to estimate differences in glycolytic metabolism between highly metastatic (4T1, n = 7) and metastatically dormant (4T07, n = 7) murine breast cancer models. The apparent conversion rate of pyruvate-to-lactate (k_PL) and lactate-to-pyruvate area-under-the-curve ratio (AUC_L/P) were estimated from the metabolite images and compared with biochemical metabolic measures and immunohistochemistry (IHC). A non-significant trend of increasing k_PL (p = 0.17) and AUC_L/P (p = 0.11) from 4T07 to 4T1 tumors was observed. No significant differences in tumor IHC lactate dehydrogenase-A (LDHA), monocarboxylate transporter-1 (MCT1), cluster of differentiation 31 (CD31), and hypoxia inducible factor-α (HIF-1α), tumor lactate-dehydrogenase (LDH) activity, or blood lactate or glucose levels were found between the two tumor lines. However, AUC_L/P was significantly correlated with tumor LDH activity (ρ_spearman = 0.621, p = 0.027) and blood glucose levels (ρ_spearman = −0.474, p = 0.042). k_PL displayed a similar, non-significant trend for LDH activity (ρ_spearman = 0.480, p = 0.114) and blood glucose levels (ρ_spearman = −0.414, p = 0.088). Neither k_PL nor AUC_L/P were significantly correlated with blood lactate levels or tumor LDHA or MCT1. The significant positive correlation between AUC_L/P and tumor LDH activity indicates the potential of AUC_L/P as a biomarker of glycolytic metabolism in breast cancer models. However, the lack of a significant difference between in vivo tumor metabolism for the two models suggest similar pyruvate-to-lactate conversion despite differing metastatic potential. Full article

(This article belongs to the Special Issue Applications of Magnetic Resonance (MR)-Based Metabolic Imaging in Medicine)

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13 pages, 1704 KiB

Open AccessArticle

Zero Echo Time ¹⁷O-MRI Reveals Decreased Cerebral Metabolic Rate of Oxygen Consumption in a Murine Model of Amyloidosis

by Celine Baligand, Olivier Barret, Amélie Tourais, Jean-Baptiste Pérot, Didier Thenadey, Fanny Petit, Géraldine Liot, Marie-Claude Gaillard, Julien Flament, Marc Dhenain and Julien Valette

Metabolites 2021, 11(5), 263; https://doi.org/10.3390/metabo11050263 - 22 Apr 2021

Cited by 3 | Viewed by 2048

Abstract

The cerebral metabolic rate of oxygen consumption (CMRO₂) is a key metric to investigate the mechanisms involved in neurodegeneration in animal models and evaluate potential new therapies. CMRO₂ can be measured by direct ¹⁷O magnetic resonance imaging (¹⁷ [...] Read more.

The cerebral metabolic rate of oxygen consumption (CMRO₂) is a key metric to investigate the mechanisms involved in neurodegeneration in animal models and evaluate potential new therapies. CMRO₂ can be measured by direct ¹⁷O magnetic resonance imaging (¹⁷O-MRI) of H₂¹⁷O signal changes during inhalation of ¹⁷O-labeled oxygen gas. In this study, we built a simple gas distribution system and used 3D zero echo time (ZTE-)MRI at 11.7 T to measure CMRO₂ in the APP_swe/PS1_dE9 mouse model of amyloidosis. We found that CMRO₂ was significantly lower in the APP_swe/PS1_dE9 brain than in wild-type at 12–14 months. We also estimated cerebral blood flow (CBF) from the post-inhalation washout curve and found no difference between groups. These results suggest that the lower CMRO₂ observed in APP_swe/PS1_dE9 is likely due to metabolism impairment rather than to reduced blood flow. Analysis of the ¹⁷O-MRI data using different quantification models (linear and 3-phase model) showed that the choice of the model does not affect group comparison results. However, the simplified linear model significantly underestimated the absolute CMRO₂ values compared to a 3-phase model. This may become of importance when combining several metabolic fluxes measurements to study neuro-metabolic coupling. Full article

(This article belongs to the Special Issue Applications of Magnetic Resonance (MR)-Based Metabolic Imaging in Medicine)

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14 pages, 2717 KiB

Open AccessArticle

In Vivo Assessment of Metabolic Abnormality in Alport Syndrome Using Hyperpolarized [1-¹³C] Pyruvate MR Spectroscopic Imaging

by Nguyen-Trong Nguyen, Eun-Hui Bae, Luu-Ngoc Do, Tien-Anh Nguyen, Ilwoo Park and Sang-Soo Shin

Metabolites 2021, 11(4), 222; https://doi.org/10.3390/metabo11040222 - 06 Apr 2021

Cited by 2 | Viewed by 2275

Abstract

Alport Syndrome (AS) is a genetic disorder characterized by impaired kidney function. The development of a noninvasive tool for early diagnosis and monitoring of renal function during disease progression is of clinical importance. Hyperpolarized ¹³C MRI is an emerging technique that enables [...] Read more.

Alport Syndrome (AS) is a genetic disorder characterized by impaired kidney function. The development of a noninvasive tool for early diagnosis and monitoring of renal function during disease progression is of clinical importance. Hyperpolarized ¹³C MRI is an emerging technique that enables non-invasive, real-time measurement of in vivo metabolism. This study aimed to investigate the feasibility of using this technique for assessing changes in renal metabolism in the mouse model of AS. Mice with AS demonstrated a significant reduction in the level of lactate from 4- to 7-week-old, while the levels of lactate were unchanged in the control mice over time. This reduction in lactate production in the AS group accompanied a significant increase of PEPCK expression levels, indicating that the disease progression in AS triggered the gluconeogenic pathway and might have resulted in a decreased lactate pool size and a subsequent reduction in pyruvate-to-lactate conversion. Additional metabolic imaging parameters, including the level of lactate and pyruvate, were found to be different between the AS and control groups. These preliminary results suggest that hyperpolarized ¹³C MRI might provide a potential noninvasive tool for the characterization of disease progression in AS. Full article

(This article belongs to the Special Issue Applications of Magnetic Resonance (MR)-Based Metabolic Imaging in Medicine)

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15 pages, 2971 KiB

Open AccessArticle

L-Carnitine Stimulates In Vivo Carbohydrate Metabolism in the Type 1 Diabetic Heart as Demonstrated by Hyperpolarized MRI

by Dragana Savic, Vicky Ball, M. Kate Curtis, Maria da Luz Sousa Fialho, Kerstin N. Timm, David Hauton, James West, Julian Griffin, Lisa C. Heather and Damian J. Tyler

Metabolites 2021, 11(3), 191; https://doi.org/10.3390/metabo11030191 - 23 Mar 2021

Cited by 6 | Viewed by 2741

Abstract

The diabetic heart is energetically and metabolically abnormal, with increased fatty acid oxidation and decreased glucose oxidation. One factor contributing to the metabolic dysfunction in diabetes may be abnormal handling of acetyl and acyl groups by the mitochondria. L-carnitine is responsible for their [...] Read more.

The diabetic heart is energetically and metabolically abnormal, with increased fatty acid oxidation and decreased glucose oxidation. One factor contributing to the metabolic dysfunction in diabetes may be abnormal handling of acetyl and acyl groups by the mitochondria. L-carnitine is responsible for their transfer across the mitochondrial membrane, therefore, supplementation with L-carnitine may provide a route to improve the metabolic state of the diabetic heart. The primary aim of this study was to use hyperpolarized magnetic resonance imaging (MRI) to investigate the effects of L-carnitine supplementation on the in vivo metabolism of [1-¹³C]pyruvate in diabetes. Male Wistar rats were injected with either vehicle or streptozotocin (55 mg/kg) to induce type-1 diabetes. Three weeks of daily i.p. treatment with either saline or L-carnitine (3 g/kg/day) was subsequently undertaken. In vivo cardiac function and metabolism were assessed with CINE and hyperpolarized MRI, respectively. L-carnitine supplementation prevented the progression of hyperglycemia, which was observed in untreated streptozotocin injected animals and led to reductions in plasma triglyceride and ß-hydroxybutyrate concentrations. Hyperpolarized MRI revealed that L-carnitine treatment elevated pyruvate dehydrogenase flux by 3-fold in the diabetic animals, potentially through increased buffering of excess acetyl-CoA units in the mitochondria. Improved functional recovery following ischemia was also observed in the L-carnitine treated diabetic animals. Full article

(This article belongs to the Special Issue Applications of Magnetic Resonance (MR)-Based Metabolic Imaging in Medicine)

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11 pages, 3330 KiB

Open AccessFeature PaperArticle

Implantable NMR Microcoils in Rats: A New Tool for Exploring Tumor Metabolism at Sub-Microliter Scale?

by Justine Deborne, Noël Pinaud and Yannick Crémillieux

Metabolites 2021, 11(3), 176; https://doi.org/10.3390/metabo11030176 - 17 Mar 2021

Cited by 3 | Viewed by 2232

Abstract

The aim of this study was to evaluate the potential of a miniaturized implantable nuclear magnetic resonance (NMR) coil to acquire in vivo proton NMR spectra in sub-microliter regions of interest and to obtain metabolic information using magnetic resonance spectroscopy (MRS) in these [...] Read more.

The aim of this study was to evaluate the potential of a miniaturized implantable nuclear magnetic resonance (NMR) coil to acquire in vivo proton NMR spectra in sub-microliter regions of interest and to obtain metabolic information using magnetic resonance spectroscopy (MRS) in these small volumes. For this purpose, the NMR microcoils were implanted in the right cortex of healthy rats and in C6 glioma-bearing rats. The dimensions of the microcoil were 450 micrometers wide and 3 mm long. The MRS acquisitions were performed at 7 Tesla using volume coil for RF excitation and microcoil for signal reception. The detection volume of the microcoil was measured equal to 450 nL. A gain in sensitivity equal to 76 was found in favor of implanted microcoil as compared to external surface coil. Nine resonances from metabolites were assigned in the spectra acquired in healthy rats (n = 5) and in glioma-bearing rat (n = 1). The differences in relative amplitude of choline, lactate and creatine resonances observed in glioma-bearing animal were in agreement with published findings on this tumor model. In conclusion, the designed implantable microcoil is suitable for in vivo MRS and can be used for probing the metabolism in localized and very small regions of interest in a tumor. Full article

(This article belongs to the Special Issue Applications of Magnetic Resonance (MR)-Based Metabolic Imaging in Medicine)

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17 pages, 1874 KiB

Open AccessArticle

Quantitative Assessment of Occipital Metabolic and Energetic Changes in Parkinson’s Patients, Using In Vivo ³¹P MRS-Based Metabolic Imaging at 7T

by Xiao-Hong Zhu, Byeong-Yeul Lee, Paul Tuite, Lisa Coles, Abhishek G. Sathe, Chi Chen, Jim Cloyd, Walter C. Low, Clifford J. Steer and Wei Chen

Metabolites 2021, 11(3), 145; https://doi.org/10.3390/metabo11030145 - 01 Mar 2021

Cited by 9 | Viewed by 2507

Abstract

Abnormal energy metabolism associated with mitochondrial dysfunction is thought to be a major contributor to the progression of neurodegenerative diseases such as Parkinson’s disease (PD). Recent advancements in the field of magnetic resonance (MR) based metabolic imaging provide state-of-the-art technologies for non-invasively probing [...] Read more.

Abnormal energy metabolism associated with mitochondrial dysfunction is thought to be a major contributor to the progression of neurodegenerative diseases such as Parkinson’s disease (PD). Recent advancements in the field of magnetic resonance (MR) based metabolic imaging provide state-of-the-art technologies for non-invasively probing cerebral energy metabolism under various brain conditions. In this proof-of-principle clinical study, we employed quantitative ³¹P MR spectroscopy (MRS) imaging techniques to determine a constellation of metabolic and bioenergetic parameters, including cerebral adenosine triphosphate (ATP) and other phosphorous metabolite concentrations, intracellular pH and nicotinamide adenine dinucleotide (NAD) redox ratio, and ATP production rates in the occipital lobe of cognitive-normal PD patients, and then we compared them with age-sex matched healthy controls. Small but statistically significant differences in intracellular pH, NAD and ATP contents and ATPase enzyme activity between the two groups were detected, suggesting that subtle defects in energy metabolism and mitochondrial function are quantifiable before regional neurological deficits or pathogenesis begin to occur in these patients. Pilot data aiming to evaluate the bioenergetic effect of mitochondrial-protective bile acid, ursodeoxycholic acid (UDCA) were also obtained. These results collectively demonstrated that in vivo ³¹P MRS-based neuroimaging can non-invasively and quantitatively assess key metabolic-energetic metrics in the human brain. This provides an exciting opportunity to better understand neurodegenerative diseases, their progression and response to treatment. Full article

(This article belongs to the Special Issue Applications of Magnetic Resonance (MR)-Based Metabolic Imaging in Medicine)

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21 pages, 5353 KiB

Open AccessArticle

Resistance to Androgen Deprivation Leads to Altered Metabolism in Human and Murine Prostate Cancer Cell and Tumor Models

by Jinny Sun, Robert A. Bok, Justin DeLos Santos, Deepti Upadhyay, Romelyn DeLos Santos, Shubhangi Agarwal, Mark Van Criekinge, Daniel B. Vigneron, Rahul Aggarwal, Donna M. Peehl, John Kurhanewicz and Renuka Sriram

Metabolites 2021, 11(3), 139; https://doi.org/10.3390/metabo11030139 - 26 Feb 2021

Cited by 14 | Viewed by 2394

Abstract

Currently, no clinical methods reliably predict the development of castration-resistant prostate cancer (CRPC) that occurs almost universally in men undergoing androgen deprivation therapy. Hyperpolarized (HP) ¹³C magnetic resonance imaging (MRI) could potentially detect the incipient emergence of CRPC based on early metabolic [...] Read more.

Currently, no clinical methods reliably predict the development of castration-resistant prostate cancer (CRPC) that occurs almost universally in men undergoing androgen deprivation therapy. Hyperpolarized (HP) ¹³C magnetic resonance imaging (MRI) could potentially detect the incipient emergence of CRPC based on early metabolic changes. To characterize metabolic shifts occurring upon the transition from androgen-dependent to castration-resistant prostate cancer (PCa), the metabolism of [U-¹³C]glucose and [U-¹³C]glutamine was analyzed by nuclear magnetic resonance spectroscopy. Comparison of steady-state metabolite concentrations and fractional enrichment in androgen-dependent LNCaP cells and transgenic adenocarcinoma of the murine prostate (TRAMP) murine tumors versus castration-resistant PC-3 cells and treatment-driven CRPC TRAMP tumors demonstrated that CRPC was associated with upregulation of glycolysis, tricarboxylic acid metabolism of pyruvate; and glutamine, glutaminolysis, and glutathione synthesis. These findings were supported by ¹³C isotopomer modeling showing increased flux through pyruvate dehydrogenase (PDH) and anaplerosis; enzymatic assays showing increased lactate dehydrogenase, PDH and glutaminase activity; and oxygen consumption measurements demonstrating increased dependence on anaplerotic fuel sources for mitochondrial respiration in CRPC. Consistent with ex vivo metabolomic studies, HP [1-¹³C]pyruvate distinguished androgen-dependent PCa from CRPC in cell and tumor models based on significantly increased HP [1-¹³C]lactate. Full article

(This article belongs to the Special Issue Applications of Magnetic Resonance (MR)-Based Metabolic Imaging in Medicine)

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17 pages, 4377 KiB

Open AccessArticle

Early Noninvasive Metabolic Biomarkers of Mutant IDH Inhibition in Glioma

by Marina Radoul, Donghyun Hong, Anne Marie Gillespie, Chloé Najac, Pavithra Viswanath, Russell O. Pieper, Joseph F. Costello, Hema Artee Luchman and Sabrina M. Ronen

Metabolites 2021, 11(2), 109; https://doi.org/10.3390/metabo11020109 - 13 Feb 2021

Cited by 15 | Viewed by 3622

Abstract

Approximately 80% of low-grade glioma (LGGs) harbor mutant isocitrate dehydrogenase 1/2 (IDH1/2) driver mutations leading to accumulation of the oncometabolite 2-hydroxyglutarate (2-HG). Thus, inhibition of mutant IDH is considered a potential therapeutic target. Several mutant IDH inhibitors are currently in clinical trials, including [...] Read more.

Approximately 80% of low-grade glioma (LGGs) harbor mutant isocitrate dehydrogenase 1/2 (IDH1/2) driver mutations leading to accumulation of the oncometabolite 2-hydroxyglutarate (2-HG). Thus, inhibition of mutant IDH is considered a potential therapeutic target. Several mutant IDH inhibitors are currently in clinical trials, including AG-881 and BAY-1436032. However, to date, early detection of response remains a challenge. In this study we used high resolution ¹H magnetic resonance spectroscopy (¹H-MRS) to identify early noninvasive MR (Magnetic Resonance)-detectable metabolic biomarkers of response to mutant IDH inhibition. In vivo ¹H-MRS was performed on mice orthotopically-implanted with either genetically engineered (U87IDHmut) or patient-derived (BT257 and SF10417) mutant IDH1 cells. Treatment with either AG-881 or BAY-1436032 induced a significant reduction in 2-HG. Moreover, both inhibitors led to a significant early and sustained increase in glutamate and the sum of glutamate and glutamine (GLX) in all three models. A transient early increase in N-acetylaspartate (NAA) was also observed. Importantly, all models demonstrated enhanced animal survival following both treatments and the metabolic alterations were observed prior to any detectable differences in tumor volume between control and treated tumors. Our study therefore identifies potential translatable early metabolic biomarkers of drug delivery, mutant IDH inhibition and glioma response to treatment with emerging clinically relevant therapies. Full article

(This article belongs to the Special Issue Applications of Magnetic Resonance (MR)-Based Metabolic Imaging in Medicine)

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Review

Jump to: Research

16 pages, 1774 KiB

Open AccessReview

Deuterium Metabolic Imaging—Rediscovery of a Spectroscopic Tool

by Ilona Polvoy, Hecong Qin, Robert R. Flavell, Jeremy Gordon, Pavithra Viswanath, Renuka Sriram, Michael A. Ohliger and David M. Wilson

Metabolites 2021, 11(9), 570; https://doi.org/10.3390/metabo11090570 - 25 Aug 2021

Cited by 11 | Viewed by 3421

Abstract

The growing demand for metabolism-specific imaging techniques has rekindled interest in Deuterium (²H) Metabolic Imaging (DMI), a robust method based on administration of a substrate (glucose, acetate, fumarate, etc.) labeled with the stable isotope of hydrogen and the observation of its [...] Read more.

The growing demand for metabolism-specific imaging techniques has rekindled interest in Deuterium (²H) Metabolic Imaging (DMI), a robust method based on administration of a substrate (glucose, acetate, fumarate, etc.) labeled with the stable isotope of hydrogen and the observation of its metabolic fate in three-dimensions. This technique allows the investigation of multiple metabolic processes in both healthy and diseased states. Despite its low natural abundance, the short relaxation time of deuterium allows for rapid radiofrequency (RF) pulses without saturation and efficient image acquisition. In this review, we provide a comprehensive picture of the evolution of DMI over the course of recent decades, with a special focus on its potential clinical applications. Full article

(This article belongs to the Special Issue Applications of Magnetic Resonance (MR)-Based Metabolic Imaging in Medicine)

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17 pages, 6610 KiB

Open AccessReview

Hyperpolarized Metabolic MRI—Acquisition, Reconstruction, and Analysis Methods

by Peder Eric Zufall Larson and Jeremy W. Gordon

Metabolites 2021, 11(6), 386; https://doi.org/10.3390/metabo11060386 - 14 Jun 2021

Cited by 10 | Viewed by 2949

Abstract

Hyperpolarized metabolic MRI with

^{13}

C-labeled agents has emerged as a powerful technique for in vivo assessments of real-time metabolism that can be used across scales of cells, tissue slices, animal models, and human subjects. Hyperpolarized contrast agents have unique properties compared to [...] Read more.

Hyperpolarized metabolic MRI with

^{13}

C-labeled agents has emerged as a powerful technique for in vivo assessments of real-time metabolism that can be used across scales of cells, tissue slices, animal models, and human subjects. Hyperpolarized contrast agents have unique properties compared to conventional MRI scanning and MRI contrast agents that require specialized imaging methods. Hyperpolarized contrast agents have a limited amount of available signal, irreversible decay back to thermal equilibrium, bolus injection and perfusion kinetics, cellular uptake and metabolic conversion kinetics, and frequency shifts between metabolites. This article describes state-of-the-art methods for hyperpolarized metabolic MRI, summarizing data acquisition, reconstruction, and analysis methods in order to guide the design and execution of studies. Full article

(This article belongs to the Special Issue Applications of Magnetic Resonance (MR)-Based Metabolic Imaging in Medicine)

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22 pages, 1763 KiB

Open AccessReview

Comprehensive Literature Review of Hyperpolarized Carbon-13 MRI: The Road to Clinical Application

by Michael Vaeggemose, Rolf F. Schulte and Christoffer Laustsen

Metabolites 2021, 11(4), 219; https://doi.org/10.3390/metabo11040219 - 03 Apr 2021

Cited by 16 | Viewed by 2882

Abstract

This review provides a comprehensive assessment of the development of hyperpolarized (HP) carbon-13 metabolic MRI from the early days to the present with a focus on clinical applications. The status and upcoming challenges of translating HP carbon-13 into clinical application are reviewed, along [...] Read more.

This review provides a comprehensive assessment of the development of hyperpolarized (HP) carbon-13 metabolic MRI from the early days to the present with a focus on clinical applications. The status and upcoming challenges of translating HP carbon-13 into clinical application are reviewed, along with the complexity, technical advancements, and future directions. The road to clinical application is discussed regarding clinical needs and technological advancements, highlighting the most recent successes of metabolic imaging with hyperpolarized carbon-13 MRI. Given the current state of hyperpolarized carbon-13 MRI, the conclusion of this review is that the workflow for hyperpolarized carbon-13 MRI is the limiting factor. Full article

(This article belongs to the Special Issue Applications of Magnetic Resonance (MR)-Based Metabolic Imaging in Medicine)

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