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

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.

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

Metabolites ◽

10.3390/metabo11080504 ◽

2021 ◽

Vol 11 (8) ◽

pp. 504

Author(s):

Seunggwi Park ◽

Hashizume Rintaro ◽

Seul Kee Kim ◽

Ilwoo Park

Keyword(s):

Metabolic Imaging ◽

Metabolic Profiles ◽

Rodent Models ◽

In Vivo Metabolism ◽

Hyperpolarized 13C ◽

Noninvasive Assessment ◽

Diffuse Midline Glioma ◽

Mr Spectroscopic Imaging

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.

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In vivo redox metabolic imaging of mitochondria assesses disease progression in non-alcoholic steatohepatitis

Scientific Reports ◽

10.1038/s41598-017-17447-2 ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 6

Author(s):

Ryosuke Nakata ◽

Fuminori Hyodo ◽

Masaharu Murata ◽

Hinako Eto ◽

Tomoko Nakaji ◽

...

Keyword(s):

Disease Progression ◽

Metabolic Imaging ◽

Alcoholic Steatohepatitis

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In vivo application of sub-second spiral chemical shift imaging (CSI) to hyperpolarized 13C metabolic imaging: Comparison with phase-encoded CSI

Journal of Magnetic Resonance ◽

10.1016/j.jmr.2010.03.005 ◽

2010 ◽

Vol 204 (2) ◽

pp. 340-345 ◽

Cited By ~ 30

Author(s):

Dirk Mayer ◽

Yi-Fen Yen ◽

Yakir S. Levin ◽

James Tropp ◽

Adolf Pfefferbaum ◽

...

Keyword(s):

Chemical Shift ◽

Chemical Shift Imaging ◽

Metabolic Imaging ◽

Hyperpolarized 13C

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Metabolic Imaging by Hyperpolarized 13C Magnetic Resonance Imaging for In vivo Tumor Diagnosis

Cancer Research ◽

10.1158/0008-5472.can-06-2564 ◽

2006 ◽

Vol 66 (22) ◽

pp. 10855-10860 ◽

Cited By ~ 432

Author(s):

Klaes Golman ◽

René in't Zandt ◽

Mathilde Lerche ◽

Rikard Pehrson ◽

Jan Henrik Ardenkjaer-Larsen

Keyword(s):

Magnetic Resonance Imaging ◽

Magnetic Resonance ◽

Tumor Diagnosis ◽

Metabolic Imaging ◽

Resonance Imaging ◽

Hyperpolarized 13C

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CBMT-41. IMAGING A HALLMARK OF CANCER: HYPERPOLARIZED 13C-MAGNETIC RESONANCE SPECTROSCOPY CAN NON-INVASIVELY MONITOR TERT EXPRESSION IN LOW-GRADE GLIOMAS IN VIVO

Neuro-Oncology ◽

10.1093/neuonc/noz175.163 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi42-vi42

Author(s):

Pavithra Viswanath ◽

Georgios Batsios ◽

Anne Marie Gillespie ◽

Russell O Pieper ◽

Sabrina Ronen

Keyword(s):

Lactate Production ◽

Metabolic Imaging ◽

Imaging Biomarkers ◽

Resonance Spectroscopy ◽

Low Grade ◽

Normal Brain ◽

Non Invasive ◽

Glucose Flux ◽

Tert Expression

Abstract Telomerase reverse transcriptase (TERT) expression is a hallmark of cancer, including in primary glioblastomas and low-grade oligodendrogliomas. Since TERT is essential for glioma proliferation and is an attractive therapeutic target, metabolic imaging of TERT status can inform on tumor progression and response to therapy. To that end, the goal of this study was to identify non-invasive, translational, hyperpolarized 13C-magnetic resonance spectroscopy-detectable metabolic imaging biomarkers of TERT in low-grade oligodendrogliomas. Unbiased metabolomic analysis of immortalized normal human astrocytes without (NHAcontrol) and with TERT (NHAtert) indicated that TERT induced unique metabolic reprogramming. Notably, TERT increased NADPH and NADH levels. Glucose flux through the pentose phosphate pathway (PPP) is a major producer of NADPH. Non-invasive imaging of PPP flux using hyperpolarized [U-13C,U-2H]-glucose indicated that production of the PPP metabolite 6-phosphogluconate (6-PG) was elevated in NHAtert cells relative to NHAcontrol. Importantly, hyperpolarized [U-13C,U-2H]-glucose flux to 6-PG clearly differentiated tumor from normal brain in orthotopic NHAtert tumor xenografts. Next, we exploited the observation that TERT expression increased NADH, which is essential for the metabolism of hyperpolarized [1-13C]-alanine to lactate. Lactate production from hyperpolarized [1-13C]-alanine was higher in NHAtert cells relative to NHAcontrol. Importantly, hyperpolarized [1-13C]-alanine imaging in orthotopic NHAtert tumors revealed pronounced differences in lactate production between tumor tissue and normal brain. Mechanistically, TERT increased expression of glucose-6-phosphate dehydrogenase (G6PDH), the rate-limiting enzyme for 6-PG and NADPH production, and of nicotinamide phosphoribosyltransferase (NAMPT), a rate-limiting enzyme for NADH biosynthesis. Silencing TERT reversed G6PDH and NAMPT expression and normalized hyperpolarized [U-13C,U-2H]-glucose and [1-13C]-alanine metabolism, validating our imaging biomarkers. Finally, hyperpolarized [U-13C,U-2H]-glucose and [1-13C]-alanine could monitor TERT status in the clinically relevant, patient-derived BT54 oligodendroglioma model. In summary, we demonstrate, for the first time, non-invasive in vivo imaging of TERT status in gliomas that can enable longitudinal analysis of tumor burden and treatment response in the clinic.

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Metabolic Imaging of the Human Brain with Hyperpolarized 13C Pyruvate Demonstrates 13C Lactate Production in Brain Tumor Patients

Cancer Research ◽

10.1158/0008-5472.can-18-0221 ◽

2018 ◽

Vol 78 (14) ◽

pp. 3755-3760 ◽

Cited By ~ 62

Author(s):

Vesselin Z. Miloushev ◽

Kristin L. Granlund ◽

Rostislav Boltyanskiy ◽

Serge K. Lyashchenko ◽

Lisa M. DeAngelis ◽

...

Keyword(s):

Brain Tumor ◽

Human Brain ◽

Lactate Production ◽

Metabolic Imaging ◽

Tumor Patients ◽

Hyperpolarized 13C

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In vivo Detection of Radiation-induced Tissue Alterations by Hyperpolarized 13C Metabolic Imaging

International Journal of Radiation Oncology*Biology*Physics ◽

10.1016/j.ijrobp.2009.07.132 ◽

2009 ◽

Vol 75 (3) ◽

pp. S48-S49

Author(s):

L. Senadheera ◽

D. Mayer ◽

M.M. Darpolor ◽

Y. Yen ◽

D.M. Spielman ◽

...

Keyword(s):

Metabolic Imaging ◽

Hyperpolarized 13C ◽

In Vivo Detection ◽

Radiation Induced ◽

Tissue Alterations

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Central inhibition of P2Y12R differentially regulates survival and neuronal loss in MPTP-induced Parkinsonism in mice

10.1101/2021.02.03.256941 ◽

2021 ◽

Author(s):

András Iring ◽

Adrián Tóth ◽

Mária Baranyi ◽

Lilla Otrokocsi ◽

László V. Módis ◽

...

Keyword(s):

Disease Progression ◽

Disease Onset ◽

Neuronal Loss ◽

Cell Loss ◽

P2y12 Receptor ◽

Mapk Activity ◽

Central Inhibition ◽

The Central Nervous System ◽

And Control

AbstractParkinson’s disease (PD) is a chronic, progressive neurodegenerative condition; characterized with the degeneration of the nigrostriatal dopaminergic pathway and neuroinflammation. During PD progression, microglia, the resident immune cells in the central nervous system (CNS) display altered activity, but their role in maintaining PD development has remained unclear to date. The purinergic P2Y12 receptor (P2Y12R), which is exclusively expressed on the microglia in the CNS has been shown to regulate microglial activity and responses; however, the function of the P2Y12R in PD is unknown. Here we show that while pharmacological or genetic targeting of P2Y12R previous to disease onset augments acute mortality, these interventions protect against neurodegenerative cell loss and the development of neuroinflammation in vivo. Pharmacological inhibition of receptors during disease development reverses the symptoms of PD and halts disease progression. We found that P2Y12R regulate ROCK and p38 MAPK activity and control cytokine production. Understanding protective and detrimental P2Y12 receptor-mediated actions in the CNS may reveal novel approaches to control neuroinflammation and modify disease progression in PD.

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Metabolic Changes in Different Stages of Liver Fibrosis: In vivo Hyperpolarized 13C MR Spectroscopy and Metabolic Imaging

Molecular Imaging and Biology ◽

10.1007/s11307-019-01322-9 ◽

2019 ◽

Vol 21 (5) ◽

pp. 842-851 ◽

Cited By ~ 4

Author(s):

Chung-Man Moon ◽

Sang-Soo Shin ◽

Suk-Hee Heo ◽

Hyo-Soon Lim ◽

Myeong-Ju Moon ◽

...

Keyword(s):

Liver Fibrosis ◽

Mr Spectroscopy ◽

Metabolic Changes ◽

Metabolic Imaging ◽

Hyperpolarized 13C

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TAMI-40. PEDIATRIC H3K27M MUTANT GLIOMAS UNDERGO METABOLIC REPROGRAMMING THAT CAN BE LEVERAGED FOR NON-INVASIVE METABOLIC IMAGING

Neuro-Oncology ◽

10.1093/neuonc/noab196.824 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi206-vi207

Author(s):

Meryssa Tran ◽

Georgios Batsios ◽

Céline Taglang ◽

Anne Marie Gillespie ◽

Javad Nazarian ◽

...

Keyword(s):

Magnetic Resonance ◽

Phospholipid Metabolism ◽

Metabolic Reprogramming ◽

Metabolic Imaging ◽

Resonance Spectroscopy ◽

1H Mrs ◽

Hyperpolarized 13C ◽

Non Invasive ◽

13C Mrs

Abstract Diffuse midline gliomas (DMGs) are a universally lethal form of childhood cancer. The infiltrative nature of DMGs makes them difficult to visualize by conventional magnetic resonance imaging. Genomics studies indicate that DMGs are driven by unique histone H3K27M mutations that result in broad epigenetic dysregulation. Many of the resulting changes in gene expression have the potential to induce metabolic reprogramming, which has been identified as a hallmark of cancer. The goal of this study was to dissect metabolic reprogramming in preclinical DMG models in order to identify novel magnetic resonance spectroscopy (MRS)-detectable metabolic biomarkers that can be exploited for non-invasive imaging. First, we used 1H-MRS, which reports on steady-state metabolism, to examine H3K27M mutant SF7761 cells and H3 wild-type normal human astrocytes (NHA). Lactate, glutathione and phosphocholine, which are involved in glycolysis, redox and phospholipid metabolism respectively, were elevated in SF7761 cells relative to NHAs. Mechanistically, these metabolic alterations were associated with upregulation of key enzymes including hexokinase 2, glutamate cysteine ligase and choline kinase a. Importantly, in vivo 1H-MRS showed elevated lactate, glutathione and total choline (combined signal from choline, phosphocholine and glycerophosphocholine) in mice bearing orthotopic SF7761 tumors relative to tumor-free controls. We then examined alterations in dynamic metabolic pathways in our models. Using thermally-polarized 13C-MRS, we identified elevated production of [2-13C]-lactate from [2-13C]-glucose in SF7761 cells relative to NHAs. Hyperpolarized 13C-MRS is a method of enhancing the 13C-MR signal such that metabolic fluxes can be interrogated with high sensitivity. Hyperpolarized [1-13C]-pyruvate flux to [1-13C]-lactate non-invasively monitors glycolysis and is in clinical trials in adult glioma patients. Importantly, hyperpolarized [1-13C]-pyruvate metabolism to lactate was elevated in SF7761 cells relative to NHAs. Collectively, our studies suggest that H3K27M mutant DMGs undergo reprogramming of glucose, redox and phospholipid metabolism that can be leveraged for non-invasive 1H- and hyperpolarized 13C-MRS-based imaging.

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