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MRI with hyperpolarised [1-13C]pyruvate detects advanced pancreatic preneoplasia prior to invasive disease in a mouse model.

ABSTRACT: OBJECTIVES:Pancreatic cancer (PCa) is treatable by surgery when detected at an early stage. Non-invasive imaging methods able to detect both established tumours and their precursor lesions are needed to select patients for surgery. We investigated here whether pancreatic preneoplasia could be detected prior to the development of invasive cancers in genetically engineered mouse models of PCa using metabolic imaging. DESIGN:The concentrations of alanine and lactate and the activities of lactate dehydrogenase (LDH) and alanine aminotransferase (ALT) were measured in extracts prepared from the pancreas of animals at different stages of disease progression; from pancreatitis, through tissue with predominantly low-grade and then high-grade pancreatic intraepithelial neoplasia and then tumour. (13)C magnetic resonance spectroscopic imaging ((13)C-MRSI) was used to measure non-invasively changes in (13)C labelling of alanine and lactate with disease progression, following injection of hyperpolarised [1-(13)C]pyruvate. RESULTS:Progressive decreases in the alanine/lactate concentration ratio and ALT/LDH activity ratio with disease progression were accompanied by a corresponding decrease in the [1-(13)C]alanine/[1-(13)C]lactate signal ratio observed in (13)C-MRSI images of the pancreas. CONCLUSIONS:Metabolic imaging with hyperpolarised [1-(13)C]pyruvate enables detection and monitoring of the progression of PCa precursor lesions. Translation of this MRI technique to the clinic has the potential to improve the management of patients at high risk of developing PCa.

SUBMITTER: Serrao EM

PROVIDER: S-EPMC4789827 | biostudies-other | 2016 Mar

REPOSITORIES: biostudies-other

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MRI with hyperpolarised [1-13C]pyruvate detects advanced pancreatic preneoplasia prior to invasive disease in a mouse model.

Serrao Eva M EM Kettunen Mikko I MI Rodrigues Tiago B TB Dzien Piotr P Wright Alan J AJ Gopinathan Aarthi A Gallagher Ferdia A FA Lewis David Y DY Frese Kristopher K KK Almeida Jaime J Howat William J WJ Tuveson David A DA Brindle Kevin M KM

Gut 20150907 3

<h4>Objectives</h4>Pancreatic cancer (PCa) is treatable by surgery when detected at an early stage. Non-invasive imaging methods able to detect both established tumours and their precursor lesions are needed to select patients for surgery. We investigated here whether pancreatic preneoplasia could be detected prior to the development of invasive cancers in genetically engineered mouse models of PCa using metabolic imaging.<h4>Design</h4>The concentrations of alanine and lactate and the activitie ...[more]

PMID: 26347531

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Project description:MRI using hyperpolarized (HP) carbon-13 pyruvate is being investigated in clinical trials to provide non-invasive measurements of metabolism for cancer and cardiac imaging. In this project, we applied HP [1-13 C]pyruvate dynamic MRI in prostate cancer to measure the conversion from pyruvate to lactate, which is expected to increase in aggressive cancers. The goal of this work was to develop and test analysis methods for improved quantification of this metabolic conversion. In this work, we compared specialized kinetic modeling methods to estimate the pyruvate-to-lactate conversion rate, kPL , as well as the lactate-to-pyruvate area-under-curve (AUC) ratio. The kinetic modeling included an "inputless" method requiring no assumptions regarding the input function, as well as a method incorporating bolus characteristics in the fitting. These were first evaluated with simulated data designed to match human prostate data, where we examined the expected sensitivity of metabolism quantification to variations in kPL , signal-to-noise ratio (SNR), bolus characteristics, relaxation rates, and B1 variability. They were then applied to 17 prostate cancer patient datasets. The simulations indicated that the inputless method with fixed relaxation rates provided high expected accuracy with no sensitivity to bolus characteristics. The AUC ratio showed an undesired strong sensitivity to bolus variations. Fitting the input function as well did not improve accuracy over the inputless method. In vivo results showed qualitatively accurate kPL maps with inputless fitting. The AUC ratio was sensitive to bolus delivery variations. Fitting with the input function showed high variability in parameter maps. Overall, we found the inputless kPL fitting method to be a simple, robust approach for quantification of metabolic conversion following HP [1-13 C]pyruvate injection in human prostate cancer studies. This study also provided initial ranges of HP [1-13 C]pyruvate parameters (SNR, kPL , bolus characteristics) in the human prostate.

Project description:Higher dietary intakes of saturated fatty acid increase the risk of developing Alzheimer's disease and dementia, and even in people without diabetes higher glucose levels may be a risk factor for dementia. The mechanisms causing neuronal dysfunction and dementia by consuming high-fat diet degrading the integrity of the blood-brain barrier (BBB) has been suggested but are not yet fully understood, and metabolic state of the brain by this type of insult is still veiled. The objective of this study was to investigate the effect of high-fat diet on the brain metabolism by a multimodal imaging method using the hyperpolarizedcarbon 13 (13C)-pyruvate magnetic resonance (MR) spectroscopy and dynamic contrast-enhanced MR imaging in conjunction with the biochemical assay and the behavior test in a mouse model fed high-fat diet (HFD). In mice were fed 60% HFD for 6?months, hyperpolarized [1-13C] pyruvate MR spectroscopy showed decreased perfusion (p?<?0.01) and increased conversion from pyruvate to lactate (p?<?0.001) in the brain. The hippocampus and striatum showed the highest conversion ratio. The functional integrity of the blood-brain barrier tested by dynamic contrast-enhanced MR imaging showed no difference to the control. Lactate was increased in the cortex (p?<?0.01) and striatum (p?<?0.05), while PDH activity was decreased in the cortex (p?<?0.01) and striatum (p?<?0.001) and the phosphorylated PDH was increased in the striatum (p?<?0.05). Mice fed HFD showed less efficiency in learning memory compared with control (p?<?0.05). To determine whether hyperpolarized 13C-pyruvate magnetic resonance (MR) spectroscopy could detect a much earier event in the brain. Mice fed HFD for 3?months did not show a detectable cognitive decline in water maze based learning memory. Hyperpolarized [1-13C] pyruvate MR spectroscopy showed increased lactate conversion (P?<?.001), but no difference in cerebral perfusion. These results suggest that the increased hyperpolarized [1-13C] lactate signal in the brain of HFD-fed mice represent that altered metabolic alteration toward to glycolysis and hypoperfusion by the long-term metabolic stress by HFD further promote to glycolysis. The hyperpolarized [1-13C] pyruvate MR spectroscopy can be used to monitor the brain metabolism and will provide information helpful to understand the disease process.

Project description:While pancreatic cancer (PC) survival rates have recently shown modest improvement, the disease remains largely incurable. Early detection of pancreatic cancer may result in improved outcomes and therefore, methods for early detection of cancer, even premalignant lesions, may provide more favorable outcomes. Pancreatic intraepithelial neoplasias (PanINs) have been identified as premalignant precursor lesions to pancreatic cancer. However, conventional imaging methods used for screening high-risk populations do not have the sensitivity to detect PanINs. Here, we have employed hyperpolarized metabolic imaging in vivo and nuclear magnetic resonance (1H-NMR) metabolomics ex vivo to identify and understand metabolic changes, towards enabling detection of early PanINs and progression to advanced PanINs lesions that precede pancreatic cancer formation. Progression of disease from tissue containing predominantly low-grade PanINs to tissue with high-grade PanINs showed a decreasing alanine/lactate ratio from high-resolution NMR metabolomics ex vivo. Hyperpolarized magnetic resonance spectroscopy (HP-MRS) allows over 10,000-fold sensitivity enhancement relative to conventional magnetic resonance. Real-time HP-MRS was employed to measure non-invasively changes of alanine and lactate metabolites with disease progression and in control mice in vivo, following injection of hyperpolarized [1-13C] pyruvate. The alanine-to-lactate signal intensity ratio was found to decrease as the disease progressed from low-grade PanINs to high-grade PanINs. The biochemical changes of alanine transaminase (ALT) and lactate dehydrogenase (LDH) enzyme activity were assessed. These results demonstrate that there are significant alterations of ALT and LDH activities during the transformation from early to advanced PanINs lesions. Furthermore, we demonstrate that real-time conversion kinetic rate constants (kPA and kPL) can be used as metabolic imaging biomarkers of pancreatic premalignant lesions. Findings from this emerging HP-MRS technique can be translated to the clinic for detection of pancreatic premalignant lesion in high-risk populations.

Dataset Information

MRI with hyperpolarised [1-13C]pyruvate detects advanced pancreatic preneoplasia prior to invasive disease in a mouse model.

Publications

MRI with hyperpolarised [1-13C]pyruvate detects advanced pancreatic preneoplasia prior to invasive disease in a mouse model.

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