Imaging Brain Metabolism Using Hyperpolarized 13C Magnetic Resonance Spectroscopy

Abstract

Hyperpolarized 13C MRS is an emerging metabolic imaging technique that provides in vivo assessment of enzymatic fluxes after injection of hyperpolarized probes ( e. g., [1-13C]pyruvate).This technology provides valuable diagnostic and treatment monitoring information in the oncological and cardiovascular fields, where measurement of hyperpolarized pyruvate-to-lactate conversion has been translated to the clinic.The technique has recently been applied preclinically in several non-oncological neurological disorders, successfully detecting metabolic impairment.Valuable metabolic data assessing hyperpolarized pyruvate-to-lactate conversion have been acquired in animal models of multiple sclerosis, traumatic brain injury, neuroinflammation, cognitive impairment, and stroke.Clinical trials on healthy volunteers and traumatic brain injury patients are currently underway. Aberrant metabolism is a key factor in many neurological disorders. The ability to measure such metabolic impairment could lead to improved detection of disease progression, and development and monitoring of new therapeutic approaches. Hyperpolarized 13C magnetic resonance spectroscopy (MRS) is a developing imaging technique that enables non-invasive measurement of enzymatic activity in real time in living organisms. Primarily applied in the fields of cancer and cardiac disease so far, this metabolic imaging method has recently been used to investigate neurological disorders. In this review, we summarize the preclinical research developments in this emerging field, and discuss future prospects for this exciting technology, which has the potential to change the clinical paradigm for patients with neurological disorders. Aberrant metabolism is a key factor in many neurological disorders. The ability to measure such metabolic impairment could lead to improved detection of disease progression, and development and monitoring of new therapeutic approaches. Hyperpolarized 13C magnetic resonance spectroscopy (MRS) is a developing imaging technique that enables non-invasive measurement of enzymatic activity in real time in living organisms. Primarily applied in the fields of cancer and cardiac disease so far, this metabolic imaging method has recently been used to investigate neurological disorders. In this review, we summarize the preclinical research developments in this emerging field, and discuss future prospects for this exciting technology, which has the potential to change the clinical paradigm for patients with neurological disorders. Metabolic changes are increasingly being recognized as key players in neurological diseases, and may reveal exciting new avenues for treatment of these disorders. It is critical to develop new tools for monitoring brain metabolism through disease progression and in response to treatment, but such development remains complex due to our inability to easily sample brain tissue. New neuroimaging methods are beginning to address the crucial need for non-invasive assessment of brain metabolism. Hyperpolarized 13C MRS/magnetic resonance spectroscopic imaging (MRSI, see Glossary) is an emerging technology that enables in vivo acquisition of dynamic metabolic data, providing unprecedented insights into the in vivo metabolic status of the organ of interest. 1H and nonhyperpolarized, thermal 13C MRS have both been used to acquire clinical data on steady-state human brain metabolism [1.Albrecht D. S. et al.In vivo imaging of human neuroinflammation.ACS Chem. Neurosci. 2016; 7: 470-483Crossref PubMed Scopus (126) Google Scholar, 2.Cheshkov S. et al.Oxidation of [U-(13) C]glucose in the human brain at 7T under steady state conditions.Magn. Reson. Med. 2017; 78: 2065-2071Crossref PubMed Scopus (19) Google Scholar, 3.Boumezbeur F. et al.Altered brain mitochondrial metabolism in healthy aging as assessed by in vivo magnetic resonance spectroscopy.J. Cereb. Blood Flow Metab. 2010; 30: 211-221Crossref PubMed Scopus (184) Google Scholar]. However, these methods are not used widely in the clinic and, in particular, thermal 13C MRS requires long scan times and infusions of 13C-labeled substrate. Hyperpolarized 13C MRS brings new information to the field of metabolic imaging. First published in 2003 [4.Ardenkjaer-Larsen J. H. et al.Increase in signal-to-noise ratio of > 10,000 times in liquid-state NMR.Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 10158-10163Crossref PubMed Scopus (2222) Google Scholar], this method requires the hyperpolarization and rapid liquid dissolution of a 13C-labeled compound, typically pyruvate, a process typically carried out in an automated fashion using a hyperpolarizer. Hyperpolarization of a compound causes it to become more than 10 000-fold more visible by magnetic resonance imaging (MRI), due to the increased signal:noise ratio. Figure 1 (Key Figure) summarizes the typical steps of a hyperpolarized 13C MRS/I preclinical experiment. Given that the hyperpolarized state lasts only for a short time once in solution (referred to as the relaxation time, or T1), injection into the biological system of interest (cells, animal model, or human) must be rapid (10–15 s in animals) and coincide with the time of data acquisition. Typical MR hardware is then used to obtain 13C MR spectra (slab, 2D or 3D, single time point or dynamic), where the resonances of the injected substrate and its downstream metabolic products can be seen. Following injection of hyperpolarized [1-13C]pyruvate, the most commonly used probe, the resonances of hyperpolarized [1-13C]lactate, hyperpolarized [1-13C]alanine, and, in some cases, hyperpolarized 13C bicarbonate, are observed in the living brain, reflecting enzymatic conversion via lactate dehydrogenase (LDH), alanine aminotransferase (ALT), and pyruvate dehydrogenase (PDH), respectively. Many new compounds for injection are under development, and are discussed later. MR spectra showing area(s) under the curve(s), corresponding metabolic ratios of product:substrate ( e. g., lactate:pyruvate), or kinetic pseudo-rate constants for substrate to product conversion ( e. g., kPL) can then be reported from hyperpolarized data. By using preclinical models, hyperpolarized 13C metabolic data can be validated either through correlation analyses with ‘ground truth’ ex vivo biochemical analyses, or through comparison to more widely applied clinical imaging techniques to assess the added value of the method. Clinically, hyperpolarized 13C MRS/I can to metabolic the of human brain far, hyperpolarized 13C MRS/I has been applied in the fields of cancer and, to a cardiovascular with clinical in both exciting data have been acquired in preclinical models of neurological and neuroinflammation, in which metabolic changes have been observed with disease progression and new of neurological may our of in vivo brain metabolism not only but in hyperpolarized 13C MRS/I has been translated to the In this review, we summarize the of hyperpolarized 13C MRS/I in the non-oncological neurological field, and discuss prospects for future The conversion of pyruvate to lactate at a key in metabolism with being in most the enzymatic is in a of and, in response to a an ability to pyruvate to lactate conversion the to in disease monitoring and assessment of therapeutic hyperpolarized 13C MRS/I data from the healthy brain at is is to investigate disease development and treatment The brain has been by hyperpolarized 13C MRS/I in several preclinical The of using both hyperpolarized to brain metabolism using a of MR and has been with conversion of hyperpolarized to hyperpolarized and hyperpolarized 13C in and brain via imaging at 1 or et pyruvate brain metabolism with at Reson. 2017; PubMed Scopus Google Scholar, et and metabolism of hyperpolarized using MR spectroscopic Cereb. Blood Flow Metab. 2010; 30: PubMed Scopus Google Scholar, D. et and metabolic imaging of hyperpolarized in the brain using a Reson. Med. PubMed Scopus Google Scholar]. Hyperpolarized has been this is to from the the healthy brain et pyruvate brain metabolism with at Reson. 2017; PubMed Scopus Google Scholar]. to the with the clinical reported in hyperpolarized 13C MRS/I to be in the healthy brain using a clinical MR system and the clinical et hyperpolarized MR metabolic imaging of Reson. Med. PubMed Scopus Google Scholar]. for hyperpolarized 13C to be to in our only preclinical to has used hyperpolarized 13C MRS/I to investigate brain in conversion of hyperpolarized to hyperpolarized at multiple and and observed that this conversion with et to lactate metabolic changes using hyperpolarized 13C imaging in Neurosci. 2016; PubMed Scopus Google Scholar]. However, brain as by the added value of metabolic imaging et to lactate metabolic changes using hyperpolarized 13C imaging in Neurosci. 2016; PubMed Scopus Google Scholar]. In the healthy aging brain, hyperpolarized 13C MRS/I research remains is for neurological disorders, such as disease et for brain in PubMed Scopus Google Scholar]. an into the aging field, hyperpolarized 13C MRS has been used to healthy of a pyruvate dehydrogenase to hyperpolarized to hyperpolarized impairment in observed with treatment time, assessed using a A. et is for acquisition but not in PubMed Scopus Google Scholar]. to the metabolic that of in response to or is to many brain diseases, methods that the imaging of from the system and are metabolic that to or S. A. Metabolic in Google Scholar]. hyperpolarized 13C MRS/I is a technique for detecting and monitoring with have been to and conversion of pyruvate into lactate S. A. Metabolic in Google Scholar]. In in using hyperpolarized after using the hyperpolarized 13C increased with et detection of in models using hyperpolarized PubMed Scopus Google Scholar]. increased ratio by an in activity and increased and of 1 and in an increased lactate in the information hyperpolarized to the of a In with these a single injection of in the brain in increased hyperpolarized and hyperpolarized 13C at the of injection et magnetic resonance spectroscopy in PubMed Scopus Google Scholar]. changes in with increased of and of and the metabolism J. and PubMed Scopus Google have been using hyperpolarized a hyperpolarized 13C with et rapid detection of metabolic in human by hyperpolarized magnetic PubMed Scopus Google Scholar]. and metabolism have been in most S. metabolism in and J. 2017; PubMed Scopus Google et of metabolism in 2016; PubMed Scopus Google Scholar]. are multiple causes of in brain metabolism that may from to the brain as a of in far, only a of preclinical have used hyperpolarized 13C MRS/I to assess metabolic impairment in the brain the oncological field, and these are to hyperpolarized In models of traumatic brain injury hyperpolarized 13C increased at the injury and for several et al.In vivo metabolic imaging of traumatic brain 2017; 7: PubMed Scopus Google S. J. et imaging of metabolism in traumatic brain injury using hyperpolarized 2017; 7: PubMed Scopus Google Scholar]. hyperpolarized 13C at time injury S. J. et imaging of metabolism in traumatic brain injury using hyperpolarized 2017; 7: PubMed Scopus Google Scholar]. these changes to be to activity with changes in The these metabolic changes and most multiple such as and of the is due to of the brain, and However, at to be a to the increased hyperpolarized 13C via of a that the et al.In vivo metabolic imaging of traumatic brain 2017; 7: PubMed Scopus Google Scholar]. that can be for the observed increased hyperpolarized 13C from models of multiple et MR metabolic imaging can in vivo in a multiple Natl. Acad. Sci. U. S. A. 2017; PubMed Scopus Google et imaging of brain using hyperpolarized 13C of pyruvate and in a of multiple of the for in for in Scholar]. is an disease that to of and in and cognitive D. S. et J. Med. PubMed Scopus Google Scholar]. hyperpolarized 13C in brain where of changes to the to of activity and increased lactate not in that not an response due to of the S. et of by and PubMed Scopus Google Scholar]. Hyperpolarized successfully used to metabolic in a of by of the et magnetic resonance imaging can metabolic changes of in 2017; PubMed Scopus Google Scholar]. Hyperpolarized and hyperpolarized [1-13C]lactate, but not hyperpolarized 13C increased in the with the ex vivo these an increased of hyperpolarized increased is to increased or the as as an increased conversion into which the increased enzymatic in hyperpolarized 13C in the of a for a and with but not in the and S. et pyruvate MR spectroscopy in the brain of a PubMed Scopus Google Scholar]. this the to a correlation the hyperpolarized 13C and cognitive in this via a in a of a for a hyperpolarized 13C 13C increased in the S. et increased in the in PubMed Scopus Google Scholar]. vivo analyses of increased lactate that not by of but with the a metabolic in the of Following 13C MRS/I of hyperpolarized increased brain hyperpolarized 13C and hyperpolarized 13C the of clinical and of these ratios with disease progression et assessment of metabolism an lactate in the brain of with Google Scholar]. In this it is not is being in either the brain or the tissue. through ex vivo analyses of these on the of in injury, and that lactate from metabolism is a crucial factor in the development of brain The of hyperpolarized have been discussed but are many hyperpolarized probes in probes could valuable information on the metabolism in disease and assessment of treatment many metabolic are of potential interest in neurological disorders, not can be as a hyperpolarized probe, the of interest have the can be with 13C at the of interest is either be a liquid at or in a at and a an MR both substrate and products of interest need to have MR and relaxation times long to be a MR experiment. from a biological the of interest be to the organ of interest through the be and be in the these many hyperpolarized probes in development have so been for in healthy Hyperpolarized from the widely used only by the of the 13C for its are However, from a metabolic hyperpolarized enables of the 13C in the in the products of not only but and J. et mitochondrial metabolism in brain in vivo using MR spectroscopy of hyperpolarized PubMed Scopus Google Scholar]. of is not a and may be on multiple biological and et al.In vivo 13C spectroscopy in the brain using hyperpolarized and Reson. 2010; PubMed Scopus Google Scholar]. acquired in the brain injection of hyperpolarized pyruvate, a used for its ability to more easily the a lactate to that observed hyperpolarized injection et imaging in the brain using hyperpolarized pyruvate and Reson. 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PubMed Scopus Google Scholar]. such in the In preclinical imaging requires of the and it be to that not with the However, in could become the it be valuable in the of and of and the to human is to to the observed in vivo for of from or can to address this the of the hyperpolarized technique to both in et detection of in models using hyperpolarized PubMed Scopus Google and et spectroscopy and an system for the of Reson. Med. 2010; PubMed Scopus Google Scholar]. in these such as the of resonance S. et of metabolic in using a hyperpolarized resonance 2017; PubMed Scopus Google or of multiple of ex vivo biochemical analyses, the of models, and metabolic could address these et MR metabolic imaging can in vivo in a multiple Natl. Acad. Sci. U. S. A. 2017; PubMed Scopus Google Scholar]. Clinically, are both and biological to the hyperpolarized 13C MRS/I technology clinical in neurological disorders, as discussed The clinical are at some and are with new of an new from the is and of new probes have to be for and data acquisition. It be most valuable data are clinical this is that of data acquisition and be of healthy brain metabolism using several hyperpolarized probes multiple and, multiple be to a which to assess disease of the biological of clinical hyperpolarized data be but is the ability to the human tissue. of hyperpolarized pyruvate remains valuable it can and brain tissue. In the short hyperpolarized can be used in clinical of neurological it is and the hardware and data are in for brain in an of Hyperpolarized has been recently and to data, in multiple models of neurological and are many hyperpolarized probes for in vivo enzymatic assessment of several metabolic that have been and applied in the healthy to models of neurological disease is a and for such for hyperpolarized technology in the field of brain clinical is in patients with and healthy volunteers and in in the it at this point to on acquisition and hyperpolarized that of multiple metabolic the human brain in and could the monitoring of response to In with imaging the hyperpolarized 13C technology provides an exciting to our of in vivo brain and in the to clinical in a of neurological 13C MRS/I of can metabolic impairment in several preclinical models of neurological disorders. this metabolic imaging technique the and of in patients with brain in metabolism have been by hyperpolarized 13C MRS/I of in ex vivo and in vivo preclinical this method be used to in more acquisition and be to MR and we a metabolic for healthy brain that is for disease state preclinical that hyperpolarized to conversion is to metabolic response to in several models of neurological hyperpolarized 13C MRS/I be used to and response to in neurological and are changes in these observed changes in typical metabolic have been to be with hyperpolarized hyperpolarized 13C MRS/I be used to obtain a of metabolic changes in neurological using hyperpolarized Hyperpolarized 13C MRS/I of can metabolic impairment in several preclinical models of neurological disorders. this metabolic imaging technique the and of in patients with brain in metabolism have been by hyperpolarized 13C MRS/I of in ex vivo and in vivo preclinical this method be used to in more acquisition and be to MR and we a metabolic for healthy brain that is for disease state preclinical that hyperpolarized to conversion is to metabolic response to in several models of neurological hyperpolarized 13C MRS/I be used to and response to in neurological and are changes in these observed changes in typical metabolic have been to be with hyperpolarized hyperpolarized 13C MRS/I be used to obtain a of metabolic changes in neurological using hyperpolarized by research and research and the for in the The and the with of hyperpolarized 13C injection of hyperpolarized in preclinical and clinical and and in preclinical typically used for and of of of the MR of is widely used in the clinic and can information for brain and of such as or spectra can be from multiple of the brain at to information on steady-state enables of steady-state of brain are in the of spectroscopy enables detection of several with a in the ( e. g., or spectroscopy is due to the of the 13C long acquisition times or of compounds are

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