In vivo ¹³C and ¹H‐[¹³C] MRS studies of neuroenergetics and neurotransmitter cycling, applications to neurological and psychiatric disease and brain cancer

Abstract

In the last 25 years 13 C MRS has been established as the only noninvasive method for measuring glutamate neurotransmission and cell specific neuroenergetics. Although technically and experimentally challenging 13 C MRS has already provided important new information on the relationship between neuroenergetics and neuronal function, the high energy cost of brain function in the resting state and the role of altered neuroenergetics and neurotransmitter cycling in disease. In this paper we review the metabolic and neurotransmitter pathways that can be measured by 13 C MRS and key findings on the linkage between neuroenergetics, neurotransmitter cycling, and brain function. Applications of 13 C MRS to neurological and psychiatric disease as well as brain cancer are reviewed. Recent technological developments that may help to overcome spatial resolution and brain coverage limitations of 13 C MRS are discussed. | INTRODUCTIONBrain cells are highly specialized metabolically and functionally. Prior to the advent of 13 C MRS there was no method of studying cell specific brain metabolism in vivo. As described in this review 13 C MRS in combination with selectively 13 C labeled substrates has allowed the study of how metabolism supports function in the three major brain cell types, glutamatergic neurons, GABAergic neurons, and glia. Glutamatergic neurons Abbreviations: ANLS, astrocyte neuronal lactate shuttle; ATP, adenosine tri phosphate; AV, arterio-venous; CMRglc (ox), cerebral metabolic rate of oxidative glucose consumption; CMRglc (ox)-N, cerebral metabolic rate of neuronal oxidative glucose consumption; CMRglc, cerebral metabolic rate of glucose consumption; DMI, deuterium metabolic imaging; EEG, electroencephalogram;GABA, gamma amino butyric acid; GBM, glioblastoma; HSQC, heteronuclear single quantum coherence; MDD, major depressive disorder; MRS, magnetic resonance spectroscopy; MRSI, magnetic resonance spectroscopic imaging; NMDA, N methyl D aspartate; nOe, nuclear Overhauser effect; PET, positron emission tomography; SAR, specific absorption rate; T1DM, type 1 diabetes mellitus; TCA, tricarboxylic acid cycle; Vcycle, Velocity (flux) of the glutamate/GABA/glutamine cycle.; VTCA, velocity of the tricarboxylic acid cycle release the major excitatory neurotransmitter glutamate and GABAergic neurons release the major inhibitory neurotransmitter gamma amino butyric acid (GABA). Information transfer in the brain is largely coded by the pattern and timing of glutamate and GABA neurotransmitter release in vesicles with glutamate release leading to depolarization at the postsynaptic terminal and GABA release leading to hyperpolarization 1 . As described in this review, studies primarily using 13 C MRS have shown that the energy required to support neuronal signaling is the dominant energy cost of the brain even under resting awake conditions. The large majority of glutamate and a significant fraction of GABA is taken up by a class of cells called glia. Glia are not directly involved in brain communication but are critical f...

Glutamate and GABA Homeostasis and Neurometabolism in Major Depressive Disorder

“…In addition, 13 C-MRS in conjunction with administration of 13 C-labeled respiratory substrates (glucose and acetate) allows analysis of the cell-specific metabolic activity in animals as well as in the human brain. This provides a non-invasive measurement of the cerebral metabolic rate of glucose oxidation, ATP production and neurotransmitter cycling (32,33).…”

In Vivo Measurement of Carbon-13 Labeling of Glutamate and Glutamine in Human Brain Using Proton Magnetic Resonance Spectroscopy

“…The within-subject CV 26 of the fractional enrichment values were estimated from the last two post-13 C spectra for each subject, which were acquired at 113 ± 9 min after oral administration of [U- 13 C]glucose. The 13 C enrichment of Glu H4 is expected to have approximately reached its maximum value at this stage 1,14 . Spectra and corresponding ts for the pre-13C MRS scan and the last post-13C scan of subject 1.…”

Simultaneous Recording of the Uptake and Conversion of Glucose and Choline in Tumors by Deuterium Metabolic Imaging (DMI)

“…Plasma was derived from the blood samples by centrifugation for 5 minutes at 5000 rpm to separate it from cells. 2 H NMR spectra of 200 µl plasma samples were recorded at 500 MHz on a Bruker AVANCE III vertical bore NMR system (Bruker BioSpin, Germany) at a bandwidth of 12 ppm with 5k data points and 512 acquisitions. The repetition time was 5 seconds.…”

“…However, this method cannot monitor subsequent glucose catabolism. For in vivo applications 13 C MR spectroscopy has been used to probe uptake and metabolic conversions of non-radioactive 13 C labeled glucose in tumors into lactate and other compounds [2,3]. The low SNR of the method precluded to employ it as an imaging method although recently reported denoising methods may favor better imaging conditions [4].…”