Localized in vivo¹³C NMR spectroscopy of the brain

Abstract

Localized 13C NMR spectroscopy provides a new investigative tool for studying cerebral metabolism. The application of 13 C NMR spectroscopy to living intact humans and animals presents the investigator with a number of unique challenges. This review provides in the first part a tutorial insight into the ingredients required for achieving a successful implementation of localized 13 C NMR spectroscopy. The difficulties in establishing 13 C NMR are the need for decoupling of the one-bond 13 C-1 H heteronuclear J coupling, the large chemical shift range, the low sensitivity and the need for localization of the signals. The methodological consequences of these technical problems are discussed, particularly with respect to (a) RF front-end considerations, (b) localization methods, (c) the low sensitivity, and (d) quantification methods. Lastly, some achievements of in vivo localized 13 C NMR spectroscopy of the brain are reviewed, such as: (a) the measurement of brain glutamine synthesis and the feasibility of quantifying glutamatergic action in the brain; (b) the demonstration of significant anaplerotic fluxes in the brain; (c) the demonstration of a highly regulated malate-aspartate shuttle in brain energy metabolism and isotope flux; (d) quantification of neuronal and glial energy metabolism; and (e) brain glycogen metabolism in hypoglycemia in rats and humans. We conclude that the unique and novel insights provided by 13 19-24 Most of these studies have involved the administration of a 13 C-enriched precursor. When the enriched 13 C label is transferred to molecules in the metabolic pathway, sensitivity can not only be increased, but important information on metabolic pathways can also be obtained. For example, recent studies showed that the information content of 13 C NMR spectroscopy can be amplified considerably, such as the resolved observation of GABA labeling in the human brain, as well as the first detection of lactate labeling in normal human brain. 8 In addition to its importance in assessing metabolism in intact brain, 13 C NMR spectroscopy has become an important and useful tool in assessing compartmentation of metabolism in brain cells using extracts. 25,26 In addition to its low sensitivity, 13 C NMR spectroscopy is methodologically more challenging than 1 H or even 31 P NMR spectroscopy. However, 13C NMR provides its own unique insight and advantages over 1 H NMR spectroscopy. The uniqueness of 13 C NMR stems mainly from its increased chemical shift dispersion, which can, for example, be used in two-dimensional NMR to increase spectral resolution following specific labeling of the protein. 27 As shall be elaborated further below, 13 C NMR spectroscopy in living tissue provides a unique window on in vivo metabolism as it occurs. In the

Technical and experimental features of Magnetic Resonance Spectroscopy of brain glycogen metabolism

“…In fact, because 13 C-MRS sequences applied in the aforementioned studies are essentially pulseacquire, this technique is suited for compounds with an ultrashort T 2 , such as glycogen. Therefore, 13 C-MRS is the state-of-theart technique to assess cerebral glycogen in vivo and shares very similar technical challenges with 13 C-MRS detection of other carbohydrates, previously reviewed by, e.g., Gruetter et al 2003 and de Graaf et al 2011 [73,74], and in this issue as well. Nonetheless, specific properties of brain glycogen make it worth highlighting how its detection by 13 C-MRS in vivo benefits from a careful optimization of technical settings and experimental parameters.…”

“…1/ T 2 * ¼ 1/T 2 þgDB 0 . The effect of field inhomogeneity (gDB 0 ) on the FWHMs of 13 C resonances is reduced four-fold compared to that observed for 1 H resonances due to g 13C /g 1H ¼ 0.25 [74]. Nonetheless, the influence of field inhomogeneity on 13 C resonances becomes substantial especially when large VOIs in combination of high magnetic fields are commonly used for 13 C-MRS detection of glycogen, in benefit of improved sensitivity.…”

“…Besides coil design, it is also crucial to eliminate any unwanted noise introduced in the paths of RF chains, which can be afforded by inserting bandpass ( 1 H pass, 13 C stop)/lowpass ( 13 C pass, 1 H stop) filters in between the corresponding paths of RF chains [73,74,79].…”

“…Other factors, including T 1 , T 2 and NOE, have to be taken in to account between the external reference phantom solution and in vivo scans. In addition, some imperfections can be corrected by the external reference method, namely off-resonances effects [74]. As mentioned in the previous section, the intrinsic characteristic of the applied adiabatic half passage pulses for excitation is to offer the same nutation flip angles (e.g.…”

1H‐[13C] NMR spectroscopy of the rat brain during infusion of [2‐13C] acetate at 14.1 T

“…Dynamic detection of 13 C label incorporation by 13 C NMR spectroscopy in conjunction with 13 C label administration allows the investigation of neuroglial metabolism in vivo (see de Graaf et al (1) and Gruetter et al (2). for reviews).…”