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Detection of an Antioxidant Profile in the Human Brain in Vivo Via Double FULL PAPERS Magnetic Resonance in Medicine 56:1192–1199 (2006) Detection of an Antioxidant Profile in the Human Brain In Vivo Via Double Editing With MEGA-PRESS Melissa Terpstra,* Malgorzata Marjanska, Pierre-Gilles Henry, Ivan Tka´cˇ, and Rolf Gruetter Vitamin C (ascorbate) and glutathione (GSH) are the two most enzymatic antioxidant, is membrane bound and present at concentrated non-enzymatic antioxidants in the human brain. micromolar concentrations, it is not detected in vivo. Double editing with (DEW) MEGA-PRESS at 4T was designed in However, the adequacy of vitamin E antioxidant defenses this study to measure both antioxidants in the same amount of is likely reflected by Asc and GSH levels, since Asc and time previously required to measure one. In the occipital lobe of GSH have been shown to regenerate and spare vitamin E four human subjects, resolved ascorbate (Asc) and GSH reso- nances were detected repeatedly and simultaneously using DEW (4). Therefore, the simultaneous quantification of Asc and MEGA-PRESS. The Asc and GSH concentrations measured using GSH (i.e., the antioxidant profile) may be a suitable non- .LCModel analysis of DEW MEGA-PRESS spectra were 0.8 ؎ 0.1 invasive assay for determining tissue antioxidant capacity and 1.0 ؎ 0.1 ␮mol/g (mean ؎ SD), with average Cramer-Rao This assay could be used to study: the role of antioxidants lower bounds (CRLB) of 10% and 7%, respectively. Aside from the in neuroprotection, factors that impact brain antioxidant effects of J-modulation at a common echo time (TE), double ed- levels, and the role of reactive oxygen species in acute and iting did not compromise sensitivity. To determine the extent to chronic mechanisms of CNS damage. which the oxidized forms of Asc and GSH contribute to DEW Homonuclear edited 1H MRS has been used extensively MEGA-PRESS spectra in vivo, chemical shifts and coupling con- stants for dehydroascorbate (DHA) and oxidized glutathione to separate a single J-coupled resonance of interest, such as ␥ (GSSG) were measured at physiologic pH and temperature. DHA -aminobutyric acid (GABA), reduced GSH, or lactate from does not contribute to the 3.73 ppm DEW MEGA-PRESS Asc overlapping resonances (5,6). Recently, MEGA-PRESS ed- resonance. GSSG contributions to the DEW MEGA-PRESS GSH ited spectroscopy was similarly applied to uncover a re- resonance (3.0 ppm) are negligible under physiologic conditions, solved resonance from ascorbate (Asc) in the human brain and would be evidenced by a distinct GSSG resonance (3.3 ppm) in vivo (7). The goal of the present study was to measure at exceptionally high concentrations. Magn Reson Med 56: resolved resonances of both GSH and Asc in the same 1192–1199, 2006. © 2006 Wiley-Liss, Inc. amount of time previously required to measure one. Con- Key words: antioxidant profile; ascorbate (vitamin C, Asc); glu- current detection of Asc and GSH was attempted via ex- tathione (GSH); magnetic resonance spectroscopy (MRS) tension of the difference editing principle. Instead of omit- ting the frequency-selective editing pulses (“off”) on alter- Vitamin C (ascorbate, Asc) and reduced glutathione (GSH) nate scans, we encoded additional information by are the most concentrated non-enzymatic antioxidants in inserting editing pulses selective for a second J-coupled the central nervous system (CNS) (1). Compartmentation spin system. As such, the traditional “on”/ “off” scheme of Asc predominantly to neurons and GSH predominantly was replaced by a novel “on A”/ “on B” scheme. That is, to glia (1) suggests that sufficient levels of both are impor- the refocused spectrum for each of two edited neurochemi- tant for protection against oxidative damage. On the other cals served as a reference spectrum for the other. Our hand, the capacity for Asc and GSH to regenerate each previously described MEGA-PRESS editing schemes for other (2), and the presence of transport mechanisms be- tween neurons and glia (3) suggest that the sum of these separate detection of GSH and Asc (7,8) were readily com- concentrations may be the best indicator of antioxidant bined for double editing with (DEW) MEGA-PRESS. capacity. Because vitamin E, the other important non- Although the concentrations of oxidized glutathione (GSSG) and dehydroascorbate (the oxidized forms of GSH and Asc, respectively) are assumed to be below the detec- tion threshold of in vivo 1H MRS under physiologic con- Center for Magnetic Resonance Research, University of Minnesota, Minne- apolis, Minnesota, USA. ditions, it is of interest to understand the extent to which R. Gruetter’s current address is the Center for Biomedical Imaging, Lausanne, resonances from these compounds could contribute to Switzerland. DEW MEGA-PRESS spectra under nonphysiologic condi- Grant sponsor: National Institutes of Health; Grant number: R01NS038672; Grant sponsor: NCRR; Grant number: P41RR008079; Grant sponsor: Na- tions. GSSG is 50 times less concentrated than GSH under tional Science Foundation; Grant number: BIR-961477; Grant sponsor: Uni- normal conditions (9,10). Dehydroascorbate (DHA) is rel- versity of Minnesota Medical School; Grant Sponsor: Minnesota Medical atively unstable at physiologic pH and temperature (11). Foundation; Grant sponsor: Whitaker Foundation. *Correspondence to: Melissa Terpstra, Ph.D., 2021 6th St. SE, Minneapolis, Asc undergoes one-electron oxidation to form ascorbyl MN 55455. E-mail: [email protected] radical, and a second one-electron transfer to produce Received 17 January 2006; revised 11 August 2006; accepted 14 August DHA (12). Because it is a free radical, ascorbyl is present at 2006. extremely low concentrations (ϳ10–20 nM) in biological DOI 10.1002/mrm.21086 1 Published online 6 November 2006 in Wiley InterScience (www.interscience. fluids (13) and far below the H MRS detection threshold wiley.com). in living organisms. Biochemical process efficiently con- © 2006 Wiley-Liss, Inc. 1192 Antioxidant Profile via DEW MEGA-PRESS 1193 FIG. 1. a: RF portion of the MEGA-PRESS timing diagram (15). The main editing com- ponents are frequency-selective inversion pulses. The difference-edited spectrum is obtained by subtracting “on” scans from “off” scans. b: RF portion of the DEW MEGA-PRESS timing diagram as designed for difference editing of two J-coupled spin systems. Frequency-selective editing pulses are applied to refocus a second J- coupled system in the case of double edit- ing, as opposed to remaining “off.” The DEW MEGA-PRESS spectrum is obtained by subtracting “on A” scans from “on B” scans. vert DHA back to Asc before it is rapidly degraded to 40 mT/m in 400 ␮s (Sonata, Siemens, Erlangen, Germany), diketo-gulonic acid with a halflife of about 6 min (14). and a surface 1H quadrature transceiver (18). Quantification MATERIALS AND METHODS DEW MEGA-PRESS Asc and GSH concentrations were quantified using LCModel analysis (19) of DEW MEGA-PRESS spectra (8) Double editing for Asc and GSH was achieved by adapting between 1.0 and 3.82 ppm. The basis spectra for Asc, MEGA-PRESS (15) as illustrated in Fig. 1. The key to myo-inositol (Ins), lactate (Lac), phosphorylcholine (PC), double editing was replacement of the editing pulse phosphorylethanolamine (PE), and glycerophosphoryl- (180°s) “on”/“off” pattern typical of difference editing by choline (GPC) were measured previously at 112-ms echo an” “on A”/“on B” scheme (where “A” symbolizes Asc, time (TE) for MEGA-PRESS editing of Asc from pure me- 6 and “B” symbolizes GSH). In detail, the 3.73 ppm CH2 tabolite solutions at physiologic pH and temperature. A Asc resonance was refocused during every other scan by MEGA-PRESS metabolite-nulled (20) experiment at 4 T applying a 40-ms Gaussian RF pulse at 4.13 ppm such that provided a basis spectrum for macromolecules (MMs). The the chemical shift of the coupled 4.01 ppm 5CH was well basis spectrum for glycerophosphorylethanolamine (GPE) within the bandwidth (39 Hz) of the editing pulse, as was estimated by shifting the measured GPC spectrum previously described (7). The second resonance chosen for such that the GPC resonance at 3.67 ppm appeared at ␤ observation, the cysteine -CH2 of GSH (2.95), was refo- 3.29 ppm, a previously reported (21) chemical shift for cused on alternate scans by applying a 40-ms Gaussian GPE. The GSH basis spectrum was measured using DEW pulse at 4.56 ppm, the chemical shift of the coupled cys- MEGA-PRESS at physiologic pH and temperature. The teine ␣-CH resonance, as previously described for GSH N-acetylaspartate (NAA) basis spectrum for DEW MEGA- editing (8) except at the longer TE optimal for Asc detec- PRESS was simulated. Global frequency referencing of the tion (TE ϭ 112 ms). The double-edited spectrum was ob- in vivo edited spectrum was based on GSH and Asc model tained by subtracting the GSH refocused spectrum (“on B”) spectra. The integral intensity of the singlet at 2.01 ppm in from the Asc refocused spectrum (“on A”). To enable the sum of the “on Asc” and “on GSH” scans, correspond- comparison of double-edited spectra with constituent sin- ing to the acetyl moiety of NAA, was used as an internal gle-edited resonances, pure reference spectra (180°s “off”) reference for quantification, similar to a previously de- were also measured in vitro and in vivo. To estimate the scribed method (22). The in vivo NAA concentration was efficiency of Asc and GSH signal recovery, both DEW referenced at 10 ␮mol/g based on previous findings (17). MEGA-PRESS and pulse-acquire spectra were simulated (16) using MATLAB software (Mathworks, Natick, MA, Human Subjects and Protocol USA), measured chemical shifts and J-couplings for Asc (see below), and previously reported chemical shifts and Four volunteers (one male and three females, average J-couplings for GSH (17). Simulated resonances were line- age ϭ 23 years) gave informed consent for this study, broadened (7 Hz) to mimic in vivo line shapes before which was conducted according to procedures approved efficiency was calculated.
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