Contribution of macromolecules to brain 1 H MR spectra: Experts' consensus recommendations
Language English Country England, Great Britain Media print-electronic
Document type Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
Grant support
P41 EB027061
NIBIB NIH HHS - United States
P30 NS076408
NINDS NIH HHS - United States
P41 EB015909
NIBIB NIH HHS - United States
P 30701
Austrian Science Fund FWF - Austria
R01 MH109159
NIMH NIH HHS - United States
PubMed
33236818
PubMed Central
PMC10072289
DOI
10.1002/nbm.4393
Knihovny.cz E-resources
- Keywords
- brain macromolecules, fitting, metabolite quantification, mobile lipids, parameterization, proton magnetic resonance spectroscopy, quantification, spectral analysis,
- MeSH
- Adult MeSH
- Consensus * MeSH
- Middle Aged MeSH
- Humans MeSH
- Lipids chemistry MeSH
- Magnetic Resonance Imaging MeSH
- Macromolecular Substances metabolism MeSH
- Metabolome MeSH
- Young Adult MeSH
- Brain diagnostic imaging MeSH
- Signal Processing, Computer-Assisted MeSH
- Proton Magnetic Resonance Spectroscopy * MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Models, Theoretical MeSH
- Expert Testimony * MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Young Adult MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
- Names of Substances
- Lipids MeSH
- Macromolecular Substances MeSH
Proton MR spectra of the brain, especially those measured at short and intermediate echo times, contain signals from mobile macromolecules (MM). A description of the main MM is provided in this consensus paper. These broad peaks of MM underlie the narrower peaks of metabolites and often complicate their quantification but they also may have potential importance as biomarkers in specific diseases. Thus, separation of broad MM signals from low molecular weight metabolites enables accurate determination of metabolite concentrations and is of primary interest in many studies. Other studies attempt to understand the origin of the MM spectrum, to decompose it into individual spectral regions or peaks and to use the components of the MM spectrum as markers of various physiological or pathological conditions in biomedical research or clinical practice. The aim of this consensus paper is to provide an overview and some recommendations on how to handle the MM signals in different types of studies together with a list of open issues in the field, which are all summarized at the end of the paper.
Center for Biomedical Imaging Ecole Polytechnique Fédérale de Lausanne Lausanne Vaud Switzerland
Center for Stroke Research Berlin Charité Universitätsmedizin Berlin Berlin Germany
Centre for Human Brain Health and School of Psychology University of Birmingham Birmingham UK
Christian Doppler Laboratory for Clinical Molecular MR Imaging Vienna Austria
Cleveland Clinic Foundation Imaging Institute Cleveland Ohio USA
Czech Academy of Sciences Institute of Scientific Instruments Brno Czech Republic
Department of Radiology and Biomedical Imaging Yale University New Haven Connecticut USA
Departments of Biomedical Engineering and Radiology Columbia University New York USA
Departments of Radiology and Biomedical Research University of Bern Bern Switzerland
Faculty of Science Eberhard Karls Universität Tübingen Tübingen Germany
High Field Magnetic Resonance Max Planck Institute for Biological Cybernetics Tübingen Germany
IMPRS for Cognitive and Systems Neuroscience Eberhard Karls Universität Tübingen Tübingen Germany
See more in PubMed
Kunz N, Cudalbu C, Mlynarik V, Hüppi PS, Sizonenko SV., Gruetter R. Diffusion-weighted spectroscopy: A novel approach to determine macromolecule resonances in short-echo time 1H-MRS. Magn Reson Med. 2010;64(4):939–946. PubMed
Graaf RA de Brown PB, Mcintyre S Nixon TW, Behar KL Rothman DL. High Magnetic Field Water and Metabolite Proton T 1 and T 2 Relaxation in Rat Brain In Vivo. Magn Reson Med. 2006;56(2):386–94. PubMed
Behar KL, Ogino T. Assignment of resonances in the 1H spectrum of rat brain by two-dimensional shift correlated and J-resolved NMR spectroscopy. Magn Reson Med. 1991;17(2):285–303. PubMed
Behar KL, Ogino T. Characterization of macromolecule resonances in the 1H NMR spectrum of rat brain. Magn Reson Med. 1993;30(1):38–44. PubMed
Arus C, Yen-Chung C, Barany M. Proton magnetic resonance spectra of excised rat brain. Assignments of resonances. Physiol Chem Phys Med NMR. 1985;17(1):23–33. PubMed
Kauppinen RA, Kokko H, Williams SR. Detection of Mobile Proteins by Proton Nuclear Magnetic Resonance Spectroscopy in the Guinea Pig Brain Ex Vivo and Their Partial Purification. J Neurochem. 1992;58(3):967–74. PubMed
Kauppinen RA, Niskanen T, Hakumäki J, Williams SR. Quantitative analysis of 1H NMR detected proteins in the rat cerebral cortex in vivo and in vitro. NMR Biomed. 1993;6(4):242–7. PubMed
Behar KL, Rothman DL, Spencer DD, Petroff OAC. Analysis of macromolecule resonances in1H NMR spectra of human brain. Magn Reson Med. 1994;32(3):294–302. PubMed
Mori S, van Zijl PCM, Johnson MON, Berg JM. Water Exchange Filter (WEX Filter) for Nuclear Magnetic Resonance Studies of Macromolecules. J Am Chem Soc. 1994;116(26):11982–11984.
van Zijl PCM, Yadav NN. Chemical exchange saturation transfer (CEST): what is in a name and what isn’t? Magn Reson Med. 2011;65(4):927–48. PubMed PMC
Heo HY, Jones CK, Hua J, et al. Whole-brain amide proton transfer (APT) and nuclear overhauser enhancement (NOE) imaging in glioma patients using low-power steady-state pulsed chemical exchange saturation transfer (CEST) imaging at 7T. J Magn Reson Imaging. 2016;44(1):41–50. PubMed PMC
Candiota AP, Majós C, Bassols A, et al. Assignment of the 2.03 ppm resonance in in vivo 1H MRS of human brain tumour cystic fluid: contribution of macromolecules. Magn Reson Mater Physics, Biol Med. 2004;17(1):36–46. PubMed
Mountford C, Quadrelli S, Lin A, Ramadan S. Six fucose-α(1–2) sugars and α-fucose assigned in the human brain using in vivo two-dimensional MRS. NMR Biomed. 2015;28(3):291–6. PubMed
Soares AF, Gruetter R, Lei H. Technical and experimental features of Magnetic Resonance Spectroscopy of brain glycogen metabolism. Anal Biochem. 2017;529:117–126. PubMed
Kauppinen RA, Nissinen T, Kärkkäinen AM, et al. Detection of thymosin β4 in situ in a guinea pig cerebral cortex preparation using 1H NMR spectroscopy. J Biol Chem. 1992;15(267(14)):9905–10. PubMed
Woody RW, Roberts GCK, Clark DC, Bayley PM. 1 H NMR evidence for flexibility in microtubule-associated proteins and microtubule protein oligomers. FEBS Lett. 1982;141(2):181–184. PubMed
Woody RW, Clark DC, Roberts GCK, Martin SR, Bayley PM. Molecular Flexibility in Microtubule Proteins: Proton Nuclear Magnetic Resonance Characterization. Biochemistry. 1983;22(9):2186–2192. PubMed
Wüthrich K The way to NMR structures of proteins. Nat Struct Biol. 2001;8:923–925. PubMed
Wüthrich K Protein structure determination in solution by NMR spectroscopy. J Biol Chem. 1990;265(36):22059–62. PubMed
Marassi FM, Opella SJ. NMR structural studies of membrane proteins. Curr Opin Struct Biol. 1998;8(5):640–648. PubMed PMC
Craveiro M, Clément-Schatlo V, Marino D, Gruetter R, Cudalbu C. In vivo brain macromolecule signals in healthy and glioblastoma mouse models: 1H magnetic resonance spectroscopy, post-processing and metabolite quantification at 14.1 T. J Neurochem. 2014;129(5):806–815. PubMed
Behar KL. Dealing with macromolecules. In: ISMRM, Morning Categorical Course “Spectroscopy: The Brain and Beyond”.; 2004.
Mielke SP, Krishnan VV. Characterization of protein secondary structure from NMR chemical shifts. Prog Nucl Magn Reson Spectrosc. 2009;54(3–4):141–165. PubMed PMC
De Dios AC, Pearson JG, Oldfield E. Secondary and tertiary structural effects on protein NMR chemical shifts: An ab initio approach. Science (80-). 1993;260(5113):1491–6. PubMed
Borbath T, Murali-Manohar S, Wright AM, Henning A. T2 Relaxation Times of Macromolecules in Human Brain Spectra at 9.4 T. 27th Annu Meet Exhib Int Soc Magn Reson Med (ISMRM 2019), Montréal, QC, Canada. 2019.
Borbáth T, Murali-Manohar S, Henning A. Towards a Fitting Model of Macromolecular Spectra: Amino Acids. In: ISMRM.; 2019:1068.
Schaller B, Xin L, Gruetter R. Is the macromolecule signal tissue-specific in healthy human brain? a 1H MRS study at 7 tesla in the occipital lobe. Magn Reson Med. 2014;72(4):934–940. PubMed
Snoussi K, Gillen JS, Horska A, et al. Comparison of brain gray and white matter macromolecule resonances at 3 and 7 Tesla. Magn Reson Med. 2015;74(3):607–613. PubMed PMC
Lopez-Kolkovsky AL, Mériaux S, Boumezbeur F. Metabolite and Macromolecule T1 and T2 Relaxation Times in the Rat Brain in vivo at 17.2T. Magn Reson Med. 2016;75(2):503–514. PubMed
Beach EF, Munks B, Robinson A. The Amino Acid Composition of Animal Tissue Protein. J Biol Chem. 1943;148:431–439.
Robinson N, Williams CB. Amino acids in human brain. Clin Chim Acta. 1965;12:311–317.
Smith MH. The amino acid composition of proteins. J Theor Biol. 1966;13:261–282.
Clouet DH, Gaitonde MK. THE CHANGES WITH AGE IN THE PROTEIN COMPOSITION OF THE RAT BRAIN. J Neurochem. 1956;1(2):126–133. PubMed
Hofmann L, Slotboom J, Boesch C, Kreis R. Characterization of the macromolecule baseline in localized 1H-MR spectra of human brain. Magn Reson Med. 2001;46(5):855–863. PubMed
Kreis R, Boer V, Choi I-Y, et al. Terminology for the characterization of in vivo MR spectroscopy methods and MR spectra: Background and experts’ consensus recommendations. NMR Biomed. 2019;submitted. PubMed PMC
Tkác I, Andersen P, Adriany G, Merkle H, Ugurbil K, Gruetter R. In vivo 1H NMR spectroscopy of the human brain at 7 T. Magn Reson Med. 2001;46(3):451–6. PubMed
Juchem C, de Graaf RA. B0 magnetic field homogeneity and shimming for in vivo magnetic resonance spectroscopy. Anal Biochem. 2017;529:17–29. PubMed PMC
Juchem C, Boer VO, Cudalbu C, et al. B0 Shimming for In Vivo MR Spectroscopy: Experts’ consensus recommendations. NMR Biomed. PubMed
Giapitzakis IA, Avdievich N, Henning A. Characterization of macromolecular baseline of human brain using metabolite cycled semi-LASER at 9.4T. Magn Reson Med. 2018;80(2):462–473. PubMed
Döring A, Adalid V, Boesch C, Kreis R. On the exploitation of slow macromolecular diffusion for baseline estimation in MR spectroscopy using 2D simultaneous fitting. In: Joint 26th Meeting of ISMRM and 35th Meeting of the ESMRMB, Paris (F).; 2018:1315.
Cudalbu C, Mlynárik V, Xin L, Gruetter R. Comparison of T1 Relaxation Times of the Neurochemical Profile in Rat Brain at 9.4 Tesla and 14.1 Tesla. Magn Reson Med. 2009;62(4):862–867. PubMed
Michaeli S, Garwood M, Zhu X, et al. Proton T 2 Relaxation Study of Water, N-acetylaspartate, and Creatine in Human Brain Using Hahn and Carr-Purcell Spin Echoes at 4T and 7T. 2002;633:629–633. PubMed
Wyss PO, Bianchini C, Scheidegger M, et al. In vivo estimation of transverse relaxation time constant (T2) of 17 human brain metabolites at 3T. Magn Reson Med. 2018;80(2):452–461. PubMed
Xin L, Gambarota G, Cudalbu C, Mlynárik V, Gruetter R. Single spin-echo T 2 relaxation times of cerebral metabolites at 14.1 T in the in vivo rat brain. Magn Reson Mater Physics, Biol Med. 2013;26(6):549–554. PubMed
Deelchand DK, Henry P-G, Ugurbil K, Marjanska M. Measurement of Transverse Relaxation Times of J-Coupled Metabolites in the Human Visual Cortex at 4 T. Magn Reson Med. 2012;67:891–897. PubMed PMC
Deelchand DK, Auerbach EJ, Kobayashi N, Marjanska M. Transverse Relaxation Time Constants of the Five Major Metabolites in Human Brain Measured In Vivo Using LASER and PRESS at 3 T. Magn Reson Med. 2018;79:1260–1265. PubMed PMC
Marjańska M, Auerbach EJ, Valabrègue R, Moortele P Van De, Adriany G, Garwood M. Localized 1 H NMR spectroscopy in different regions of human brain in vivo at 7T : T 2 relaxation times and concentrations of cerebral metabolites. NMR Biomed. 2012;25:332–339. PubMed PMC
Choi IY, Lee P. Doubly selective multiple quantum chemical shift imaging and T1relaxation time measurement of glutathione (GSH) in the human brain in vivo. NMR Biomed. 2013;26(1):28–34. PubMed PMC
Murali-Manohar S, Wright AM, Borbath T, Henning A. Longitudinal Relaxation times of Macromolecular Resonances at 9.4 T in Human Brain. 27th Annu Meet Exhib Int Soc Magn Reson Med (ISMRM 2019), Montréal, QC, Canada. 2019.
Murali-Manohar S, Borbath T, Wright AM, Soher B, Mekle R, Henning A. T2 relaxation times of macromolecules and metabolites in the human brain at 9.4 T. Magn Reson Med. 2020:Epub ahead of print. PubMed
Považan M, Strasser B, Hangel G, et al. Simultaneous mapping of metabolites and individual macromolecular components via ultra-short acquisition delay 1 H MRSI in the brain at 7T. Magn Reson Med. 2017;79(3):1231–1240. PubMed PMC
Ligneul C, Palombo M, Valette J. Metabolite diffusion up to very high b in the mouse brain in vivo: Revisiting the potential correlation between relaxation and diffusion properties. Magn Reson Med. 2017;77(4):1390–1398. PubMed PMC
Bloembergen N, Purcell EM, Pound RV. Relaxation effects in nuclear magnetic resonance absorption. Phys Rev. 1948;73(7):679–712.
Pfeuffer J, Tkáč I, Gruetter R. Extracellular-intracellular distribution of glucose and lactate in the rat brain assessed noninvasively by diffusion-weighted 1H nuclear magnetic resonance spectroscopy in vivo. J Cereb Blood Flow Metab. 2000;20(4):736–746. PubMed
Ligneul C, Palombo M, Hernández-Garzón E, et al. Diffusion-weighted magnetic resonance spectroscopy enables cell-specific monitoring of astrocyte reactivity in vivo. Neuroimage. 2019;191:457–469. PubMed
Cudalbu C, Mlynarik V, Gruetter R. Handling macromolecule signals in the quantification of the neurochemical profile. J Alzheimers Dis. 2012;31 Suppl 3:S101–15. PubMed
Cudalbu C, Mlynrik V, Xin L, Gruetter R. Quantification of in vivo short echo-time proton magnetic resonance spectra at 14.1 T using two different approaches of modelling the macromolecule spectrum. Meas Sci Technol. 2009;20:104034 (7pp).
Mlynárik V, Cudalbu C, Xin L, Gruetter R. 1H NMR spectroscopy of rat brain in vivo at 14.1 Tesla: Improvements in quantification of the neurochemical profile. J Magn Reson. 2008;194(2):163–168. PubMed
Marjanska M, Deelchand DK, Hodges JS, et al. Altered macromolecular pattern and content in the aging human brain. NMR Biomed. 2018;(31:e3865):1–8. PubMed PMC
Vanhamme L, Van Huffel S. AMARES: Advanced Method for Accurate, Robust and Efficient Spectral fitting of MRS data with use of prior knowledge. 1997;43(129):1–2. PubMed
Govindaraju V, Young K, Maudsley AA. Proton NMR chemical shifts and coupling constants for brain metabolites. NMR Biomed. 2000;13:129–153. PubMed
Chong DGQ, Kreis R, Bolliger CS, Boesch C, Slotboom J. Two-dimensional linear-combination model fitting of magnetic resonance spectra to define the macromolecule baseline using FiTAID, a Fitting Tool for Arrays of Interrelated Datasets. Magn Reson Mater Physics, Biol Med. 2011;24(3):147–164. PubMed
Kreis R, Slotboom J, Hofmann L, Boesch C. Integrated data acquisition and processing to determine metabolite contents, relaxation times, and macromolecule baseline in single examinations of individual subjects. Magn Reson Med. 2005;54:761–8. PubMed
Marjańska M, Deelchand DK, Hodges JS, et al. Altered macromolecular pattern and content in the aging human brain. NMR Biomed. 2018;31(2):1–8. PubMed PMC
Bhogal AA, Schür RR, Houtepen LC, et al. 1H–MRS processing parameters affect metabolite quantification: The urgent need for uniform and transparent standardization. NMR Biomed. 2017;30(11):1–9. PubMed
Lee HH, Kim H. Parameterization of spectral baseline directly from short echo time full spectra in 1H-MRS. Magn Reson Med. 2017;78(3):836–847. PubMed
Seeger U, Klose U, Mader I, Grodd W, Na T. Parameterized Evaluation of Macromolecules and Lipids in Proton MR Spectroscopy of Brain Diseases. 2003;28:19–28. PubMed
Považan M, Hangel G, Strasser B, et al. Mapping of brain macromolecules and their use for spectral processing of 1H-MRSI data with an ultra-short acquisition delay at 7T. Neuroimage. 2015;121:126–135. PubMed
Pfeuffer J, Juchem C, Merkle H, Nauerth A, Logothetis NK. High-field localized 1H NMR spectroscopy in the anesthetized and in the awake monkey. Magn Reson Imaging. 2004;22(10):1361–1372. PubMed
Otazo R, Mueller B, Ugurbil K, Wald L, Posse S. Signal-to-Noise Ratio and Spectral Linewidth Improvements Between 1.5 and 7 Tesla in Proton Echo-Planar Spectroscopic Imaging. 2006;56:1200–1210. PubMed
Birch R, Peet AC, Dehghani H, Wilson M. Influence of Macromolecule Baseline on 1 H MR Spectroscopic Imaging Reproducibility. Magn Reson Med. 2017;77:34–43. PubMed PMC
Hong S-T, Balla DZ, Shajan G, Choi C, Uğurbil K, Pohmann R. Enhanced Neurochemical Profile of the Rat Brain using In Vivo 1H NMR spectroscopy at 16.4T. Magn Reson Med. 2011;65(1):28–34. PubMed
Hoefemann M, Bolliger C, van derVeen JW, Kreis R. About the need for a comprehensive description of the macromolecular baseline signal for MR fingerprinting and multidimensional fitting of MR spectra. In: ISMRM.; 2019:1069.
Wright AM, Murali-Manohar S, Henning A. Relaxation corrected and Sequence-dependent Macromolecule Baseline Model. In: ISMRM.; 2019:2247.
Kassem MNE, Bartha R. Quantitative proton short-echo-time LASER spectroscopy of normal human white matter and hippocampus at 4 Tesla incorporating macromolecule subtraction. Magn Reson Med. 2003;49(5):918–27. PubMed
Penner J, Bartha R. Semi-LASER 1H MR spectroscopy at 7 Tesla in human brain: Metabolite quantification incorporating subject-specific macromolecule removal. Magn Reson Med. 2015;74(1):4–12. PubMed
Bartha R, Drost DJ, Williamson PC. Factors affecting the quantification of short echo in-vivo1H MR spectra: Prior knowledge, peak elimination, and filtering. NMR Biomed. 1999;12(4):205–216. PubMed
Pfeuffer J, Tkac I, Provencher SW, Gruetter R. Towards an In Vivo Neurochemical Profile : Quantification of 18 Metabolites in Short-Echo-Time 1H NMR Spectra of the Rat Brain. J Magn Reson. 1999;141:104–120. PubMed
Hofmann L, Slotboom J, Jung B, Maloca P, Boesch C, Kreis R. Quantitative 1H-magnetic resonance spectroscopy of human brain: Influence of composition and parameterization of the basis set in linear combination model-fitting. Magn Reson Med. 2002;48(3):440–453. PubMed
Giapitzakis IA, Borbath T, Murali-Manohar S, Avdievich N, Henning A. Investigation of the influence of macromolecules and spline baseline in the fitting model of human brain spectra at 9.4T. Magn Reson Med. 2018;(June 2018):746–758. PubMed
Schaller B, Xin L, Cudalbu C, Gruetter R. Quantification of the neurochemical profile using simulated macromolecule resonances at 3 T. NMR Biomed. 2013;26(5):593–599. PubMed
Gottschalk M, Lamalle L, Segebarth C. Short-TE localised 1 H MRS of the human brain at 3 T : quantification of the metabolite signals using two approaches to account for macromolecular signal contributions. 2008;(21):507–517. PubMed
Henning A Advanced spectral quantification: Parameter handling, nonparametric pattern modeling, and multidimensional fitting. eMagRes. 2016:981–994.
Provencher SW. Estimation of metabolite concentrations from localized in vivo proton NMR spectra. Magn Reson Med. 1993;30(6):672–679. PubMed
Coenradie Y, Beer R De, Ormondt D Van, Lyon B. Background-signal Parameterization in In Vivo MR Spectroscopy. Time.:6–8.
Ratiney H, Sdika M, Coenradie Y, Cavassila S, van Ormondt D, Graveron-Demilly D. Time-domain semi-parametric estimation based on a metabolite basis set. NMR Biomed. 2005;18(1):1–13. PubMed
Cudalbu C, Beuf O, Cavassila S. In vivo short echo time localized 1H MRS of the rat brain at 7 T: Influence of two strategies of background-accommodation on the metabolite concentration estimation using QUEST. J Signal Process Syst. 2009;55(1–3).
Cudalbu C, Mlynárik V, Xin L, Gruetter R. Comparison of two approaches to model the macromolecule spectrum for the quantification of short TE 1H MRS spectra. In: IST 2008 - IEEE Workshop on Imaging Systems and Techniques Proceedings.; 2008.
Choi I-Y, Andronesi O, Barker P, et al. Spectral editing in 1H magnetic resonance spectroscopy: Experts’ consensus recommendations. NMR Biomed. PubMed PMC
Rothman DL, Petroff OA, Behar KL, Mattson RH. Localized 1H NMR measurements of gamma-aminobutyric acid in human brain in vivo. Proc Natl Acad Sci. 1993;90(12):5662–5666. PubMed PMC
Terpstra M, Ugurbil K, Gruetter R. Direct in vivo measurement of human cerebral GABA concentration using MEGA-editing at 7 Tesla. Magn Reson Med. 2002;47(5):1009–1012. PubMed
Choi IY, Lee SP, Merkle H, Shen J. Single-shot two-echo technique for simultaneous measurement of GABA and creatine in the human brain in vivo. Magn Reson Med. 2004;51(6):1115–21. PubMed
Donahue MJ, Near J, Blicher JU, Jezzard P. Baseline GABA concentration and fMRI response. Neuroimage. 2010;53:392–8. PubMed
Aguila MER, Lagopoulos J, Leaver AM, et al. Elevated levels of GABA+ in migraine detected using 1H-MRS. NMR Biomed. 2015;28:890–7. PubMed
O’Gorman RL, Michels L, Edden RA, Murdoch JB, Martin E. In vivo detection of GABA and glutamate with MEGA-PRESS: Reproducibility and gender effects. J Magn Reson Imaging. 2011;33:1262–7. PubMed PMC
Choi IY, Lee SP, Shen J. In vivo single-shot three-dimensionally localized multiple quantum spectroscopy of GABA in the human brain with improved spectral selectivity. J Magn Reson. 2005;172(1):9–16. PubMed
Bhattacharyya PK. Macromolecule contamination in GABA editing using MEGA-PRESS should be properly accounted for. Neuroimage. 2014;84:1111–1112. PubMed
McLean MA, Barker GJ. Concentrations and magnetization transfer ratios of metabolites in gray and white matter. Magn Reson Med. 2006;56(6):1365–1370. PubMed
Pan JW, Mason GF, Pohost GM, Hetherington HP. Spectroscopic imaging of human brain glutamate by water-suppressed J-refocused coherence transfer at 4.1 T. Magn Reson Med. 1996;36(1):7–12. PubMed
Moser P, Hingerl L, Strasser B, et al. Whole-slice mapping of GABA and GABA + at 7T via adiabatic MEGA-editing, real-time instability correction, and concentric circle readout. Neuroimage. 2019;184(April 2018):475–489. PubMed PMC
Harris AD, Glaubitz B, Near J, et al. Impact of frequency drift on gamma-aminobutyric acid-edited MR spectroscopy. Magn Reson Med. 2014;72:941–8. PubMed PMC
Harris AD, Puts NAJ, Wijtenburg SA, et al. Normalizing data from GABA-edited MEGA-PRESS implementations at 3 Tesla. Magn Reson Imaging. 2017;42:8–15. PubMed PMC
Hetherington HP, Newcomer BR, Pan JW. Measurements of human cerebral GABA at 4.1 T using numerically optimized editing pulses. Magn Reson Med. 1998;39:6–10. PubMed
Henry PG, Dautry C, Hantraye P, Bloch G. Brain gaba editing without macromolecule contamination. Magn Reson Med. 2001;45:517–20. PubMed
Edden RAE, Puts NAJ, Barker PB. Macromolecule-suppressed GABA-edited magnetic resonance spectroscopy at 3T. Magn Reson Med. 2012;68:657–61. PubMed PMC
Henry PG, Van De Moortele PF, Giacomini E, Nauerth A, Bloch G. Field-frequency locked in vivo proton MRS on a whole-body spectrometer. Magn Reson Med. 1999;42:636–42. PubMed
Bogner W, Gagoski B, Hess AT, et al. 3D GABA imaging with real-time motion correction, shim update and reacquisition of adiabatic spiral MRSI. Neuroimage. 2014;103:290–302. PubMed PMC
Mikkelsen M, Barker PB, Bhattacharyya PK, et al. Big GABA : Edited MR spectroscopy at 24 research sites. Neuroimage. 2017;159:32–45. PubMed PMC
Mader I, Seeger U, Karitzky J, Erb M, Schick F, Klose U. Proton magnetic resonance spectroscopy with metabolite nulling reveals regional differences of macromolecules in normal human brain. J Magn Reson Imaging. 2002;16(5):538–46. PubMed
Lam F, Li Y, Clifford B, Liang ZP. Macromolecule mapping of the brain using ultrashort-TE acquisition and reference-based metabolite removal. Magn Reson Med. 2018;79(5):2460–2469. PubMed
Sibbitt WL, Haseler LJ, Griffey RR, Friedman SD, Brooks WM. Neurometabolism of active neuropsychiatric lupus determined with proton MR spectroscopy. Am J Neuroradiol. 1997;18(7):1271–1277. PubMed PMC
Saunders DE, Howe F a, van den Boogaart A, Griffiths JR, Brown MM. Discrimination of metabolite from lipid and macromolecule resonances in cerebral infarction in humans using short echo proton spectroscopy. J Magn Reson Imaging. 1997;7(6):1116–21. PubMed
Graham GD, Hwang J-H, Rothman DL, Prichard JW. Spectroscopic Assessment of Alterations in Macromolecule and Small-Molecule Metabolites in Human Brain After Stroke. Stroke. 2001;32(12):2797–2802. PubMed
Mader I, Seeger U, Weissert R, et al. Proton MR spectroscopy with metabolite-nulling reveals elevated macromolecules in acute multiple sclerosis. Brain. 2001;124(5):953–961. PubMed
Howe FA, Opstad KS. 1H MR spectroscopy of brain tumours and masses. NMR Biomed. 2003;16(3):123–31. PubMed
Povazan M, Hnilicova P, Hangel G, et al. Detection of MM using metabolite-nulled MEGA-LASER at 3T – A possible effect on GABA+ signal. Proc Intl Soc Mag Reson Med. 2017;25.
Hnilicová P, Považan M, Strasser B, et al. Spatial variability and reproducibility of GABA-edited MEGA-LASER 3D-MRSI in the brain at 3 T. NMR Biomed. 2016;29(11):1656–1665. PubMed PMC
Andronesi OC, Bhat H, Reuter M, Mukherjee S, Caravan P, Rosen BR. Whole brain mapping of water pools and molecular dynamics with rotating frame MR relaxation using gradient modulated low-power adiabatic pulses. Neuroimage. 2014;89:92–109. PubMed PMC
Geades N, Wismans C, Damen M, et al. Evidence for regional and spectral differences of macromolecule signals in human brain using a crusher coil at 7 Tesla. In: Proc. Intl. Soc. Mag. Reson. Med. 24 (2016).; 2016.
Xin L, Mlynarik V, Lei H, Gruetter R. Influence of regional macromolecule baseline on the quantification of neurochemical profile in rat brain. In: Proc. Intl. Soc. Mag. Reson. Med.; 2010:5.
Tkac I, Rao R, Georgieff MK, Gruetter R. Developmental and regional changes in the neurochemical profile of the rat brain determined by in vivo 1H NMR spectroscopy. Magn Reson Med. 2003;50(1):24–32. PubMed
Schmitz JE, Kettunen MI, Hu DE, Brindle KM. 1H MRS-visible lipids accumulate during apoptosis of lymphoma cells in vitro and in vivo. Magn Reson Med. 2005;54:43–50. PubMed
Wolinsky JS, Narayana PA, Fenstermacher MJ. Proton magnetic resonance spectroscopy in multiple sclerosis. Neurology. 1990;40(11):1764–9. PubMed
García-Gómez JM, Luts J, Julià-Sapé M, et al. Multiproject–multicenter evaluation of automatic brain tumor classification by magnetic resonance spectroscopy. Magn Reson Mater Physics, Biol Med. 2009;22(1):5–18. PubMed PMC
Durmo F, Rydelius A, Cuellar Baena S, et al. Multivoxel 1H-MR Spectroscopy Biometrics for Preoprerative Differentiation Between Brain Tumors. Tomogr (Ann Arbor, Mich). 2018;4(4):172–181. PubMed PMC
Pedrosa de Barros N, Meier R, Pletscher M, et al. On the relation between MR spectroscopy features and the distance to MRI-visible solid tumor in GBM patients. Magn Reson Med. 2018;80(6):2339–2355. PubMed
Howe FA, Barton SJ, Cudlip SA, et al. Metabolic profiles of human brain tumors using quantitative in vivo 1H magnetic resonance spectroscopy. Magn Reson Med. 2003;49(2):223–232. PubMed
Opstad KS, Griffiths JR, Bell BA, Howe FA. Apparent T 2 Relaxation Times of Lipid and Macromolecules : A Study of High-Grade Tumor Spectra. 2008;184:178–184. PubMed
Opstad KS, Wright AJ, Bell BA, Griffiths JR, Howe FA. Correlations between in vivo 1H MRS and ex vivo 1H HRMAS metabolite measurements in adult human gliomas. J Magn Reson Imaging. 2010;31(2):289–97. PubMed
Oz G, Alger JR, Barker PB, et al. The MRS Consensus Group. Clinical proton MR spectroscopy in central nervous system disorders. Radiology. 2014;270(3):658–79. PubMed PMC
Hwang JH, Graham GD, Behar KL, Alger JR, Prichard JW, Rothman DL. Short echo time proton magnetic resonance spectroscopic imaging of macromolecule and metabolite signal intensities in the human brain. Magn Reson Med. 1996;35(5):633–9. PubMed
Petroff OAC, Graham GD, Blamire AM, et al. Spectroscopic imaging of stroke in humans: Histopathology correlates of spectral changes. Neurology. 1992;42(7):1349–54. PubMed
Singh K, Trivedi R, Verma A, et al. Altered metabolites of the rat hippocampus after mild and moderate traumatic brain injury – a combined in vivo and in vitro 1H–MRS study. NMR Biomed. 2017;30:e3764. PubMed
Opstad KS, Bell BA, Griffiths JR, Howe FA. An investigation of human brain tumour lipids by high-resolution magic angle spinning 1 H MRS and histological analysis. NMR Biomed. 2008;21(7):677–685. PubMed
Oz G, Tkac I, LR C, et al. Assessment of adrenoleukodystrophy lesions by high field MRS in non-sedated pediatric patients. Neurology. 2005;64(3):434–441. PubMed
Tkáč I, Öz G, Adriany G, Uǧurbil K, Gruetter R. In vivo 1H NMR spectroscopy of the human brain at high magnetic fields: Metabolite quantification at 4T vs. 7T. Magn Reson Med. 2009;62(4):868–879. PubMed PMC
Bhattacharyya PK, Lowe KJ. Macromolecule-suppressed GABA acquisition at 7T with commonly available Gaussian editing pulses. In: ISMRM.; 2018:26:1285.
Choi IY, Lee SP, Merkle H, Shen J. In vivo detection of gray and white matter differences in GABA concentration in the human brain. Neuroimage. 2006;33(1):85–93. PubMed
Bhattacharyya PK, Phillips MD, Stone LA, Lowe MJ. In vivo magnetic resonance spectroscopy measurement of gray-matter and white-matter gamma-aminobutyric acid concentration in sensorimotor cortex using a motion-controlled MEGA point-resolved spectroscopy sequence. Magn Reson Imaging. 2011;29(3):374–9. PubMed PMC