PURPOSE: Reliable detection and fitting of macromolecules (MM) are crucial for accurate quantification of brain short-echo time (TE) 1 H-MR spectra. An experimentally acquired single MM spectrum is commonly used. Higher spectral resolution at ultra-high field (UHF) led to increased interest in using a parametrized MM spectrum together with flexible spline baselines to address unpredicted spectroscopic components. Herein, we aimed to: (1) implement an advanced methodological approach for post-processing, fitting, and parametrization of 9.4T rat brain MM spectra; (2) assess the concomitant impact of the LCModel baseline and MM model (ie, single vs parametrized); and (3) estimate the apparent T2 relaxation times for seven MM components. METHODS: A single inversion recovery sequence combined with advanced AMARES prior knowledge was used to eliminate the metabolite residuals, fit, and parametrize 10 MM components directly from 9.4T rat brain in vivo 1 H-MR spectra at different TEs. Monte Carlo simulations were also used to assess the concomitant influence of parametrized MM and DKNTMN parameter in LCModel. RESULTS: A very stiff baseline (DKNTMN ≥ 1 ppm) in combination with a single MM spectrum led to deviations in metabolite concentrations. For some metabolites the parametrized MM showed deviations from the ground truth for all DKNTMN values. Adding prior knowledge on parametrized MM improved MM and metabolite quantification. The apparent T2 ranged between 12 and 24 ms for seven MM peaks. CONCLUSION: Moderate flexibility in the spline baseline was required for reliable quantification of real/experimental spectra based on in vivo and Monte Carlo data. Prior knowledge on parametrized MM improved MM and metabolite quantification.

Animal Imaging and Technology EPFL Lausanne Switzerland

Center for Magnetic Resonance Research Department of Radiology University of Minnesota Minneapolis Minnesota USA

CIBM Center for Biomedical Imaging Switzerland

Faculty of Science University of Tübingen Tübingen Germany

High Field Magnetic Resonance Max Planck Institute for Biological Cybernetics Tübingen Germany

Institute of Scientific Instruments Czech Academy of Sciences Brno Czech Republic

Laboratory for functional and metabolic imaging EPFL Lausanne Switzerland

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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;46:855‐863. PubMed

Cudalbu C, Mlynárik V, Gruetter R. Handling macromolecule signals in the quantification of the neurochemical profile. J Alzheimer's Dis. 2012;31:S101‐S115. PubMed

Cudalbu C, Behar KL, Bhattacharyya PK, et al. Contribution of macromolecules to brain 1H MR spectra: experts’ consensus recommendations. NMR Biomed. 2021;34:e4393. PubMed PMC

Behar KL, Ogino T. Characterization of macromolecule resonances in the 1H NMR spectrum of rat brain. Magn Reson Med. 1993;30:38‐44. 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;17:285‐303. PubMed

Behar KL, Rothman DL, Spencer DD, Petroff OAC. Analysis of macromolecule resonances in 1H NMR spectra of human brain. Magn Reson Med. 1994;32:294‐302. 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;6:242‐247. 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;58:967‐974. 10.1111/j.1471-4159.1992.tb09350.x. PubMed DOI

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;84:542‐558. PubMed

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;129:806‐815. PubMed

Považan M, Strasser B, Hangel G, et al. Simultaneous mapping of metabolites and individual macromolecular components via ultra‐short acquisition delay 1H MRSI in the brain at 7T. Magn Reson Med. 2018;79:1231‐1240. PubMed PMC

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;64:939‐946. PubMed

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;75:503‐514. PubMed

Near J, Harris AD, Juchem C, et al. Preprocessing, analysis and quantification in single‐voxel magnetic resonance spectroscopy: experts’ consensus recommendations. NMR Biomed. 2021;34:e4257. PubMed PMC

Mader I. Proton MR spectroscopy with metabolite‐nulling reveals elevated macromolecules in acute multiple sclerosis. Brain. 2001;124:953‐961. PubMed

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;80:2339‐2355. 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;49:223‐232. PubMed

Opstad KS, Griffiths JR, Bell BA, Howe FA. Apparent T2 relaxation times of lipid and macromolecules: a study of high‐grade tumor spectra. J Magn Reson Imaging. 2008;27:178‐184. 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;31:289‐297. PubMed

Oz G, Tkac I, Charnas LR, et al. Assessment of adrenoleukodystrophy lesions by high field MRS in non‐sedated pediatric patients. Neurology. 2005;64:434‐441. PubMed

Seeger U, Klose U, Mader I, Grodd W, Nägele T. Parameterized evaluation of macromolecules and lipids in proton MR spectroscopy of brain diseases. Magn Reson Med. 2003;49:19‐28. 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;22:1361‐1372. PubMed

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 16.4 T. Magn Reson Med. 2011;65:28‐34. PubMed

Lee HH, Kim H. Parameterization of spectral baseline directly from short echo time full spectra in 1H‐MRS. Magn Reson Med. 2017;78:836‐847. PubMed

Provencher S. LCModel Manual. Stephen Provencher; 2019.

Provencher SW. Automatic quantitation of localized in vivo 1H spectra with LCModel. NMR Biomed. 2001;14:260‐264. PubMed

Pfeuffer J, Tkáč I, Provencher SW, Gruetter R. Toward 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

Deelchand DK, Marjańska M, Hodges JS, Terpstra M. Sensitivity and specificity of human brain glutathione concentrations measured using short‐TE 1H MRS at 7 T. NMR Biomed. 2016;29:600‐606. PubMed PMC

Terpstra M, Ugurbil K, Tkac I. Noninvasive quantification of human brain ascorbate concentration using1H NMR spectroscopy at 7 T. NMR Biomed. 2010;23:227‐232. PubMed PMC

Near J, Andersson J, Maron E, et al. Unedited in vivo detection and quantification of γ‐aminobutyric acid in the occipital cortex using short‐TE MRS at 3T. NMR Biomed. 2013;26:1353‐1362. 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. 2019;81:746‐758. PubMed

Marjańska M, Terpstra M. Influence of fitting approaches in LCModel on MRS quantification focusing on age‐specific macromolecules and the spline baseline. NMR Biomed. 2021;34:e4197. PubMed PMC

De Graaf RA, Brown PB, McIntyre S, Nixon TW, Behar KL, Rothman DL. High magnetic field water and metabolite proton T1 and T2 relaxation in rat brain in vivo. Magn Reson Med. 2006;56:386‐394. PubMed

Landheer K, Gajdošík M, Treacy M, Juchem C. Concentration and effective T2 relaxation times of macromolecules at 3T. Magn Reson Med. 2020;84:2327‐2337. PubMed

Hoefemann M, Bolliger CS, Chong DGQ, Veen JW, Kreis R. Parameterization of metabolite and macromolecule contributions in interrelated MR spectra of human brain using multidimensional modeling. NMR Biomed. 2020;33:e4328. PubMed

Gruetter R, Tkáč I. Field mapping without reference scan using asymmetric echo‐planar techniques. Magn Reson Med. 2000;43:319‐323. PubMed

Mlynárik V, Gambarota G, Frenkel H, Gruetter R. Localized short‐echo‐time proton MR spectroscopy with full signal‐intensity acquisition. Magn Reson Med. 2006;56:965‐970. 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;194:163‐168. PubMed

Craveiro M, Cudalbu C, Gruetter R. Regional alterations of the brain macromolecule resonances investigated in the mouse brain using an improved method for the pre‐processing of the macromolecular signal. Proceedings of the 20th Annual Meeting ISMRM, Melbourne, Australia, 2012. Abstract 1748.

Xin L, Mlynarik V, Lei H, Gruetter R. Influence of regional macromolecule baseline on the quantification of neurochemical profile in rat brain. In Proceedings of the 18th Annual Meeting of ISMRM, Stockholm, Sweden, 2010. Abstract 321.

Tkáč I, Starčuk Z, Choi IY, Gruetter R. In vivo 1H NMR spectroscopy of rat brain at 1 ms echo time. Magn Reson Med. 1999;41:649‐656. PubMed

Vanhamme L, Van Den Boogaart A, Van Huffel S. Improved method for accurate and efficient quantification of MRS data with use of prior knowledge. J Magn Reson. 1997;129:35‐43. PubMed

Lee HH, Kim H. Parameterization of spectral baseline directly from short echo time full spectra in 1H‐MRS. Magn Reson Med. 2017;78:836‐847. PubMed

Fowler CF, Madularu D, Dehghani M, Devenyi GA, Near J. Longitudinal quantification of metabolites and macromolecules reveals age‐ and sex‐related changes in the healthy Fischer 344 rat brain. Neurobiol Aging. 2021;101:109‐122. PubMed

Kreis R, Boer V, Choi I‐Y, et al. Terminology and concepts for the characterization of in vivo MR spectroscopy methods and MR spectra: Background and experts’ consensus recommendations. NMR Biomed. 2021;34:e4347. PubMed PMC

Wilson M. Adaptive baseline fitting for MR spectroscopy analysis. Magn Reson Med. 2021;85:13‐29. 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;74:607‐613. PubMed PMC

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. Magn Reson Med. 2006;56:1200‐1210. PubMed

Heckova E, Považan M, Strasser B, et al. Effects of different macromolecular models on reproducibility of FID‐MRSI at 7T. Magn Reson Med. 2020;83:12‐21. PubMed PMC

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 Phys, Biol Med. 2011;24:147‐164. PubMed

Marjańska M, Deelchand DK, Hodges JS, et al. Altered macromolecular pattern and content in the aging human brain. NMR Biomed. 2018;31:e3865. PubMed PMC

Coenradie Y, De Beer R, Van Ormondt D, Lyon B. Background‐signal parametrization in In Vivo MR Spectroscopy. ProRISC, IEEE Benelux. 2002;248‐254.

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;55:25‐34.

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;33:1262‐1267. PubMed PMC

Govindaraju V, Young K, Maudsley AA. Proton NMR chemical shifts and coupling constants for brain metabolites. NMR Biomed. 2000;13:129‐153. 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 Phys, Biol Med. 2013;26:549‐554. PubMed