{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T13:29:43Z","timestamp":1768570183558,"version":"3.49.0"},"posted":{"date-parts":[[2025,4,1]]},"group-title":"Radiology and Imaging","reference-count":43,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,4,1]],"date-time":"2025-04-01T00:00:00Z","timestamp":1743465600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background and Purpose<\/jats:title>\n                  <jats:p>In-vivo magnetic resonance spectroscopy (MRS) of 2-hydroxyglutarate (2HG) may provide diagnostic and monitoring biomarkers in isocitrate dehydrogenase (IDH)-mutated glioma. A previous meta-analysis has shown good diagnostic accuracy of TE-optimized PRESS for IDH-mutated glioma, but most studies feature IDH-wildtype glioma as a comparison. However, when considering newly identified brain lesions that may mimic glioma, full characterization of its diagnostic utility should also consider the accuracy of 2HG measurement in non-tumor tissue. Therefore, we tested how well TE-optimized 2HG levels distinguish between IDH-mutated glioma and non-tumor tissue, in this case, normal-appearing brain. We further examined the impact of different spectral modeling strategies (baseline stiffness, macromolecule inclusion, and basis set composition).<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Materials and Methods<\/jats:title>\n                  <jats:p>48 patients with diagnosed\/suspected IDH-mutated glioma were enrolled. 3T MRS data were acquired from tumor and contralateral non-tumor tissue with PRESS localization (TE = 97 ms, optimized for 2HG detection) and analyzed with \u2018LCModel\u2019 software. Receiver operating characteristic analysis evaluated 2HG estimates\u2019 ability to distinguish IDH-mutated glioma from non-tumor brain tissue. Modeling interactions between 2HG and other metabolites were evaluated to identify reasons for potential false-positive 2HG detection.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>TE-optimized PRESS distinguished IDH-mutated glioma from non-tumor tissue with lower sensitivity (range 0.76-0.62) and specificity (0.85-0.78) than literature suggests for IDH-mutated vs. IDH-wildtype glioma. Strong negative correlations between gamma-aminobutyric acid (GABA) and 2HG persisted across all modeling strategies and may lead to false-positive 2HG detection in non-tumor tissue. We further present a cautionary example from a patient on a ketogenic diet, showing that the ketone body acetone can interfere with 2HG detection.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Spectral overlap with GABA and acetone can lead to false-positive 2HG detection in non-tumor tissue. Clinicians need to be mindful of these pitfalls when interpreting 2HG estimates.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.03.31.25324828","type":"posted-content","created":{"date-parts":[[2025,4,2]],"date-time":"2025-04-02T01:10:45Z","timestamp":1743556245000},"source":"Crossref","is-referenced-by-count":0,"title":["Pitfalls in 2HG detection with TE-optimized MRS at 3T"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9447-4906","authenticated-orcid":false,"given":"Seyma","family":"Alcicek","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dunja","family":"Simicic","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7335-4537","authenticated-orcid":false,"given":"Lindsay","family":"Blair","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Max","family":"Saint-Germain","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7148-292X","authenticated-orcid":false,"given":"Helge J.","family":"Z\u00f6llner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher W.","family":"Davies-Jenkins","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthias","family":"Holdhoff","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Laterra","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chetan","family":"Bettegowda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karisa C.","family":"Schreck","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Doris D.","family":"Lin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter B.","family":"Barker","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David O.","family":"Kamson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3083-9811","authenticated-orcid":false,"given":"Georg","family":"Oeltzschner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025040302000688000_2025.03.31.25324828v1.1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1164382"},{"key":"2025040302000688000_2025.03.31.25324828v1.2","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0000000000002583"},{"key":"2025040302000688000_2025.03.31.25324828v1.3","doi-asserted-by":"crossref","unstructured":"Louis DN , Perry A , Wesseling P , et al. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro-Oncol 2021;23:1231\u201351.","DOI":"10.1093\/neuonc\/noab106"},{"key":"2025040302000688000_2025.03.31.25324828v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/nature08617"},{"key":"2025040302000688000_2025.03.31.25324828v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2015.06.023"},{"key":"2025040302000688000_2025.03.31.25324828v1.6","doi-asserted-by":"crossref","unstructured":"Du X , Hu H . The Roles of 2-Hydroxyglutarate. Front Cell Dev Biol 2021;9.","DOI":"10.3389\/fcell.2021.651317"},{"key":"2025040302000688000_2025.03.31.25324828v1.7","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2304194"},{"key":"2025040302000688000_2025.03.31.25324828v1.8","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1038\/s41582-024-00967-7","article-title":"IDH inhibition in gliomas: from preclinical models to clinical trials","volume":"20","year":"2024","journal-title":"Nat Rev Neurol"},{"key":"2025040302000688000_2025.03.31.25324828v1.9","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2682"},{"key":"2025040302000688000_2025.03.31.25324828v1.10","doi-asserted-by":"crossref","unstructured":"Andronesi OC , Arrillaga-Romany IC , Ly KI , et al. Pharmacodynamics of mutant-IDH1 inhibitors in glioma patients probed by in vivo 3D MRS imaging of 2-hydroxyglutarate. Nat Commun 2018;9:1474.","DOI":"10.1038\/s41467-018-03905-6"},{"key":"2025040302000688000_2025.03.31.25324828v1.11","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3002796"},{"key":"2025040302000688000_2025.03.31.25324828v1.12","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-15-0656"},{"key":"2025040302000688000_2025.03.31.25324828v1.13","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/noy113"},{"key":"2025040302000688000_2025.03.31.25324828v1.14","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/nox214"},{"key":"2025040302000688000_2025.03.31.25324828v1.15","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/nov307"},{"key":"2025040302000688000_2025.03.31.25324828v1.16","doi-asserted-by":"crossref","unstructured":"Hangel G , Cadrien C , Lazen P , et al. High-resolution metabolic imaging of high-grade gliomas using 7T-CRT-FID-MRSI. NeuroImage Clin 2020;28:102433.","DOI":"10.1016\/j.nicl.2020.102433"},{"key":"2025040302000688000_2025.03.31.25324828v1.17","doi-asserted-by":"publisher","DOI":"10.1002\/mrm.29252"},{"key":"2025040302000688000_2025.03.31.25324828v1.18","doi-asserted-by":"publisher","DOI":"10.1002\/mrm.28942"},{"key":"2025040302000688000_2025.03.31.25324828v1.19","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.1016\/j.jmoldx.2022.08.006","article-title":"Optimizing Insertion and Deletion Detection Using Next-Generation Sequencing in the Clinical Laboratory","volume":"24","year":"2022","journal-title":"J Mol Diagn JMD"},{"key":"2025040302000688000_2025.03.31.25324828v1.20","doi-asserted-by":"publisher","DOI":"10.1002\/mrm.22234"},{"key":"2025040302000688000_2025.03.31.25324828v1.21","doi-asserted-by":"crossref","unstructured":"Lin A , Andronesi O , Bogner W , et al. Minimum Reporting Standards for in vivo Magnetic Resonance Spectroscopy (MRSinMRS): Experts\u2019 consensus recommendations. NMR Biomed 2021;34.","DOI":"10.1002\/nbm.4484"},{"key":"2025040302000688000_2025.03.31.25324828v1.22","doi-asserted-by":"crossref","unstructured":"Oeltzschner G , Z\u00f6llner HJ , Hui SCN , et al. Osprey: Open-source processing, reconstruction & estimation of magnetic resonance spectroscopy data. J Neurosci Methods 2020;343:108827.","DOI":"10.1016\/j.jneumeth.2020.108827"},{"key":"2025040302000688000_2025.03.31.25324828v1.23","doi-asserted-by":"publisher","DOI":"10.1002\/mrm.1910300604"},{"key":"2025040302000688000_2025.03.31.25324828v1.24","doi-asserted-by":"publisher","DOI":"10.1002\/mrm.29370"},{"key":"2025040302000688000_2025.03.31.25324828v1.25","doi-asserted-by":"publisher","DOI":"10.1002\/1099-1492(200005)13:3<129::AID-NBM619>3.0.CO;2-V"},{"key":"2025040302000688000_2025.03.31.25324828v1.26","doi-asserted-by":"publisher","DOI":"10.1002\/MRM.27742"},{"key":"2025040302000688000_2025.03.31.25324828v1.27","doi-asserted-by":"crossref","unstructured":"Kreis R , Boer V , Choi I , et al. Terminology and concepts for the characterization of in vivo MR spectroscopy methods and MR spectra: Background and experts\u2019 consensus recommendations. NMR Biomed 2021;34.","DOI":"10.1002\/nbm.4347"},{"key":"2025040302000688000_2025.03.31.25324828v1.28","doi-asserted-by":"crossref","unstructured":"Hui SCN , Murali-Manohar S , Z\u00f6llner HJ , et al. Integrated Short-TE and Hadamard-edited Multi-Sequence (ISTHMUS) for advanced MRS. J Neurosci Methods 2024;409:110206.","DOI":"10.1016\/j.jneumeth.2024.110206"},{"key":"2025040302000688000_2025.03.31.25324828v1.29","doi-asserted-by":"crossref","unstructured":"Friston KJ , ed. Statistical parametric mapping: the analysis of funtional brain images. 1st ed. Amsterdam; Boston: Elsevier\/Academic Press; 2007.","DOI":"10.1016\/B978-012372560-8\/50002-4"},{"key":"2025040302000688000_2025.03.31.25324828v1.30","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1002\/(SICI)1522-2586(199904)9:4<531::AID-JMRI4>3.0.CO;2-L","article-title":"NMR relaxation times in the human brain at 3.0 tesla","volume":"9","year":"1999","journal-title":"J Magn Reson Imaging JMRI"},{"key":"2025040302000688000_2025.03.31.25324828v1.31","doi-asserted-by":"publisher","DOI":"10.1002\/mrm.20901"},{"key":"2025040302000688000_2025.03.31.25324828v1.32","doi-asserted-by":"crossref","unstructured":"Kern M , Auer TA , Picht T , et al. T2 mapping of molecular subtypes of WHO grade II\/III gliomas. BMC Neurol 2020;20:8.","DOI":"10.1186\/s12883-019-1590-1"},{"key":"2025040302000688000_2025.03.31.25324828v1.33","doi-asserted-by":"publisher","DOI":"10.1002\/nbm.994"},{"key":"2025040302000688000_2025.03.31.25324828v1.34","doi-asserted-by":"crossref","unstructured":"Gong T , Zhang X , Wei X , et al. GSH and GABA decreases in IDH1-mutated low-grade gliomas detected by HERMES spectral editing at 3 T in vivo. Neurochem Int 2020;141:104889.","DOI":"10.1016\/j.neuint.2020.104889"},{"key":"2025040302000688000_2025.03.31.25324828v1.35","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1002\/mrm.26347","article-title":"Detection of 2-hydroxyglutarate in brain tumors by triple- refocusing MR spectroscopy at 3T in vivo","volume":"78","year":"2017","journal-title":"Magn Reson Med"},{"key":"2025040302000688000_2025.03.31.25324828v1.36","doi-asserted-by":"crossref","first-page":"e3886","DOI":"10.1002\/nbm.3886","article-title":"A comparison of 2-hydroxyglutarate detection at 3 and 7 T with long-TE semi-LASER","volume":"31","year":"2018","journal-title":"NMR Biomed"},{"key":"2025040302000688000_2025.03.31.25324828v1.37","doi-asserted-by":"publisher","DOI":"10.1002\/mrm.25568"},{"key":"2025040302000688000_2025.03.31.25324828v1.38","first-page":"e953","article-title":"Feasibility and Biological Activity of a Ketogenic\/Intermittent-Fasting Diet in Patients With Glioma","volume":"97","year":"2021","journal-title":"Neurology"},{"key":"2025040302000688000_2025.03.31.25324828v1.39","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1002\/jmri.29422","article-title":"2D H sLASER Long-TE and 3D P Chemical Shift Imaging at 3 T for Monitoring Fasting-Induced Changes in Brain Tumor Tissue","volume":"61","year":"2025","journal-title":"J Magn Reson Imaging"},{"key":"2025040302000688000_2025.03.31.25324828v1.40","doi-asserted-by":"publisher","DOI":"10.3174\/ajnr.A6287"},{"key":"2025040302000688000_2025.03.31.25324828v1.41","doi-asserted-by":"publisher","DOI":"10.1101\/2024.09.11.612503"},{"key":"2025040302000688000_2025.03.31.25324828v1.42","doi-asserted-by":"crossref","unstructured":"Berrington A , Voets NL , Plaha P , et al. Improved Localization for 2-Hydroxyglutarate Detection at 3 T Using Long-TE Semi-LASER. Tomography 2016;2:94.","DOI":"10.18383\/j.tom.2016.00139"},{"key":"2025040302000688000_2025.03.31.25324828v1.43","doi-asserted-by":"crossref","first-page":"4030","DOI":"10.1200\/JCO.2016.67.1222","article-title":"Prospective Longitudinal Analysis of 2- Hydroxyglutarate Magnetic Resonance Spectroscopy Identifies Broad Clinical Utility for the Management of Patients With IDH-Mutant Glioma","volume":"34","year":"2016","journal-title":"J Clin Oncol"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.03.31.25324828","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T20:32:53Z","timestamp":1768509173000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.1101\/2025.03.31.25324828"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,1]]},"references-count":43,"URL":"https:\/\/doi.org\/10.1101\/2025.03.31.25324828","relation":{},"subject":[],"published":{"date-parts":[[2025,4,1]]},"subtype":"preprint"}}