{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T03:30:42Z","timestamp":1788233442636,"version":"build-2803163510"},"reference-count":22,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2025,7,31]],"date-time":"2025-07-31T00:00:00Z","timestamp":1753920000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pediatric Blood &amp; Cancer"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Methotrexate (MTX)\u2010induced leukoencephalopathy is a significant neurological complication in pediatric acute lymphoblastic leukemia (ALL) treatment. Magnetic resonance spectroscopy (MRS) is a noninvasive method to assess metabolic changes associated with neurotoxicity. This study aimed to evaluate the diagnostic and prognostic value of MRS\u2010derived metabolite levels, particularly <jats:italic>N<\/jats:italic>\u2010acetylaspartate and <jats:italic>N<\/jats:italic>\u2010acetylaspartylglutamate (tNAA), in MTX\u2010induced leukoencephalopathy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Procedure<\/jats:title><jats:p>We retrospectively analyzed 89 pediatric patients with ALL who underwent brain magnetic resonance imaging (MRI) and MRS at Kanagawa Children's Medical Center between 2009 and 2022. A total of 261 MRS datasets were examined, focusing on metabolic changes in the centrum semiovale. Using mixed logistic regression, we evaluated the association between tNAA levels and leukoencephalopathy onset, as well as their correlation with clinical recovery after MTX discontinuation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Patients with leukoencephalopathy had significantly lower tNAA levels than those of controls. A predictive model indicated that a 1.0\u2010point decrease in pretreatment tNAA levels was associated with an approximately 3.22\u2010fold increase in the odds of developing MTX\u2010induced leukoencephalopathy. Furthermore, increasing tNAA levels over time were significantly correlated with clinical improvement.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This study suggests that tNAA levels measured using MRS may serve as a potential biomarker for diagnosing and monitoring MTX\u2010induced leukoencephalopathy. Integrating MRS into clinical assessments may represent a promising future approach to facilitate earlier intervention, inform treatment strategies, and potentially improve patient outcomes, pending validation by future prospective studies. These findings highlight the importance of MRS in the real\u2010time evaluation of disease progression and therapeutic responses in pediatric patients undergoing MTX treatment.<\/jats:p><\/jats:sec>","DOI":"10.1002\/pbc.31957","type":"journal-article","created":{"date-parts":[[2025,7,31]],"date-time":"2025-07-31T07:09:30Z","timestamp":1753945770000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Metabolite Levels Measured Using Magnetic Resonance Spectroscopy in Pediatric Methotrexate\u2010Induced Leukoencephalopathy"],"prefix":"10.1002","volume":"72","author":[{"given":"Daisuke","family":"Hirokawa","sequence":"first","affiliation":[{"name":"Department of Neurosurgery Yokohama City University Graduate School of Medicine  Yokohama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moyoko","family":"Tomiyasu","sequence":"additional","affiliation":[{"name":"Department of Radiology Kanagawa Children's Medical Center  Yokohama Japan"},{"name":"Department of Molecular Imaging and Theranostics National Institute for Quantum and Radiological Science and Technology  Chiba Japan"},{"name":"Department of Radiology Johns Hopkins University School of Medicine  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4612-5728","authenticated-orcid":false,"given":"Masaki","family":"Sonoda","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Yokohama City University Graduate School of Medicine  Yokohama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Suenaga","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Yokohama City University Graduate School of Medicine  Yokohama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroaki","family":"Goto","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology Department of Pediatrics Kanagawa Children's Medical Center  Yokohama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noriko","family":"Aida","sequence":"additional","affiliation":[{"name":"Department of Radiology Kanagawa Children's Medical Center  Yokohama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsuya","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Yokohama City University Graduate School of Medicine  Yokohama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,7,31]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2013.53.0808"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2352\u20103026(16)30110\u20107"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1159\/000069773"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2020.268565"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.radcr.2022.11.057"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnene.2013.00011"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1023\/a:1023250721185"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.21037\/qims\u201021\u2010748"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0360\u20103016(01)01513\u20109"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awq200"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.2463\/mrms.rev.2021\u20100055"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0082746"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mri.2016.07.006"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10545\u2010009\u20109022\u20109"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.2463\/mrms.rev.2021\u20100085"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12185\u2010018\u20102440\u20104"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.24.00811"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749\u20106632.1987.tb32915.x"},{"key":"e_1_2_9_20_1","unstructured":"S.Provencher LCModel & LCMgui User's Manual 2021."},{"issue":"5","key":"e_1_2_9_21_1","first-page":"833","article-title":"Diffuse Metabolic Abnormalities in Reversible Posterior Leukoencephalopathy Syndrome","volume":"23","author":"Barker F. S.","year":"2002","journal-title":"AJNR American Journal of Neuroradiology"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.5966\/sctm.2016\u20100087"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00234\u2010015\u20101638\u2010x"}],"container-title":["Pediatric Blood &amp; Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/pbc.31957","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,26]],"date-time":"2025-08-26T03:47:10Z","timestamp":1756180030000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/pbc.31957"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,31]]},"references-count":22,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2025,10]]}},"alternative-id":["10.1002\/pbc.31957"],"URL":"https:\/\/doi.org\/10.1002\/pbc.31957","archive":["Portico"],"relation":{},"ISSN":["1545-5009","1545-5017"],"issn-type":[{"value":"1545-5009","type":"print"},{"value":"1545-5017","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,31]]},"assertion":[{"value":"2025-03-27","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-07-11","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-07-31","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e31957"}}