{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T02:34:56Z","timestamp":1788230096884,"version":"build-2803163510"},"reference-count":45,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2020,12,17]],"date-time":"2020-12-17T00:00:00Z","timestamp":1608163200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Develop Med Child Neuro"],"published-print":{"date-parts":[[2021,5]]},"abstract":"<jats:sec><jats:title>Aim<\/jats:title><jats:p>To explore the cerebrospinal fluid (CSF) metabolite features in acute neuroinflammatory diseases and identify potential biomarkers to diagnose and monitor neuroinflammation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Method<\/jats:title><jats:p>A cohort of 14 patients (five females, nine males; mean [median] age 7y 9mo [9y], range 6mo\u201313y) with acute encephalitis (acute disseminated encephalomyelitis <jats:italic>n<\/jats:italic>=6, unknown suspected viral encephalitis <jats:italic>n<\/jats:italic>=3, enteroviral encephalitis <jats:italic>n<\/jats:italic>=2, seronegative autoimmune encephalitis <jats:italic>n<\/jats:italic>=2, herpes simplex encephalitis <jats:italic>n<\/jats:italic>=1) and age\u2010matched non\u2010inflammatory neurological disease controls (<jats:italic>n<\/jats:italic>=14) were investigated using an untargeted metabolomics approach. CSF metabolites were analyzed with liquid chromatography coupled to high resolution mass spectrometry, followed by subsequent multivariate and univariate statistical methods.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A total of 35 metabolites could be discriminated statistically between the groups using supervised orthogonal partial least squares discriminant analysis and analysis of variance. The tryptophan\u2010kynurenine pathway contributed nine key metabolites. There was a statistical increase of kynurenine, quinolinic acid, and anthranilic acid in patients with encephalitis, whereas tryptophan, 3\u2010hydroxyanthrnailic acid, and kynurenic acid were decreased. The nitric oxide pathway contributed four metabolites, with elevated asymmetric dimethylarginine and argininosuccinic acid, and decreased arginine and citrulline in patients with encephalitis. An increase in the CSF kynurenine\/tryptophan ratio (<jats:italic>p&lt;<\/jats:italic>0.001), anthranilic acid\/3\u2010hydroxyanthranilic acid ratio (<jats:italic>p&lt;<\/jats:italic>0.001), asymmetric dimethylarginine\/arginine ratio (<jats:italic>p&lt;<\/jats:italic>0.001), and neopterin (<jats:italic>p&lt;<\/jats:italic>0.001) strongly predicted neuroinflammation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>The combination of alterations in the tryptophan\u2010kynurenine pathway, nitric oxide pathway, and neopterin represent a useful potential panel for neuroinflammation and holds potential for clinical translation practice.<\/jats:p><\/jats:sec><jats:sec><jats:title>What this paper adds<\/jats:title><jats:p>\n<jats:list list-type=\"bullet\">\n\n<jats:list-item><jats:p>The kynurenine\/tryptophan and anthranilic acid\/3\u2010hydroxyanthranilic acid ratios hold great potential as biomarkers of neuroinflammation.<\/jats:p><\/jats:list-item>\n\n<jats:list-item><jats:p>Elevation of the asymmetric dimethylarginine\/arginine ratio in acute brain inflammation shows dysregulation of the nitric oxide pathway.<\/jats:p><\/jats:list-item>\n<\/jats:list>\n<\/jats:p><\/jats:sec>","DOI":"10.1111\/dmcn.14774","type":"journal-article","created":{"date-parts":[[2020,12,18]],"date-time":"2020-12-18T15:35:03Z","timestamp":1608305703000},"page":"552-559","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Cerebrospinal fluid metabolites in tryptophan\u2010kynurenine and nitric oxide pathways: biomarkers for acute neuroinflammation"],"prefix":"10.1111","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0970-1570","authenticated-orcid":false,"given":"Jingya","family":"Yan","sequence":"first","affiliation":[{"name":"Centre for Forensic Science University of Technology Sydney Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0582-6779","authenticated-orcid":false,"given":"Unnikrishnan","family":"Kuzhiumparambil","sequence":"additional","affiliation":[{"name":"Climate Change Cluster University of Technology Sydney Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashvin","family":"Bandodkar","sequence":"additional","affiliation":[{"name":"Clinical School The Children\u2019s Hospital at Westmead Faculty of Medicine and Health University of Sydney Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5000-4518","authenticated-orcid":false,"given":"Sushil","family":"Bandodkar","sequence":"additional","affiliation":[{"name":"Clinical School The Children\u2019s Hospital at Westmead Faculty of Medicine and Health University of Sydney Sydney New South Wales Australia"},{"name":"Department of Clinical Biochemistry The Children\u2019s Hospital at Westmead Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2495-1826","authenticated-orcid":false,"given":"Russell C","family":"Dale","sequence":"additional","affiliation":[{"name":"Clinical School The Children\u2019s Hospital at Westmead Faculty of Medicine and Health University of Sydney Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6238-3612","authenticated-orcid":false,"given":"Shanlin","family":"Fu","sequence":"additional","affiliation":[{"name":"Centre for Forensic Science University of Technology Sydney Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,12,17]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1212\/CPJ.0000000000000036"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.7861\/clinmedicine.18-2-155"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0007045"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2016.00183"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchromb.2008.05.001"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11306-016-1041-6"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11306-018-1449-2"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.trac.2019.115665"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.aca.2012.05.049"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.dib.2018.10.113"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1017\/S0950268810000725"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpbi.86"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1177\/1178646919868978"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.2741\/4363"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.4103\/1673-5374.198971"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-019-0401-9"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-018-1366-3"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.4137\/IJTR.S4282"},{"key":"e_1_2_8_20_1","volume-title":"Statistical Power Analysis for the Behavioral Sciences","author":"Cohen J","year":"1988"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiz048"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-017-1041-0"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0186000"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneuroim.2018.03.007"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jix553"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.4137\/IJTR.S36464"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.4137\/IJTR.S4321"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2015.03.002"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells8020084"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2019.03.015"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneuroim.2019.577088"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.20090"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.12230"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mehy.2018.06.021"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1080\/13550280802093927"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0387-7604(02)00217-6"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.1010550"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2018.00672"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1155\/2018\/3897295"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1017\/S0007114511004648"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-8749.2008.03225.x"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40478-017-0495-8"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tim.2012.03.009"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrneurol.2017.188"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1155\/2015\/708306"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.16275"}],"container-title":["Developmental Medicine &amp; Child Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/dmcn.14774","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/dmcn.14774","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/dmcn.14774","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,18]],"date-time":"2023-08-18T00:25:09Z","timestamp":1692318309000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/dmcn.14774"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,17]]},"references-count":45,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2021,5]]}},"alternative-id":["10.1111\/dmcn.14774"],"URL":"https:\/\/doi.org\/10.1111\/dmcn.14774","archive":["Portico"],"relation":{},"ISSN":["0012-1622","1469-8749"],"issn-type":[{"value":"0012-1622","type":"print"},{"value":"1469-8749","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,17]]},"assertion":[{"value":"2020-11-13","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-12-17","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}