{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T07:33:39Z","timestamp":1793000019342,"version":"4.5.0"},"reference-count":21,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T00:00:00Z","timestamp":1784073600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T00:00:00Z","timestamp":1784073600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["headachejournal.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Headache"],"published-print":{"date-parts":[[2026,10]]},"abstract":"Abstract<\/jats:title>\n \n Objective<\/jats:title>\n This study was conducted to characterize plasma arginine, histidine, 1\u2010methylhistidine, and 3\u2010methylhistidine in chronic migraine and to evaluate their discriminatory ability and association with early clinical response to onabotulinumtoxinA (BoNT\u2010A).<\/jats:p>\n <\/jats:sec>\n \n Background<\/jats:title>\n Alterations in nitric oxide\u2010 and histamine\u2010related metabolic pathways may contribute to chronic migraine biology and may provide circulating biomarkers for disease stratification and treatment monitoring. Targeted liquid chromatography\u2013tandem mass spectrometry profiling enables precise quantification of candidate amino acids and derivatives implicated in these pathways.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n This retrospective secondary analysis was conducted as a case\u2013control study with an embedded uncontrolled pre\u2010post analysis and included 30 adults with chronic migraine receiving BoNT\u2010A and 30 age\u2010 and sex\u2010matched healthy controls from Istanbul Atlas University Hospital, based on clinical and laboratory data collected between May 15, 2023, and December 15, 2024. Plasma arginine, histidine, 1\u2010methylhistidine, and 3\u2010methylhistidine were quantified by liquid chromatography\u2013tandem mass spectrometry. In the chronic migraine group, pain intensity (visual analog scale [VAS]) and monthly migraine attack frequency were assessed at baseline and 1\u2009month after BoNT\u2010A. Between\u2010group comparisons and within\u2010subject pre\u2010post comparisons were performed, and exploratory analyses evaluated relationships between metabolite levels and clinical outcomes.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n At baseline, compared with controls, patients with chronic migraine had higher plasma arginine (57.3\u2009\u00b1\u200913.8 vs. 35.9\u2009\u00b1\u200910.1\u2009\u03bcmol\/L;\n p<\/jats:italic>\n \u2009<\u20090.001) and 3\u2010methylhistidine (1.0\u2009\u00b1\u20090.4 vs. 0.7\u2009\u00b1\u20090.4\u2009\u03bcmol\/L;\n p<\/jats:italic>\n \u2009=\u20090.004), and lower histidine (51.7\u2009\u00b1\u200910.2 vs. 61.5\u2009\u00b1\u20096.8\u2009\u03bcmol\/L;\n p<\/jats:italic>\n \u2009<\u20090.001); 1\u2010methylhistidine did not differ significantly (\n p<\/jats:italic>\n \u2009=\u20090.217). After BoNT\u2010A, median VAS decreased from 8.0 (7.0\u20139.0) to 2.0 (0.0\u20133.0) (\n p<\/jats:italic>\n \u2009<\u20090.001) and median monthly migraine attack frequency decreased from 11.0 (6.0\u201314.8) to 1.0 (0.0\u20131.8) (\n p<\/jats:italic>\n \u2009<\u20090.001). Histidine increased from 54.10\u2009\u03bcmol\/L (45.27\u201359.81) to 60.23\u2009\u03bcmol\/L (57.87\u201364.45);\n p<\/jats:italic>\n \u2009=\u20090.003) whereas 3\u2010methylhistidine decreased from 0.85\u2009\u03bcmol\/L (0.69\u20131.23) to 0.66\u2009\u03bcmol\/L (0.59\u20130.83);\n p<\/jats:italic>\n \u2009<\u20090.001). 1\u2010Methylhistidine did not change significantly, with median values of 5.39\u2009\u03bcmol\/L (3.41\u201314.28) at baseline and 6.84\u2009\u03bcmol\/L (3.36\u201315.33) at month 1 (\n p<\/jats:italic>\n \u2009=\u20090.658). Arginine also did not change significantly with median values of 56.74\u2009\u03bcmol\/L (46.56\u201365.95) at baseline and 52.83\u2009\u03bcmol\/L (44.22\u201366.30) at month 1 (\n p<\/jats:italic>\n \u2009=\u20090.248). Change in histidine was not associated with \u0394VAS, and exploratory regression analyses did not identify a robust independent association between baseline variables and pain reduction. In receiver operating characteristic analyses, histidine (area under the curve [AUC]\u2009=\u20090.79) and 3\u2010methylhistidine (AUC\u2009=\u20090.71) showed moderate discrimination, whereas arginine showed higher apparent discrimination (AUC\u2009=\u20090.91). An exploratory combined biomarker model incorporating arginine, histidine, and 3\u2010methylhistidine showed higher apparent discrimination (AUC\u2009=\u20090.94; leave\u2010one\u2010out cross\u2010validated AUC\u2009=\u20090.92).\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n Chronic migraine is associated with an arginine\u2010histidine metabolic signature characterized by elevated arginine and 3\u2010methylhistidine and reduced histidine. Early response to BoNT\u2010A is accompanied by substantial clinical improvement and selective modulation of histidine\u2010related metabolites. Histidine and 3\u2010methylhistidine may have value as candidate biomarkers within a broader chronic migraine stratification framework, warranting validation in larger prospective cohorts.<\/jats:p>\n \n \n \n image<\/jats:alt-text>\n <\/jats:graphic>\n <\/jats:boxed-text>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1111\/head.70179","type":"journal-article","created":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T10:57:51Z","timestamp":1784113071000},"page":"2041-2053","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeted liquid chromatography\u2013tandem mass spectrometry profiling of arginine and histidine derivatives in chronic migraine: Discriminatory performance and changes after\n onabotulinumtoxinA<\/scp>\n therapy"],"prefix":"10.1111","volume":"66","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8893-2926","authenticated-orcid":false,"given":"Seyma","family":"Dumur","sequence":"first","affiliation":[{"name":"Department of Medical Biochemistry, Faculty of Medicine Istanbul Atlas University Istanbul Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kadidiatou","family":"Diarra","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry, Faculty of Medicine Istanbul Atlas University Istanbul Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joudy","family":"Sewidan","sequence":"additional","affiliation":[{"name":"Lincoln College University of Oxford Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie Jalila","family":"Kalmoni","sequence":"additional","affiliation":[{"name":"Department of Chemistry Imperial College London London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Demet","family":"Aygun","sequence":"additional","affiliation":[{"name":"Department of Neurology, Faculty of Medicine Istanbul Atlas University Istanbul Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dildar","family":"Konukoglu","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry, Cerrahpasa Faculty of Medicine Istanbul University\u2010Cerrahpasa Istanbul Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hafize","family":"Uzun","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry, Faculty of Medicine Istanbul Atlas University Istanbul 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