{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T14:16:00Z","timestamp":1782742560104,"version":"3.54.5"},"reference-count":35,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T00:00:00Z","timestamp":1758844800000},"content-version":"vor","delay-in-days":25,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100013327","name":"H. Lundbeck A\/S","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100013327","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005275","name":"Region Hovedstaden","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005275","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005111","name":"Rigshospitalet","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005111","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Euro J of Neurology"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Estimates of pituitary adenylate cyclase\u2010activating peptide\u201038's (PACAP\u201038) activity in cluster headache are sparse. We investigated whether plasma levels of PACAP\u201038 differ between disease states (i.e., bout, remission, chronic) and compared to headache\u2010free controls. Secondly, we assessed a possible correlation between plasma levels of PACAP\u201038 and Calcitonin gene\u2010related peptide (CGRP).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In an observational case\u2013control setup, prospectively collected interictal plasma samples from participants in the Danish Cluster Headache Biobank were analyzed for plasma levels of PACAP\u201038 and CGRP. All participants had blood samples drawn; once if chronic cluster headache or controls, and twice if episodic cluster headache (in bout and in remission phase). Plasma levels were measured with validated immunoassays.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Plasma was derived from 205 patients with cluster headache according to ICHD\u20103 criteria and 101 sex\u2010 and age\u2010matched headache\u2010free controls. PACAP\u201038 plasma levels were significantly higher in all three disease states of cluster headache: compared to controls, they collectively had a 34.3% (95% CI: 20%\u201349%, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001) higher mean PACAP\u201038 level. Chronic cluster headache showed the greatest difference by 49.8% (95% CI: 26.7\u201377.2, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001) higher PACAP\u201038 levels, while episodic cluster headache in bout and remission showed respectively 39.5% (95% CI: 18.8\u201363.8, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001) and 34.1% (95% CI: 14.2\u201357.5, <jats:italic>p<\/jats:italic>\u2009=\u20090.0005) higher plasma levels. No correlation between plasma levels of PACAP\u201038 and CGRP was demonstrated (Spearmans <jats:italic>r<\/jats:italic>\u2009=\u20090.08, <jats:italic>p<\/jats:italic>\u2009=\u20090.10).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This large\u2010scale study demonstrated increased PACAP\u201038 levels in all disease states of cluster headache compared to headache\u2010free controls, strengthening the hope of a possible effect of PACAP\u201038 targeting treatments in future trials. The lacking correlation between PACAP\u201038 and CGRP levels should be interpreted with caution and needs to be investigated in future studies.<\/jats:p><\/jats:sec>","DOI":"10.1111\/ene.70341","type":"journal-article","created":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T12:24:56Z","timestamp":1758889496000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["<scp>PACAP<\/scp>\u201038 in Cluster Headache: A Prospective, Case\u2013Control Study of a Potential Treatment Target"],"prefix":"10.1111","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6015-6814","authenticated-orcid":false,"given":"Marie\u2010Louise K.","family":"S\u00f8borg","sequence":"first","affiliation":[{"name":"Danish Headache Center, Department of Neurology University of Copenhagen, Rigshospitalet\u2010Glostrup  Glostrup Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nunu","family":"Lund","sequence":"additional","affiliation":[{"name":"Danish Headache Center, Department of Neurology University of Copenhagen, Rigshospitalet\u2010Glostrup  Glostrup Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agneta","family":"Snoer","sequence":"additional","affiliation":[{"name":"Danish Headache Center, Department of Neurology University of Copenhagen, Rigshospitalet\u2010Glostrup  Glostrup Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mads","family":"Barloese","sequence":"additional","affiliation":[{"name":"Danish Headache Center, Department of Neurology University of Copenhagen, Rigshospitalet\u2010Glostrup  Glostrup Denmark"},{"name":"Centre for Functional and Diagnostic Imaging and Research Hvidovre Hospital  Hvidovre Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rigmor H\u00f8jland","family":"Jensen","sequence":"additional","affiliation":[{"name":"Danish Headache Center, Department of Neurology University of Copenhagen, Rigshospitalet\u2010Glostrup  Glostrup Denmark"},{"name":"Department of Clinical Medicine, Faculty of Health and Medical Sciences University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0125-6038","authenticated-orcid":false,"given":"Anja Sofie","family":"Petersen","sequence":"additional","affiliation":[{"name":"Danish Headache Center, Department of Neurology University of Copenhagen, Rigshospitalet\u2010Glostrup  Glostrup 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