biostudies-literatureUnknown32(9)Soborg MKH. Lundbeck A/SRigshospitaletRegion Hovedstaden<h4>Background</h4>Estimates of pituitary adenylate cyclase-activating peptide-38's (PACAP-38) activity in cluster headache are sparse. We investigated whether plasma levels of PACAP-38 differ between disease states (i.e., bout, remission, chronic) and compared to headache-free controls. Secondly, we assessed a possible correlation between plasma levels of PACAP-38 and Calcitonin gene-related peptide (CGRP).<h4>Methods</h4>In an observational case-control setup, prospectively collected interictal plasma samples from participants in the Danish Cluster Headache Biobank were analyzed for plasma levels of PACAP-38 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.<h4>Results</h4>Plasma was derived from 205 patients with cluster headache according to ICHD-3 criteria and 101 sex- and age-matched headache-free controls. PACAP-38 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%-49%, p < 0.0001) higher mean PACAP-38 level. Chronic cluster headache showed the greatest difference by 49.8% (95% CI: 26.7-77.2, p < 0.0001) higher PACAP-38 levels, while episodic cluster headache in bout and remission showed respectively 39.5% (95% CI: 18.8-63.8, p < 0.0001) and 34.1% (95% CI: 14.2-57.5, p = 0.0005) higher plasma levels. No correlation between plasma levels of PACAP-38 and CGRP was demonstrated (Spearmans r = 0.08, p = 0.10).<h4>Conclusions</h4>This large-scale study demonstrated increased PACAP-38 levels in all disease states of cluster headache compared to headache-free controls, strengthening the hope of a possible effect of PACAP-38 targeting treatments in future trials. The lacking correlation between PACAP-38 and CGRP levels should be interpreted with caution and needs to be investigated in future studies.European journal of neurologye70341https://www.ebi.ac.uk/biostudies/studies/S-EPMC12465007biostudies-literaturePACAP-38 in Cluster Headache: A Prospective, Case-Control Study of a Potential Treatment Target.PMC12465007Soborg MKSnoer AJensen RHLund NBarloese MPetersen ASfalsePACAP-38 in Cluster Headache: A Prospective, Case-Control Study of a Potential Treatment Target.<h4>Background</h4>Estimates of pituitary adenylate cyclase-activating peptide-38's (PACAP-38) activity in cluster headache are sparse. We investigated whether plasma levels of PACAP-38 differ between disease states (i.e., bout, remission, chronic) and compared to headache-free controls. Secondly, we assessed a possible correlation between plasma levels of PACAP-38 and Calcitonin gene-related peptide (CGRP).<h4>Methods</h4>In an observational case-control setup, prospectively collected interictal plasma samples from participants in the Danish Cluster Headache Biobank were analyzed for plasma levels of PACAP-38 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.<h4>Results</h4>Plasma was derived from 205 patients with cluster headache according to ICHD-3 criteria and 101 sex- and age-matched headache-free controls. PACAP-38 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%-49%, p < 0.0001) higher mean PACAP-38 level. Chronic cluster headache showed the greatest difference by 49.8% (95% CI: 26.7-77.2, p < 0.0001) higher PACAP-38 levels, while episodic cluster headache in bout and remission showed respectively 39.5% (95% CI: 18.8-63.8, p < 0.0001) and 34.1% (95% CI: 14.2-57.5, p = 0.0005) higher plasma levels. No correlation between plasma levels of PACAP-38 and CGRP was demonstrated (Spearmans r = 0.08, p = 0.10).<h4>Conclusions</h4>This large-scale study demonstrated increased PACAP-38 levels in all disease states of cluster headache compared to headache-free controls, strengthening the hope of a possible effect of PACAP-38 targeting treatments in future trials. The lacking correlation between PACAP-38 and CGRP levels should be interpreted with caution and needs to be investigated in future studies.2025-01-01T00:00:00Z2025 Sep2026-06-03T21:21:31.04Z2026-05-01T03:10:52.779ZS-EPMC124650074100210410.1111/ene.70341