Large Registry Study Questions Utility of Plasma CGRP as Diagnostic Biomarker for Migraine

A large cross-sectional registry study revealed that patients with migraine did not have higher plasma concentrations of calcitonin gene-related peptide (CGRP) compared to healthy individuals, adding to growing evidence that circulating CGRP may have limited value as a diagnostic biomarker for migraine despite its established role in migraine pathophysiology.¹

Published in Neurology, the analysis included more than 1,700 participants from the Danish Registry for Migraine (REFORM) and found no significant differences in plasma CGRP levels between participants with episodic migraine, chronic migraine, or healthy controls after adjustment for demographic and clinical factors. Study authors concluded that plasma CGRP concentrations should not currently be considered a reliable biomarker for migraine diagnosis.¹

Senior author Håkan Ashina, MD, PhD, headache specialist at the Copenhagen University Hospital–Rigshospitalet, and investigators analyzed plasma CGRP concentrations from 1,544 individuals with migraine and 203 healthy controls enrolled in the REFORM registry. The migraine cohort included 1,285 patients with episodic migraine and 259 with chronic migraine. Blood samples were collected during headache-free periods using standardized collection and processing protocols to minimize preanalytical variability.¹

The primary objective was to determine whether plasma CGRP concentrations differed between migraine and control populations. Secondary analyses evaluated associations between CGRP levels and migraine subtype, monthly headache frequency, monthly migraine days, allodynia, aura status, preventive CGRP-targeted therapy, sex, hormonal status, and other clinical characteristics.¹

After multivariable adjustment, investigators found no statistically significant differences in plasma CGRP concentrations between participants with episodic migraine, chronic migraine, and healthy controls. Likewise, CGRP levels were not associated with monthly migraine frequency, headache burden, or cutaneous allodynia. Patients receiving CGRP-targeted preventive therapies also demonstrated plasma concentrations comparable to those not receiving these agents.¹

Subgroup analyses similarly failed toidentify clinically meaningful differences according to migraine with aura versus migraine without aura or between episodic and chronic migraine. Although women generally exhibited higher circulating CGRP concentrations than men, these differences appeared related to physiologic hormonal influences rather than migraine status itself. Investigators also observed expected variations according to pregnancy and hormonal factors previously described in the literature.¹

The findings contrast with the well-established biologic role of CGRP in migraine. Activation of the trigeminovascular system results in CGRP release, and infusion of CGRP can trigger migraine attacks in susceptible individuals. These mechanistic observations have led to the successful development of CGRP-targeted monoclonal antibodies and small-molecule antagonists, several of which are now widely used for migraine prevention and acute treatment.⁴

The investigators suggested several explanations for the negative findings. Plasma obtained from peripheral venous blood may not adequately reflect localized CGRP release within the trigeminovascular system during migraine attacks. In addition, CGRP has a short plasma half-life and is influenced by numerous physiologic factors unrelated to migraine, potentially limiting its diagnostic specificity.¹

Because samples were collected during headache-free intervals, the study also cannot exclude transient changes in CGRP concentrations occurring during acute migraine attacks. Furthermore, although the study represents one of the largest biomarker investigations conducted in migraine to date, its cross-sectional design precludes assessment of dynamic changes in CGRP over time.

Taken together, the findings suggest that while CGRP remains a validated therapeutic target in migraine, measurement of peripheral plasma CGRP alone is unlikely to serve as a clinically useful diagnostic biomarker. Future research may instead focus on more disease-specific biomarkers, composite biomarker panels, or alternative approaches that better capture trigeminovascular activation.

REFERENCES
1. Karlsson W, Christensen R, Al-Khazali H, et al. Plasma CGRP Levels in Migraine A Registry for Migraine Study. Neurol. 2026;107(1): e218152
2. Edvinsson L, Haanes KA, Warfvinge K, Krause DN. CGRP as the target of new migraine therapies - successful translation from bench to clinic. Nat Rev Neurol. 2018;14(6):338-350. doi:10.1038/s41582-018-0003-1