Migraine molecular phenotyping through the study of the calcitonin gene-related peptide: towards precision medicine

Abstract

It is established that the calcitonin gene-related peptide (CGRP) plays an essential role in the pathophysiology of migraine and that its blockade represents a breakthrough in the preventive treatment of migraine with successful clinical results. This thesis emcompasses two related articles. In the first study, the most appropriate methodology is developed to quantify the CGRP in saliva of young women with low-frequency episodic migraine, and a longitudinal analysis is carried out through the different phases of the migraine attack. In the second study, and applying the same methodology, the number of participants is increased with greater variety in terms of sex (men are included), migraine frequency (patients with high-frequency episodic migraine (HFEM) and chronic migraine (CM) are included) as well as the presence of comorbidities (depressive symptoms). In addition, the relationship between molecular levels of CGRP and treatment with an anti-CGRP monoclonal antibody (erenumab 140 mg) is established. In the first study, it is found that the quantification of CGRP in saliva is more reliable than in plasma, that participants with migraine have higher levels of CGRP than controls between attacks and that this levels fluctuate throughout the migraine attack, differentiating attacks in which these levels are clearly increased and attacks in which the opposite occurs. This makes it possible to differentiate between two clear patient profiles. Those who have migraine attacks in which CGRP is elevated also have clinical symptoms of photophobia and phonophobia. In the second study, it is found that quantifying CGRP in saliva is reproducible, that the presence of depressive symptoms increases CGRP levels, that basal levels are capable of differentiating HFEM and CM from healthy controls, as well as predicting the response to treatment with erenumab in some patients (HFEM, not CM). Finally, it is also shown that treatment with anti-CGRP is capable of modulating the levels of this molecule in such a way that they converge after 3 months of treatment. Therefore, this doctoral thesis supports the quantification of CGRP in saliva as a potential diagnostic biomarker in migraine, predictive and therapeutic response to treatment with anti-CGRP monoclonal antibodies, which represents a step forward in the development of precision medicine in this illness. This doctoral thesis has a translational application. Quantification of CGRP in saliva is a non-invasive method and can be performed in the outpatient consultation. Currently the diagnosis of migraine is clinical, specific treatments are indicated based on financing conditions and not based on the characteristics of the patient.

Date of Award	19 Jan 2023
Original language	English
Supervisor	Patricia Pozo Rosich (Director) & Jose Alvarez Sabin (Director)