Background CGRP plays a key role in the transmission and modulation of nociceptive signals and is a critical component in the pathogenesis of migraine. Objective To assess saliva as a substrate to measure CGRP by comparing interictal levels in patients with episodic migraine and controls; and to evaluate CGRP’s temporal profile during migraine attacks. Methods This prospective observational pilot study included young women with episodic migraine and healthy controls. We monitored salivary CGRP-like immunoreactivity (CGRP-LI) during 30 consecutive days and during migraine attacks. We considered six timepoints for the analysis: interictal (72h headache free), preictal (PRE-24h before the attack), ictal (headache onset, after 2h, after 8h), postictal (POST-24h after the attack). CGRP levels were quantified by ELISA. Results 44 women (22 with episodic migraine, 22 healthy controls) were recruited. Differences in interictal salivary levels of CGRP between patients and controls (Me [IQR]: 98.0 [80.3] (95% CI 56.6, 124.0) vs. 54.3 [44.0] (95% CI 42.2, 70.1) pg/mL, p = 0.034) were found. An increase in CGRP levels during migraine attacks was detected (pre:169.0 [95% CI 104.2–234.0]; headache onset: 247.0 [181.9–312.0]; after 2h: 143.0 [77.6–208.0]; after 8h: 169.0 [103.5–234.0], post: 173.0 [107.8–238.0]). Patients were classified as having CGRP-dependent (79.6%) and non-CGRP dependent migraine attacks (20.4%) according to the magnitude of change between preictal and ictal phase. Accompanying symptoms such as photophobia and phonophobia were significantly associated to the first group. Conclusions Salivary CGRP-LI levels, which interictally are elevated in episodic migraine patients, usually increase during a migraine attack in the majority of patients. However, not every attack is CGRP-dependent, which in turn, might explain different underlying pathophysiology and response to treatment.
Objective We aimed (1) to analyze salivary calcitonin gene‐related peptide (CGRP) levels in patients with migraine, (2) to predict erenumab response from baseline CGRP levels, and (3) to evaluate CGRP change post‐treatment. Methods This is a prospective observational study that measured salivary CGRP levels in healthy controls (HCs), patients with episodic migraine (EM) and patients with chronic migraine (CM). Participants collected saliva samples at baseline and, the patients who were candidates to receive erenumab, also collected saliva after 3 doses of treatment. We quantified CGRP‐like immunoreactivity (CGRP‐LI) by enzyme‐linked immunosorbent assay (ELISA) and we performed an analysis at baseline and post‐treatment through generalized linear mixed models. Results At baseline, a higher headache frequency was associated with higher CGRP levels, those being even higher in the presence of depressive symptoms. A cutoff point (mean, 95% confidence interval [CI]) of 103.93 (95% CI = 103.35–104.51) pg/ml was estimated to differentiate migraine from controls with an area under the receiver operating characteristic (ROC) curve (AUC, 95% CI) of 0.801 (95% CI = 0.798–0.804). We also found that higher pretreatment salivary CGRP levels were statistically significantly associated to a higher probability of having 50% or greater reduction in headache frequency in patients with EM, but not in patients with CM. After 12 weeks of treatment with erenumab, salivary CGRP levels from patients within all spectrum of migraine frequency converged to similar CGRP values. In contrast, in patients with concomitant depressive symptoms, this convergence did not happen. Interpretation Patients with migraine not only have higher CGRP levels compared with HCs, but also the presence of depressive symptoms seems to increase salivary CGRP levels and we have evidence, for the first time, that baseline salivary CGRP concentration is associated with treatment response to erenumab. ANN NEUROL 2022;92:846–859
Background Several studies have described potential microRNA (miRNA) biomarkers associated with migraine, but studies are scarcely reproducible primarily due to the heterogeneous variability of participants. Increasing evidence shows that disease-related intrinsic factors together with lifestyle (environmental factors), influence epigenetic mechanisms and in turn, diseases. Hence, the main objective of this exploratory study was to find differentially expressed miRNAs (DE miRNA) in peripheral blood mononuclear cells (PBMC) of patients with migraine compared to healthy controls in a well-controlled homogeneous cohort of non-menopausal women. Methods Patients diagnosed with migraine according to the International Classification of Headache Disorders (ICHD-3) and healthy controls without familial history of headache disorders were recruited. All participants completed a very thorough questionnaire and structured-interview in order to control for environmental factors. RNA was extracted from PBMC and a microarray system (GeneChip miRNA 4.1 Array chip, Affymetrix) was used to determine the miRNA profiles between study groups. Principal components analysis and hierarchical clustering analysis were performed to study samples distribution and random forest (RF) algorithms were computed for the classification task. To evaluate the stability of the results and the prediction error rate, a bootstrap (.632 + rule) was run through all the procedure. Finally, a functional enrichment analysis of selected targets was computed through protein–protein interaction networks. Results After RF classification, three DE miRNA distinguished study groups in a very homogeneous female cohort, controlled by factors such as demographics (age and BMI), life-habits (physical activity, caffeine and alcohol consumptions), comorbidities and clinical features associated to the disease: miR-342-3p, miR-532-3p and miR-758-5p. Sixty-eight target genes were predicted which were linked mainly to enriched ion channels and signaling pathways, neurotransmitter and hormone homeostasis, infectious diseases and circadian entrainment. Conclusions A 3-miRNA (miR-342-3p, miR-532-3p and miR-758-5p) novel signature has been found differentially expressed between controls and patients with migraine. Enrichment analysis showed that these pathways are closely associated with known migraine pathophysiology, which could lead to the first reliable epigenetic biomarker set. Further studies should be performed to validate these findings in a larger and more heterogeneous sample.
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