Migraine 18 Jul, 2024 Read Time: 5 mins

Salivary calcitonin gene-related peptide as a potential biomarker for migraine

Levels of calcitonin gene-related peptide (CGRP) are higher in patients with migraine in the interictal period and change over the course of a migraine. As CGRP can be measured in saliva, it may be a useful biomarker for migraine and for predicting response to anti-CGRP monoclonal antibody (mAb) treatment. At IHC 2023, Cephalalgia Award recipient Professor Patricia Pozo-Rosich, Head of Section of the Neurology Department, at the Vall d’Hebron University Hospital in Barcelona, Spain, discussed the research her team carried out investigating salivary levels of CGRP in people with episodic or chronic migraine. Although similar work has been carried out before, this was one of the few studies to measure such levels longitudinally (over 30 days) and 3 months before and after the administration of an anti-CGRP mAb. These studies confirmed that basal salivary CGRP levels are higher in people with migraine and showed that levels correlate with migraine frequency. Results also showed that, while levels typically vary across the migraine cycle, around 20% of migraine attacks were ‘non-CGRP dependent.’ Having a better response to an anti-CGRP mAb treatment was associated with higher basal CGRP levels. For people with depressive symptoms, CGRP levels increased more and differentiated episodic and chronic migraine patients. Salivary CGRP was shown to be a feasible and reproducible means to measure levels of this neuropeptide in people with migraine.

Calcitonin gene-related peptide (CGRP) and migraine

CGRP, a potent vasodilator, is a neuropeptide found widely in the central and peripheral nervous systems.1 CGRP levels can differ over the course of a migraine attack2,3 but are often increased even in the interictal period.4,5 CGRP levels may be predictive of treatment response: for example, higher basal CGRP levels correspond with better response to botulinum toxin treatment.6

Basal CGRP levels may be predictive of response to preventive migraine treatment6,8

Professor Pozo-Rosich discussed her team’s work at the Headache Unit, Vall d’Hebron University Hospital in Barcelona, Spain, as detailed in two recent papers first authored by Dr Alicia Alpuente (named Study 1 and Study 2 here).7,8 The studies included preventive treatment naïve females aged 18−35 with episodic migraine (EM; n=22 Study 1, n=27 Study 2)7,8 or chronic migraine (CM; n=16 Study 2),8 compared to healthy controls (HCs; n=22 Study 1, n=27 Study 2). Demographics were similar between the groups.7,8 

Saliva was chosen as the means to analyse CGRP levels due to proximity of salivary glands to the trigeminal nerve and studies showing measurable levels of CGRP in this fluid.3,9,10 

The primary objective of Study 1 was to, over 30 days, monitor the temporal profile of salivary CGRP during ictal and interictal migraine phases by collecting samples daily, and during and after the headache period.7 Secondary objectives were to assess salivary CGRP as a migraine diagnostic biomarker7,8 and a biofluid to measure CGRP;7 to analyse changes in salivary CGRP levels before and after anti-CGRP monoclonal antibody (mAb) treatment; and to evaluate basal salivary CGRP levels as a predictor of anti-CGRP mAb response.8

Study 1 results

In the migraine group, Professor Pozo-Rosich reported that interictal mean CGRP salivary levels were significantly higher compared to HCs. Using pairwise comparisons, CGRP levels were shown to rise significantly from baseline to headache onset (p≤0.001), decrease significantly 2 hours after headache onset (p≤0.01), and return to interictal levels 8 hours after headache onset. Of note though, absolute mean levels of CGRP overlapped between the different time periods.7 However, Professor Pozo-Rosich highlighted that, in around 20% of migraine attacks, there was no significant increase in CGRP. Incidences of photophobia (p=0.024), phonophobia (p=0.036), and dizziness (p=0.047) were significantly lower in the non-CGRP-dependent attacks.7

Migraine symptoms may be CGRP-dependent or -independent

Use of either a non-steroidal anti-inflammatory drug or a triptan mostly led to similar CGRP patterns; however, at the 8-hour timepoint, CGRP levels increased, to levels that were similar to those observed at headache onset.7

Study 2 results

Overall, both migraine groups had mean basal CGRP levels that were significantly higher than HCs (p<0.05). Results showed that 72.1% of migraine patients but only 7.4% of HCs had a baseline salivary CGRP level above 104 pg/mL. According to Professor Pozo-Rosich, this cut-off could be used when measuring salivary CGRP as a potential biomarker for migraine. Following anti-CGRP mAb administration, 41.7% of patients were stratified as treatment responders [≥50% reduction in monthly headache days (RR)] and 58.3% as non-responders (<50% RR). For people with EM, but not CM, treatment response was predicted by baseline salivary CGRP levels and the interaction of this variable and baseline headache frequency.8

Salivary CGRP levels differ in people with migraine and concomitant depressive symptoms 

Patients with depressive symptoms were included in Study 2 as it has been shown that the occurrence of these symptoms increases when migraine frequency increases.11 Additionally, CGRP levels are altered in animal models of depression.12 Analysis of high-frequency EM and CM participants showed that higher mean basal CGRP salivary levels were associated with occurrence of depressive symptoms (p=0.030), as well as age (p<0.001), greater headache frequency (p=0.002), and both headache frequency and depressive symptoms (p=0.007).8 For patients with depressive symptoms, the CM group had significantly higher CGRP levels than the EM and HC group.8 Findings of differences in CGRP levels following treatment in the depressive symptoms group8 led Professor Pozo-Rosich to propose that “if you have depressive symptoms, you may need more months of treatment to converge CGRP levels.”

Conclusions

While changes in CGRP levels over the course of a migraine have been shown before,2,3 Professor Pozo-Rosich highlighted that these studies also show these changes longitudinally.7,8 “Maybe,” she postulated “CGRP salivary levels can help us to perform personalized medicine in migraine.” According to Professor Pozo-Rosich, the collection and analysis methods used for these studies proved to be overall “an easy and non-invasive way of monitoring CGRP.”7,8

Our correspondent’s highlights from the symposium are meant as a fair representation of the scientific content presented. The views and opinions expressed on this page do not necessarily reflect those of Lundbeck.

References

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