Longitudinal differences in iron deposition in periaqueductal gray matter and anterior cingulate cortex are associated with response to erenumab in migraine

Abstract

Objectives The objective of this longitudinal study was to determine whether brain iron accumulation, measured using magnetic resonance imaging magnetic transverse relaxation rates (T2*), is associated with response to erenumab for the treatment of migraine. Methods Participants (n = 28) with migraine, diagnosed using international classification of headache disorders 3rd edition criteria, were eligible if they had six to 25 migraine days during a four-week headache diary run-in phase. Participants received two treatments with 140 mg erenumab, one immediately following the pre-treatment run-in phase and a second treatment four weeks later. T2* data were collected immediately following the pre-treatment phase, and at two weeks and eight weeks following the first erenumab treatment. Patients were classified as erenumab responders if their migraine-day frequency at five-to-eight weeks post-initial treatment was reduced by at least 50% compared to the pre-treatment run-in phase. A longitudinal Sandwich estimator approach was used to compare longitudinal group differences (responders vs non-responders) in T2* values, associated with iron accumulation. Group visit effects were calculated with a significance threshold of p = 0.005 and cluster forming threshold of 250 voxels. T2* values of 19 healthy controls were used for a reference. The average of each significant region was compared between groups and visits with Bonferroni corrections for multiple comparisons with significance defined as p < 0.05. Results Pre- and post-treatment longitudinal imaging data were available from 28 participants with migraine for a total of 79 quantitative T2* images. Average subject age was 42 ± 13 years (25 female, three male). Of the 28 subjects studied, 53.6% were erenumab responders. Comparing longitudinal T2* between erenumab responders vs non-responders yielded two comparisons which survived the significance threshold of p < 0.05 after correction for multiple comparisons: the difference at eight weeks between the erenumab-responders and non-responders in the periaqueductal gray (mean ± standard error; responders 43 ± 1 ms vs non-responders 32.5 ± 1 ms, p = 0.002) and the anterior cingulate cortex (mean ± standard error; responders 50 ± 1 ms vs non-responders 40 ± 1 ms, p = 0.01). Conclusions Erenumab response is associated with higher T2* in the periaqueductal gray and anterior cingulate cortex, regions that participate in pain processing and modulation. T2* differences between erenumab responders vs non-responders, a measure of brain iron accumulation, are seen at eight weeks post-treatment. Less iron accumulation in the periaqueductal gray and anterior cingulate cortex might play a role in the therapeutic mechanisms of migraine reduction associated with erenumab.

The Registry for Migraine (REFORM) study: methodology, demographics, and baseline clinical characteristics

“…In a third study of 32 participants receiving erenumab, responders exhibited differences in resting-state functional connectivity and central processing of thermal painful stimuli after eight weeks of treatment [ 12 ]. This study also found that after eight weeks of treatment, responders showed significantly less iron deposition in key areas for pain processing, including the periaqueductal gray (PAG) and anterior cingulate cortex [ 13 ]. However, limitations included lack of healthy controls, use of abortive migraine medications, and limited sample size [ 12 , 13 ].…”

“…This study also found that after eight weeks of treatment, responders showed significantly less iron deposition in key areas for pain processing, including the periaqueductal gray (PAG) and anterior cingulate cortex [ 13 ]. However, limitations included lack of healthy controls, use of abortive migraine medications, and limited sample size [ 12 , 13 ]. We sought to address these limitations in the REFORM study.…”

“…Predictive biomarkers represent a promising approach, in which a candidate biomarker is measured in a patient before treatment, and can, if proven valid, be used to predict the response to a particular drug [ 7 , 8 ]. In recent years, studies have investigated candidate biomarkers for prediction of erenumab efficacy in patients with migraine, using CGRP measurements in blood or saliva [ 9 – 11 ] and magnetic resonance imaging (MRI) [ 12 , 13 ]. These studies have provided some insights but were limited by methodological issues and small samples [ 9 – 13 ].…”

“…In recent years, studies have investigated candidate biomarkers for prediction of erenumab efficacy in patients with migraine, using CGRP measurements in blood or saliva [ 9 – 11 ] and magnetic resonance imaging (MRI) [ 12 , 13 ]. These studies have provided some insights but were limited by methodological issues and small samples [ 9 – 13 ].…”

Brain structural and functional abnormalities associated with acute post-traumatic headache: iron deposition and functional connectivity

“…Recent studies suggest that iron deposits play a role in migraine chronification [ 15 , 16 ]. T 2 * changes have been observed in longitudinal studies of migraine treatment, suggesting that effective migraine treatment impacts brain iron accumulation [ 21 ]. There are fewer investigations into iron concentrations among participants with PTH.…”