TY - JOUR

T1 - Investigating macrophage-mediated inflammation in migraine using ultrasmall superparamagnetic iron oxide-enhanced 3T magnetic resonance imaging

AU - Khan, Sabrina

AU - Amin, Faisal Mohammad

AU - Fliedner, Frederikke Petrine

AU - Christensen, Casper Emil

AU - Tolnai, Daniel

AU - Younis, Samaira

AU - Olinger, Anne Christine Rye

AU - Birgens, Henrik

AU - Daldrup-Link, Heike

AU - Kjær, Andreas

AU - Larsson, Henrik Bo Wiberg

AU - Lindberg, Ulrich

AU - Ashina, Messoud

PY - 2019

Y1 - 2019

N2 - Background: Initiating mechanisms of migraine headache remain poorly understood and a biomarker of migraine does not exist. Inflammation pertaining to the wall of cerebral arteries and brain parenchyma has been suggested to play a role in migraine pathophysiology. Objective: We conducted the first experimental human study to investigate macrophage-mediated inflammation as a possible biomarker of migraine. Methods: Using ultrasmall superparamagnetic iron oxide (USPIO)-enhanced 3T magnetic resonance imaging (MRI), we investigated the presence of macrophages in cerebral artery walls and in brain parenchyma of patients with migraine without aura. We used the phosphodiesterase-3-inhibitor cilostazol as an experimental migraine trigger, and investigated both patients who received sumatriptan treatment, and patients who did not. To validate our use of USPIO-enhanced MRI, we included a preclinical mouse model with subcutaneous capsaicin injection in the trigeminal V1 area. The study is registered at ClinicalTrials.gov with the identifier NCT02549898. Results: A total of 28 female patients with migraine without aura underwent a baseline MRI scan, ingested cilostazol, developed a migraine-like attack, and underwent an USPIO-enhanced MRI scan > 24 hours after intravenous administration of USPIO. Twelve patients treated their attack with 6 mg s.c. sumatriptan, while the remaining 16 patients received no migraine-specific rescue medication. The preclinical model confirmed that USPIO-enhanced MRI detects macrophage-mediated inflammation. In patients, however, migraine attacks were not associated with increased USPIO signal on the pain side of the head compared to the non-pain side. Conclusion: Our findings suggest that migraine without aura is not associated with macrophage-mediated inflammation specific to the head pain side.

AB - Background: Initiating mechanisms of migraine headache remain poorly understood and a biomarker of migraine does not exist. Inflammation pertaining to the wall of cerebral arteries and brain parenchyma has been suggested to play a role in migraine pathophysiology. Objective: We conducted the first experimental human study to investigate macrophage-mediated inflammation as a possible biomarker of migraine. Methods: Using ultrasmall superparamagnetic iron oxide (USPIO)-enhanced 3T magnetic resonance imaging (MRI), we investigated the presence of macrophages in cerebral artery walls and in brain parenchyma of patients with migraine without aura. We used the phosphodiesterase-3-inhibitor cilostazol as an experimental migraine trigger, and investigated both patients who received sumatriptan treatment, and patients who did not. To validate our use of USPIO-enhanced MRI, we included a preclinical mouse model with subcutaneous capsaicin injection in the trigeminal V1 area. The study is registered at ClinicalTrials.gov with the identifier NCT02549898. Results: A total of 28 female patients with migraine without aura underwent a baseline MRI scan, ingested cilostazol, developed a migraine-like attack, and underwent an USPIO-enhanced MRI scan > 24 hours after intravenous administration of USPIO. Twelve patients treated their attack with 6 mg s.c. sumatriptan, while the remaining 16 patients received no migraine-specific rescue medication. The preclinical model confirmed that USPIO-enhanced MRI detects macrophage-mediated inflammation. In patients, however, migraine attacks were not associated with increased USPIO signal on the pain side of the head compared to the non-pain side. Conclusion: Our findings suggest that migraine without aura is not associated with macrophage-mediated inflammation specific to the head pain side.

KW - dura mater

KW - ferumoxytol

KW - Headache

KW - inflammation

KW - meningeal nociceptor

KW - USPIO

U2 - 10.1177/0333102419848122

DO - 10.1177/0333102419848122

M3 - Journal article

C2 - 31104505

AN - SCOPUS:85066874225

VL - 39

SP - 1407

EP - 1420

JO - Cephalalgia

JF - Cephalalgia

SN - 0800-1952

IS - 11

ER -