Paradoxical association between age and cerebrovascular reactivity in migraine: A cross-sectional study

Background: Previous studies reported an increased risk of ischemic stroke in younger migraineurs. We aimed to investigate the association between age and cerebrovascular reactivity (CVR) to vasodilatory stimuli in cerebral arteries in patients with migraine and normal controls. Methods: In this cross-sectional study, we recruited 248 patients with migraine and 105 normal controls at Samsung Medical Center between October 2015 and July 2018. CVR was measured interictally by using the transcranial Doppler breath -holding test. For the arteries which showed a correlation between age and CVR, we conducted univariable and multivariable linear regression analysis to assess the independent effect of age on CVR. The path analysis was performed to assess mediating effects of the age of onset and disease duration on the age-CVR association. Results: Patients had reduced CVR in all tested arteries compared to normal controls. A correlation between age and CVR was present in the posterior cerebral artery (PCA) only in patients (Pearson's correlation coefficient = 0.160, p = 0.012). In patients, younger age was independently associated with lower CVR in the PCA (multivariable B = 0.003, 95% CI = 0.0002-0.005, p = 0.033 adjusted for sex, migraine subtype, and headache frequencies). The path analysis showed that the age of onset fully mediated the effect of age on PCA CVR, while longer disease duration negatively modified the effect of age of onset (p for interaction = 0.018). Conclusions: In migraineurs, younger age was associated with CVR reduction in the PCA. Younger age of onset may be a hidden risk factor mediating the paradoxical association between age and CVR. This association might explain an increased risk of stroke in younger migraineurs.