To identify a plasma-based metabolite signature useful for discriminating individuals with active migraine from individuals never reporting headache and also individuals reporting non-migraine headache.

Migraine is a leading cause of disability worldwide, particularly among women, affecting ~15% of the population. Individuals with migraine may have different plasma biomarker profiles even when measured interictally (i.e. between attacks).  A metabolite signature for migraine may reveal pathophysiology of migraine and enable objective measures for diagnosis. 

We measured a comprehensive panel of plasma metabolites among ~1500 pre-menopausal women aged 45-54, matched and divided equally among those with migraine, those with non-migraine headache, and those who do not experience headache.  Plasma for the women with migraine was almost certainly interictal.  We assessed whether migraine-associated plasma metabolites met formal statistical criteria for distinguishing individuals with and without a diagnosis of migraine.

A total of 10 endogenous (non-xenobiotic) and 9 xenobiotic metabolites met significance standards for association with migraine compared to controls consistent with a multiple testing threshold accounting for correlation across the metabolites. There were no significant associations for non-migraine headache.  The endogenous metabolites implicate biology related to androgenic steroids, fatty acid and amino acid metabolism emphasizing carnitine transactions, and tocopherol ratio, and overlap with known biological correlates of migraine.  The xenobiotics suggest non-prescription analgesic use, specifically acetaminophen or ibuprofen.  Among women, a classifier for migraine compared to no headache combining the metabolites and clinical characteristics attains a cross-validated AUC of 0.68 versus 0.53 for clinical characteristics alone.  The AUC is estimated as high as 0.76 in a hypothetical population of both women and men including the metabolites, clinical characteristics, and a polygenic risk score for migraine. 

The metabolite profile facilitates/advances quantitative discrimination of migraine and highlights biological functions that may be relevant to its pathophysiology and to novel therapeutic strategies.