METABOLIC PROFILE CHANGES IN SERUM OF MIGRAINE PATIENTS DETECTED USING 1H-NMR SPECTROSCOPY 31 2 Introduction Migraine is a common multifactorial brain disorder with a lifetime prevalence of 15-20%, causing disability worldwide and a three times higher prevalence in woman compared to men.1, 2 Migraine is characterized by recurrent episodes of severe often unilateral pulsating headache accompanied by nausea, vomiting and/or photo- and phonophobia lasting for 4-72 hours.3 Although much progress has been made with unravelling its (non)genetic disease mechanisms,4 a diagnosis of migraine is still made by interview and physical examination or questionnaire, as no diagnostic biomarker is available. The lack of biomarkers, for instance in a biofluid such as blood, has also hampered the development of novel treatments. Metabolomics is an established valuable approach for biomarker identification and has been successful in revealing the metabolic underpinnings of various human diseases.5-10 Validated biomarkers can greatly improve diagnosis, prognosis and assessing effectivity of treatment of patients, as was already shown for several diseases other than migraine.11, 12 Various attempts have been made to identify reliable biomarkers (either clinical, genetic, radiological or biochemical) in migraine.13-16 without much success, also not for biochemical studies in blood17 or cerebrospinal fluid.14 Especially the identification of metabolites in an easily accessible body fluid such as peripheral blood is urgently needed.18 When using metabolomics either a targeted approach that typically focuses on one or more related selected pathways of interest or an untargeted approach that aims to simultaneously measure as many metabolites as possible from a biological sample, can be employed. Several biochemical studies in migraine in the past two decades explored the targeted approach by examining a limited number of compounds, such as amino acids,19, 20 inflammatory markers,21-23 vasoactive neuropeptides,24-26 and (cardio)vascular risk factors,27-29 because of their presumed role in migraine pathophysiology. More recently, mainly because of the advent of novel treatment antagonizing calcitonin gene-related peptide (CGRP) or its receptor,30, 31 the field of biomarker research in peripheral blood regained interest,32 with reports of promising possible peripheral biomarkers in migraine.33, 34 To search for migraine metabolite profiles in serum we used an untargeted, hypothesis-free, approach and performed high-throughput proton nuclear magnetic resonance (1H-NMR) spectroscopy.This method allows for a rapid, robust, simultaneous identification and quantification of a variety of metabolites in large numbers of samples.35 Here we analysed metabolite profiles in serum samples of migraine patients and controls from the Erasmus Rucphen Family population, a large Dutch population-based family study from the Southwest of the Netherlands in which we previously had identified migraine cases.36 We set out to investigate whether metabolites identified by 1H-NMR spectroscopy are associated with migraine by comparing metabolic profiles of migraine patients and controls in a “real-life variation” cohort.
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