METABOLIC PROFILE CHANGES IN SERUM OF MIGRAINE PATIENTS DETECTED USING 1H-NMR SPECTROSCOPY 39 2 is synthesized from glucose 6-phosphate. Pyruvate is the conjugate base of pyruvic acid and is a key intermediate in several metabolic pathways throughout the cell. Pyruvic acid can be produced from glucose through glycolysis and it can supply energy to the cell via the Krebs cycle in the mitochondria. One study has investigated the lactic and pyruvic acid levels in the plasma of the migraine patients it was shown that both were significantly higher in migraine patients than in normal controls.66 In addition, multiple amino acids were part of our prediction model for active migraine status, namely leucine, isoleucine, methionine, valine, proline and serine. Over the last decades, multiple amino acids have been hypothesized to play a role in migraine pathophysiology.19 Leucine, isoleucine and valine are branched-chain amino acids (BCAAs), BCAAs have emerged as potential biomarkers of disease as they are associated with risk of cardiovascular disease, end-stage renal failure, and ischemic stroke.67 In a small study of 37 migraine patients and 40 controls elevated levels of isoleucine in blood serum were found.68 A recent study investigated amine pathways in 20 patients with migraine without aura, and 20 healthy subjects in serum with liquid chromatography coupled to mass spectrometry (LC-MS).69 This LC-MS study found decreased levels of leucine, isoleucine and methionine in migraine patients compared to controls. The valine, proline and serine concentration was not assessed directly in this study.69 Although glutamate/glutamine has been repeatedly linked to migraine,70, 71 in our study the levels of glutamine/glutamate were not part of the predictive profile for migraine status. As far as we know the other metabolites we found to be associated with active migraine status (acetate, dimethylglycine and creatinine) have thus far not been associated with migraine. Acetate is a monocarboxylic acid anion, which is metabolized mostly in peripheral tissues. Dimethylglycine, which is a derivative of the amino acid glycine, but it can also be a by-product of the metabolism of choline. Dimethylglycine has been suggested as a treatment for mitochondrial diseases72 and in that sense might be associated with the migraine-glucose dysregulation. Creatine is involved in the conversion from adenosine diphosphate (ADP) back to ATP in muscle and is synthesized mainly in the liver from amino acids glycine and arginine. We here identified a metabolite profile predictive for active migraine, a finding supported by the observation that several of its metabolites have already been reported in literature to be individually (in)directly associated with migraine. We would like to emphasize again that the focus of this study was to explore whether metabolite profiles can be linked to migraine status and less to show direct clinical relevance of individual metabolites. A limitation of our study is that, the set of metabolites we studied using our metabolic profiling method covers only a small part of the human metabolome. Future, complementary, studies using different, more advanced, platforms may identify additional metabolites associated with migraine status. Additionally, in our study population we know to what extent patients are related and have the opportunity to correct for this. Future studies have to show to what extent our findings
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