SUMMARY 237 & predictive profiles consisting of 6 metabolites for lifetime migraine status and 22 metabolites for active migraine status were identified. These predictive metabolites included lipids, amino acids, and metabolites of glucose metabolism. This data suggests an overall disturbance of the metabolic profile in migraine patients. In Chapter 3 the aim was to determine the relationship in amine levels between blood plasma and CSF. The CSF is the biofluid of choice in central nervous system disorders, such as migraine, as it is closest to the brain and thus best reflects the brains neurochemistry at the level of metabolites in it. Given that lumbar puncture is an invasive method it is not always feasible or ethical to perform. Blood measurements would be a much preferred to assess the biochemical aspects of a disease. In order to use amine levels in blood instead of CSF it is, however, essential to determine to what extent blood is representative of the amine levels in CSF. Therefore, the amine levels in blood were compared to those in CSF of 95 healthy people. What was observed is that the amine concentrations in plasma did not directly correlate with amine concentrations in CSF. This means that plasma concentrations are poor predictors of CSF concentrations for most amines, when studied as direct correlations ( ). However, when studied as ratios (i.e., ) there was a significant correlation between plasma and CSF. The ratio correlations were significantly higher than the related single metabolite correlation for 308 of the 741 amine combinations.This indicates using ratio correlations is a superior method of comparing amine concentration of blood in relation to CSF. In addition, these results imply that the ratios are tightly regulated by blood-brain barrier transport systems most likely indicating the cotransport of amines. As a first proof-of-concept, the amine ratios in 95 healthy controls were also compared with those in 197 migraine patients and significant changes for some of the migraine ratios were observed, suggesting that amines seem to have a role in migraine pathophysiology. In Chapter 4 the biochemical alterations in endocannabinoids in the blood plasma of migraine patients outside of an attack were investigated. The endocannabinoid system is a relevant target for migraine research as endocanabinoids have a strong influence on neurotransmission, the neuroimmune and neuroendocrine systems, which are all implicated in the pathophysiology of migraine. Another interesting aspect is the role of the endocannabinoid system has in depression, an established comorbid condition of migraine. Multiple clinical studies in patients with (major) depressive disorders have identified a dysregulation of the endocannabinoid system. Several previous studies in migraine patients have investigated endocannabinoid levels but have shown inconsistent results. In our study the levels of endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and the endocannabinoid analogue docosahexaenoylethanolamine (DHEA) in the CSF could be reliably measured in 94 healthy volunteers and 97 migraine with aura patients and 97 migraine without aura patients outside of an attack. The endocannabinoid concentrations were measured via previously validated micro-liquid chromatography – tandem mass spectrometry (micro-LC-MS/MS). Given the number of possibly confounding factors on endocannabinoid levels, timing and processing of the samples was strictly protocolized and our
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