APPENDICES 236 S Summary This thesis explores biochemical and genetical changes associated with migraine and cluster headache. The research aimed to enhance our knowledge on the pathophysiology and pathways involved in these diseases and hopefully will provide first steps in the identification of new treatment targets. Uncovering the biological mechanisms on how patients differ from those without disease leads to a better understanding of the pathophysiology of primary headache disorders.The biological systems in our body are related to each other, and are based on the genomic blueprint and lead via epigenetics, transcription and translation to proteins and biomolecules. By investigating the various molecular levels, we hope to get a better insight in how headache disorders are brought about. The research is divided into two parts. Part 1, (Chapters 2 - 5) is aimed at the investigation of biomolecules in biofluids (i.e. blood and cerebrospinal fluid (CSF)) in migraine patients, whereas Part 2 (Chapters 6 - 9) is focused on the genetical underpinnings of cluster headache migraine and related disorders. Part I Biochemistry of migraine Part 1 describes biochemical studies for which various molecules and metabolites were measured in people with migraine and compared to those in people without migraine. Migraine is a primary headache disorder that is characterized by recurrent episodes of severe often unilateral pulsating headache accompanied by nausea, vomiting and/or photo- and phonophobia. In one third of patients the attacks are preceded by an aura phase. Typically, a migraine attack consists of a preictal, ictal (aura and/or headache), and postictal (postdromal) phase. Although over the years much progress has been made with understanding the pathophysiological mechanisms involved in migraine, it is still unclear why some people get migraine and others do not and why those with migraine get attacks at certain timepoints, and which factors trigger attacks. The aim of Part 1 was to uncover biochemical underpinnings of migraine to better understand the pathways involved. The studies focused on the measurement of a wide variety of biomolecules, either via a targeted or untargeted approach.The studies focused on both blood and CSF and investigated the comparability of the two biofluids specifically in relation to amine concentrations. Furthermore, in all but one chapter (Chapters 2,3 and 4) we investigated these biofluids outside of an attack and in the remaining chapter (Chapter 5) over the course of a provoked migraine attack. This way different aspects of migraine were put under investigation. For Chapter 2 the metabolic profile of migraine patients was compared to those without migraine using an untargeted approach based on high-throughput proton nuclear magnetic resonance (1H-NMR) spectroscopy. In total, 100 signals representing 49 different metabolites in the fasting serum samples from 189 migraine patients and 1,360 controls were detected. Migraine status was divided in lifetime migraine (migraine diagnosis during lifetime) and active migraine (defined as having at least one severe migraine in the last 12 months). Using elastic net regression analysis
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