CORRELATING RATIOS OF AMINES IN PLASMA AND CEREBROSPINAL FLUID 51 3 Introduction The cerebrospinal fluid (CSF) is the body fluid closest to the brain and, therefore, of major interest for central nervous system (CNS) disorders. Hence, it is believed that the CSF should more faithfully reflect changes in brain metabolites than blood, which is typically sampled to study metabolites related to the brain’s neurochemistry, also in the context of a brain disease. Novel metabolomics techniques can quantify an increasing number of metabolites, making it possible to better study the metabolomic composition of CSF in both health and disease.1, 2 However, CSF collected via lumbar puncture putt subjects at risk of post-dural puncture headache,3 although small non-traumatic needles lead to an important reduction of this risk.4, 5 Hence, ideally, blood measurements are used to reflect disease-relevant metabolomic changes in the brain over time. Moreover, as repeated CSF collection is not a realistic and patient-centered, alternative blood measurements are especially needed when repeated measures are necessary to study short-interval longitudinal disease pathophysiology, such as in the case of paroxysmal brain disorders where repeated measurement towards attacks may be particularly insightful. With that approach, metabolomic profiles may be obtained in the interictal, pre-ictal, ictal, and postictal phases of subjects, who suffer from a paroxysmal brain disorder. Also for studying pharmacodynamic effects of drugs targeting the CNS, it may be helpful to better understand the relationship between blood and CSF. Although some CNS disorder, such as cerebral amyloid angiopathy display important biomarkers, such as amyloid that can be used for follow-up studies6-8 this is less helpful for paroxysmal CNS disorder where the time-frame for repeated measurements typically is within hours (up to days), instead of years. One relevant class of metabolites for paroxysmal CNS disorders are amines such as amino acids and biogenic amines. This class of metabolites includes important neurotransmitters and their precursors, such as glutamate, γ-aminobutyric acid (GABA), glutamine, serotonin, and tryptophan.9 Studies in the distant past showed that the levels of only a few amines seem to correlate between blood plasma and CSF.10, 11 Of note, it was shown that there was a strong correlation of the “CSF/plasma ratio” between different amines, which was explained by the fact that amines are transported across the blood-brain barrier by the same transporter.11 Correlation was particularly prominent with five neutral amino acids, namely isoleucine, leucine, phenylalanine, valine and tyrosine.11 This finding may imply that any correlation between blood plasma and CSF is not shown by the concentrations themselves, but mere ratios of amines. As current measurement techniques have greatly advanced - whereas older studies were primarily focused on proteinogenic amino acids - and are able to measure a much broader range of amines with higher precision, we aimed to employ our validated amine metabolomics platform for CSF and plasma,12 to investigate to which extent amines correlate between both body fluids. We extrapolated our approach from healthy participants to those with migraine, a common paroxysmal brain disease, to assess whether concentrations and/or ratios of amines differed between those with and without migraine.
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