3 CHAPTER 3 66 Discussion By investigating 40 amino acids and biogenic amines, targeted by our validated mass spectrometry platform, in plasma and CSF in healthy controls, we show that amine concentrations in plasma do not correlate well with those in CSF. Hence, plasma concentrations per se are poor predictors of CSF concentrations for the majority of these metabolites. However, when studied as ratios, several amines correlated much better, indicating that ratios have an increased predictive ability. A possible explanation for this finding is that ratios are tightly regulated by blood-brain-barrier (BBB) transport systems and most likely indicating the cotransport of amines, but not so much the distribution of individual amines over the various body fluid compartments. There have been a limited number of studies on the correlation between plasma and CSF concentrations of amines. The studies typically focused on proteinogenic amino acids and similar to our results did not yield overt correlations.10, 11 However, in our study, we measured additional amines and four of them showed strong correlation, namely homocitrulline, S-methylcysteine, methionine sulfone, and L-alpha-aminobutyric acid. Homocitruline has been associated with energy metabolism and cerebellar disfunction in the animal studies 18, 19 and S-methylcysteine can act neuroprotective after certain types of damage,20 however, their exact biological roles in the brain are not fully known. Previous studies did not study whether ratios of amines correlate between plasma and CSF. In our study, ratios showed better correlation, especially for pairs of amino acids. The regulation of nutrient and metabolite movement between blood and the brain is co-regulated by the action of the blood-brain-barrier. As one of its consequences, there is a concentration gradient between the brain and the rest of the body with the concentration of amino acids in the brain typically being lower than in plasma,21, 22 this was in line with our study where we saw lower concentration in the CSF for most amines compared to plasma. Both this gradient and several transporters regulate the transport of amino acids across the BBB.23-26 The amino acids that showed high correlation in their ratios (L-leucine/L-methionine, L-leucine/L-asparagine, L-valine/L-phenylalanine) are all transported by the L amino acid transport system (LAT/L1), this is a sodium-independent transmembrane antiporter, consisting of two protein subunits, either a catalytic permease SLC7A5/ LAT1 or SLC7A8/LAT2 and a regulatory glycoprotein (SLC3A2).24, 27, 28 Substrates carried by L1 are asparagine, glutamine, leucine, valine, methionine, histidine, isoleucine, tyrosine, tryptophan, phenylalanine, and threonine.24 The L1 system is the most important source by which essential neutral amino acids (NAAs) gain access to the brain.24 L1 imports large and neutral amino acids in exchange for intracellular amino acids. 29 The high correlations that were observed in our study hence may reflect tight regulation by this transporter. It is likely that the relative concentration, i.e. the abundance of one amino acid compared to a second amino acid, is important for transport. Classic neurotransmitters glutamic acid and GABA did not show strong correlations between plasma and CSF concentrations, neither on their own nor as ratio. Concentrations of amines
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