Association between microglial activation and serum kynurenine pathway metabolites in multiple sclerosis patients

Background: Microglial activation associates with MS progression but it is unclear what drives their persistent pro-inflammatory state. Metabolites of the kynurenine pathway (KP), the main metabolism route of tryptophan, can influence the function of brain innate immune cells. Objective: To investigate whether tryptophan metabolites in blood associate with TSPO-PET measurable microglial activation in MS brain. Methods: Microglial activation was detected using PET imaging and the TSPO-binding radioligand [¹¹C]PK11195. Distribution volume ratios (DVR) for specific [¹¹C]PK11195-binding in the normal appearing white matter (NAWM), lesions, and thalamus were calculated. Ultrahigh performance liquid chromatography-tandem mass spectrometry was used to measure serum levels of tryptophan and kynurenine pathway metabolites. Results: The study cohort consisted of 48 MS patients. Increased DVR in the NAWM and thalamus correlated with decreased serum 3-hydroxykynurenine level (R = -0.31, p = 0.031 and R = -0.32, p = 0.028). Increased EDSS correlated with decreased 3-hydroxykynurenine and xanthurenic acid (R = -0.36, p = 0.012 and R = -0.31, p = 0.034) and increased DVR in the NAWM and thalamus (R = 0.33, p = 0.023 and R = 0.34, p = 0.020, respectively). Conclusions: This clinical study demonstrates an association between low serum 3-hydroxykynurenine and high microglial activation in MS. Further investigations are warranted for elucidation of the biological mechanisms behind this association.