To investigate whether blood tryptophan metabolites associate with 18-kDa translocator protein (TSPO)-PET-measurable microglial activation in multiple sclerosis (MS) brain.

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, have been shown to promote neuronal damage and microglial activation. To date, associations between microglial activation in MS patient brain and KP metabolites are largely unexplored.

Microglial activation was detected in vivo with PET imaging using the TSPO-binding radioligand [¹¹C]PK11195 in 48 MS patients (44 RRMS and 4 SPMS). Distribution volume ratio (DVR) was used to evaluate specific [¹¹C]PK11195-binding in the NAWM, T1 and T2 lesions, and thalamus. Serum levels of KP metabolites were measured with ultrahigh performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Associations between KP metabolites, microglial activation and Expanded Disability Status Scale (EDSS) were evaluated using Spearman correlation analysis and a multiple linear regression model adjusted for age, disease duration, gender and disease modifying treatment.

Increased DVR in the NAWM and thalamus correlated with decreased 3-hydroxykynurenine (3HK) level (R= -0.31, p=0.031 and R= -0.32, p=0.028). Increased EDSS correlated with decreased 3HK (R= -0.36, p=0.012) and increased DVR in the NAWM and thalamus (R=0.33, p=0.023 and R=0.34, p=0.020, respectively). A negative association between 3HK and NAWM DVR was sustained in the multiple regression analysis adjusted for age, disease duration, gender and disease modifying treatment [estimate (*10^-4): -6.13* (95 % CL -11.5 - -0.79), p=0.026)].

The association between low 3HK level and increased microglial activation implies that low serum 3HK concentration could serve as an easily measurable blood biomarker of the excessive diffuse widespread inflammation in MS brain. The present study rises the importance of further investigation of the KP in conjunction with MS progression.