TY - JOUR
T1 - Association between microglial activation and serum kynurenine pathway metabolites in multiple sclerosis patients
AU - Saraste, Maija
AU - Matilainen, Markus
AU - Rajda, Cecilia
AU - Galla, Zsolt
AU - Sucksdorff, Marcus
AU - Vécsei, László
AU - Airas, Laura
N1 - Funding Information:
This work was supported by the Academy of Finland grant for clinical researcher [330,902], Sigrid Juselius Foundation, the InFLAMES Flagship Programme of the Academy of Finland [337,530], GINOP-2.3.2–15–2016–00034, TUDFO/47,138–1/2019-ITM, MTA-SZTE Neuroscience Research Group and OTKA138–125-K. The funders had no role in study design, in the collection, analysis and interpretation of data, in the writing of the report or in the decision to submit the article for publication.
Publisher Copyright:
© 2022 The Author(s)
PY - 2022/3
Y1 - 2022/3
N2 - 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.
AB - 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.
KW - 3-hydroxykynurenine
KW - Kynurenine pathway
KW - Microglia
KW - Multiple sclerosis
KW - PET-imaging
KW - TSPO
UR - http://www.scopus.com/inward/record.url?scp=85124480857&partnerID=8YFLogxK
U2 - 10.1016/j.msard.2022.103667
DO - 10.1016/j.msard.2022.103667
M3 - Article
C2 - 35151985
AN - SCOPUS:85124480857
SN - 2211-0348
VL - 59
JO - Multiple Sclerosis and Related Disorders
JF - Multiple Sclerosis and Related Disorders
M1 - 103667
ER -