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

Maija Saraste; Markus Matilainen; Cecilia Rajda; Zsolt Galla; Marcus Sucksdorff; László Vécsei; Laura Airas

doi:10.1016/j.msard.2022.103667

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

Maija Saraste^*, Markus Matilainen, Cecilia Rajda, Zsolt Galla, Marcus Sucksdorff, László Vécsei, Laura Airas

^*Corresponding author for this work

Turku PET Centre

Research output: Contribution to journal › Article › Scientific › peer-review

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Abstract

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.

Original language	English
Article number	103667
Journal	Multiple Sclerosis and Related Disorders
Volume	59
DOIs	https://doi.org/10.1016/j.msard.2022.103667
Publication status	Published - Mar 2022
MoE publication type	A1 Journal article-refereed

Funding

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.

Keywords

3-hydroxykynurenine
Kynurenine pathway
Microglia
Multiple sclerosis
PET-imaging
TSPO

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10.1016/j.msard.2022.103667

Association between microglial activation and serum kynurenine pathway metabolites in multiple sclerosis patientsFinal published version, 1.06 MBLicence: CC BY

https://urn.fi/URN:NBN:fi-fe2023030329506

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@article{07e91115788e4f41b8232122b2d45a6d,

title = "Association between microglial activation and serum kynurenine pathway metabolites in multiple sclerosis patients",

abstract = "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.",

keywords = "3-hydroxykynurenine, Kynurenine pathway, Microglia, Multiple sclerosis, PET-imaging, TSPO",

author = "Maija Saraste and Markus Matilainen and Cecilia Rajda and Zsolt Galla and Marcus Sucksdorff and L{\'a}szl{\'o} V{\'e}csei and Laura Airas",

note = "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: {\textcopyright} 2022 The Author(s)",

year = "2022",

month = mar,

doi = "10.1016/j.msard.2022.103667",

language = "English",

volume = "59",

journal = "Multiple Sclerosis and Related Disorders",

issn = "2211-0348",

publisher = "Elsevier",

}

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 - https://www.scopus.com/pages/publications/85124480857

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 -

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

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