Association between microglial activation and serum kynurenine pathway metabolites in multiple sclerosis patients
Maija Saraste1, Markus Matilainen2, Cecilia Rajda3
1Turku PET Centre, Turku University Hospital and University of Turku, Kiinanmyllynkatu 4-8, 20521 Turku, Finland; Neurocenter, Turku University Hospital, Turku, Finland; Clinical Neurosciences, University of Turku, Turku, Finland.
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.
Insights
Low levels of the tryptophan metabolite 3-hydroxykynurenine in multiple sclerosis (MS) patients were linked to increased microglial activation in the brain. This finding suggests a potential biomarker for MS progression.
Area of Science:
- Neuroimmunology
- Neuroinflammation
- Metabolomics
Background:
- Microglial activation is implicated in multiple sclerosis (MS) progression, but the drivers of their sustained pro-inflammatory state remain unclear.
- Metabolites from the kynurenine pathway (KP), which processes tryptophan, can modulate the activity of brain immune cells.
Purpose of the Study:
- To determine if blood levels of tryptophan metabolites correlate with microglial activation in the MS brain, measured by Positron Emission Tomography (PET).
Main Methods:
- Microglial activation was assessed using PET imaging with the tracer [11C]PK11195.
- Distribution volume ratios (DVR) of [11C]PK11195 binding were calculated in normal-appearing white matter (NAWM), lesions, and thalamus.
- Serum levels of tryptophan and KP metabolites were quantified using ultrahigh performance liquid chromatography-tandem mass spectrometry.
Main Results:
- In 48 MS patients, higher [11C]PK11195 binding in NAWM and thalamus correlated with lower serum 3-hydroxykynurenine levels (r = -0.31 to -0.32, p = 0.028-0.031).
- Higher Expanded Disability Status Scale (EDSS) scores were associated with lower 3-hydroxykynurenine and xanthurenic acid levels (r = -0.31 to -0.36, p = 0.012-0.034).
- Increased EDSS also correlated with higher [11C]PK11195 binding in NAWM and thalamus (r = 0.33 to 0.34, p = 0.020-0.023).
Conclusions:
- This study reveals an association between reduced serum 3-hydroxykynurenine and heightened microglial activation in MS patients.
- Further research is needed to understand the underlying biological mechanisms connecting these findings.
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