The kynurenine pathway and markers of neurodegeneration and cerebral small vessel disease: The Maastricht Study

Background: The kynurenine pathway, the main metabolic pathway of tryptophan degradation, has been mostly studied in neurodegenerative disorders, while its role in cerebrovascular pathology is less clear. We investigated whether kynurenines are associated with markers of neurodegeneration and cerebrovascular pathology in the general population. Methods: Cross-sectional data was used from 1589 individuals (60.0 +/- 8.0 years, 54.3 % men) who participated in The Maastricht Study, an observational population-based cohort study. Plasma concentrations of tryptophan, kynurenines, and neopterin were quantified. Neurodegeneration was measured by volumes of intracranial cerebrospinal fluid (CSF), while cerebrovascular pathology was measured by white matter hyperintensity (WMH) volume and presence of cerebral small vessel disease (cSVD), defined as the presence of lacunar infarcts, cerebral microbleeds or a Fazekas score >= 2, all derived from 3 T MRI. Associations of kynurenines with these markers were investigated using linear, logistic, and restricted cubic spline regression models adjusted for confounders. Results: Fully adjusted analyses indicated that higher levels of 3-hydroxyanthranilic acid, kynurenine, kynurenic acid, quinolinic acid, and neopterin were associated with lower CSF volume. For the latter four, associations were non-linear and restricted to participants with already below average concentrations. Higher levels of tryptophan and anthranilic acid were associated with higher CSF volumes in participants with above-average levels. Higher levels of the kynurenine-tryptophan ratio were associated with a lower WMH volume. No evidence was found for associations between individual kynurenines and WMH volume or cSVD presence. Conclusions: These findings suggest that several kynurenines are associated with neurodegeneration in community-dwelling older adults, but not with cerebrovascular damage.