The tryptophan-kynurenine-NAD+ (TK) pathway may provide accurate cerebrospinal fluid (CSF) biomarkers, according to a study published in the Journal of Infectious Diseases.
The TK pathway is a major pathway for catabolism of endogenous tryptophan; the pathway’s intermediates are involved with immunomodulation, neuromodulation, and both cytotoxic and cytoprotective effects. The TK pathway exerts neuroprotective effects by being associated with immune cell regulation toward less inflammatory phenotypes. Recent evidence has suggested that kynurenine concentrations in the central nervous system (CNS) increased during bacterial meningitis and inhibited 2 key enzymes of the TK pathway that exacerbated meningitis. This suggests that this pathway exerts a net neuroprotective effect at least in this model. Further investigating the TK pathway regulation would improve understanding of pathophysiology and end-organ damage, as well as provide potential for the TK pathway to be used as a source of diagnostic and prognostic biomarkers. Therefore, this study performed a detailed analysis of kynurenine, tryptophan, and the kynurenine/tryptophan ration in CSF samples from patients with bacterial and viral infections, autoimmune neuroinflammatory diseases, and non-inflamed neuropathologies to assess differences in the induction of the pathway among these disorders and to assess the potential of these 3 parameters as diagnostic CSF biomarkers.
Concentrations of kynurenine and tryptophan were measured in 220 CSF samples from patients with bacterial and viral (herpes simplex, varicella zoster, enteroviruses) meningitis/encephalitis, neuroborreliosis, autoimmune neuroinflammation (anti-N-methyl-D-aspartate (NMDA)-receptor encephalitis, multiple sclerosis), and patients with noninflammatory conditions (Bell palsy, normal pressure hydrocephalus, Tourette syndrome) who served as controls. The limits of detection for kynurenine and tryptophan were found to be 0.15 and 0.25 µM, respectively.
Results showed that kynurenine and tryptophan concentrations correlate differentially with the extent of neuroinflammation. In many of the noninflamed and less inflamed samples, kynurenine concentrations were less than the limits of detection but were detected at greater than the limits of detection with increasing frequency as the degree of inflammation increased. When kynurenine and tryptophan concentrations were assessed with CSF inflammation, kynurenine concentrations were 5.6-fold and 9.4-fold elevated in the inflamed (infected and noninfected, respectively) compared with the noninflamed samples. However, tryptophan concentrations were significantly lower in the inflamed samples.
Kynurenine concentrations correlated strongly with CSF markers of neuroinflammation, which included leukocyte count, lactate, and blood-CSF-barrier dysfunction. Further, multiple logistic regression analysis showed combinations of kynurenine, tryptophan, and kynurenine/tryptophan ratio with leukocyte count (for kynurenine, P=4.9-43) or lactate were accurate biomarkers for the clinical differentiation between neuroborreliosis, viral CNS infections, and autoimmune neuroinflammation, with kynurenine having the strongest correlation.
The results of this study provided the first evidence that there is significant induction of the TK pathway in the case of CNS infection. Overall, the study authors concluded that, “Since our study was not designed to assess clinical outcomes, it remains to be studied to what extent induction of the TK pathway contributes to the balance between cytoprotective, cytotoxic, and neuromodulatory processes in human CNS infections.”
Sühs KW, Novoselova N, Kuhn M, et al. Kynurenine is a cerebrospinal fluid biomarker for bacterial and viral CNS infections [published online February 5, 2019] J Infect Dis. doi: 10.1093/infdis/jiz048