Dysregulation of the kynurenine pathway is related to persistent cognitive impairment in tick-borne encephalitis

Abstract

Background: Tick-borne encephalitis (TBE) patients frequently suffer cognitive and neuropsychiatric sequelae, which may be severe and long-lasting. The underlying mechanisms remain poorly understood, but likely involve dysregulation of immunological and neuroinflammatory processes. Here, we investigated the activity of the kynurenine pathway (KP), an immunologically induced set of enzymes generating neuroactive metabolites via degradation of the amino acid tryptophan and their correlation with the cognitive performance in TBE patients.

Methods: KP metabolite concentrations were measured in serum and cerebrospinal fluid (CSF) samples from patients taken during hospitalization for acute TBE (n = 87) and a control group (n = 12) by UPLC/MS-MS. At two follow-up occasions, 6 and 18 months after hospital discharge, additional serum samples were obtained from TBE patients and their cognitive performance was evaluated by the Matrics Consensus Cognitive Battery.

Results: Relative to controls, TBE patients exhibited a robust induction of the KP in both the central nervous system and peripheral blood during the acute phase of the disease, with drastic elevations of the neuroactive QUIN and KYNA in CSF. KP activity remained significantly elevated in serum of TBE patients at the 6- and 18-month follow-ups. Several inverse associations between cognitive performance and measurements of KP activity recorded in both CSF and serum were found by rank correlation analysis. Further, via ROC analysis, serum rKT was found to be an accurate predictor of impaired overall cognition (<35 T-score) 6 months after acute TBE (AUC 0.79, CI 0.64-0.93, p < 0.01 for rKT measured during acute TBE; AUC 0.68, CI 0.50-0.86, p < 0.05 for rKT measured at 6 months).

Interpretation: We have found evidence of both acute and chronic dysregulation of KP activity in TBE patients, which correlated with degree of cognitive impairment at long-term follow-up. Our findings suggest that KP metabolites may serve as biomarkers for TBE-related cognitive sequelae, and more broadly, that the KP may offer avenues for development of novel treatments.

Keywords: Cognition; Flavivirus; Kynurenic acid; Kynurenine pathway; Neuroinfection; Neuroinflammation; Quinolinic acid; Tick-borne encephalitis.