Age‐ and disease‐specific changes of the kynurenine pathway in Parkinson’s and Alzheimer’s disease

Abstract

The kynurenine (Kyn) pathway, which regulates neuroinflammation and N‐methyl‐ d‐aspartate receptor activation, is implicated in Parkinson’s disease (PD) and Alzheimer’s disease (AD). Age‐related changes in Kyn metabolism and altered cerebral Kyn uptake along large neutral amino acid transporters, could contribute to these diseases. To gain further insight into the role and prognostic potential of the Kyn pathway in PD and AD, we investigated systemic and cerebral Kyn metabolite production and estimations of their transporter‐mediated uptake in the brain. Kyn metabolites and large neutral amino acids were retrospectively measured in serum and cerebrospinal fluid (CSF) of clinically well‐characterized PD patients ( n = 33), AD patients ( n = 33), and age‐matched controls ( n = 39) using solid‐phase extraction‐liquid chromatographic‐tandem mass spectrometry. Aging was disease independently associated with increased Kyn, kynurenic acid and quinolinic acid in serum and CSF. Concentrations of kynurenic acid were reduced in CSF of PD and AD patients ( p = 0.001; p = 0.002) but estimations of Kyn brain uptake did not differ between diseased and controls. Furthermore, serum Kyn and quinolinic acid levels strongly correlated with their respective content in CSF and Kyn in serum negatively correlated with AD disease severity ( p = 0.002). Kyn metabolites accumulated with aging in serum and CSF similarly in PD patients, AD patients, and control subjects. In contrast, kynurenic acid was strongly reduced in CSF of PD and AD patients. Differential transporter‐mediated Kyn uptake is unlikely to majorly contribute to these cerebral Kyn pathway disturbances. We hypothesize that the combination of age‐ and disease‐specific changes in cerebral Kyn pathway activity could contribute to reduced neurogenesis and increased excitotoxicity in neurodegenerative disease.

Abstract

To study the role and diagnostic potential of the kynurenine (Kyn) pathway in age‐related neurodegenerative disease, time‐linked serum, and cerebrospinal fluid (CSF) samples from Alzheimer’s disease (AD) patients, Parkinson’s disease (PD) patients and age‐matched cognitively healthy controls were retrospectively selected. Kyn metabolites and large neutral amino acids (LNAAs), which compete with Kyn metabolites to cross the blood–brain barrier, were analyzed by mass spectrometry. Age‐related increases of several Kyn metabolites were similar in controls, AD, and PD. Concentrations of kynurenic acid (KA), which plays a role in glutamate toxicity and neuronal development, were strongly reduced in CSF of PD and AD patients.