Some CSF Kynurenine Pathway Intermediates Associated with Disease Evolution in Amyotrophic Lateral Sclerosis

Abstract

The aim of this study was to evaluate the kynurenine pathway (KP) and amino acids profile, using mass spectrometry, in the cerebrospinal fluid (CSF) of 42 amyotrophic lateral sclerosis (ALS) patients at the diagnosis and 40 controls to detect early disorders of these pathways. Diagnostic and predictive ability (based on weight loss, forced vital capacity, ALS Functional Rating Scale—Revised evolution over 12 months, and survival time) of these metabolites were evaluated using univariate followed by supervised multivariate analysis. The multivariate model between ALS and controls was not significant but highlighted some KP metabolites (kynurenine (KYN), kynurenic acid (KYNA), 3-Hydroxynurenine (3-HK)/KYNA ratio), and amino acids (Lysine, asparagine) as involved in the discrimination between groups (accuracy 62%). It revealed a probable KP impairment toward neurotoxicity in ALS patients and in bulbar forms. Regarding the prognostic effect of metabolites, 12 were commonly discriminant for at least 3 of 4 disease evolution criteria. This investigation was crucial as it did not show significant changes in CSF concentrations of amino acids and KP intermediates in early ALS evolution. However, trends of KP modifications suggest further exploration. The unclear kinetics of neuroinflammation linked to KP support the interest in exploring these pathways during disease evolution through a longitudinal strategy.

First Metabolomic Signature of Blood-Brain Barrier Opening Induced by Microbubble-Assisted Ultrasound

“…To explore further tissue inflammation after acoustically-mediated BBBO, a previously described targeted metabolomic approach using HPLC-MS was applied ( Lefevre et al, 2019 ; Alarcan et al, 2021 ). We dosed the TRP derivates, especially metabolites from the KP cascade in the brain tissue, in the CSF, and in the blood serum.…”

“…To the best of our knowledge, the effects of acoustically-mediated BBBO on neurotransmission have never been investigated; this study explored these bioeffects by dosing 5-HT and its derivates originating from the TRP metabolism by a targeted HPLC-MS approach ( Lefevre et al, 2019 ; Alarcan et al, 2021 ). Indeed, the striatum is involved in dopaminergic, cholinergic, and GABAergic neurotransmissions.…”

“…During the full-scan acquisition (full MS, AGC target of 10 6 , maximum injection time of 250 ms), which ranged from 58 to 870 m/z, the instrument operated at 70,000 resolution (m/z = 200). Finally, tryptophan’s derivates were quantified within brain tissues, CSF, and blood serum as described in Lefevre et al (2019) ; Alarcan et al (2021) .…”

A Review of the Health Benefits of Food Enriched with Kynurenic Acid

“…The presence of KYNA in human cerebrospinal fluid has been repeatedly reported ( Table S2 ). The content of KYNA in cerebrospinal fluid obtained from adult healthy humans ranges from 0.0009 to 0.005 μM [ 16 , 20 , 21 , 31 , 32 , 33 , 34 , 35 , 36 , 37 ]. The content of KYNA in cerebrospinal fluid obtained from children is within the same limits [ 38 ].…”

Tryptophan metabolism: Mechanism-oriented therapy for neurological and psychiatric disorders

“…QUIN was significantly elevated in neurons and microglia in the cerebrospinal fluid, motor cortex, and spinal cord of ALS patients, while cerebrospinal fluid IDO, TRP, and KYN were significantly elevated, and the 3-HK/KYNA and QUIN/KYNA ratios tended to be elevated ( 131 ). Since QUIN and 3-HK may have neurotoxic and KYNA neuroprotective effects, these findings may reflect the impairment of neurotoxic compounds by KP ( 149 ). It has been found that both reduced and elevated NMDAR functions are associated with autism spectrum disorder (ASD), and its deviation in either direction leads to ASD, demonstrating the importance of a normal range of NMDAR function.…”