Cerebrospinal fluid kynurenines in multiple sclerosis; relation to disease course and neurocognitive symptoms

Aeinehband, Shahin; Brenner, Philip; Ståhl, Sara; Bhat, Maria; Fidock, Mark; Khademi, Mohsen; Olsson, Tomas; Engberg, Göran; Jokinen, Jussi; Erhardt, Sophie; Piehl, Fredrik

doi:10.1016/j.bbi.2015.07.016

Cited by 57 publications

(84 citation statements)

References 54 publications

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“…Rejdak and coworkers found higher CSF levels of KYNA during relapse and lower levels during remission in relapsing pwMS [39,40]. Interestingly, we have not found changes in CSF KYNA levels, similarly to Aeinehband and coworkers [36]. After stratification based upon the different disease subgroups, relapsing pwMS had a metabolic shift of the kynurenine pathway towards the neurotoxic path (elevated QUIN), while progressing pwMS displayed a trend toward downregulation of the kynurenic pathway.…”

Section: Discussionsupporting

confidence: 83%

“…After stratification based upon the different disease subgroups, relapsing pwMS had a metabolic shift of the kynurenine pathway towards the neurotoxic path (elevated QUIN), while progressing pwMS displayed a trend toward downregulation of the kynurenic pathway. Secondary and primary progressive pwMS differed in KYNA levels, which was much lower in the former group of patients [36].…”

Section: Discussionmentioning

confidence: 81%

“…The initial locations of these injuries were in the dendrites [34], and this resulted in apoptosis or necrosis of the neuron, depending on the extent of the damage [35]. In human studies, QUIN levels were increased in both the serum and CSF of pwMS [36]. Lim and coworkers found that QUIN can differentiate MS subtypes [37].…”

Section: Discussionmentioning

confidence: 99%

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Cerebrospinal Fluid Neurofilament Light Chain Is Associated with Kynurenine Pathway Metabolite Changes in Multiple Sclerosis

Rajda

Galla

Polyák

et al. 2020

IJMS

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Neurofilament light (NFL) has proved to be a good prognostic factor in multiple sclerosis (MS), as its level is proportionally elevated with extended neuraxonal damage. The involvement of the kynurenine pathway in neuroinflammation has been proved. The precursor of this pathway is the essential amino acid tryptophan, which is catabolized 95% towards kynurenine metabolites. Quinolinic acid (QUIN) within the brain is only produced in activated microglia and macrophages, leading to axonal degeneration via the activation of N-Methyl-D-aspartate receptors. Neopterin is a biomarker for inflammation produced by macrophages. The association of these biomarkers has not previously been investigated. Our aim was to assess whether there is an association of the neurodegenerative biomarker NFL with the markers of neuroinflammation, e.g., kynurenine metabolites and neopterin, in the cerebrospinal fluid (CSF). CSF samples of patients with MS (pwMS; n = 37) and age-matched controls (n = 22) were compared for NFL levels by ELISA, while the kynurenine pathway metabolites tryptophan and neopterin were detected with mass spectrometry. Spearman’s correlation showed that NFL is an independent predictor of neurological disability in the MS group. Significant correlations were found between NFL, neopterin, and QUIN, and between kynurenine and neopterin. Receiver operating characteristic (ROC) curve analysis was used to plot the top three best predictors of MS-related disability that yielded the best specificity and sensitivity. Normalized NFL (AUC: 0.923), QUIN (AUC: 0.803), and neopterin (AUC: 0.843) were the best independent predictors of neurological disability in pwMS. The CSF NFL and CSF QUIN, together with neopterin, were elevated in the CSF of pwMS compared to controls. The combination of the neurodegenerative biomarkers together with biomarkers of neuroinflammation could provide additional information on the underlying pathomechanism of disease activity, which is essential for the identification of patients at risk of developing cumulative disabilities.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 81%

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Cerebrospinal Fluid Neurofilament Light Chain Is Associated with Kynurenine Pathway Metabolite Changes in Multiple Sclerosis

Rajda

Galla

Polyák

et al. 2020

IJMS

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“…Tryptophan catabolism occurs in both the central nervous system and the periphery and is regulated by complex and dynamic mechanisms involving inflammatory mediators during the immune response [30]. Recently, evidence has indicated that kynurenine dysregulation is most prominent during the acute phases of MS, whereas kynurenine metabolite levels in MS patients in remission are similar to those of controls [31]. In particular, inhibition of the first enzyme that converts tryptophan to kynurenine metabolite (indoleamine 2,3-dioxygenase) seems to be associated with the reduction of disease activity [32], evidence in line with our findings documenting an increase in tryptophan level during IFN ß treatment.…”

Section: Discussionmentioning

confidence: 99%

Assessing the Metabolomic Profile of Multiple Sclerosis Patients Treated with Interferon Beta 1a by 1H-NMR Spectroscopy

et al. 2019

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Metabolomic research has emerged as a promising approach to identify potential biomarkers in multiple sclerosis (MS). The aim of the present study was to determine the effect of interferon beta (IFN ß) on the metabolome of MS patients to explore possible biomarkers of disease activity and therapeutic response. Twenty-one MS patients starting IFN ß therapy (Rebif® 44 μg; s.c. 3 times per week) were enrolled. Blood samples were obtained at baseline and after 6, 12, and 24 months of IFN ß treatment and were analyzed by high-resolution nuclear magnetic resonance spectroscopy. Changes in metabolites were analyzed. After IFN ß exposure, patients were divided into responders and nonresponders according to the Bno evidence of disease activity^(NEDA-3) definition (absence of relapses, disability progression, and magnetic resonance imaging activity), and samples obtained at baseline were analyzed to evaluate the presence of metabolic differences predictive of IFN ß response. The results of the investigation demonstrated differential distribution of baseline samples compared to those obtained during IFN ß exposure, particularly after 24 months of treatment (R 2 X = 0.812, R 2 Y = 0.797, Q 2 = 0.613, p = 0.003). In addition, differences in the baseline metabolome between responder and nonresponder patients with respect to lactate, acetone, 3-OH-butyrate, tryptophan, citrate, lysine, and glucose levels were found (R 2 X = 0.442, R 2 Y = 0.768, Q 2 = 0.532, p = 0.01). In conclusion, a metabolomic approach appears to be a promising, noninvasive tool that could potentially contribute to predicting the efficacy of MS therapies.

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“…The QA/KYNA ratio was higher in primary progressive MS, secondary progressive MS, and relapsing-remitting MS. KYNA levels were the highest in primary progressive MS, but lower in progressive MS [132]. Significantly elevated QA/KYN and QA/KYNA ratios were observed in the CSF of the relapsing subgroup of relapsing-remitting MS. TRP, KYNA, and QA levels were increased in primary progressive MS, while TRP and KYNA levels were decreased in secondary progressive MS [133]. KAT I and KAT II activities were significantly increased in the red blood cells (RBCs), and KYNA levels were significantly increased in the plasma of MS patients [134].…”

Section: Systematic Reviews On Kynurenines In Major Neurodegenerativementioning

confidence: 99%

Exploring the Etiological Links behind Neurodegenerative Diseases: Inflammatory Cytokines and Bioactive Kynurenines

Tanaka

Toldi

Vécsei

2020

IJMS

177

197

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Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most common neurodegenerative diseases (NDs), presenting a broad range of symptoms from motor dysfunctions to psychobehavioral manifestations. A common clinical course is the proteinopathy-induced neural dysfunction leading to anatomically corresponding neuropathies. However, current diagnostic criteria based on pathology and symptomatology are of little value for the sake of disease prevention and drug development. Overviewing the pathomechanism of NDs, this review incorporates systematic reviews on inflammatory cytokines and tryptophan metabolites kynurenines (KYNs) of human samples, to present an inferential method to explore potential links behind NDs. The results revealed increases of pro-inflammatory cytokines and neurotoxic KYNs in NDs, increases of anti-inflammatory cytokines in AD, PD, Huntington’s disease (HD), Creutzfeldt–Jakob disease, and human immunodeficiency virus (HIV)-associated neurocognitive disorders, and decreases of neuromodulatory KYNs in AD, PD, and HD. The results reinforced a strong link between inflammation and neurotoxic KYNs, confirmed activation of adaptive immune response, and suggested a possible role in the decrease of neuromodulatory KYNs, all of which may contribute to the development of chronic low grade inflammation. Commonalities of multifactorial NDs were discussed to present a current limit of diagnostic criteria, a need for preclinical biomarkers, and an approach to search the initiation factors of NDs.

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Cerebrospinal fluid kynurenines in multiple sclerosis; relation to disease course and neurocognitive symptoms

Cited by 57 publications

References 54 publications

Cerebrospinal Fluid Neurofilament Light Chain Is Associated with Kynurenine Pathway Metabolite Changes in Multiple Sclerosis

Cerebrospinal Fluid Neurofilament Light Chain Is Associated with Kynurenine Pathway Metabolite Changes in Multiple Sclerosis

Assessing the Metabolomic Profile of Multiple Sclerosis Patients Treated with Interferon Beta 1a by 1H-NMR Spectroscopy

Exploring the Etiological Links behind Neurodegenerative Diseases: Inflammatory Cytokines and Bioactive Kynurenines

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