The kynurenine pathway and cognitive performance in community-dwelling older adults. The Hordaland Health Study

Solvang, Stein-Erik Hafstad; Nordrehaug, Jan Erik; Tell, Grethe S.; Nygård, Ottar; McCann, Adrian; Ueland, Per Magne; Midttun, Øivind; Meyer, Klaus; Vedeler, Christian A.; Aarsland, Dag; Refsum, Helga; Smith, A.D.

doi:10.1016/j.bbi.2018.10.003

Cited by 55 publications

(51 citation statements)

References 69 publications

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“…We have previously observed a relationship between KTR, neopterin, and poor cognitive performance in healthy older adults 38 and a non-linear association between KYN and MMSE performance in this study, but not with MMSE decline rates. 39 Tryptophan deficiency has been widely reported in AD, whereas kynurenine concentrations have shown conflicting findings, where one study on neuropathologically confirmed cases found equivalent or decreased kynurenines.…”

Section: Discussioncontrasting

confidence: 50%

The Associations Between Cognitive Prognosis and Kynurenines Are Modified by the Apolipoprotein ε4 Allele Variant in Patients With Dementia

Ervik

Solvang

Nordrehaug

et al. 2019

Int J�Tryptophan�Res

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Background: The apolipoprotein E ε4 gene variant (APOEε4) confers considerable risk for dementia and affects neuroinflammation, brain metabolism, and synaptic function. The kynurenine pathway (KP) gives rise to neuroactive metabolites, which have inflammatory, redox, and excitotoxic effects in the brain. Aim: To assess whether the presence of at least one APOEε4 allele modifies the association between kynurenines and the cognitive prognosis. Methods: A total of 152 patients with sera for metabolite measurements and APOE genotype were included from the Dementia Study of Western Norway. The participants had mild Alzheimer disease and Lewy body dementia. Apolipoprotein E ε4 gene variant allele status was classified as one or more ε4 versus any other. Mini-Mental State Examination (MMSE) was measured at baseline and for 5 consecutive years. Mann-Whitney U tests and linear mixed-effects models were used for statistical analysis. Results: There were no significant differences in serum concentrations of tryptophan and kynurenine according to the presence or absence of APOEε4. High serum concentrations of kynurenic acid, quinolinic acid, and picolinic acid, and a higher kynurenine-to-tryptophan ratio, were all associated with more cognitive decline in patients without APOEε4 compared to those with the APOEε4 allele ( P-value of the interactions < .05). Conclusions: Kynurenic acid, quinolinic acid, picolinic acid, and the kynurenine-to-tryptophan ratio were associated with a significant increase in cognitive decline when the APOEε4 variant was absent, whereas there was a relatively less decline when the APOEε4 variant was present.

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Section: Discussioncontrasting

confidence: 50%

The Associations Between Cognitive Prognosis and Kynurenines Are Modified by the Apolipoprotein ε4 Allele Variant in Patients With Dementia

Ervik

Solvang

Nordrehaug

et al. 2019

Int J�Tryptophan�Res

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“…This is the case for the Kyn/Trp ratio. For example, an increased Kyn/Trp ratio was found to be associated with increased frailty (63), reduced cognitive performance (64), increased risk of cardiovascular disease (65, 66) and mortality (56, 66) in aged individuals. Other Kyn metabolites, including the 3-hydroxyanthranilic acid/anthranilic acid ratio and kynurenic acid, have also been associated with inflammation and poor outcome in the context of (age-related) diseases of the brain (67, 68).…”

Section: Tryptophan Metabolism As a Biomarker And Therapeutic Target mentioning

confidence: 99%

Tryptophan Metabolism in Inflammaging: From Biomarker to Therapeutic Target

et al. 2019

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Inflammation aims to restore tissue homeostasis after injury or infection. Age-related decline of tissue homeostasis causes a physiological low-grade chronic inflammatory phenotype known as inflammaging that is involved in many age-related diseases. Activation of tryptophan (Trp) metabolism along the kynurenine (Kyn) pathway prevents hyperinflammation and induces long-term immune tolerance. Systemic Trp and Kyn levels change upon aging and in age-related diseases. Moreover, modulation of Trp metabolism can either aggravate or prevent inflammaging-related diseases. In this review, we discuss how age-related Kyn/Trp activation is necessary to control inflammaging and alters the functioning of other metabolic faiths of Trp including Kyn metabolites, microbiota-derived indoles and nicotinamide adenine dinucleotide (NAD+). We explore the potential of the Kyn/Trp ratio as a biomarker of inflammaging and discuss how intervening in Trp metabolism might extend health- and lifespan.

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“…Recently, elevated circulating kynurenine (KYN), a tryptophan metabolite, was found in COPD [12]. The authors proposed KYN as a novel biomarker of systemic inflammation, but this marker has also been associated with impaired cognition and depression in non-COPD subjects [13,14]. Moreover, KYN could be a link between muscle impairment and disturbed mental health in COPD: Circulating KYN can cross the blood–brain barrier and in the brain KYN metabolites may negatively affect mental health.…”

Section: Introductionmentioning

confidence: 99%

Impaired Skeletal Muscle Kynurenine Metabolism in Patients with Chronic Obstructive Pulmonary Disease

Gosker

Clarke

Theije

et al. 2019

JCM

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Background: Loss of peripheral muscle oxidative phenotype, cognitive impairment, and depression are well-recognized systemic manifestations of chronic obstructive pulmonary disease (COPD). Kynurenine (KYN), known to be associated with disturbed mental health, can be metabolized in muscle by kynurenine aminotransferases (KAT) 1–4. These KATs are regulated by peroxisome proliferator-activated receptor gamma (PPARγ) coactivator-1α (PGC1α). We hypothesize that impaired PGC1α signaling in COPD is associated with reduced muscle KAT expression and increased KYN plasma levels. Methods: Retrospective collected and metabolically phenotyped muscle tissue and blood obtained from 29 well-characterized COPD patients and 15 healthy controls were analyzed. KYN was measured in plasma and KAT1–4 expression and major constituents of PGC1α signaling were assessed in quadriceps muscle biopsies. Results: Circulating KYN levels were increased in COPD. Furthermore, both gene and protein expression levels of KAT4 were reduced in muscle tissue from COPD patients. Finally, in the whole group (even when controlled for airflow obstruction) and in each subgroup separately, KAT4 gene expression correlated significantly with constituents of the PGC1α signaling pathway. Conclusions: These data support our hypothesis that KYN plasma levels are elevated in COPD through impaired KYN clearance in muscle. Our findings show a pathway via which exercise training and/or nutritional modulation may improve physical and mental health in COPD patients.

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The kynurenine pathway and cognitive performance in community-dwelling older adults. The Hordaland Health Study

Cited by 55 publications

References 69 publications

The Associations Between Cognitive Prognosis and Kynurenines Are Modified by the Apolipoprotein ε4 Allele Variant in Patients With Dementia

The Associations Between Cognitive Prognosis and Kynurenines Are Modified by the Apolipoprotein ε4 Allele Variant in Patients With Dementia

Tryptophan Metabolism in Inflammaging: From Biomarker to Therapeutic Target

Impaired Skeletal Muscle Kynurenine Metabolism in Patients with Chronic Obstructive Pulmonary Disease

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