Kynurenine pathway metabolites in cerebrospinal fluid and blood as potential biomarkers in Huntington's disease

Rodrigues, Filipe B; Byrne, Lauren M.; Lowe, Alexander J.; Tortelli, Rosanna; Heins, Mariette; Flik, Gunnar; Johnson, Eileanoir B.; Vita, Enrico De; Scahill, Rachael I.; Giorgini, Flaviano; Wild, Edward J.

doi:10.1111/jnc.15360

Cited by 23 publications

(16 citation statements)

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“…The activation of neuroinflammatory response and microglia could further increase the activity of IDO and KP downstream ( 4 ). A recent study conducted on 40 premanifest HD patients, 40 manifest HD patients, and 20 HCs, denied the alteration of KP during HD pathogenesis ( 108 ). In contrast, we found that blood levels of TRP and KYN were significantly lower in HD patients than controls (SMD=-0.90, 95% CI=-1.71 to -0.10, p=0.028, I2 = 91.0%, k=5, n=369) ( Table 6 ).…”

Section: Discussionmentioning

confidence: 99%

Dynamic changes in metabolites of the kynurenine pathway in Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease: A systematic Review and meta-analysis

et al. 2022

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BackgroundTryptophan (TRP) is an essential amino acid that must be provided in the diet. The kynurenine pathway (KP) is the main route of TRP catabolism into nicotinamide adenosine dinucleotide (NAD+), and metabolites of this pathway may have protective or degenerative effects on the nervous system. Thus, the KP may be involved in neurodegenerative diseases.ObjectivesThe purpose of this systematic review and meta-analysis is to assess the changes in KP metabolites such as TRP, kynurenine (KYN), kynurenic acid (KYNA), Anthranilic acid (AA), 3-hydroxykynurenine (3-HK), 5-Hydroxyindoleacetic acid (5-HIAA), and 3-Hydroxyanthranilic acid (3-HANA) in Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD) patients compared to the control group.MethodsWe conducted a literature search using PubMed/Medline, Scopus, Google Scholar, Web of Science, and EMBASE electronic databases to find articles published up to 2022. Studies measuring TRP, KYN, KYNA, AA, 3-HK, 5-HIAA, 3-HANA in AD, PD, or HD patients and controls were identified. Standardized mean differences (SMDs) were used to determine the differences in the levels of the KP metabolites between the two groups.ResultsA total of 30 studies compromising 689 patients and 774 controls were included in our meta-analysis. Our results showed that the blood levels of TRP was significantly lower in the AD (SMD=-0.68, 95% CI=-0.97 to -0.40, p=0.000, I2 = 41.8%, k=8, n=382), PD (SMD=-0.77, 95% CI=-1.24 to -0.30, p=0.001, I2 = 74.9%, k=4, n=352), and HD (SMD=-0.90, 95% CI=-1.71 to -0.10, p=0.028, I2 = 91.0%, k=5, n=369) patients compared to the controls. Moreover, the CSF levels of 3-HK in AD patients (p=0.020) and the blood levels of KYN in HD patients (p=0.020) were lower compared with controls.ConclusionOverall, the findings of this meta-analysis support the hypothesis that the alterations in the KP may be involved in the pathogenesis of AD, PD, and HD. However, additional research is needed to show whether other KP metabolites also vary in AD, PD, and HD patients. So, the metabolites of KP can be used for better diagnosing these diseases.

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Section: Discussionmentioning

confidence: 99%

Dynamic changes in metabolites of the kynurenine pathway in Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease: A systematic Review and meta-analysis

et al. 2022

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“…However, there are too few studies on these two genes, and we cannot yet explain the relationship of these two genes with the phenotype. Furthermore, among the genes with nominal significance levels, many were associated with grip strength and depression: (1) FNBP1 can affect neuronal dendrites [ 64 ] and actin [ 65 ], which may affect grip strength and depression; (2) MOG is associated with multiple sclerosis [ 66 , 67 ], the main symptoms of which include depression and decreased muscle strength; (3) the SACS gene can affect motor and sensory neuropathy [ 68 ], and is associated with complex neurological disorders [ 69 ]; (4) the KMO gene is associated with depression [ 70 , 71 ] and Huntington’s disease [ 72 ], the symptoms of which include muscle atrophy; (5) the TECPR2 gene is tightly linked to the nervous system [ 73 – 76 ] and may influence depression and grip strength by affecting nerves; and (6) MGTA5 can affect the severity of multiple sclerosis [ 77 , 78 ]. MGTA5 may also be associated with attempted suicide [ 79 ], and therefore may be associated with depression.…”

Section: Discussionmentioning

confidence: 99%

A genetic correlation and bivariate genome-wide association study of grip strength and depression

Zhang

Luo

et al. 2022

PLoS ONE

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Grip strength is an important biomarker reflecting muscle strength, and depression is a psychiatric disorder all over the world. Several studies found a significant inverse association between grip strength and depression, and there is also evidence for common physiological mechanisms between them. We used twin data from Qingdao, China to calculate genetic correlations, and we performed a bivariate GWAS to explore potential SNPs, genes, and pathways in common between grip strength and depression. 139 pairs of Dizygotic twins were used for bivariate GWAS. VEAGSE2 and PASCAL software were used for gene-based analysis and pathway enrichment analysis, respectively. And the resulting SNPs were subjected to eQTL analysis and pleiotropy analysis. The genetic correlation coefficient between grip strength and depression was -0.41 (-0.96, -0.15). In SNP-based analysis, 7 SNPs exceeded the genome-wide significance level (P<5×10−8) and a total of 336 SNPs reached the level of suggestive significance (P<1×10−5). Gene-based analysis and pathway-based analysis identified genes and pathways related to muscle strength and the nervous system. The results of eQTL analysis were mainly enriched in tissues such as the brain, thyroid, and skeletal muscle. Pleiotropy analysis shows that 9 of the 15 top SNPs were associated with both grip strength and depression. In conclusion, this bivariate GWAS identified potentially common pleiotropic SNPs, genes, and pathways in grip strength and depression.

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“…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 ].…”

Section: Distribution Of Kynurenic Acidmentioning

confidence: 99%

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

et al. 2022

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Kynurenic acid (KYNA), a metabolite of tryptophan, is an endogenous substance produced intracellularly by various human cells. In addition, KYNA can be synthesized by the gut microbiome and delivered in food. However, its content in food is very low and the total alimentary supply with food accounts for only 1–3% of daily KYNA excretion. The only known exception is chestnut honey, which has a higher KYNA content than other foods by at least two orders of magnitude. KYNA is readily absorbed from the gastrointestinal tract; it is not metabolized and is excreted mainly in urine. It possesses well-defined molecular targets, which allows the study and elucidation of KYNA’s role in various pathological conditions. Following a period of fascination with KYNA’s importance for the central nervous system, research into its role in the peripheral system has been expanding rapidly in recent years, bringing some exciting discoveries. KYNA does not penetrate from the peripheral circulation into the brain; hence, the following review summarizes knowledge on the peripheral consequences of KYNA administration, presents data on KYNA content in food products, in the context of its daily supply in diets, and systematizes the available pharmacokinetic data. Finally, it provides an analysis of the rationale behind enriching foods with KYNA for health-promoting effects.

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Kynurenine pathway metabolites in cerebrospinal fluid and blood as potential biomarkers in Huntington's disease

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 23 publications

References 64 publications

Dynamic changes in metabolites of the kynurenine pathway in Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease: A systematic Review and meta-analysis

Dynamic changes in metabolites of the kynurenine pathway in Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease: A systematic Review and meta-analysis

A genetic correlation and bivariate genome-wide association study of grip strength and depression

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

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