The Tryptophan Catabolite or Kynurenine Pathway in Alzheimer’s Disease: A Systematic Review and Meta-Analysis

Almulla, Abbas F.; Supasitthumrong, Thitiporn; Amrapala, Arisara; Tunvirachaisakul, Chavit; Jaleel, Al-Karrar Kais Abdul; Oxenkrug, Gregory F.; Al‐Hakeim, Hussein Kadhem; Maes, Michaël

doi:10.3233/jad-220295

Cited by 22 publications

(25 citation statements)

References 78 publications

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“…The effect size was described as large, moderate, and small based on the SMD values of 0.80, 0.5, and 0.20, respectively (Cohen 1988). In accordance with prior meta-analyses (Almulla, Vasupanrajit et al 2022, Vasupanrajit, Jirakran et al 2022), heterogeneity was determined by calculating tau-squared statistics, although we also show the Q and I 2 metrics. To identify the causes of heterogeneity in the present meta-analysis, a meta-regression was conducted.…”

Section: Methodsmentioning

confidence: 60%

“…Nonetheless, our negative results concerning TRYCAT and IDO levels do not support the theory that activation of IDO/TDO is involved in MDD/BD (Maes 2015). While the TRYCAT pathway is activated during severe IRS responses, such as acute COVID-19 infection (Almulla, Supasitthumrong et al 2022) and IFN-α therapy (Bonaccorso, Marino et al 2002), no such changes may be observed in conditions of mild chronic inflammation, such as MDD/BD (this study) and Alzheimer’s disease (Almulla, Supasitthumrong et al 2022). Since plasma/serum TRP concentrations are around 50 μmol/L while KYN concentrations are around 3 μmol/L, TRP is abundantly available as a substrate for KYN formation.…”

Section: Discussionmentioning

confidence: 71%

“…When TRP concentrations are low, catalytically inactive ferric IDO1 may accumulate during turnover and the enzyme may autooxidize (Booth, Basran et al 2015). Second, the IDO enzyme is inhibited by nitric oxide (NO), which is significantly increased in MDD and BD (Savaş, Herken et al 2002, Talarowska, Gałecki et al 2012, Maes, Simeonova et al 2019).…”

Section: Discussionmentioning

confidence: 99%

“…The neurotoxicity index and ratios were compared between patients and controls by computing the mean values of the outcomes while assuming dependence. Thus, we compared the neurotoxic TRYCATs profile of patients with affective disorders and healthy controls by entering the relevant TRYCATs in the meta-analysis, and we analyzed the KYN/TRP, KA/KYN and 3HK/KYN ratios as an indexes for IDO, KAT and KMO enzyme activities respectively (Almulla, Vasupanrajit et al 2022). IDO enzyme activity is estimated by selecting a positive effect size direction for increasing KYN and a negative direction for lowered TRP levels in patients, KAT activity was assessed by setting KA as positive and KYN as negative, KMO by setting 3HK as positive and KYN as negative, and the TRP/CAAs ratio by setting TRP as positive and CAA as negative.…”

Section: Methodsmentioning

confidence: 99%

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The tryptophan catabolite or kynurenine pathway in major depressive and bipolar disorder: a systematic review and meta-analysis

Almulla

Thipakorn

Maes

et al. 2022

Preprint

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Background: There is now evidence that affective disorders including major depressive disorder (MDD) and bipolar disorder (BD) are mediated by immune-inflammatory and nitro-oxidative pathways. Activation of these pathways may be associated with activation of the tryptophan catabolite (TRYCAT) pathway leading to depletion of tryptophan (TRP) and increases in tryptophan catabolites (TRYCATs). Aims: To systematically review and meta-analyze TRP, its competing amino-acids (CAAs) and TRYCAT data in MDD and BD. Methods: This review searched PubMed, Google Scholar and SciFinder and included 121 full-text articles and 15470 individuals, including 8024 MDD/BD patients and 7446 healthy controls. Results: TRP levels (either free and total) and the TRP/CAAs ratio were significantly decreased (p<0.0001) in MDD/BD as compared with controls with a moderate effect size (standardized mean difference for TRP: SMD=-0.513, 95% confidence interval, CI: -0.611; -0.414; and TRP/CAAs: SMD=-0.558, CI: -0.758; -0.358). Kynurenine (KYN) levels were significantly decreased in patients as compared with controls with a small effect size (p<0.0001, SMD= -0.213, 95%CI: -0.295; -0.131). These differences were significant in plasma (p<0.0001, SMD=-0.304, 95%CI: -0.415, -0.194) but not in serum (p=0.054) or the central nervous system (CNS, p=0.771). The KYN/TRP ratio, frequently used as an index of indoleamine-dioxygenase (IDO) activity, and neurotoxicity indices based on downstream TRYCATs were unaltered or even lowered in MDD/BD. Conclusions: Our findings revealed that MDD/BD are accompanied by TRP depletion without IDO and TRYCAT pathway activation. Lowered TRP availability is probably the consequence of lowered serum albumin during the inflammatory response in affective disorders.

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Section: Methodsmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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The tryptophan catabolite or kynurenine pathway in major depressive and bipolar disorder: a systematic review and meta-analysis

Almulla

Thipakorn

Maes

et al. 2022

Preprint

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“…The last author (MM) was consulted in the case of controversial results. The last author slightly adjusted the "immune confounder scale (ICS)" published previously [36][37][38] to estimate the methodological quality of TRY CAT studies. This ICS and the related repoint checklist are shown in Additional file 1: Table S2.…”

Section: Screening and Data Extractionmentioning

confidence: 99%

The tryptophan catabolite or kynurenine pathway in COVID-19 and critical COVID-19: a systematic review and meta-analysis

et al. 2022

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Background Coronavirus disease 2019 (COVID-19) is accompanied by activated immune-inflammatory pathways and oxidative stress, which both induce indoleamine-2,3-dioxygenase (IDO), a key enzyme of the tryptophan (TRP) catabolite (TRYCAT) pathway. The aim of this study was to systematically review and meta-analyze the status of the TRYCAT pathway, including the levels of TRP and kynurenine (KYN) and the activity of IDO, as measured by the ratio of KYN/TRP. Methods This systematic review searched PubMed, Google Scholar, and Web of Sciences and included 14 articles that compared TRP and tryptophan catabolites (TRYCATs) in COVID-19 patients versus non-COVID-19 controls, as well as severe/critical versus mild/moderate COVID-19. The analysis was done on a total of 1269 people, including 794 COVID-19 patients and 475 controls. Results The results show a significant (p < 0.0001) increase in the KYN/TRP ratio (standardized mean difference, SMD = 1.099, 95% confidence interval, CI: 0.714; 1.484) and KYN (SMD = 1.123, 95% CI: 0.730; 1.516) and significantly lower TRP (SMD = − 1.002, 95%CI: − 1.738; − 0.266) in COVID-19 versus controls. The KYN/TRP ratio (SMD = 0.945, 95%CI: 0.629; 1.262) and KYN (SMD = 0.806, 95%CI: 0.462; 1.149) were also significantly (p < 0.0001) higher and TRP lower (SMD = − 0.909, 95% CI: − 1.569; − 0.249) in severe/critical versus mild/moderate COVID-19. No significant difference was detected in kynurenic acid (KA) and the KA/KYN ratio between COVID-19 patients and controls. Conclusions Our results indicate increased activity of the IDO enzyme in COVID-19 and severe/critical patients. The TRYCAT pathway is implicated in the pathophysiology and progression of COVID-19 and may signal a worsening outcome of the disease.

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The tryptophan catabolite or kynurenine pathway in autism spectrum disorder; a systematic review and meta‐analysis

Almulla,

Thipakorn,

Tunvirachaisakul

et al. 2023

Autism Research

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Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social communication and interaction, as well as rigid and unchanging interests and behaviors. Several studies have reported that activated immune‐inflammatory and nitro‐oxidative pathways are accompanied by depletion of plasma tryptophan (TRP), increased competing amino acid (CAAs) levels, and activation of the TRP catabolite (TRYCAT) pathway. This study aims to systematically review and meta‐analyze data on peripheral TRP, CAAs, TRYCAT pathway activity, and individual TRYCATs, including kynurenine (KYN) and kynurenic acid (KA) levels, in the blood and urine of ASD patients. After extensively searching PubMed, Google Scholar, and SciFinder, a total of 25 full‐text papers were included in the analysis, with a total of 6653 participants (3557 people with ASD and 3096 healthy controls). Our results indicate that blood TRP and the TRP/CAAs ratio were not significantly different between ASD patients and controls (standardized mean difference, SMD = −0.227, 95% confidence interval, CI: −0.540; 0.085, and SMD = 0.158, 95% CI: −0.042; 0.359), respectively. The KYN/TRP ratio showed no significant difference between ASD and controls (SMD = 0.001, 95% CI: −0.169; 0.171). Blood KYN and KA levels were not significantly changed in ASD. Moreover, there were no significant differences in urine TRP, KYN, and KA levels between ASD and controls. We could not establish increases in neurotoxic TRYCATs in ASD. In conclusion, this study demonstrates no abnormalities in peripheral blood TRP metabolism, indoleamine 2,3‐dioxygenase enzyme (IDO) activity, or TRYCAT production in ASD. Reduced TRP availability and elevated neurotoxic TRYCAT levels are not substantial contributors to ASD's pathophysiology.

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The Tryptophan Catabolite or Kynurenine Pathway in Alzheimer’s Disease: A Systematic Review and Meta-Analysis

Cited by 22 publications

References 78 publications

The tryptophan catabolite or kynurenine pathway in major depressive and bipolar disorder: a systematic review and meta-analysis

The tryptophan catabolite or kynurenine pathway in major depressive and bipolar disorder: a systematic review and meta-analysis

The tryptophan catabolite or kynurenine pathway in COVID-19 and critical COVID-19: a systematic review and meta-analysis

The tryptophan catabolite or kynurenine pathway in autism spectrum disorder; a systematic review and meta‐analysis

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