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

Article type: Systematic Review

Authors: Almulla, Abbas F.^{a; b} | Supasitthumrong, Thitiporn^a | Amrapala, Arisara^a | Tunvirachaisakul, Chavit^{a; c} | Jaleel, Al-Karrar Kais Abdul^b | Oxenkrug, Gregory^d | Al-Hakeim, Hussein K.^e | Maes, Michael^{a; f; g; *}

Affiliations: [a] Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand | [b] Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf, Iraq | [c] Cognitive Impairment and Dementia Research Unit, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand | [d] Department of Psychiatry, Tufts University School of Medicine and Tufts Medical Center, Boston, MA, USA | [e] Department of Chemistry, College of Science, University of Kufa, Kufa, Iraq | [f] Department of Psychiatry, Medical University of Plovdiv, Plovdiv, Bulgaria | [g] Department of Psychiatry, IMPACT Strategic Research Centre, Deakin University, Geelong, VIC, Australia

Correspondence: [*] Correspondence to: Prof. Dr. Michael Maes, MD, PhD, Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand. E-mail: [email protected].

Abstract: Background:Alzheimer’s disease (AD), which is characterized by progressive brain dysfunction and memory loss, is one of the most significant global health concerns for older adults. Neuroinflammation and increased oxidative stress contribute to the pathophysiology of AD, thereby presumably inducing tryptophan (TRP) degradation through the TRP catabolite (TRYCAT) pathway. Objective:To delineate the activity of the TRYCAT pathway along with levels of TRP and tryptophan catabolites (TRYCATs) in AD patients. Methods:We used PubMed, Google Scholar, Web of Science, and SciFinder during the month of January 2022 to gather the pertinent publications. We found 19 eligible articles which involved 738 patients and 665 healthy controls. Results:Our results revealed a significant difference (p = 0.008) in the kynurenine (KYN)/TRP ratio (standardized mean difference, SMD = 0.216, 95% confidence interval, CI: 0.057; 0.376), and a significant decrease in TRP in AD patients (SMD = –0.520, 95% CI: –0.738; –0.302, p < 0.0001). Moreover, we also found a significant increase in the central nervous system (CNS), brain, and cerebrospinal fluid kynurenic acid (KA)/KYN ratio but not in peripheral blood, as well as a significant decrease in plasma KA and xanthurenic acid in the CNS and blood. Conclusion:AD is characterized by TRP depletion but not by an overactivity of the TRYCAT pathway. IDO-induced production of neurotoxic TRYCATs is not a key factor in the pathophysiology of AD.

Keywords: Biomarkers, inflammation, kynurenine, neuro-immune, oxidative stress, psychiatry

DOI: 10.3233/JAD-220295

Journal: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1325-1339, 2022