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. 2024 Aug 29:38:100328.
doi: 10.1016/j.scog.2024.100328. eCollection 2024 Dec.

Neuroinflammation and kynurenines in schizophrenia: Impact on cognition depending on cognitive functioning and modulatory properties in relation to cognitive remediation and aerobic exercise

Jacopo Sapienza  1   2 , Giulia Agostoni  1 , Stefano Comai  3   4   5   6 , Sofia Nasini  3 , Stefano Dall'Acqua  3 , Stefania Sut  3 , Marco Spangaro  1 , Francesca Martini  1 , Margherita Bechi  1 , Mariachiara Buonocore  1 , Giorgia Bigai  7 , Federica Repaci  1 , Daniela Nocera  7 , Chiara Ave  7 , Carmelo Guglielmino  1 , Federica Cocchi  1 , Roberto Cavallaro  1   7 , Giacomo Deste  8 , Marta Bosia  1   7
Affiliations

Neuroinflammation and kynurenines in schizophrenia: Impact on cognition depending on cognitive functioning and modulatory properties in relation to cognitive remediation and aerobic exercise

Jacopo Sapienza et al. Schizophr Res Cogn. .

Abstract

Background: In the last decade, the kynurenine pathway (KP) has gained attention in the pathogenesis of cognitive impairment in schizophrenia being at the croassroad between neuroinflammation and glutamatergic and cholinergic neurotransmission. However, clinical findings are scarse and conflicting, and the specific contributions of these two systems to the neurobiology of cognitive symptoms are far from being elucidated. Furthermore, little is known about the molecular underpinnings of non-pharmacological interventions for cognitive improvement, including rehabilitation strategies.

Methods: The current study examined 72 patients with schizophrenia, divided in two clusters depending on the severity of the cognitive impairment, with the aim to evaluate the impact of inflammatory biomarkers and KP metabolites depending on cognitive functioning. Moreover, we studied their possible link to the cognitive outcome in relation to sessions of cognitive remediation therapy (CRT) and aerobic exercise (AE) in a longitudinal arm of 42 patients.

Results: Neuroinflammation appeared to exert a more pronounced influence on cognition in patients exhibiting a higher cognitive functioning, contrasting with the activation of the KP, which had a greater impact on individuals with a lower cognitive profile. Cognitive improvements after the treatments were negatively predicted by levels of TNF-α and positively predicted by the 3-hydroxykynurenine (3-HK)/kynurenine (KYN) ratio, an index of the kynurenine-3-monooxygenase (KMO) enzyme activity.

Conclusion: Overall, these findings add novel evidence on the biological underpinnings of cognitive impairment in schizophrenia pointing at a differential role of neuroinflammation and KP metabolites in inducing cognitive deficits depending on the cognitive reserve and predicting outcomes after rehabilitation.

Keywords: Cognition; Interleukines; Kynurenine 3-monooxygenase; Kynurenine pathway; Non-pharmacological treatments; TNF-α.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1
Fig. 1
Study design and flowchart.
Fig. 2
Fig. 2
Separation of the silhouettes based on cognition for Cluster 1 and Cluster 2.
Fig. 3
Fig. 3
Effect of 3HK/KYN ratio and 3HK/KYN and QUIN/KYNA ratio on Processing Speed.
Fig. 4
Fig. 4
Effect of TNF-α on Visual Learning.
See this image and copyright information in PMC

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