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. 2025 Aug 12;24(1):48.
doi: 10.1186/s12991-025-00591-9.

Effects of proinflammatory cytokines and programmed cell death on cognitive domains in older age patients with bipolar disorder

Pei-Ying Lee  1 , Chih Chiang Chiu  1   2 , Po-Hsiu Kuo  3   4 , Cho-Yin Huang  1   3 , Shang-Ying Tsai  2   5 , Chian-Jue Kuo  1   2   5 , Wen-Yin Chen  6   7   8
Affiliations

Effects of proinflammatory cytokines and programmed cell death on cognitive domains in older age patients with bipolar disorder

Pei-Ying Lee et al. Ann Gen Psychiatry. .

Abstract

Objectives: Proinflammatory cytokines are linked to cognitive deficits in bipolar disorder (BD). The programmed cell death (PD) pathway, involved in immune regulation, may impact mood disorders and dementia. Older age BD (OABD) patients face a heightened risk of cognitive decline, yet studies exploring the underlying mechanisms in this population are scarce. Aim of this study is to investigate proinflammatory cytokines and the PD pathway in OABD, for their correlation with clinical features and neuroaxonal integrity, and the impact on cognitive domains.

Methods: Eighty-seven euthymic OABD patients were assessed using the Brief Assessment of Cognition in Affective Disorders. We measured CRP, IL-6, TNF-α, TNF-R1, TNF-R2, PD-1, and PD-L1. Neurofilament light chain (NfL) was used to gauge neuroaxonal integrity. Associations between cytokines, PD-1/PD-L1, and cognition were examined using linear regression models.

Results: The average age of the OABD patients was 59.64 with a mean illness duration of 27.19 years. NfL levels positively correlated with TNF-R2 levels. Regression analysis revealed a negative association between TNF-R1 and motor speed and verbal fluency, while TNF-R2 showed positive associations with these cognitive domains. PD-1 was negatively associated with composite score, especially in motor speed and working memory, while PD-L1 was positively associated with executive function.

Conclusion: This is the first study to simultaneously examine the proinflammatory system and the PD-1/PD-L1 pathway in a clinical OABD sample, with findings suggesting that both systems impact cognitive function in OABD patients. Further research is needed to explore the neuroinflammatory mechanisms underlying BD's neurodegenerative course.

Keywords: Cytokines; Neuroaxonal integrity; Neuroinflammatory; Older age bipolar disorders (OABD); Programmed cell death.

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Conflict of interest statement

Declarations. Ethics statement: The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008. All procedures involving human subjects were approved by the Research Ethics Committee of Taipei City Hospital (TCHIRB- 11201001). Written informed consent was obtained from all participants. Competing interests: The authors declare no competing interests.

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