Neuroinflammation and white matter microstructure as mediators of cognitive deficits in offspring of parents with bipolar disorder.

Overview

1. Department of Affective Disorder, The Affiliated Brain Hospital, Guangzhou Medical University, Guangzhou 510145, Guangdong, P.R. China
2. Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou Medical University, Guangzhou 510145, Guangdong, P.R. China
3. Department of Psychology, The University of Hong Kong, Hong Kong 000000, P.R. China
4. Department of Psychiatry and Neuroscience, College of Medicine, China Medical University, Taichung 406040, Taiwan
5. Department of Psychiatry and Behavioral Sciences, School of Medicine, The Chinese University of Hong Kong, Shenzhen (CUHK-Shenzhen), Shenzhen ‌518172, Guangdong, P.R. China
6. Department of Neurology, Lecong Hospital of Shunde, Foshan 528315, Guangdong, P.R. China
7. The Third Affiliated Hospital of Henan Medical University, Xinxiang 453000, Henan, P.R. China

Abstract

Neuroinflammation and white matter disruptions have been implicated in cognitive impairments associated with bipolar disorder, particularly in information processing speed (IPS). These neurological factors may manifest in at-risk offspring, even prior to the full development of the disorder, emphasizing the importance of investigating their role in early cognitive changes associated with bipolar disorder. This study examines these associations in offspring with varying levels of risk for bipolar disorder. Offspring of parents with bipolar disorder were classified as asymptomatic (AO, n = 41) or symptomatic (SO, n = 35) groups and age-matched healthy controls (HCs, n = 32). We assessed serum interleukin-6 (IL-6) levels, IPS performance and fractional anisotropy (FA) of the forceps major (FM) connecting the occipital lobes. Compared to AO, SO demonstrated significantly higher IL-6 levels, reduced FM FA and lower IPS performance, while the AO group exhibited preserved FM FA and IPS performance comparable to HCs. Serial mediation analysis revealed that symptomatic status among offspring at familial risk exerted a significant total indirect effect (β = −3.83, 95% CI [−7.28, −0.84]) on IPS performance through the pathways involving IL-6 and FM FA. This indirect effect accounted for 42.46% of the total effect, indicating significant full mediation. Our findings suggest that neuroinflammation and FM microstructure mediate the association between symptomatic status for bipolar disorder offspring and IPS deficits in offspring. This highlights potential neural mechanisms underlying cognitive dysfunction in pre-symptomatic and symptomatic stages of bipolar disorder.

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Version 2, 28 September 2026

• Funding: added National Natural Science Foundation of China: 82171531, U22A20301, NSFC: U22A20301, NSFC:81671347, 81671347, NSFC: 82171531

Version 1, 28 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 8 authors, 5 keywords, 60 references.

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This paper

Li, X., Zou, W., Shao, R., Lu, W., Chao, L., Zhao, X., Su, K.-P., & Lin, K. (2026). Neuroinflammation and white matter microstructure as mediators of cognitive deficits in offspring of parents with bipolar disorder. Brain communications, 8(3), fcag181. https://doi.org/10.1093/braincomms/fcag181

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