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

Neuroinflammation and white matter disruptions have been implicated in cognitive impairments associated with bipolar disorder (BD), 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 BD. This study examines these associations in offspring with varying levels of risk for BD. Offspring of parents with BD 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 BD offspring and IPS deficits in offspring. This highlights potential neural mechanisms underlying cognitive dysfunction in pre-symptomatic and symptomatic stages of BD.