Protein expression is associated with brain white matter in Veterans with Bipolar disorder and suicide attempts

Brain Behav Immun. 2026 May 25:106836. doi: 10.1016/j.bbi.2026.106836. Online ahead of print.

ABSTRACT

BACKGROUND: Among individuals with neuropsychiatric disorders, those with bipolar disorder (BD) have one of the highest rates of suicide with this risk even further elevated in the Veteran population. The assessment of suicide risk is clinically challenging, but one of the best predictors of a future suicide attempt is having a prior attempt. Although prior studies have implicated proteomic abnormalities separately in BD and among those with a suicide attempt history, little is known regarding their combined contribution to suicide risk in BD and/or their relationship to the brain white matter.

METHODS: We analyzed 368 proteins targeting disease and pathway specific biomarkers using the OLINK platform in Veterans with BD either having (BD/SA + ) or not having (BD/SA-) a past suicide attempt (SA) history and healthy control (HC) Veterans. We used neurite orientation and dispersion density imaging to derive average indices of fiber coherence (i.e., orientation dispersion index, ODI), axon and dendrite density (i.e., neurite density, NDI) and extracellular free-water indicative of diffusion (isotropic volume fraction, ISOVF) within the brain white matter.

RESULTS: Three proteins (NEP, KYNU and IL-12B) had significantly lower expression in both the BD/SA + and BD/SA- groups compared to HC. In the combined group of individuals with BD, lower expression of these 3 proteins correlated significantly with lower neurite density across the brain white matter. Two proteins had significantly higher (i.e., AZU1 and CEACAM8) and one significantly lower (i.e., MMP7) expression in the BD/SA + group compared to both the BD/SA- and HC groups. In the BD/SA + group, higher protein expression of AZU1 and CEACAM8 was associated with a higher ISOVF in the brain white matter. Pathway analysis indicated enrichment of innate immune, neutrophil degranulation, and cytokine signaling pathways among the differentially expressed proteins.

DISCUSSION: In this exploratory study we found that among all individuals with BD, proteomic abnormalities were associated with an index of neurite density (i.e., axonal and dendritic packing) within brain white matter, whereas in BD/SA + abnormal protein expression was associated with a higher ISOVF, potentially reflecting inflammation, edema and/or atrophy. Immune-related biology may represent a mechanistic link between peripheral inflammatory signals and alterations in brain microstructure among individuals with BD at heightened risk of suicide, but should be considered preliminary until replicated in larger cohorts.

PMID:42190847 | DOI:10.1016/j.bbi.2026.106836