Unveiling causal relationships between inflammatory cytokines and neurite orientation dispersion and density imaging phenotypes: Insights from bidirectional Mendelian randomization and bibliometric analysis

BACKGROUND: Inflammatory factors interact with brain imaging-derived phenotypes (IDPs); however, the specific causal relationships between inflammatory factors and brain white matter (WM)-related IDPs remain unclear. Thus, we sought to analyze the potential causal effects of inflammatory factors on brain WM-related IDPs using Mendelian randomization (MR). METHODS: We obtained the data of 41 inflammatory factors from a genome-wide association study (GWAS) from the Cardiovascular Risk in Young Finns Study and the FINRISK surveys, as well as the data of 144 neurite orientation dispersion and density imaging (NODDI) IDPs including intracellular volume fraction (ICVF), isotropic volume fraction (ISOVF), and orientation dispersion index (ODI) from the United Kingdom Biobank (UKB). We then conducted two-sample MR analyses to examine their causal interactions by employing the inverse variance weighting (IVW), MR Egger, weighted median, simple mode, and weighted mode methods, collectively enhancing the robustness of our results. Besides, bibliometric analysis was employed to investigate the overview of inflammatory factor-brain WM research. RESULTS: Pronounced correlations are discerned between extensive inflammatory factors and NODDI IDPs, primarily involving cerebellar peduncle, corpus callosum, uncinate fasciculus, posterior thalamic radiation, posterior corona radiata, medial lemniscus, superior longitudinal fasciculus, superior fronto-occipital fasciculus, and internal capsule. Besides, bibliometric analysis demonstrates that microglia play an important role in inflammation-mediated white matter changes. CONCLUSIONS: This study identified genetic evidence indicating that dysbiosis of inflammatory factors exerts causal effects on microstructural diffusion properties of brain WM. Our findings provide novel insights into the diagnostic and therapeutic management of central nervous system (CNS) disorders.