Cerebral Small Vessel Disease-driven Inflammatory Cytokines, Brain Structural Alterations, and Cognitive Function: A Mendelian Randomization Study

OBJECTIVE: This study aimed to investigate the role of circulating inflammatory cytokines in the pathway linking cerebral small vessel disease (CSVD) to cognitive impairment (CI), and to further elucidate the neuroimaging mechanism of CSVD-driven inflammatory cytokines on cognitive function. METHODS: We conducted a two-step, two-sample Mendelian randomization (MR) analysis to evaluate the causal effect of CSVD on circulating inflammatory cytokines and CSVD-driven inflammatory cytokines on the risk of CI. Using a separate two-sample MR analysis, we explored the potential mechanisms by which these inflammatory cytokines affect cognition, with cytokines identified as mediators between CSVD and CI treated as exposure and brain structural imaging as outcomes. RESULTS: Genetically predicted CSVD was causally associated with the levels of 11 circulating inflammatory cytokines. Among these CSVD-driven inflammatory cytokines, growth-regulated oncogene alpha (GROα) was associated with poorer verbal and numerical reasoning, stem cell factor (SCF) was associated with better working memory, and tumor necrosis factor-alpha (TNF-α) was associated with reduced processing speed. SCF mediated the association between small-vessel ischemic stroke and numeric memory performance, with a mediation effect of 10%. Furthermore, circulating SCF levels showed causal relationships with the volumes of multiple brain regions within the default mode network and with the integrity of seven white matter tracts. CONCLUSION: SCF, GROα, and TNF-α play important roles in the pathway linking CSVD to CI. Circulating SCF may influence cognitive function by modulating brain volume and white matter integrity.