Inflammatory markers (IL-6 and CRP) in childhood and their association with brain structure and psychotic experiences in adulthood

• Childhood inflammation is associated with differences in adult brain structure. • Interleukin-6 is linked to reduced brain volume in regions involved in memory, language, and self-reflection. • C-reactive protein is linked to increased brain volume only in individuals with psychotic experiences. • Findings suggest heightened vulnerability to CRP effects on the brain in those who later develop psychotic experiences. • Results provide a mechanistic pathway linking inflammation as a developmental risk factor for psychosis. Inflammation is a risk factor for psychosis, yet the mechanisms underlying this association remain unclear. Elevated levels of the inflammatory markers C-reactive protein (CRP) and interleukin-6 (IL-6) in childhood have been associated with increased risk of developing later psychotic experiences (PEs) and psychotic disorders. This study investigates whether CRP and IL-6 levels at age 9 are associated with brain grey matter volume at age 20, and whether this association differs between individuals with and without PEs. We hypothesise that childhood inflammation will be linked to altered grey matter volumes in adulthood, and this association will be strongest among those who develop PEs. In the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort, MRI scans were acquired at age 20 years in participants with PEs (n = 71) and controls without PEs (n = 173). Voxel-based morphometry examined the association between childhood CRP or IL-6 and grey matter volume in adulthood, with interaction analyses testing for group differences by PEs status. In all participants (PEs and controls) elevated IL-6 in childhood was associated with smaller grey matter volume in adulthood, in several cortical regions which did not reach significance. After excluding 4 subjects with potential acute infection, IL-6 was associated with smaller grey matter volume in the left supramarginal gyrus ( p FWE = 0.028, Z = 4.24, family-wise error (FWE) corrected), right parahippocampal gyrus ( p FWE = 0.047; Z = 4.21; 292 voxels), and left precuneus ( p FWE = 0.035; Z = 3.65). No interaction between IL-6 and PEs group on grey matter volume was found. A significant interaction between CRP and PEs group was observed on grey matter volume ( p FWE = 0.013, Z = 4.13). Elevated CRP levels in childhood were associated with larger right superior frontal gyrus volume in individuals with PEs, whereas CRP did not impact grey matter volume in controls. Effect sizes reduced after excluding 5 subjects with potential acute infection. These findings suggest that individuals who go on to develop PEs were more vulnerable to the effects of circulating CRP on grey matter volume, consistent with a possible disease-specific pathway linking inflammation to psychosis. In contrast, IL-6 was associated with smaller volume in regions of the default mode network regardless of PEs, suggesting a more general effect on brain development.