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

Merritt, Kate, Palmer, Edward R., Laguna, Pedro Luque, Sethi, Arjun, Rogers, Jack C., Evans, C. John ORCID: https://orcid.org/0000-0002-6619-4245, Reichenberg, Abraham, Khandaker, Golam M., Upthegrove, Rachel, Lewis, Glyn, Jones, Derek ORCID: https://orcid.org/0000-0003-4409-8049 and David, Anthony S. 2026. Inflammatory markers (IL-6 and CRP) in childhood and their association with brain structure and psychotic experiences in adulthood. Brain, Behavior, and Immunity 133 , 106247. 10.1016/j.bbi.2025.106247

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Abstract

Aims 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. Methods 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. Results 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 (pFWE = 0.028, Z = 4.24, family-wise error (FWE) corrected), right parahippocampal gyrus (pFWE = 0.047; Z = 4.21; 292 voxels), and left precuneus (pFWE = 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 (pFWE = 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. Conclusions 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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Psychology Research Institutes & Centres > Cardiff University Brain Research Imaging Centre (CUBRIC)
Publisher:	Elsevier BV
ISSN:	0889-1591
Date of First Compliant Deposit:	2 February 2026
Date of Acceptance:	24 December 2025
Last Modified:	02 Feb 2026 13:45
URI:	https://orca.cardiff.ac.uk/id/eprint/184343

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