Altered activation of innate immunity associates with white matter volume and diffusion in first-episode psychosis

Abstract

First-episode psychosis (FEP) is associated with inflammatory and brain structural changes, but few studies have investigated whether systemic inflammation associates with brain structural changes in FEP. Thirty-seven FEP patients (median 27 days on antipsychotic medication), and 19 matched controls were recruited. Serum levels of 38 chemokines and cytokines, and cardiovascular risk markers were measured at baseline and 2 months later. We collected T1- and diffusion-weighted MRIs with a 3 T scanner from the patients at baseline. We analyzed the association of psychosis-related inflammatory markers with gray and white matter (WM) volume using voxel-based morphometry and WM diffusion using tract-based spatial statistics with whole-brain and region-of-interest (ROI) analyses. FEP patients had higher CCL22 and lower TGFα, CXCL1, CCL7, IFN-α2 and ApoA-I than controls. CCL22 decreased significantly between baseline and 2 months in patients but was still higher than in controls. The association between inflammatory markers and FEP remained significant after adjusting for age, sex, smoking and BMI. We did not observe a correlation of inflammatory markers with any symptoms or duration of antipsychotic treatment. Baseline CCL22 levels correlated negatively with WM volume and positively with mean diffusivity and radial diffusivity bilaterally in the frontal lobes in ROI analyses. Decreased serum level of ApoA-I was associated with smaller volume of the medial temporal WM. In whole-brain analyses, CCL22 correlated positively with mean diffusivity and radial diffusivity, and CXCL1 associated negatively with fractional anisotropy and positively with mean diffusivity and radial diffusivity in several brain regions. This is the first report to demonstrate an association between circulating chemokine levels and WM in FEP patients. Interestingly, CCL22 has been previously implicated in autoimmune diseases associated with WM pathology. The results suggest that an altered activation of innate immunity may contribute to WM damage in psychotic disorders.

Fig 1. The associations of serum CCL22 levels with white matter volume (WMV) and diffusion measures within the patient group.

(A) CCL22 level correlated negatively with WMV within the frontal regions of interest (ROIs) (see main text for ROI definitions) bilaterally. Voxels with p < 0.005 (uncorrected, for visualization only; see corrected p-values in Table 4) within frontal ROIs are shown in hot colors on an SPM’s canonical single subject T1 image. Color bar for the t-values depicted in (A) is shown on the right. In (B–C), the FMRIB58 FA mean skeleton is shown in green on a T1 template image. (B) Mean diffusivity and (C) radial diffusivity were positively correlated with CCL22 levels; clusters with p < 0.05 TFCE-corrected for family-wise error rate within unilateral ROIs are shown. On the right of (B) and (C), a color bar shows the corrected p-level for these images. Crosshair in all the images is at x = -12, y = 34, z = 10. In the images, left hemisphere is on the left.

Fig 2. A positive correlation with serum levels of apolipoprotein A-I and white matter volume in right temporal ROI was observed within patients.

Voxels with p < 0.005 (uncorrected, for visualization only; see corrected p-values in Table 4) within the ROI are shown in hot colors on an SPM’s canonical single subject T1-image. Depicted are the sagittal, coronal, and axial views at x = 18, y = -42, z = 7. At the bottom right, a color plate shows the t-value. Left hemisphere is on the left.