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.

Macrophage-Derived Chemokine: A Putative Marker of Pharmacological Therapy Response in Major Depression?

“…Further studies are required that com- pare untreated depressed patients with healthy subjects, in order for it to be stated that MDC is a suitable marker of MDD/BP. Mäntylä et al [29] also found changes in the MDC levels of first-episode psychosis, which could be negatively correlated with white matter volume within specific frontal regions of interest (ROIs), and positively with mean diffusivity and radial diffusivity bilaterally in the frontal lobes in ROI analyses. With regard to treatment response in schizophrenic patients, in the study by Ramsey et al [27] , MDC levels were significantly elevated with a sex-specific effect after 6 weeks of antipsychotic treatment.…”

Childhood adversities and clinical symptomatology in first-episode psychosis

“…The patients participating in the Helsinki Psychosis Study (Keinänen et al, 2015;Mäntylä et al, 2015;Raij et al, 2015;Rikandi et al, 2017) were aged 18-40, with first psychiatric treatment contact for psychosis in hospitals and outpatient clinics of the City of Helsinki and Helsinki University Hospital between December 2010 and July 2016. As a criterion for inclusion, we defined psychosis as a score of at least 4 in the items assessing unusual thought content (delusions) or hallucinations in the Brief Psychiatric Rating Scale, Expanded version 4.0, BPRS (Ventura et al, 1993), corresponding to mild but definite delusions or hallucinations.…”

Elevated serum chemokine CCL22 levels in first-episode psychosis: associations with symptoms, peripheral immune state and in vivo brain glial cell function

“…For the PET study, fasting serum was sampled before radiotracer injection at 8-9 a.m. on the day of PET. The HEPS sample included 34 patients and 17 controls from our previous report 17 , but we used unthawed serum samples from these participants and reanalyzed them as a part of the current project.…”

“…Associating TSPO tracer V T to auxiliary immune parameters, such as cyto/ chemokine networks, have been suggested to facilitate the interpretation of the source and functional association of variation in TSPO V T 10 . We have previously studied a panel of 38 cytokines and chemokines in patients with first-episode psychosis (FEP) and healthy controls, and found elevated serum chemokine CCL22 levels associating with white matter volume and diffusion in FEP patients 17 . Here, we used two Finnish cohorts of FEP patients and matched controls to study (a) differences in serum cytokine and chemokine levels in FEP patients and controls, (b) the role of potential confounding factors, namely age, sex, smoking, cannabis use, body mass index (BMI), and antipsychotic medication type, duration, and dose, (c) the persistence of any changes during one-year follow-up, and (d) the relationship between the observed changes and clinical characteristics such as the severity of symptoms and achieving remission in the one-year follow-up.…”