title: 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.
authors.affiliation: Mental Health Unit, National Institute for Health and Welfare, Helsinki, Finland; Brain Research Unit, O.V. Lounasmaa Laboratory and Advanced Magnetic Imaging Centre, Aalto NeuroImaging, Aalto University School of Science, Espoo, Finland; Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland.
authors.forename: Teemu
authors.initials: T
authors.lastname: Mäntylä
authors.affiliation: Mental Health Unit, National Institute for Health and Welfare, Helsinki, Finland; Department of Psychiatry, Helsinki University Central Hospital, Helsinki, Finland; Institute of Clinical Medicine, Department of Psychiatry, Helsinki University, Helsinki, Finland.
authors.forename: Outi
authors.initials: O
authors.lastname: Mantere
authors.affiliation: Brain Research Unit, O.V. Lounasmaa Laboratory and Advanced Magnetic Imaging Centre, Aalto NeuroImaging, Aalto University School of Science, Espoo, Finland; Department of Psychiatry, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Tuukka T
authors.initials: TT
authors.lastname: Raij
authors.affiliation: Mental Health Unit, National Institute for Health and Welfare, Helsinki, Finland; Department of Psychiatry, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Tuula
authors.initials: T
authors.lastname: Kieseppä
authors.affiliation: Vaccination Programme Unit, National Institute for Health and Welfare, Helsinki, Finland.
authors.forename: Hanna
authors.initials: H
authors.lastname: Laitinen
authors.affiliation: Genomics and Biomarkers Unit, National Institute for Health and Welfare, Helsinki, Finland.
authors.forename: Jaana
authors.initials: J
authors.lastname: Leiviskä
authors.affiliation: Mental Health Unit, National Institute for Health and Welfare, Helsinki, Finland; Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Minna
authors.initials: M
authors.lastname: Torniainen
authors.affiliation: Turku PET centre, University of Turku, Turku, Finland; Department of Psychiatry, University of Turku, Turku, Finland.
authors.forename: Lauri
authors.initials: L
authors.lastname: Tuominen
authors.affiliation: Respiratory, Inflammatory and Autoimmunity, Innovative Medicine, AstraZeneca R & D, Mölndal, Sweden; Institute of Clinical Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Outi
authors.initials: O
authors.lastname: Vaarala
authors.affiliation: Mental Health Unit, National Institute for Health and Welfare, Helsinki, Finland.
authors.forename: Jaana
authors.initials: J
authors.lastname: Suvisaari
mesh_terms: D000293:Adolescent; D000328:Adult; D016880:Anisotropy; D014150:Antipsychotic Agents / Q000627:therapeutic use; D016632:Apolipoprotein A-I / Q000097:blood / Q000276:immunology*; D016022:Case-Control Studies; D054422:Chemokine CCL22 / Q000097:blood / Q000276:immunology*; D054410:Chemokine CCL7 / Q000097:blood / Q000276:immunology; D054360:Chemokine CXCL1 / Q000097:blood / Q000276:immunology; D038524:Diffusion Magnetic Resonance Imaging; D056324:Diffusion Tensor Imaging; D005260:Female; D005625:Frontal Lobe / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression / Q000276:immunology; D066128:Gray Matter / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007113:Immunity, Innate; D016898:Interferon-alpha / Q000097:blood / Q000276:immunology; D008297:Male; D011618:Psychotic Disorders / Q000097:blood / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D016211:Transforming Growth Factor alpha / Q000097:blood / Q000276:immunology; D066127:White Matter / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
chemical_list: D014150:Antipsychotic Agents; D016632:Apolipoprotein A-I; C515482:CCL22 protein, human; C515450:CCL7 protein, human; C475829:CXCL1 protein, human; D054422:Chemokine CCL22; D054410:Chemokine CCL7; D054360:Chemokine CXCL1; D016898:Interferon-alpha; D016211:Transforming Growth Factor alpha