title: Association between altered brain morphology and elevated peripheral endothelial markers--implications for psychotic disorders.
abstract: BACKGROUND
  Increased inflammation, endothelial dysfunction, and structural brain abnormalities have been reported in both schizophrenia and bipolar disorder, but the relationships between these factors are unknown. We aimed to identify associations between markers of inflammatory and endothelial activation and structural brain variation in psychotic disorders.
  
  
  METHODS
  We measured von Willebrand factor (vWf) as a marker of endothelial cell activation and six inflammatory markers (tumor necrosis factor-receptor 1, osteoprotegerin, interleukin-1-receptor antagonist, interleukin-6, C-reactive protein, CD40 ligand) in plasma and 16 brain structures obtained from MRI scans of 356 individuals (schizophrenia spectrum; n=121, affective spectrum; n=95, healthy control subjects; n=140). The relationship between the inflammatory and endothelial markers and brain measurements were investigated across groups.
  
  
  RESULTS
  There was a positive association (p=2.5×10(-4)) between plasma levels of vWf and total volume of the basal ganglia which remained significant after correction for multiple testing. Treatment with first generation antipsychotics was associated with basal ganglia volume only (p=0.009). After adjusting for diagnosis and antipsychotic medication, vWf remained significantly associated with increased basal ganglia volume (p=0.008), in particular the right globus pallidus (p=3.7×10(-4)). The relationship between vWf and basal ganglia volume was linear in all groups, but the intercept was significantly higher in the schizophrenia group (df=2, F=8.2, p=3.4×10(-4)).
  
  
  CONCLUSIONS
  Our results show a strong positive correlation between vWf levels and basal ganglia volume, in particular globus pallidus, independent of diagnosis. vWf levels were significantly higher in schizophrenia, which could indicate a link between endothelial cell activation and basal ganglia morphology in schizophrenia patients.
authors.affiliation: KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo, Norway. Electronic address: ingrid.dieset@medisin.uio.no.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Dieset
authors.affiliation: KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway.
authors.forename: Unn Kristin
authors.initials: UK
authors.lastname: Haukvik
authors.affiliation: KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Melle
authors.affiliation: KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Jan Ivar
authors.initials: JI
authors.lastname: Røssberg
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: Thor
authors.initials: T
authors.lastname: Ueland
authors.affiliation: KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Sigrun
authors.initials: S
authors.lastname: Hope
authors.affiliation: Department of Radiology, University of California San Diego, La Jolla, CA, USA; Department of Neuroscience, University of California San Diego, La Jolla, CA, USA; Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
authors.forename: Anders M
authors.initials: AM
authors.lastname: Dale
authors.affiliation: KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Medical Genetics, Oslo University Hospital Ullevål, Oslo, Norway.
authors.forename: Srdjan
authors.initials: S
authors.lastname: Djurovic
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Faculty of Medicine, University of Oslo, Oslo, Norway; Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Norway.
authors.forename: Pål
authors.initials: P
authors.lastname: Aukrust
authors.affiliation: KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Agartz
authors.affiliation: KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Ole A
authors.initials: OA
authors.lastname: Andreassen
mesh_terms: D000328:Adult; D001798:Blood Proteins / Q000378:metabolism*; D001921:Brain / Q000473:pathology*; D002097:C-Reactive Protein / Q000378:metabolism; D016207:Cytokines / Q000097:blood*; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D016014:Linear Models; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D053244:Osteoprotegerin / Q000097:blood; D011569:Psychiatric Status Rating Scales; D011618:Psychotic Disorders / Q000097:blood* / Q000473:pathology*; D055815:Young Adult; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D001798:Blood Proteins; D016207:Cytokines; D053244:Osteoprotegerin; D014841:von Willebrand Factor; D002097:C-Reactive Protein
keywords: Basal ganglia; Brain morphology; Endothelial markers; Inflammation