title: Inflammatory cytokines influence measures of white matter integrity in Bipolar Disorder.
abstract: Bipolar Disorder (BD) is associated with elevated biomarkers of cell-mediated immune activation and inflammation and with signs of widespread disruption of white matter (WM) integrity in adult life. Consistent findings in animal models link WM damage in inflammatory diseases of the brain and serum levels of cytokines.
  
  
  
  With an exploratory approach, we tested the effects of 22 serum analytes, including pro- and anti-inflammatory cytokines and neurotrophic/hematopoietic factors, on DTI measures of WM microstructure in a sample of 31 patients with a major depressive episode in course of BD. We used whole brain tract-based spatial statistics in the WM skeleton with threshold-free cluster enhancement of DTI measures of WM microstructure: axial (AD), radial (RD), and mean diffusivity (MD), and fractional anisotropy (FA).
  
  
  
  The inflammation-related cytokines TNF-α, IL-8, IFN-γ and IL-10, and the growth factors IGFBP2 and PDGF-BB, shared the same significant associations with lower FA, and higher MD and RD, in large overlapping networks of WM fibers mostly located in the anterior part of the brain and including corpus callosum, cingulum, superior and inferior longitudinal fasciculi, inferior fronto-occipital fasciculi, uncinate, forceps, corona radiata, thalamic radiation, internal capsule.
  
  
  
  Higher RD is thought to signify increased space between fibers, suggesting demyelination or dysmyelination. The pattern of higher RD and MD with lower FA suggests that inflammation-related cytokine and growth factor levels inversely associate with integrity of myelin sheaths. The activated inflammatory response system might contribute to BD pathophysiology by hampering structural connectivity in critical cortico-limbic networks.
authors.affiliation: Department of Clinical Neurosciences, Scientific Institute Ospedale San Raffaele, Milano, University Vita-Salute San Raffaele, Milano, Italy; C.E.R.M.A.C. (Centro di Eccellenza Risonanza Magnetica ad Alto Campo), University Vita-Salute San Raffaele, Milano, Italy. Electronic address: benedetti.francesco@hsr.it.
authors.forename: Francesco
authors.initials: F
authors.lastname: Benedetti
authors.affiliation: Department of Clinical Neurosciences, Scientific Institute Ospedale San Raffaele, Milano, University Vita-Salute San Raffaele, Milano, Italy; C.E.R.M.A.C. (Centro di Eccellenza Risonanza Magnetica ad Alto Campo), University Vita-Salute San Raffaele, Milano, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Poletti
authors.affiliation: Department of Immunology, Erasmus University Medical Centre, Rotterdam, Netherlands.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Hoogenboezem
authors.affiliation: Department of Clinical Neurosciences, Scientific Institute Ospedale San Raffaele, Milano, University Vita-Salute San Raffaele, Milano, Italy; C.E.R.M.A.C. (Centro di Eccellenza Risonanza Magnetica ad Alto Campo), University Vita-Salute San Raffaele, Milano, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Mazza
authors.affiliation: Department of Psychiatry, University of Münster, Münster, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Ambrée
authors.affiliation: Department of Immunology, Erasmus University Medical Centre, Rotterdam, Netherlands.
authors.forename: Harm
authors.initials: H
authors.lastname: de Wit
authors.affiliation: Department of Immunology, Erasmus University Medical Centre, Rotterdam, Netherlands.
authors.forename: Annemarie J M
authors.initials: AJ
authors.lastname: Wijkhuijs
authors.affiliation: Department of Clinical Neurosciences, Scientific Institute Ospedale San Raffaele, Milano, University Vita-Salute San Raffaele, Milano, Italy; C.E.R.M.A.C. (Centro di Eccellenza Risonanza Magnetica ad Alto Campo), University Vita-Salute San Raffaele, Milano, Italy.
authors.forename: Clara
authors.initials: C
authors.lastname: Locatelli
authors.affiliation: Department of Clinical Neurosciences, Scientific Institute Ospedale San Raffaele, Milano, University Vita-Salute San Raffaele, Milano, Italy; C.E.R.M.A.C. (Centro di Eccellenza Risonanza Magnetica ad Alto Campo), University Vita-Salute San Raffaele, Milano, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Bollettini
authors.affiliation: Department of Clinical Neurosciences, Scientific Institute Ospedale San Raffaele, Milano, University Vita-Salute San Raffaele, Milano, Italy; C.E.R.M.A.C. (Centro di Eccellenza Risonanza Magnetica ad Alto Campo), University Vita-Salute San Raffaele, Milano, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Colombo
authors.affiliation: Department of Psychiatry, University of Münster, Münster, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Arolt
authors.affiliation: Department of Immunology, Erasmus University Medical Centre, Rotterdam, Netherlands.
authors.forename: Hemmo A
authors.initials: HA
authors.lastname: Drexhage
mesh_terms: D000328:Adult; D016880:Anisotropy; D001714:Bipolar Disorder / Q000276:immunology* / Q000473:pathology*; D016207:Cytokines / Q000097:blood*; D003865:Major Depressive Disorder / Q000276:immunology / Q000473:pathology; D056324:Diffusion Tensor Imaging; D005260:Female; D006801:Humans; D020772:Internal Capsule / Q000276:immunology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D066127:White Matter / Q000276:immunology* / Q000473:pathology*
chemical_list: D016207:Cytokines
keywords: Bipolar Disorder; Cytokines; Diffusion tensor imaging; Inflammation; White matter