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1.
J Affect Disord ; 202: 1-9, 2016 Sep 15.
Article in English | MEDLINE | ID: mdl-27253210

ABSTRACT

BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.


Subject(s)
Bipolar Disorder/immunology , Bipolar Disorder/pathology , Cytokines/blood , White Matter/immunology , White Matter/pathology , Adult , Anisotropy , Depressive Disorder, Major/immunology , Depressive Disorder, Major/pathology , Diffusion Tensor Imaging , Female , Humans , Internal Capsule/immunology , Internal Capsule/pathology , Male , Middle Aged
2.
Pediatr Res ; 59(3): 428-33, 2006 Mar.
Article in English | MEDLINE | ID: mdl-16492984

ABSTRACT

Epidemiologic and experimental findings implicate maternal infection in the etiology of injury to brain white matter, which may lead to cerebral palsy in preterm newborns. In the present study, inflammation and brain damage in 1- and 7-d-old rats were investigated after maternal inflammation. Intraperitoneal injection of 300 microg/kg of Escherichia coli lipopolysaccharide was administered to pregnant Wistar rats at d 19 and 20 of gestation (LPS group). Control females received a saline injection. Proinflammatory cytokines IL-1beta, tumor necrosis factor-alpha, and IL-6 expression in the fetal brain were determined by reverse transcription quantitative polymerase chain reaction. Brain injury was examined in 16-mum coronal brain sections by GFAP, MBP, caspase-3 immunohistochemistry, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling. Expression of IL-1beta was significantly increased 3 d after maternal administration (P1). A significant increase in cell death occurred at P1 and P7 in specific brain areas, i.e. in the subventricular striatal zone at P1, and in 1) the periventricular striatum, 2) the periventricular white matter, and 3) the germinative ventricular zone at P7. We also observed typical astrogliosis and strong hypomyelination in the external and internal capsule in the LPS group at P7. These results demonstrate that maternal LPS treatment induces persistent fetal inflammatory reactions associated with significant white matter injury in progeny at P1 and P7. This model should be relevant for the study of the pathophysiological mechanisms involved in cerebral white matter damage in preterm human newborns and in the development of therapeutic strategies.


Subject(s)
Apoptosis/physiology , Cerebral Cortex/pathology , Internal Capsule/pathology , Lipopolysaccharides/immunology , Myelin Sheath/metabolism , Animals , Animals, Newborn , Astrocytes/cytology , Astrocytes/metabolism , Caspase 3 , Caspases/metabolism , Cerebral Cortex/anatomy & histology , Cerebral Cortex/immunology , Cytokines/immunology , Female , Humans , In Situ Nick-End Labeling , Internal Capsule/anatomy & histology , Internal Capsule/immunology , Myelin Basic Protein/metabolism , Pregnancy , Rats , Rats, Wistar
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