حساسیت دیفرانسیلی دستگاه ماده سفید به واسطه های التهابی در اسکیزوفرنی: مطالعه یکپارچه DTI

Background The pathophysiological underpinnings of impaired anatomical and functional connectivity are not precisely known. Emerging data suggest that immune mediators may underlie such dysconnectivity. We examined anatomical brain connections using diffusion tensor imaging (DTI) data in relation to interleukin-6 (IL-6) and C-reactive protein (CRP) levels among early-course clinically stable schizophrenia subjects compared to healthy controls (HC). Methods DTI data were acquired in 30 directions with 2 averages. Fractional anisotropy (FA) and radial diffusivity (RD) maps were separately processed using FSL4.1.9 and Tract-Based Spatial Statistics (TBSS). Threshold free cluster enhancements (TFCE) were examined employing familywise error (FWE) corrections for multiple testing within linear regression models including age, sex and socioeconomic status as covariates. IL-6 and CRP were assayed using highly sensitive and specific sandwich immunosorbent assays. Results The groups did not differ in age and sex as well as in the IL-6 and CRP levels. IL-6 levels were negatively correlated with the FA and positively correlated with RD among schizophrenia subjects but not HC. The voxel clusters that showed significant correlations were localized to the forceps major, the inferior longitudinal fasciculus and the inferior fronto-occipital fasciculus. CRP levels showed similar pattern except for lack of correlation with RD on any cluster that corresponded to the forceps major. Discussion Our results suggest that the IL-6 and CRP contribute to impaired anisotropy of water diffusion in selected pathways that have been previously associated with schizophrenia suggesting differential susceptibility of selected neural pathways to immune mediators.

Impairments in both anatomical (Ellison-Wright and Bullmore, 2009) and functional (Fitzsimmons et al., 2013) connectivity suggest that schizophrenia may be a dysconnection syndrome. Elucidating the factors that contribute to the dysconnection is critical to identify novel targets for drug discovery. Several lines of evidence strongly suggest the role of immune mediators in the pathophysiology of schizophrenia (Heath et al., 1967, Rothermundt et al., 2001, Saetre et al., 2007 and Muller and Schwarz, 2010). Postmortem studies note activated microglia/macrophages (Bayer et al., 1999, Radewicz et al., 2000 and Wierzba-Bobrowicz et al., 2005), elevated expression of inflammatory markers in the prefrontal cortex (PFC) neurons (Fillman et al., 2013) and vasculature (Harris et al., 2008), and autoantibodies against frontal (Henneberg et al., 1994), cingulate (Ganguli et al., 1987, Kelly et al., 1987 and Henneberg et al., 1994), hippocampal cortices (Ganguli et al., 1987), and glutamate receptors (Tsutsui et al., 2012) in schizophrenia. Autoimmune disorders may elevate the risk for schizophrenia both independently (Benros et al., 2011 and Chen et al., 2012) and in combination with exposure to infectious agents (Benros et al., 2011). A meta-analysis noted elevated peripheral blood inflammatory cytokines in schizophrenia compared to healthy controls (HC) (Potvin et al., 2008). Genome-wide association studies replicate the association of Major Histocompatibility Complex (MHC) region variants (where a majority of immune genes are located) with schizophrenia (Purcell et al., 2009, Shi et al., 2009, Stefansson et al., 2009 and Ripke et al., 2011). Non-steroidal anti-inflammatory drugs may reduce psychotic symptom severity (Muller et al., 2002, Muller et al., 2010 and Sommer et al., 2012). However, the mechanisms through which immune mediators affect cognitive impairments and psychopathology are under active investigation. Characterizing peripheral immune markers that are relevant to the pathophysiology of schizophrenia is critical for early diagnosis, novel drug discovery, monitoring treatment response and predicting risk. We examined the association of the C-reactive protein (CRP)—an acute phase reactant, and interleukin-6 (IL-6)—a predominantly pro-inflammatory cytokine with the anisotropy of water diffusion using diffusion tensor imaging (DTI). CRP is a pattern recognition molecule that is phylogenetically highly conserved and is primarily expressed in liver following induction by IL-6 (Black et al., 2004). Although extrahepatic expression of CRP in the neurons (Yasojima et al., 2000) and lymphocytes (Kuta and Baum, 1986) are described, plasma levels mainly reflect hepatic synthesis (Black et al., 2004). CRP may be either pro- or anti-inflammatory depending on the context (Eisenhardt et al., 2009). IL-6 is mainly a pro-inflammatory cytokine secreted by T cells and macrophages (Kato et al., 2009). Quantitative reviews have reported elevated levels of IL-6 (Potvin et al., 2008) and CRP (Miller et al., 2014) in schizophrenia with variations related to antipsychotic use, associated comorbidities and stage of illness. Elevated CRP is associated with cognitive deficits in schizophrenia both independently (Dickerson et al., 2007) and through interaction with exposure to Herpes Simplex Virus 1—a neurotropic virus (Dickerson et al., 2012). Although quantitative reviews suggest elevated IL-6 in schizophrenia, few studies have examined the association of IL-6 with in vivo neurobiology of schizophrenia. Among middle-aged and elderly healthy subjects, elevated IL-6 was associated with cognitive impairments (Weaver et al., 2002 and Marsland et al., 2006) and hippocampal volume reductions (Marsland et al., 2008). However, the association of CRP and IL-6 with brain connections in schizophrenia is not examined adequately. DTI offers insights into axonal integrity by characterizing anisotropy of water diffusion. DTI is based on the principle that water tends to diffuse more freely along the longitudinal axis (λ1) than along the transverse axes (λ2, λ3) of axons. The fractional anisotropy (FA)—diffusion along the λ1 compared to λ2 and λ3, and the radial diffusivity (RD)—the diffusion perpendicular to the axon orientation—index white matter integrity (Beaulieu, 2002). Factors affecting impaired anisotropy of water diffusion that could impact connectivity are unclear. DTI studies report altered diffusivity in the association (superior longitudinal fasciculus (SLF), uncinate fasciculus) (Friedman et al., 2008), commissural (corpus callosum, forceps minor) (Friedman et al., 2008) and projection (internal capsule and cingulum) (Kubicki et al., 2005 and Cheung et al., 2008) fibers in schizophrenia compared to controls. A meta-analysis noted reduced anisotropy in the left frontal and left temporal deep white matter (Ellison-Wright and Bullmore, 2009) suggesting impaired prefrontal-thalamic and fronto-temporo-occipital connections. Our functional imaging study revealed increased activation in the PFC and thalamus among schizophrenia subjects compared to HC during episodic memory challenge (Stolz et al., 2012). Our goal was to examine whether selected immune mediators (IL-6 and CRP) affected the anisotropy measures in these tracts. Specifically, we predicted that the IL-6 and CRP levels would be negatively correlated with FA and positively correlated with RD in the fronto-thalamic and fronto-temporo-occipital white matter tracts. Since FA and RD represent diffusion in orthogonal directions and may be negatively correlated with each other, we explored the correlation between the FA and RD extracted from the significant voxel clusters that show correlation with IL-6 and CRP within FSL.