Full length articleDifferential susceptibility of white matter tracts to inflammatory mediators in schizophrenia: An integrated DTI study
Introduction
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, Muller and Schwarz, 2010). Postmortem studies note activated microglia/macrophages (Bayer et al., 1999, Radewicz et al., 2000, 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, 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, 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, Ripke et al., 2011). Non-steroidal anti-inflammatory drugs may reduce psychotic symptom severity (Muller et al., 2002, Muller et al., 2010, 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, 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, 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.
Section snippets
Clinical evaluations
We enrolled 68 young adults (schizophrenia/schizoaffective disorder = 39, HC = 29). Of these participants, 64 subjects were included in the CRP analysis (SZ = 37; HC = 27) and 56 (SZ = 33, HC = 23) in the IL-6 analysis based on the availability of blood samples and assay qualities. The diagnosis of schizophrenia/schizoaffective disorder was obtained by administering the Structured Clinical Interview for DSM-IV (SCID)(First, 1997) and confirmed through consensus diagnosis by reviewing follow-up and medical
Demographic and clinical characteristics
The distribution of sex and mean age of subjects within the groups were not significantly different. The IL-6 and CRP levels were not significantly different between the groups. Mean duration of illness of schizophrenia subjects was about 3 years from the onset of first psychotic symptoms (Table 1).
Comparison of diffusion measures
Schizophrenia subjects showed significant reductions in FA in the left (p = 0.022) and right (p = 0.016) SLF, forceps minor (p = 0.04), and the right uncinate fasciculus (p = 0.04) regions compared to HC. No
Discussion
Our main finding is that the CRP and IL-6 levels correlated with anisotropy of water diffusion in selected tracts among schizophrenia subjects. Although the case–control differences in anisotropy measures were observed in the forceps minor, uncinate fasciculus and SLF, the CRP and IL-6 levels were correlated with FA and RD in distinctly different fiber tracts in the dorsal brain. The mean CRP and IL-6 levels did not differ between the groups; however, higher levels of each immune mediator were
Role of funding source
This work was supported by research grants from the National Institute of Mental Health MH72995, MH93540 and the Stanley Medical Research Institute (07T-722) (KMP). Funding agencies did not have any further role in the analysis and reporting of the results.
Contributors
Dr. Konasale Prasad conceived the idea and designed the study. Dr. Prasad and Ms. Catherine Upton conducted the data processing and analysis. Drs. Nimgaonkar and Keshavan discussed the concept, reviewed the manuscript, suggested further analyses and interpreted the results along with other authors. All authors took part in the preparation, editing and reviewing the manuscript carefully.
Conflict of interest
None of the authors disclose any conflict of interest to declare that would impinge on the design, execution, analysis or reporting and discussion of the results
Acknowledgments
This work was supported by research grants from the National Institute of Mental Health MH72995, MH93540 and the Stanley Medical Research Institute (07T-722) (KMP). We thank Dr. Debra Montrose, Dr. Elizabeth Radomsky, Mr. Kevin Eklund, Ms. Diana Dworakowski and Ms. Alicia Thomas for enrolment and characterization of research participants. We also thank Ms. Jean Miewald and Ms. Karol Rosengarth for their help in data management and quality assurance.
References (71)
Age-related myelin breakdown: a developmental model of cognitive decline and Alzheimer's disease. Neurobiol Aging 25(1), 5-18; author reply 49-62.Bartzokis, G., 2004. Age-related myelin breakdown: a developmental model of cognitive decline and Alzheimer's disease
Neurobiol. Aging
(2004)- et al.
Evidence for activation of microglia in patients with psychiatric illnesses
Neurosci. Lett.
(1999) - et al.
C-reactive protein
J. Biol. Chem.
(2004) - et al.
The cognitive and neuroanatomical correlates of multitasking
Neuropsychologia
(2000) - et al.
C-reactive protein is associated with the severity of cognitive impairment but not of psychiatric symptoms in individuals with schizophrenia
Schizophr. Res.
(2007) - et al.
Additive effects of elevated C-reactive protein and exposure to Herpes Simplex Virus type 1 on cognitive impairment in individuals with schizophrenia
Schizophr. Res.
(2012) - et al.
Meta-analysis of diffusion tensor imaging studies in schizophrenia
Schizophr. Res.
(2009) - et al.
Increased prevalence of antibrain antibodies in the sera from schizophrenic patients
Schizophr. Res.
(1994) - et al.
White matter integrity and prediction of social and role functioning in subjects at ultra-high risk for psychosis
Biol. Psychiatry
(2009) - et al.
IL-6R distribution in normal human and cynomolgus monkey tissues
Regul. Toxicol. Pharmacol. RTP
(2009)
Antibody to discrete areas of the brain in normal individuals and patients with schizophrenia
Biol. Psychiatry
DTI and MTR abnormalities in schizophrenia: analysis of white matter integrity
NeuroImage
Extensive white matter abnormalities in patients with first-episode schizophrenia: a Diffusion Tensor Imaging (DTI) study
Schizophr. Res.
Secretory products of multiple sclerosis B cells are cytotoxic to oligodendroglia in vitro
J. Neuroimmunol.
Reduced white matter integrity and cognitive deficit in never-medicated chronic schizophrenia: a diffusion tensor study using TBSS
Behav. Brain Res.
A combined DTI and structural MRI study in medicated-naïve chronic schizophrenia
Magn. Reson. Imaging
Interleukin-6 covaries inversely with hippocampal grey matter volume in middle-aged adults
Biol. Psychiatry
Internal capsule, corpus callosum and long associative fibers in good and poor outcome schizophrenia: a diffusion tensor imaging survey
Schizophr. Res.
Celecoxib treatment in an early stage of schizophrenia: results of a randomized, double-blind, placebo-controlled trial of celecoxib augmentation of amisulpride treatment
Schizophr. Res.
White matter defects in first episode psychosis patients: a voxelwise analysis of diffusion tensor imaging
NeuroImage
Inflammatory cytokine alterations in schizophrenia: a systematic quantitative review
Biol. Psychiatry
Oligodendrocyte precursor cells from different brain regions express divergent properties consistent with the differing time courses of myelination in these regions
Dev. Biol.
Review of immunological and immunopathological findings in schizophrenia
Brain Behav. Immun.
Tract-based spatial statistics: voxelwise analysis of multi-subject diffusion data
NeuroImage
Brain activation patterns during visual episodic memory processing among first-degree relatives of schizophrenia subjects
NeuroImage
Age-induced white matter changes in the human brain: a stereological investigation
Neurobiol. Aging
Soluble interleukin-6 (IL-6) receptor/IL-6 fusion protein enhances in vitro differentiation of purified rat oligodendroglial lineage cells
Mol. Cell. Neurosci.
Human neurons generate C-reactive protein and amyloid P: upregulation in Alzheimer's disease
Brain Res.
The multimodal connectivity of the hippocampal complex in auditory and visual hallucinations
Mol. Psychiatry
The basis of anisotropic water diffusion in the nervous system—a technical review
NMR Biomed.
Determinants of anisotropic water diffusion in nerves
Magn. Reson. Med.
Autoimmune diseases and severe infections as risk factors for schizophrenia: a 30-year population-based register study
Am. J. Psychiatry
Prevalence of autoimmune diseases in in-patients with schizophrenia: nationwide population-based study
Br. J. Psychiatry
A diffusion tensor imaging study of structural dysconnectivity in never-medicated, first-episode schizophrenia
Psychol. Med.
Impaired attention, genetics, and the pathophysiology of schizophrenia
Schizophr. Bull.
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Formerly of the Department of Psychiatry, University of Pittsburgh School of Medicine.