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      PET imaging of putative microglial activation in individuals at ultra-high risk for psychosis, recently diagnosed and chronically ill with schizophrenia


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          We examined putative microglial activation as a function of illness course in schizophrenia. Microglial activity was quantified using [ 11C]( R)-(1-[2-chrorophynyl]- N-methyl- N-[1-methylpropyl]-3 isoquinoline carboxamide ( 11C-(R)-PK11195) positron emission tomography (PET) in: (i) 10 individuals at ultra-high risk (UHR) of psychosis; (ii) 18 patients recently diagnosed with schizophrenia; (iii) 15 patients chronically ill with schizophrenia; and, (iv) 27 age-matched healthy controls. Regional-binding potential (BP ND) was calculated using the simplified reference-tissue model with four alternative reference inputs. The UHR, recent-onset and chronic patient groups were compared to age-matched healthy control groups to examine between-group BP ND differences in 6 regions: dorsal frontal, orbital frontal, anterior cingulate, medial temporal, thalamus and insula. Correlation analysis tested for BP ND associations with gray matter volume, peripheral cytokines and clinical variables. The null hypothesis of equality in BP ND between patients (UHR, recent-onset and chronic) and respective healthy control groups (younger and older) was not rejected for any group comparison or region. Across all subjects, BP ND was positively correlated to age in the thalamus ( r=0.43, P=0.008, false discovery rate). No correlations with regional gray matter, peripheral cytokine levels or clinical symptoms were detected. We therefore found no evidence of microglial activation in groups of individuals at high risk, recently diagnosed or chronically ill with schizophrenia. While the possibility of 11C-(R)-PK11195-binding differences in certain patient subgroups remains, the patient cohorts in our study, who also displayed normal peripheral cytokine profiles, do not substantiate the assumption of microglial activation in schizophrenia as a regular and defining feature, as measured by 11C-(R)-PK11195 BP ND.

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          Most cited references31

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          Parametric imaging of ligand-receptor binding in PET using a simplified reference region model.

          A method is presented for the generation of parametric images of radioligand-receptor binding using PET. The method is based on a simplified reference region compartmental model, which requires no arterial blood sampling, and gives parametric images of both the binding potential of the radioligand and its local rate of delivery relative to the reference region. The technique presented for the estimation of parameters in the model employs a set of basis functions which enables the incorporation of parameter bounds. This basis function method (BFM) is compared with conventional nonlinear least squares estimation of parameters (NLM), using both simulated and real data. BFM is shown to be more stable than NLM at the voxel level and is computationally much faster. Application of the technique is illustrated for three radiotracers: [11C]raclopride (a marker of the D2 receptor), [11C]SCH 23390 (a marker of the D1 receptor) in human studies, and [11C]CFT (a marker of the dopamine transporter) in rats. The assumptions implicit in the model and its implementation using BFM are discussed. Copyright 1997 Academic Press.
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            Increased inflammatory markers identified in the dorsolateral prefrontal cortex of individuals with schizophrenia.

            Upregulation of the immune response may be involved in the pathogenesis of schizophrenia with changes occurring in both peripheral blood and brain tissue. To date, microarray technology has provided a limited view of specific inflammatory transcripts in brain perhaps due to sensitivity issues. Here we used SOLiD Next Generation Sequencing to quantify neuroimmune mRNA expression levels in the dorsolateral prefrontal cortex of 20 individuals with schizophrenia and their matched controls. We detected 798 differentially regulated transcripts present in people with schizophrenia compared with controls. Ingenuity pathway analysis identified the inflammatory response as a key change. Using quantitative real-time PCR we confirmed the changes in candidate cytokines and immune modulators, including interleukin (IL)-6, IL-8, IL-1β and SERPINA3. The density of major histocompatibility complex-II-positive cells morphologically resembling microglia was significantly increased in schizophrenia and correlated with IL-1β expression. A group of individuals, most of whom had schizophrenia, were found to have increased inflammatory mRNA expression. In summary, we have demonstrated changes in an inflammatory response pathway that are present in ∼40% of people diagnosed with schizophrenia. This suggests that therapies aimed at immune system attenuation in schizophrenia may be of direct benefit in the brain.
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              Microglia activation in recent-onset schizophrenia: a quantitative (R)-[11C]PK11195 positron emission tomography study.

              Schizophrenia is a brain disease involving progressive loss of gray matter of unknown cause. Most likely, this loss reflects neuronal damage, which should, in turn, be accompanied by microglia activation. Microglia activation can be quantified in vivo using (R)-[(11)C]PK11195 and positron emission tomography (PET). The purpose of this study was to investigate whether microglia activation occurs in patients with recent-onset schizophrenia. Ten patients with recent-onset schizophrenia and 10 age-matched healthy control subjects were included. A fully quantitative (R)-[(11)C]PK11195 PET scan was performed on all subjects, including arterial sampling to generate a metabolite-corrected input curve. Compared with control subjects, binding potential of (R)-[(11)C]PK11195 in total gray matter was increased in patients with schizophrenia. There were no differences in other PET parameters. Activated microglia are present in schizophrenia patients within the first 5 years of disease onset. This suggests that, in this period, neuronal injury is present and that neuronal damage may be involved in the loss of gray matter associated with this disease. Microglia may form a novel target for neuroprotective therapies in schizophrenia.

                Author and article information

                Transl Psychiatry
                Transl Psychiatry
                Translational Psychiatry
                Nature Publishing Group
                August 2017
                29 August 2017
                1 August 2017
                : 7
                : 8
                : e1225
                [1 ]Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne and Melbourne Health , Carlton South, VIC, Australia
                [2 ]Department of Psychiatry, The University of Melbourne , Parkville, VIC Australia
                [3 ]Melbourne School of Engineering, The University of Melbourne , Parkville, VIC Australia
                [4 ]Department of Molecular Imaging and Therapy, The University of Melbourne , Heidelberg, VIC Australia
                [5 ]Department of Medicine, The University of Melbourne , and La Trobe University, Austin Hospital , Heidelberg, VIC, Australia
                [6 ]Discipline of Psychiatry, The University of Adelaide , Adelaide, SA, Australia
                [7 ]Neuroscience Research Australia , Randwick, NSW, Australia
                [8 ]Schizophrenia Research Institute , Randwick, NSW, Australia
                [9 ]School of Psychiatry, University of New South Wales , Sydney, NSW, Australia
                [10 ]Orygen, The National Centre of Excellence in Youth Mental Health , Parkville, VIC, Australia
                [11 ]Centre for Youth Mental Health, The University of Melbourne , Parkville, VIC, Australia
                [12 ]Brain & Mind Centre, The University of Sydney , Camperdown, NSW, Australia
                [13 ]Medical Radiation Sciences, The University of Sydney , Camperdown, NSW, Australia
                [14 ]Department of Neuroimaging, King’s College London , London, UK
                [15 ]VU University Medical Center , Amsterdam, The Netherlands
                [16 ]North Western Mental Health, Melbourne Health , Parkville, VIC, Australia
                [17 ]Florey Institute for Neurosciences and Mental Health , Parkville, VIC, Australia
                [18 ]Centre for Neural Engineering, Department of Electrical and Electronic Engineering, The University of Melbourne , Carlton South, VIC, Australia
                [19 ]Cooperative Research Centre for Mental Health , Carlton, VIC, Australia
                Author notes
                [* ]Melbourne Neuropsychiatry Centre, Level 3, Alan Gilbert Building, The University of Melbourne , Carlton South, VIC 3053, Australia, E-mail: dibiasem@ 123456unimelb.edu.au

                Joint senior (equally contributed).

                Copyright © 2017 The Author(s)

                This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/

                : 28 May 2017
                : 23 June 2017
                Original Article

                Clinical Psychology & Psychiatry
                Clinical Psychology & Psychiatry


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