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      Bridging Autism Spectrum Disorders and Schizophrenia through inflammation and biomarkers - pre-clinical and clinical investigations

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          Abstract

          In recent years, evidence supporting a link between inflammation and neuropsychiatric disorders has been mounting. Autism spectrum disorders (ASD) and schizophrenia share some clinical similarities which we hypothesize might reflect the same biological basis, namely, in terms of inflammation. However, the diagnosis of ASD and schizophrenia relies solely on clinical symptoms, and to date, there is no clinically useful biomarker to diagnose or monitor the course of such illnesses.

          The focus of this review is the central role that inflammation plays in ASD and schizophrenia. It spans from pre-clinical animal models to clinical research and excludes in vitro studies. Four major areas are covered: (1) microglia, the inflammatory brain resident myeloid cells, (2) biomarkers, including circulating cytokines, oxidative stress markers, and microRNA players, known to influence cellular processes at brain and immune levels, (3) effect of anti-psychotics on biomarkers and other predictors of response, and (4) impact of gender on response to immune activation, biomarkers, and response to anti-psychotic treatments.

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          Most cited references 255

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          Fate mapping analysis reveals that adult microglia derive from primitive macrophages.

          Microglia are the resident macrophages of the central nervous system and are associated with the pathogenesis of many neurodegenerative and brain inflammatory diseases; however, the origin of adult microglia remains controversial. We show that postnatal hematopoietic progenitors do not significantly contribute to microglia homeostasis in the adult brain. In contrast to many macrophage populations, we show that microglia develop in mice that lack colony stimulating factor-1 (CSF-1) but are absent in CSF-1 receptor-deficient mice. In vivo lineage tracing studies established that adult microglia derive from primitive myeloid progenitors that arise before embryonic day 8. These results identify microglia as an ontogenically distinct population in the mononuclear phagocyte system and have implications for the use of embryonically derived microglial progenitors for the treatment of various brain disorders.
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            Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs.

            Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17-29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 ± 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 ± 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 ± 0.06 s.e.), and ADHD and major depressive disorder (0.32 ± 0.07 s.e.), low between schizophrenia and ASD (0.16 ± 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohn's disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.
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              Neuroglial activation and neuroinflammation in the brain of patients with autism.

              Autism is a neurodevelopmental disorder characterized by impaired communication and social interaction and may be accompanied by mental retardation and epilepsy. Its cause remains unknown, despite evidence that genetic, environmental, and immunological factors may play a role in its pathogenesis. To investigate whether immune-mediated mechanisms are involved in the pathogenesis of autism, we used immunocytochemistry, cytokine protein arrays, and enzyme-linked immunosorbent assays to study brain tissues and cerebrospinal fluid (CSF) from autistic patients and determined the magnitude of neuroglial and inflammatory reactions and their cytokine expression profiles. Brain tissues from cerebellum, midfrontal, and cingulate gyrus obtained at autopsy from 11 patients with autism were used for morphological studies. Fresh-frozen tissues available from seven patients and CSF from six living autistic patients were used for cytokine protein profiling. We demonstrate an active neuroinflammatory process in the cerebral cortex, white matter, and notably in cerebellum of autistic patients. Immunocytochemical studies showed marked activation of microglia and astroglia, and cytokine profiling indicated that macrophage chemoattractant protein (MCP)-1 and tumor growth factor-beta1, derived from neuroglia, were the most prevalent cytokines in brain tissues. CSF showed a unique proinflammatory profile of cytokines, including a marked increase in MCP-1. Our findings indicate that innate neuroimmune reactions play a pathogenic role in an undefined proportion of autistic patients, suggesting that future therapies might involve modifying neuroglial responses in the brain.
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                Author and article information

                Contributors
                joanappr@gmail.com
                susana.santos@ineb.up.pt
                Ines.Almeida@ineb.up.pt
                rmnscoelho@mail.telepac.pt
                mbarbosa@i3s.up.pt
                Journal
                J Neuroinflammation
                J Neuroinflammation
                Journal of Neuroinflammation
                BioMed Central (London )
                1742-2094
                4 September 2017
                4 September 2017
                2017
                : 14
                Affiliations
                [1 ]ISNI 0000 0001 1503 7226, GRID grid.5808.5, FMUP-Faculty of Medicine, , University of Porto, ; Al. Prof. Hernâni Monteiro, 4200-319 Porto, Portugal
                [2 ]ISNI 0000 0001 1503 7226, GRID grid.5808.5, i3S-Instituto de Investigação e Inovação em Saúde, , University of Porto, ; Rua Alfredo Allen 208, 4200-135 Porto, Portugal
                [3 ]ISNI 0000 0001 1503 7226, GRID grid.5808.5, INEB-Instituto de Engenharia Biomédica, , University of Porto, ; Rua Alfredo Allen 208, 4200-135 Porto, Portugal
                [4 ]ISNI 0000 0001 1503 7226, GRID grid.5808.5, ICBAS-Instituto de Ciências Biomédicas Abel Salazar, , University of Porto, ; Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal
                938
                10.1186/s12974-017-0938-y
                5584030
                28870209
                © The Author(s). 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                Funding
                Funded by: Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF)
                Award ID: NORTE-01-0145-FEDER-000012
                Funded by: FCT - Fundação para a Ciência e a Tecnologia
                Award ID: SFRH/BPD/91011/2012
                Categories
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                © The Author(s) 2017

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