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      Immunology of Schizophrenia



      S. Karger AG

      Psychoneuroimmunology , Inflammation, Schizophrenia

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          Increased proinflammatory markers like cytokines have been described in the blood and cerebrospinal fluid of patients suffering from schizophrenia. Animal models have shown that a hit in early life to the immune system might trigger a lifelong increased immune reactivity. Many epidemiological and clinical studies show the role of various infectious agents as risk factors for schizophrenia with overlap to other psychoses. The first large-scale epidemiological study in psychiatry from Denmark clearly demonstrates severe infections and autoimmune disorders during lifetime to be risk factors for schizophrenia. Genetic studies have shown the strongest signal for schizophrenia on chromosome 6p22.1, in a region related to the major histocompatibility complex and other immune functions. The vulnerability-stress-inflammation model is important as stress may increase proinflammatory cytokines and even contribute to a lasting proinflammatory state. The immune system itself is considered an important further piece in the puzzle, as in autoimmune disorders in general, which are always linked to three factors: genes, the environment and the immune system. Alterations of dopaminergic, serotonergic, noradrenergic and glutamatergic neurotransmission have been shown with low-level neuroinflammation and may directly be involved in the generation of schizophrenic symptoms. Loss of central nervous system volume and microglial activation has been demonstrated in schizophrenia in neuroimaging studies, which supports the assumption of a low-level neuroinflammatory process. Further support comes from the therapeutic benefit of anti-inflammatory medications in specific studies and the anti-inflammatory and immunomodulatory intrinsic effects of antipsychotics.

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          Most cited references 70

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          Cortical demyelination and diffuse white matter injury in multiple sclerosis.

          Focal demyelinated plaques in white matter, which are the hallmark of multiple sclerosis pathology, only partially explain the patient's clinical deficits. We thus analysed global brain pathology in multiple sclerosis, focusing on the normal-appearing white matter (NAWM) and the cortex. Autopsy tissue from 52 multiple sclerosis patients (acute, relapsing-remitting, primary and secondary progressive multiple sclerosis) and from 30 controls was analysed using quantitative morphological techniques. New and active focal inflammatory demyelinating lesions in the white matter were mainly present in patients with acute and relapsing multiple sclerosis, while diffuse injury of the NAWM and cortical demyelination were characteristic hallmarks of primary and secondary progressive multiple sclerosis. Cortical demyelination and injury of the NAWM, reflected by diffuse axonal injury with profound microglia activation, occurred on the background of a global inflammatory response in the whole brain and meninges. There was only a marginal correlation between focal lesion load in the white matter and diffuse white matter injury, or cortical pathology, respectively. Our data suggest that multiple sclerosis starts as a focal inflammatory disease of the CNS, which gives rise to circumscribed demyelinated plaques in the white matter. With chronicity, diffuse inflammation accumulates throughout the whole brain, and is associated with slowly progressive axonal injury in the NAWM and cortical demyelination.
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            Brain volume in first-episode schizophrenia: systematic review and meta-analysis of magnetic resonance imaging studies.

            Studies of people with schizophrenia assessed using magnetic resonance imaging (MRI) usually include patients with first-episode and chronic disease, yet brain abnormalities may be limited to those with chronic schizophrenia. To determine whether patients with a first episode of schizophrenia have characteristic brain abnormalities. Systematic review and meta-analysis of 66 papers comparing brain volume in patients with a first psychotic episode with volume in healthy controls. A total of 52 cross-sectional studies included 1424 patients with a first psychotic episode; 16 longitudinal studies included 465 such patients. Meta-analysis suggests that whole brain and hippocampal volume are reduced (both P<0.0001) and that ventricular volume is increased (P<0.0001) in these patients relative to healthy controls. Average volumetric changes are close to the limit of detection by MRI methods. It remains to be determined whether schizophrenia is a neurodegenerative process that begins at about the time of symptom onset, or whether it is better characterised as a neurodevelopmental process that produces abnormal brain volumes at an early age.
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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

                S. Karger AG
                February 2014
                14 February 2014
                : 21
                : 2-3
                : 109-116
                Department of Psychiatry and Psychotherapy, Ludwig-Maximilian University of Munich, Munich, Germany
                Author notes
                *Prof. Dr. med. Dipl.-Psych. Norbert Müller, Department of Psychiatry and Psychotherapy, Ludwig-Maximilian University, Nussbaumstrasse 7, DE-80336 Munich (Germany), E-Mail Norbert.Mueller@med.uni-muenchen.de
                356538 Neuroimmunomodulation 2014;21:109-116
                © 2014 S. Karger AG, Basel

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                Pages: 8
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