Atlas of the Human Brain.

Multiple lines of evidence support the pathogenic role of neuroinflammation in psychiatric illness. While systemic autoimmune diseases are well-documented causes of neuropsychiatric disorders, synaptic autoimmune encephalitides with psychotic symptoms often go under-recognized. Parallel to the link between psychiatric symptoms and autoimmunity in autoimmune diseases, neuroimmunological abnormalities occur in classical psychiatric disorders (for example, major depressive, bipolar, schizophrenia, and obsessive-compulsive disorders). Investigations into the pathophysiology of these conditions traditionally stressed dysregulation of the glutamatergic and monoaminergic systems, but the mechanisms causing these neurotransmitter abnormalities remained elusive. We review the link between autoimmunity and neuropsychiatric disorders, and the human and experimental evidence supporting the pathogenic role of neuroinflammation in selected classical psychiatric disorders. Understanding how psychosocial, genetic, immunological and neurotransmitter systems interact can reveal pathogenic clues and help target new preventive and symptomatic therapies.

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Neuroinflammation and psychiatric illness

Schizophrenia is a psychiatric disorder which has a lifetime prevalence of ~1%. Multiple candidate mechanisms have been proposed in the pathogenesis of schizophrenia. One such mechanism is the involvement of neuroinflammation. Clinical studies, including neuroimaging, peripheral biomarkers and randomized control trials, have suggested the presence of neuroinflammation in schizophrenia. Many studies have also measured markers of neuroinflammation in postmortem brain samples from schizophrenia patients. The objective of this study was to conduct a systematic search of the literature on neuroinflammation in postmortem brains of schizophrenia patients indexed in MEDLINE, Embase and PsycINFO. Databases were searched up until 20th March 2016 for articles published on postmortem brains in schizophrenia evaluating microglia, astrocytes, glia, cytokines, the arachidonic cascade, substance P and other markers of neuroinflammation. Two independent reviewers extracted the data. Out of 5385 articles yielded by the search, 119 articles were identified that measured neuroinflammatory markers in schizophrenic postmortem brains. Glial fibrillary acidic protein expression was elevated, lower or unchanged in 6, 6 and 21 studies, respectively, and similar results were obtained for glial cell densities. On the other hand, microglial markers were increased, lower or unchanged in schizophrenia in 11, 3 and 8 studies, respectively. Results were variable across all other markers, but SERPINA3 and IFITM were consistently increased in 4 and 5 studies, respectively. Despite the variability, some studies evaluating neuroinflammation in postmortem brains in schizophrenia suggest an increase in microglial activity and other markers such as SERPINA3 and IFITM. Variability across studies is partially explained by multiple factors including brain region evaluated, source of the brain, diagnosis, age at time of death, age of onset and the presence of suicide victims in the cohort.

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Postmortem evidence of cerebral inflammation in schizophrenia: a systematic review

The levels of kynurenic acid (KYNA), an astrocyte-derived metabolite of the branched kynurenine pathway (KP) of tryptophan degradation and antagonist of α7 nicotinic acetylcholine and N-methyl-D-aspartate receptors, are elevated in the prefrontal cortex (PFC) of individuals with schizophrenia (SZ). Because endogenous KYNA modulates extracellular glutamate and acetylcholine levels in the PFC, these increases may be pathophysiologically significant. Using brain tissue from SZ patients and matched controls, we now measured the activity of several KP enzymes (kynurenine 3-monooxygenase [KMO], kynureninase, 3-hydroxyanthranilic acid dioxygenase [3-HAO], quinolinic acid phosphoribosyltransferase [QPRT], and kynurenine aminotransferase II [KAT II]) in the PFC, ie, Brodmann areas (BA) 9 and 10. Compared with controls, the activities of KMO (in BA 9 and 10) and 3-HAO (in BA 9) were significantly reduced in SZ, though there were no significant differences between patients and controls in kynureninase, QPRT, and KAT II. In the same samples, we also confirmed the increase in the tissue levels of KYNA in SZ. As examined in rats treated chronically with the antipsychotic drug risperidone, the observed biochemical changes were not secondary to medication. A persistent reduction in KMO activity may have a particular bearing on pathology because it may signify a shift of KP metabolism toward enhanced KYNA synthesis. The present results further support the hypothesis that the normalization of cortical KP metabolism may constitute an effective new treatment strategy in SZ.

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Impaired Kynurenine Pathway Metabolism in The Prefrontal Cortex of Individuals With Schizophrenia

S100B is a Ca2+ -binding protein mainly concentrated in astrocytes. Its levels in biological fluids (cerebrospinal fluid, peripheral and cord blood, urine, saliva, amniotic fluid) are recognized as a reliable biomarker of active neural distress. Although the wide spectrum of diseases in which the protein is involved (acute brain injury, neurodegenerative diseases, congenital/perinatal disorders, psychiatric disorders) reduces its specificity, its levels remain an important aid in monitoring the trend of the disorder. Mounting evidence now points to S100B as a Damage-Associated Molecular Pattern molecule which, when released at high concentration, through its Receptor for Advanced Glycation Endproducts, triggers tissue reaction to damage in a series of different neural disorders. This review addresses this novel scenario, presenting data indicating that S100B levels and/or distribution in the nervous tissue of patients and/or experimental models of different neural disorders, for which the protein is used as a biomarker, are directly related to the progress of the disease: acute brain injury (ischemic/hemorrhagic stroke, traumatic injury), neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis), congenital/perinatal disorders (Down syndrome, spinocerebellar ataxia-1), psychiatric disorders (schizophrenia, mood disorders), inflammatory bowel disease. In many cases, over-expression/administration of the protein induces worsening of the disease, whereas its deletion/inactivation produces amelioration. This review points out that the pivotal role of the protein resulting from these data, opens the perspective that S100B may be regarded as a therapeutic target for these different diseases, which appear to share some common features reasonably attributable to neuroinflammation, regardless their origin.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/jnc.14574

The S100B story: from biomarker to active factor in neural injury.

S100B-immunopositive glia is elevated in paranoid as compared to residual schizophrenia: a morphometric study.

Objectives. Abnormalities of brain white matter and oligodendroglia are replicated findings in schizophrenia research. The largely oligodendroglia-associated enzyme ADAM (A disintegrin and metalloprotease) 12 might be involved in the patho-physiology of schizophrenia, because the gene coding for human ADAM12 is located on chromosome 10q26.3, a gene locus which has been linked to schizophrenia, and some of its putative substrates are altered in schizophrenia. Methods. We studied the numerical density of ADAM12 expressing oligodendrocytes in post-mortem prefrontal brains of patients with haloperidol treated, chronic schizophrenia and matched controls. Results. A significantly reduced numerical density of ADAM12 immunoreactive oligodendrocytes was found in the white matter of the anterior cingulate cortex of schizophrenic patients. Conclusions. Although the pathophysiological implications of this finding are currently unknown, it is well conveyable that reduced ADAM12 protein contributes to a deviant...

Reduced density of ADAM 12-immunoreactive oligodendrocytes in the anterior cingulate white matter of patients with schizophrenia

Dear Editor,

I am Dr Hans-Gert Bernstein from the Department of Psychiatry, University of Magdeburg, Germany. Although it is now a well-established fact that mothers with schizophrenia are at higher risk for obstetric complications (preterm births, preeclampsia, low birthweight [LBW] and small-for-gestational-age babies), a putative paternal impact was largely ignored until recently. Now a comprehensive, population-based study in Taiwan, China has revealed that infants whose fathers had schizophrenia were much more likely to have LBW than those whose fathers did not (12.6% vs. 8.0%) 1. Unlike the situation with schizophrenic mothers, in whom inadequate prenatal care was identified as one major cause for obstetric complications 2, it remains to be established how the mental illness of the father may influence the outcome of a pregnancy. Although social factors cannot be ruled out, mainly biological factors are supposed to contribute to the increased risk of LBW of children sired by schizophrenic fathers 1. The expression of paternal genes might significantly influence placental and fetal growth development 3. The identity of such paternal factors remained largely unknown, as yet. However, from several points of view, A disintegrin and metalloprotease (ADAM)12, which in many ways may influence the outcome of a pregnancy, emerges as an interesting candidate. ADAM12, which is highly expressed in the placenta, has been proposed to be a regulator of trophoblast fusion, which is a crucial event of major importance for the preservation of a healthy pregnancy. This process takes place throughout pregnancy and is crucial for the maintenance of the syncytiotrophoblast layer, the direct border between maternal blood and fetal tissues 4. Recent evidence also suggests a prominent involvement of ADAM12 in promoting the uterine decidualization, which is characterized by the proliferation of stromal cells and their differentiation into specialized decidual cells, surrounding the implanting blastocyst 5. Proper decidualization is another prerequisite for a healthy pregnancy. Further, a truncated form of ADAM12 is released from the trophoblast into maternal blood and regulates by degradation the levels of insulin-like growth factors, which are prominently involved in the control of fetal growth and development 6. Lastly, ADAM12 is an established sheddase of placental leucine aminopeptidase (oxytocinase) 7, an enzyme critically involved in the induction of labour and hence probably having an important role in preterm births 8. Support of pathophysiological functions of ADAM12 in obstetric complications comes from observations of reduced maternal blood levels of ADAM12 in cases of small-for-gestational-age fetuses 6 and preeclampsia 9. Although there is yet no evidence for a paternal imprinting of ADAM12, a considerable paternal influence on the placental expression of this enzyme must be assumed. The possible link between ADAM12 expression/activity and genetic aspects of paternal schizophrenia is given by the location of the ADAM12 gene on human chromosome 10q26.3. This gene locus has repeatedly been linked to schizophrenia, and there is recent evidence showing that at least one SNP within the human ADAM12 gene is significantly associated with this disease (reviewed in Farkas et al. 10). Moreover, we recently could show that in postmortem brains of male and female patients with schizophrenia the cellular expression of ADAM12 is indeed significantly reduced 10.

Thus, a possible link between paternal schizophrenia and LWB might be existing through reduced ADAM12 expression levels. However, unlike for other obstetric complications, a decreased ADAM12 expression during pregnancy that contributes to LWB has not been shown yet, and is thus a hypothesis worth to be tested in andrological/gynecological practice.

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Nadine Farkas

Papers

S100B-immunopositive glia is elevated in paranoid as compared to residual schizophrenia: a morphometric study.

Reduced density of ADAM 12-immunoreactive oligodendrocytes in the anterior cingulate white matter of patients with schizophrenia

Association between paternal schizophrenia and low birthweight: ADAM12 may matter.