Postmortem evidence of cerebral inflammation in schizophrenia: a systematic review

Abstract

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.

Positron Emission Tomography Studies of the Glial Cell Marker Translocator Protein in Patients With Psychosis: A Meta-analysis Using Individual Participant Data

“…Therefore, increases in numbers or activity of these cells in schizophrenia have been hypothesized (48,49). In postmortem studies, higher levels of brain glial cell markers, such as human leukocyte antigenantigen D related and CD11b, have been observed in patients, although results have been mixed (50)(51)(52). With regard to astrocyte markers, there is no evidence of any overall FC, frontal cortex; H0, null hypothesis; H1, hypothesis 1; H2, hypothesis 2; H0:H1, BF denoting evidence in favor of H0 over H1; H1:H0, BF denoting evidence in favor of H1 over H0; H0:H2, BF denoting evidence in favor of H0 over H2; H2:H0, BF denoting evidence in favor of H2 over H0; H1:H2, BF denoting evidence in favor of H1 over H2; H2:H1, BF denoting evidence in favor of H2 over H1; HIP, hippocampus; M1, Model 1; TC, temporal cortex; TSPO, translocator protein; V T , total distribution volume.…”

“…Meta-analysis of TSPO in Patients With Psychosis differences between patients and control subjects (51,52). In the case of TSPO, which is expressed in microglia and astrocytes among other cells (8,9,53), autoradiographic studies have reported both higher (28) and lower (54) binding in patients as compared with HCs.…”

Effect of ApoA4 on SERPINA3 mediated by nuclear receptors NR4A1 and NR1D1 in hepatocytes

“…SERPINA3 has been involved in the pathology of a number of devastating human diseases including Parkinson’s disease and Alzheimer’s disease. The disease can arise from gene expression disturbances that result in excess uncontrolled target protease activity and disruption of the downstream pathway [6, 10, 11]. It was reported that Nur77 (NR4A1) regulate SERPINA3 expression in astrocytes and HepG2 human liver cancer cells [12].…”

Translocator Protein-18 kDa (TSPO) Positron Emission Tomography (PET) Imaging and Its Clinical Impact in Neurodegenerative Diseases

“…Multiple lines of evidence from immunohistochemical cell counting studies to clinical trials of a non-selective microglial inhibitor support the fact that microglia is involved in the pathophysiology of SCZ [181]. Nevertheless, as with post mortem studies [182], microglia PET studies provided conflicting results. Indeed, some studies revealed significantly higher TSPO radioligand binding in SCZ patients in total gray matter [171,175], especially in the frontal and temporal lobes [175] and the hippocampus [172] than in controls subjects.…”