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| VBM-based pairwise group comparison of associations between S100B concentration and white matter brain structure (interaction analysis): controls (C) vs. first episode patients (FEP). Clusters shown are significant as stated and numbered in Table 4 and are shown as overlay to the T1 average image in axial and sagittal plane for each group comparison as indicated below anatomical images. The T1 averaged image was obtained from images of all participants of this study. Positive interaction (regression of group A > B) is indicated by red/yellow color, negative interaction (A < B) by blue color (colorbar with corresponding T-values shown in Figure 3). Numbering of clusters is as according to Table 4. Scatter plots showing S100B concentration against white matter values (obtained from 1st Eigenvariate of its corresponding cluster) and corresponding regression lines are demonstrated exemplarily for each found interaction pattern. Color coding in scatter plots: gray, C, controls; red, FEP, first episode patients; blue, REP, recurrent episode patients.
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Background:
Schizophrenia can be conceptualized as a form of dysconnectivity between brain regions.To investigate the neurobiological foundation of dysconnectivity, one approach is to analyze white matter structures, such as the pathology of fiber tracks. S100B is considered a marker protein for glial cells, in particular oligodendrocytes and astr...
Citations
... Elevated serum S100B was also associated with a disturbed white matter volume; this suggests cerebral dysconnectivity, a major cause of cognitive impairment. 36 It has been proposed that high levels of the peripheral S100B protein could be induced by glial activation. 37 This is also related to the increased inflammatory regulation factors and higher severity of symptoms in schizophrenia patients. ...
Cognitive impairment is a prominent cause of disability in schizophrenia. Although antipsychotic drugs can rescue the psychotic symptoms, the cognitive impairments persist, with no treatment available. Alterations of BDNF, VEGF, TNF‐α, and S100B have been linked to cognitive impairment in several neurological disorders. However, it remains unclear whether their levels are correlated with the cognitive functions of schizophrenia patients. Forty‐one chronic, medicated schizophrenia patients were included in this study. Enzyme‐linked, immunosorbent assays were used to measure the serum concentrations of BDNF, VEGF, TNF‐α, and S100B. Associations between serum protein levels and various domains of the cognitive functions of the schizophrenia patients were observed. We found significant, positive correlations between serum BDNF and the processing speed and attention levels of the patients. Serum VEGF was also positively correlated with their memory and learning functions. In contrast, serum S100B and TNF‐α were negatively correlated with the processing speed and attention of the schizophrenia patients. The findings warrant further investigation of these molecules as potential prognostic markers or treatment targets for cognitive impairment in schizophrenia patients. Associations between serum protein levels and domains of the cognitive functions of the schizophrenia patients were investigated. The results show 1) positive correlations between serum BDNF and the processing speed and attention levels, 2) positive correlations between serum VEGF and the memory and learning functions, and 3) negative correlation between serum S100B and TNF‐α and the processing speed and attention.
... Therefore, it is speculated that fewer oligodendrocytes are maturating in schizophrenia brains. After using voxel-based morphometry to detect the white-matter structures as obtained from T1-weighted MR-images and measuring serum S100B levels, some researchers found that there were significantly different correlations between S100B levels and local white-matter formations between the first episode and recurrent episode patients [87]. That is to say, S100B is involved in an ongoing dynamic process associated with local structural changes in the white brain matter of schizophrenic patients. ...
Schizophrenia, consisting of a group of severe psychiatric disorders with a complex etiology, is a leading cause of disability globally. Due to the lack of objective indicators, accurate diagnosis and selection of effective treatments for schizophrenia remain challenging. The association between schizophrenia and alarmins levels has been proposed for many years, but without solid evidence. Alarmins are prestored molecules that do not require processing and can be released upon cell death or damage, making them an ideal candidate for an early initiator of inflammation. Immunological biomarkers seem to be related to disease progression and treatment effectiveness. Several studies suggest strong associations among the high-mobility group box 1 protein (HMGB1), interleukin-1α, interleukin-33, S100B, heat-shock proteins, and uric acid with schizophrenic disorders. The purpose of this review is to discuss the evidence of central and peripheral immune findings in schizophrenia, their potential causes, and the effects of immunomodulatory therapies on symptoms and outline potential applications of these markers in managing the illness. Although there are currently no effective markers for diagnosing or predicting treatment effects in patients with schizophrenia, we believe that screening immune-inflammatory biomarkers that are closely related to the pathological mechanism of schizophrenia can be used for early clinical identification, diagnosis, and treatment of schizophrenia, which may lead to more effective treatment options for people with schizophrenia.
... Study of astrocytes and other glial cells in schizophrenia has been mainly limited to structural imaging studies, measurement of peripheral markers and tissue examination. FEP patients exhibit elevated blood levels of S100 calcium-binding protein B (S100B), a protein expressed predominantly in astrocytes and oligodendrocytes [140]. Blood levels of S100B typically reflect astrocyte damage and BBB permeability, given the role of astrocytes in maintaining the BBB. ...
... Blood levels of S100B typically reflect astrocyte damage and BBB permeability, given the role of astrocytes in maintaining the BBB. Moreover, these higher S100B levels correlate with structural changes in the white matter [140]. Acute psychotic episodes are also associated with elevated S100B levels [141], and chronic increases in S100B are associated with more severe negative symptoms [142]. ...
Schizophrenia is a debilitating psychiatric illness that remains poorly understood. While the bulk of symptomatology has classically been associated with disrupted brain functioning, accumulating evidence demonstrates that schizophrenia is characterized by systemic inflammation and disturbances in metabolism. Indeed, metabolic disease is a major determinant of the high mortality rate associated with schizophrenia. Antipsychotic drugs (APDs) have revolutionized management of psychosis, making it possible to rapidly control psychotic symptoms. This has ultimately reduced relapse rates of psychotic episodes and improved overall quality of life for people with schizophrenia. However, long-term APD use has also been associated with significant metabolic disturbances including weight gain, dysglycemia, and worsening of the underlying cardiometabolic disease intrinsic to schizophrenia. While the mechanisms for these intrinsic and medication-induced metabolic effects remain unclear, inflammation appears to play a key role. Here, we review the evidence for roles of inflammatory mechanisms in the disease features of schizophrenia and how these mechanisms interact with APD treatment. We also discuss the effects of common inflammatory mediators on metabolic disease. Then, we review the evidence of intrinsic and APD-mediated effects on systemic inflammation in schizophrenia. Finally, we speculate about possible treatment strategies. Developing an improved understanding of inflammatory processes in schizophrenia may therefore introduce new, more effective options for treating not only schizophrenia but also primary metabolic disorders.
... This MMP9/RAGE mechanism is a primary interest as some evidence implicates MMP9 and RAGE in SZ pathophysiology. For instance, patient serum contains higher levels of AGEs and S100B than serum from healthy controls [76,77]. Different studies have reported conflicting results on the levels of sRAGE in serum, showing increased [30] or decreased sRAGE [77,78] in patient serum. ...
Various mechanisms involved in schizophrenia pathophysiology, such as dopamine dysregulation, glutamate/NMDA receptor dysfunction, neuroinflammation or redox imbalance, all appear to converge towards an oxidative stress “hub” affecting parvalbumine interneurones (PVI) and their perineuronal nets (PNN) (Lancet Psychiatry. 2015;2:258–70); (Nat Rev Neurosci. 2016;17:125–34). We aim to investigate underlying mechanisms linking oxidative stress with neuroinflammatory and their long-lasting harmful consequences. In a transgenic mouse of redox dysregulation carrying a permanent deficit of glutathione synthesis (gclm−/−), the anterior cingulate cortex presented early in the development increased oxidative stress which was prevented by the antioxidant N-acetylcysteine (Eur J Neurosci. 2000;12:3721–8). This oxidative stress induced microglia activation and redox-sensitive matrix metalloproteinase 9 (MMP9) stimulation, leading to the receptor for advanced glycation end-products (RAGE) shedding into soluble and nuclear forms, and subsequently to nuclear factor-kB (NF-kB) activation and secretion of various cytokines. Blocking MMP9 activation prevented this sequence of alterations and rescued the normal maturation of PVI/PNN, even if performed after an additional insult that exacerbated the long term PVI/PNN impairments. MMP9 inhibition thus appears to be able to interrupt the vicious circle that maintains the long-lasting deleterious effects of the reciprocal interaction between oxidative stress and neuroinflammation, impacting on PVI/PNN integrity. Translation of these experimental findings to first episode patients revealed an increase in plasma soluble RAGE relative to healthy controls. This increase was associated with low prefrontal GABA levels, potentially predicting a central inhibitory/excitatory imbalance linked to RAGE shedding. This study paves the way for mechanistically related biomarkers needed for early intervention and MMP9/RAGE pathway modulation may lead to promising drug targets.
... Our meta-analysis includes ten studies on S100B (Arora et al., 2019;Ayyildiz et al., 2018;Chen et al., 2017;Falcone et al., 2010;Goff et al., 2018;Hendouei et al., 2016;Hong et al., 2016;Milleit et al., 2016;Morera-Fumero et al., 2017;Tao et al., 2019) that were neither included in previous meta-analyses on S100B in schizophrenia (Aleksovska et al., 2014;Schroeter et al., 2009;Schumberg et al., 2016) or affective disorders (da Rosa et al., 2016;Kroksmark and Vinberg, 2018;Schroeter et al., 2011). Nonetheless, our findings of increased blood levels of S100B are congruous with the previous meta-analyses. ...
Background
Blood-brain barrier (BBB) pathology may be associated with mental disorders. The aim of this systematic review and meta-analysis is to identify, evaluate and summarize available evidence on whether potential biomarkers of BBB pathology are altered in patients with schizophrenia spectrum disorders, major depression and bipolar disorder compared to healthy controls.
Methods
The primary outcome is blood S100B, while secondary outcomes include biomarkers in blood and/or cerebrospinal fluid, i.e. albumin ratio, fibrinogen, immunoglobulin G, glial fibrillary acidic protein, amyloid beta (Aβ), matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases, endothelial glycocalyx constituents, and cell adhesion molecules (CAMs). A systematic search in PubMed, Embase and PsycINFO resulted in 131 eligible studies, of which 93 were included in the meta-analysis. Meta- and subgroup analyses were undertaken using random-effects modelling. The protocol was a priori registered on PROSPERO (CRD42020152721).
Results
S100B was increased in schizophrenia spectrum disorders (24 studies; 1107 patients; standardized mean difference (SMD)=0.82; 95% confidence interval (CI)=0.51 to 1.13; I²=90%), major depression (13 studies; 584 patients; SMD=0.57; 95% CI=0.31 to 0.83; I²=73%) and bipolar disorder (4 studies; 142 patients; SMD=0.55; 95% CI=0.16 to 0.94; I²=48%). Similarly, numerous secondary outcomes, including albumin ratio, fibrinogen, Aβ, MMPs and CAMs, were altered. Results of the included studies varied considerably, and important confounders were often not accounted for.
Conclusions
The findings implicate occurrence of BBB pathology in patients with schizophrenia spectrum disorders, major depression and bipolar disorder compared to healthy controls. However, definite conclusions cannot be drawn, mainly because the investigated biomarkers are indirect measures of BBB pathology.
... While S100b is elevated in traumatic brain injury and linked to neurodegeneration in Alzheimer's, in schizophrenia, S100b appears to be more a marker of astrocyte activation [6] rather than of frank cell injury or blood brain barrier leakage [5,7]. It not clear whether S100b is associated with neurodegeneration in schizophrenia or is a product of neuroprotective processes [8]; regardless, as compared to healthy control subjects, consistent elevations in schizophrenia have been well described, including in first episode patients [3,6,8]. ...
... While S100b is elevated in traumatic brain injury and linked to neurodegeneration in Alzheimer's, in schizophrenia, S100b appears to be more a marker of astrocyte activation [6] rather than of frank cell injury or blood brain barrier leakage [5,7]. It not clear whether S100b is associated with neurodegeneration in schizophrenia or is a product of neuroprotective processes [8]; regardless, as compared to healthy control subjects, consistent elevations in schizophrenia have been well described, including in first episode patients [3,6,8]. ...
The calcium-binding protein S100b is secreted by glial cells in the brain and is also expressed by melanocytes. In nanomolar concentrations, S100b is considered to be a neurotrophic factor, but in micromolar concentrations, it is thought to reflect CNS injury and inflammation. Seen as a potential biomarker in traumatic brain injury, meta-analytic data from several studies report that S100b levels are significantly higher in persons with long standing schizophrenia, but also among first-episode patients compared to healthy control subjects. However, ethnic or racial differences are typically not mentioned when reporting levels of S100b. We assessed serum S100b levels in persons with schizophrenia (n = 136) who were participants in two independent research studies using the same enzyme-linked immunoassay (ELISA). African-American subjects had significantly higher levels of S100b (41.9 pg/ml ± 62.2) than Caucasian subjects (24.9 pg/ml ± 45.4) in the combined dataset (Mann-Whitney U = 1307, p < 0.001), as well as in each independent study. There were no significant differences in S100b levels between men and women. No significant correlations were observed between S100b levels and demographic or clinical variables. These data suggest that ethnicity or race should be given serious consideration when studying and interpreting S100b levels in persons with schizophrenia.
... Reports on S100B levels in schizophrenia patients have been inconsistent. Accurately, some reported no diff-erences in S100B bet-ween schizophrenia patients and healthy controls (21,22), while others reported an increased (23) or decreased S100B (16) in patients with schizophrenia compared with healthy controls. Both the first-generation antipsychotic drug (haloperidol) and the second-generation drug (risperidone) are shown to inhibit interleukin-6-induced S100B secretion in C6 glioma cells (24). ...
Background: The study aimed to examine the antipsychotic treatment effect on the serum S100B and oxidative stress in patients with schizophrenia. Methods: Subjects consisted of patients with schizophrenia of first-episode drug-naive and drug-free acute phases, and met the DSM-IV diagnostic criteria for schizophrenia. All patients were treated with risperidone for eight weeks. Positive and Negative Syndrome Scale (PANSS) was evaluated, and serum levels of S100B and parameters of oxidative stress including total oxidative status (TOS) and malondialdehyde (MDA) were measured before and after antipsychotic treatment. A general linear random-effect model was used for data analysis. Results: Antipsychotic treatment with risperidone reduced the levels of S100B significantly in the first episode drug-naive patients with schizophrenia (Beta=24.89; p=0.0087) and marginally in the drug-free acute phase (Beta=15.65; p=0.093), no significant difference in the effect on S100B between patient groups (p=0.4785). In contrast, antipsychotic treatment increased the levels of MDA in drug-free acute phase schizophrenia (Beta=-6.55; p<0.0001) but not in the first episode drug-naive patients (beta=-0.57; p=0.6631); the effects on MDA were significantly different between two patient groups (p=0.0020). We found that the levels of S100B were only associated with the PANSS negative score in the drug-free acute phase patients who were treated with antipsychotics. Conclusion: Antipsychotic treatment with risperidone reduced the levels of S100B in first-episode, drug-naive patients with schizophrenia, but may increase the levels of MDA in drug-free acute phase schizophrenia.
... weighted MR-images, has been reported in unmedicated schizophrenia patients (Milleit et al, 2016). ...
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.
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... Hence, the increased S100B in the drug-free group may represent a more chronic phenomenon that repeats over time in some patients, which could lead to gradual but irreversible alterations of neurocircuitry and neurochemistry in specific brain regions, contributing, for example, to the cognitive deficits. A recent study by Milleit et al. (Milleit et al., 2016) investigated the associations between S100B and structural white matter abnormalities in unmedicated schizophrenia patients (first and recurrent episode) and healthy controls. Using voxel based morphometry (VBM), they found that the first episode patients had a negative correlation of S100B concentration to the white matter Fig. 1. ...
... Nevertheless, recurrent episode patients had a positive association in all of the above regions. Therefore, this suggests S100B is involved in an ongoing and dynamic process that is related to structural changes of brain at different stages of schizophrenia (Milleit et al., 2016), which is a possible mechanism explaining the present results that positive correlation between S100B concentration and positive symptoms was found only in the drug-naïve group, whereas significant negative correlation between S100B and neurocognition performance was seen only in the drug-free group. On the other hand, since the increase in S100B in drug-naïve patients was related to positive symptoms which may unpredictably affect cognitive performance, this could lead to the absence of association between S100B and cognition in this group. ...
... Identifying possible biomarkers of brain aging is a key challenge (Academy of Medical Sciences, 2016; Jylhävä et al., 2017), and serum S100b is one of the logical candidates, yet data on S100b and multimodal brain analyses in older participants are lacking. Two prior cross-sectional studies indicate that serum S100b is specifically associated with poorer white matter microstructure (assessed with diffusion tensor MRI) in a small sample of healthy participants (N ¼ 41, effect found in females only; Streitbürger et al., 2012), and in a small study of schizophrenia patients versus controls (total N ¼ 39; Milleit et al., 2016). Neither study found a significant association between S100b and gray matter (GM)dhowever, it should be noted that both adopted a voxel-basedemorphometry approach which results in reduced power in the large areas of the cortex that show highly individualized patterns of gyrification, and insensitivity to discrete lesions; Tisserand et al., 2004). ...
... Given that S100b concentration in blood may rise due to age, central nervous system (CNS) damage, and BBB disruption, we hypothesized that relatively higher and increasing concentrations of plasma S100b would be coupled with lower and decreasing measures of brain structural and microstructural health. Prior evidence indicates that S100b is particularly strongly expressed in the human brain's white matter tracts (histological data showed co-localization of S100b with oligodendrocyte markers in the human brain; Streitbürger et al., 2012), and that serum S100b is cross-sectionally associated with poorer white matter microstructure (assessed with diffusion tensor MRI) in small mixed samples (N 102) with wide age ranges (Milleit et al., 2016;Streitbürger et al., 2012). Thus, we hypothesize that elevated and increasing serum S100b would be particularly pertinent to poorer and decreasing white matter structure, beyond measures of global atrophy and GM volume. ...
... Thus, these general, latent, factors reflect common microstructural properties (FA and MD) across white matter pathways. Finally, based on evidence of local white matter variation in S100b expression (most strongly expressed in the corpus callosum and cingulum bundle) and cross-sectional associations between FA and S100b (Streitbürger et al., 2012;Milleit et al., 2016;van der Leeuw et al., 2017; Allen Institute for Brain Science, 2010), we used the same framework as above to examine associations between S100b and tract-specific microstructure in each white matter tract of interest for FA and MD. ...
Elevated serum and cerebrospinal fluid concentrations of S100β, a protein predominantly found in glia, are associated with intracranial injury and neurodegeneration, although concentrations are also influenced by several other factors. The longitudinal association between serum S100β concentrations and brain health in nonpathological aging is unknown. In a large group (baseline N = 593; longitudinal N = 414) of community-dwelling older adults at ages 73 and 76 years, we examined cross-sectional and parallel longitudinal changes between serum S100β and brain MRI parameters: white matter hyperintensities, perivascular space visibility, white matter fractional anisotropy and mean diffusivity (MD), global atrophy, and gray matter volume. Using bivariate change score structural equation models, correcting for age, sex, diabetes, and hypertension, higher S100β was cross-sectionally associated with poorer general fractional anisotropy (r = -0.150, p = 0.001), which was strongest in the anterior thalamic (r = -0.155, p < 0.001) and cingulum bundles (r = -0.111, p = 0.005), and survived false discovery rate correction. Longitudinally, there were no significant associations between changes in brain imaging parameters and S100β after false discovery rate correction. These data provide some weak evidence that S100β may be an informative biomarker of brain white matter aging.
