Johann Steiner

Identification of a biological signature for schizophrenia in serum

Biomarkers are now used in many areas of medicine but are still lacking for psychiatric conditions such as schizophrenia (SCZ). We have used a multiplex molecular profiling approach to measure serum concentrations of 181 proteins and small molecules in 250 first and recent onset SCZ, 35 major depressive disorder (MDD), 32 euthymic bipolar disorder (BPD), 45 Asperger syndrome and 280 control subjects. Preliminary analysis resulted in identification of a signature comprised of 34 analytes in a cohort of closely matched SCZ (n=71) and control (n=59) subjects. Partial least squares discriminant analysis using this signature gave a separation of 60–75% of SCZ subjects from controls across five independent cohorts. The same analysis also gave a separation of ∼50% of MDD patients and 10–20% of BPD and Asperger syndrome subjects from controls. These results demonstrate for the first time that a biological signature for SCZ can be identified in blood serum. This study lays the groundwork for development of a diagnostic test that can be used as an aid for distinguishing SCZ subjects from healthy controls and from those affected by related psychiatric illnesses with overlapping symptoms.

Glutamatergic and Resting-State Functional Connectivity Correlates of Severity in Major Depression – The Role of Pregenual Anterior Cingulate Cortex and Anterior Insula

Glutamatergic mechanisms and resting-state functional connectivity alterations have been recently described as factors contributing to major depressive disorder (MDD). Furthermore, the pregenual anterior cingulate cortex (pgACC) seems to play an important role for major depressive symptoms such as anhedonia and impaired emotion processing. We investigated 22 MDD patients and 22 healthy subjects using a combined magnetic resonance spectroscopy (MRS) and resting-state functional magnetic resonance imaging (fMRI) approach. Severity of depression was rated using the 21-item Hamilton depression scale (HAMD) and patients were divided into severely and mildly depressed subgroups according to HAMD scores. Because of their hypothesized role in depression we investigated the functional connectivity between pgACC and left anterior insular cortex (AI). The sum of Glutamate and Glutamine (Glx) in the pgACC, but not in left AI, predicted the resting-state functional connectivity between the two regions exclusively in depressed patients. Furthermore, functional connectivity between these regions was significantly altered in the subgroup of severely depressed patients (HAMD > 15) compared to healthy subjects and mildly depressed patients. Similarly the Glx ratios, relative to Creatine, in the pgACC were lowest in severely depressed patients. These findings support the involvement of glutamatergic mechanisms in severe MDD which are related to the functional connectivity between pgACC and AI and depression severity.

Glial cells in schizophrenia: pathophysiological significance and possible consequences for therapy

In the last 10 years, structural, molecular and functional changes in glial cells have become a major focus of interest in the search for the neurobiological foundations of schizophrenia. While neuronal degeneration, as seen in typical degenerative brain diseases, cannot be found in post-mortem brains of psychotic disorders called ‘schizophrenia’, many studies show abnormalities in the connecting elements between the nerve cell bodies (synapses, dendrites and axons) and in all three types of glial cells. There is accumulating evidence of reduced numbers of oligodendrocytes and altered gene expression of myelin/oligodendrocyte-related genes that might explain white matter abnormalities and disturbed inter- and intra-hemispheric connectivity, which have frequently been described in schizophrenia. Earlier reports of increased astrocyte densities as a sign of gliosis could not be confirmed by later studies; however, the expression of several astrocyte-related genes is abnormal. Since astrocytes play a key role in the synaptic metabolism of glutamate and monamines, astrocyte dysfunction may well be related to the current transmitter theories of schizophrenia. Results in increased densities of microglial cells, which act as the main cells for immune defence in the brain, are more controversial. There are, however, higher microglial cell numbers in psychotic patients dying from suicide, and several studies reported altered expression of microglia-related surface markers in schizophrenia, suggesting that immunological/inflammatory factors may be relevant for the pathophysiology of psychosis. Searches for future therapeutic options should aim at compensating disturbed functions of oligodendrocytes, astrocytes and microglial cells, by which at least some aspects of the pathophysiology of the very inhomogeneous clinical syndrome of schizophrenia might be explained.

Validation of a Blood-Based Laboratory Test to Aid in the Confirmation of a Diagnosis of Schizophrenia

We describe the validation of a serum-based test developed by Rules-Based Medicine which can be used to help confirm the diagnosis of schizophrenia. In preliminary studies using multiplex immunoassay profiling technology, we identified a disease signature comprised of 51 analytes which could distinguish schizophrenia (n = 250) from control (n = 230) subjects. In the next stage, these analytes were developed as a refined 51-plex immunoassay panel for validation using a large independent cohort of schizophrenia (n = 577) and control (n = 229) subjects. The resulting test yielded an overall sensitivity of 83% and specificity of 83% with a receiver operating characteristic area under the curve (ROC-AUC) of 89%. These 51 immunoassays and the associated decision rule delivered a sensitive and specific prediction for the presence of schizophrenia in patients compared to matched healthy controls.

The Role of Dopamine in Schizophrenia from a Neurobiological and Evolutionary Perspective: Old Fashioned, but Still in Vogue

Dopamine is an inhibitory neurotransmitter involved in the pathology of schizophrenia. The revised dopamine hypothesis states that dopamine abnormalities in the mesolimbic and prefrontal brain regions exist in schizophrenia. However, recent research has indicated that glutamate, GABA, acetylcholine, and serotonin alterations are also involved in the pathology of schizophrenia. This review provides an in-depth analysis of dopamine in animal models of schizophrenia and also focuses on dopamine and cognition. Furthermore, this review provides not only an overview of dopamine receptors and the antipsychotic effects of treatments targeting them but also an outline of dopamine and its interaction with other neurochemical models of schizophrenia. The roles of dopamine in the evolution of the human brain and human mental abilities, which are affected in schizophrenia patients, are also discussed.

Increased levels of circulating insulin-related peptides in first-onset, antipsychotic naïve schizophrenia patients

Increased levels of circulating insulin-related peptides in first-onset, antipsychotic naive schizophrenia patients

Glial cells as key players in schizophrenia pathology: recent insights and concepts of therapy

The past decade has witnessed an explosion of knowledge on the impact of glia for the neurobiological foundation of schizophrenia. A plethora of studies have shown structural and functional abnormalities in all three types of glial cells. There is convincing evidence of reduced numbers of oligodendrocytes, impaired cell maturation and altered gene expression of myelin/oligodendrocyte-related genes that may in part explain white matter abnormalities and disturbed inter- and intra-hemispheric connectivity, which are characteristic signs of schizophrenia. Earlier reports of astrogliosis could not be confirmed by later studies, although the expression of a variety of astrocyte-related genes is abnormal in psychosis. Since astrocytes play a key role in the synaptic metabolism of glutamate, GABA, monoamines and purines, astrocyte dysfunction may contribute to certain aspects of disturbed neurotransmission in schizophrenia. Finally, increased densities of microglial cells and aberrant expression of microglia-related surface markers in schizophrenia suggest that immunological/inflammatory factors are of considerable relevance for the pathophysiology of psychosis. This review describes current evidence for the multifaceted role of glial cells in schizophrenia and discusses efforts to develop glia-directed therapies for the treatment of the disease.

S100B protein in neurodegenerative disorders

Abstract “Classic” neurodegenerative disorders, such as Alzheimers disease and amyotrophic lateral sclerosis share common pathophysiological features and involve progressive loss of specific neuronal populations, axonal or synaptic loss and dysfunction, reactive astrogliosis, and reduction in myelin. Furthermore, despite the absence of astrogliosis, impaired expression of astrocyte- and oligodendrocyte-related genes has been observed in patients with major psychiatric disorders, including schizophrenia and mood disorders. Because S100B is expressed in astrocytes and oligodendrocytes, its concentration in cerebrospinal fluid (CSF) or serum has been considered a suitable surrogate marker for the diagnostic or prognostic assessment of neurodegeneration. This review summarizes previous postmortem, CSF and serum studies regarding the role of S100B in this context. A general drawback is that only small single-center studies have been performed. Many potential confounding factors exist because of the wide extra-astrocytic and extracerebral expression of S100B. Due to lack of disease specificity, reliance on S100B concentrations for differential diagnostic purposes in cases of suspected neurodegenerative disorders is not recommended. Moreover, there is no consistent evidence for a correlation between disease severity and concentrations of S100B in CSF or serum. Therefore, S100B has limited usefulness for monitoring disease progression.

Elevated serum levels of the glial marker protein S100B are not specific for schizophrenia or mood disorders

Elevated serum levels of the glial marker protein S100B are not specific for schizophrenia or mood disorders

High Field fMRI Reveals Thalamocortical Integration of Segregated Cognitive and Emotional Processing in Mediodorsal and Intralaminar Thalamic Nuclei

Thalamocortical loops, connecting functionally segregated, higher order cortical regions, and basal ganglia, have been proposed not only for well described motor and sensory regions, but also for limbic and prefrontal areas relevant for affective and cognitive processes. These functions are, however, more specific to humans, rendering most invasive neuroanatomical approaches impossible and interspecies translations difficult. In contrast, non-invasive imaging of functional neuroanatomy using fMRI allows for the development of elaborate task paradigms capable of testing the specific functionalities proposed for these circuits. Until recently, spatial resolution largely limited the anatomical definition of functional clusters at the level of distinct thalamic nuclei. Since their anatomical distinction seems crucial not only for the segregation of cognitive and limbic loops but also for the detection of their functional interaction during cognitive–emotional integration, we applied high resolution fMRI on 7 Tesla. Using an event-related design, we could isolate thalamic effects for preceding attention as well as experience of erotic stimuli. We could demonstrate specific thalamic effects of general emotional arousal in mediodorsal nucleus and effects specific to preceding attention and expectancy in intralaminar centromedian/parafascicular complex. These thalamic effects were paralleled by specific coactivations in the head of caudate nucleus as well as segregated portions of rostral or caudal cingulate cortex and anterior insula supporting distinct thalamo–striato–cortical loops. In addition to predescribed effects of sexual arousal in hypothalamus and ventral striatum, high resolution fMRI could extent this network to paraventricular thalamus encompassing laterodorsal and parataenial nuclei. We could lend evidence to segregated subcortical loops which integrate cognitive and emotional aspects of basic human behavior such as sexual processing.