GRIN3B missense mutation as an inherited risk factor for schizophrenia: whole-exome sequencing in a family with a familiar history of psychotic disorders.

Glutamate is the most important excitatory neurotransmitter in the brain. The N-methyl-D-aspartate (NMDA) receptor is a glutamate-gated ionotropic cation channel that is composed of several subunits and modulated by a glycine binding site. Many forms of synaptic plasticity depend on the influx of calcium ions through NMDA receptors, and NMDA receptor dysfunction has been linked to a number of neuropsychiatric disorders, including schizophrenia. Whole-exome sequencing was performed in a family with a strong history of psychotic disorders over three generations. We used an iterative strategy to obtain condense and meaningful variants. In this highly affected family, we found a frameshift mutation (rs10666583) in the GRIN3B gene, which codes for the GluN3B subunit of the NMDA receptor in all family members with a psychotic disorder, but not in the healthy relatives. Matsuno et al., also reported this null variant as a risk factor for schizophrenia in 2015. In a broader sample of 22 patients with psychosis, the allele frequency of the rs10666583 mutation variant was increased compared to those of healthy population samples and unaffected relatives. Compared to the 1000 Genomes Project population, we found a significant increase of this variant with a large effect size among patients. The amino acid shift degrades the S1/S2 glycine binding domain of the dominant modulatory GluN3B subunit of the NMDA receptor, which subsequently affects the permeability of the channel pore to calcium ions. A decreased glycine affinity for the GluN3B subunit might cause impaired functional capability of the NMDA receptor and could be an important risk factor for the pathogenesis of psychotic disorders.

Distinct Neuropsychological Correlates in Positive and Negative Formal Thought Disorder Syndromes: The Thought and Language Disorder Scale in Endogenous Psychoses.

The correlation of formal thought disorder (FTD) symptoms and subsyndromes with neuropsychological dimensions is as yet unclear. Evidence for a dysexecutive syndrome and semantic access impairments has been discussed in positive FTD, albeit focusing mostly on patients with schizophrenia. We investigated the correlation of the full range of positive and negative as well as subjective and objective FTD with neuropsychological domains in different patient groups. Patients with ICD-10 schizophrenia (n = 51), depression (n = 51), and bipolar mania (n = 18), as well as healthy subjects (n = 60), were interviewed with the Rating Scale for the Assessment of Objective and Subjective Formal Thought and Language Disorder (TALD) and assessed using a multidimensional neuropsychological test battery (executive function, semantic and lexical verbal fluency, attention, working memory, and abstract thinking). Partial correlation analysis, controlling for age and word knowledge, revealed significant results for the objective positive FTD dimension and executive dysfunctions. Objective negative FTD was associated with deficits in lexico-semantic retrieval, as well as attention and working memory dysfunctions. The results suggest that different neuropsychological substrates correlate with the multidimensional and phenomenologically different FTD syndromes. FTD is a complex, multidimensional syndrome with a variety of neuropsychological impairments, which should be accounted for in future studies investigating the pathogenesis of FTD.

Neuropsychological and cerebral morphometric aspects of negative symptoms in schizophrenia: negative symptomatology is associated with specific mnestic deficits in schizophrenic patients.

BACKGROUND: The prevalence of negative symptoms in schizophrenic patients seems to be an important indicator for treatment response and prognosis. Although negative symptoms have often been attributed to frontal lobe anomalies, neuropsychological and anatomical findings do not explicitly support this assumption. Since knowledge about the cerebral correlate of negative symptoms in schizophrenia might have a strong impact on therapeutic and psychopharmacological interventions, we aimed to answer this question by investigating the relationship between negative symptoms, neuropsychological functioning and cerebral volumes in schizophrenic patients. METHODS: Twenty schizophrenic patients and 32 healthy controls were examined using a neuropsychological test battery for the assessment of temporal (mnestic) and frontal (executive) faculties. Volumetric measurements of temporal (hippocampus and amygdala) and frontal (orbitofrontal, dorsolateral prefrontal, and anterior cingulate area) brain areas were performed. Negative symptoms were assessed using the Scale for the Assessment of Negative Symptoms (SANS). RESULTS: Schizophrenic patients performed worse than healthy controls in tests assessing verbal and visuospatial learning and memory functions and on the Stroop interference task. After dividing the schizophrenic group in patients with high and low SANS scores almost all of these deficits were restricted to the former group. There were no overall group differences regarding cerebral subarea volumes. Overall negative symptoms were significantly correlated with verbal memory functions but not with frontal lobe faculties. CONCLUSIONS: Negative symptoms in schizophrenia could specifically associated with verbal memory deficits.

The German translation and validation of the scale for the assessment of thought, language and communication: a factor analytic study.

The Scale for the Assessment of Thought, Language and Communication (TLC) represents an instrument for the assessment of formal thought disorder (FTD). The factorial dimensionality of the TLC has yielded ambiguous results for a distinction between positive (e.g. circumstantiality) and negative (e.g. poverty of speech) FTD. The purpose of the current study was to first translate and validate the TLC scale in German. Second, the internal structure was explored in order to identify different FTD dimensions. Two hundred and ten participants (146 patients with ICD-10 diagnoses: depression n = 63, schizophrenia n = 63, mania n = 20; 64 healthy subjects) were interviewed and FTD was rated with the TLC. The principal component analysis of the German TLC version revealed a 3-factor solution, reflecting a disorganized factor, an emptiness factor and a linguistic control factor. The current investigation yielded similar results to those originally reported for the TLC. Thus, a distinction between a positive disorganized, a negative and a semantic word level factor can be supported for the German translation.

Intra-day variations of blood reelin levels in healthy individuals.

INTRODUCTION: Reelin (RELN) is an extracellular glycoprotein best known to be crucial for neuronal migration during the embryonic period and regulation of synaptic plasticity in the adult brain, with recent studies pointing to reelin playing an important part in the organization of peripheral organs as well. Abnormalities in RELN function are associated with a variety of medical conditions in human beings. These alterations partly also reflect in RELN's blood levels, which gives it a clinical relevance as a potential biomarker. Requirement for a possible clinical use is a profound understanding of RELN's physiology. We hypothesized blood RELN levels could underlie time-dependent variations and therefore examined individuals' serum reelin concentrations in the course of one day. MATERIAL AND METHODS: We obtained blood samples from healthy individuals (n = 10) at several times of measurement over a time period of 24 h. We subsequently determined the respective serum RELN concentrations utilizing an enzyme-linked immunosorbent assay and tested for intra- and interindividual variations in serum RELN concentrations over time. RESULTS: All tested individuals' serum RELN levels displayed significant intraindividual variations in the course of 24 h. Test subjects' reelin day profiles showed substantial divergence among each other. CONCLUSIONS: Our findings point to short-term fluctuations in blood RELN levels being part of physiological RELN homeostasis. This is of special interest with regard to a potential clinical use of RELN as a biomarker.

Increased Blood-Reelin-Levels in First Episode Schizophrenia.

BACKGROUND: Reelin is an extracellular glycoprotein involved in several functions of brain development, synaptogenesis and dendritic proliferation. Numerous studies found perturbation in the reelin system and altered serum reelin levels in neuropsychiatric patients using the western blot procedure. In the international literature, this is the first study that made use of an enzyme-linked immunosorbent assay to analyze serum reelin protein concentration quantitatively. RATIONALE: In order to study possible alterations in reelin blood levels in schizophrenia, we analyzed this signal in schizophrenic patients with a first episode hallucinatory and paranoid syndrome and control subjects in a pilot study design. RESULTS: We found increased blood reelin protein concentration in schizophrenic patients compared to healthy controls. DISCUSSION: Our findings point to a relevant role of reelin metabolism in the pathogenesis of schizophrenia.Reelin could be a biomarker for the course of disease or psychopharmacological treatment. CONCLUSION: We conclude that the reelin protein blood concentration might be a relevant signal with respect to the pathophysiology of schizophrenia.

Working memory in schizophrenia: behavioral and neural evidence for reduced susceptibility to item-specific proactive interference.

BACKGROUND: Susceptibility to item-specific proactive interference (PI) contributes to interindividual differences in working memory (WM) capacity and complex cognition relying on WM. Although WM deficits are a well-recognized impairment in schizophrenia, the underlying pathophysiological effects on specific WM control functions, such as the ability to resist item-specific PI, remain unknown. Moreover, opposing hypotheses on increased versus reduced PI susceptibility in schizophrenia are both justifiable by the extant literature. METHODS: To provide first insights into the behavioral and neural correlates of PI-related WM control in schizophrenia, a functional magnetic resonance imaging experiment was conducted in a sample of 20 patients and 20 well-matched control subjects. Demands on item-specific PI were experimentally manipulated in a recent-probes task (three runs, 64 trials each) requiring subjects to encode and maintain a set of four target items per trial. RESULTS: Compared with healthy control subjects, schizophrenia patients showed a significantly reduced PI susceptibility in both accuracy and latency measures. Notably, reduced PI susceptibility in schizophrenia was not associated with overall WM impairments and thus constituted an independent phenomenon. In addition, PI-related activations in inferior frontal gyrus and anterior insula, typically assumed to support PI resistance, were reduced in schizophrenia, thus ruling out increased neural efforts as a potential cause of the patients' reduced PI susceptibility. CONCLUSIONS: The present study provides first evidence for a diminished vulnerability of schizophrenia patients to item-specific PI, which is presumably a consequence of the patients' more efficient clearing of previously relevant WM traces and the accordingly reduced likelihood for item-specific PI to occur.

A rating scale for the assessment of objective and subjective formal Thought and Language Disorder (TALD).

Formal thought disorder (FTD) is a core syndrome of schizophrenia. However, patients with other diagnoses, such as mania and depression amongst others, also present with FTD. We introduce a novel, comprehensive clinical rating scale, capturing the full variety of FTD phenomenology including subjective experiences. The 30-item Thought and Language Disorder (TALD) scale is based on a detailed review of the literature, encompassing all formal thought disorder symptoms reported from the early 20th century onwards. Objectively observable symptoms as well as subjective phenomena were included. Two hundred and ten participants (146 patients ICD-10 diagnoses: depression n=63, schizophrenia n=63, mania n=20; 64 healthy control subjects) were interviewed and symptoms rated with the TALD, TLC, HAMD, YMRS and SAPS/SANS. A principal component analyses was performed for the TALD to differentiate sub-syndromes. The principal component analysis revealed four FTD factors; objective and subjective as well as positive and negative factor dimensions. The correlation analyses with the TLC and the SAPS/SANS FTD sub-scores demonstrated the factor validity for the objective factors. The different diagnoses showed a distinct pattern of symptom severity in each of the factors, with mania patients exhibiting the highest value in the positive, objective dimension. The scale showed good psychometric results, which makes it a practicable, nosologically-open instrument for the detailed assessment of all FTD dimensions. The results strengthen the importance of subjective symptom assessment reported by the patient.

Therapeutic hypothermia in cerebral air embolism: a case report.

BACKGROUND: Cerebral air embolism is a life-threatening complication of various diagnostic and therapeutic procedures. Hyperbaric oxygenation is considered to be the cornerstone of its treatment. CASE DESCRIPTION: We report a patient with cerebral air embolism after endoscopy of a perineal abscess. Immediate CT imaging confirmed the diagnosis and MRI showed cortically localized areas of restricted diffusion along the gyri. Since hyperbaric oxygenation was not available, moderate hypothermia was applied for neuroprotection. CONCLUSION: This case illustrates a rare complication of endoscopic interventions, and imaging characteristics of cerebral air embolism were described. Furthermore, we discuss the potential utility of therapeutic hypothermia in cerebral air embolism.