CNR1, central cannabinoid receptor gene, associated with susceptibility to hebephrenic schizophrenia.
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To examine the cannabinoid hypothesis for pathogenesis of schizophrenia, we examined two kinds of polymorphisms of the CNR1 gene, which encodes human CB1 receptor, a subclass of central cannabinoid receptors, in schizophrenics and age-matched controls in the Japanese population. Allelic and genotypic distributions of polymorphism 1359G/A at codon 453 in the coding region and AAT triplet repeats in the 3' flanking region in the Japanese population were quite different from those in Caucasians. Although the polymorphism 1359G/A was not associated with schizophrenia, the triplet repeat polymorphism of the CNR1 gene was significantly associated with schizophrenia, especially the hebephrenic subtype (P = 0.0028). Hebephrenic schizophrenia showed significantly increased rate of the 9 repeat allele (P = 0.032, OR = 2.30, 95% CI (1.91-2.69)), and decreased rate of the 17 repeat allele (P = 0.011, OR = 0.208, 95% CI (0.098-0.439)). The present findings indicated that certain alleles or genotypes of the CNR1 gene may confer a susceptibility of schizophrenia, especially of the hebephrenic type. (+info)
Cortical coordination dynamics and the disorganization syndrome in schizophrenia.
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There has been a long history of investigation in the fields of neuropsychology and cognitive psychology into the question of functional integration in the brain. Each of the several dominant themes in that history can be interpreted as representing an important feature of a unitary general mechanism that integrates distributed processes in the cerebral cortex. This mechanism must allow local areas to function within the large-scale anatomical structure of the cortex so as to satisfy competing requirements for stability and flexibility. Each specialized cortical area must perform a unique role by expressing its own form of information, yet must have its performance constrained by interactions with other areas to which it is connected. In order to generate adaptive behavior within changing and not fully predictable environments, the cortex as a whole must be able to rapidly coordinate the activities of variable assemblages of areas that can collectively express consensual information that is appropriate for the functional requirements engendered by each successive stage of behavioral performance. This paper proposes that the phase synchronization of neuronal population activity from different cortical areas may serve a role in large-scale coordination. Theoretical studies suggest that the cortex normally operates in a metastable dynamic regime in which groups of areas are able to coordinate rapidly and reversibly their activities through changes in their degree of phase synchronization. A disruption of phase synchronization, leading to an excess of local information expression by cortical areas, is proposed as a contributing factor to the disorganization syndrome in schizophrenia. (+info)
No association between the sigma receptor type 1 gene and schizophrenia: results of analysis and meta-analysis of case-control studies.
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BACKGROUND: Several lines of evidence have supported possible roles of the sigma receptors in the etiology of schizophrenia and mechanisms of antipsychotic efficacy. An association study provided genetic evidence that the sigma receptor type 1 gene (SIGMAR1) was a possible susceptibility factor for schizophrenia, however, it was not replicated by a subsequent study. It is necessary to evaluate further the possibility that the SIGMAR1 gene is associated with susceptibility to schizophrenia. METHODS: A case-control association study between two polymorphisms of the SIGMAR1 gene, G-241T/C-240T and Gln2Pro, and schizophrenia in Japanese population, and meta-analysis including present and previous studies. RESULTS: There was no significant association of any allele or genotype of the polymorphisms with schizophrenia. Neither significant association was observed with hebephrenic or paranoid subtype of schizophrenia. Furthermore, a meta-analysis including the present and previous studies comprising 779 controls and 636 schizophrenics also revealed no significant association between the SIGMAR1 gene and schizophrenia. CONCLUSION: In view of this evidence, it is likely that the SIGMAR1 gene does not confer susceptibility to schizophrenia. (+info)
The cognitive basis of disorganization symptomatology in schizophrenia and its clinical correlates: toward a pathogenetic approach to disorganization.
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This article focuses on the schizophrenic disorganization syndrome, which was initially described by Bleuler (who used the term "dissociation") as lying at the heart of schizophrenia. While adopting a neo-Bleulerian approach, we describe schizophrenic disorganization using a pathogenetic hypothesis and a three-part structure. First, we discuss previous approaches to characterizing and defining schizophrenic disorganization, providing arguments in favor of a complementary approach to describing schizophrenic disorganization that relies on a pathogenetic analysis of the disorganization syndrome, and especially thought and language disorders. Second, we present two possible cognitive pathophysiological mechanisms that may explain schizophrenic disorganization: (1) a deficit in the integration of contextual information, based on the results of semantic priming studies; and (2) a theory of mind deficit, based on the results of studies of the attribution of mental states to others. We propose a cognitive model of schizophrenic dysfunctioning on the basis of these two anomalies. Third, we summarize our published findings to examine the implications of these two cognitive pathophysiological mechanisms for schizophrenic disorganization. On the basis of the same two anomalies, we then propose and illustrate a neo-Bleulerian approach to the assessment of communication disorders that is critical to the improvement of schizophrenic disorganization's clinical description. (+info)
The assessment of "prodromal schizophrenia": unresolved issues and future directions.
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Because of the novelty of research with clinical high risk ("prodromal") patients, many unresolved issues exist concerning how the prodromal state is defined and measured. Data are presented from the Recognition and Prevention (RAP) program at the Zucker Hillside Hospital to address several outstanding questions. Baseline attenuated positive symptoms were rated in 42 putatively prodromal patients in the RAP program using the Scale of Prodromal Symptoms (SOPS). Followup data of 6 months or more were available on 34 of these subjects; 9 of these (26.5%) developed psychotic disorders. Patients who developed psychosis had significantly higher SOPS positive symptom scores at baseline than those who did not. Various thresholds, using both total SOPS positive symptom scores and highest single item score, significantly predicted transition to psychosis, which calls into question appropriate cutoffs for the distinction between health, prodromal status, and psychosis. The SOPS positive symptom "conceptual disorganization" was found to be significantly related to disorganized behavior but not to other positive symptoms or to psychotic outcome, suggesting the importance of examining dimensions of psychopathology. The dimensional quantification of prodromal symptom severity may be an important direction for future studies of the assessment of at-risk states. (+info)
Adult metachromatic leukodystrophy: disorganized schizophrenia-like symptoms and postpartum depression in 2 sisters.
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We describe the cases of 2 sisters with adult metachromatic leukodystrophy (MLD). Whereas one sister presented with disorganized schizophrenia-like symptoms as the initial manifestation of MLD, the other remained symptom free except for a 4-week period of postpartum depression. In both patients, there was some residual activity of leukocyte arylsulfatase A (1.7% and 5.5% of normal), and a marked increase in urinary sulfatides was present, as measured by tandem mass spectrometry. An arylsulfatase A pseudodeficiency was therefore excluded. The most common mutations of the adult phenotype, Ile-179-Ser and Pro-426-Leu, were not found. In the literature, only 1 case of adult MLD manifesting as disorganized schizophrenia-like symptoms has been described, whereas postpartum depression has been so far unknown as a presenting symptom of MLD. (+info)
Genome-wide linkage scan of schizophrenia: a cross-isolate study.
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Genetic isolates are exceptional resources for the detection of susceptibility genes for complex diseases because of the potential reduction in genetic and clinical heterogeneity. However, the outcome of these mapping efforts is dependent upon the demographic history of a given isolated population, with the most significant factors being a constant population size, the number of generations since founding, and the pathogenic loci and their allele frequencies among founders. Here we employed a cross-isolate genome-wide multipoint linkage study design using uniform genetic and clinical methods in four Daghestan ethnically and demographically diverse isolates with an aggregation of schizophrenia. Our previous population-genetics study showed that Daghestan has an extremely high genetic diversity between ethnic populations and a low genetic diversity within them. The isolates selected for this study include some with more than 200 and some with fewer than 100 generations of demographical history since their founding. Updated clinical data using DSM-IV criteria showed between-isolate differences in aggregation of distinct types of schizophrenia: one of the isolates had a predominant aggregation of disorganized schizophrenia, while the other three had predominantly paranoid schizophrenia. The summarized cross-isolate results indicated prominent within and between-isolate differences in clinical and genetic heterogeneity: the most ancient isolates have roughly twofold fewer incidences of distinct clinical phenotypes and fewer linked genomic regions compared to the demographically younger isolates, which exhibit higher clinical and genetic heterogeneity. Affected individuals in the demographically ancient isolate of ethnic Dargins (No. 6022) who suffered from disorganized schizophrenia showed the highest linkage evidence at 17p11-p12 (LOD=3.73), while isolates with a predominant aggregation of paranoid schizophrenia (Nos. 6005, 6011, and 6034) showed the highest linkage evidence at 22q11 (LOD=3.0 and 4.4). The unified clinical, genomic, and statistical design we used enabled us to separate the linked and unlinked pedigrees in an unbiased fashion for each genomic location. Overall maximized heterogeneity lod scores for the combined pedigrees ranging from 3.5 to 8.7 were found at 2p24, 10q26, 11q23, 12q24, 17p11-p12, 22q11, and 22q13. The cross-isolate homogeneity in linkage patterns may be ascribed to an identical-by-descent "metahaplotype" block with pathogenic loci derived from the Daghestan ethnic groups' common ancestral metapopulation, while the cross-isolate differences may reflect differences in gene drift and recombination events in the history of local isolates. The results obtained support the notion that mapping genes of any complex disease (e.g., schizophrenia) in demographically older genetic isolates may be more time and cost effective in comparison with demographically younger isolates, especially in genetically heterogeneous outbred populations, due to higher clinical and genetic homogeneity of the primary isolates. A study at higher genotyping density across the regions of interest and fluorescence in situ hybridization analyses are currently underway. (+info)
Electrophysiological insights into conceptual disorganization in schizophrenia.
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Disorganized speech, or thought disorder, in schizophrenia may reflect abnormal processing of meaningful concepts. To examine whether schizophrenia involves abnormalities in how a meaningful context influences processing of concepts strongly, weakly, or not related to it, we used the N400, an event-related brain potential (ERP) index of semantic relatedness. ERPs were recorded from schizophrenia patients (n=18) and normal controls (n=18) while they viewed category definitions (e.g., a type of fruit), each followed by a target word that was either a high-typicality category exemplar (apple), low-typicality exemplar (cherry), or non-exemplar (clamp). Participants' task was to indicate via button-press whether or not the target belonged to the category. In both patients and controls, N400 amplitude was largest (most negative) for non-exemplars, intermediate for low-typicality exemplars, and smallest (least negative) for high-typicality exemplars. Compared to controls, patients showed a trend toward reduced N400 amplitude differences between non-exemplars and low-typicality exemplars. Most importantly, within patients, reduced N400 amplitude differences between high- and low-typicality exemplars were correlated with psychotic symptoms. This association of an N400 index of semantic processing with psychotic symptoms suggests that psychosis in schizophrenia may be associated with greater similarity in how concepts strongly and weakly meaningfully related to their context are processed. (+info)