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Biomedical subjects

Josef Parnas

Publications and source records attributed to Josef Parnas.

At least 19 recordsLinked to original sources

Competing definitions of schizophrenia: what can be learned from polydiagnostic studies?

The contemporary diagnoses of schizophrenia (sz)-Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition(DSM-IV) and International Classification of Diseases, 10th Revision(ICD-10)-are widely considered as important scientific achievements. However, these algorithms were not a product of explicit conceptual analyses and empirical studies but defined through consensus with the purpose of improving reliability. The validity status of current definitions and of their predecessors remains unclear. The so-called "polydiagnostic approach" applies different definitions of a disorder to the same patient sample in order to compare these definitions on potential validity indicators. We reviewed 92 polydiagnostic sz studies published since the early 1970s. Different sz definitions show a considerable variation concerning frequency, concordance, reliability, outcome, and other validity measures. The DSM-IV and the ICD-10 show moderate reliability but both definitions appear weak in terms of concurrent validity, eg, with respect to an aggregation of a priori important features. The first-rank symptoms of Schneider are not associated with family history of sz or with prediction of poor outcome. The introduction of long duration criteria and exclusion of affective syndromes tend to restrict the diagnosis to chronic stable patients. Patients fulfilling the majority of definitions (core sz patients) do not seem to constitute a strongly valid subgroup but rather a severely ill subgroup. Paradoxically, it seems that a century after the introduction of the sz concept, research is still badly needed, concerning conceptual and construct validity of sz, its essential psychopathological features, and phenotypic boundaries.

Adult↗

Schizophrenia and oxidative stress: glutamate cysteine ligase modifier as a susceptibility gene.

Oxidative stress could be involved in the pathophysiology of schizophrenia, a major psychiatric disorder. Glutathione (GSH), a redox regulator, is decreased in patients' cerebrospinal fluid and prefrontal cortex. The gene of the key GSH-synthesizing enzyme, glutamate cysteine ligase modifier (GCLM) subunit, is strongly associated with schizophrenia in two case-control studies and in one family study. GCLM gene expression is decreased in patients' fibroblasts. Thus, GSH metabolism dysfunction is proposed as one of the vulnerability factors for schizophrenia.

Case-Control Studies↗

Premorbid neurocognitive functioning in schizophrenia spectrum disorder.

A prospective study based on the U.S. National Collaborative Perinatal Project and using the Wechsler Intelligence Scale for Children (WISC) found lower test scores for the Coding subtest in preschizophrenic children than in their unaffected siblings. Using data on cognitive functioning in adolescence, the aim of the present prospective study was to examine whether low scores on Coding is associated with the risk of developing schizophrenia spectrum disorders. The 12 subtests of the WISC were administered to 311 children and adolescents with a mean age of 15.1 years (range: 8 to 20 years), and the diagnostic assessment (DSM-IIIR) was conducted by senior clinicians 25 years later. The group with schizophrenia spectrum disorder consisted of 84 individuals, and this group obtained significantly lower scores on Coding than nonschizophrenic controls. This difference could not be explained by differences in WISC IQ. Logistic regression analysis controlling for age at examination, gender, and social status yielded a significant, but relatively weak, association between low Coding test score and risk of schizophrenia spectrum disorder. For each unit increase in the Coding raw score, the adjusted odds ratio was 0.97 (95% CI 0.94-1.00) (p = .022), and the risk of schizophrenia spectrum disorder decreased by 3% (95% CI 6 to 0%). The Coding deficit on the WISC may indicate deficits in perceptual motor speed or in working memory processing speed in young individuals who later develop schizophrenia, schizotypal personality disorder, or other disorders within the schizophrenia spectrum.

Adolescent↗

Delayed early proprioceptive information processing in schizophrenia.

It was first suggested that disordered proprioception was a core feature of schizophrenia by Sandor Rado in 1953. Using a recently designed proprioceptive event-related potential paradigm based on a change of load, we studied 12 unmedicated male out-patients with schizophrenia and 24 controls. In the patients, the early contralateral parietal activity was delayed and later central activity had increased amplitude, but gating was unaffected. The results could be understood within the "deficiency of corollary discharge" model of schizophrenia but not within the "filtering" theory. Further studies, including psychiatric controls, are necessary to verify the specificity of the abnormality.

Adolescent↗

Developing a SNP panel for forensic identification of individuals.

Single nucleotide polymorphisms (SNPs) are likely in the near future to have a fundamental role in forensics in both human identification and description. However, considerable research is necessary to establish adequate scientific foundations for these applications. In the case of identification, because allele frequencies can vary greatly among populations, the population genetics of match probabilities is a critical issue. Some SNPs, however, show little allele frequency variation among populations while remaining highly informative. We describe here both an efficient strategy for identifying and characterizing such SNPs, and test that strategy on a broad representation of world populations. Markers with high heterozygosity and little frequency variation among African American, European American, and East Asian populations are selected for additional screening on seven populations that provide a sampling of genetic variation from the world's major geographical regions. Those with little allele frequency variation on the seven populations are then screened on a total of 40 populations ( approximately 2100 individuals) and the most promising retained. The preliminary panel of 19 SNPs, from an initial selection of 195 SNPs, gives an average match probability of <10(-7) in most of 40 populations studied and no greater than 10(-6) in the most isolated, inbred populations. Expansion of this panel to approximately 50 comparable SNPs should give match probabilities of about 10(-15) with a small global range.

DNA Fingerprinting↗

Parallel Factor Analysis as an exploratory tool for wavelet transformed event-related EEG.

In the decomposition of multi-channel EEG signals, principal component analysis (PCA) and independent component analysis (ICA) have widely been used. However, as both methods are based on handling two-way data, i.e. two-dimensional matrices, multi-way methods might improve the interpretation of frequency transformed multi-channel EEG of channel x frequency x time data. The multi-way decomposition method Parallel Factor (PARAFAC), also named Canonical Decomposition (CANDECOMP), was recently used to decompose the wavelet transformed ongoing EEG of channel x frequency x time (Miwakeichi, F., Martinez-Montes, E., Valdes-Sosa, P.A., Nishiyama, N., Mizuhara, H., Yamaguchi, Y., 2004. Decomposing EEG data into space-time-frequency components using parallel factor analysis. Neuroimage 22, 1035-1045). In this article, PARAFAC is used for the first time to decompose wavelet transformed event-related EEG given by the inter-trial phase coherence (ITPC) encompassing ANOVA analysis of differences between conditions and 5-way analysis of channel x frequency x time x subject x condition. A flow chart is presented on how to perform data exploration using the PARAFAC decomposition on multi-way arrays. This includes (A) channel x frequency x time 3-way arrays of F test values from a repeated measures analysis of variance (ANOVA) between two stimulus conditions; (B) subject-specific 3-way analyses; and (C) an overall 5-way analysis of channel x frequency x time x subject x condition. The PARAFAC decompositions were able to extract the expected features of a previously reported ERP paradigm: namely, a quantitative difference of coherent occipital gamma activity between conditions of a visual paradigm. Furthermore, the method revealed a qualitative difference which has not previously been reported. The PARAFAC decomposition of the 3-way array of ANOVA F test values clearly showed the difference of regions of interest across modalities, while the 5-way analysis enabled visualization of both quantitative and qualitative differences. Consequently, PARAFAC is a promising data exploratory tool in the analysis of the wavelets transformed event-related EEG.

Adult↗

Anomalous subjective experience among first-admitted schizophrenia spectrum patients: empirical investigation.

Our research group has for several years conducted philosophically informed, phenomenological-empirical studies of morbid alterations of conscious experience (subjectivity) in schizophrenia (Sz) and its spectrum of disorders. Some of these experiential alterations constitute, in our view, the vulnerability markers to Sz--indicators that are intrinsic to this disorder and which were historically considered as constituting the phenotypic anchor of the very concept and the diagnostic validity of Sz spectrum disorders. In a more pragmatic clinical context, these indicators, considered here as symptoms, may be potentially effective for early differential diagnosis. In this study, 151 consecutive first-admitted patients (with bipolar, melancholic and organic patients excluded) diagnosed according to the ICD-10, were evaluated on a number of expressive and experiential psychopathological dimensions, with special emphasis on the experiences of perplexity, disorders of self-awareness, perceptual disorders and anomalous bodily experiences. The a priori scales derived from the item pool of a slightly modified OPCRIT and BSABS were used for analyses. Sz and schizotypal disorder scored equally on the subjective dimensions, suggesting a basic phenomenological affinity of these disorders. In contrast, anomalies of subjective experience were clearly more pronounced among the patients within, as compared to those outside the Sz spectrum.

Adult↗

Thinking within the spectrum: schizophrenic thought disorder in six Danish pedigrees.

Formal thought disorder (FTD), a major symptom of schizophrenia, is known to aggregate in families. Our aim was to examine the specificity of FTD in the schizophrenia spectrum disorders and the hypothesized linear aggregation of FTD within pedigrees. Six individuals with a diagnosis of schizophrenia were identified in the Copenhagen High-Risk study and each pedigree was centered on one of the six original schizophrenic probands' nuclear families. The 329 pedigree members in the study were considered at risk for schizophrenia spectrum disorders because most were genetically related to the originating schizophrenic probands. The participants were administered the Copenhagen Interview of Functional Illness to determine diagnoses and the Thought Disorder Index (TDI) was used to assess FTD. Individuals with a schizophrenia diagnosis had higher global levels of FTD, exhibited more severe types of FTD, and had a qualitatively different type of FTD than did participants with other diagnoses or no mental illness. Individuals with Cluster A diagnoses exhibited more FTD and FTD similar in quality to participants with schizophrenia. These results support the construct of a spectrum of schizophrenia conditions. There was a generally high level of FTD in the pedigrees, in part due to assortative mating in this sample. However, there was no apparent pattern of linear aggregation of FTD within the families.

Adolescent↗

Reliability of clinical ICD-10 schizophrenia diagnoses.

Concern has been expressed as to the reliability of clinical ICD-10 diagnosis of schizophrenia. This study was designed to assess the diagnostic reliability of the clinical ICD-10 diagnosis of schizophrenia in a random sample of Danish in- and outpatients with a history of psychosis. A sample of 100 subjects was assessed using the operational criteria OPCRIT checklist for psychotic and affective illness. The most recent principal and clinical ICD-10 diagnosis was compared with diagnoses generated by the OPCRIT instrument. Data documented very high sensitivity (93%) and positive predictive value (87%) of ICD-10 schizophrenia and an overall good agreement between clinical and OPCRIT-derived diagnoses (kappa=0.60). An even higher positive predictive value was obtained when diagnoses were amalgamated into a diagnostic entity of schizophrenia-spectrum disorders (98%). Near perfect agreement was seen between OPCRIT-derived ICD-10 and DSM-IV diagnoses (kappa=0.87). Thus, this study demonstrates high reliability of the clinical diagnosis of schizophrenia and even more so of the diagnosis of schizophrenia-spectrum disorder.

Adult↗

Considerable haplotype diversity within the 23kb encompassing the ADH7 gene.

BACKGROUND: Of the seven known human alcohol dehydrogenase (ADH) genes, the non-liver expressed ADH7 gene codes for the enzyme with the highest maximal activity for ethanol. Previous study from our laboratory has suggested that ADH7 has an epistatic role for protection against alcoholism based on a single ADH7 SNP. METHODS: We have now studied seven SNPs, additional populations for the SNP previously examined, and six more new SNPs, across 23 kb of ADH7 in 38 population samples originating from different geographical regions of the world. RESULTS: The overall linkage disequilibrium is moderate to strong across this region even though considerable 7-SNP haplotype diversity is observed. This uncommonly high haplotype diversity is explained by high LD within each "half," the three upstream SNPs and the four downstream SNPs, but near randomization between the "halves." This division significantly simplified the haplotype pattern: only four major haplotypes account for almost all chromosomes in all populations in each "half." CONCLUSIONS: The low linkage disequilibrium between these two "halves" suggests multiple recombination(s) have occurred in this region, specifically, within intron 7. The absence of strong LD between the functional variation in ADH1B that is strongly associated with alcoholism and any of the variation in ADH7 supports the genetic independence of ADH7 in association studies. Thus, the previously observed epistatic effect of ADH7 cannot be explained by its linkage disequilibrium with a causative factor in ADH1B.

Alcohol Dehydrogenase↗

Clinical detection of schizophrenia-prone individuals: critical appraisal.

Issues that undermine the early detection of schizophrenia include an inadequate grasp of the construct validity of the concept of schizophrenia, insufficient conceptualisation of psychosis and of the illness onset, and a general lack of a theoretical framework for psychopathology. Subjective experience is emphasised as a potentially promising domain for future research.

Humans↗

Clinical characteristics of first-admitted patients with ICD-10 schizotypal disorder.

BACKGROUND: The clinical picture of schizotypal disorders is rarely comprehensively described. AIMS: To describe psychopathological profiles of patients with ICD-10 schizotypal disorder. METHOD: A total of 151 first-admitted patients (with affective and somatic disorders excluded) were given a comprehensive psychopathological evaluation, including the Bonn Scale for the Assessment of Basic Symptoms. Patients with schizotypal disorder (n=50) were compared with those with psychosis (n=51) and those outside the schizophrenia spectrum (other diagnoses, n=50) on a number of psychopathological scales. RESULTS: Patients with schizotypal disorder scored intermediately between patients with psychosis and other diagnoses on scales related to positive and negative symptoms, disorders of emotional contact and formal thought disorder, but had the same scores as patients with schizophrenia for subtle aberrations of subjective experience. Schizotypal criteria were not normally distributed with an excess of patients between 2 and 6 criteria. Family history of schizophrenia was equally elevated among those with schizotypal disorder and those with psychosis. CONCLUSIONS: ICD-10 schizotypy represents a milder, less psychotic, variant of schizophrenia but there is no clear-cut division between the two disorders.

Adult↗

Linkage of eye movement dysfunction to chromosome 6p in schizophrenia: additional evidence.

Establishing the genetics of physiological traits associated with schizophrenia may be an important first step in building a neurobiological bridge between the disease phenotype and its genetic underpinnings. One of the best known of the traits associated with schizophrenia is a disorder of smooth pursuit eye tracking (ETD), which is present in 50-80% of schizophrenia patients. ETD is more than three times more prevalent in the families of a schizophrenia patient than is schizophrenia itself. Arolt et al. [1999] estimated LOD scores for ETD of 2.85 for D6S282 and 3.70 for D6S271, two markers on 6p21.1, as well as obtaining an indication of possible linkage for schizophrenia. Our sample comprised two large families in Denmark. Markers in the region that was implicated by the study of Arolt et al. [1996, 1999] were analyzed as part of a genome scan using the "latent trait (L.T.) model" for the co-transmission of schizophrenia and ETD that we had previously fitted to segregation analysis data from Norway. We obtained a LOD score of 2.05 for D6S1017, a marker within 3 cM of the positive markers obtained by Arolt et al. [1996, 1999]. We regard our results as independent evidence supporting the findings of Arolt et al. [1996, 1999] and also as support for the L.T. model as a way of combining the traits ETD and schizophrenia.

Case-Control Studies↗

Schizophrenia, consciousness, and the self.

In recent years, there has been much focus on the apparent heterogeneity of schizophrenic symptoms. By contrast, this article proposes a unifying account emphasizing basic abnormalities of consciousness that underlie and also antecede a disparate assortment of signs and symptoms. Schizophrenia, we argue, is fundamentally a self-disorder or ipseity disturbance (ipse is Latin for "self" or "itself") that is characterized by complementary distortions of the act of awareness: hyperreflexivity and diminished self-affection. Hyperreflexivity refers to forms of exaggerated self-consciousness in which aspects of oneself are experienced as akin to external objects. Diminished self-affection or self-presence refers to a weakened sense of existing as a vital and self-coinciding source of awareness and action. This article integrates recent psychiatric research and European phenomenological psychiatry with some current work in cognitive science and phenomenological philosophy. After introducing the phenomenological approach along with a theoretical account of normal consciousness and self-awareness, we turn to a variety of schizophrenic syndromes. We examine positive, then negative, and finally disorganization symptoms-attempting in each case to illuminate shared distortions of consciousness and the sense of self. We conclude by discussing the possible relevance of this approach for identifying early schizophrenic symptoms.

Affect↗

Population variation in linkage disequilibrium across the COMT gene considering promoter region and coding region variation.

Catechol-O-methyl transferase (COMT) catalyzes the first step in one of the major pathways in the degradation of catecholamines. The COMT gene on chromosome 22 has been considered a candidate gene for many neuropsychiatric disorders, in part because an exon 4 single nucleotide polymorphism (SNP) in COMT causes an amino acid substitution associated with significantly altered enzyme activity. This functional variant, detected as an NlaIII restriction site polymorphism (RSP), is polymorphic in populations from around the world. A four-site haplotype spanning 28 kb effectively encompasses COMT. This haplotype is comprised of two novel polymorphisms [a tetranucleotide short tandem repeat polymorphism (STRP) in intron 1 and a HindIII RSP at the 5' end of COMT], the NlaIII site, and another previously published site - a BglI RSP at the 3' end of the gene. Overall linkage disequilibrium (LD) for this haplotype is strong and significant in 32 population samples from around the world. Conditional probabilities indicate that, in spite of moderate to strong disequilibrium in most non-African populations, the NlaIII site, although often used for prediction, would not always be a reliable predictor of allelic variation at the other sites. Because other functional variation might exist, especially regulatory variation, these findings indicate that haplotypes would be more effective indicators of possible involvement of COMT in disease etiology.

Base Sequence↗