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Polymorphisms in schizophrenia candidate gene UFD1L may contribute to cognitive deficits
... Diagnosis was confirmed using the Brazilian Portuguese version of the Semi-Structured Clinical Interview for DSM-IV -Axis I Disorders (SCID). 25 Clinical assessment also encompassed application of the Positive and Negative Syndrome Scale (PANSS) 26 and Global Assessment of Functioning (GAF). 27 All patients had been taking atypical antipsychotics at stable doses for at least 6 weeks prior to inclusion. ...
... Previous studies have shown that this task is a valid option when comparing the cognitive performance of subjects with SZ to that of healthy individuals. [25][26][27] Letter tasks were performed first, followed by semantic tasks. Finally, participants were assigned an updating task. ...
Objective:
To investigate if verbal fluency impairment in schizophrenia reflects executive function deficits or results from degraded semantic store or inefficient search and retrieval strategies.
Method:
Two groups were compared: 141 individuals with schizophrenia and 119 healthy age and education-matched controls. Both groups performed semantic and phonetic verbal fluency tasks. Performance was evaluated using three scores, based on 1) number of words generated; 2) number of clustered/related words; and 3) switching score. A fourth performance score based on the number of clusters was also measured.
Results:
SZ individuals produced fewer words than controls. After controlling for the total number of words produced, a difference was observed between the groups in the number of cluster-related words generated in the semantic task. In both groups, the number of words generated in the semantic task was higher than that generated in the phonemic task, although a significant group vs. fluency type interaction showed that subjects with schizophrenia had disproportionate semantic fluency impairment. Working memory was positively associated with increased production of words within clusters and inversely correlated with switching.
Conclusion:
Semantic fluency impairment may be attributed to an inability (resulting from reduced cognitive control) to distinguish target signal from competing noise and to maintain cues for production of memory probes.
... Protein within a complex that is necessary for the degradation of ubiquitinated proteins UFD1 is located at chromosome 22q11.2 and single nucleotide polymorphisms within this gene were associated with schizophrenia or its phenotypes (De Luca et al., 2001;Ota et al., 2010;Ota et al., 2013;Xie et al., 2008). Patients with 22q11.2 ...
... Moreover, UFD1L gene expression was reported to be upregulated in the blood cells of ultra-high-risk subjects (Santoro et al., 2015). As for a role in cognition, only one study reported that rs5992403 AA genotype carriers had higher preservation error scores in the Wisconsin Card Sorting test (Ota et al., 2013). CDC45, the human homolog of a yeast cell cycle protein, is located in a genomic region telomeric and adjacent to UFD1L (McKie et al., 1998). ...
22q11.2 heterozygous multigene deletions confer an increased risk of schizophrenia with marked impairment of cognition. We explored whether genes on 22q11.2 are associated with cognitive performance in patients with idiopathic schizophrenia. A total of 240 schizophrenia patients and 240 healthy controls underwent the Japanese-language version of the Brief Assessment of Cognition in Schizophrenia (BACS) and were genotyped for 115 tag single-nucleotide polymorphisms (tag SNPs) at the 22q11.2 region using the golden gate assay (Illumina®). Associations between z-scores of the BACS cognitive domains and SNPs and haplotypes were analyzed using linear regression in PLINK 1.07. An additional set of 149 patients with bipolar disorder were included for cognitive assessment and selected SNPs were genotyped using real-time PCR. Patients with schizophrenia and bipolar disorder showed qualitatively comparable profiles of cognitive impairment across BACS subdomains, as revealed by significant correlation between the two groups in the resulting cognitive effect sizes relative to controls. rs4819522 (TBX1) and rs2238769 (UFD1L) were significantly and nominally associated, respectively, with symbol coding in patients with schizophrenia. Haplotype analyses revealed that haplotypes containing the A allele at rs4819522 and G allele at rs2238769 showed significant negative associations with symbol coding in patients with schizophrenia. There was no effect of any haplotypes on cognition in patients with bipolar disorder. Our results have implications for the understanding of the role of haplotypes of UFD1L and TBX1 genes associated with symbol coding in patients with schizophrenia. Further replication studies in a cohort of newly diagnosed patients and other ethnicities are warranted.
... Neuroimaging data from healthy individuals support the unity/diversity model in that the updating mechanism appears to mainly recruit areas in the lateral prefrontal cortex, 12 that switching between mental sets is thought to depend on the medial prefrontal cortex, 13 and that inhibition tasks mainly activate the orbitofrontal cortex. 14 In schizophrenia, some of these skills present consistent evidence of impairment, 15-17 association with diagnostic gene candidates, 18,19 association with peripheral levels of chemokines, brain-derived neurotrophic factor (BDNF) and oxidative markers, 20 and potentially available homologous animal models. 21 Among psychopathologies, the largest EF deficits have been found in schizophrenia, with large effect sizes in measures of shifting, inhibition, updating, and other aspects of working memory. ...
Objective:
In schizophrenia, scores reflecting deficits in different cognitive processes are strongly correlated, making it difficult to establish a solid relationship between different cognitive mechanisms and other features of this disorder. The objective of this study was to explore whether three frequently postulated executive functions (updating, shifting, and inhibition) could be compared between groups and considered independently in terms of their respective roles in functional outcome.
Methods:
This study relied on confirmatory factor analysis of schizophrenia patients (n=141) and healthy controls (n=119). The main analyses examined the degree to which three executive functions (updating, set-shifting, and inhibition) could be separated in schizophrenia and compared this model among groups. Structural equation modeling analysis was also performed to examine the extent to which executive function components contribute to functional outcome in schizophrenia.
Results:
Multiple-group confirmatory factor analysis with unconstrained model parameters indicated that the full three-factor model may fit the data in both groups (χ2 = 61.48, degrees of freedom = 34, p < 0.001, comparative fit index = 0.95; standardized root mean square residual = 0.037; root mean square error of approximation = 0.04; Akaike's information criteria = 169.49; normed fit index = 0.90), although there was also a good data fit for the patient group with a two-factor model. In the patient group, structural equation modeling suggested that shifting and (principally) updating were associated with the general measure of functional outcome (regression path coefficients: 0.34, p < 0.005; 0.39, p < 0.005, respectively), although when combined the mechanisms fail to contribute.
Conclusion:
This data suggests that the factor structure may be similar but not identical between groups, and both updating and shifting may play an important role in functional outcome in schizophrenia.
... It is suggested that UFD1L is directly associated with stress response in endoplasmatic reticulum (ER)-associated degradation (ERAD) [42], since this protein, in complex with others, extracts misfolded proteins from ER to be degraded in cytosol by the proteasome [43]. Polymorphism of UFD1L was previously associated with the disease [40,44], with age of onset [40], and cognitive deficits in SCZ [45], but not to treatment resistance. In other study of our group, increased UFD1L expression was described in early stage of psychosis, comparing gene expression between individuals in ultrahigh risk (UHR), those with first episode of psychosis (FEP), and HC. ...
Schizophrenia (SCZ) is a mental disorder arising from a complex interaction of genetic and environmental factors. It has been suggested that treatment-resistant schizophrenia (TRS) is a distinct, more severe, and homogenous subgroup of schizophrenia that could present specific biological markers. Our aim was to characterize expression of target genes in blood of TRS patients compared with non-TRS (NTRS) patients and healthy controls (HC). TRS has been defined using failure to respond to two previous antipsychotic trials. We hypothesized that genes involved in neurodevelopment, myelination, neuroplasticity, neurotransmission, and miRNA processing could be involved in treatment resistance; then, we investigated 13 genes related to those processes in 256 subjects, being 94 healthy controls and 162 schizophrenia patients treated with antipsychotics. Of those, 78 were TRS patients and 84 were NTRS patients. Peripheral blood samples were collected from all subjects and RNA was isolated. Gene expression analysis was performed using the TaqMan low-density array (TLDA) technology. To verify the influence of expression quantitative trait loci (eQTLs), we evaluated single-nucleotide polymorphism (SNP) of all genes using data from GTEx Project. SNP genotypes were obtained from HumanOmniExpress BeadChip. We did not detect gene expression differences between TRS and NTRS subjects, indicating candidate genes specific to treatment resistance. We detected an upregulation of CNR1 and UFD1L gene expression in patients (TRS and NTRS groups) when compared to controls, that may be associated with the release of neurotransmitters, which can influence neuronal plasticity, or with a stress response-activating protein degradation. DICER1 and AKT1 expression increased slightly across the groups and could differentiate only the extreme opposite groups, HC and TRS. Both genes act in heterogeneous pathways, such as cell signaling and miRNA processing, and seem to have an increased demand in the TRS group. We did not detect any eQTLs in our sample that could explain differences in mRNA levels, suggesting a possible regulation by other mechanism, not driven by genotypes. Our data strengthen the importance of several biological pathways involved in the schizophrenia refractoriness and severity, adding knowledge to develop more effective treatments in the future.
... UFD1L SNP, rs5992403, has been associated with schizophrenia (De Luca et al. 2001), with earlyonset of the disorder (Ota et al. 2010) and with a defi cit in the set-shifting task (which represents a defi cit in fundamental dimensions of cognition in schizophrenia) (Ota et al. 2013). Moreover, its genomic region (22q11.2) is deleted in DiGeorge syndrome, which is considered one of the main genetic risk factors, beside monozygotic twins, for schizophrenia ( ∼ 25% displays psychotic symptoms in early adulthood) (Bassett et al. 2005). ...
This study aimed to investigate peripheral blood gene expression in ultra-high-risk subjects (UHR) compared to first-episode psychosis individuals (FEP) and healthy controls (HC).
We enrolled 22 UHR, 66 FEP and 67 HC and investigated the expression of 12 genes using Taqman assays. We used the Univariate General Linear Model, as well as Bonferroni correction for multiple comparisons.
We found that UFD1L (ubiquitin fusion degradation 1 like (yeast)) gene was upregulated in UHR group compared to HC and FEP (P = 3.44 × 10(-6) ; P = 9.41 × 10(-6)). MBP (myelin basic protein) was downregulated in UHR compared to FEP (P = 6.07 × 10(-6)). DISC1 (disrupted in schizophrenia 1) was also upregulated in UHR compared to FEP but lost statistical significance when corrected for age.
These genes are directly related to neurodevelopmental processes and have been associated to schizophrenia. Recent findings described that DISC1 overexpression can disrupt MBP expression, thus, we think that these alterations in UHR individuals could be associated with a common process. UFD1L showed a different pattern of expression only for UHR group, suggesting that they can be under an acute endoplasmatic reticulum stress, demanding elevated levels of Ufd1. Further studies can improve knowledge on disease progression and putative targets to preventive strategies.
A new test of verbal learning and memory, the Hopkins Verbal Learning Test, was developed. The test consists of three trials of free-recall of a 12-item, semantically categorized list, followed by yes/no recognition. Six parallel forms yielded equivalent results in normals. The performance of patients with Alzheimer's disease and chronic amnesia is described. The test is likely to be useful in patients too impaired for more comprehensive memory assessments and where repeated testing is necessary.
In an investigation of task-set reconfiguration, participants switched between 2 tasks on every 2nd trial in 5 experiments and on every 4th trial in a final experiment. The tasks were to classify either the digit member of a pair of characters as even/odd or the letter member as consonant/vowel. As the response–stimulus interval increased up to 0.6 s, the substantial cost to performance of this predictable task-switch fell: Participants could partially reconfigure in advance of the stimulus. However, even with 1.2 s available for preparation, a large asymptotic reaction time (RT) cost remained, but only on the 1st trial of the new task. This is attributed to a component of reconfiguration triggered exogenously, i.e., only by a task-relevant stimulus. That stimuli evoke associated task-sets also explains why RT and switch costs increased when the stimulus included a character associated with the currently irrelevant task. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Chromosome 22q11.2 deletion syndrome (22q11DS) is associated with neurocognitive impairments. The neural substrates of cognitive impairments in 22q11DS remain poorly understood. Because the corpus callosum (CC) is found to be abnormal in a variety of neurodevelopmental disorders, we obtained volumetric measurements of the CC and its subregions, examined the relationship between these regions and neurocognition and selected genotypes within candidate genes in the 22q11.2 interval in 59 children with 22q11DS and 53 control subjects. The total CC, splenium and genu were significantly larger in children with 22q11DS and the enlargement was associated with better neurocognitive functioning in the 22q11DS group, suggestive of a compensatory increase in the CC volumes. The expected age-related increase in the volume of the CC was not seen in children with 22q11DS, indicative of dysmaturation of the CC in these children. The increased volumes in the genu, splenium and total CC in the 22q11DS group were associated with polymorphisms within the candidate genes: COMT (rs4680), ZDHHC8 (rs175174) and UFD1L (rs5992403). These findings indicate that alterations in the CC volume in children with 22q11DS are associated with cognition and specific genotypes in the 22q11.2 interval.
To evaluate previously reported associations of copy number variants (CNVs) with schizophrenia and to identify additional associations, the authors analyzed CNVs in the Molecular Genetics of Schizophrenia study (MGS) and additional available data.
After quality control, MGS data for 3,945 subjects with schizophrenia or schizoaffective disorder and 3,611 screened comparison subjects were available for analysis of rare CNVs (<1% frequency). CNV detection thresholds were chosen that maximized concordance in 151 duplicate assays. Pointwise and genewise analyses were carried out, as well as analyses of previously reported regions. Selected regions were visually inspected and confirmed with quantitative polymerase chain reaction.
In analyses of MGS data combined with other available data sets, odds ratios of 7.5 or greater were observed for previously reported deletions in chromosomes 1q21.1, 15q13.3, and 22q11.21, duplications in 16p11.2, and exon-disrupting deletions in NRXN1. The most consistently supported candidate associations across data sets included a 1.6-Mb deletion in chromosome 3q29 (21 genes, TFRC to BDH1) that was previously described in a mild-moderate mental retardation syndrome, exonic duplications in the gene for vasoactive intestinal peptide receptor 2 (VIPR2), and exonic duplications in C16orf72. The case subjects had a modestly higher genome-wide number of gene-containing deletions (>100 kb and >1 Mb) but not duplications.
The data strongly confirm the association of schizophrenia with 1q21.1, 15q13.3, and 22q11.21 deletions, 16p11.2 duplications, and exonic NRXN1 deletions. These CNVs, as well as 3q29 deletions, are also associated with mental retardation, autism spectrum disorders, and epilepsy. Additional candidate genes and regions, including VIPR2, were identified. Study of the mechanisms underlying these associations should shed light on the pathophysiology of schizophrenia.
Early detection and prospective evaluation of clinical high-risk (CHR) individuals who may develop schizophrenia or other psychotic disorders is critical for predicting psychosis onset and for testing preventive interventions.
To elucidate the neuropsychology of the CHR syndrome, to determine the association of neuropsychological function with conversion to psychosis and family history of psychosis, and to examine whether baseline neuropsychological functioning predicts subsequent psychosis.
Longitudinal study with 2(1/2) years of follow-up.
Eight centers participating in the North American Prodrome Longitudinal Study.
Three hundred four prospectively identified CHR individuals meeting Structured Interview for Prodromal Syndromes criteria, 52 non-CHR persons with a family history of psychosis in first- or second-degree relatives (family high-risk group), and 193 normal controls with neither a family history of psychosis nor a CHR syndrome, all of whom underwent baseline neuropsychological evaluations.
A neurocognitive composite score, 8 individual neuropsychological measures, an IQ estimate, and high-risk status.
Global ("composite") neuropsychological functioning was comparably impaired in the CHR and family high-risk groups compared with controls, but profiles differed significantly between groups. Neuropsychological functioning in the CHR group was significantly lower in persons who progressed to psychosis than in those who did not and was worst in the subgroup with a family history of psychosis. Tests of processing speed and verbal learning and memory were most sensitive in discriminating CHR individuals from controls, although reductions were less severe than in established schizophrenia. Neuropsychological functioning did not contribute uniquely to the prediction of psychosis beyond clinical criteria, but worse verbal memory predicted more rapid conversion.
These findings document that CHR individuals have significant neuropsychological difficulties, particularly those who later develop psychosis. This dysfunction is generally of moderate severity but less than in first-episode schizophrenia, suggesting that further decline may occur after baseline CHR assessment.
Earlier efforts to localize the symptoms of schizophrenia in a single brain region have been replaced by models that postulate
a disruption in parallel distributed or dynamic circuits. Based on empirical data derived from both magnetic resonance and
positron emission tomography, we have developed a model that implicates connectivity among nodes located in prefrontal regions,
the thalamic nuclei, and the cerebellum. A disruption in this circuitry produces “cognitive dysmetria,” difficulty in prioritizing,
processing, coordinating, and responding to information. This “poor mental coordination” is a fundamental cognitive deficit
in schizophrenia and can account for its broad diversity of symptoms.
Working memory impairment is common in schizophrenia and is possibly a cause of multiple features of the disorder. However few studies have replicated such findings of impairment patterns in Brazilian samples. The main target of this study was to assess auditory and visual working memory in patients with schizophrenia, to assess if they work as separate systems, and to correlate working memory deficits with executive functions.
Twenty subjects with schizophrenia and twenty healthy subjects matched by gender, age, and schooling have participated. The abilities assessed were auditory and visual working memory, selective attention, inhibitory control, cognitive flexibility, and planning.
Patients showed declines in all measures evaluated, except for a measure reaction time of inhibitory control. Auditory working memory was correlated to selective attention, inhibition, flexibility and planning while Visual working memory to planning and flexibility.
The present study suggests that working memory and executive functions deficits are present in patients with schizophrenia in the Brazilian sample evaluated. Alterations in executive functions may lead to incapacity of operation of processes of working memory. These findings may contribute to delineate and develop new strategies of schizophrenia treatment in the Brazilian population.
Compromised neurocognition is a core feature of schizophrenia. Following Heinrichs and Zakzanis's (1998) seminal meta-analysis of middle-aged and predominantly chronic schizophrenia samples, the aim of this study is to provide a meta-analysis of neurocognitive findings from 47 studies of first-episode (FE) schizophrenia published through October 2007. The meta-analysis uses 43 separate samples of 2,204 FE patients with a mean age of 25.5 and 2,775 largely age- and gender-matched control participants. FE samples demonstrated medium-to-large impairments across 10 neurocognitive domains (mean effect sizes from -0.64 to -1.20). Findings indicate that impairments are reliably and broadly present by the FE, approach or match the degree of deficit shown in well-established illness, and are maximal in immediate verbal memory and processing speed. Larger IQ impairments in the FE compared to the premorbid period, but comparable to later phases of illness suggests deterioration between premorbid and FE phases followed by deficit stability at the group level. Considerable heterogeneity of effect sizes across studies, however, underscores variability in manifestations of the illness and a need for improved reporting of sample characteristics to support moderator variable analyses.
This overview describes the goals and objectives of the third conference conducted as part of the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS) initiative. This third conference was focused on selecting specific paradigms from cognitive neuroscience that measured the constructs identified in the first CNTRICS meeting, with the goal of facilitating the translation of these paradigms into use in clinical trials contexts. To identify such paradigms, we had an open nomination process in which the field was asked to nominate potentially relevant paradigms and to provide information on several domains relevant to selecting the most promising tasks for each construct (eg, construct validity, neural bases, psychometrics, availability of animal models). Our goal was to identify 1-2 promising tasks for each of the 11 constructs identified at the first CNTRICS meeting. In this overview article, we describe the on-line survey used to generate nominations for promising tasks, the criteria that were used to select the tasks, the rationale behind the criteria, and the ways in which breakout groups worked together to identify the most promising tasks from among those nominated. This article serves as an introduction to the set of 6 articles included in this special issue that provide information about the specific tasks discussed and selected for the constructs from each of 6 broad domains (working memory, executive control, attention, long-term memory, perception, and social cognition).
Microdeletions of chromosome 22q11 are the most common genetic defects associated with cardiac and craniofacial anomalies
in humans. A screen for mouse genes dependent on dHAND, a transcription factor implicated in neural crest development, identified
Ufd1, which maps to human 22q11 and encodes a protein involved in degradation of ubiquitinated proteins. Mouse Ufd1 was specifically expressed in most tissues affected in patients with 22q11 deletion syndrome. The human UFD1L gene was deleted in all 182 patients studied with 22q11 deletion, and a smaller deletion of approximately 20 kilobases that
removed exons 1 to 3 ofUFD1L was found in one individual with features typical of 22q11 deletion syndrome. These data suggest that UFD1Lhaploinsufficiency contributes to the congenital heart and craniofacial defects seen in 22q11 deletion.
The AAA-ATPase, p97/Cdc48p, has been implicated in many different pathways ranging from membrane fusion to ubiquitin-dependent protein degradation. Binding of the p47 complex directs p97 to act in the post-mitotic fusion of Golgi membranes. We now describe another binding complex comprising mammalian Ufd1 and Npl4. Yeast Ufd1p is required for ubiquitin-dependent protein degradation whereas yeast Npl4p has been implicated in nuclear transport. In rat liver cytosol, Ufd1 and Npl4 form a binary complex, which exists either alone or bound to p97. Ufd1/Npl4 competes with p47 for binding to p97 and so inhibits Golgi membrane fusion. This suggests that it is involved in another cellular function catalysed by p97, the most likely being ubiquitin-dependent events during mitosis. The fact that the binding of p47 and Ufd1/Npl4 is mutually exclusive suggests that these protein complexes act as adapters, directing a basic p97 activity into different cellular pathways.
There are many published twin studies of schizophrenia. Although these studies have been reviewed previously, to our knowledge, no review has provided quantitative summary estimates of the impact of genes and environment on liability to schizophrenia that also accounted for the different ascertainment strategies used.
To calculate meta-analytic estimates of heritability in liability and shared and individual-specific environmental effects from the pooled twin data.
We used a structured literature search to identify all published twin studies of schizophrenia, including MEDLINE, dissertation, and books-in-print searches.
Of the 14 identified studies, 12 met the minimal inclusion criteria of systematic ascertainment.
By using a multigroup twin model, we found evidence for substantial additive genetic effects-the point estimate of heritability in liability to schizophrenia was 81% (95% confidence interval, 73%-90%). Notably, there was consistent evidence across these studies for common or shared environmental influences on liability to schizophrenia-joint estimate, 11% (95% confidence interval, 3%-19%).
Despite evidence of heterogeneity across studies, these meta-analytic results from 12 published twin studies of schizophrenia are consistent with a view of schizophrenia as a complex trait that results from genetic and environmental etiological influences. These results are broadly informative in that they provide no information about the specific identity of these etiological influences, but they do provide a component of a unifying empirical basis supporting the rationality of searches for underlying genetic and common environmental etiological factors.
Understanding the prevalence of schizophrenia has important implications for both health service planning and risk factor epidemiology. The aims of this review are to systematically identify and collate studies describing the prevalence of schizophrenia, to summarize the findings of these studies, and to explore selected factors that may influence prevalence estimates.
Studies with original data related to the prevalence of schizophrenia (published 1965-2002) were identified via searching electronic databases, reviewing citations, and writing to authors. These studies were divided into "core" studies, "migrant" studies, and studies based on "other special groups." Between- and within-study filters were applied in order to identify discrete prevalence estimates. Cumulative plots of prevalence estimates were made and the distributions described when the underlying estimates were sorted according to prevalence type (point, period, lifetime, and lifetime morbid risk). Based on combined prevalence estimates, the influence of selected key variables was examined (sex, urbanicity, migrant status, country economic index, and study quality). A total of 1,721 prevalence estimates from 188 studies were identified. These estimates were drawn from 46 countries, and were based on an estimated 154,140 potentially overlapping prevalent cases. We identified 132 core studies, 15 migrant studies, and 41 studies based on other special groups. The median values per 1,000 persons (10%-90% quantiles) for the distributions for point, period, lifetime, and lifetime morbid risk were 4.6 (1.9-10.0), 3.3 (1.3-8.2), 4.0 (1.6-12.1), and 7.2 (3.1-27.1), respectively. Based on combined prevalence estimates, we found no significant difference (a) between males and females, or (b) between urban, rural, and mixed sites. The prevalence of schizophrenia in migrants was higher compared to native-born individuals: the migrant-to-native-born ratio median (10%-90% quantile) was 1.8 (0.9-6.4). When sites were grouped by economic status, prevalence estimates from "least developed" countries were significantly lower than those from both "emerging" and "developed" sites (p = 0.04). Studies that scored higher on a quality score had significantly higher prevalence estimates (p = 0.02).
There is a wealth of data about the prevalence of schizophrenia. These gradients, and the variability found in prevalence estimate distributions, can provide direction for future hypothesis-driven research.
Little is known about the general population prevalence or severity of DSM-IV mental disorders.
To estimate 12-month prevalence, severity, and comorbidity of DSM-IV anxiety, mood, impulse control, and substance disorders in the recently completed US National Comorbidity Survey Replication.
Nationally representative face-to-face household survey conducted between February 2001 and April 2003 using a fully structured diagnostic interview, the World Health Organization World Mental Health Survey Initiative version of the Composite International Diagnostic Interview.
Nine thousand two hundred eighty-two English-speaking respondents 18 years and older.
Twelve-month DSM-IV disorders.
Twelve-month prevalence estimates were anxiety, 18.1%; mood, 9.5%; impulse control, 8.9%; substance, 3.8%; and any disorder, 26.2%. Of 12-month cases, 22.3% were classified as serious; 37.3%, moderate; and 40.4%, mild. Fifty-five percent carried only a single diagnosis; 22%, 2 diagnoses; and 23%, 3 or more diagnoses. Latent class analysis detected 7 multivariate disorder classes, including 3 highly comorbid classes representing 7% of the population.
Although mental disorders are widespread, serious cases are concentrated among a relatively small proportion of cases with high comorbidity.
Confirmatory factor analysis was used to examine a proposed factor structure of a comprehensive neuropsychological battery used to study patients with schizophrenia and related psychotic disorders (n = 209). An a priori six-factor model and five nested models were evaluated successively, using maximum likelihood confirmatory factor analysis. In all multifactor models, the factors were significantly intercorrelated. A six-factor model with two pairs of correlated errors fit the neuropsychological data significantly better than competing models with fewer factors. The six factors included verbal crystallized, attention/working memory, verbal episodic memory, speed of information processing, visual episodic memory, and reasoning/problem solving. Severity of negative symptoms was significantly associated with worse performance on attention/working memory and verbal crystallized factors, but positive symptoms, depression, and a summary measure of psychopathology were not significantly related to neuropsychological performance. Impairment on a performance-based measure of functional capacity was significantly related to all neuropsychological factors. A simultaneous confirmatory factor analysis using the original sample and a group of healthy subjects (n = 131) demonstrated that the six-factor model of cognition was generalizable and applied equally well to both groups.
The Consortium on the Genetics of Schizophrenia (COGS) is a 7-site collaboration that examines the genetic architecture of quantitative endophenotypes in families with schizophrenia. Here we review the background and rationale for selecting neurocognitive tasks as endophenotypic measures in genetic studies. Criteria are outlined for the potential of measures as endophenotypic vulnerability markers. These include association with illness, state independence (ie, adequate test-retest stability, adequate between-site reliability, impairments in patients not due to medications, impairments observed regardless of illness state), heritability, findings of higher rates in relatives of probands than in the general population, and cosegregation within families. The COGS required that, in addition, the measures be "neurocognitive" and thus linked to neurobiology and that they be feasible in multisite studies. The COGS neurocognitive assessment includes measures of attention, verbal memory, working memory, and a computerized neurocognitive battery that also includes facial processing tasks. Here we describe data demonstrating that these neurobehavioral measures meet criteria for endophenotypic candidacy. We conclude that quantitative neurocognitive endophenotypes need further evidence for efficacy in identifying genetic effects but have the potential of providing unprecedented insight into gene-environment interaction related to dimensions of brain and behavior in health and disease.
Recent psychological and neuropsychological research suggests that executive functions--the cognitive control processes that regulate thought and action--are multifaceted and that different types of executive functions are correlated but separable. The present multivariate twin study of 3 executive functions (inhibiting dominant responses, updating working memory representations, and shifting between task sets), measured as latent variables, examined why people vary in these executive control abilities and why these abilities are correlated but separable from a behavioral genetic perspective. Results indicated that executive functions are correlated because they are influenced by a highly heritable (99%) common factor that goes beyond general intelligence or perceptual speed, and they are separable because of additional genetic influences unique to particular executive functions. This combination of general and specific genetic influences places executive functions among the most heritable psychological traits. These results highlight the potential of genetic approaches for uncovering the biological underpinnings of executive functions and suggest a need for examining multiple types of executive functions to distinguish different levels of genetic influences.
Errors in Byline, Author Affiliations, and Acknowledgment. In the Original Article titled “Prevalence, Severity, and Comorbidity of 12-Month DSM-IV Disorders in the National Comorbidity Survey Replication,” published in the June issue of the ARCHIVES (2005;62:617-627), an author’s name was inadvertently omitted from the byline on page 617. The byline should have appeared as follows: “Ronald C. Kessler, PhD; Wai Tat Chiu, AM; Olga Demler, MA, MS; Kathleen R. Merikangas, PhD; Ellen E. Walters, MS.” Also on that page, the affiliations paragraph should have appeared as follows: Department of Health Care Policy, Harvard Medical School, Boston, Mass (Drs Kessler, Chiu, Demler, and Walters); Section on Developmental Genetic Epidemiology, National Institute of Mental Health, Bethesda, Md (Dr Merikangas). On page 626, the acknowledgment paragraph should have appeared as follows: We thank Jerry Garcia, BA, Sara Belopavlovich, BA, Eric Bourke, BA, and Todd Strauss, MAT, for assistance with manuscript preparation and the staff of the WMH Data Collection and Data Analysis Coordination Centres for assistance with instrumentation, fieldwork, and consultation on the data analysis. We appreciate the helpful comments of William Eaton, PhD, Michael Von Korff, ScD, and Hans-Ulrich Wittchen, PhD, on earlier manuscripts. Online versions of this article on the Archives of General Psychiatry Web site were corrected on June 10, 2005.
A series of experiments on short-term memory is summarized. The results imply that when possible the following rules should be observed in presenting information to an operator who must keep track of a changing situation: (a) Each variable of which he must keep track should have its own exclusive set of possible states. (b) There should be few variables with many possible states, not many variables with few states, (c) A variable should not change state any more often than necessary. Three other conclusions may be useful to system designers as background information: capacity for random information is low; regularity within the sequence of states assumed by an individual variable is not particularly helpful; and orderly relations among the present states of different variables can be very helpful, at least in the extreme cases that were considered.
Two experiments are reported which suggest that a dynamic memory updating task, running memory, requires two independent mechanisms — the articulatory loop and a component of the central executive. Experiment 1 shows that irrelevant speech and articulatory suppression impair the serial recall component of the running memory task but not the updating component. Updating memory affects performance independently of the effects of irrelevant speech and suppression. The second experiment produced the same pattern of results with a close to span memory load. These results are interpreted in terms of the working memory model outlined by Baddeley (1986). It is concluded that the updating of working memory in real time is coordinated by a central executive component of the model.
Executive dysfunction is a core feature of schizophrenia, but our understanding of the developmental course of this neuropsychological domain in the disease remains largely unexplored. A review of the research evidence points to a number of persistent debates about the course of executive functioning and its relation to illness course. A better understanding of the neurocognitive trajectories of executive functioning in schizophrenia could help identify the risk and modifying factors that influence the onset, severity and course of disease, and the chance to re-direct or re-shape that course and improve outcomes. To accomplish this requires assessment of the diverse and integrated nature of those abilities, and the changes over time in those abilities requires multiple instruments and techniques in order to improve the research methods and understanding of an important area of impairment in schizophrenia.
The current systematic review and meta-analysis provides an extended and comprehensive overview of the associations between neurocognitive and social cognitive functioning and different types of functional outcome. Literature searches were conducted in MEDLINE and PsycINFO and reference lists from identified articles to retrieve relevant studies on cross-sectional associations between neurocognition, social cognition and functional outcome in individuals with non-affective psychosis. Of 285 studies identified, 52 studies comprising 2692 subjects met all inclusion criteria. Pearson correlations between cognition and outcome, demographic data, sample sizes and potential moderator variables were extracted. Forty-eight independent meta-analyses, on associations between 12 a priori identified neurocognitive and social cognitive domains and 4 domains of functional outcome yielded a number of 25 significant mean correlations. Overall, social cognition was more strongly associated with community functioning than neurocognition, with the strongest associations being between theory of mind and functional outcomes. However, as three-quarters of variance in outcome were left unexplained, cognitive remediation approaches need to be combined with therapies targeting other factors impacting on outcome.
We report the genomic organization, RNA and protein expression patterns of the gene encoding for the human homolog of the yeast ubiquitin fusion-degradation protein-1 (UFD1L). This enzyme is involved in a ubiquitin-dependent proteolytic pathway (UFD), firstly described in yeast. The human UFD1L gene is organized into 12 exons ranging in size from 33 to 161 bp. Sequence analysis of the 5'-flanking region of the gene revealed a high GC content, multiple CCAAT-binding motifs, CREB, CFT, and AP-2 sites. RNA transcripts were detected in all tissues and cell lines examined, including thymus, thymocytes, T- and B-cells, fibroblasts, chorionic villi, and amniocytes. In Western blot, the UFD1L antibody demonstrated the presence of multiple protein isoforms in all the tested tissues. Expression profile and promoter characteristics suggest UFD1L is a housekeeping gene with implications in the pathogenesis of DiGeorge/velo-cardio-facial syndrome, due to 22q11.2 deletions.
Recent controversy surrounds the use of the Trail Making Test as a measure of cognitive flexibility, given that the Trail Making Test, Part B (TMT-B) also differs from Part A (TMT-A) in factors of motor control and perceptual complexity. The present study compared performance in the TMT and a set-switching task in order to test the assumption that cognitive flexibility is captured in TMT-B performance. Set-switching tasks have low motor and perceptual selection demands, and therefore provide a clearer index of executive function. In this study, participants made category judgments for digits, letters, or symbols across a series of trials, and performance for consecutive same-task trials was compared with task-switch trials. Results of the set-switching task indicated significant switch cost, but only for the situation of task alternation (e.g., an ABA series), suggesting that task-set inhibition may play a role in this effect. Alternating-switch cost was significantly correlated with TMT-B performance, especially with the TMT-B to TMT-A ratio (B/A). Cost for alternating switches was especially large for participants with B/A ratio > 3. These results provide direct evidence that the B/A ratio of performance in the TMT provides an index of executive function.
Schizophrenia or schizoaffective disorders are often found in patients affected by DiGeorge/velo-cardio-facial syndrome (DGS/VCFS) as a result of hemizygosity of chromosome 22q11.2. We evaluated the UFD1L gene, mapping within the DGS/VCFS region, as a potential candidate for schizophrenia susceptibility. UFD1L encodes for the ubiquitin fusion degradation 1 protein, which is expressed in the medial telencephalon during mouse development. Using case control, simplex families (trios), and functional studies, we provided evidence for association between schizophrenia and a single nucleotide functional polymorphism, -277A/G, located within the noncoding region upstream the first exon of the UFD1L gene. The results are supportive of UFD1L involvement in the neurodevelopmental origin of schizophrenia and contribute in delineating etiological and pathogenetic mechanism of the schizophrenia subtype related to 22q11.2 deletion syndrome.
Research over the last few years has revealed significant haplotype structure in the human genome. The characterization of these patterns, particularly in the context of medical genetic association studies, is becoming a routine research activity. Haploview is a software package that provides computation of linkage disequilibrium statistics and population haplotype patterns from primary genotype data in a visually appealing and interactive interface.
Availability:http://www.broad.mit.edu/mpg/haploview/
Contact:jcbarret@broad.mit.edu
One of the primary goals in the NIMH initiative to encourage development of new interventions for cognitive deficits in schizophrenia, Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS), has been to develop a reliable and valid consensus cognitive battery for use in clinical trials. Absence of such a battery has hampered standardized evaluation of new treatments and, in the case of pharmacological agents, has been an obstacle to FDA approval of medications targeting cognitive deficits in schizophrenia. A fundamental step in developing such a battery was to identify the major separable cognitive impairments in schizophrenia. As part of this effort, we evaluated the empirical evidence for cognitive performance dimensions in schizophrenia, emphasizing factor analytic studies. We concluded that seven separable cognitive factors were replicable across studies and represent fundamental dimensions of cognitive deficit in schizophrenia: Speed of Processing, Attention/Vigilance, Working Memory, Verbal Learning and Memory, Visual Learning and Memory, Reasoning and Problem Solving, and Verbal Comprehension. An eighth domain, Social Cognition, was added due to recent increased interest in this area and other evidence of its relevance for clinical trials aiming to evaluate the impact of potential cognitive enhancers on cognitive performance and functional outcome. Verbal Comprehension was not considered appropriate for a cognitive battery intended to be sensitive to cognitive change, due to its resistance to change. The remaining seven domains were recommended for inclusion in the MATRICS-NIMH consensus cognitive battery and will serve as the basic structure for that battery. These separable cognitive dimensions also have broader relevance to future research aimed at understanding the nature and structure of core cognitive deficits in schizophrenia.
Executive dysfunctions in relatives of schizophrenic patients may be trait markers of genetic liability and thus help us to elucidate the aetiology of schizophrenia. As a large amount of data has been published, a synthesis through a meta-analysis was needed to demonstrate the existence of executive impairments in relatives of schizophrenic patients and to assess their magnitude.
We conducted a meta-analysis of articles that compared performances of controls and relatives of schizophrenic patients on the four tests most frequently used to assess executive functions: the Wisconsin Card Sorting Test (WCST), the Trail Making Test (TMT), the Stroop Test and the Verbal Fluency (VF) Test. When needed and possible, published data were supplemented with information from the authors. After assessing the homogeneity of the data, effect sizes were estimated and publication bias was tested by use of funnel plots.
Relatives of schizophrenic patients performed less well than controls on all executive tests analysed. Effect estimates were in the small to moderate range (from 0.26 to 0.49) for Stroop, WCST and TMT, but were greater for the fluency tests (0.65 for phonological and 0.87 for semantic VF).
Relatives of schizophrenic patients appear to have wide, although not severe, executive dysfunctions. As the sensitivity of the different tests for impairments in relatives is not the same, the choice of test and method used should be carefully assessed.
Memory deficits have been clearly demonstrated in schizophrenic patients. However, studies of memory performances in their relatives compared to normal controls provide conflicting results. A meta-analysis was carried out to synthesize all the published data. Unlike previous meta-analyses, which were based on composite scores, we analyzed each memory test separately. This prevents theoretically questionable choices in grouping variables, leads to results with clearer implications for applied research (e.g. the best choice of a test according to its sensitivity) and is more productive in suggesting explanatory hypotheses.
We initially selected 77 potentially relevant articles, but only 19 met our inclusion criteria. These articles provided data on eight different tasks, from five different memory tests: four tests from the Wechsler Memory Scale (WMS) and the California Verbal Learning Test (CVLT). For each task, we assessed data homogeneity, identified the outliers if any and then estimated effect sizes and tested publication bias using funnel plots.
Adult relatives of schizophrenic patients were significantly impaired on most, but not all, tasks. The largest deficits were observed for the verbal paired associates test, the logical stories the digit span forward test and the digit span backward test. We found no significant differences in tasks of delayed recall, when deficits in immediate conditions (reflecting encoding) were taken into account.
Adult relatives of schizophrenic patients have wide but not severe memory impairments. The size of estimated effects suggests that encoding processes are impaired, whereas storage and retrieval processes are relatively unaffected.
There is evidence that cognitive task performance breaks down into the same broad domains in schizophrenia as in healthy populations. However, this does not mean that the domains are independent of one another or that the interrelationships among domains are the same between groups. We used confirmatory factor analysis (CFA) to compare the latent structure of a broad neuropsychological battery in schizophrenia patients (n = 148) and healthy controls (n = 157). Main analyses examined the fit of a hierarchical six-factor model, in which associations among the factors were assumed to reflect their strong shared relationship to a general cognitive ability factor. The model incorporated the factors of verbal comprehension, perceptual organization, verbal memory, spatial memory, processing speed, and executive/working memory. The hierarchical model provided a good overall fit to data from both groups. However multiple groups CFA revealed significant differences in factor loadings between groups, reflecting a more generalized latent structure of cognitive ability in schizophrenia. This was also evident in higher bivariate correlations among cognitive domain composite scores calculated from the observed test data. Cognitive ability, as reflected in test performance, appears to be more unitary in schizophrenia than in healthy subjects. This finding may have measurement and treatment implications.
The Positive and Negative Syndrome Scale (PANSS) is a widely used instrument to measure severe psychopathology in schizophrenia. Recently, its widely accepted 5-factor solution is questioned using confirmatory factor analysis (CFA). This article examines the appropriateness of applying CFA to PANSS data and the dimensionality of the PANSS in a large sample of persons with chronic schizophrenia, schizophreniform disorder, and schizoaffective disorder.
Data reduction was conducted on PANSS baseline assessments from 2 multicenter clinical trials consisting of 1284 persons' available PANSS data at baseline and Week 8. Supplementary analyses were conducted for separate trials and for noncompleters at baseline (n = 1872).
Examination of the data indicated that the statistical requirements of CFA (eg, multivariate normality) were not met by the data. Multidimensional scaling and a scree plot of principal components superimposed on simulated random data converged to indicate that 5 dimensions are generally a parsimonious fit to the PANSS at baseline, whereas 4 dimensions emerged after 8 weeks of treatment. The components included negative symptoms, positive symptoms, disorganized (baseline only), anxiety/depression, and excited.
The results demonstrate realistic alternatives to CFA when studying the PANSS, support a 5-component model of PANSS ratings at baseline, and indicate that the structure of symptoms change after 8 weeks of treatment. These results seem to be robust because they generally replicate within trials for completers and at baseline for the entire sample.
The present work was undertaken to investigate the association of the UFD1L locus with schizophrenia among 304 Chinese family trios of Han descent. We detected four single nucleotide polymorphisms (SNPs) in the 5'-end region of the UFD1L gene. The transmission disequilibrium test (TDT) revealed allelic associations for rs5746744 (chi(2) = 8.02, P = 0.005) and rs1547931 (chi(2) = 7.18, P = 0.007), but failed to replicate disease association for rs5992403 present in the promoter region, which was initially found in Italian and Canadian samples. The allelic association for rs5746744 and rs1547931 was replicated with independently recruited case-control samples. The 2-SNP haplotype analysis showed an association for the rs5992403-rs5746744 haplotypes (chi(2) = 18.92, df = 3, P = 0.0003), the rs5746744-rs1547931 haplotypes (chi(2) = 11.06, df = 3, P = 0.011) and the rs1547931-rs2238769 haplotypes (chi(2) = 18.88, df = 3, P = 0.0003). The 4-SNP haplotype analysis also showed strong association with illness (chi(2) = 29.54, df = 9, P = 0.0005) but there were more than one individual haplotypes with a low frequency excessively non-transmitted. The four SNPs tested were not located in the same LD block among the Chinese population. This study raises the possibility that a disease-resistant variant may be carried by two or more haplotypes at the UFD1L locus due to frequent recombination during meiosis.
Executive functioning refers to a set of processes involved in complex, goal-directed thought and behavior involving multiple brain regions (e.g., prefrontal cortex, parietal cortex, basal ganglia) and multiple neurotransmitters (e.g., dopamine, glutamate, gamma-aminobutyric acid). People with schizophrenia exhibit executive functioning deficits that are associated with treatment-refractory aspects of the disorder. Although there is general consensus about what cognitive tasks involve executive functioning, there is disagreement about the specific cognitive mechanisms that comprise executive functioning.
This article discusses a number of possible candidate executive functioning mechanisms and provides a summary of the consensus reached by the executive functioning discussion group at the first CNTRICS (Cognitive Neuroscience for Treatment Research to Improve Cognition in Schizophrenia) meeting in Washington, DC.
The consensus was that two constructs have a well-founded basis in basic cognitive neuroscience research and seem to be impaired in schizophrenia: 1) rule generation and selection; and 2) dynamic adjustments in control (i.e., after conflict and errors).
The consensus of the first CNTRICS meeting was that immediate translation of measures of these constructs for use in schizophrenia should be pursued. A number of other constructs (e.g., scheduling, sequencing) could also be very important for schizophrenia and are in need of more basic and more clinical research.
Wisconsin Card Sorting Test: 64-Card Computerized Version
- S K Kongs
- L L Thompson
- G L Iverson
- R K Heaton
Kongs, S.K., Thompson, L.L., Iverson, G.L., Heaton, R.K., 2000. Wisconsin Card Sorting Test: 64-Card Computerized Version. Psychological Assessment Resources, Odessa, FL.
Teste não verbal de inteligência
- R Oliveira
Oliveira, R., 2002. Teste não verbal de inteligência. Vetor Editora Psico–Pedagógica, São Paulo.
Teste de stroop computadorizado
- A G Seabra
- N M Dias
- E Macedo
Seabra, A.G., Dias, N.M., Macedo, E., Teste de stroop computadorizado. Sao Paulo,
Editora Memnon (in press).