Catechol-O-methyltransferase (COMT) polymorphisms modulate working memory in individuals with schizophrenia and healthy controls

Objective: Cognitive impairment is a core feature of schizophrenia, related to dopaminergic dysfunction in the prefrontal cortex (PFC). It is hypothesized that functional single nucleotide polymorphism (SNP) rs4680 of the catechol-O-methyltransferase (COMT) gene could mediate the relationship between cognition and dopamine activity in the PFC. Other COMT SNPs could also play a role. Methods: We evaluated the role of three COMT SNPs (rs737865, rs165599, and rs4680) in schizophrenia and their impact on three working memory tasks. For genetic association analyses, 212 individuals with schizophrenia and 257 healthy controls (HCs) were selected. The Visual Working Memory (VWM) Task, Keep Track Task, and Letter Memory Task were administered to 133 schizophrenics and 93 HCs. Results: We found a significant association of rs737865, with the GG genotype exerting a protective effect and the GA haplotype (rs4680/rs165599) exerting a risk effect for schizophrenia. COMT rs4680 AA carriers and rs737865 AA carriers scored lowest on the Keep Track Task. When the genotype* group interaction effect was evaluated, rs165599 exerted opposite effects for VWM and Keep Track task performance in patients and controls, with AA carriers scoring lowest on both tests among controls, but highest among patients. Conclusion: These data support the hypothesis that COMT polymorphisms may be associated with schizophrenia and modulate cognition in patients and controls.Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP), BrazilUniv Fed Sao Paulo UNIFESP, Dept Psiquiatria, Sao Paulo, SP, BrazilFMABC, Dept Saude Colet, Santo Andre, SP, BrazilUniv Fed Sao Paulo, Lab Interdisciplinar Neurociencias Clin LiNC, Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Dept Morfol & Genet, Disciplina Genet, Sao Paulo, SP, BrazilCtr Univ Fundcao Inst Ensino Osasco UNIFIEO, Dept Psicol Educ, Osasco, SP, BrazilUniv Fed Sao Paulo, Dept Psicobiol, Sao Paulo, SP, BrazilUniv Fed Sao Paulo UNIFESP, Dept Psiquiatria, Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Lab Interdisciplinar Neurociencias Clin LiNC, Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Dept Morfol & Genet, Disciplina Genet, Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Dept Psicobiol, Sao Paulo, SP, BrazilFAPESP: 2007/58736-1FAPESP: 2011/50740-5Web of Scienc

The Role of Innate APOBEC3G and Adaptive AID Immune Responses in HLA-HIV/SIV Immunized SHIV Infected Macaques

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Different Pattern of Immunoglobulin Gene Usage by HIV-1 Compared to Non-HIV-1 Antibodies Derived from the Same Infected Subject

A biased usage of immunoglobulin (Ig) genes is observed in human anti-HIV-1 monoclonal antibodies (mAbs) resulting probably from compensation to reduced usage of the VH3 family genes, while the other alternative suggests that this bias usage is due to antigen requirements. If the antigen structure is responsible for the preferential usage of particular Ig genes, it may have certain implications for HIV vaccine development by the targeting of particular Ig gene-encoded B cell receptors to induce neutralizing anti-HIV-1 antibodies. To address this issue, we have produced HIV-1 specific and non-HIV-1 mAbs from an infected individual and analyzed the Ig gene usage. Green-fluorescence labeled virus-like particles (VLP) expressing HIV-1 envelope (Env) proteins of JRFL and BaL and control VLPs (without Env) were used to select single B cells for the production of 68 recombinant mAbs. Ten of these mAbs were HIV-1 Env specific with neutralizing activity against V3 and the CD4 binding site, as well as non-neutralizing mAbs to gp41. The remaining 58 mAbs were non-HIV-1 Env mAbs with undefined specificities. Analysis revealed that biased usage of Ig genes was restricted only to anti-HIV-1 but not to non-HIV-1 mAbs. The VH1 family genes were dominantly used, followed by VH3, VH4, and VH5 among anti-HIV-1 mAbs, while non-HIV-1 specific mAbs preferentially used VH3 family genes, followed by VH4, VH1 and VH5 families in a pattern identical to Abs derived from healthy individuals. This observation suggests that the biased usage of Ig genes by anti-HIV-1 mAbs is driven by structural requirements of the virus antigens rather than by compensation to any depletion of VH3 B cells due to autoreactive mechanisms, according to the gp120 superantigen hypothesis

Investigation of cognition in schizophrenia: psychometric properties of instruments for assessing working memory updating

Objective This study describes the development of two updating measures of working memory (WM): Letter Updating Test (LUT) and Word Updating Test (WUT). Methods In stage 1, items were created and the instruments were assessed by experts and laymen. In stage 2, tests were given to 15 patients with schizophrenia and 15 paired controls. All were able to understand and respond to the instruments. In stage 3, 141 patients with schizophrenia and 119 healthy controls aged 18 to 60 took part; they were assessed on WM, processing speed (PS) and functional outcome. Results The results showed adequate rates of internal consistency for both measures developed, for both the total sample and each group separately, as well as evidence of convergent validity, discriminant validity and sensitivity to differentiate performance among the groups. Principal component analysis yielded two components, one for updating tests and other for PS measures, indicating factorial validity. Positive and significant, yet low, correlations were found with functionality measures. Conclusion These results provide adequate psychometric parameters for the measures developed, applicable to cognitive research settings in schizophrenia

Neuropsychological correlates of remission in chronic schizophrenia subjects: The role of general and task-specific executive processes

Background: Although cognitive deficits have consistently been characterized as core features of schizophrenia, they have not been incorporated into definitions of remission. Furthermore, just a few studies have examined the relationship between cognitive deficits and symptomatic remission. The main aim of the present study is to evaluate the executive functioning of nonremitted schizophrenia patients. Methods: 72 remitted and 42 nonremitted schizophrenia patients, and 119 healthy controls were examined. Subjects were tested with a comprehensive battery of cognitive tests, including a measure to assess the general components of executive functioning and individual tasks to tap the three specific executive dimensions assessed in the present study, namely updating, shifting and inhibition. Results: Schizophrenia subjects performed poorly on general executive functioning and shifting tasks in comparison to healthy controls. Remitted subjects performed better than nonremitted on inhibition and updating tasks. Whereas being a male and showing decreases in updating increase the chances of being in the nonremitted schizophrenia subjects group, increases in shifting and updating enhance the odds of being in the healthy control group. Conclusion: The present findings suggest that executive function deficits are present in chronic schizophrenic patients. In addition, specific executive processes might be associated to symptom remission. Future studies examining prospectively first-episode, drug naive patients diagnosed with schizophrenia may be especially elucidative

Component mechanisms of executive function in schizophrenia and their contribution to functional outcomes

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

Recognition of bipolar disorder type I before the first manic episode: challenges and developments

Bipolar disorder (BD) usually follows a neurobiological progression pathway, but a relatively long interval between the first symptoms of the disorder and the correct diagnosis and treatment takes place in most patients. Strategies used to recognize BD at an early stage and even prior to the first manic episode could help identify the risk and modifying factors that influence the onset and course of disease, and improve outcomes. Drawing on current research results, this article presents considerations on risk factors for the development of BD, including genetic/familial risk, endophenotypes and clinical characteristics. Taken together, this article provides a framework and tools for research on the BD prodrome, as well as for the early recognition and timely treatment of patients prior to and immediately after the emergence of BD.Universidade Federal de São Paulo, Dept Psychiat, Program Recognit & Intervent Individuals Risk Men, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Psychiat, Interdisciplinary Lab Clin Neurosci LINC, São Paulo, BrazilUniv Toronto, CAMH, Toronto, ON, CanadaUniv Toronto, Univ Hlth Network, Mood Disorders Psychopharmacol Unit, Toronto, ON, CanadaZucker Hillside Hosp, Div Psychiat Res, Glen Oaks, NY USAHofstra North Shore LIJ Sch Med, Hempstead, NY USAUniversidade Federal de São Paulo, Dept Psychiat, Program Recognit & Intervent Individuals Risk Men, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Psychiat, Interdisciplinary Lab Clin Neurosci LINC, São Paulo, BrazilWeb of Scienc