Neurocognitive Endophenotypes for Bipolar Disorder Identified in Multiplex Multigenerational Families

Olin Neuropsychiatry Research Center, Whitehall Research Building, Institute of Living, Hartford, CT 06106, USA.
Archives of general psychiatry (Impact Factor: 14.48). 02/2010; 67(2):168-77. DOI: 10.1001/archgenpsychiatry.2009.184
Source: PubMed


Although genetic influences on bipolar disorder are well established, localization of genes that predispose to the illness has proven difficult. Given that genes predisposing to bipolar disorder may be transmitted without expression of the categorical clinical phenotype, a strategy for identifying risk genes is to identify and map quantitative intermediate phenotypes or endophenotypes.
To adjudicate neurocognitive endophenotypes for bipolar disorder.
All participants underwent diagnostic interviews and comprehensive neurocognitive evaluations. Neurocognitive measures found to be heritable were entered into analyses designed to determine which test results are impaired in affected individuals, are sensitive to the genetic liability for the illness, and are genetically correlated with affection status.
Central valley of Costa Rica; Mexico City, Mexico; and San Antonio, Texas.
Seven hundred nine Latino individuals participated in the study. Of these, 660 were members of extended pedigrees with at least 2 siblings diagnosed as having bipolar disorder (n = 230). The remaining subjects were community control subjects drawn from each site who did not have a personal or family history of bipolar disorder or schizophrenia.
Neurocognitive test performance.
Two of the 22 neurocognitive variables were not significantly heritable and were excluded from subsequent analyses. Patients with bipolar disorder were impaired on 6 cognitive measures compared with nonrelated healthy controls. Nonbipolar first-degree relatives were impaired on 5 of these, and the following 3 tests were genetically correlated with affection status: Digit Symbol Coding Task, Object Delayed Response Task, and immediate facial memory.
This large-scale extended pedigree study of cognitive functioning in bipolar disorder identifies measures of processing speed, working memory, and declarative (facial) memory as candidate endophenotypes for bipolar disorder.

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    • "These studies addressed the influence of antecedents of schizophrenia or psychosis in the cognitive functioning of schizophrenic or bipolar patients but little is known regarding the influence of family loading of mood disorders on cognitive performance in these patients. However, there is evidence reporting that euthymic healthy first-degree relatives of bipolar patients showed impairment in cognitive domains, such as response inhibition, set shifting, verbal memory and target detection (Bora et al., 2010), and processing speed, working memory, and declarative memory (Glahn et al., 2010). Both studies lend support to the presence of cognitive impairment in family members of patients with affective disorders. "
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    ABSTRACT: Schizophrenia and other psychoses are complex disorders with high rates of cognitive impairment and a considerable degree of genetic and environmental influence on its etiology. Whether cognitive impairment is related to dimensional scores of familial liability is still matter of debate. We conducted a cross-sectional study including 169 patients with psychotic disorders and 26 healthy controls. Attention, memory and executive functions were assessed, and familial loading scores for schizophrenia and mood disorders were calculated. The relationships between familial liability and neuropsychological performance were examined with Spearman׳s correlation coefficients. In addition, patients were classified into three groups by family loading tertiles, and comparisons were performed between the patients in the top and bottom tertiles. Low familial loading scores for schizophrenia showed a significant association with poor executive functioning and delayed visual memory. And these results were also achieved when the subset of psychotic patients in the two extreme tertiles of family loadings of schizophrenia and mood disorders were compared. Low familial liability to schizophrenia seems to be a contributing factor for the severity of cognitive impairment in patients with a broad putative schizophrenia spectrum diagnosis. Copyright © 2015. Published by Elsevier Ireland Ltd.
    04/2015; 227(2-3). DOI:10.1016/j.psychres.2015.03.024
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    • "A spate of systematic reviews and meta-analyses in bipolar disorder (BD) indicate that these cognitive impairments are similar in range to those seen in schizophrenia, but that they are usually of lesser magnitude (Arts et al., 2008; Bora et al., 2009, 2010, 2011; Bourne et al., 2013; Kurtz and Gerraty, 2009; Mann-Wrobel et al., 2011; Murphy and Sahakian, 2001; Robinson and Ferrier, 2006; Torres et al., 2007). There are also suggestions that neuropsychological impairments may represent a putative 'endophenotype' for BD, or intermediate phenotype between genotype and the clinical syndrome (Daban et al., 2012; Glahn et al., 2010, 2006; Robbins et al., 2012). A recent review of cognitive dysfunction in BD and schizophrenia concluded that there were differences in the deficits observed prior to illness onset (partly associated with differences in pre-morbid intellectual functioning; IQ), but that postillness onset, BD and schizophrenia were associated with common deficits across diagnostic boundaries (Lewandowski et al., 2011). "
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    ABSTRACT: Broad neuropsychological deficits have been consistently demonstrated in well-established bipolar disorder. The aim of the current study was to systematically review neuropsychological studies in first-episode bipolar disorders to determine the breadth, extent and predictors of cognitive dysfunction at this early stage of illness through meta-analytic procedures. Electronic databases were searched for studies published between January 1980 and December 2013. Twelve studies met eligibility criteria (N = 341, mean age = 28.2 years), and pooled effect sizes (ES) were calculated across eight cognitive domains. Moderator analyses were conducted to identify predictors of between-study heterogeneity. Controlling for known confounds, medium to large deficits (ES ≥ 0.5) in psychomotor speed, attention and working memory, and cognitive flexibility were identified, whereas smaller deficits (ES 0.20-0.49) were found in the domains of verbal learning and memory, attentional switching, and verbal fluency. A medium to large deficit in response inhibition was only detected in non-euthymic cases. Visual learning and memory functioning was not significantly worse in cases compared with controls. Overall, first-episode bipolar disorders are associated with widespread cognitive dysfunction. Since euthymia was not associated with superior cognitive performance in most domains, these results indicate that even in the earliest stages of disease, cognitive deficits are not mood-state dependent. The current findings have important implications for whether cognitive impairments represent neurodevelopmental or neurodegenerative processes. Future studies need to more clearly characterise the presence of psychotic features, and the nature and number of previous mood episodes.
    Journal of Psychiatric Research 06/2014; 57:1-11. DOI:10.1016/j.jpsychires.2014.06.019 · 3.96 Impact Factor
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    • "The JANET includes tests selected on evidence of significant heritability and sensitivity to schizophrenia, bipolar disorder and other brain-related illnesses. The validity and reliability of these tests have already been established and these have been used for large scale studies in North and Latin American populations thus establishing their utility in samples with variable cultural and linguistic background8. Additionally, the availability of these tests in computerized form minimizes rater bias and measurement errors. "
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    ABSTRACT: Background & objectives: Despite the central role of cognition for mental disorders most studies have been conducted in western countries. Similar research from other parts of the world, particularly India, is very limited. As a first step in closing this gap this cross-cultural comparability study of the South Texas Assessment of Neurocognition (STAN) battery was conducted between USA and India. Methods: One hundred healthy adults from Kerala, India, were administered six language independent subtests of the Java Neuropsychological Test (JANET) version of the STAN, assessing aspects of general intellectual ability (Matrix Reasoning), attention (Identical Pairs Continuous Performance, 3 Symbol Version Test; IPCPTS), working memory (Spatial Capacity Delayed Response Test; SCAP), response inhibition (Stop Signal Reaction Time; SSRT), Emotional Recognition and Risk taking (Balloon Analogue Risk Task; BART). Test results were compared to a demographically matched US sample. Results: Overall test performance in the Kerala sample was comparable to that of the US sample and commensurate to that generally described in studies from western countries. Interpretation & conclusions: Our results support the metric equivalence of currently available cognitive test batteries developed in western countries for use in India. However, the sample was restricted to individuals who were literate and had completed basic primary and secondary education.
    The Indian Journal of Medical Research 08/2012; 136(2):280-8. · 1.40 Impact Factor
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