Article

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

ABSTRACT

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: Introduction: Phenotype definition of psychotic disorders has a strong impact on the degree of familial aggregation. Nevertheless, the extent to which distinct classification systems affect familial aggregation (ie, familiality) remains an open question. This study was aimed at examining the familiality associated with 4 nosologic systems of psychotic disorders (DSM-IV, ICD-10, Leonhard's classification and a data-driven approach) and their constituting diagnoses in a sample of multiplex families with psychotic disorders. Methods: Participants were probands with a psychotic disorder, their parents and at least one first-degree relative with a psychotic disorder. The sample was made of 441 families comprising 2703 individuals, of whom 1094 were affected and 1709 unaffected. Results: The Leonhard classification system had the highest familiality (h (2) = 0.64), followed by the empirical (h (2) = 0.55), DSM-IV (h (2) = 0.50), and ICD-10 (h (2) = 0.48). Familiality estimates for individual diagnoses varied considerably (h (2) = 0.25-0.79). Regarding schizophrenia diagnoses, Leonhard's systematic schizophrenia (h (2) = 0.78) had the highest familiality, followed by latent class core schizophrenia (h (2) = 0.74), DSM-IV schizophrenia (h (2) = 0.48), and ICD-10 schizophrenia (h (2) = 0.41). Psychotic mood disorders showed substantial familiality across nosologic systems (h (2) = 0.60-0.77). Domains of psychopathology other than reality-distortion symptoms showed moderate familiality irrespective of diagnosis (h (2) = 0.22-0.52) with the deficit syndrome of schizophrenia showing the highest familiality (h (2) = 0.66). Conclusions: While affective psychoses showed relatively high familiality estimates across classification schemes, those of nonaffective psychoses varied markedly as a function of the diagnostic scheme with a narrow schizophrenia phenotype maximizing its familial aggregation. Leonhard's classification of psychotic disorders may be better suited for molecular genetic studies than the official diagnostic systems.
    No preview · Article · Dec 2015 · Schizophrenia Bulletin
    • "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.
    No preview · Article · Apr 2015
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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.
    Full-text · Article · Jun 2014 · Journal of Psychiatric Research
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