Heritable anisotropy associated with cognitive impairments among patients with schizophrenia and their non-psychotic relatives in multiplex families.

BACKGROUND: To test the functional implications of impaired white matter (WM) connectivity among patients with schizophrenia and their relatives, we examined the heritability of fractional anisotropy (FA) measured on diffusion tensor imaging data acquired in Pittsburgh and Philadelphia, and its association with cognitive performance in a unique sample of 175 multigenerational non-psychotic relatives of 23 multiplex schizophrenia families and 240 unrelated controls (total = 438). METHODS: We examined polygenic inheritance (h2r) of FA in 24 WM tracts bilaterally, and also pleiotropy to test whether heritability of FA in multiple WM tracts is secondary to genetic correlation among tracts using the Sequential Oligogenic Linkage Analysis Routines. Partial correlation tests examined the correlation of FA with performance on eight cognitive domains on the Penn Computerized Neurocognitive Battery, controlling for age, sex, site and mother's education, followed by multiple comparison corrections. RESULTS: Significant total additive genetic heritability of FA was observed in all three-categories of WM tracts (association, commissural and projection fibers), in total 33/48 tracts. There were significant genetic correlations in 40% of tracts. Diagnostic group main effects were observed only in tracts with significantly heritable FA. Correlation of FA with neurocognitive impairments was observed mainly in heritable tracts. CONCLUSIONS: Our data show significant heritability of all three-types of tracts among relatives of schizophrenia. Significant heritability of FA of multiple tracts was not entirely due to genetic correlations among the tracts. Diagnostic group main effect and correlation with neurocognitive performance were mainly restricted to tracts with heritable FA suggesting shared genetic effects on these traits.

Mechanisms of functional improvement in a 2-year trial of cognitive enhancement therapy for early schizophrenia.

BACKGROUND: Cognitive rehabilitation has emerged as an effective treatment for addressing cognitive impairments and functional disability in schizophrenia; however, the degree to which changes in various social and non-social cognitive processes translate into improved functioning during treatment remains unclear. This research sought to identify the neurocognitive and social-cognitive mechanisms of functional improvement during a 2-year trial of cognitive enhancement therapy (CET) for early-course schizophrenia. METHOD: Patients in the early course of schizophrenia were randomly assigned to CET (n=31) or an enriched supportive therapy control (n=27) and treated for up to 2 years. A comprehensive neurocognitive assessment battery and the Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT) were completed annually, along with measures of functioning. Mediator analyses using mixed-effects growth models were conducted to examine the effects of neurocognitive and social-cognitive improvement on functional change. RESULTS: Improvements over 2 years in neurocognition and the emotion management branch of the MSCEIT were found to be significantly related to improved functional outcome in early-course schizophrenia patients. Neurocognitive improvement, primarily in executive functioning, and social-cognitive change in emotion management also mediated the robust effects of CET on functioning. CONCLUSIONS: Improvements in neurocognition and social cognition that result from cognitive rehabilitation are both significant mediators of functional improvement in early-course schizophrenia. Cognitive rehabilitation programs for schizophrenia may need to target deficits in both social and non-social cognition to achieve an optimal functional response.

Executive functions and cognitive deficits in schizophrenia: comparisons between probands, parents and controls in India.

BACKGROUND: Cognitive impairment is said to be a core feature of schizophrenia. Executive function is an important cognitive domain. AIM: This study was undertaken to assess cognitive impairment among Indian patients with schizophrenia (Sz) or schizoaffective disorder (SzA), compared with their parents and unaffected individuals (controls). SETTINGS AND DESIGN: Executive functions as measured by Trail-making Test (TMT), of patients and their parents were compared with controls. The patients were recruited from the Outpatients' Department (OPD) of a government hospital. MATERIALS AND METHODS: Patients diagnosed as Sz or SzA (n=172) and their parents (n=196: families n=132, 119 fathers and 77 mothers) participated. We also included 120 persons with no history of psychiatric illness. Cognitive function was assessed with the TMT. The Information Score of the Post Graduate Institute Battery of Brain Dysfunction test, developed in India for Indian subjects was used as a proxy for general fixed knowledge. STATISTICAL ANALYSIS: Logistic and linear regression was used to compare cognitive deficits of cases, parents and controls. RESULTS: Cases and their parents took significantly more time than controls on Part B of the TMT. There were no statistically significant differences between cases and parents on any of the TMT parameters. Using regression analysis, the most significant correlates of all TMT parameters among cases were with occurrence of auditory hallucinations and current age. CONCLUSION: Cases, as well as their parents showed more cognitive impairment than controls on the TMT.

Are neurologic examination abnormalities heritable? A preliminary study.

BACKGROUND: Neurologic examination abnormalities (NEA) are more prevalent among patients with schizophrenia as well as their unaffected relatives when compared with healthy controls, suggesting that NEA may be endophenotypes for schizophrenia. We estimated the heritability of NEA in moderately sized pedigrees. We also evaluated correlations between NEA and cognitive performance in order to examine their construct validity. METHODS: Members of eight extended families, each consisting of two first degree relatives with schizophrenia/schizoaffective disorders, as well as available first- to fifth-degree relatives were examined (n=96 participants). A modification of the Neurological Evaluation Scale (NES) was employed, augmented with localizing signs. Where feasible, we used untransformed data such as error counts and completion time, rather than ordinal measures. Heritability was estimated using the variance component method, implemented in SOLAR. RESULTS: Statistically significant heritability (h2) estimates were obtained for several measures (p<0.05, h2+/-standard error: rapid alternating movements, right-sided completion time, 0.99+/-0.19; alternating fist-palm test, completion time, 0.77+/-0.19 s, errors, 0.70+/-0.32; fist-ring test, right-sided completion time, 0.53+/-0.23 s, left-sided completion time, 0.70+/-0.21 s; go-no go task, correct responses, 0.93+/-0.33; audio-visual integration, correct responses, 0.79+/-0.54). For most items, heritability analysis was hampered by insufficient data variability (infrequent errors). Correlational analyses show some degree of divergence among types of NEA, repetitive motor tasks being associated with most domains of cognitive functioning other than executive functioning, and cognitive-perceptual tasks being associated with memory and executive functioning. CONCLUSIONS: Significant familial influences on certain aspects of neurologic performance were detected. These heritable measures were also correlated with heritable neurocognitive measures.

Genetic and environmental influences on schizotypy: a community-based twin study.

This study investigated the factor structure and etiology of four self-report schizotypy questionnaires during young adulthood (age 18-27) in 98 monozygotic and 59 same-sex dizygotic twin pairs from the community. A single phenotypic factor was identified that was primarily associated with Perceptual Aberration, Magical Ideation, and the Rust Inventory of Schizotypal Cognitions scales, and less so with Social Anhedonia. Univariate etiologic models suggested that in addition to nonshared environmental influences, Perceptual Aberration and Social Anhedonia were significantly influenced by either genes or shared family environment, whereas Magical Ideation and the Rust Inventory were influenced by shared family environment, but not genes. Multivariate twin analyses detected a common schizotypy factor, primarily defined by Perceptual Aberration, Magical Ideation, and the Rust Inventory scales, that was influenced by genes or shared environment as well as nonshared environment. Contrary to expectations, these results suggest that, at least in community-based samples, these "positive" schizotypy questionnaires are not strongly genetically influenced.

Genetic and environmental causes of covariation among blood pressure, body mass and serum lipids during young adulthood: a twin study.

OBJECTIVE: To determine the extent to which the correlation of systolic blood pressure, diastolic blood pressure, body mass, fasting total cholesterol and fasting triglycerides in young adulthood reflects common genetic or environmental influences. DESIGN: Cardiovascular risk factors were measured in a community sample of 129 monozygotic and 67 dizygotic twin pairs, ages 18-30 years. METHODS: Multivariate twin structural equation modelling allows estimation of the extent to which the covariation of two or more variables is attributable to common genetic and environmental factors and was used to analyse the correlation among systolic blood pressure, diastolic blood pressure, body mass index, fasting total cholesterol and triglycerides. RESULTS: The covariation of risk factors was partially attributable to a single common genetic factor, while the covariation of systolic blood pressure, body mass index and triglycerides was also, in part, attributable to a common non-shared environmental factor. CONCLUSIONS: Genetic and, to a lesser extent, non-shared environmental factors contribute to the covariation of cardiovascular risk factors in young adult twins. Nonetheless, it should be noted that these common influences account for a relatively small percentage of the variance in each risk factor compared to genetic and environmental factors that are risk factor-specific.

Familial liability to schizophrenia: a sibling study of negative symptoms.

Negative symptoms are important features in schizophrenia, so in milder form they might also serve as indicators of "unexpressed" liability to schizophrenia among patients' adult relatives without schizophrenia. To address this question, we assessed negative symptoms in 39 stable schizophrenia or schizoaffective outpatients, 39 of their siblings, 38 well control probands, and 38 of their siblings. Negative symptom measures included standard behavior ratings of the core negative symptoms of affective flattening and alogia, as well as a self-report measure of social anhedonia. As expected, even stable outpatients with schizophrenia exhibited significantly more negative symptoms than control probands and control siblings. However, negative behavioral symptoms of affective flattening, alogia, and anhedonia did not significantly differentiate the siblings of the schizophrenia patients from the control probands or their siblings, although there were some trends for anhedonia. The findings suggest that core negative symptoms of observed affective flattening and poverty of speech are not likely to be useful as strong indicators of "unexpressed" liability to schizophrenia.

Human novelty-seeking personality traits and dopamine D4 receptor polymorphisms: a twin and genetic association study.

Although it is well-established that genetic variation is important in causing individual differences in many human personality traits or based on family, twin, and adoption studies, the first reports that specific genetic polymorphisms might influence a normal dimension of personality were only recently published. Specifically, two studies have described significant associations between a dopamine D4 receptor (D4DR) exon III 48-base pair (bp) insertion/deletion polymorphism and the personality traits of novelty-seeking and positive emotional experience [Benjamin et al. (1996): Nat Genet 12: 81-84; Ebstein et al. (1996): Nat Genet 12:78-80]. The present study was undertaken to attempt to replicate these important and heuristic initial findings. Personality questionnaires measuring novelty-seeking and positive emotional experience were administered to 306 male and female young adult twins (monozygotic 92 pairs, dizygotic 61 pairs) from the general population, 281 of whom were genotyped for D4DR exon I and III polymorphisms. No significant associations were observed between novelty-seeking or positive emotional experience and these D4DR polymorphisms. This failure to replicate the initial reports seems unlikely to represent measurement or genetic differences across studies, although environmental differences may be possible. Adequate statistical power in the present study suggests that these results are unlikely to be statistical "false negatives" and instead may reduce confidence in the generality of the initial positive findings.

A multidimensional measurement model for cardiovascular reactivity: stability and cross-validation in two adult samples.

The factor structure for measures of stress-related cardiovascular reactivity was examined in 2 samples: a university campus employee sample (N = 72) and a sample of young adult twins (N = 113). In both samples, 5 noninvasive cardiovascular measures were monitored during a series of challenging laboratory tasks. We developed a 2-factor model depicting vascular and cardiac influences on responding. With confirmatory factor analysis, this model was shown to be consistent with the data across both samples, across 2 testing sessions, and across 2 sets of tasks. Latent variables measuring cardiac and vascular reactivity were highly reliable on retest as well. Individual differences in cardiovascular reactivity to mental stress may be characterized by a stable, 2-dimensional pattern of response.

The nature of environmental influences on weight and obesity: a behavior genetic analysis.

The nature of environmental influences on individual differences in weight and obesity is presently unclear. To resolve this issue, behavior genetic studies are reviewed for their relevance to environmental influences on weight and obesity. Results are consistent in suggesting that environmental experiences are important for weight and obesity, although they account for much less variation than do the effects of genes. Furthermore, only environmental experiences that are not shared among family members appear to be important. In contrast, experiences that are shared among family members appear largely irrelevant in determining individual differences in weight and obesity. These conclusions are consistent with a growing body of evidence on the relative unimportance of such shared experiences for many psychological characteristics.

Hospitalization and the cognitive deficits of schizophrenia. The influences of age and education.

The study investigated the relationship between length of hospitalization and increasing cognitive deficit in schizophrenics. Using Halstead-Reitan Battery data obtained from 245 schizophrenic patients, multiple regression analyses were performed using age, education, and length of hospitalization as independent variables and various summary test indices as dependent variables. These analyses showed that there was not a statistically significant change in percentage of explained variance when length of hospitalization was entered into the multiple regression equations. On the basis of these analyses, it was concluded that the association between increasing deficit and length of hospitalization experienced by schizophrenic patients is no greater than what would be anticipated on the basis of aging.

Poverty of speech in schizophrenia and depression during in-patient and post-hospital periods.

Poverty of speech, a prominent feature of the negative symptom construct in schizophrenia, was assessed longitudinally in 12 schizophrenic and 13 depressed subjects at hospital admission and about seven months after discharge in order to evaluate hypotheses concerning course and diagnostic specificity. Multiple measures of the poverty of speech construct were employed, including both clinical and quantitative indices. During the in-patient period, poverty of speech was more pronounced among depressed than schizophrenic subjects. Examination of this specific negative symptom across in-patient and follow-up evaluations indicated that poverty of speech increased among schizophrenic subjects, but remained relatively stable or declined among depressed subjects. These results suggest that the processes underlying poverty of speech may differ in schizophrenia and depression.

Negative symptoms in schizophrenia: their longitudinal course and prognostic importance.

Negative and positive symptoms were investigated longitudinally in 39 young schizophrenic patients at two followup assessments approximately 2.5 and 5 years after hospital discharge. Negative symptoms, such as flat affect and poverty of speech, which were assessed at the first followup, were found to be effective prognostic signs in schizophrenic patients for predicting later poor role functioning at the second followup. The prognostic importance of negative symptoms was predominantly due to their tendency to occur in patients who were already functioning poorly in social and instrumental areas at the first followup, and who tended to continue doing poorly at the second followup. Contrary to some current hypotheses, positive symptoms, such as delusions and hallucinations, were also found to be prognostic of later deficits in role functioning at the second followup. Negative symptoms appeared to be generally persistent over time, although there was some tendency toward remission. Potential models of the etiology of negative symptoms and their role in schizophrenia are proposed.

Negative and positive symptoms in schizophrenia and depression: a followup.

Negative and positive symptoms were investigated in a sample of 72 young schizophrenic and depressed patients at followup approximately 1 1/2 years after hospital discharge. Flat affect, poverty of speech, and psychomotor retardation were included as negative symptoms, and delusions, hallucinations, and florid thought disorder as positive symptoms. Marked negative symptoms were found to occur in a subgroup of schizophrenic subjects at followup, but were infrequent in depressed subjects. Educational difficulties and poor social functioning before initial hospitalization were associated with later negative symptoms at followup for schizophrenic subjects. Negative symptoms were also related to concurrent outcome measures of instrumental and social functioning at followup. Contrary to some hypotheses, negative and positive symptoms, when assessed concurrently, were not at opposite ends of a bipolar continuum. Rather, they appeared to be independent phenomena in schizophrenia during the early posthospital phase. Overall, these results suggest that negative symptoms are important for a subgroup of schizophrenic patients during the early course of their disorder and that they have important correlates with specific aspects of role functioning.