William S. Kremen

Distinct Genetic Influences on Cortical Surface Area and Cortical Thickness

Neuroimaging studies examining the effects of aging and neuropsychiatric disorders on the cerebral cortex have largely been based on measures of cortical volume. Given that cortical volume is a product of thickness and surface area, it is plausible that measures of volume capture at least 2 distinct sets of genetic influences. The present study aims to examine the genetic relationships between measures of cortical surface area and thickness. Participants were men in the Vietnam Era Twin Study of Aging (110 monozygotic pairs and 92 dizygotic pairs). Mean age was 55.8 years (range: 51-59). Bivariate twin analyses were utilized in order to estimate the heritability of cortical surface area and thickness, as well as their degree of genetic overlap. Total cortical surface area and average cortical thickness were both highly heritable (0.89 and 0.81, respectively) but were essentially unrelated genetically (genetic correlation = 0.08). This pattern was similar at the lobar and regional levels of analysis. These results demonstrate that cortical volume measures combine at least 2 distinct sources of genetic influences. We conclude that using volume in a genetically informative study, or as an endophenotype for a disorder, may confound the underlying genetic architecture of brain structure.

Comparative gene expression analysis of blood and brain provides concurrent validation of SELENBP1 up-regulation in schizophrenia

Microarray techniques hold great promise for identifying risk factors for schizophrenia (SZ) but have not yet generated widely reproducible results due to methodological differences between studies and the high risk of type I inferential errors. Here we established a protocol for conservative analysis and interpretation of gene expression data from the dorsolateral prefrontal cortex of SZ patients using statistical and bioinformatic methods that limit false positives. We also compared brain gene expression profiles with those from peripheral blood cells of a separate sample of SZ patients to identify disease-associated genes that generalize across tissues and populations and further substantiate the use of gene expression profiling of blood for detecting valid SZ biomarkers. Implementing this systematic approach, we: (i) discovered 177 putative SZ risk genes in brain, 28 of which map to linked chromosomal loci; (ii) delineated six biological processes and 12 molecular functions that may be particularly disrupted in the illness; (iii) identified 123 putative SZ biomarkers in blood, 6 of which (BTG1, GSK3A, HLA-DRB1, HNRPA3, SELENBP1, and SFRS1) had corresponding differential expression in brain; (iv) verified the differential expression of the strongest candidate SZ biomarker (SELENBP1) in blood; and (v) demonstrated neuronal and glial expression of SELENBP1 protein in brain. The continued application of this approach in other brain regions and populations should facilitate the discovery of highly reliable and reproducible candidate risk genes and biomarkers for SZ. The identification of valid peripheral biomarkers for SZ may ultimately facilitate early identification, intervention, and prevention efforts as well.

A comparative profile analysis of neuropsychological functioning in patients with schizophrenia and bipolar psychoses

Evidence for neuropsychological deficits in schizophrenia is substantial whereas evidence for the specificity of dysfunction is relatively sparse. To assess specificity, we compared neuropsychological function in patients with chronic schizophrenia, patients with chronic psychotic bipolar disorder and normal controls. Groups were comparable on age, ethnicity and expected intellectual ability (based on single word reading). Patients with schizophrenia and bipolar psychoses were also relatively similar on age at onset and number of hospitalizations. Using multivariate analyses of variance with sex and parental SES as covariates (our primary analyses), patients with schizophrenia were significantly more impaired than controls on seven of eight neuropsychological functions (all but verbal ability), and were significantly more impaired than bipolar patients on abstraction, perceptual-motor speed and vigilance. Bipolar patients were significantly impaired compared to controls on declarative verbal memory, and showed moderate-to-large effect size decrements on abstraction, perceptual-motor speed and vigilance. Results were not attenuated when IQ was controlled, which was significantly lower in patients with schizophrenia. Analyses indicated that the two psychiatric groups had similar profile patterns, but that patients with schizophrenia had a more severe impairment than patients with bipolar psychoses. Further research is required to determine whether similar mechanisms underly the neurocognitive deficits in these disorders.

Neuropsychologic functioning among the nonpsychotic relatives of schizophrenic patients: the effect of genetic loading

BACKGROUND We previously reported that the nonpsychotic relatives of schizophrenic patients exhibited disturbances in executive functioning, verbal and visual memory, auditory attention, mental control, and verbal ability. In a 4-year follow-up, we showed that the discriminating power of most of these tests was stable over time. METHODS In this report we compare 41 nonpsychotic persons who have only one schizophrenic first-degree relative (simplex families) with 36 nonpsychotic persons who have two schizophrenic first-degree relatives (multiplex families). Our goal was to test a hypothesis that neuropsychologic deficits would be worse among the latter. RESULTS Relatives from multiplex families differed significantly from controls on estimated intelligence, immediate and delayed logical memories, and immediate visual reproductions. In contrast, in comparisons with controls, relatives from simplex families only differed on immediate logical memories. Comparisons between relatives from multiplex and simplex families showed that the former group had significantly worse scores for estimated intelligence, immediate and delayed logical memories, and immediate visual reproductions. We also found group x gender interactions: the worse performance of the multiplex group was seen for females. CONCLUSIONS These results are consistent with the idea that neuropsychologic deficits in relatives of schizophrenic patients reflect their degree of genetic predisposition to schizophrenia. They also suggest hypotheses about gender differences in the familial transmission of the disorder.

Hierarchical Genetic Organization of Human Cortical Surface Area

Building the Brain Brain connectivity is often described as a network of discrete independent cables analogous to a switchboard, but how is the physical structure of the brain constructed (see the Perspective by Zilles and Amunts)? Wedeen et al. (p. 1628) used high-resolution diffusion tensor imaging in humans and four species of nonhuman primates to identify and compare the geometric structure of large fiber tracts in the brain. Fiber tracts followed a highly constrained and regular geometry, which may provide an efficient solution for pathfinding during ontogenetic development. Much of development occurs through elaboration and assembly of semiautonomous building blocks. Chen et al. (p. 1634) applied statistical analysis to the form of the human cortex in brain-imaging studies that compared more than 400 di- and mono-zygotic twins. The findings suggest that the structure of the human cortex is defined by genetics. Human brain structure is genetically controlled in a hierarchical, modular, and symmetric fashion. Surface area of the cerebral cortex is a highly heritable trait, yet little is known about genetic influences on regional cortical differentiation in humans. Using a data-driven, fuzzy clustering technique with magnetic resonance imaging data from 406 twins, we parceled cortical surface area into genetic subdivisions, creating a human brain atlas based solely on genetically informative data. Boundaries of the genetic divisions corresponded largely to meaningful structural and functional regions; however, the divisions represented previously undescribed phenotypes different from conventional (non–genetically based) parcellation systems. The genetic organization of cortical area was hierarchical, modular, and predominantly bilaterally symmetric across hemispheres. We also found that the results were consistent with human-specific regions being subdivisions of previously described, genetically based lobar regionalization patterns.

Genetic and environmental influences on the size of specific brain regions in midlife: The VETSA MRI study

The impact of genetic and environmental factors on human brain structure is of great importance for understanding normative cognitive and brain aging as well as neuropsychiatric disorders. However, most studies of genetic and environmental influences on human brain structure have either focused on global measures or have had samples that were too small for reliable estimates. Using the classical twin design, we assessed genetic, shared environmental, and individual-specific environmental influences on individual differences in the size of 96 brain regions of interest (ROIs). Participants were 474 middle-aged male twins (202 pairs; 70 unpaired) in the Vietnam Era Twin Study of Aging (VETSA). They were 51-59 years old, and were similar to U.S. men in their age range in terms of sociodemographic and health characteristics. We measured thickness of cortical ROIs and volume of other ROIs. On average, genetic influences accounted for approximately 70% of the variance in the volume of global, subcortical, and ventricular ROIs and approximately 45% of the variance in the thickness of cortical ROIs. There was greater variability in the heritability of cortical ROIs (0.00-0.75) as compared with subcortical and ventricular ROIs (0.48-0.85). The results did not indicate lateralized heritability differences or greater genetic influences on the size of regions underlying higher cognitive functions. The findings provide key information for imaging genetic studies and other studies of brain phenotypes and endophenotypes. Longitudinal analysis will be needed to determine whether the degree of genetic and environmental influences changes for different ROIs from midlife to later life.

Age and neuropsychologic function in schizophrenia: a decline in executive abilities beyond that observed in healthy volunteers

BACKGROUND Kraepelin originally conceptualized schizophrenia as a degenerative brain disorder. It remains unclear whether the illness is characterized by a static encephalopathy or a deterioration of brain function, or periods of each condition. Assessments of cognitive function, as measured by neuropsychologic assessment, can provide additional insight into this question. Few studies of patients with schizophrenia have investigated the effect of aging on executive functions, in an extensive neuropsychologic battery across a wide age range, compared to healthy volunteers. METHODS We examined the interaction of aging and neuropsychologic function in schizophrenia through a cross-sectional study in patients (n = 87) and healthy control subjects (n = 94). Subjects were divided into three age groups (20-35, 36-49, and 50-75), and performance on an extensive neuropsychologic battery was evaluated. RESULTS Compared to control subjects, patients with schizophrenia demonstrated similar age-related declines across most neuropsychologic functions, with the exception of abstraction ability, in which significant evidence of a more accelerated decline was observed. CONCLUSIONS These results are consistent with previous reports indicating similar age effects on most aspects of cognition in patients with schizophrenia and healthy adults, but they support the hypothesis that a degenerative process may result in a more accelerated decline of some executive functions in older age in schizophrenia.

Prenatal exposure to maternal infection and executive dysfunction in adult schizophrenia.

OBJECTIVE Executive dysfunction is one of the most prominent and functionally important cognitive deficits in schizophrenia. Although strong associations have been identified between executive impairments and structural and functional prefrontal cortical deficits, the etiological factors that contribute to disruption of this important cognitive domain remain unclear. Increasing evidence suggests that schizophrenia has a neurodevelopmental etiology, and several prenatal infections have been associated with risk of this disorder. The authors examined whether prenatal infection is associated with executive dysfunction in patients with schizophrenia. METHOD The authors assessed the relationship between serologically documented prenatal exposure to influenza and toxoplasmosis and performance on the Wisconsin Card Sorting Test and the Trail Making Test, part B (Trails B), as well as other measures of executive function, in 26 patients with schizophrenia from a large and well-characterized birth cohort. RESULTS Patients who were exposed to infection in utero committed significantly more total errors on the Wisconsin Card Sorting Test and took significantly more time to complete the Trails B than unexposed patients. Exposed patients also exhibited deficits on figural fluency, letter-number sequencing, and backward digit span. CONCLUSIONS Prenatal infections previously associated with schizophrenia are related to impaired performance on the Wisconsin Card Sorting Test and Trails B. The pattern of results suggests that cognitive set-shifting ability may be particularly vulnerable to this gestational exposure. Further work is needed to elucidate the specificity of prenatal infection to these executive function measures and to examine correlates with neuroanatomic and neurophysiologic anomalies.

Structural brain alterations in schizophrenia following fetal exposure to the inflammatory cytokine interleukin-8.

BACKGROUND Maternal infection during pregnancy has been repeatedly associated with increased risk for schizophrenia. Nevertheless, most viruses do not cross the placenta; therefore, the damaging effects to the fetus appear to be related to maternal antiviral responses to infection (e.g. proinflammatory cytokines). Fetal exposure to the proinflammatory cytokine interleukin-8 (IL-8) has been significantly associated with risk of schizophrenia in offspring. This study sought to determine the association between fetal exposure to IL-8 and structural brain changes among schizophrenia cases and controls. METHODS Subjects were 17 cases diagnosed with schizophrenia from the Developmental Insult and Brain Anomaly in Schizophrenia (DIBS) study. Psychiatric diagnoses were determined among offspring with semi-structured interviews and medical records review. IL-8 was determined from assays in archived prenatal sera and volumetric analyses of neuroanatomical regions were obtained from T1-weighted magnetic resonance imaging in adulthood. Eight controls were included for exploratory purposes. RESULTS Among cases, fetal exposure to increases in IL-8 was associated with significant increases in ventricular cerebrospinal fluid, significant decreases in left entorhinal cortex volumes and significant decreases in right posterior cingulate volumes. Decreases that approached significance also were found in volumes of the right caudate, the putamen (bilaterally), and the right superior temporal gyrus. No significant associations were observed among controls. CONCLUSION Fetal exposure to elevations in maternal IL-8 led to structural neuroanatomic alterations among cases in regions of the brain consistently implicated in schizophrenia research. In utero exposure to elevations in IL-8 may partially account for brain disturbances commonly found in schizophrenia.

Intelligence quotient and Neuropsychological profiles in patients with schizophrenia and in normal volunteers

BACKGROUND The objective of this study was to examine neuropsychological performance at different intelligence quotient (IQ) levels in schizophrenia. METHODS Thirty-six patients with schizophrenia were matched with 36 normal control subjects in two IQ groups: low average (81-94) and average (95-119). Performance level (IQ group main effects) and profile shape (IQ group x function interactions) were compared. RESULTS Current IQ was lower than estimated premorbid intellectual ability in both patient groups. Patients also displayed poorer neuropsychological function than same-IQ control subjects, suggesting neuropsychological dysfunction beyond their already compromised IQ. Patients had different profile shapes than control subjects, but profile shapes were consistent within patients and control subjects at each IQ level. Patients at both levels had higher verbal and lower performance IQ than control subjects. Abstraction-executive function was one of the lowest neuropsychological scores in both patient groups. Average IQ patients had nonsignificantly better overall neuropsychological performance than low average control subjects, but the effect size (.43) was quite small relative to the IQ difference (effect size = 2.57). CONCLUSIONS Neuropsychological patterns in schizophrenia tend to be consistent at different IQ levels. Even schizophrenia patients with normal current IQs manifest substantial neuropsychological compromise relative to their level of general intellectual ability. The results strengthen the argument that neurocognitive deficits are core deficits of schizophrenic illness.