Hippocampal volumes in schizophrenic twins

CONTEXT: The effects of genes and environment on brain abnormalities in schizophrenia remain unclear. OBJECTIVE: To examine the contributions of genes and environment to hippocampal volume reduction in schizophrenia. DESIGN: Population-based twin cohort study. SETTING: Finland. PARTICIPANTS: Seven monozygotic (MZ) twin pairs concordant for schizophrenia and 16 MZ and 32 dizygotic (DZ) twin pairs discordant for schizophrenia, ascertained so as to be representative of all such probands in a Finnish birth cohort, along with 28 MZ and 26 DZ healthy comparison twin pairs without a family history of psychosis. MAIN OUTCOME MEASURES: Hippocampal volume measurements taken from high-resolution magnetic resonance images. RESULTS: Hippocampal volumes of probands were smaller than those of their nonschizophrenic MZ and DZ co-twins and healthy twins. Hippocampal volumes of probands' non-ill co-twins were smaller than those of healthy twins, but those of non-ill MZ and DZ co-twins of schizophrenic patients were similar. The intraclass correlations for hippocampal volumes among healthy and discordant MZ pairs were larger than those among the respective DZ pairs. The intraclass correlation for healthy MZ pairs was larger than that for discordant MZ pairs, and the variance component estimate for additive genetic effects was lower in discordant twins than in healthy twins. CONCLUSIONS: Although hippocampal volume in healthy individuals is largely affected by genetic factors, it is subject to substantially greater modulation by environmental factors in schizophrenic patients and their relatives. The results are discussed in view of assumptions underlying classic twin methods.     

Prefrontal and Striatal Volumes in Monozygotic Twins Concordant and Discordant for Schizophrenia

Frontostriatal networks mediating important cognitive and motor functions have been shown to be abnormal structurally and functionally in schizophrenia. However, the influence of genetic risk for schizophrenia on structural abnormalities in these areas is not well established. This study therefore aimed to investigate prefrontal and striatal volume alterations in schizophrenia and to define the extent to which they are dependent on genetic vulnerability for the condition. We employed structural magnetic resonance imaging (sMRI) in monozygotic (MZ) twins with or without schizophrenia. A sample of 129 twins completed sMRI, consisting of 21 MZ twin pairs concordant for schizophrenia, 17 MZ schizophrenic twins and 18 MZ nonschizophrenic twins drawn from 19 pairs discordant for schizophrenia, and 26 MZ control twin pairs without schizophrenia. Groups did not significantly differ in age, gender, handedness, height, level of education, parental socioeconomic status, and ethnicity. Using a region-of-interest approach, we measured the gray matter volumes (in cm³) of superior, middle, inferior, and orbital frontal cortices (SFC, MFC, IFC, and OFC, respectively); the caudate; and putamen. Covarying for whole-brain volume, age, and gender, we found that concordant but not discordant twins with schizophrenia had significantly lower volumes of MFC and OFC than control twins. In contrast, both patient groups had significantly lower SFC volumes than both groups of nonschizophrenic twins. There were no significant group differences in IFC and the striatum. We conclude that the prefrontal cortex shows a heterogeneous pattern of genetic influences on volumetric reductions in schizophrenia.     

Birthweight and obstetric complications in schizophrenic twins.

Birthweight and obstetric complications were registered retrospectively in 24 monozygotic (MZ) twin pairs. Sixteen pairs were discordant and 8 pairs were concordant for DSM-III-R schizophrenia. There was no significant intrapair difference in birthweight between the 2 groups of MZ twins. Prematurity was more often observed in the discordant pairs, but neither differences in prematurity nor differences in obstetric complications between the concordant and discordant twins reached significance. No difference in respect of family history of schizophrenia between the 2 groups of MZ twins was found. In the discordant pairs, no significant difference between the schizophrenic twin and the nonschizophrenic co-twin was observed regarding birth order, birthweight or physical condition at birth.     

Neurological abnormalities in schizophrenic twins.

BACKGROUND: Neurological abnormalities (NAs) are well recognized in schizophrenia, though their genetic and environmental determinants, and pathophysiological significance, are poorly understood. METHODS: Sixty-three twin pairs, varying in their zygosity and concordance for schizophrenia, and 73 unaffected control twin pairs were examined for total, primary and integrative NAs using the Neurological Evaluation Scale. RESULTS: NAs were increased in probands with schizophrenia compared to nonschizophrenic co-twins and to healthy control twins but there were no significant differences between patients from the concordant and discordant pairs. NAs in the nonpsychotic co-twins from discordant pairs were increased compared to control twins. There were no significant differences in NAs between the nonschizophrenic co-twins from monozygotic (MZ) and dizygotic (DZ) discordant pairs, but the within pair correlations were greater in the MZ compared to DZ pairs. NAs were modified in all groups by pre-morbid schizotypal traits, and in patients by anti-psychotic medication. CONCLUSIONS: NAs in schizophrenia are determined in part by genetic risk for the illness but the presence of premorbid schizotypal traits, and anti-psychotic medication confer additional risk for NAs.     

A controlled study of brain structure in monozygotic twins concordant and discordant for schizophrenia.

BACKGROUND: We examined monozygotic twins concordant and discordant for schizophrenia to clarify the role of genetic and environmental factors in determining brain abnormalities. METHODS: Magnetic resonance imaging brain scans were obtained from 14 monozygotic twin pairs concordant and 10 monozygotic pairs discordant for schizophrenia, as well as 17 pairs of monozygotic control twins. Twenty-two discordant sibling-pairs and 56 pairs of unrelated control subjects were included to assess the extent of genetic control over these structures. RESULTS: Within-pair similarities for whole brain volume increased as pair members were more closely related genetically (monozygotic twins > siblings > unrelated control subjects). Schizophrenic twins, whether from concordant or discordant pairs, had smaller whole brain volumes than control twins. The probands of discordant pairs showed more abnormalities in hippocampal, third and lateral ventricular volumes than concordant twins. CONCLUSIONS: Whole brain volume is under high genetic control and smaller whole brain volume is a reflection of the genetic liability to develop schizophrenia. The variation in hippocampal and ventricular volumes within discordant monozygotic pairs indicates a role for environmental factors in determining these volume abnormalities in schizophrenia. Such factors may also underlie the more extensive morphometric deviations in patients from monozygotic discordant twins than in their counterparts from concordant twins.     

Antisaccade performance in monozygotic twins discordant for schizophrenia: the Maudsley twin study

OBJECTIVE: Deficiency in antisaccade performance has been proposed as a schizophrenia endophenotype. METHOD: The authors assessed performance on an antisaccade task (and a prosaccade control condition) by 10 monozygotic twin pairs discordant for DSM-IV schizophrenia and 10 monozygotic healthy twin pairs matched for age, sex, and parental socioeconomic status. The authors computed antisaccade gain, latency, and error rate, as well as prosaccade gain and latency. RESULTS: The schizophrenic twins made more antisaccade reflexive errors than the nonschizophrenic co-twins and comparison twins, who did not significantly differ from each other. The nonschizophrenic members of discordant pairs performed worse than the comparison twins on antisaccade gain and latency but did not differ from their schizophrenic co-twins on these variables. There were no differences on prosaccade performance. Antisaccade errors were correlated with negative symptoms in the patients. CONCLUSIONS: Antisaccade spatial accuracy and latency deficits may serve as markers of genetic liability for schizophrenia.     

Thalamic and caudate volumes in monozygotic twins discordantfor schizophrenia

OBJECTIVE: The thalamus and caudate nucleus are key subcortical structures in the fronto-striato-thalamic pathways that have been implicated in the pathogenesis of schizophrenia. Previous studies have been inconsistent in identifying structural and functional abnormalities in these structures. However, methodologies in these studies have been unreliable and some have not adequately matched patients and controls. METHODS: Using algebraically-manipulated double-echomagnetic resonance (MR) images, we developed a reliable method to estimate caudate and thalamic volumes in a group of 13 monozygotic(MZ) twins; eight discordant for schizophrenia and five normal.Initially, volumes were measured on four image types: proton density(PD), T2-weighted, summed (PD + T2) and subtracted (PD-T2) to determine the most reliable method. RESULTS: There was a significant method by region interaction, where caudate volumes measured on PD images were significantly larger than those measured on T2-weighted images, while the opposite was found for thalamic volumes. However, there was no interaction of method by diagnosis. Test-retest reliability was highest for the summed images. Using summed images to measure the volumes of the caudate and thalamus in each twin, we found significantly increased caudate volumes in affected twins compared to their unaffected cotwins,but no significant difference in thalamic volume. CONCLUSIONS: Our results in a small sample of MZ twins discordant for schizophrenia do not support the presence of structural abnormalities in the thalamus. The findings in the caudate are consistent with previously reported effects of antipsychotic medication. We also report a reliable method for assessing the volumes of subcortical structures. However, volumetric estimates of brain structures may be dependent on which method is used and the structure being assessed. Such interactions need to be considered in future studies investigating brain structural abnormalities in schizophrenia and other disorders.     

Fatty acids in plasma phospholipids and cholesterol esters from identical twins concordant and discordant for schizophrenia.

The fatty acid compositions of plasma phospholipids and cholesterol esters were measured in 18 pairs of twins discordant for schizophrenia and 20 pairs concordant for schizophrenia. In the twins discordant for schizophrenia the only significant abnormalities were elevations of adrenic (22:4n-6) and docosapentaenoic (22:5n-6) acids in the schizophrenic twins. These fatty acids have also recently been reported to be elevated in brains from schizophrenics. The twins concordant for schizophrenia showed many differences from the normal discordant twins. 22:4n-6 and 22:5n-6 were even more abnormal than in the schizophrenic discordant twins. In addition, linoleic acid was significantly reduced, an abnormality which has been found consistently in other schizophrenic populations. These observations are consistent with the concept that unsaturated fat metabolism may be abnormal in schizophrenia.     

Magnetic resonance relaxometry in monozygotic twins discordant and concordant for schizophrenia.

T1 and T2 relaxation times were examined in four pairs of monozygotic (MZ) twins discordant and concordant for schizophrenia with low and high genetic loading for the illness and five healthy control MZ twin pairs. Patients with schizophrenia (n = 11) showed significant prolongation in T1 relaxation times in the globus pallidus (GP) bilaterally (P < 0.005, Bonferroni corrected) when compared to 14 healthy MZ twins.     

Abnormal-pursuit eye movements in schizophrenia. Evidence for a genetic indicator

Disordered smooth-pursuit eye movements occur in a high percentage of schizophrenic patients and their first-degree relatives. A Test of the hypothesis that these disorders represent a genetic indicator of schizophrenia was undertaken by testing pursuit eye movements in a sample of monozygotic and dizygotic twins discordant for clinical schizophrenia. Deviant eye tracking is significantly concordant within monozygotic twin pairs, and less so with dizygotic twin pairs discordant for schizophrenia. A genetic interpretation is consistent with these results.     

Language lateralization in monozygotic twins discordant and concordant for schizophrenia. A functional MRI pilot study.

AIM: Previous studies have suggested altered structural and functional asymmetry of the brain in schizophrenia. METHODS: Functional MRI was used to assess differences in cortical activation during a verbal task in Broca's area and its contralateral homologue in four pairs of right-handed monozygotic (MZ) twins discordant and concordant for schizophrenia with low and high familial loading for the illness and four healthy control MZ twin pairs. RESULTS: Pooled data from all subjects with schizophrenia showed increased activation in the right homologue of Broca's area in contrast to healthy individuals. Concordant twins (i.e. high familial loading group) showed prominent between co-twin differences in lateralization index within given region of interest. Intra-pair differences in lateralization index were significantly higher in concordant twins compared to the controls (0.69+/-0.4 vs. 0.13+/-0.13, P<0.03), albeit no significant differences in the variable were shown between the discordant and control groups. CONCLUSION: This study provides evidence of reduced cerebral dominance for language processing in patients with schizophrenia. The findings further suggest the need for additional research on relative proportion of genetic and environmental factors underlying deviations of functional asymmetry in schizophrenia.     

Monozygotic twins exhibit numerous epigenetic differences: clues to twin discordance?

The goal of this pilot study was to explore the putative molecular mechanisms underlying the phenotypic discordance of monozygotic (MZ) twins. Thus, patterns of epigenetic DNA modification were investigated in the 5'-regulatory region of the dopamine D2 receptor gene (DRD2) in two pairs of monozygotic twins, one concordant and one discordant for schizophrenia. The bisulfite DNA modification-based approach was used to fine-map methylated cytosines in DRD2 in genomic DNA extracted from lymphocytes. Numerous DNA methylation differences were identified in the analyzed region both within and between the pairs of MZ twins. "Epigenetic distances" between MZ twins were calculated and used for the comparison of twin DRD2 methylation profiles. It was detected that the affected twin from the pair discordant for schizophrenia was epigenetically "closer" to the affected concordant twins than to his unaffected MZ co-twin. Although the epigenetic analysis was conducted for only several hundred base pairs of DRD2, the fact that numerous studies identified nonuniform methylation patterns across the clones of bisulfite-modified DNA from the same individual, as well as nonuniform patterns across different individuals, argues for the universality of intra- and interindividual epigenetic variation. Epigenetic studies should provide insight into the molecular causes of differential susceptibility to a disease in genetically identical organisms that may generalize to singletons.     

Gene expression analysis in absence epilepsy using a monozygotic twin design

Purpose: To identify genes involved in idiopathic absence epilepsies by analyzing gene expression using a monozygotic (MZ) twin design. Methods: Genome‐wide gene expression in lymphoblastoid cell lines (LCLs) was determined using microarrays derived from five discordant and four concordant MZ twin pairs with idiopathic absence epilepsies and five unaffected MZ twin pairs. Gene expression was analyzed using three strategies: discordant MZ twins were compared as matched pairs, MZ twins concordant for epilepsy were compared to control MZ twins, and a singleton design of affected versus unaffected MZ twin individuals was used irrespective of twin pairing. An overlapping gene list was generated from these analyses. Dysregulation of genes recognized from the microarray experiment was validated using quantitative real time PCR (qRT‐PCR) in the twin sample and in an independent sample of 18 sporadic absence cases and 24 healthy controls. Results: Sixty‐five probe sets were identified from the three combined microarray analysis strategies. Sixteen genes were chosen for validation and nine of these genes confirmed by qRT‐PCR in the twin sample. Differential expression for EGR1 (an immediate early gene) and RCN2 (coding for the calcium‐binding protein Reticulocalbin 2) were reconfirmed by qRT‐PCR in the independent sample. Discussion: Using a unique sample of discordant MZ twins, our study identified genes with altered expression, which suggests novel mechanisms in idiopathic absence epilepsy. Dysregulation of EGR1 and RCN2 is implicated in idiopathic absence epilepsy.     

Genetic influence on auditory information processing in schizophrenia: P300 in monozygotic twins.

BACKGROUND: It is widely accepted that schizophrenia is to some extent genetically determined. Abnormalities of the P300 component are one of the most robust biological findings in schizophrenia. They outlast clinical impairment and are present also in relatives of schizophrenic patients. In the present study on schizophrenic twins, the heritability of auditory P300 abnormalities and the influence of task difficulty on heritability was examined. METHODS: Twenty-two monozygotic twin pairs were included into this study (eight pairs discordant, five pairs concordant for schizophrenia or schizoaffective psychosis according to ICD-10 criteria, and nine control pairs). Two different versions of the auditory oddball paradigm were used to control for deficient stimulus perception. RESULTS: Compared to healthy controls, P300 amplitudes were significantly smaller in affected twins as well as in the non-affected co-twins of the discordant pairs. CONCLUSIONS: Our results suggest that P300 amplitude reduction is a genetically transmitted vulnerability marker for schizophrenia. Because the findings were independent of the difficulty of the task and could be demonstrated even when pitch disparity was adjusted to the subjects' ability to discriminate tones, the findings can not be related to the genetic influence on higher information processing.     

Further evidence that congenital dermatoglyphic abnormalities are associated with psychosis: a twin study

The presence of abnormal palmar flexion creases (APFC) and dermatoglyphic ridge dissociation (RD) may constitute enduring evidence of a prenatal insult that occurred before the third trimester of intrauterine life. We examined these dermatoglyphic abnormalities in a twin study of psychotic disorders. RD and APFC were analyzed in a monozygotic (MZ) twin sample from the Maudsley Hospital in London (11 normal control pairs, 16 pairs concordant for psychosis, 9 pairs discordant for psychosis, 1 concordant triplet, and 1 triplet with one affected member). The risk of either RD or APFC was 44 percent in affected twins and 20 percent in nonaffected twins (odds ratio = 3.25, 95% confidence interval: 1.03-10.31; one-sided p = 0.023). In the group of MZ twins discordant for psychosis, discordance for RD or APFC always paralleled discordance for psychosis (one-sided p = 0.078), suggesting the operation of nongenetic factors. The results confirm previous work suggesting the possibility that nongenetic factors early in pregnancy contribute to the liability to develop psychosis in later life.     

Dementia of the Alzheimer type: clinical and family study of 22 twin pairs

We studied 22 twin pairs in which one or both twins had dementia of the Alzheimer type (DAT). In four twins, diagnosis was confirmed by autopsy. Seven monozygotic (MZ) pairs were concordant for DAT; 10 MZ pairs were discordant. Two dizygotic (DZ) pairs were concordant for DAT, and 3 DZ pairs were discordant. The current concordance rate was 41% for MZ twins and 40% for DZ twins. The study supports the belief that, etiologically, DAT cannot be entirely accounted for by a single autosomal dominant gene. The data also suggest that in certain genetic circumstances, disease expression may be delayed in females.     

Adhesio interthalamica in male patients with schizophrenia

OBJECTIVE: The authors investigated whether absence of the adhesio interthalamica in patients with schizophrenia constitutes a marker of early developmental neuropathological changes. METHOD: Thirty male patients with schizophrenia and 30 healthy male subjects were recruited for study. Magnetic resonance imaging was performed, and the presence or absence of the adhesio interthalamica was determined for each subject. The length and volume of the third ventricle were also measured. RESULTS: No differences in the presence or absence of the adhesio interthalamica were found between patients with schizophrenia and normal comparison subjects. Patients without the adhesio interthalamica had significantly higher scores for negative symptoms than patients with the adhesio interthalamica. There was no correlation between absence of the adhesio interthalamica and length and volume of the third ventricle in either patients or comparison subjects. CONCLUSIONS: The findings suggest that patients with schizophrenia who do not have the adhesio interthalamica are characterized by more severe negative symptoms.     

Monozygotic twins discordant for schizophrenia

Summary The study of MZ twins discordant for schizophrenia can shed light on important experiential factors in the development of at least some cases of schizophrenia. The gradual development of paranoid schizophrenia was described in an MZ male twin who later recovered completely from his illness. His life pattern was compared with that of his non-psychotic co-twin, and his early characteristics and development were contrasted with features of schizophrenic twins in discordant pairs in a recently reported summary of such cases. It is suggested that late onset paranoid schizophrenia is different in many ways from other subtypes of schizophrenia beginning in adolescence.From Queen's University, Kingston, Ontario, Canada, this paper was submitted to theQuarterly on June 16, 1969.     

A magnetic resonance imaging study of the adhesio interthalamica in schizophrenia

Several recent studies have found a relationship between midline cerebral malformations (cavum septi pellucidum, absence of the adhesio interthalamica) and schizophrenia. In this study, we investigated whether the adhesio interthalamica is more often absent in patients with schizophrenia than healthy cases and whether the absence of the adhesio interthalamica may be related to the volume of the third ventricle. Twenty-six patients (11 male, 15 female) in the schizophrenia group and twenty-nine (11 male, 18 female) cases in the control group were examined by MRI. The adhesio interthalamica was found to be absent more often among patients with schizophrenia compared with control subjects and patients without adhesio interthalamica did not have significantly larger third ventricle volumes. The absence of the adhesio interthalamica may be important in explaining the association between the abnormalities of brain midline structures and schizophrenia.     

Smoking and Parkinson's disease in twins

OBJECTIVE: To test the hypothesis that cigarette smoking protects against the development of PD. BACKGROUND: Smoking has been inversely associated with PD in many studies, but whether this reflects a biologic effect on the underlying disease process or merely confounding or selection bias remains uncertain. METHODS: The authors compared smoking histories in male twin pairs identified from the National Academy of Sciences--National Research Council World War II Veteran Twins Cohort. The amount of cigarettes smoked (in pack-years) was collected until the time of PD onset in the affected twin or until the time of death for the unaffected twin, whichever came first. Differences in pack-years smoked until PD onset and until 10 and 20 years before onset were compared using paired t-tests. Comparisons were made overall and stratified by zygosity and concordance for PD. To assess the role of shared environment, correlation for smoking behaviors was compared between pairs concordant and discordant for PD. RESULTS: Detailed smoking histories were available for 113 twin pairs in which at least one twin had PD (discordant pairs: 43 monozygotic [MZ], 50 dizygotic [DZ]; concordant pairs: 10 MZ, 10 DZ). Within-pair correlation for ever smoking was high in MZ pairs (phi = 0.47, p = 0.001) but not in DZ pairs (phi = 0.007, p = 0.96). In 33 discordant MZ pairs and 39 discordant DZ pairs in which at least one twin had smoked, the twins without PD smoked more than their brothers smoked (32.5 vs. 22.7 pack-years, p = 0.026). This was more marked in the MZ pairs (37.1 vs. 25.3 pack-years, p = 0.077) than in the DZ pairs (28.6 vs. 20.5 pack-years, p = 0.17). A similar relationship was seen when smoking dose was calculated only until 10 years before PD onset, suggesting that the lower dose of smoking in the twin with PD was not the result of early, undiagnosed disease. CONCLUSION: Within twin pairs, risk of PD is inversely correlated with the dose (in pack-years) of cigarette smoking. This effect is most pronounced in MZ twins, despite the high correlation for smoking. Because MZ twins are genetically identical and are similar behaviorally, this difference is unlikely to result from either genetic factors or environmental confounders. These results are compatible with a true biologic protective effect of cigarette smoking.