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.     

Verbal recall and recognition in twins discordant for schizophrenia

The nature, neural underpinnings, and etiology of deficits in verbal declarative memory in patients with schizophrenia remain unclear. To examine the contributions of genes and environment to verbal recall and recognition performance in this disorder, the California Verbal Learning Test was administered to a large population-based Finnish twin sample, which included schizophrenic and schizoaffective patients, their non-ill monozygotic (MZ) and dizygotic (DZ) co-twins, and healthy control twins. Compared with controls, patients and their co-twins showed relatively greater performance deficits on free recall compared with recognition. Intra-pair differences between patients and their non-ill co-twins in hippocampal volume and memory performance were highly positively correlated. These findings are consistent with the view that genetic influences are associated with reduced verbal recall in schizophrenia, but that non-genetic influences further compromise these abnormalities in patients who manifest the full-blown schizophrenia phenotype, with this additional degree of disease-related declarative memory deficit mediated in part by hippocampal pathology.     

Twin concordance for DSM-III-R schizophrenia.

The monozygotic (MZ)/dizygotic (DZ) concordance rates for schizophrenia and the relationship between schizophrenia and schizophrenic spectrum disorders were studied in a sample of 31 MZ and 28 DZ schizophrenic probands and their co-twins. All subjects were personally interviewed with structured diagnostic instruments and classified according to DSM-III-R criteria. The concordance rates of 48% for MZ twins and 4% for DZ twins indicate a genetic transmission of DSM-III-R schizophrenia. In addition to the schizophrenic co-twins, 3 MZ co-twins had a noneffective psychotic disorder, thus supporting the hypothesis that genes are involved in the development of Axis I schizophrenic spectrum disorders. Schizotypal and paranoid personality disorders were observed in both MZ and DZ co-twins. These disorders may be familially related to schizophrenia, but a genetic relationship was not confirmed for the Axis II spectrum disorders. A substantial number of MZ co-twins of schizophrenic probands had no mental disorder.     

Subtypes of schizophrenia--evidence from a twin-family study

In a combined twin-family study, the concordance for subtype of schizophrenia was investigated. The sample included 31 monozygotic (MZ) and 28 dizygotic (DZ) twin probands fulfilling the criteria of DSM-III-R schizophrenia. Their co-twins and first-degree relatives were personally interviewed and diagnosed in accordance with DSM-III-R. Any twin or relative diagnosed as schizophrenic was subclassified as either paranoid or nonparanoid. Schizophrenia was more often observed in co-twins of MZ probands with nonparanoid schizophrenia than in MZ probands with paranoid schizophrenia, indicating a stronger genetic influence in nonparanoid schizophrenia. Fifteen MZ pairs were concordant for schizophrenia, and 13 of these pairs were also concordant for subtype. Such a relationship was not observed in the first-degree relatives with schizophrenia. Our results indicate a complex etiology of subtypes in schizophrenia, and to some extent the etiology of subtypes may differ from the etiology of schizophrenia.     

A twin study of genetic contributions to hippocampal morphology in schizophrenia

Our goal was to establish whether altered hippocampal morphology represents a trait marker for genetic vulnerability in schizophrenia. We outlined the hippocampi on high-resolution MR images obtained from matched samples of control and discordant monozygotic and dizygotic co-twins (N = 40 pairs). Hippocampal measures were used in statistical tests specifically designed to identify disease-associated genetic and nongenetic influences on morphology. 3D surface average maps of the hippocampus were additionally compared in biological risk groups. Smaller hippocampal volumes were confirmed in schizophrenia. Dizygotic affected co-twins showed smaller left hippocampi compared to their healthy siblings. Disease-associated effects were not present between monozygotic discordant co-twins. Monozygotic, but not dizygotic, unaffected co-twins exhibited smaller left hippocampi compared to control twins, supporting genetic influences. Surface areas and posterior volumes similarly revealed schizophrenia and genetic liability effects. Results suggest that hippocampal volume reduction may be a trait marker for identifying individuals possessing a genetic predisposition for schizophrenia.     

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.     

Magnetic resonance imaging of the thalamus and adhesio interthalamica in twins with schizophrenia

CONTEXT: Abnormalities of the thalamus are thought to be central to the pathophysiology of schizophrenia. These abnormalities include altered structure and shape of the thalamus itself and possibly changes to the adhesio interthalamica (or massa intermedia), the gray matter bridge connecting the 2 thalamic lobes. However, it is not clear to what extent these abnormalities are determined by the genetic liability for schizophrenia. OBJECTIVE: To investigate thalamic volume and the presence of the adhesio interthalamica in monozygotic (MZ) twins concordant or discordant for schizophrenia. DESIGN: Study of MZ twins. SETTING: Patients were drawn from inpatient and outpatient clinics. Twin controls were recruited from a volunteer twin register and through media advertisements. PARTICIPANTS: A total of 123 twins participated: 19 MZ twin pairs concordant for schizophrenia, 15 MZ schizophrenic twins and 16 MZ nonschizophrenic twins drawn from 17 pairs discordant for schizophrenia, and 27 MZ twin pairs without schizophrenia. Groups were matched for age, sex, handedness, level of education, parental socioeconomic status, and ethnicity. MAIN OUTCOME MEASURES: The volume of the thalamus (including right and left hemispheres) was measured (in cubic centimeters) and the presence of the adhesio interthalamica was ascertained from structural magnetic resonance images. RESULTS: Concordant twin pairs displayed significantly reduced thalamic volume compared with control twins, even when covarying for effects of whole-brain volume, age, and sex. There was a significant linear decrease in thalamic volume (control greater than discordant nonschizophrenic greater than discordant schizophrenic greater than concordant). In all groups, right thalamus was larger than left thalamus. There was no difference across groups in the frequency of the adhesio interthalamica. CONCLUSIONS: Volumetric thalamic abnormalities in schizophrenia occur in twin pairs concordant for schizophrenia. These abnormalities may mark the substantial genetic contribution to the illness seen in concordant twin pairs, whereas the adhesio interthalamica is unlikely to be affected in schizophrenia.     

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.     

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.     

A twin study of Tourette syndrome

In 43 pairs of same-sex twins, in which at least one co-twin had Tourette syndrome (TS), 30 pairs were probably monozygotic (MZ) and 13 were probably dizygotic (DZ). Concordances for TS were 53% and 8% for MZ and DZ pairs, respectively. When diagnostic criteria were broadened to include any tics in co-twins, concordance rates were 77% and 23% for MZ and DZ pairs, respectively. These concordances are consistent with genetic etiology. However, the fact that only 53% of MZ twins were fully concordant indicates nongenetic factors affect expression of TS. Presence of tics in discordant co-twins and timing of onset in partially concordant co-twins support an association between TS and tics in families with TS present. The data are inconclusive on whether some MZ twins with discordant co-twins are etiologically different from those who are concordant.     

Genetic and state variables of neurocognitive dysfunction in schizophrenia: a twin study

To characterize the familiality of cognitive dysfunction in schizophrenia, we studied performance on three tasks (visuospatial attention; visuolinguistic conflict, arrow-word; and Wisconsin Card Sorting Test [WCST]) by monozygotic (MZ) and dizygotic (DZ) twin pairs discordant for schizophrenia. The subject sample consisted of six MZ twin pairs, nine DZ twin pairs, and one MZ and one DZ nonschizophrenia cotwin of a patient with schizophrenia. There were two sources of cognitive dysfunction: a nonheritable, state component and a heritable, trait component. Deficits surfaced during the WCST in nonschizophrenia MZ cotwins; this impairment resolved following training in nonschizophrenia MZ cotwins, but not in the probands with schizophrenia, who performed abnormally in all tasks. The results suggest that nonheritable protective factors modulate the specific, plastic, and sometimes subtle neurocognitive deficits related to the schizophrenia genotype.     

Gray and white matter volume abnormalities in monozygotic and same-gender dizygotic twins discordant for schizophrenia.

BACKGROUND: Whole brain tissue volume decreases in schizophrenia have been related to both genetic risk factors and disease-related (possibly nongenetic) factors; however, whether genetic and environmental risk factors in the brains of patients with schizophrenia are differentially reflected in gray or white matter volume change is not known. METHODS: Magnetic resonance imaging (1.5 T) brain scans of 11 monozygotic and 11 same-gender dizygotic twin pairs discordant for schizophrenia were acquired and compared with 11 monozygotic and 11 same-gender dizygotic healthy control twin pairs. RESULTS: Repeated-measures volume analysis of covariance revealed decreased whole brain volume in the patients with schizophrenia as compared with their co-twins and with healthy twin pairs. Decreased white matter volume was found in discordant twin pairs compared with healthy twin pairs, particularly in the monozygotic twin pairs. A decrease in gray matter was found in the patients compared with their co-twins and compared with the healthy twins. CONCLUSIONS: The results suggest that the decreases in white matter volume reflect the increased genetic risk to develop schizophrenia, whereas the decreases in gray matter volume are related to environmental risk factors. Study of genes involved in the (maintenance) of white matter structures may be particularly fruitful 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.     

Contributions of genetic risk and fetal hypoxia to hippocampal volume in patients with schizophrenia or schizoaffective disorder,their unaffected siblings,and healthy unrelated volunteers

OBJECTIVE: The authors examined in an epidemiologic sample the contributions of genetic predisposition and history of fetal hypoxia to hippocampal volume in patients with psychosis. METHOD: High-resolution magnetic resonance imaging was used to measure hippocampal volumes in 72 psychotic probands (60 with schizophrenia and 12 with schizoaffective disorder, ascertained so as to be representative of all such probands in a Helsinki birth cohort), 58 nonpsychotic full siblings of the probands, and 53 demographically similar healthy comparison subjects with no family history of psychosis. RESULTS: Hippocampal volume differences occurred in a stepwise fashion with each increase in genetic load for schizophrenia. The probands had smaller hippocampal volumes than did their full siblings, who in turn had smaller hippocampal volumes than did the healthy comparison subjects. Among the probands, smaller hippocampal volumes were seen in those who experienced fetal hypoxia than in those who did not, a difference not noted within the other two groups. Finally, within the schizophrenic/schizoaffective disorder patients, smaller hippocampal volumes correlated positively with age at onset independent of duration of illness. CONCLUSIONS: These findings suggest that in patients with schizophrenia spectrum disorders, hippocampal volume is influenced in part by schizophrenia susceptibility genes and an interaction of these genes with fetal hypoxia. They further suggest that hippocampal volume in schizophrenia or schizoaffective disorder may be linked to time of disease onset.     

Prefrontal cortex gyrification index in twins: an MRI study

Cortical development and folding seems to be under environmental as well as genetic control. The aim of our study was to estimate the genetic influence on gyrification and cortical volumes, comparing prefrontal gyrification index (GI) in monozygotic (MZ) and dizygotic (DZ) twin pairs, and unrelated pairs. Twenty-four subjects (6 pairs of MZ and 6 pairs of DZ twins) were included in this study. Prefrontal cortical folding (gyrification) was measured by an automated and manual version of the gyrification index (A-GI, M-GI) according to previously published protocols. MR-imaging was performed and 3 representative slices were selected from coronar MR-imaging scans. The volumes of the total brain, temporal lobes, prefrontal lobes, and cerebellum were analyzed, too. To evaluate similarity in GI, absolute differences in GI, and brain volumes as well as intraclass correlations of twin pairs were compared with regard to twin status. Finally, a control group of unrelated pairs was assembled from the first two study groups and analyzed. Compared to unrelated pairs, twin pairs exhibited more similarity concerning different brain volumes and a trend to more similarity concerning A-GI. MZ twins did not present more similarity concerning GI (automatically and manually measured) and volume measurements compared to DZ twins. Different factors, like intrauterine factors, postnatal development conditions, and especially environmental factors might account for the differences between related and unrelated pairs. The nonexistence of a pronounced similarity in MZ twins compared to DZ twins concerning prefrontal GI raises questions about the extent of genetic influence on GI.     

A discordant twin study of premorbid cognitive ability in schizophrenia

Twin studies are advantageous because sources of genetic and environmental variation are equated in ways that are not possible in standard case-control designs. We examined premorbid cognitive ability by comparing Armed Forces Qualification Test scores administered at the time of military enlistment in 21 schizophrenia-discordant twin pairs and 860 matched control twins. Scores were significantly lower in schizophrenia probands than in their nonpsychotic co-twins; co-twins were midway between probands and control twins. Effects were reduced when the discordant pairs were extended to include 33 psychosis-discordant pairs. Compared with controls, education at enlistment was significantly lower in psychosis probands and in co-twins from both schizophrenia- and psychosis-disordant pairs. Co-twins from psychosis-discordant pairs had significantly lower education at midlife than controls. Results suggest that cognitive ability is influenced by familial vulnerability for schizophrenia or psychosis, and that premorbid cognitive ability is lower in schizophrenia versus psychosis in general. Educational advancement may be slightly slowed by this familial vulnerability, but results were equivocal with regard to attenuation of one's ultimate educational attainment.     

Differentiating between low and high susceptibility to schizophrenia in twins: the significance of dermatoglyphic indices in relation to other determinants of brain development.

Both the skin and the brain develop from the same ectoderm and it is thought, therefore, that dermatoglyphics are informative for early disturbances in brain development in schizophrenia. This study was aimed at investigating the differences in both digital and palmar dermatoglyphic indices between twins discordant for schizophrenia and control twins. Furthermore, the significance of dermatoglyphic indices in relation to other determinants of brain development with regard to the susceptibility to schizophrenia was investigated. Data on dermatoglyphic indices of the hand and the palm were obtained from 21 same-sex discordant and 37 same-sex control twins. For 19 discordant and 25 control twins, there was also data available on brain volumes. Non-genetic intra-uterine circumstances early in pregnancy (10-13 weeks of gestation) are associated with a susceptibility to schizophrenia, since both the twins with schizophrenia and the unaffected co-twins showed more fluctuating asymmetry of the finger ridges (P<0.01), and marginally higher absolute finger ridge counts (P=0.06) than control twin pairs. Fluctuating asymmetry of the finger ridges was as important as whole brain and left hippocampal volumes in differentiating twins with a high susceptibility to schizophrenia from those with a low susceptibility.     

Parkinson's disease in twins studied with 18F-dopa and positron emission tomography.

We used 18F-dopa PET to examine concordance for dysfunction of the nigrostriatal dopaminergic system in 18 co-twins of patients with Parkinson's disease (PD) and scanned one clinically concordant monozygotic (MZ) twin pair, 17 asymptomatic co-twins (10 MZ, 7 dizygotic [DZ]), and 13 twins with PD (8 MZ, 5 DZ). Mean 18F-dopa uptake of the twins with PD was significantly reduced in putamen to 38% and in caudate to 66% of normal. Mean putamen 18F-dopa uptake for the 17 asymptomatic co-twins was also significantly reduced (86% of normal), as was putamen tracer uptake for the 10 MZ (87% of normal) and seven DZ (83% of normal) asymptomatic co-twin subgroups. Four of 10 MZ and two of seven DZ asymptomatic co-twins had putamen 18F-dopa uptake reduced more than 2 SDs below the normal mean. Three of these four asymptomatic MZ co-twins had tremor on examination at the time of PET and one has now developed PD 2 years later. Our PET findings give concordances for nigral dysfunction of 45% in the MZ pairs and 29% in the DZ pairs at a 2-SD threshold, and 18% in MZ and 0% in DZ pairs at a 3-SD threshold of significance. These data suggest that the concordance for nigral pathology in PD twins may be higher than previously realized and that the presence of an isolated postural or rest tremor may be a phenotypic expression of PD.     

A twin study of DSM-III-R anxiety disorders

The prevalence of anxiety disorders was studied in a sample of 20 monozygotic (MZ) and 29 dizygotic (DZ) co-twins of anxiety disorder probands. A comparison group of co-twins of 12 MZ and 20 DZ twin probands with other non-psychotic mental disorders was also studied. All subjects were personally interviewed with the Structured Clinical Interview for DSM-III-R Axis I (SCID-I). Panic disorder was significantly more prevalent in co-twins of panic probands. Generalized anxiety disorder (GAD) was more prevalent in co-twins of GAD probands with a history of mood disorder (NS). Post-traumatic stress disorder was significantly more prevalent in co-twins of anxiety probands and was more prevalent in MZ than in DZ co-twins. The prevalences of social and simple phobia were equal in co-twins of anxiety and comparison probands. For both panic disorder and generalized anxiety disorder the MZ:DZ concordance ratio was more than 2:1. The results support the hypothesis of a genetic contribution in the etiology of panic disorder, generalized anxiety disorder and post-traumatic stress disorder. The hypothesis that simple and social phobia are mainly caused by environmental experiences was also supported.     

3H-imipramine binding in human platelets: a study in normal twins

3H-imipramine binding was determined in freshly prepared intact platelets from 17 monozygotic (MZ) and 15 dizygotic (DZ) twin pairs, all of them male, adult, drug-free, and healthy volunteers. Sixteen males served as controls for determination of intraindividual variation of binding parameters. Both MZ and DZ twin pairs exhibited high intraclass correlations of Bmax values, but DZ twins were nearly as similar as MZ pairs. Interindividual variation of binding parameters is not large enough to reveal a significant genetic control.