Neuropsychological performance of monozygotic twins discordant for bipolar disorder.

BACKGROUND: A paradigm that involves cognitive assessment of monozygotic (MZ) twins discordant for a neuropsychiatric disorder (here bipolar illness) allows for the examination of both disease-specific impairments (in the comparison of affected to unaffected twins) and risk factors (in the comparison of unaffected twins to normal twins). METHODS: Neuropsychological functions were evaluated in seven MZ twin pairs discordant for bipolar illness and seven pairs of normal MZ twins in an attempt to highlight cognitive abilities associated with manifestations of disease and genetic risk factors. At the time of testing, 3 of the affected twins were euthymic, 2 had depressive symptoms, and 2 had manic symptoms; all were receiving medication. All twins receive neuropsychological tests to evaluate intelligence, attention, visuospatial skills, language, learning and memory, and problem solving. RESULTS: Statistical analyses revealed that the affected twins were significantly impaired as compared to the unaffected (and normal) twins on some measures of visuospatial functioning and some verbal memory measures. In contrast to a sample of MZ twins discordant for schizophrenia studied previously, the cognitive impairments we observed in bipolar twins were mild in nature and fairly circumscribed. The unaffected twins performed significantly worse than normal controls on a Brown-Petersen memory task, verbal list learning, and overall Wechsler Memory Quotient. CONCLUSIONS: These data suggest that while some visuospatial deficits and verbal memory deficits may be features of bipolar disorder related to disease parameters, mild attenuations in overall memory or retrieval function may be related to genetic factors associated with the illness.     

Morphometry of the corpus callosum in monozygotic twins discordant for schizophrenia: a magnetic resonance imaging study.

The corpus callosum (CC) has been the focus of several morphometric studies of patients with schizophrenia, but the results of these studies have been contradictory. In an attempt to improve the reliability of morphometric measurements of the corpus callosum, a computerised image analysis system was used to measure the shape, area, thickness and length of the CC on magnetic resonance imaging (MRI) in 12 pairs of monozygotic twins discordant for schizophrenia (SC). No differences in CC area (anterior, middle, posterior thirds and total), length or vertical thickness of the CC body (at three levels) were demonstrated by t test comparisons of the affected SC and unaffected twins. Statistical analysis of a Fourier expansion series suggested differences in shape between normal and SC cotwins in the second harmonic of the anterior and middle segments and effects of gender on posterior CC shape. These results fail to replicate previous findings of altered length, thickness and area in the schizophrenic CC, but implicate disease-related shape differences in the anterior and middle segment of the corpus callosum and gender-related differences in splenium shape. The disease-related shape distortion suggest ventriculomegaly rather than an intrinsic abnormality of the corpus callosum.     

Aberrant DNA methylation associated with bipolar disorder identified from discordant monozygotic twins

To search DNA methylation difference between monozygotic twins discordant for bipolar disorder, we applied a comprehensive genome scan method, methylation-sensitive representational difference analysis (MS-RDA) to lymphoblastoid cells derived from the twins. MS-RDA isolated 10 DNA fragments derived from 5' region of known genes/ESTs. Among these 10 regions, four regions showed DNA methylation differences between bipolar twin and control co-twin confirmed by bisulfite sequencing. We performed a case-control study of DNA methylation status of these four regions by pyrosequencing. Two regions, upstream regions of spermine synthase (SMS) and peptidylprolyl isomerase E-like (PPIEL) (CN265253), showed aberrant DNA methylation status in bipolar disorder. SMS, a gene on X chromosome, showed significantly higher DNA methylation level in female patients with bipolar disorder compared with control females. However, there was no difference of mRNA expression. In PPIEL, DNA methylation level was significantly lower in patients with bipolar II disorder than in controls. The expression level of PPIEL was significantly higher in bipolar II disorder than in controls. We found strong inverse correlation between gene expression and DNA methylation levels of PPIEL. These results suggest that altered DNA methylation statuses of PPIEL might have some significance in pathophysiology of bipolar disorder..     

A functional magnetic resonance imaging study of cortical asymmetry in bipolar disorder

Objectives:  Individuals with bipolar disorder (BPD) exhibit motor, perceptual, and cognitive disturbances involving predominantly right hemisphere dysfunction. This asymmetry has been used to advance the hypothesis that the pathogenesis of bipolar disorder may be related to disturbances of the right cerebral hemisphere. We employed functional magnetic resonance imaging to examine hemispheric asymmetries in manic and depressed BPD. A secondary goal of the study was to examine effects of psychotropic medications on blood volume changes in the motor cortices.
Methods:  We studied 18 right-handed BPD and 13 right-handed normal healthy comparison subjects. Blood oxygen level dependent (BOLD) responses in the primary motor area (M1) and supplementary motor area (SMA) of both hemispheres were elicited during reaction time (RT) tasks.
Results:  Healthy subjects activated the SMA in a reciprocal fashion with significantly greater activity in the left SMA for right hand trials and the right SMA for left hand trials. Depressed BPD subjects failed to show this normal reciprocity indicating a failure to suppress unwanted activity in the ipsilateral right SMA, whereas manic BPD subjects failed to suppress unwanted ipsilateral SMA activity in both hemispheres. Manic and depressed BPD subjects exhibited greater activity in the left primary motor area suggesting increased cortical excitability. BPD subjects treated with antipsychotics or mood-stabilizing medications exhibited longer RTs, lower BOLD responses in M1 and SMA, and a loss of normal hemispheric asymmetry in the SMA than untreated subjects.
Conclusions:  The presence of a right hemisphere disturbance in BPD is consistent with the hypothesis that the right hemisphere may be dominant in mood regulation. The presence of both left and right hemisphere disturbances in mania may explain the coexisting psychotic and affective symptoms observed in this condition.     

Hypermethylation of serotonin transporter gene in bipolar disorder detected by epigenome analysis of discordant monozygotic twins

Bipolar disorder (BD) is a severe mental disorder characterized by recurrent episodes of mania and depression. Serotonin transporter (HTT) is a target of antidepressants and is one of the strongest candidate molecules of mood disorder, however, genetic study showed equivocal results. Here, we performed promoter-wide DNA methylation analysis of lymphoblastoid cell lines (LCLs) derived from two pairs of monozygotic twins discordant for BD. To rule out the possible discordance of copy number variation (CNV) between twins, we performed CNV analysis and found the copy number profiles were nearly identical between the twin pairs except for immunoglobulin-related regions. Among the three genes we obtained as candidate regions showing distinct difference of DNA methylation between one of the two pairs, hypermethylation of SLC6A4, encoding HTT, in the bipolar twin was only confirmed by bisulfite sequencing. Then, promoter hypermethylation of SLC6A4 in LCLs of BD patients was confirmed in a case–control analysis. DNA methylation of SLC6A4 was significantly correlated with its mRNA expression level in individuals with the S/S genotype of HTTLPR, and mRNA expression level was lower in BD patients carrying the S/S genotype. Finally, DNA methylation of the same site was also higher in the postmortem brains of BD patients. This is the first study to report the role of epigenetic modification of SLC6A4 in BD using an unbiased approach, which provides an insight for its pathophysiology.     

A functional magnetic resonance imaging study of emotional Stroop in euthymic bipolar disorder

Bipolar disorder is regarded as a disorder of mood and initial studies have focused on structural abnormalities in limbic networks, known to subserve mood. More recently, functional imaging studies allude to affect processing deficits, which may involve frontostriatal networks. This study sought to explore disturbances in networks involved in the processing of negative affect in euthymic bipolar patients. We used simultaneous functional magnetic resonance imaging and galvanic skin responsivity to explore disturbances in these networks. When processing negative affect, controls recruited a distributed subcortical-prefrontal network. In contrast, patients could only activate a subcortical network that included the amygdala and hippocampus. This study provides evidence for a disconnection in the transfer of information within frontostriatal networks in bipolar disorder.     

Anatomic brain abnormalities in monozygotic twins discordant for attention deficit hyperactivity disorder

OBJECTIVE: To examine brain-behavior relationships in attention deficit hyperactivity disorder (ADHD), the authors obtained magnetic resonance imaging (MRI) scans of monozygotic twins discordant for ADHD. METHOD: National recruitment was followed by in-person assessment. MRI scans were measured algorithmically for nine pairs of monozygotic twins discordant for ADHD. RESULTS: The affected twins had significantly smaller caudate volumes (mean difference=-0.56 ml, CI=-0.92 to -0.21) than their unaffected co-twins. CONCLUSIONS: These results provide further support for striatal models of ADHD pathophysiology.     

Offspring of monozygotic twins discordant for schizophrenia

We studied the incidence of psychopathologic disorder in offspring of monozygotic twins discordant for schizophrenia. The original material was based on a complete national sample of twins who were hospitalized for functional psychosis in Norway. A comparison of adult offspring of schizophrenic monozygotic twins with offspring of their nonpsychotic cotwins showed that although there are more schizophrenic and schizophreniclike cases in the first group, an observation that may be ascribed to environmental factors, the difference is not statistically significant.     

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.     

Synaesthesia: a case study of discordant monozygotic twins

We describe a study of 11-year-old twin sisters who are physically identical in appearance but who have considerably different conscious experiences. One twin appears to be a synaesthete in that she states that she has specific colour experiences (i.e. photisms) whenever she views, hears or thinks of digits. The other twin does not report such conscious experiences when viewing, hearing or thinking about digits. A genotypic analysis using eight microsatellite loci plus the gender of the twins and their parents confirmed that the twins are monozygotic. A phenotypic analysis using a modification of the Stroop task confirmed that only one twin is a synaesthete. We suggest that the discordance in synaesthesia may be due to either an epigenetic event, X chromosome inactivation, or a mutation of a synaesthesia gene.     

Orbitofrontal dysfunction in a monozygotic twin discordant for postpartum affective psychosis: a functional magnetic resonance imaging study

BACKGROUND: Incomplete concordance for psychosis in monozygotic (MZ) twins has been interpreted as indicative of non-genetic cofactors in transmission of the illness. In this case study, we consider childbirth a landmark in the onset of psychotic symptoms, leading to the diagnosis of puerperal psychosis and then to bipolar/schizoaffective disorder. At the end of the third trimester, there is a sudden drop in estrogen, which exerts prominent effects on the serotonergic system in the orbitofrontal cortex (OFC). OBJECTIVES: The purpose of the present study was to investigate OFC activation during emotional processing in MZ twins discordant for affective psychosis. METHODS: Blood-oxygen-level-dependent activation using functional magnetic resonance imaging was measured during the passive viewing of emotional film excerpts. RESULTS: Consistent with our hypothesis, a significant locus of activation was found in the left OFC in the normal MZ twin, but not in the psychosis MZ twin. CONCLUSIONS: The personality changes noted in the psychosis MZ twin (postpartum psychosis) may be related to dysfunctional OFC. Ms J's childbirth may have triggered the onset of psychotic symptoms, leading to the diagnosis of bipolar or schizoaffective disorder.     

Synaesthesia: discordant male monozygotic twins

Grapheme-color synaesthesia, a condition in which achromatic graphemes elicit vivid experiences of color is believed to be a genetically determined trait. We describe a study of 10-year-old twin brothers who are physically identical in appearance but who have considerably different conscious experiences. A phenotypic analysis that measured the consistency of grapheme-color pairings over test-retest confirmed that one twin has grapheme-color synaesthesia and the other twin does not. A genotypic analysis using sixteen microsatellite loci confirmed that the twins are monozygotic. These findings are problematic for previous suggestions that synaesthesia is an X-linked dominant trait. At the very least, the findings show that the penetrance of the genotype for synaesthesia is incomplete and that any view suggesting that synaesthesia is simply an X-linked dominant trait is therefore also incomplete and possibly even incorrect. The findings also negate a previous suggestion, based on a study of female monozygotic twins, that discordance of synaesthesia in identical twins is due to X-inactivation. In general, the findings raise serious questions regarding whether it is possible at this time to establish the genetic contribution to synaesthesia.     

Neuropsychological assessment of monozygotic twins discordant for schizophrenia

A comparison of monozygotic twins discordant for schizophrenia controls for genetic variance and reduces variance due to environmental circumstances, thus serving to highlight differences due to phenotypic-related variables. In this study, we assessed 16 such twin pairs on a wide range of neuropsychological tests. The affected twins tended to perform worse than their unaffected counterparts on most of the tests. Deficits were especially severe on tests of vigilance, memory, and concept formation, suggesting that dysfunction is greatest in the frontotemporal cortex. While manifest symptoms were not highly associated with neuropsychological scores, global level of functioning was. To address the issue of genetic liability, we also compared the sample of discordant unaffected twins with a sample of seven pairs of normal monozygotic twins. No significant differences between the groups were found for any neuropsychological test. In fact, the results suggest that neuropsychological dysfunction is a consistent feature of schizophrenia and that it is related primarily to the clinical disease process and not to genetic or nonspecific environmental factors.