Repair of tetralogy of Fallot (ToF) using a transannular patch can result in severe pulmonary insufficiency (PI) and subsequent right ventricular (RV) dilation. Use of a Dacron (Maquet Cardiovascular ...LLC, Wayne, NJ) limited transannular patch with nominal pulmonary annular expansion (LTAP) attempts to limit PI. We sought to evaluate the degree of PI and RV dilation resulting from a LTAP or annular sparing (AS) approach.
Infants less than 1 year of age undergoing ToF repair between 2000 and 2010 were divided into 2 groups: LTAP and AS RV outflow tract patch. Echocardiograms were used to determine RV dimensions and corresponding Z-values.
From 94 infants, 48 required a LTAP and 46 required an AS patch. The preoperative pulmonary valve annulus Z-value was significantly smaller in the LTAP versus AS group (-2.7 ± 1.4 versus -0.9 ± 1.5; p < 0.001). Mean follow-up was obtained at 7.9 ± 3.4 years. Ten-year freedom from severe pulmonary insufficiency was 78.5% versus 93.2% (p = 0.3) in the LTAP and AS groups, respectively. There was no significant difference in the diameter of the RV base Z-value between groups (LTAP: 0.9 ± 0.8 versus AS: 0.0 ± 2.3; p = 0.1). Further, the freedom from reoperation at 10 years was also not significantly different between the LTAP and AS groups (95.6% versus 91.8%; p = 0.5).
When required, a LTAP results in a similar change in RV chamber size and rate of reoperation at an intermediate-term follow-up.
Catechol-O-methyltransferase (COMT) regulates dopamine degradation and is located in a genomic region that is deleted in a syndrome associated with psychosis, making it a promising candidate gene for ...schizophrenia. COMT also has been shown to influence prefrontal cortex processing efficiency. Prefrontal processing dysfunction is a common finding in schizophrenia, and a background of inefficient processing may modulate the effect of other candidate genes. Using the NIMH sibling study (SS), a non-independent case-control set, and an independent German (G) case-control set, we performed conditional/unconditional logistic regression to test for epistasis between SNPs in COMT (rs2097603, Val158Met (rs4680), rs165599) and polymorphisms in other schizophrenia susceptibility genes. Evidence for interaction was evaluated using a likelihood ratio test (LRT) between nested models. SNPs in RGS4, G72, GRM3, and DISC1 showed evidence for significant statistical epistasis with COMT. A striking result was found in RGS4: three of five SNPs showed a significant increase in risk LRT P-values: 90387 = 0.05 (SS); SNP4 = 0.02 (SS), 0.02 (G); SNP18 = 0.04 (SS), 0.008 (G) in interaction with COMT; main effects for RGS4 SNPs were null. Significant results for SNP4 and SNP18 were also found in the German study. We were able to detect statistical interaction between COMT and polymorphisms in candidate genes for schizophrenia, many of which had no significant main effect. In addition, we were able to replicate other studies, including allelic directionality. The use of epistatic models may improve replication of psychiatric candidate gene studies.
Background Shared neuropathological characteristics of patients with schizophrenia and their siblings might represent intermediate phenotypes that could be used to investigate genetic susceptibility ...to the illness. We sought to discover previously unidentified gray matter volume differences in patients with schizophrenia and their siblings with optimized voxel-based morphometry. Methods We studied 169 patients with schizophrenia, 213 of their unaffected siblings, and 212 healthy volunteers from the Clinical Brain Disorders Branch/National Institute of Mental Health Genetic Study of Schizophrenia with magnetic resonance imaging. Results Patients with schizophrenia had significant regional gray matter decreases in the frontal, temporal, and parietal cortices compared with healthy volunteers. Their unaffected siblings tended to share gray matter decreases in the medial frontal, superior temporal, and insular cortices, but these decreases were not significant after correction for multiple comparisons, even when we looked at a subgroup of siblings with a past history of mood disorder. As an exploratory analysis, we estimated heritability with regions of interest from the VBM analysis as well as from the hippocampus. Hippocampal volume was significantly correlated within sibling-pairs. Conclusions Our findings confirm and extend previous voxel-based morphometry analyses in ill subjects with schizophrenia. Furthermore, these data argue that although siblings might share some regional gray matter decreases with their affected siblings, the pattern of regional differences might be a weak intermediate phenotype for schizophrenia.
Prefrontal cortical dopamine (DA) regulates various executive cognitive functions, including attention and working memory. Efforts to enhance prefrontal-related cognition, which have focused on ...catecholaminergic stimulant drugs, have been unsatisfactory. Recently, the demonstration that a functional polymorphism in the catecholamine-O-methyltransferase (COMT) gene impacts prefrontal cognition raises the possibility of a novel pharmacological approach for the treatment of prefrontal lobe executive dysfunction. To explore in a proof of concept study the effects of tolcapone, a CNS penetrant specific COMT inhibitor, we performed a randomized, double blind, placebo controlled, and crossover design of this drug in normal subjects stratified by COMT (val158met) genotype. COMT enzyme activity was determined in peripheral blood. Forty-seven normal volunteers with no family history of psychiatric disorders underwent neuropsychological testing and 34 of those subjects underwent physiological measurement of prefrontal information processing assessed by blood oxygen level-dependent functional magnetic resonance imaging (fMRI). We found significant drug effects on measures of executive function and verbal episodic memory and a significant drug by genotype interaction on the latter, such that individuals with val/val genotypes improved, whereas individuals with met/met genotypes worsened on tolcapone. fMRI revealed a significant tolcapone-induced improvement in the efficiency of information processing in prefrontal cortex during a working memory test. This study demonstrates enhancement of prefrontal cortical function in normal human subjects with a nonstimulant drug having COMT inhibitory activity. Our results are consistent with data from animal studies and from computational models of the effects of selective enhancement of DA signaling in the prefrontal cortex.
It has been suggested that in healthy persons higher-order cognitive processing engaged by incremental working memory load hierarchically employs more dorsal than ventral prefrontal resources in ...healthy individuals. Given that working memory performance is impaired in schizophrenia, especially at higher executive loads, the authors investigated how this prefrontal functional organization might be altered in disease, independent of performance deficits.
Using N-back working memory functional magnetic resonance imaging (fMRI) data, the authors studied 15 patients with schizophrenia and 26 healthy comparison subjects. Subgroups based on median performance accuracy at 2-back were analyzed; high performers included eight schizophrenia patients and 14 comparison subjects, and low performers included seven patients and 12 comparison subjects.
High-performing but not low-performing comparison subjects responded to incremental working memory executive load with disproportionately greater dorsal but not ventral prefrontal cortex activation, which also predicted performance accuracy. In the high- and low-performing patient groups, incremental working memory load caused a disproportionate increase in ventral but not dorsal prefrontal cortex activation relative to the respective comparison group, which also correlated with accuracy. Functional connectivity between the ventral prefrontal cortex and posterior parietal cortex was relatively greater in patients, whereas comparison subjects had greater functional connectivity between the dorsal prefrontal cortex and posterior parietal cortex.
The hierarchical organization of the prefrontal cortex may be compromised in schizophrenia, resulting in loss of functional specialization and integration at the dorsal prefrontal cortex and in compensatory activation from the ventral prefrontal cortex, which may ultimately affect working memory and executive cognition.
Background Catechol-O-methyltransferase (COMT) val108/158 met ( rs4680 ) is thought to affect dopamine regulated prefrontal cortical activity during working memory (WM) tasks, and to weakly increase ...risk for developing schizophrenia. Recently, other single nucleotide polymorphisms (SNPs) across the gene have emerged as additional risk factors for schizophrenia: namely rs737865 , rs165599 , and rs2097603 . In a large sample, we examined whether these SNPs affect WM. Methods Schizophrenic probands ( n = 325), their nonpsychotic siblings ( n = 359), and normal control subjects ( n = 330) completed tests of WM function. Data were analyzed with a series of mixed model analyses of variance (ANOVAs). Results Val homozygotes performed most poorly on all conditions of the n-back, irrespective of diagnosis. Additionally, there was a trend towards a disease-only val108/158 met effect on a test of attentional set-shifting; val homozygote probands performed most poorly. Significant or near-significant effects of rs737865 were found on all conditions of the n-back, with G homozygotes performing worst. There also was a disease-only COMT rs737865 effect on the 0-back. None of the other SNPs showed main effects by themselves. A haplotype constructed from promoter and val108/158 met SNPs showed main effects on WM parameters, consistent with inverted U models of dopamine signaling. Conclusions We extended earlier findings of a val108/158 met effect on WM function, and suggest that combinations of alleles within COMT may modulate the val108/158 met effect in a nonlinear manner.
False positives in imaging genetics Meyer-Lindenberg, Andreas; Nicodemus, Kristin K.; Egan, Michael F. ...
NeuroImage (Orlando, Fla.),
04/2008, Letnik:
40, Številka:
2
Journal Article
Recenzirano
Imaging genetics provides an enormous amount of functional–structural data on gene effects in living brain, but the sheer quantity of potential phenotypes raises concerns about false discovery. Here, ...we provide the first empirical results on false positive rates in imaging genetics.
We analyzed 720 frequent coding SNPs without significant association with schizophrenia and a subset of 492 of these without association with cognitive function. Effects on brain structure (using voxel-based morphometry, VBM) and brain function, using two archival imaging tasks, the n-back working memory task and an emotional face matching task, were studied in whole brain and regions of interest and corrected for multiple comparisons using standard neuroimaging procedures. Since these variants are unlikely to impact relevant brain function, positives obtained provide an upper empirical estimate of the false positive association rate. In a separate analysis, we randomly permuted genotype labels across subjects, removing any true genotype–phenotype association in the data, to derive a lower empirical estimate.
At a set correction level of 0.05, in each region of interest and data set used, the rate of positive findings was well below 5% (0.2–4.1%). There was no relationship between the region of interest and the false positive rate. Permutation results were in the same range as empirically derived rates.
The observed low rates of positives provide empirical evidence that the type I error rate is well controlled by current commonly used correction procedures in imaging genetics, at least in the context of the imaging paradigms we have used. In fact, our observations indicate that these statistical thresholds are conservative.
Abstract Background Verbal and visual memory deficits are prominent trait markers for schizophrenia, with impairments also observed in first-degree relatives Snitz, B.E., Macdonald, A.W., 3rd, & ...Carter, C.S. (2006). Cognitive deficits in unaffected first-degree relatives of schizophrenia patients: a meta-analytic review of putative endophenotypes. Schizophr Bull , 32(1), 179–194. It remains unclear whether deficits lie in encoding or savings, and whether the deficit is heritable. Objective To determine which features of memory performance are impaired in both patients and their healthy siblings, possibly reflecting shared genetic effects. Method We tested episodic memory using Logical Memory (LM) and Visual Reproduction (VR) tasks of the Wechsler Memory Scale (Revised). Participants included patients with schizophrenia ( n = 162), their nonpsychotic siblings ( n = 146), and controls ( n = 205), recruited for the “CBDB/NIMH Sibling Study”. We assessed immediate encoding and 30 minute and 24 hour delayed recall as well as savings scores for the “short delay” (immediate to 30 min) and “long delay” (30 min to 24 h) intervals. Results We observed marked verbal recall deficits in both patients and siblings compared to controls for all stages ( p < .0001). Only patients experienced significant verbal and visual savings deficits over short delays ( p < .0001) as well as verbal deficits over long delays ( p < .005). In siblings, no saving score difficulty was apparent for either measure. Conclusions Our results confirm shared impairment in verbal learning, but not memory, for both patients and siblings, therefore marking it as a potential schizophrenia-associated intermediate phenotype. The results implicate neural systems involved in immediate encoding and stabilization of memory representations in genetic risk for schizophrenia. In contrast, visual recall and savings impairments appear to be illness, i.e. state, deficits.
Background Impairments of executive functioning, such as set-shifting ability, are seen as core deficits of schizophrenia and are of interest as candidate intermediate phenotype markers. The ...Intradimensional/Extradimensional (ID/ED) shift task offers a differentiated assessment of shifting from previously reinforced stimuli as well as shifting from previously reinforced features and has proven to be sensitive to the impairment seen in patients with schizophrenia. Methods We examined ID/ED performance in 147 patients with schizophrenia, 131 of their healthy siblings, and 303 healthy control subjects. Participants were recruited from local and national sources as volunteers for the Clinical Brain Disorders Branch/National Institute of Mental Health “sibling study”. Results Nearly all control subjects (87%) finished the task successfully, as did 80% of siblings. In contrast only 54% of patients with schizophrenia were able to complete the task. Despite the apparent similarity of performance across the sibling and healthy comparison group, the two groups differed significantly in terms of the number of stages until failure. This difference, however, was not present at any particular stage or any other measure of performance. Conclusions Patients demonstrated robust ID/ED deficits. However, their siblings were minimally impaired, and this impairment did not seem to run in families. These results suggest that impairments on attentional set shifting assessed by ID/ED task are strongly associated with clinical illness, but these impairments are not a promising intermediate phenotype.
Background: Patients with schizophrenia have impairments in several domains of cognition, including working memory/executive function, verbal memory, language, oculomotor scanning/psychomotor speed, ...and general intelligence. Impairments have also been found in unaffected siblings, suggesting they could be heritable. To assess the suitability of cognitive dysfunction for use in genetic studies, we estimated relative risk (λ) in a large cohort of siblings.
Methods: One hundred forty-seven patients with schizophrenia, 193 of their siblings, and 47 control subjects were studied using a neuropsychological test battery, which included intelligence quotient (IQ), Wide Range Achievement Test, Wisconsin Card Sort, Wechsler Memory Scale (revised), California Verbal List Test, Trails A and B, and Letter and Category Fluency. Relative risk was estimated using a cutoff score of 1 SD below the control mean.
Results: As expected, patients performed markedly worse than control subjects on all tests except the Wide Range Achievement Test. Siblings had impaired performance on the Wisconsin Card Sort and Trails B, with trends for reduction (
p = .01–.05) on the California Verbal List Test and Letter Fluency. Relative risk to siblings was elevated on the Trails B (λ = 4.0) and California Verbal List Test (λ = 2.8). Trends (
p = .01–.05) for increased λ were also seen for Wisconsin Card Sort, Letter Fluency, Wechsler Memory Scale and decline in IQ (λ = 1.74–2.4). Correlations between tests of different cognitive functions were weak, indicating they measure relatively independent processes.
Conclusion: Unselected siblings of patients with schizophrenia have impairments in several cognitive domains. Relative risk scores were in the moderate range, suggesting a significant genetic component. Impairments on one test only weakly predicted impairments on other tests. Thus, cognitive phenotypes identify distinct, familial traits associated with schizophrenia. Using this dimensional approach to subdividing schizophrenia may reduce the clinical and genetic heterogeneity of schizophrenia and improve the power of genetic studies.
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