Structure of SO2946 orphan from Shewanella oneidensis shows "jelly-roll" fold with carbohydrate-binding module.

The crystal structure of the uncharacterized protein SO2946 from Shewanella oneidensis MR-1 was determined with single-wavelength anomalous diffraction (SAD) and refined to 2.0 A resolution. The SO2946 protein consists of a short helical N-terminal domain and a large C-terminal domain with the "jelly-roll" topology. The protein assembles into a propeller consisting of three C-terminal blades arranged around a central core formed by the N-terminal domains. The function of SO2946 could not be inferred from the sequence since the protein represents an orphan with no sequence homologs, but the protein's structure bears a fold similar to that of proteins containing carbohydrate-binding modules. Features such as fold conservation, the presence of a conserved groove and a metal binding region are indicative that SO2946 may be an enzyme and could be involved in binding carbohydrate molecules.

Relative risk of neurological signs in siblings of patients with schizophrenia.

OBJECTIVE: First-degree relatives of patients with schizophrenia appear to have subtle neurological signs, suggesting that these measures could serve as intermediate phenotypes in genetic studies of schizophrenia. The strength of a possible genetic component is unknown, however, leaving it uncertain whether such traits could increase the power to find schizophrenia susceptibility loci. The authors' goal was to investigate the strength of this possible genetic component. METHOD: They estimated the relative risk of neurological impairments in a large group of siblings of patients with schizophrenia. Two standard neurological scales (the Neurological Evaluation Scale and the Woods Scale) were used to examine 115 patients, 185 of their siblings, and 88 normal comparison subjects. RESULTS: There were significant differences between the siblings of patients with schizophrenia and the normal comparison subjects only on the Woods Scale. Relative risk of neurological impairment was significantly increased in the sibling group, but the significance was weak to moderate. Neurological impairment was not redundant with several other intermediate phenotypic measures based on cognitive impairment. CONCLUSIONS: These data suggest that neurological signs cluster in patients with schizophrenia and their families and could possibly identify a unique component of genetic variance for risk of schizophrenia. However, the fairly low relative risk and the uncertain pathophysiology of such signs may limit their usefulness.

A quantitative immunohistochemical study of astrocytes in the entorhinal cortex in schizophrenia, bipolar disorder and major depression: absence of significant astrocytosis.

A number of macroscopic changes have been reported in the temporal lobe in schizophrenia. We have evaluated the density of glial fibrillary acidic protein (GFAP)-positive astrocytes in cortical layers 2 through 6 in the intermediate subarea of entorhinal cortex in two cohorts: the first, 15 cases, made up of schizophrenic (n = 7) and normal nonpsychiatric control subjects (n = 8), and the second, 56 cases, composed of schizophrenic (n = 14), bipolar disorder (n = 13), major depressive (n = 14) and normal control subjects (n = 15). No significant difference in density of GFAP-positive astrocytes was detected between the psychiatric diagnostic groups and the normal controls in either of the two cohorts. In both cohorts there was a positive correlation between increasing age and astrocytic density which reached statistical significance in only the larger cohort (r = 0.38, p = 0.004). Our results find no evidence for astrocytosis in the entorhinal cortex in several mental illnesses. Although other studies have reported macroscopic and other structural abnormalities in this region, we have not detected astrocytic proliferation, which is a typical hallmark of atrophy and/or progressive neuronal loss.

Relative risk for cognitive impairments in siblings of patients with schizophrenia.

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 (lambda) 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 (lambda = 4.0) and California Verbal List Test (lambda = 2.8). Trends (p = .01-.05) for increased lambda were also seen for Wisconsin Card Sort, Letter Fluency, Wechsler Memory Scale and decline in IQ (lambda = 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.

Cognitive impairments in patients with schizophrenia displaying preserved and compromised intellect.

BACKGROUND: Although intellectual and neurocognitive deficits accompany schizophrenia, there are inconsistencies in the literature concerning issues of intellectual decline, premorbid deficits, a modal deficit pattern, and preserved abilities. METHODS: A battery of neuropsychological tests was administered once to 117 consecutively admitted patients with chronic schizophrenia and a group of 27 healthy control subjects to examine patterns of premorbid and current intellect (measured by means of reading scores and IQ, respectively) and the attendant cognitive profiles in schizophrenia using classification methods based on clinically derived (IQ levels) and atheoretical (cluster) techniques. RESULTS: Sixty patients (51%) with schizophrenia who displayed a general intellectual decline of 10 points or greater from estimated premorbid levels also exhibited deficits of executive function, memory, and attention. Twenty-eight patients (23%) with consistently low estimated premorbid intellect and current intellectual levels who displayed no evidence of IQ decline exhibited language and visual processing deficits in addition to deficits present in the intellectually declining group. The remaining 29 patients (25%) who displayed average estimated premorbid intellectual levels did not show IQ decline and exhibited a cognitive profile similar to normal, with the exception of executive function and attention impairment. Atheoretical analyses support the findings from clinically derived subgroups. CONCLUSIONS: These results suggest that IQ decline, although modal in schizophrenia, is not universally characteristic and that executive function and attention deficits may be core features of schizophrenia, independent of IQ variations.

Relative risk of attention deficits in siblings of patients with schizophrenia.

OBJECTIVE: Impaired attention has frequently been observed in studies of unaffected siblings of patients with schizophrenia. To assess the suitability of impaired attention for use as an intermediate phenotype in genetic studies, the authors estimated the relative risk of impaired attention in a large group of siblings. METHOD: The authors used the Continuous Performance Test, 1-9 version, with and without a distraction condition, to study 147 patients with schizophrenia, 193 of their siblings, and 47 normal comparison subjects. Relative risk (l) was estimated by using cutoff scores that were one, two, and three standard deviations below the mean sensitivity index value (d cent) of the normal comparison group in both Continuous Performance Test conditions. RESULTS: Patients but not their siblings performed worse than the normal comparison subjects in both conditions. Fifty percent of the patients, 24% of their siblings, and 18% of the normal comparison subjects scored one standard deviation below the mean score of the comparison group for the more difficult distraction version of the Continuous Performance Test. The patients with Continuous Performance Test scores one standard deviation below the mean score of the comparison group had a total of 97 siblings. Compared with the comparison group, this subgroup of siblings had significantly lower Continuous Performance Test scores. Relative risk was also significantly higher for the siblings of patients whose scores were one standard deviation (l=2. 1) and two standard deviations (l=3.3) below the mean of comparison subjects. Attempts to assess ascertainment bias suggest that this may be an underestimate. CONCLUSIONS: Poor performance on the Continuous Performance Test appears to be familial and, possibly, genetic. Relative risk estimates were in the moderate range. Given the ease of administering the Continuous Performance Test, the use of impaired attention as an intermediate phenotype could increase the power of genetic studies of schizophrenia.

Evaluation of superior vermal Purkinje cell placement in mental illness.

BACKGROUND: A number of neuroimaging and neuropathological studies have reported abnormalities in the cerebellar vermis in schizophrenia and bipolar disorder. In an effort to further understand vermal abnormalities in mental illness, we have analyzed ectopic placement of Purkinje-like cells. METHODS: The superior cerebellar vermis was evaluated in 39 cases of severe mental illness [schizophrenia (n = 12), bipolar disease (n = 12), and depression (n = 15)]. We also examined 9 subjects with polysubstance abuse and 15 normal controls. All normally placed Purkinje cells and displaced Purkinje-like cells (i.e., in the internal granule layer and intrafoliar white matter) were counted in the same foliar field. The ratio of displaced Purkinje-like cells to total Purkinje cells and Purkinje cell density were calculated. RESULTS: No significant difference in the ratio of displaced to normally placed Purkinje cells or in Purkinje cell density between groups of subjects was found. CONCLUSIONS: Our study does not support a hypothesis of abnormalities of Purkinje cell migration or other events related to their displacement as a basis for the vermal abnormalities reported previously in schizophrenia and bipolar disorder.

Clonidine does not potentiate the antipsychotic effects of neuroleptics in chronically ill patients.

Clonidine is a centrally acting antihypertensive and has been prescribed widely for more than 20 years. Because it decreases central norepinephrine activity, clonidine has been investigated as an antipsychotic. In most of the preliminary studies, clonidine was tested as the sole antipsychotic agent. We performed a double-blind, placebo-controlled, crossover study to compare a placebo plus a neuroleptic to clonidine plus a neuroleptic in a group of 16 chronically psychotic patients. Of these 16, 3 dropped out secondary to side effects of the clonidine and 1 withdrew from the study. The clonidine dosage varied from 0.2 to 0.6 mg per day. The concurrent neuroleptic (one of the following: haloperidol, thiothixene, thioridazine, mesoridazine, or fluphenazine) averaged 34 mg per day of haloperidol equivalents. Symptoms were monitored using the Psychiatric Symptoms Assessment Scale. The data provided evidence that a clonidine/neuroleptic combination was not more effective than a neuroleptic alone in this group of patients. These data suggest that the central antinorepinephrine activity of a neuroleptic is not potentiated further by clonidine.

Prodynorphin mRNA expression is increased in the patch vs matrix compartment of the caudate nucleus in suicide subjects.

Experimental and clinical studies suggest an involvement of the opioid neuropeptide system in psychiatric disorders. Notably, opioid peptide immunoreactivity is altered in the cerebrospinal fluid of chronic schizophrenics and manic-depressive subjects. Despite these clinical findings, few postmortem investigations have examined the association of endogenous opioid neuropeptides with schizophrenia and suicide. Anatomically, a tight interaction exists within the neostriatum between the opioid peptide (dynorphin and enkephalin) system and classical neurotransmitters such as dopamine which has been implicated in both the psychotic symptoms and the cognitive deficits that characterize schizophrenia (see review). The neostriatum is differentially organized into patch and matrix neurochemical mosaic compartments anatomically connected to limbic- and sensorimotor-related brain regions, respectively. Moreover, the human neostriatum is characterized by a heterogenous expression of the prodynorphin opioid gene: high in the patch, but low in the matrix compartment. The present results show for the first time a differential alteration of prodynorphin within distinct striatal compartments in postmortem tissue from nonschizophrenic suicide subjects. The prodynorphin patch/matrix mRNA expression was elevated in the caudate nucleus of suicide subjects as compared to normal controls and schizophrenics in which no alterations in opioid peptides or D1 and D2 mRNA expression were apparent. Altogether the findings suggest that discrete dysfunction of the endogenous opioid dynorphin system might contribute to depression and the risk of suicide in nonschizophrenic subjects.

Glutamate receptors in the postmortem striatum of schizophrenic, suicide, and control brains.

INTRODUCTION: Previous postmortem studies of glutamate receptors and uptake sites have shown decreased D-aspartate (D-Asp) (a marker for the high affinity glutamate uptake site) and elevated (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d]cyclohepten-5,10-imine maleate (MK-801) binding in the putamen in schizophrenia and elevated alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor binding in the caudate nucleus of schizophrenics who committed suicide. The relative effects of schizophrenia, suicide, and neuroleptic treatment in these findings is unclear. This study further explores binding to glutamate receptors (NMDA, kainic acid, and AMPA) and uptake sites in postmortem striatal structures in schizophrenics relative to three control groups (normal controls, neuroleptic-treated controls, and nonpsychotic suicides). METHODS: We compared the binding densities of tritium-labeled ligands 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), kainic acid (KA), MK-801, and D-Asp, which target the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), KA, and N-methyl-D-aspartic acid (NMDA) ionotropic receptor sites and the glutamate uptake site, respectively, in postmortem striatal/accumbens tissue from six DSM-III-R schizophrenics, eight normal controls, eight neuroleptic-treated controls, and eight suicide victims using standard receptor autoradiographic methods. RESULTS: Binding of [3H] CNQX (AMPA receptors) was significantly different among the four groups across the subdivisions of the striatum: caudate, putamen, and nucleus accumbens (ANOVA P = .0007, .002, and .004, respectively). The schizophrenia group had higher mean CNQX binding in the caudate nucleus than normal (P = .005) and neuroleptic controls (P = .006) but not suicides (P = .6), who were also higher than normals and neuroleptic-treated controls (P = .05). The binding densities of tritiated MK-801, KA, and D-Asp were not significantly different among the four groups of subjects in any of the striatal regions examined. CONCLUSIONS: The data suggest there may be an increased density of AMPA receptor sites in the caudate nucleus in schizophrenia that is not apparently due to neuroleptic treatment. A similar increase was also seen the suicide group. Although these data do not confirm previous reports of an increase in [3H]MK-801 or a decrease in [3H]D-Asp binding in the basal ganglia in schizophrenia, the increased caudate AMPA binding observed here could reflect decreased cortical glutamatergic innervation of the caudate. Its implication for suicide is unclear.

Dextroamphetamine enhances "neural network-specific" physiological signals: a positron-emission tomography rCBF study.

Previous studies in animals and humans suggest that monoamines enhance behavior-evoked neural activity relative to nonspecific background activity (i.e., increase signal-to-noise ratio). We studied the effects of dextroamphetamine, an indirect monoaminergic agonist, on cognitively evoked neural activity in eight healthy subjects using positron-emission tomography and the O15 water intravenous bolus method to measure regional cerebral blood flow (rCBF). Dextroamphetamine (0.25 mg/kg) or placebo was administered in a double-blind, counterbalanced design 2 hr before the rCBF study in sessions separated by 1-2 weeks. rCBF was measured while subjects performed four different tasks: two abstract reasoning tasks--the Wisconsin Card Sorting Task (WCST), a neuropsychological test linked to a cortical network involving dorsolateral prefrontal cortex and other association cortices, and Ravens Progressive Matrices (RPM), a nonverbal intelligence test linked to posterior cortical systems--and two corresponding sensorimotor control tasks. There were no significant drug or task effects on pCO2 or on global blood flow. However, the effect of dextroamphetamine (i.e., dextroamphetamine vs placebo) on task-dependent rCBF activation (i.e., task - control task) showed double dissociations with respect to task and region in the very brain areas that most distinctly differentiate the tasks. In the superior portion of the left inferior frontal gyrus, dextroamphetamine increased rCBF during WCST but decreased it during RPM (ANOVA F (1,7) = 16.72, p < 0.0046). In right hippocampus, blood flow decreased during WCST but increased during RPM (ANOVA F(1,7) = 18.7, p < 0.0035). These findings illustrate that dextroamphetamine tends to "focus" neural activity, to highlight the neural network that is specific for a particular cognitive task. This capacity of dextroamphetamine to induce cognitively specific signal augmentation may provide a neurobiological explanation for improved cognitive efficiency with dextroamphetamine.

Possible relationship between conditions associated with chronic hypoxia and brain mitochondrial DNA deletions.

The brain relies heavily on aerobic metabolism which requires functional mitochondria. Mitochondria are subcellular organelles with their own genome which codes for 13 essential protein subunits. By employing PCR assays to examine brain tissue from 43 age-comparable individuals (between ages 34 and 73), we found a correlation between mitochondrial DNA deletion mutations, mtDNA4977 deletions, and conditions associated with chronic hypoxia. In prior studies, utilizing only 6 to 12 clinical samples, mtDNA4977 deletions were reported to increase in specific regions of the brain with aging. However, we found 12-fold and 5-fold higher levels of mtDNA4977 deletions in the putamen and the superior frontal gyrus of the cortex, respectively, from individuals who had conditions associated with chronic hypoxia when compared with individuals without evidence of such conditions. These findings suggest that chronic hypoxia should be more closely examined in the pathophysiology of central nervous system diseases.

Genetic risk of neuropsychological impairment in schizophrenia: a study of monozygotic twins discordant and concordant for the disorder.

We used a paradigm involving monozygotic (MZ) twin pairs discordant for schizophrenia (n = 20) and concordant for schizophrenia (n = 8), as well as normal MZ twin pairs (n = 7) in order to study cognitive measures of genetic risk in schizophrenia. A comparison between the unaffected twins from the discordant sample and the normal twins indicated subtle attenuations in some aspects of memory and executive functioning in the unaffected group and thus provided evidence for cognitive markers of a genetic component in schizophrenia. A comparison of the affected twins from the discordant pairs and the concordant twins yielded virtually no differences, suggesting that a distinction between familial and sporadic cases is not valid in this sample. Large differences between unaffected and affected members of discordant pairs on a wide variety of variables, including IQ, attention, memory, and executive function, highlighted the magnitude of disease-specific factors.

Distribution of putative D4 dopamine receptors in postmortem striatum from patients with schizophrenia.

The identification of five dopamine receptor subtypes has given the dopamine hypothesis of schizophrenia new life. The D4 receptor is particularly intriguing because it binds clozapine with high affinity. Putative D4 receptors were labeled in postmortem human brain by subtracting the binding of a saturating concentration of 3H-raclopride (6 nM, which labels D2 and D3 receptors) from that labeled by a saturating concentration of [3H]YM 09151-2 (1-1.3 nM, which labels D2, D3, and D4 receptors). In the control brain, putative D4 receptors show a homogenous distribution in striatum and nucleus accumbens. This is also true in schizophrenic brains, although the levels are significantly higher (twofold). These data are inconsistent with mRNA studies that have shown negligible amounts in striatum and accumbens, with modest amounts reported in most of cerebral cortex. These findings suggest that the putative D4 receptors are not synthesized in this region, but are presynaptically localized on striatal afferent terminals. Our findings confirm and extend the report of Seeman et al. (1993). Extension of these findings into the nucleus accumbens is important because of its extensive connections to the limbic system while the putamen is exclusively "motor" striatum.

Neuropsychological effects of amphetamine may correlate with personality characteristics.

Although the stimulant properties of amphetamine are well established, its effects on cognitive test performance in unfatigued normal adults are poorly documented. Seventeen healthy individuals received a single oral dose of dextroamphetamine (0.25 mg/kg) in a double-blind, placebo-controlled, crossover study. Neurocognitive tests, motor tests, and behavioral observations were performed. Personality information, based on the Tridimensional Personality Questionnaire (TPQ) was also gathered to explore a relationship between personality factors and response to the stimulant. With the exception of two measures of reaction time, there were no overall changes in performance on measures of memory or other cognitive functions. There was decreased reaction time on the continuous performance task (CPT) and increased accuracy of performance under minimal delay conditions in the spatial delay response task while subjects were receiving amphetamine. In addition, the novelty-seeking subscale was found to correlate with a measure of verbal memory. Individuals with higher scores on the novelty-seeking scale deteriorated under amphetamine, while those who had lower scores improved. These results suggest that some cognitive abilities of persons who may have relatively high dopaminergic tone are disrupted by amphetamine, while those with relatively low dopaminergic tone may have their performance enhanced.

Quantitative autoradiography of dopamine-D1 receptors, D2 receptors, and dopamine uptake sites in postmortem striatal specimens from schizophrenic patients.

A number of previously published homogenate receptor binding studies have postulated that dopaminergic dysfunction in schizophrenia may be related to abnormalities in dopamine receptors. In this study, postmortem striatal specimens from patients with schizophrenia, normal controls, and psychiatric controls that had received neuroleptics were studied with quantitative autoradiography for dopamine receptors. Autoradiography with single concentrations of [3H]-SCH 23390 for D1 receptors, [3H]-raclopride for D2 receptors, and [3H]-CFT for dopamine uptake sites failed to define significant differences between the study groups. [3H]-CFT bound in a patchy distribution in the striatum that is believed to correspond to striosomal and matrix striatal compartments. There were no differences between groups when [3H]-CFT binding density was examined in the striosomal and matrix compartments. There were also no differences between groups in the percentage of striatal area occupied by striosomal or matrix compartments as defined by [3H]-CFT binding. We conclude that abnormalities of these dopamine receptor subtypes are probably not primary features of the schizophrenic syndrome in the brain collection examined. Previous reports of elevated D2 receptor binding in schizophrenia may have been related to drug treatment effects. Alternatively, the relatively high affinity of ligands used in previous studies for D4 receptors may explain the discrepancy in our findings. Unchanged [3H]-CFT binding in the schizophrenic group also suggests that the density of mesostriatal neuronal terminals is not altered in schizophrenia.

Is there cognitive decline in schizophrenia? A cross-sectional study.

The issue of progressive cognitive decline in patients with schizophrenia has been debated. We performed a cross-sectional study of patients with chronic schizophrenia, aged from 18 to 69 years, in order to address this issue. The patients included in this study passed a rigorous screen for any comorbid condition with an adverse impact on central nervous system function. We assessed intellectual deterioration with a battery of neuropsychological tests known to be sensitive to cognitive impairment in progressive dementia. No evidence of accelerated intellectual decline was found. No significant differences were found between the five age-derived cohorts (18-29, 30-39, 40-49, 50-59, and 60-69 years of age) on the Mini-Mental State Examination, Dementia Rating Scale, or other tests sensitive to dementia. While performance on the Boston Naming Test significantly declined with age, this was mainly due to age rather than duration of illness. However, it is important to note that mean performances on the majority of the tests were abnormal across all cohorts studied. These results suggest that intellectual function does not markedly decline during the adulthood of patients with schizophrenia. The course of schizophrenia is more consistent with a static encephalopathy than a dementing disorder.

Prenatal origin of schizophrenia in a subgroup of discordant monozygotic twins.

Neuropathological, obstetrical, and epidemiological evidence increasingly suggest that some cases of adult-onset schizophrenia have prenatal or neonatal etiological roots. We evaluated the developmental histories of 23 monozygotic twin pairs discordant for schizophrenia to determine when they markedly and permanently began diverging from each other in motor skills or unusual behavior. Seven of the twins (30%) who later developed schizophrenia had become permanently different from their cotwins by age 5 years. The early divergence group differed from the others by multivariate tests (p = 0.002) for within-twin pair effects and by univariate tests for physical anomaly scores (p = 0.01), total finger ridge counts (p = 0.001), family history of psychosis (p = 0.004), and serious perinatal complications or low birth weight (p = 0.05). It is concluded that some cases of adult-onset schizophrenia are associated with prenatal events, which may include neurodevelopmental abnormalities or specific insults such as anoxia or infectious agents.