Spatial working memory deficits in schizophrenia patients and their first degree relatives from Palau,Micronesia

Spatial working memory deficits associated with dorsolateral prefrontal dysfunction have been found in Caucasian samples of schizophrenia patients and their first‐degree relatives. This study evaluated spatial working memory function in affected and unaffected members of multiplex schizophrenia families from the Republic of Palau to determine whether the spatial working memory deficits associated with schizophrenia extend to this non‐Caucasian population. Palau is an isolated island nation in Micronesia with an elevated prevalence of schizophrenia and an aggregation of cases in large multigenerational families. Our objective was to evaluate the potential for spatial working memory function to serve as one of multiple endophenotypes in a genetic linkage study of these Palauan schizophrenia families. A spatial delayed response task requiring resistance to distraction and a sensorimotor control task were used to assess spatial working memory in 32 schizophrenia patients, 28 of their healthy first‐degree relatives, and 19 normal control subjects. Schizophrenia patients and their relatives were significantly less accurate than normal control subjects on the spatial delayed response task but not on the sensorimotor control task. On both tasks, patients and relatives were slower to respond than the normal controls. There were no age or gender effects on accuracy, and working memory performance in schizophrenia patients was not significantly correlated with medication dosage. In summary, spatial working memory deficits that have been found in Caucasian schizophrenia patients and relatives were confirmed in this isolated Pacific Island family sample. These results suggest that spatial working memory deficits may be a potentially useful addition to the endophenotypic characterization of family members to be used in a comprehensive genome wide linkage analysis of these Palauan families. © 2002 Wiley‐Liss, Inc.     

精神分裂症患者及一级亲属的脑结构非对称性异常

目的:探讨脑结构非对称性与精神分裂症遗传易感性之间的关系。方法:对符合美国精神障碍诊断和统计手册第四版(Diagnostic and Statistical Manual of Mental Disorders,Fourth Edition,DSM-Ⅳ)精神分裂症诊断标准的门诊和住院首发精神分裂症患者、与患者来自不同家族的一级亲属和正常对照三组各19人进行核磁共振扫描脑结构成像。使用统计学参数图软件SPM2计算全脑灰质结构非对称性指数,并比较三组人群非对称性指数的差异。结果:患者组和正常对照相比,颞上回、后扣带回、小脑、顶叶、基底节的结构非对称性降低,差异有统计学意义(P0.01)。一级亲属和正常对照相比,颞上回和顶叶的结构非对称性降低,差异有统计学意义(P0.01)。患者组和一级亲属相比,小脑、顶叶、基底节的非对称性降低,差异有统计学意义(P0.01)。结论:颞上回和顶叶的结构非对称性降低可能是精神分裂症的遗传易感性指标,而后扣带回、小脑、基底节的结构非对称性降低可能与精神分裂症患病状态有关。     

Immediate memory, attention and communication disturbances in schizophrenia patients and their relatives

BACKGROUND: Schizophrenia has been defined in part by disturbances of thought and language. The non-schizophrenic relatives of patients also have been found to show subtle disturbances of language that may be associated with vulnerability. Investigators have hypothesized that these phenomena in patients and their relatives are, at least in part, the result of weaknesses in facets of attention and memory. METHODS: The present study assessed some neuropsychological process correlates of three different measures of thought and language symptoms in 55 stable out-patients, using tests of immediate auditory memory impairment and auditory distractability, and carefully controlling for generalized deficit effects. A parallel assessment was made of referential communication disturbances in 59 non-schizophrenic relatives of patients and 24 control subjects matched to the relatives. RESULTS: In patients, formal thought disorder, disorganization, and referential communication disturbances were all associated with each other and with auditory distractability. In addition, as expected, referential communication disturbances were associated with immediate auditory memory impairment. Referential disturbance ratings for relatives were similar in magnitude to those for the stable out-patients, and much higher than for controls. However, the relatives' language ratings were not associated specifically with weaknesses in attention or memory as measured. CONCLUSIONS: Impairments in immediate auditory memory and attention are associated differentially with different types of communication disturbances in schizophrenia patients. The cognitive substrate for referential communication disturbances in relatives appears to differ qualitatively from that for patients.     

Genetic epidemiological study of schizophrenia in Palau, Micronesia: prevalence and familiality

We are studying the genetic etiology of schizophrenia in the Republic of Palau, a remote island nation in Micronesia that has been geographically and ethnically isolated for approximately 2,000 years. The first epidemiological phase sought to estimate the lifetime prevalence of schizophrenia and evaluate the familiality of the illness based on complete ascertainment of cases and families segregating schizophrenia. A total of 160 strictly defined cases of schizophrenia were ascertained in a population of 13,750 adults who were 15 years of age and older. The lifetime prevalence of strictly defined schizophrenia in Palau was 1.99% overall and 2.77% in males vs. 1.24% in females. This greater than 2:1 male-to-female risk ratio for schizophrenia was accompanied by an earlier mean age of onset for males (23.3 years) than for females (27.5 years). These 160 cases of strict schizophrenia represent 59 separate families each identified by a single common founder. Eleven of these families have 5 to 14 cases and represent nearly half of the strict schizophrenia cases in Palau. Although schizophrenia is clearly aggregating in these 11 families, cases are distributed sparsely throughout the large sibships. In the entire sample of 160 cases of strict schizophrenia, there were only 11 sib-pairs and 2 sib-trios. When a family was defined to include third-degree relatives, only 11 cases (6.9%) were nonfamilial. The majority of the ascertained cases can be linked together into extended pedigrees with complex multilineal inheritance patterns. These intricately interconnected families may pose challenges for traditional linkage techniques. However, these Palauan families represent a valuable resource for studying the genetic etiology of schizophrenia because there may be fewer susceptibility genes for schizophrenia in this genetic isolate than in the heterogeneous populations that are common throughout the world today.     

Lipid metabolism parameters in patients with Alzheimer's disease and their first degree relatives

Recently, it was suggested that the presence of total cholesterol (TC), age and sex interaction in Alzheimer's type dementia (AD) is linked with the apolipoprotein E (APOE) genotype. Our objective was to determine whether the serum lipid profile in AD patients and their first degree non-demented relatives of a certain age (NDR) was dependent on APOE genotype. We included 28 mild to moderate AD and 30 NDR according to DSM-III-R and NINCDS-ADRDA criteria. NDR individuals were investigated in an age group similar to the AD group (brother-sister relationship) and in a group including younger individuals (AD patients-children relationship). Our data indicate significant differences between decreased total cholesterol and low density lipoprotein cholesterol ratio in the group of AD patients versus NDR individuals of similar age, independent of APOE genotype, and an increased total cholesterol and low density lipoprotein cholesterol ratio in a group of AD patients versus their children of the same genotype. There was no significant correlation between triglycerides and high density lipoprotein levels with APOE genotype in any of the tested groups. In conclusion, there was a decreased selected lipid serum profile parameters in AD compared to age matched non demented first degree relatives.     

Non-reproductive heritable disorders in infertile couples and their first degree relatives

The genetic safety of intracytoplasmic sperm injection (ICSI) remains a matter of continuing debate. One source of concern is the limited knowledge about the general genetic constitution and background of patients who need sophisticated reproductive technology to procreate. It has been postulated that such individuals could be carriers of genetic lesions that might result in an increased prevalence of heritable disorders among their offspring. To investigate this issue, we determined the frequency of potentially heritable non-reproductive diseases in 621 infertile couples and their first degree relatives. A total of 1302 fertile couples who underwent genetic counselling prior to prenatal diagnosis served as controls. The infertile patients had a slightly higher prevalence of potentially heritable non-reproductive disorders ('significant genetic risk factors') than the controls (1. 9 versus 0.9%; P = 0.015). In contrast, such diseases were less prevalent in their families than in the fertile couples' families. Our data do not support the hypothesis that their familial genetic background predisposes children born after ICSI to malformations or other non-reproductive genetic diseases.     

Abnormal immunoregulation in patients with insulin dependent diabetes mellitus and their healthy first degree relatives

Autoantibodies, cell-mediated autoimmunity, and impaired suppressor T cell function, suggesting abnormal immunoregulation, have been implicated in the pathogenesis of juvenile-onset insulin dependent diabetes mellitus (IDDM). To examine one of the parameters of immunoregulation, and to explore its relationship to the disease, we tested suppressor cell function in IDDM patients, their clinically healthy relatives, and in normal unrelated controls. 9/15 IDDM had impaired suppressor cell function compared to 1/8 age-matched healthy sibs (p less than 0.04) and to 0/9 unrelated controls (p less than 0.005). There was no correlation between abnormal suppressor cell function and the patient's age, sex, preprandial blood glucose levels, age at the time of diagnosis, or duration of the disease. However, there was a trend for a higher proportion of HLA Dr3 positive diabetics to have abnormal suppressor cell function compared to DR3 negative patients. Impaired suppressor cell function was also found in 5/23 clinically healthy first degree relatives; 4/5 were related to a diabetic who demonstrated abnormal suppressor cell function. These findings raise the possibility that underlying familial, probably genetically determined abnormalities in immunoregulation, acting in concert with other environmental or genetic factors, may contribute to disease susceptibility in IDDM.     

Trauma-related deficits in working memory

Introduction. The aim of the study was to evaluate trauma-related impairments of working memory in psychiatric outpatients, and the mediating role of processing speed, anxiety and depression in the cognitive decrements. Methods. This research applied a comprehensive assessment protocol including an evaluation of psychopathological and neuropsychological functioning in psychiatric outpatients. Patients with trauma history (n = 33) were compared to patients without such a history (n = 30). We collected information regarding age, gender, culture level, profession level, alcohol abuse, anxiety, and depression symptoms. Working memory and speed processing were assessed with standardised neuropsychological instruments. Data analysis was accomplished using parametric statistics, and a hierarchical multiple regression model was used to regress working memory performance scores against the trauma variable, anxiety-depression scores, and speed processing. Results. The groups differed by gender, not by age, education level, socioeconomic status and alcohol abuse. Analysis of cognitive data revealed specific trauma-related deficits in working memory. Moreover, the trauma-exposed subjects scored higher on anxiety/depression scales, and lower on processing speed tests. The regression revealed significant impairment in working memory partially mediated by speed processing, but not by anxiety or depression. Conclusions. These findings confirmed the trauma-related impairments in working memory and the paramount importance for these impairments of reduced processing speed rather than emotional factors.     

Familial mesothelioma in first degree relatives

Occupational asbestos exposure is believed to be the primary etiologic link to mesothelioma. However, in the evaluation of familial mesothelioma, it is important to consider the possibility of household exposure to asbestos. In this study, we report a family in which the father with prolonged occupational asbestos exposure developed malignant pleural mesothelioma and his daughter 14 years later mesothelioma in situ with focally early invasion. Several reports of familial aggregations of mesothelioma strongly support that genetic factors in collaboration with environmental exposure may contribute etiologically to an as yet unknown fraction of occurrence of this disease. Diagn. Cytopathol. 2013. © 2012 Wiley Periodicals, Inc.     

Early processing deficits in object working memory in first-episode schizophreniform psychosis and established schizophrenia

BACKGROUND: While there are many studies showing working-memory deficits in schizophrenia there are only a few that disentangle impairments for working-memory subprocesses such as perceptual, attentional, mnemonic and executive function. METHOD: In this study of delay-dependent memory, 55 patients with schizophreniform psychosis, 50 with established schizophrenia and 56 healthy controls were investigated. Using the delayed matching-to-sample task from the Cambridge Neuropsychological Test Automated Battery (CANTAB), performance deficits were found in both patient groups after controlling for age and pre-morbid IQ. RESULTS: Even after controlling for simultaneous matching-to-sample ability (i.e. perceptual matching), impaired performance in both patient groups was found as soon as the stimuli were no longer present. Impaired performance was not due to different types of errors in patients versus controls. Performance in both patient groups was comparable, except for a slight decrease of overall task performance. This suggests that the deficit is relatively stable during the course of the illness. CONCLUSIONS: Our results suggest a deficit in patients with psychotic illness in the initial processes necessary to actively maintain information, such as the ability to form an internal representation of complex objects.     

Socioaffective factors modulate working memory in schizophrenia patients

Working memory deficit in schizophrenia is a core cognitive feature of the disorder and is reliably associated with abnormalities of the prefrontal circuitry. Working memory deficits are also associated with impaired social functioning and present a major obstacle toward successful rehabilitation in schizophrenia. Although the role of prefrontal cortex in working memory has been extensively investigated, the intricate relations among the prefrontal circuitry, working memory and social behaviors are not clearly understood. In this study, we manipulated social context and observed its effects on spatial working memory. In experiment 1, the effects of social and asocial reinforcements on spatial working memory were examined in schizophrenic patients and healthy controls. The results show that social but not asocial reinforcements facilitated spatial working memory in schizophrenic patients. In experiment 2, the effects of human voice reinforcements (with or without affect) on working memory was investigated. Voice reinforcements did not facilitate working memory relative to the no-reinforcement condition. There was no difference between high-affect vs flat-affect voice conditions. In experiment 3, the effects of direct and indirect social interactions on spatial working memory were studied. Direct but not indirect social interaction facilitated working memory in schizophrenic patients. These results suggest that social context might facilitate working memory in schizophrenic patients perhaps by activating frontal lobe systems. In addition, the possibility of improving cognitive functions such as working memory using seemingly non-cognitive methods might lead to potential remediation strategies.     

L-selectin gene T668C mutation in type 1 diabetes patients and their first degree relatives

There have been some studies published recently which have suggested that L-selectin and/or other adhesion molecules could be the new markers for diabetes type 1 risk development in humans and animal models of the disease. The alterations of soluble L-selectin have been found not only in overt but also in the preclinical stage of disease development and were independent from the presence of ICA - a marker of ongoing autoimmunity, but associated with HLA related genetic predisposition to insulin-dependent diabetes mellitus (IDDM). The aim of our study was to evaluate the frequency of the L-selectin gene T668C mutation (from thymine to cytosine at position 668) resulted in F206L an amino acid substitution in patients with overt diabetes and their unaffected first degree relatives in comparison to the unselected control population. In the unaffected siblings of IDDM subjects we have observed a significantly higher frequency of the L-selectin gene T668C mutation in comparison to their relatives with type 1 diabetes and healthy controls. It was also shown that there is an association between T668C mutation and low HLA related risk of IDDM development, the highest frequency of F206L mutation in the EGF domain of L-selectin was observed in relatives with 'protective' HLA DQB1*0602 allele and nonDRB1*03-nonDRB1*04 haplotype, while in subjects with highest risk of IDDM haplotype the frequency of T668C mutation was similar to the controls. We would like to hypothesise that the T668C L-selectin gene mutation could have a (protective?) role in the development of IDDM, but further studies concerning their role in type 1 diabetes are needed.     

Antisaccade performance in schizophrenia patients,their first‐degree biological relatives,and community comparison subjects: Data from the COGS study

The antisaccade task is a widely used technique to measure failure of inhibition, an important cause of cognitive and clinical abnormalities found in schizophrenia. Although antisaccade performance, which reflects the ability to inhibit prepotent responses, is a putative schizophrenia endophenotype, researchers have not consistently reported the expected differences between first‐degree relatives and comparison groups. Schizophrenia participants (n=219) from the large Consortium on the Genetics of Schizophrenia (COGS) sample (n=1078) demonstrated significant deficits on an overlap version of the antisaccade task compared to their first‐degree relatives (n=443) and community comparison subjects (CCS; n=416). Although mean antisaccade performance of first‐degree relatives was intermediate between schizophrenia participants and CCS, a linear mixed‐effects model adjusting for group, site, age, and gender found no significant performance differences between the first‐degree relatives and CCS. However, admixture analyses showed that two components best explained the distributions in all three groups, suggesting two distinct doses of an etiological factor. Given the significant heritability of antisaccade performance, the effects of a genetic polymorphism is one possible explanation of our results.     

Neurocognitive deficits in first-episode schizophrenic patients and their first-degree relatives.

Some neuropsychological abilities, particularly those affecting memory, attention and executive function, are impaired amongst both schizophrenic patients and their unaffected relatives, implying that these deficits are at least partly genetic in origin. However neuropsychological performance can be altered by medication, and has rarely been examined in first onset, drug naive patients. The objective of this study was to determine whether selected neurocognitive abilities are impaired in first-onset schizophrenic patients and their relatives compared to controls. We examined attention and speed of information processing, memory and learning, verbal function, visuoconstructive abilities and executive function in 207 first-episode schizophrenic patients (163 of whom were drug na?ve), 322 of their first-degree relatives and 133 unrelated normal controls. The data were subjected to multilevel modeling to compare neurocognitive performance between schizophrenic probands, relatives and controls while taking into account potential correlations among members of the same family; age, gender, and years of education were included as covariates. Of the three groups, schizophrenic patients performed poorest at all neuropsychological tests, suggestive of a broad range of neurocognitive deficits. Their first-degree relatives showed a narrower pattern of poor performance at Digit Symbol, Digit Span, Trail Making, Verbal Fluency test, Tower of Hanoi, and WCST-M tests. Our findings show that selected neurocognitive deficits especially attention and executive function are impaired in the families of schizophrenic patients. These patterns of neurocognitive deficits may represent "endophenotypes" denoting varying degrees of vulnerability to schizophrenia and may be of value in future molecular genetic studies.     

Resting EEG in first-episode schizophrenia patients, bipolar psychosis patients, and their first-degree relatives

We evaluated the resting electroencephalogram (EEG) of 50 first-episode schizophrenia patients and 55 of their relatives, 31 first-episode bipolar patients and 35 of their relatives, and 113 nonpsychiatric subjects and 42 of their relatives. The frequency characteristics of the EEG showed moderate stability for a subgroup of these subjects (n= 106) who were tested twice, approximately 9 months apart. Both the schizophrenia and bipolar patients showed a generalized pattern of increased delta and theta and decreased alpha activity. The bipolar patients demonstrated additional right hemisphere activity that was not present among the schizophrenia patients and nonpsychiatric subjects, a finding consistent with hypotheses concerning nondominant hemisphere involvement in the regulation of elated mood. The schizophrenia patients' female relatives and/or relatives with affective disorders and the bipolar patients had significantly reduced peak alpha frequencies. This finding may be related to reduced information processing capacity among these subjects.     

Saccadic disinhibition in schizophrenia patients and their first-degree biological relatives

Several studies have reported that patients with schizophrenia and their relatives perform poorly on antisaccade tasks and have suggested that this deficit represents saccadic disinhibition. If this proposition is correct, then varying task parameters that specifically increase the difficulty with which unwanted saccades can be inhibited should exacerbate deficits. Forty-two schizophrenia patients, 42 of their first-degree biological relatives, 21 psychotic affective disorder patients, and 38 nonpsychiatric comparison subjects were given fixation and antisaccade tasks. The introduction of distracters and the presence of visible fixation stimuli were parameters used to vary the difficulty in suppressing unwanted saccades (inhibitory load). It is known that the presence of a fixation stimulus at the time when a saccade must be inhibited results in fewer reflexive errors on antisaccade tasks. Performance on fixation tasks without (low load) vs with distracters (high load) and antisaccade tasks that had fixation stimuli still visible (low load) vs already extinguished (high load) at the time when the reflexive saccade must be inhibited was compared. The schizophrenia patients and their first-degree biological relatives showed evidence of increased saccadic disinhibition that was most pronounced during high inhibitory load conditions. These data indicate that dysfunctional inhibitory processes, at least in the oculomotor domain, are associated with the liability to schizophrenia. Results also suggest that this genetic liability may be related to dysfunctional prefrontal cortical areas that provide top-down inhibitory control over reflexive saccade generation.     

Common sense representations of schizophrenia in patients and their relatives

This study tests whether the same dimensions that have been shown to be relevant to cognitive understanding of physical health problems may also be applied validly to severe mental health problems such as schizophrenia. 22 people with a diagnosis of schizophrenia, and 18 of their relatives, were asked open-ended questions about their understanding of schizophrenia. The responses were recorded and were sorted into common sense dimensions. Construct validity for the use of the dimensions assessed by the most recently updated Illness Perception Questionnaire (IPQ-R) was examined. The results suggest that the dimensions of the IPQ-R are present in people's understanding of schizophrenia. Copyright © 2005 John Wiley & Sons, Ltd     

Saccadic distractibility is elevated in schizophrenia patients, but not in their unaffected relatives

BACKGROUND: Saccadic distractibility, as measured by the antisaccade task, has attracted attention as a putative endophenotypic marker for schizophrenia. Some studies have suggested that this measure is elevated in the unaffected relatives of schizophrenia patients. However, recent studies have called this into question and the topic remains controversial.METHOD: Saccadic distractibility was measured in 53 patients with DSM-IV schizophrenia, 80 unaffected first-degree relatives and 41 unaffected controls.Results. Schizophrenia patients performed worse than relatives and controls combined (p<0.00001), but relatives did not differ significantly from controls. Performance in multiply affected families was no worse than that in singly affected families. Relatives with a high presumed genetic risk for schizophrenia performed no worse than other relatives. The performance of the patients did not predict that of their relatives.CONCLUSIONS:These results demonstrate that saccadic distractibility is strongly associated with disease status but not with genetic loading for schizophrenia. We conclude that saccadic distractibility is unlikely to be useful as an endophenotypic marker in schizophrenia.