Endophenotypic Marker Research Articles

Articulatory rehearsal in verbal working memory: a possible neurocognitive endophenotype that differentiates between schizophrenia and schizoaffective disorder

Working memory deficits represent candidate endophenotypes for major psychiatric disorders. The aim of the present study was to compare directly specific subcomponents of working memory in patients with schizophrenia and schizoaffective disorder as well as in healthy controls. Of each group, 11 subjects matched for gender, age and educational status underwent experimental neuropsychological testing of different components of working memory. In order to be able to attribute possible deficits to dysfunctions of underlying brain circuits we used the same Sternberg item-recognition tasks as in previous neuroimaging studies of working memory (1–4). In contrast to patients suffering from schizophrenia, schizoaffective patients did not differ significantly from healthy subjects in working memory task performance. Direct comparisons of the two patient groups revealed a specific working memory deficit of schizophrenic patients in the articulatory rehearsal task, although there was no significant difference in psychopathological rating scales between the two groups. This suggests that the functional integrity of the articulatory rehearsal mechanism may be a endophenotypic marker that differentiates between these two diagnostic groups.

Spatial Working Memory Function in Twins with Schizophrenia and Bipolar Disorder

Family studies are in conflict as to whether schizophrenia and bipolar disorder have independent genetic etiologies. Given the relatively low prevalence (approximately 1%) of these disorders, the use of quantitative endophenotypic markers of genetic liability might provide a more sensitive strategy for evaluating their genetic overlap. We have previously demonstrated that spatial working memory deficits increase in a dose-dependent fashion with increasing genetic proximity to a proband among the unaffected co-twins of schizophrenic patients. Here, we evaluated whether such deficits might also mark genetic susceptibility to bipolar disorder. The Wechsler Memory Scale-Revised Visual Memory Span and Digit Span subtests were administered to 46 schizophrenic patients, 32 of their unaffected co-twins, 22 bipolar patients, 16 of their unaffected co-twins, and 100 control twins, representing unselectively nationwide twin samples. Schizophrenic patients and their unaffected co-twins performed significantly worse than control subjects on the spatial working memory task, whereas only the schizophrenic patients performed significantly below the control subjects on the verbal working memory task. Neither bipolar patients nor their unaffected co-twins differed from control subjects on these measures. Our findings support the hypothesis that impairment in spatial working memory might effectively reflect an expression of genetic liability to schizophrenia but less clearly to bipolar disorder.

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

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. 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. 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.

Evidence for Deficit in Tasks of Ventral, but not Dorsal, Prefrontal Executive Function as an Endophenotypic Marker for Bipolar Disorder

Trait functional abnormalities in BD patients have only been reported in the ventral prefrontal cortex (VPFC). We examined whether deficits in VPFC-related inhibitory processes, but not dorsal prefrontal (DPFC) based executive functions, represent an endophenotypic marker for bipolar disorder I (BDI). We used the Wisconsin Card Sorting Test (WCST), commonly associated with DPFC function, and the Hayling Sentence Completion Task (HSCT) which engages the VPFC. Performance on these tests of 43 healthy participants was compared to that of 10 remitted BDI patients and 15 of their unaffected offspring. Compared to healthy participants, patients and their offspring made more errors in the HSCT but offspring achieved more categories and made fewer perseverative errors in the WCST. Impaired response inhibition, predominantly a VPFC related function, may reflect familial predisposition to BDI while deficits in rule attainment, a DPFC based function, may be associated only with the clinical phenotype.

Relationship between Class I and II HLA Antigens in Schizophrenia and Eye Movement Disturbances: A Preliminary Study

The region coding human leukocyte antigen (HLA) on chromosome 6q21 was shown to be associated with both the vulnerability to schizophrenia and presence of eye movement disturbances (EMD). The aim of this preliminary study was to investigate how individual class I and II HLA antigens in schizophrenic patients may be related to schizophrenia and to the intensity of two kinds of EMD: fixation and smooth pursuit. The incidence of HLA antigens was compared between 40 schizophrenic patients (17 male, 23 female) and 198 healthy control subjects (112 male, 86 female). In schizophrenic patients, the intensity of EMD assessed by infrared reflectometry and quantified on a scale from 0 to 3 was correlated with the incidence of HLA antigens. A number of differences regarding HLA antigens were found between schizophrenic patients and healthy subjects. Significant correlation was also obtained between some EMD and a number of HLA antigens. Antigens A24 and A28 were found to occur in different frequencies in schizophrenic patients and healthy control subjects. They also correlated with EMD on the fixation and smooth pursuit tests. The results obtained show an association between HLA antigens and EMD as an endophenotypic marker of schizophrenia, and may add to other findings on susceptibility loci for schizophrenia on chromosome 6p21. A limitation of this study is a small number of investigated patients with schizophrenia.

Platelet Serotonergic Markers as Endophenotypes for Obsessive-Compulsive Disorder

Although compelling evidence has shown that obsessive-compulsive disorder (OCD) has a strong genetic component, its genetic basis remains to be elucidated. Identifying biological abnormalities in nonaffected relatives is one of the strategies advocated to isolate genetic vulnerability factors in complex disorders. Since peripheral serotonergic disturbances are frequently observed in OCD patients, the aim of this study was to investigate if they could represent endophenotypes, by searching for similar abnormalities in the unaffected parents of OCD patients. We assessed whole blood serotonin (5-HT) concentration, platelet 5-HT transporter (5-HTT) and 5-HT2A receptor-binding characteristics, and platelet inositol trisphosphate (IP3) content in a sample of OCD probands (n = 48) and their unaffected parents (n = 65), and compared them with sex- and age-matched controls (n = 113). Lower whole blood 5-HT concentration, fewer platelet 5-HTT-binding sites, and higher platelet IP3 content were found in OCD probands and their unaffected parents compared to controls. Whole blood 5-HT concentration showed a strong correlation within families (p < 0.001). The only parameter that appeared to discriminate affected and unaffected subjects was 5-HT2A receptor-binding characteristics, with increased receptor number and affinity in parents and no change in OCD probands. The presence of peripheral serotonergic abnormalities in OCD patients and their unaffected parents supports a familial origin of these disturbances. These alterations may serve as endophenotypic markers in OCD, and could contribute to the study of the biological mechanisms and genetic underpinnings of the disorder.

The Association between Attentional and Executive Controls in the Expression of Borderline Personality Disorder Features: A Preliminary Study

Background: Basic neurocognitive functions such as attention and executive cognitive control represent promising endophenotypes that may improve understanding of the development and expression of borderline personality disorders (BPD). We evaluated the association between performance on the Attention Network Task (ANT) and the Wisconsin Card Sorting Test (WCST), two neurocognitive laboratory instruments, and the extent of BPD psychopathology. Sampling and Methods: We studied 22 BPD-diagnosed individuals who were independently administered these two laboratory assays. Performance on these tests was used as a predictor of the extent of BPD psychopathology. Results: Indexes of the ANT and the WCST were correlated with one another in this sample. Further, the extent of impairment in attention networks, specifically the orienting network, was associated with a greater spectrum of BPD psychopathology, independent of the effects of age and medication status. Finally, ANT and WCST performance were uncorrelated with general psychosocial functioning in this sample, implicating relative specificity to the extent, as contrasted with functional severity, of BPD psychopathology. Conclusions: Attentional and executive functions are promising endophenotypic markers of BPD psychopathology. The implications of these findings are considered from developmental, experimental, and clinical perspectives.

Spatial-anatomical mapping of NoGo-P3 in the offspring of alcoholics: evidence of cognitive and neural disinhibition as a risk for alcoholism

Objective The concept of disinhibition as a behavioral and biological trait has been considered to be involved in the etiology of alcoholism and its co-existing disorders. The magnitude and functional mapping of event-related potential P3(00) components were analyzed, in order to examine the possible response inhibition deficits in the offspring of alcoholics. Methods The P3 components were compared between 50 offspring of alcoholics (OA) and a matched normal control group (NC) using a visual Go/NoGo task. The low-resolution electromagnetic tomography (LORETA) was used to analyze the functional brain mapping between groups. Results The results indicated that the OA group manifested decreased P3 amplitude during the NoGo but not the Go condition compared to the NC group. The voxel-by-voxel analysis in LORETA showed group differences at several brain regions including prefrontal areas during the processing of NoGo but not Go signals. Conclusions The decreased NoGo-P3 suggests that cognitive and neural disinhibition in offspring of alcoholics may serve as a neurocognitive index for a phenotypic marker in the development of alcoholism and related disorders. Significance Dysfunctional neural and response inhibition in the offspring of alcoholics perhaps provides an endophenotypic marker of risk for the development of alcoholism and related disorders.

Saccadic performance in questionnaire-identified schizotypes over time

In the present study, 121 young adults (mean age=19 years), hypothesized to be at varying levels of risk for psychosis on the basis of their psychometric profiles, were administered saccadic (antisaccade and refixation) tasks at two separate assessments. At Time 1, individuals posited to be at heightened risk for the later development of schizophrenia-spectrum disorders (i.e., those individuals with elevated Social Anhedonia Scale [SAS] scores) produced significantly more antisaccade task errors than the controls. Despite apparent improvement in antisaccade task performance from initial testing to the follow-up (mean test–retest interval=59 months) across all groups, the Social Anhedonia (SocAnh) group continued to produce significantly more errors than the control group. The antisaccade task performance of the control group showed good temporal stability (Pearson's r=0.70, ICC=0.52), and the SocAnh group's performance showed excellent temporal stability (Pearson's r=0.85, ICC=0.83). The results of this investigation are twofold: First, antisaccade task performance is temporally stable, even in psychometrically identified schizotypes over long test–retest intervals; and secondly, Social Anhedonia Scale scores as well as Time 1 antisaccade task accuracy accounted for much of the variability in Time 2 antisaccade task performance. These findings add to the growing body of literature suggesting that antisaccade task deficits may serve as an endophenotypic marker of a schizophrenia diathesis.

Monoamine reuptake inhibition and nicotine receptor antagonism reduce amplitude and gating of auditory evoked potentials

Background Sensory encoding deficits have been extensively studied as endophenotypic markers of schizophrenia using auditory evoked potentials. In order to increase understanding of the neurochemical basis of such deficits, we utilized an animal model to test whether monoamine reuptake inhibition and nicotine receptor antagonism reduce the amplitude and gating of the P20 and N40 auditory components. Methods C57BL/6J mice received 12 days of chronic vehicle, bupropion, haloperidol or bupropion plus haloperidol. Auditory evoked potentials were then recorded in alert mice to measure the amplitude and gating of evoked components during a paired click paradigm similar to tasks used to measure the P50 and N100 auditory potentials in schizophrenia. Evoked potentials were recorded prior to and following acute nicotine. Results Bupropion reduced the amplitude and gating of the N40 evoked potential in mice, similar to the P50 and N100 endophenotypes associated with sensory encoding deficits in schizophrenia. This deficit was fully reversed only by the combination of haloperidol and nicotine, suggesting that dopamine reuptake inhibition and nicotine antagonism both contribute to the observed phenotype. Furthermore, nicotine increased P20 amplitude across all groups supporting a role for nicotine agonists in pre-attentive sensory encoding deficits. Conclusions We propose that the combination of monoamine inhibition and nicotine receptor antagonism may serve as a useful model for preclinical screening of pharmaceutical compounds aimed at treating sensory encoding deficits in schizophrenia.

Alcoholism is a disinhibitory disorder: neurophysiological evidence from a Go/No-Go task

Response inhibition is considered a core dimension in alcoholism and its co-existing disorders. The major objective of this study is to compare the magnitude and spatial distribution of ERP components during response activation and inhibition in alcoholics ( N = 30) and normal controls ( N = 30) using a visual Go/No-Go task. The results indicate that alcoholics manifest a decreased P3(00) amplitude during Go as well as No-Go conditions. The difference between Go and No-Go processing was more evident in controls than in alcoholics. The topography of current source density in alcoholics during the P3 response was found to be very different from that of normals, suggesting that alcoholics perhaps activated inappropriate brain circuitry during cognitive processing. The significantly reduced No-Go P3 along with the relatively less anteriorized CSD topography during No-Go condition suggests poor inhibitory control in alcoholics. It is proposed that the No-Go P3, the electrophysiological signature of response inhibition, can be considered as an endophenotypic marker in alcoholism.

Temporal stability of saccadic task performance in schizophrenia and bipolar patients

Identifying endophenotypes of schizophrenia will assist in the identification of individuals who are at heightened risk for the disorder. Investigators have proposed antisaccade task deficits as an endophenotypic marker of schizophrenia. However, the diagnostic specificity and the temporal stability of the task deficit are unresolved issues. To date, there are few published reports of test-retest stability of antisaccade task performance in psychiatric patients. Twenty-three schizophrenia out-patients and 10 bipolar out-patients were administered two saccadic (antisaccade and refixation) tasks at two separate assessments, with an average test retest interval of 33 months. The schizophrenia patients displayed high test-retest reliabilities of antisaccade task accuracy, despite changes in medication and clinical status. Additionally, the schizophrenia group's saccadic reaction times for antisaccade correct responses and task errors were moderately stable over time. In contrast, the bipolar patients did not show temporal stability in their antisaccade task accuracy or in their response latencies to either correct or incorrect antisaccade responses. The results are supportive of the trait-like characteristics of antisaccade task deficits in schizophrenia patients. These findings also suggest that antisaccade task deficits may serve as an endophenotypic marker of schizophrenia.

Neurocognitive function in unaffected first-degree relatives of patients with bipolar disorder: a preliminary report.

Patients with remitted bipolar disorder (BD) have persistent impairments in neuropsychological function, particularly in the domains of executive control and declarative memory [Br J Psychiatry 180 (2002) 293]. If these were the phenotypic expression of genetic vulnerability to BD, then healthy subjects with a genetic predisposition to BD would be expected to display the same deficits. This study, therefore, examined neuropsychological function in healthy first-degree relatives of patients with BD. A cross-sectional design was employed to compare the performance of 17 unaffected first-degree relatives of BD patients and 17 demographically matched controls on a range of neuropsychological tests. Relatives were significantly impaired on Backward Digit Span, Spatial Span and on tasks of visuospatial declarative memory in comparison with controls. Psychomotor performance and verbal declarative memory were intact, as were non-working memory aspects of executive performance. The selective deficits in executive control and declarative memory exhibited by relatives in this study have previously been reported in euthymic BD patients suggesting they may be useful endophenotypic markers of genetic vulnerability to BD.

Secondary verbal memory: a potential endophenotype of schizophrenia

This study aimed at identifying neuropsychological endophenotypes of schizophrenia which met the criteria of stability and sensitivity. Twenty-six non-schizophrenic first-degree relatives together with their affected family members (all simplex-families) underwent assessment with a comprehensive neuropsychological test battery both at baseline and 13 months follow-up. Follow-up patients were in a state of stable remission. Further, 21 unrelated, demographically balanced, non-vulnerable controls were tested one at a time. A principal components analysis of our test battery resulted in four factors: (1) Vigilance, attention, and psychomotor, (2) secondary verbal memory, (3) immediate and working memory, and (3) abstraction and problem solving. At baseline testing our study revealed a pattern of selective cognitive deficits in the relative group that is less pronounced, yet qualitatively similar, to that found in the patient sample. The most severe deficits displayed both the patients and their relatives in the secondary verbal memory domain. The dysfunctions in secondary verbal memory at baseline testing significantly correlated with negative symptoms only. Secondary verbal memory deficits proved to be relatively independent of age at onset of illness, illness duration, and neuroleptic dosage. Longitudinally, dysfunctions in the patients' secondary verbal memory fluctuated over time and with negative symptoms, and persisted in remitted patients at the same level as in their relatives. In conclusion, the secondary verbal memory met the criteria of relative stability and sensitivity in our sample of simplex-families. Thus, the secondary verbal memory seems to be a potential endophenotypic marker of schizophrenia, even for cases with a hypothetically lower genetic loading.

The feasibility of neuropsychological endophenotypes in the search for genes associated with bipolar affective disorder

Efforts to identify genetic loci for bipolar disorder (BPD) have thus far proved elusive. The identification of processes mediating between genotype and phenotype (endophenotypes) may help resolve the carrier status of family members in genetic studies of polygenetic disorders with imperfect penetrance, such as BPD. We reviewed the literature to determine if neuropsychological measures could be used as effective endophenotypes to aid molecular genetic studies searching for genes predisposing to BPD. Four prerequisites for endophenotypic markers are described, and a critical review of relevant literature was undertaken to determine if neurocognitive measures satisfy these four requirements in BPD. We found evidence that executive functions and declarative memory may be candidate neurocognitive endophenotypes for BPD. However, we cannot exclude other areas of cognition as being affected by BPD susceptibility genes, given the limits of the current knowledge of the neuropsychology of BPD. In particular, the paucity of studies measuring cognition in healthy relatives of BPD patient limits conclusion regarding familial aggregation of particular neurocognitive deficits (i.e. attention). Furthermore, the effects of clinical state and/or medication usage on cognitive functioning in BPD probands should be further explored. Molecular genetic studies of BPD may benefit from the application of select neuropsychological measures as endophenotypic markers. The use of these markers, once defined, may improve power for detecting genes predisposing to BPD and may help to better define diagnostic criteria.

Polymorphism of the brain-derived neurotrophic factor gene and performance on a cognitive prefrontal test in bipolar patients.

The aim of the study was to test a possible association between the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene and performance on a neurocognitive test, the Wisconsin Card Sorting Test (WCST), in bipolar patients. Fifty-four bipolar patients were studied, 18 male and 36 female, aged 18-72 (mean 46 years). The number of perseverative errors (WCST-P), non-perseverative errors (WCST-NP), completed corrected categories (WCST-CC), conceptual level responses (WCST-%CONC) and set to the first category (WCST-1st CAT) were measured in relation to the Val66Met genotypes of BDNF. The percentages of subjects with Val/Val, Val/Met and Met/Met genotypes were respectively 81.5, 16.7 and 1.8%. Subjects with Val/Val and Val/Met genotypes did not differ on clinical factors except for the age of onset of the illness, which was earlier in Val/Val than Val/Met genotype (27 years versus 38 years). The performance in all domains of WCST was significantly better in subjects with Val/Val BDNF genotype compared with Val/Met genotype. The results suggest a role of BDNF in prefrontal cognitive function in bipolar illness. The tests of prefrontal cognition may be considered as endophenotypic markers in bipolar illness.

Familial loading associates with impairment in visual span among healthy siblings of schizophrenia patients

Background The effect of familial loading on neurocognitive deficits in relatives of schizophrenia patients has been detected in family and twin studies. The present study examined this effect among healthy siblings of schizophrenia patients in a Finnish isolate with high prevalence of schizophrenia. Methods We assessed performance in verbal and visual span tasks, in tests measuring intelligence, and in declarative verbal memory and learning tasks in 31 and 67 healthy siblings from families with one schizophrenia patient, or with two or more patients, respectively. The differences between the groups were tested using linear mixed effects models. Results An effect of familial loading was detected in the backward visual span task, measuring immediate visual memory with requirements from the visual domain of working memory. In this task, the healthy siblings from multiply affected families performed worse than those from the singleton families. Conclusions The finding that the multiplex vs. singleton differences were selective to the backward visual span task, strengthens the view that the visual domain of working memory may provide a valuable endophenotypic marker for genetic schizophrenia studies.

Smooth pursuit and antisaccade performance evidence trait stability in schizophrenia patients and their relatives

Several forms of eye movement dysfunction (EMD) have been widely regarded as candidate endophenotypes of schizophrenia, ultimately capable of identifying individuals carrying schizophrenia susceptibility genes and elucidating the pathophysiology of schizophrenia. As an indication of their trait-like status, candidate endophenotypes optimally evidence stability over time. However, there have been few published reports of test–retest reliability of several forms of EMD in schizophrenia patients and their relatives. In the current investigation, schizophrenia patients and the first-degree biological relatives of schizophrenia patients ( n=15) were administered by an eye movement battery including smooth pursuit, antisaccade and prosaccade tasks, and re-tested after an average of 1.82 years (range=14–24 months). Adequate test–retest reliabilities of smooth pursuit closed-loop gain (Pearson r=0.72), antisaccade error rate ( r=0.73), saccade reaction time to correct antisaccade responses ( r=0.73), and prosaccade hypometria ( r=0.72) were observed. Lower reliabilities were obtained for smooth pursuit open-loop gain ( r=0.52) and prosaccade reaction time ( r=0.43). The results are supportive of the trait-like characteristics of particular forms of EMD in schizophrenia families and of the candidacy of EMD as an endophenotypic marker of schizophrenia.

The Study of Cytosolic Phospholipase A2 Gene Polymorphism in Schizophrenia Using Eye Movement Disturbances as an Endophenotypic Marker

Phospholipase A₂ (PLA2) is a key enzyme of the phospholipid metabolism which shows alteration in schizophrenia. Eye movement disturbances occur in a majority of patients with schizophrenia and in a proportion of their first-degree relatives, and they have been suggested as an endophenotypic marker in genetic studies of this illness. Here we report an association between the Ban I polymorphism of the cytosolic PLA2 gene (single nucleotide polymorphism in the first intron of the gene) and the intensity of eye movement disturbances (fixation and smooth pursuit) observed in 126 schizophrenic patients. The mean intensity of both kinds of eye movement disturbances was significantly higher in individuals homozygous for the A2 genotype compared with the remaining phenotypes. There was also a trend for greater A2 allele frequency in schizophrenic patients with a higher degree of eye movement disturbances. The relative frequency of the A2/A2 genotype was higher in patients with a greater degree of eye movement disturbances occurring during both fixation and smooth pursuit tests. Our results correspond to the other studies showing an association between the cPLA2 polymorphism and schizophrenia (predominance of the A2 allele in schizophrenic subjects).

Low olfactory bulb volume in first-degree relatives of patients with schizophrenia.

There is a substantial genetic contribution to schizophrenia but no way to readily identify individuals at risk. Biological abnormalities reflecting greater genetic vulnerability may be discovered by examining healthy family members of patients with schizophrenia. There is evidence that olfactory impairments are common in patients. The authors previously reported that patients have abnormal olfactory bulbs, assessed by magnetic resonance imaging (MRI). This study examined olfactory bulbs in patients' relatives to determine whether low bulb volume represents an endophenotypic marker of genetic vulnerability. Olfactory psychophysical measures and MRI scans of olfactory bulbs were acquired from 19 healthy first-degree relatives, 20 healthy comparison subjects with similar age and gender distributions, and the 11 patient probands of these relatives. Olfactory bulb volumes were measured by using a reliable region-of-interest procedure. The patients had impaired ability to detect odors and had lower olfactory bulb volumes than the comparison subjects. Although the family members had normal olfactory ability, they exhibited low right bulb volume. The patients had smaller left, but not right, olfactory bulbs than their own healthy relatives. The findings in family members suggest that structural abnormalities of the olfactory system in schizophrenia may partly reflect preexisting genetic vulnerability to illness. Preliminary analyses suggest that right olfactory bulb volume may serve as an endophenotypic marker of genetic vulnerability, while left bulb volume may reflect overt disease among individuals who share genetic vulnerability. Bulb abnormalities in patients are consistent with reports of cellular abnormalities affecting peripheral olfactory receptor neurons.