CNVs conferring risk of autism or schizophrenia affect cognition in controls.

In a small fraction of patients with schizophrenia or autism, alleles of copy-number variants (CNVs) in their genomes are probably the strongest factors contributing to the pathogenesis of the disease. These CNVs may provide an entry point for investigations into the mechanisms of brain function and dysfunction alike. They are not fully penetrant and offer an opportunity to study their effects separate from that of manifest disease. Here we show in an Icelandic sample that a few of the CNVs clearly alter fecundity (measured as the number of children by age 45). Furthermore, we use various tests of cognitive function to demonstrate that control subjects carrying the CNVs perform at a level that is between that of schizophrenia patients and population controls. The CNVs do not all affect the same cognitive domains, hence the cognitive deficits that drive or accompany the pathogenesis vary from one CNV to another. Controls carrying the chromosome 15q11.2 deletion between breakpoints 1 and 2 (15q11.2(BP1-BP2) deletion) have a history of dyslexia and dyscalculia, even after adjusting for IQ in the analysis, and the CNV only confers modest effects on other cognitive traits. The 15q11.2(BP1-BP2) deletion affects brain structure in a pattern consistent with both that observed during first-episode psychosis in schizophrenia and that of structural correlates in dyslexia.

Social and non-social measures of cognition for predicting self-reported and informant-reported functional outcomes in early psychosis.

The main aim of this study was to investigate the individual contributions of neurocognitive and social-cognitive domains to self-reported and informant-reported functional outcome in early psychosis. We also sought to further characterize the nature of cognitive impairments in this sample and explore the interrelationships between the social-cognitive measures and how they correlate with measures of neurocognition and clinical symptoms. In this study, 70 patients (mean age: 24.1; 87.1% males) with primary psychotic disorder diagnosed in the previous 5 years were assessed on multiple neurocognitive (processing speed, attention, working memory, immediate verbal memory, delayed recall, visual reasoning, inhibition, planning, cognitive flexibility), and social-cognitive domains (theory of mind (ToM), emotion recognition, attributional style, metacognitive overconfidence) as well as measures of clinical symptoms. Functional outcome was assessed with three self-reports and two informant-reports. On average, patients performed one or more SD below healthy controls on measures of delayed recall, ToM and metacognitive overconfidence. Emotion recognition and ToM were intercorrelated and correlated with multiple neurocognitive domains and negative symptoms. Attributional style correlated with positive symptoms. In the context of multiple variables, self-reported functional outcomes were predicted by attributional style, whereas emotion recognition and immediate verbal memory predicted variance in informant-reported community functioning. These results support the suggestion of a likely distinction between the predictive factors for self-reported and informant-reported functional outcome in early psychosis and suggest that consideration of self-assessment of functional outcome is critical when attempting to evaluate the effects attributional style has on functional disability.

Common variants conferring risk of schizophrenia.

Schizophrenia is a complex disorder, caused by both genetic and environmental factors and their interactions. Research on pathogenesis has traditionally focused on neurotransmitter systems in the brain, particularly those involving dopamine. Schizophrenia has been considered a separate disease for over a century, but in the absence of clear biological markers, diagnosis has historically been based on signs and symptoms. A fundamental message emerging from genome-wide association studies of copy number variations (CNVs) associated with the disease is that its genetic basis does not necessarily conform to classical nosological disease boundaries. Certain CNVs confer not only high relative risk of schizophrenia but also of other psychiatric disorders. The structural variations associated with schizophrenia can involve several genes and the phenotypic syndromes, or the 'genomic disorders', have not yet been characterized. Single nucleotide polymorphism (SNP)-based genome-wide association studies with the potential to implicate individual genes in complex diseases may reveal underlying biological pathways. Here we combined SNP data from several large genome-wide scans and followed up the most significant association signals. We found significant association with several markers spanning the major histocompatibility complex (MHC) region on chromosome 6p21.3-22.1, a marker located upstream of the neurogranin gene (NRGN) on 11q24.2 and a marker in intron four of transcription factor 4 (TCF4) on 18q21.2. Our findings implicating the MHC region are consistent with an immune component to schizophrenia risk, whereas the association with NRGN and TCF4 points to perturbation of pathways involved in brain development, memory and cognition.

Large recurrent microdeletions associated with schizophrenia.

Reduced fecundity, associated with severe mental disorders, places negative selection pressure on risk alleles and may explain, in part, why common variants have not been found that confer risk of disorders such as autism, schizophrenia and mental retardation. Thus, rare variants may account for a larger fraction of the overall genetic risk than previously assumed. In contrast to rare single nucleotide mutations, rare copy number variations (CNVs) can be detected using genome-wide single nucleotide polymorphism arrays. This has led to the identification of CNVs associated with mental retardation and autism. In a genome-wide search for CNVs associating with schizophrenia, we used a population-based sample to identify de novo CNVs by analysing 9,878 transmissions from parents to offspring. The 66 de novo CNVs identified were tested for association in a sample of 1,433 schizophrenia cases and 33,250 controls. Three deletions at 1q21.1, 15q11.2 and 15q13.3 showing nominal association with schizophrenia in the first sample (phase I) were followed up in a second sample of 3,285 cases and 7,951 controls (phase II). All three deletions significantly associate with schizophrenia and related psychoses in the combined sample. The identification of these rare, recurrent risk variants, having occurred independently in multiple founders and being subject to negative selection, is important in itself. CNV analysis may also point the way to the identification of additional and more prevalent risk variants in genes and pathways involved in schizophrenia.

Comparative study of machine learning methods for modeling associations between risk factors and future dementia cases.

A substantial portion of dementia risk can be attributed to modifiable risk factors that can be affected by lifestyle changes. Identifying the contributors to dementia risk could prove valuable. Recently, machine learning methods have been increasingly applied to healthcare data. Several studies have attempted to predict dementia progression by using such techniques. This study aimed to compare the performance of different machine-learning methods in modeling associations between known cognitive risk factors and future dementia cases. A subset of the AGES-Reykjavik Study dataset was analyzed using three machine-learning methods: logistic regression, random forest, and neural networks. Data were collected twice, approximately five years apart. The dataset included information from 1,491 older adults who underwent a cognitive screening process and were considered to have healthy cognition at baseline. Cognitive risk factors included in the models were based on demographics, MRI data, and other health-related data. At follow-up, participants were re-evaluated for dementia using the same cognitive screening process. Various performance metrics for all three machine learning algorithms were assessed. The study results indicate that a random forest algorithm performed better than neural networks and logistic regression in predicting the association between cognitive risk factors and dementia. Compared to more traditional statistical analyses, machine-learning methods have the potential to provide more accurate predictions about which individuals are more likely to develop dementia than others.

Blunted Cardiovascular Reactivity Predicts Worse Performance in Working Memory Tasks.

When we experience psychological challenges in the environment, our heart rate usually rises to make us more able to solve the task, but there is an individual difference in cardiovascular reactivity (CVR). Extreme CVR to environmental demands has been associated with worse health outcomes, with blunted CVR (little or no rise in heart rate) related to maladaptive behavior, including depression. The blunted CVR has been explained by motivational disengagement, which involves giving up on a task when facing obstacles. Disengagement is thought to be a habitual response that people might not be aware of, and, therefore, objective measures such as test performance might serve as a good measure of engagement. In this study, 66 participants solved different cognitive tasks while their CVR was measured. The aim was to test the association between test performance and reactivity, measured with the difference in heart rate at baseline and the mean heart rate while solving the tasks. Our results show a significant association between reactivity scores and performance in all tests, of various difficulty, indicating that blunted cardiovascular reactivity predicts poorer cognitive performance. Furthermore, we find an association between reactivity in one test and the performance in the other tests, suggesting that disengagement from environmental demands can be more general and not depend on the task at hand. The results, therefore, support earlier research suggesting that blunted CVR is associated with worse cognitive performance, and extends the literature by indicating that disengagement could be a more general maladaptive response to the environment.

Exposure factors associated with dementia among older adults in Iceland: the AGES-Reykjavik study.

The study aimed to assess whether factors related to cognitive performance were associated with the development of dementia. Additionally, the study aimed to establish whether cognitive performance at baseline or change in cognition between baseline and follow-up (five-year period) had a stronger association with whether an individual would fulfill a dementia criterion at follow-up. The data was collected from 2002 to 2011. Logistic regression was applied to the AGES-Reykjavik Study epidemiological data. The analysis, which builds upon previous data analyses of the same dataset, included 1,491 participants between the ages of 66 and 90. All those included were considered to have normal cognition at baseline; 8.2% (n = 123) of them fulfilled a dementia criterion at follow-up five years later. The study's results indicated that being high on cognitive reserve factors reduced the risk of developing dementia. Compared to other known dementia risk factors, cognitive reserve factors (education level, participation in leisure activities, and self-reported health) were more likely than others to have an association with dementia. Additionally, the study's findings showed that cognitive performance at baseline, rather than change in cognition between baseline and follow-up five years later, had a stronger association with dementia at the follow-up assessment. Together, these findings support the notion that promoting high cognitive reserve throughout the lifespan and reaching high cognitive performance is important in reducing dementia risk.

Cognition and brain health among older adults in Iceland: the AGES-Reykjavik study.

The paper aimed to compare how factors previously identified as predictive factors for cognitive decline and dementia related to cognitive performance on the one hand and brain health on the other. To that aim, multiple linear regression was applied to the AGES-Reykjavik study epidemiological data. Additionally, a regression analysis was performed for change in cognition over 5 years, using the same exposure factors. The study ran from 2002 to 2011, and the sample analyzed included 1707 participants between the ages of 66 and 90. The data contains MR imaging, cognitive testing, background data, and physiological measurements. Overall, we conclude that risk factors linked to dementia relate differently to cognition and brain health. Mobility, physical strength, alcohol consumption, coronary artery disease, and hypertension were associated with cognition and brain volume. Smoking, depression, diabetes, and body fat percentage were only associated with brain volume, not cognitive performance. Modifiable factors previously linked to cognitive reserve, such as educational attainment, participation in leisure activities, multilingualism and good self-reported health, were associated with cognitive function but did not relate to brain volume. These findings show that, within the same participant pool, cognitive reserve proxy variables have a relationship with cognitive performance but have no association with relative brain volume measured simultaneously.

Neuregulin-1 genotypes and eye movements in schizophrenia.

Neuregulin-1 (NRG-1) is a putative susceptibility gene for schizophrenia but the neurocognitive processes that may involve NRG-1 in schizophrenia are unknown. Deficits in antisaccade (AS) and smooth pursuit eye movements (SPEM) are promising endophenotypes, which may be associated with brain dysfunctions underlying the pathophysiology of schizophrenia. The aim of this study was to investigate the associations of NRG-1 genotypes with AS and SPEM in schizophrenia patients and healthy controls. Patients (N = 113) and controls (N = 106) were genotyped for two NRG-1 single nucleotide polymorphisms (SNPs); SNP8NRG222662, a surrogate marker for the originally described Icelandic NRG-1 risk haplotype, and SNP8NRG243177, which has recently been associated with individual differences in brain function. Subjects underwent infrared oculographic assessment of AS and SPEM. The study replicates previous findings of impaired AS and SPEM performance in schizophrenia patients (all P < 0.005; all d = 0.5-1.5). SNP8NRG243177 risk allele carriers had marginally increased variability of AS spatial error (P = 0.050, d = 0.3), but there were no significant genotype effects on other eye movement variables and no significant diagnosis-by-genotype interactions. Generally, risk allele carriers (G allele for SNP8NRG222662 and T allele for SNP8NRG243177) had numerically worse performance than non-carriers on most AS and SPEM variables. The results do not suggest that NRG-1 genotype significantly affects AS and SPEM task performance. However, the power of the sample to identify small effects is limited and the possibility of a type II error must be kept in mind. Larger samples may be needed to reliably investigate such gene effects on oculomotor endophenotypes.

Schizophrenia, cognition, and aging: cognitive deficits and the relationship between test performance and aging.

Most measures of cognitive function decline with age during adulthood. Research indicates that people with schizophrenia experience considerable cognitive deficits. These deficits appear to become more troublesome with increasing age, but this has been debated. The aim of this research was to better understand the age related cognitive deficits of Icelandic subjects with schizophrenia in comparison to healthy individuals. Cognition of individuals 18 to 64 years of age was evaluated with 10 neuropsychological tests. People with schizophrenia performed significantly worse on all tests, as expected, indicating widespread cognitive deficits compared to healthy individuals, independent of age. Furthermore, the results suggest that people with schizophrenia follow a similar age-related trajectory of cognitive decline as healthy individuals. Overall, we conclude that the cognitive difficulties often experienced by older people with schizophrenia are better explained by lower cognitive function at the time of diagnosis than by faster cognitive decline with increasing age.

Integrative cognitive remediation for early psychosis: A 12-month follow-up.

In recent years, a growing number of studies have attempted to treat social-cognitive impairment within neurocognitive remediation as means of improving outcome in psychotic disorders with promising results. However, the durability of the effects is still under debate and little is known about the long-term efficacy of integrated neuro- and social-cognitive remediation in early psychosis. The purpose of this study was to examine long-term effects of a 12-week integrative cognitive remediation (ICR) for early psychosis. Thirty-seven patients diagnosed with primary psychotic disorder and previously treated with ICR as part of their standard treatment were assessed on cognitive performance, psychopathology, and functional outcome at baseline, 3 months (posttest) and 12 months (follow-up). After participating in ICT, individuals showed significant improvements on most neurocognitive and social cognitive domains. A significant increase in number of participants employed was found at 12-month. The study suggests ICR may have favorable effect on long-term cognitive improvements and functional gains in early psychosis.

Case Report: Successful Implementation of Integrative Cognitive Remediation for Early Psychosis.

Many individuals demonstrate functionally relevant impairment in neurocognition as well as social cognition early on in the course of their psychotic disorder. There is robust evidence supporting cognitive remediation as an effective treatment of cognitive dysfunction in schizophrenia. Increasingly it is accepted that earlier treatment is associated with better outcome and that it is important to systematically assess and treat cognitive dysfunction before the cognitive and functional disabilities are fully realized. However, the clinical availability of these interventions remains sparse. As we move forward with implementing evidence-based interventions into multi-component treatment for early psychosis, it is important to reflect on experience as well as evidence. This case report aims to describe the implementation of an integrative cognitive remediation program in coordinated specialty care (CSC) for early psychosis in Iceland and investigate whether the intervention is sustainable in a CSC setting. Data on the number of patients treated, facilitators trained, groups conducted, and funding was used to assess the sustainability. The results show that since initial implementation in 2016, the intervention has been routinely available as part of standard care, with over 100 patients having received the treatment. The report discusses key factors in the successful implementation of the program.

P300 Analysis Using High-Density EEG to Decipher Neural Response to rTMS in Patients With Schizophrenia and Auditory Verbal Hallucinations.

Schizophrenia is a complex disorder about which much is still unknown. Potential treatments, such as transcranial magnetic stimulation (TMS), have not been exploited, in part because of the variability in behavioral response. This can be overcome with the use of response biomarkers. It has been however shown that repetitive transcranial magnetic stimulation (rTMS) can the relieve positive and negative symptoms of schizophrenia, particularly auditory verbal hallucinations (AVH). This exploratory work aims to establish a quantitative methodological tool, based on high-density electroencephalogram (HD-EEG) data analysis, to assess the effect of rTMS on patients with schizophrenia and AVH. Ten schizophrenia patients with drug-resistant AVH were divided into two groups: the treatment group (TG) received 1 Hz rTMS treatment during 10 daily sessions (900 pulses/session) over the left T3-P3 International 10-20 location. The control group (CG) received rTMS treatment over the Cz (vertex) EEG location. We used the P300 oddball auditory paradigm, known for its reduced amplitude in schizophrenia with AVH, and recorded high-density electroencephalography (HD-EEG, 256 channels), twice for each patient: pre-rTMS and 1 week post-rTMS treatment. The use of HD-EEG enabled the analysis of the data in the time domain, but also in the frequency and source-space connectivity domains. The HD-EEG data were linked with the clinical outcome derived from the auditory hallucinations subscale (AHS) of the Psychotic Symptom Rating Scale (PSYRATS), the Quality of Life Scale (QoLS), and the Depression, Anxiety and Stress Scale (DASS). The general results show a variability between subjects, independent of the group they belong to. The time domain showed a higher N1-P3 amplitude post-rTMS, the frequency domain a higher power spectral density (PSD) in the alpha and beta bands, and the connectivity analysis revealed a higher brain network integration (quantified using the participation coefficient) in the beta band. Despite the small number of subjects and the high variability of the results, this work shows a robust data analysis and an interplay between morphology, spectral, and connectivity data. The identification of a trend post-rTMS for each domain in our results is a first step toward the definition of quantitative neurophysiological parameters to assess rTMS treatment.

COMT val(158)met genotype and smooth pursuit eye movements in schizophrenia.

The association between the catechol-O-methyltransferase (COMT) val(158)met polymorphism (rs4680) and smooth pursuit eye movements (SPEM) was investigated in 110 schizophrenia patients and 96 controls. Patients had lower steady-state pursuit gain and made more frequent saccades than controls. Genotype was not associated with schizophrenia or SPEM, in either group or the combined sample. SPEM deficits in schizophrenia appear to be determined by genotypes other than rs4680, although the study may have lacked power to detect small effects.

Integrative cognitive remediation for early psychosis: Results from a randomized controlled trial.

Early application of cognitive remediation may help prevent the development of long-term functional impairments that characterize psychotic disorders. Interventions that encompass both neurocognitive and social-cognitive training may work synergistically to bridge the gap between cognitive gains and functional outcomes in early psychosis. We integrated three cognitive remediation approaches: Neuropsychological Educational Approach to Remediation (NEAR), Compensatory Cognitive Training (CCT), and Social Cognition and Interaction Training (SCIT), and evaluated the effects on cognition, clinical symptoms, self-assessed and informant-assessed social functioning in early psychosis. A total of 49 patients diagnosed with primary psychotic disorder seeking service at an early-intervention service in Iceland were randomized to either a waiting-list control group (n = 24) or a 12-week group-based integrative cognitive remediation (n = 25). Neurocognition, social cognition, community functioning and clinical symptoms were assessed at baseline and post-treatment. The intervention group showed significant improvements in verbal memory, cognitive flexibility, working memory, ToM and a significant reduction in hostile attributions, compared to those receiving standard treatment alone, but there were no differences between groups on measures of social functioning or clinical symptoms. The intervention was well tolerated and received high treatment satisfaction ratings. Findings indicate that integrated cognitive remediation has potential to improve neurocognition and social cognition in early psychosis.

Support for involvement of the AHI1 locus in schizophrenia.

Recently, markers in the Abelson Helper Integration Site 1 (AHI1) region were shown to be associated with schizophrenia in a family sample of Israeli-Arabs. Here, we report a study evaluating the relevance of the AHI1 region to schizophrenia in an Icelandic sample. Seven markers shown to confer risk in the previous report were typed in 608 patients diagnosed with broad schizophrenia and 1,504 controls. Odds ratios for the overtransmitted alleles in the Israeli-Arab families ranged from 1.15 to 1.29 in the Icelandic sample. After Bonferroni correction for the seven markers tested, two markers were significantly associated with schizophrenia. Thus, our results are in general agreement with the previous report, with the strongest association signal observed in a region upstream of the AHI1 gene.

Catechol-O-methyltransferase Val 158 Met polymorphism and antisaccade eye movements in schizophrenia.

The catechol-O-methyltransferase (COMT) enzyme catabolizes dopamine. The val(158)met single nucleotide polymorphism (rs4680) in the COMT gene has received considerable attention as a candidate gene for schizophrenia as well as for frontally mediated cognitive functions. Antisaccade performance is a good measure of frontal lobe integrity. Deficits on the task are considered a trait marker for schizophrenia. The aim of this study was to investigate the association of COMT val(158)met polymorphism with antisaccade eye movements in schizophrenia patients and healthy controls. Schizophrenia patients (N = 105) and healthy controls (N = 95) underwent infrared oculographic assessment of antisaccades. Subjects were genotyped for COMT val(158)met and divided into 3 groups according to genotype (val/val, val/met, and met/met). Patients displayed significantly more reflexive errors, longer and more variable latency, and lower amplitude gain than controls (all P < 0.02). A greater number of val(158) alleles was associated with shorter (P = 0.045) and less variable (P = 0.028) antisaccade latency and, nonsignificantly, with lower reflexive error rate (P = 0.056). None of these variables showed a group-by-genotype interaction (P > 0.1). There were no significant associations of genotype with measures of amplitude gain or spatial error (P > 0.2). The results suggest that COMT val(158) carrier status is associated with better performance on the antisaccade task. Possible explanations of this finding are discussed.

Eye movement deficits in schizophrenia: investigation of a genetically homogenous Icelandic sample.

BACKGROUND: Deficits in antisaccade (AS) and smooth pursuit eye movements (SPEM) are promising endophenotypes in genetic studies of schizophrenia. The Icelandic population lends itself ideally to genetic studies due to its ethnic homogeneity and well-documented genealogy. The primary aim of this study was to assess AS and SPEM performance in a large Icelandic sample. Additional aims were to investigate the relationship between AS and SPEM task performance and to assess internal consistency, within-session performance changes and effects of SPEM target velocity on performance. METHOD: Patients with schizophrenia (N = 118) and healthy controls (N = 109) matched for age and gender underwent infrared oculographic assessment of AS and SPEM (at target velocities of 12 degrees , 24 degrees and 36 degrees /s). RESULTS: On the AS task patients displayed significantly more reflexive errors, longer latency, increased intra-individual latency variability, and reduced amplitude gain compared to controls. On the SPEM task, patients had significantly lower velocity gain and more frequent saccades during pursuit at all velocities, but group differences in velocity gain increased with increasing target velocity. Internal consistency of performance was high for all variables in both groups (Cronbach's alpha >0.77 for AS and >0.85 for SPEM) except for AS spatial error in patients (alpha = 0.38). A moderate association was found between AS and SPEM performance. By and large, patients and controls showed similar patterns of systematic within-session performance changes. CONCLUSIONS: Our findings confirm the existence of robust eye movement deficits in schizophrenia in a large sample. These measures may be studied as endophenotypes in future studies of potential schizophrenia risk genotypes in the genetically homogenous Icelandic population.