Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways.

Susceptibility to schizophrenia is inversely correlated with general cognitive ability at both the phenotypic and the genetic level. Paradoxically, a modest but consistent positive genetic correlation has been reported between schizophrenia and educational attainment, despite the strong positive genetic correlation between cognitive ability and educational attainment. Here we leverage published genome-wide association studies (GWASs) in cognitive ability, education, and schizophrenia to parse biological mechanisms underlying these results. Association analysis based on subsets (ASSET), a pleiotropic meta-analytic technique, allowed jointly associated loci to be identified and characterized. Specifically, we identified subsets of variants associated in the expected ("concordant") direction across all three phenotypes (i.e., greater risk for schizophrenia, lower cognitive ability, and lower educational attainment); these were contrasted with variants that demonstrated the counterintuitive ("discordant") relationship between education and schizophrenia (i.e., greater risk for schizophrenia and higher educational attainment). ASSET analysis revealed 235 independent loci associated with cognitive ability, education, and/or schizophrenia at p < 5 × 10-8. Pleiotropic analysis successfully identified more than 100 loci that were not significant in the input GWASs. Many of these have been validated by larger, more recent single-phenotype GWASs. Leveraging the joint genetic correlations of cognitive ability, education, and schizophrenia, we were able to dissociate two distinct biological mechanisms-early neurodevelopmental pathways that characterize concordant allelic variation and adulthood synaptic pruning pathways-that were linked to the paradoxical positive genetic association between education and schizophrenia. Furthermore, genetic correlation analyses revealed that these mechanisms contribute not only to the etiopathogenesis of schizophrenia but also to the broader biological dimensions implicated in both general health outcomes and psychiatric illness.

Multi-Trait Analysis of GWAS and Biological Insights Into Cognition: A Response to Hill (2018).

Hill (Twin Research and Human Genetics, Vol. 21, 2018, 84-88) presented a critique of our recently published paper in Cell Reports entitled 'Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets' (Lam et al., Cell Reports, Vol. 21, 2017, 2597-2613). Specifically, Hill offered several interrelated comments suggesting potential problems with our use of a new analytic method called Multi-Trait Analysis of GWAS (MTAG) (Turley et al., Nature Genetics, Vol. 50, 2018, 229-237). In this brief article, we respond to each of these concerns. Using empirical data, we conclude that our MTAG results do not suffer from 'inflation in the FDR [false discovery rate]', as suggested by Hill (Twin Research and Human Genetics, Vol. 21, 2018, 84-88), and are not 'more relevant to the genetic contributions to education than they are to the genetic contributions to intelligence'.

Preventing Episodic Migraine With Caloric Vestibular Stimulation: A Randomized Controlled Trial.

OBJECTIVE: To evaluate the safety and efficacy of a novel solid-state, caloric vestibular stimulation (CVS) device to provide adjuvant therapy for the prevention of episodic migraine in adult migraineurs. BACKGROUND: Migraine causes significant disability in ∼12% of the world population. No current migraine preventive treatment provides full clinical relief, and many exhibit high rates of discontinuation due to adverse events. Thus, new therapeutic options are needed. CVS may be an effective and safe adjuvant-therapy for the prevention of episodic migraine. METHODS: In a multicenter, parallel-arm, block-randomized, placebo-controlled clinical trial (clinicaltrials.gov: NCT01899040), subjects completed a 3-month treatment with the TNM™ device for CVS (refer to Fig. 2 for patient enrollment and allocation). The primary endpoint was the change in monthly migraine days from baseline to the third treatment month. Secondary endpoints were 50% responder rates, change in prescription analgesic usage and difference in total subjective headache-related pain scores. Device safety assessments included evaluation of any impact on mood, cognition, or balance. RESULTS: Per-protocol, active-arm subjects showed immediate and continued steady declines in migraine frequency over the treatment period. After 3 months of treatment, active-arm subjects exhibited significantly fewer migraine days (-3.9 ± 0.6 from a baseline burden of 7.7 ± 0.5 migraine days). These improvements were significantly greater than those observed in control subjects (-1.1 ± 0.6 from a baseline burden = 6.9 ± 0.7 migraine days) and represented a therapeutic gain of -2.8 migraine days, CI = -0.9 to -4.7, P = .012. Active arm subjects also reported greater reductions in acute medication usage and monthly pain scores compared to controls. No adverse effects on mood, cognition, or balance were reported. Subjects completed the trial with an average rate of 90% treatment adherence. No serious or unexpected adverse events were recorded. The rate of expected adverse events was similar across the active and the placebo groups, and evaluation confirmed that subject blinding remained intact. CONCLUSION: The TNM™ device for CVS appears to provide a clinically efficacious and highly tolerable adjuvant therapy for the prevention of episodic migraine.

Depressive Symptoms and Risk of Postoperative Delirium.

OBJECTIVE: Previous studies have shown that elevated depressive symptoms are associated with increased risk of postoperative delirium. However, to our knowledge no previous studies have examined whether different components of depression are differentially predictive of postoperative delirium. METHODS: One thousand twenty patients were screened for postoperative delirium using the Confusion Assessment Method and through retrospective chart review. Patients underwent cognitive, psychosocial, and medical assessments preoperatively. Depression was assessed using the Geriatric Depression Scale-Short Form. RESULTS: Thirty-eight patients developed delirium (3.7%). Using a factor structure previously validated among geriatric medical patients, the authors examined three components of depression as predictors of postoperative delirium: negative affect, cognitive distress, and behavioral inactivity. In multivariate analyses controlling for age, education, comorbidities, and cognitive function, the authors found that greater behavioral inactivity was associated with increased risk of delirium (OR: 1.95 [1.11, 3.42]), whereas negative affect (OR: 0.65 [0.31, 1.36]) and cognitive distress (OR: 0.95 [0.63, 1.43]) were not. CONCLUSION: Different components of depression are differentially predictive of postoperative delirium among adults undergoing noncardiac surgery.

Genetic and environmental correlates of topiramate-induced cognitive impairment.

Topiramate is an antiepileptic drug that has marked treatment-limiting side effects on specific aspects of cognitive performance in both patients and healthy volunteers. Because these severe side effects occur only in certain individuals, identifying genetic or environmental variables that influence cognitive response would be of great utility in determining whether to administer this drug to a patient. We gave an acute 100 mg oral dose of topiramate to 158 healthy volunteers and measured how the drug changed their performance on a diverse battery of cognitive tests. We found a wide range of responses to topiramate, and we demonstrated that not all tests in the battery were equally affected. There was no correlation between the effect of topiramate and either education level or baseline cognitive performance. Of interest, there was an up to 55-fold variation in the topiramate plasma levels of the participants. Our genome-wide association study (GWAS) of cognitive response did not reveal any genome-wide significant associations; the study was powered to find variants explaining at least 25% of the variation in cognitive response. Combining the results of this GWAS with a retrospective study of cognitive complaints in 290 epilepsy patients who received topiramate as part of their treatment also did not result in a significant association. Our results support the need for additional genetic studies of topiramate that use larger sample sizes.

A genome-wide study of common SNPs and CNVs in cognitive performance in the CANTAB.

Psychiatric disorders such as schizophrenia are commonly accompanied by cognitive impairments that are treatment resistant and crucial to functional outcome. There has been great interest in studying cognitive measures as endophenotypes for psychiatric disorders, with the hope that their genetic basis will be clearer. To investigate this, we performed a genome-wide association study involving 11 cognitive phenotypes from the Cambridge Neuropsychological Test Automated Battery. We showed these measures to be heritable by comparing the correlation in 100 monozygotic and 100 dizygotic twin pairs. The full battery was tested in approximately 750 subjects, and for spatial and verbal recognition memory, we investigated a further 500 individuals to search for smaller genetic effects. We were unable to find any genome-wide significant associations with either SNPs or common copy number variants. Nor could we formally replicate any polymorphism that has been previously associated with cognition, although we found a weak signal of lower than expected P-values for variants in a set of 10 candidate genes. We additionally investigated SNPs in genomic loci that have been shown to harbor rare variants that associate with neuropsychiatric disorders, to see if they showed any suggestion of association when considered as a separate set. Only NRXN1 showed evidence of significant association with cognition. These results suggest that common genetic variation does not strongly influence cognition in healthy subjects and that cognitive measures do not represent a more tractable genetic trait than clinical endpoints such as schizophrenia. We discuss a possible role for rare variation in cognitive genomics.

Differential patterns of cognitive decline in anterior and posterior white matter hyperintensity progression.

BACKGROUND AND PURPOSE: White matter hyperintensities (WMHs) found on brain MRI in elderly individuals are largely thought to be due to microvascular disease, and its progression has been associated with cognitive decline. The present study sought to determine patterns of cognitive decline associated with anterior and posterior WMH progression. METHODS: Subjects included 110 normal controls, aged >or=60 years, who were participants in the Duke Neurocognitive Outcomes of Depression in the Elderly study. All subjects had comprehensive cognitive evaluations and MRI scans at baseline and after 2 years. Cognitive composites were created in 5 domains: complex processing speed, working memory, general memory, visual-constructional skills, and language. Change in cognition was calculated using standard regression-based models accounting for variables known to impact serial testing. A semiautomated segmentation method was used to measure WMH extent in anterior and posterior brain regions. Hierarchical multiple linear regression models were used to evaluate which of the 5 measured cognitive domains was most strongly associated with regional (anterior and posterior) and total WMH progression after adjusting for demographics (age, sex, and education). RESULTS: Decline in complex processing speed was independently associated with both anterior (r(2)=0.06, P=0.02) and total WMH progression (r(2)=0.05, P=0.04). In contrast, decline in visual-constructional skills was uniquely associated with posterior progression (r(2)=0.05, P<0.05). CONCLUSIONS: Distinct cognitive profiles are associated with anterior and posterior WMH progression among normal elders. These differing profiles need to be considered when evaluating the cognitive correlates of WMHs.

Surviving critical illness: acute respiratory distress syndrome as experienced by patients and their caregivers.

OBJECTIVE: To characterize the effects of critical illness in the daily lives and functioning of acute respiratory distress syndrome survivors. Survivors of acute respiratory distress syndrome, a systemic critical illness, often report poor quality of life based on responses to standardized questionnaires. However, the experiences of acute respiratory distress syndrome survivors have not been reported. DESIGN: We conducted semistructured interviews with 23 acute respiratory distress syndrome survivors and 24 caregivers 3 to 9 mos after intensive care unit admission, stopping enrollment after thematic saturation was reached. Transcripts were analyzed, using Colaizzi's qualitative methodology, to identify significant ways in which survivors' critical illness experience impacted their lives. SETTING: Medical and surgical intensive care units of an academic medical center and a community hospital. PATIENTS: We recruited consecutively 31 acute respiratory distress syndrome survivors and their informal caregivers. Eight patients died before completing interviews. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Participants related five key elements of experience as survivors of acute respiratory distress syndrome: 1) pervasive memories of critical care; 2) day-to-day impact of new disability; 3) critical illness defining the sense of self; 4) relationship strain and change; and 5) ability to cope with disability. Survivors described remarkable disability that persisted for months. Caregivers' interviews revealed substantial strain from caregiving responsibilities as well as frequent symptom minimization by patients. CONCLUSIONS: The diverse and unique experiences of acute respiratory distress syndrome survivors reflect the global impact of severe critical illness. We have identified symptom domains important to acute respiratory distress syndrome patients who are not well represented in existing health outcomes measures. These insights may aid the development of targeted interventions to enhance recovery and return of function after acute respiratory distress syndrome.

Executive function and depression as independent risk factors for postoperative delirium.

BACKGROUND: Postoperative delirium has been associated with greater complications, medical cost, and increased mortality during hospitalization. Recent evidence suggests that preoperative executive dysfunction and depression may predict postoperative delirium; however, the combined effect of these risk factors remains unknown. This study examined the association among preoperative executive function, depressive symptoms, and established clinical predictors of postoperative delirium among 998 consecutive patients undergoing major noncardiac surgery. METHODS: A total of 998 patients were screened for postoperative delirium (n = 998) using the Confusion Assessment Method as well as through retrospective chart review. Patients underwent cognitive, psychosocial, and medical assessments preoperatively. Executive function was assessed using the Concept Shifting Task, Letter-Digit Coding, and a modified Stroop Color Word Interference Test. Depression was assessed by the Beck Depression Inventory. RESULTS: Preoperative executive dysfunction (P = 0.007) and greater levels of depressive symptoms (P = 0.049) were associated with a greater incidence of postoperative delirium, independent of other risk factors. Secondary analyses of cognitive performance demonstrated that the Stroop Color Word Interference Test, the executive task with the greatest complexity in this battery, was more strongly associated with postoperative delirium than simpler tests of executive function. Furthermore, patients exhibiting both executive dysfunction and clinically significant levels of depression were at greatest risk for developing delirium postoperatively. CONCLUSIONS: Preoperative executive dysfunction and depressive symptoms are predictive of postoperative delirium among noncardiac surgical patients. Executive tasks with greater complexity are more strongly associated with postoperative delirium relative to tests of basic sequencing.

Measures of executive function and depression identify patients at risk for postoperative delirium.

BACKGROUND: Postoperative delirium is associated with increased morbidity and mortality. Preexisting cognitive impairment and depression have been frequently cited as important risk factors for this complication. This prospective cohort study was designed to determine whether individuals who perform poorly on preoperative cognitive tests and/or exhibited depressive symptoms would be at high risk for the development of postoperative delirium. METHODS: One hundred nondemented patients, aged 50 yr and older, scheduled to undergo major, elective noncardiac surgery completed a preoperative test battery that included measures of global cognition, executive function, and symptoms of depression. Known preoperative risk factors for delirium were collected and examined with the results of the preoperative test battery to determine the independent predictors of delirium. RESULTS: The overall incidence of delirium was 16% and was associated with increased hospital duration of stay (P < 0.05) and an increased incidence of postoperative complications (P < 0.01). Delirious subjects did not differ from their nondelirious cohorts with regard to their preoperative global cognitive function, preexisting medical comorbidities, age, anesthetic management, or history of alcohol use. Preoperative executive scores (P < 0.001) and depression (P < 0.001), as measured by the Trail Making B test and Geriatric Depression Scale-Short Form, respectively, were found to be independent predictors of postoperative delirium. CONCLUSIONS: Low preoperative executive scores and depressive symptoms independently predict postoperative delirium in older individuals. A rapid, simple test combination including tests of executive function and depression could improve physicians' ability to recognize patients who might benefit from a perioperative intervention strategy to prevent postoperative delirium.

Neurocognitive correlates of response to treatment in late-life depression.

UNLABELLED: Depression is often associated with neurocognitive deficits in older adults, particularly in the domains of information processing speed, episodic memory, and executive functions. Greater neurocognitive dysfunction while depressed is associated with a less effective treatment response; however, questions remain about the specific variables that characterize patients showing low treatment response and persistent cognitive deficiencies. OBJECTIVES: The authors examined neurocognitive variables that differentiated patients who showed robust versus weak responses to antidepressant therapy. PARTICIPANTS: The baseline sample included 110 women and 67 men, with a mean age of 69.1 years (SD = 6.9) and mean education of 14 years (SD = 3.3). DESIGN: Patients enrolled in a treatment study completed both a structured diagnostic assessment for depression and neuropsychological testing at study entry and 1-year follow-up. MEASUREMENTS: Clinicians rated patient depression using the Montgomery-Asberg Depression Rating Scale. Neuropsychological assessments consisted of prose recall and percent retention (Wechsler Memory Scale -III Logical Memory), word-list recall, attention and visuomotor processing speed (Trail Making A, Symbol Digit Modalities Test), and mental flexibility (Trail Making B). INTERVENTIONS: Patients underwent treatment for depression following the guidelines of the Duke Somatic Treatment Algorithm for Geriatric Depression approach. RESULTS: Individuals who demonstrated the greatest improvement in mood symptoms at follow-up exhibited better prose recall and faster processing speed at baseline than individuals who demonstrated weaker treatment responses. These differences remained after controlling for depression severity at both time-points. CONCLUSION: The current results suggest that better pretreatment cognitive function, particularly in verbal memory, is associated with a greater treatment response in late-life depression.

An efficient screening tool for preoperative depression: the Geriatric Depression Scale-Short Form.

BACKGROUND: Depression is highly prevalent in patients before surgery, and it has been widely shown to have a serious impact on their postoperative outcomes. It would therefore be desirable for physicians to obtain a quick, simple screen to evaluate depression to consider treatment of symptomatology and potentially optimize postoperative outcomes. METHODS: In this study, we investigated the prevalence of depression in a presurgical inpatient sample undergoing major, noncardiac surgery. In addition, we sought to establish the Geriatric Depression Scale-Short Form (GDS-SF) as a valid screening tool for depression by examining its relationship to the Beck Depression inventory (BDI) by age and gender. RESULTS: In our sample of 1043 presurgical candidates, prevalence of depression as established by the BDI was significantly higher than rates consistently found in healthy community samples. Depression was more common in women than in men (P = 0.02), and depression rates were lower in elders relative to middle-aged and younger groups (P = 0.003 and 0.003, respectively). In addition, we found that there was a high correlation between the BDI and the GDS-SF within each of the age groups. CONCLUSIONS: These data further support the need for depression screens in presurgical populations and establish the validity of the GDS-SF as a valid quick assessment alternative available to physicians.

Failure to replicate effect of Kibra on human memory in two large cohorts of European origin.

It was recently suggested that the Kibra polymorphism rs17070145 has a strong effect on multiple episodic memory tasks in humans. We attempted to replicate this using two cohorts of European genetic origin (n = 319 and n = 365). We found no association with either the original SNP or a set of tagging SNPs in the Kibra gene with multiple verbal memory tasks, including one that was an exact replication (Auditory Verbal Learning Task, AVLT). These results suggest that Kibra does not have a strong and general effect on human memory.

Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets.

Here, we present a large (n = 107,207) genome-wide association study (GWAS) of general cognitive ability ("g"), further enhanced by combining results with a large-scale GWAS of educational attainment. We identified 70 independent genomic loci associated with general cognitive ability. Results showed significant enrichment for genes causing Mendelian disorders with an intellectual disability phenotype. Competitive pathway analysis implicated the biological processes of neurogenesis and synaptic regulation, as well as the gene targets of two pharmacologic agents: cinnarizine, a T-type calcium channel blocker, and LY97241, a potassium channel inhibitor. Transcriptome-wide and epigenome-wide analysis revealed that the implicated loci were enriched for genes expressed across all brain regions (most strongly in the cerebellum). Enrichment was exclusive to genes expressed in neurons but not oligodendrocytes or astrocytes. Finally, we report genetic correlations between cognitive ability and disparate phenotypes including psychiatric disorders, several autoimmune disorders, longevity, and maternal age at first birth.

A comparison of the Cambridge Automated Neuropsychological Test Battery (CANTAB) with "traditional" neuropsychological testing instruments.

The Cambridge Neuropsychological Test Automated Battery (CANTAB) is frequently used in research protocols and increasingly in clinical practice. Despite the frequency of its use, important aspects of its measurement validity have yet to be established in healthy adults. Two hundred and fifty-five individuals completed the CANTAB and traditional neuropsychological tests commonly used in clinical practice, including selected subtests from the Wechsler Adult Intelligence Scale, Controlled Oral Word Association Test, Animal Naming, Trail Making Tests A and B, the Stroop test, and the Green Story Recall test. Results showed that CANTAB subtests were modestly correlated with traditional subtests. Correlations between CANTAB subtests and traditional subtests were less consistent when age and education were controlled for. In conclusion, the CANTAB shows modest associations with traditional neuropsychological test measures.

Contribution of pastimes and testing strategies to the performance of healthy volunteers on cognitive tests.

Clinicians routinely query factors known to impact cognitive test scores, including age and education. However, without data delineating the impact of less-frequently tracked variables, clinicians are limited to educated inferences about their effect. We explored the relationship of demographics, pastimes, and strategies with cognitive scores in a sample of 499 healthy young volunteers. As expected, age, education, ethnicity, and native language were strongly associated with most tests, while gender and dysphoria were associated with only some. Interestingly, pastimes such as playing number games and word games, and doing activities similar to the tests, were strongly associated with many measures, and testing strategies with almost all. Importantly, at least an additional 50% of the variation in Digit Span Backward and Animals scores was explained by adding covariates about pastimes and strategies to demographic covariates. These results support the utility of querying these elements.

Increasing awareness of clinical neuropsychology in the general public.

We can only benefit from raising public awareness about the unique role of clinical neuropsychology in patient care and clinical research. Public awareness of the distinctive skills of our practitioners and researchers and the utility of our products may well be linked to our viability as a field given the current healthcare and funding climates. This article discusses the goals of public awareness efforts for clinical neuropsychology, and outlines current resources that can be utilized toward this end. We review the process of creating new public awareness resources and discuss ideas for how practitioners can become involved public awareness efforts. We consider some of the many issues driving the need for public awareness activities and resources, highlight the need for practitioners and professional organizations to be self-advocates, and hope to inspire our field to the very feasible process of integrating public awareness efforts into professional practice.

Official position of the American Academy of Clinical Neuropsychology on serial neuropsychological assessments: the utility and challenges of repeat test administrations in clinical and forensic contexts.

Serial assessments are now common in neuropsychological practice, and have a recognized value in numerous clinical and forensic settings. These assessments can aid in differential diagnosis, tracking neuropsychological strengths and weaknesses over time, and managing various neurologic and psychiatric conditions. This document provides a discussion of the benefits and challenges of serial neuropsychological testing in the context of clinical and forensic assessments. Recommendations regarding the use of repeated testing in neuropsychological practice are provided.

Diversity Summit 2008: challenges in the recruitment and retention of ethnic minorities in neuropsychology.

The 2008 Diversity Summit recognized the many advantages of increasing the number of neuropsychologists from ethnically diverse backgrounds. The Summit addressed the aspiration of creating a more ethnically diverse body of neuropsychologists by increasing the recruitment of ethnic minority students to neuropsychology training programs. Challenges to successful recruitment and retention of ethnic minority students were discussion points at the Summit. This paper summarizes and expands these points and also suggests solutions to these challenges with the aim of stimulating innovative approaches to increasing the representation of ethnic minorities in neuropsychology.

Common genetic variation and performance on standardized cognitive tests.

One surprising feature of the recently completed waves of genome-wide association studies is the limited impact of common genetic variation in individually detectable polymorphisms on many human traits. This has been particularly pronounced for studies on psychiatric conditions, which have failed to produce clear, replicable associations for common variants. One popular explanation for these negative findings is that many of these traits may be genetically heterogeneous, leading to the idea that relevant endophenotypes may be more genetically tractable. Aspects of cognition may be the most important endophenotypes for psychiatric conditions such as schizophrenia, leading many researchers to pursue large-scale studies on the genetic contributors of cognitive performance in the normal population as a surrogate for aspects of liability to disease. Here, we perform a genome-wide association study with two tests of executive function, Digit Symbol and Stroop Color-Word, in 1086 healthy volunteers and with an expanded cognitive battery in 514 of these volunteers. We show that, consistent with published studies of the psychiatric conditions themselves, no single common variant has a large effect (explaining >4-8% of the population variation) on the performance of healthy individuals on standardized cognitive tests. Given that these are important endophenotypes, our work is consistent with the idea that identifying rare genetic causes of psychiatric conditions may be more important for future research than identifying genetically homogenous endophenotypes.