Deborah K. Attix

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.

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.

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.

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.

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.

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.

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.

A homopolymer polymorphism in the TOMM40 gene contributes to cognitive performance in aging

A highly polymorphic T homopolymer was recently found to be associated with late‐onset Alzheimers disease risk and age of onset.

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.

THE PREDICTION OF CHANGE: NORMATIVE NEUROPSYCHOLOGICAL TRAJECTORIES

While the application of normative standards is vital to the practice of clinical neuropsychology, data regarding normative change remains scarce despite the frequency of serial assessments. Based on 285 normal individuals, we provide co-normed baseline data with demographic adjustments and test-retest standardized regression based (SRB) models for three time points for several measures. These models delineate normal, expected change across time, and yield standardized z-scores that are comparable across tests. Using a new approach, performance on any previous trial was accounted for in the subsequent models of change, yielding serial normative formulas that model change trajectories rather than simple change from point to point. These equations provide indices of deviation from expected baseline and change for use in clinical or research settings.