Investigation of genetic determinants of cognitive change in later life.

Cognitive decline is a major health concern and identification of genes that may serve as drug targets to slow decline is important to adequately support an aging population. Whilst genetic studies of cross-sectional cognition have been carried out, cognitive change is less well-understood. Here, using data from the TOMMORROW trial, we investigate genetic associations with cognitive change in a cognitively normal older cohort. We conducted a genome-wide association study of trajectories of repeated cognitive measures (using generalised estimating equation (GEE) modelling) and tested associations with polygenic risk scores (PRS) of potential risk factors. We identified two genetic variants associated with change in attention domain scores, rs534221751 (p = 1 × 10-8 with slope 1) and rs34743896 (p = 5 × 10-10 with slope 2), implicating NCAM2 and CRIPT/ATP6V1E2 genes, respectively. We also found evidence for the association between an education PRS and baseline cognition (at >65 years of age), particularly in the language domain. We demonstrate the feasibility of conducting GWAS of cognitive change using GEE modelling and our results suggest that there may be novel genetic associations for cognitive change that have not previously been associated with cross-sectional cognition. We also show the importance of the education PRS on cognition much later in life. These findings warrant further investigation and demonstrate the potential value of using trial data and trajectory modelling to identify genetic variants associated with cognitive change.

A Neurofunctional Domains Approach to Evaluate D1/D5 Dopamine Receptor Partial Agonism on Cognition and Motivation in Healthy Volunteers With Low Working Memory Capacity.

BACKGROUND: Dopamine D1 receptor signaling plays key roles in core domains of neural function, including cognition and reward processing; however, many questions remain about the functions of circuits modulated by dopamine D1 receptor, largely because clinically viable, selective agonists have yet to be tested in humans. METHODS: Using a novel, exploratory neurofunctional domains study design, we assessed the safety, tolerability, pharmacodynamics, and pharmacokinetics of PF-06412562, a selective D1/D5R partial agonist, in healthy male volunteers who met prespecified criteria for low working memory capacity. Functional magnetic resonance imaging, electrophysiologic endpoints, and behavioral paradigms were used to assess working memory, executive function, and motivation/reward processing following multiple-dose administration of PF-06412562. A total of 77 patients were assigned PF-06412562 (3 mg twice daily and 15 mg twice daily) or placebo administered for 5 to 7 days. Due to the exploratory nature of the study, it was neither powered for any specific treatment effect nor corrected for multiple comparisons. RESULTS: Nominally significant improvements from baseline in cognitive endpoints were observed in all 3 groups; however, improvements in PF-06412562-treated patients were less than in placebo-treated participants. Motivation/reward processing endpoints were variable. PF-06412562 was safe and well tolerated, with no serious adverse events, severe adverse events, or adverse events leading to dose reduction or temporary discontinuation except for 1 permanent discontinuation due to increased orthostatic heart rate. CONCLUSIONS: PF-06412562, in the dose range and patient population explored in this study, did not improve cognitive function or motivation/reward processing more than placebo over the 5- to 7-day treatment period. CLINICALTRIALS.GOV IDENTIFIER: NCT02306876.

Computerized assessment of cognitive impairment among children undergoing radiation therapy for medulloblastoma.

PURPOSE: Advantages to computerized cognitive assessment include increased precision of response time measurement and greater availability of alternate forms. Cogstate is a computerized cognitive battery developed to monitor attention, memory, and processing speed. Although the literature suggests the domains assessed by Cogstate are areas of deficit in children undergoing treatment for medulloblastoma, the validity of Cogstate in this population has not been previously investigated. METHODS: Children participating in an ongoing prospective trial of risk-adapted therapy for newly diagnosed medulloblastoma (n = 73; mean age at baseline = 12.1 years) were administered Cogstate at baseline (after surgery, prior to adjuvant therapy) and 3 months later (6 weeks after completion of radiation therapy). Gold-standard neuropsychological measures of similar functions were administered at baseline. RESULTS: Linear mixed models revealed performance within age expectations at baseline across Cogstate tasks. Following radiation therapy, there was a decline in performance on Cogstate measures of reaction time (Identification and One Back). Females exhibited slower reaction time on One Back and Detection tasks at baseline. Higher-dose radiation therapy and younger age were associated with greater declines in performance. Pearson correlations revealed small-to-moderate correlations between Cogstate reaction time and working memory tasks with well-validated neuropsychological measures. CONCLUSIONS: Cogstate is sensitive to acute cognitive effects experienced by some children with medulloblastoma and demonstrates associations with clinical predictors established in the literature. Correlations with neuropsychological measures of similar constructs offer additional evidence of validity. The findings provide support for the utility of Cogstate in monitoring acute cognitive effects in pediatric cancer.

Relating constructs of attention and working memory to social withdrawal in Alzheimer's disease and schizophrenia: issues regarding paradigm selection.

Central nervous system diseases are not currently diagnosed based on knowledge of biological mechanisms underlying their symptoms. Greater understanding may be offered through an agnostic approach to traditional disease categories, where learning more about shared biological mechanisms across conditions could potentially reclassify sub-groups of patients to allow realisation of more effective treatments. This review represents the output of the collaborative group "PRISM", tasked with considering assay choices for assessment of attention and working memory in a transdiagnostic cohort of Alzheimer's disease and schizophrenia patients exhibiting symptomatic spectra of social withdrawal. A multidimensional analysis of this nature has not been previously attempted. Nominated assays (continuous performance test III, attention network test, digit symbol substitution, N-back, complex span, spatial navigation in a virtual environment) reflected a necessary compromise between the need for broad assessment of the neuropsychological constructs in question with several pragmatic criteria: patient burden, compatibility with neurophysiologic measures and availability of preclinical homologues.

A pilot evaluation of a computer-based psychometric test battery designed to detect impairment in patients with cirrhosis.

BACKGROUND: Psychometric testing is used to identify patients with cirrhosis who have developed hepatic encephalopathy (HE). Most batteries consist of a series of paper-and-pencil tests, which are cumbersome for most clinicians. A modern, easy-to-use, computer-based battery would be a helpful clinical tool, given that in its minimal form, HE has an impact on both patients' quality of life and the ability to drive and operate machinery (with societal consequences). AIM: We compared the Cogstate™ computer battery testing with the Psychometric Hepatic Encephalopathy Score (PHES) tests, with a view to simplify the diagnosis. METHODS: This was a prospective study of 27 patients with histologically proven cirrhosis. An analysis of psychometric testing was performed using accuracy of task performance and speed of completion as primary variables to create a correlation matrix. A stepwise linear regression analysis was performed with backward elimination, using analysis of variance. RESULTS: Strong correlations were found between the international shopping list, international shopping list delayed recall of Cogstate and the PHES digit symbol test. The Shopping List Tasks were the only tasks that consistently had P values of <0.05 in the linear regression analysis. CONCLUSION: Subtests of the Cogstate battery correlated very strongly with the digit symbol component of PHES in discriminating severity of HE. These findings would indicate that components of the current PHES battery with the international shopping list tasks of Cogstate would be discriminant and have the potential to be used easily in clinical practice.

Feasibility of baseline neurocognitive assessment using Cogstate during the first month of therapy for childhood leukemia.

PURPOSE: Neurocognitive impairment is frequently observed among acute lymphoblastic leukemia (ALL) survivors within the domains of intelligence, attention, processing speed, working memory, learning, and memory. However, few have investigated treatment-induced changes in neurocognitive function during the first months of treatment. Additionally, dysfunction during treatment may be preceded by changes in biomarkers measured within cerebrospinal fluid (CSF). Identification of acute declines in neurocognitive function, as well as predictive genotypes or biomarkers, could guide therapeutic trials of protective interventions. METHODS: This study collects CSF while prospectively assessing neurocognitive functioning (working memory, executive function, learning, processing speed, and attention) of ALL patients using the Cogstate computerized battery at six time points during and after the 2 years of leukemia treatment on a Dana-Farber Cancer Institute ALL Consortium trial. RESULTS: Baseline data collected during the first 3 weeks of induction chemotherapy indicate reliable data as all subjects (N = 34) completed Cogstate baseline testing, while completion and performance checks indicate that 100 % of subjects completed testing and complied with test requirements. The majority (85 %) exhibited normal function compared with age peers. Preliminary analysis of CSF biomarkers (folate, homocysteine, 8-isoprostane, and myelin basic protein) similarly reveals values at baseline within expected normal ranges. CONCLUSIONS: The first month of induction therapy for ALL is a reliable baseline for detecting treatment-induced changes in neurocognitive functioning. Consequently, serial data collection might identify subgroups of ALL patients at increased risk for neurocognitive decline, warranting proactive interventions to improve their level of functioning both during treatment and into survivorship.

Cognitive evolution in natalizumab-treated multiple sclerosis patients.

BACKGROUND: Cognitive dysfunction affects up to 65% of multiple sclerosis (MS) patients and progresses over time. Natalizumab has been shown to be superior to placebo in preserving cognition for the first two years of therapy. OBJECTIVES: The objectives of this study are to understand the impact of natalizumab on cognition beyond two years of therapy and to investigate whether baseline characteristics are predictive of clinical response. METHODS: This is a single-center, 24-month, observational study. Sixty-three patients treated with natalizumab were assessed prior to monthly infusions using a Cogstate battery and the Symbol Digit Modalities Test (SDMT). Patient demographics were collected at baseline. A linear mixed model was conducted with duration of natalizumab therapy as a between-subjects factor (≤2 or >2 years), assessment as a within-subjects factor, and Multiple Sclerosis Severity Score (MSSS) as a covariate. RESULTS: Aside from the MSSS (p = 0.0074), the two groups were identical. No patient showed evidence of sustained cognitive deterioration over the 24-month period. Baseline parameters including impaired cognition did not influence the trajectory of cognitive change over 24 months. CONCLUSIONS: Our results suggest that natalizumab preserves cognition following four to seven years of continuous therapy. This occurs irrespective of baseline characteristics, including impaired cognition.

Neurocognitive Changes after Sustained Ketamine Administration in Children with Chronic Pain.

INTRODUCTION: Ketamine has received attention recently as an agent for chronic pain. There are concerns, however, regarding the neurocognitive changes patients might experience after ketamine exposure. METHODS: This prospective, uncontrolled study describes the neurocognitive functioning of 11 children with chronic pain before and after 2 weeks of daily oral ketamine exposure. Neurocognitive assessment was performed at baseline, Week 2, and Week 14. We hypothesized that there would be declines in neurocognitive scores at either Week 2 or Week 14. RESULTS: No decline in neurocognitive function was detected in the children investigated. Mean scores for tests measuring executive function and memory were improved at Weeks 2 and 14 compared to baseline. DISCUSSION: This study did not detect any decline in neurocognitive scores in a small number of children exposed to 2 weeks of oral ketamine therapy. Randomized, controlled studies of the neurocognitive effects of ketamine in children are recommended to further investigate these preliminary findings.

Simultaneous Treatment of Neurocognitive and Psychiatric Symptoms in Veterans with Post-Traumatic Stress Disorder and History of Mild Traumatic Brain Injury: A Pilot Study of Mindfulness-Based Stress Reduction.

Treating patient populations with significant psychiatric and neurocognitive symptomatology can present a unique clinical dilemma: progress in psychotherapy can be significantly fettered by cognitive deficits, whereas neurocognitive rehabilitation efforts can be ineffective because of psychiatric overlay. Application of mindfulness-based interventions to address either cognitive or psychiatric symptoms in isolation appears efficacious in many contexts; however, it remains unclear whether this type of intervention might help address simultaneous neurocognitive and psychiatric symptomatology. In a pre-post mixed methods design pilot study, nine Veterans with post-traumatic stress disorder (PTSD) and a history of mild traumatic brain injury with chronic cognitive complaints participated in Mindfulness-Based Stress Reduction (MBSR). Clinical interview, questionnaires, and attention and PTSD measures were administered immediately before, immediately after, and 3 months after MBSR completion. Qualitative and quantitative findings suggest high levels of safety, feasibility, and acceptability. Measurement of attention revealed significant improvement immediately following MBSR (p < 0.05, d = 0.57) and largely sustained improvement 3 months after completion of MBSR (p < 0.10, d = 0.48). Significant reduction in PTSD symptoms was found immediately after MBSR (p < 0.05, d = -1.56), and was sustained 3 months following MBSR completion (p < 0.05, d = -0.93). These results warrant a randomized controlled trial follow-up. Potential mechanisms for the broad effects observed will be explored.

Comparison of Cognitive Performance on the Cogstate Brief Battery When Taken In-Clinic, In-Group, and Unsupervised.

OBJECTIVE: Repeat cognitive assessment comparing post-injury performance to a pre-injury baseline is common in concussion management. Although post-injury tests are typically administered in clinical settings, baseline tests may be conducted individually with one-on-one supervision, in a group with supervision, or without supervision. The extent to which these different test settings affect cognitive performance is not well understood. To assess if performance on the Cogstate Brief Battery (CBB) differs across these settings, tests completed individually with one-on-one supervision were compared to those taken either in a group with supervision or individually but without supervision. METHOD: A crossover study design was utilized to account for any effect of individual variability or test order to provide an unbiased examination of the effect of test setting on cognitive performance. Young adult participants completed an individually supervised test either before or after also completing a group or unsupervised test. RESULTS: CBB scores from the same individuals were not significantly different across test settings. Effect sizes ranged in magnitude from .09 to .12 for supervised versus unsupervised tests and from .01 to .37 for individual versus group tests across CBB tasks. CONCLUSION: These results suggest that cognitive testing with the CBB in alternate settings can provide valid cognitive data comparable to data obtained during individually supervised testing.

The nature and rate of cognitive maturation from late childhood to adulthood.

To better understand the nature and rate of cognitive change across adolescence, the Cogstate Brief Battery (CBB) was utilized to assess psychomotor function, attention, working memory, and visual learning in individuals aged 10-18 years old. Since all CBB tasks have equivalent perceptual, motor, and linguistic demands as well as being appropriate for both children and adults, this approach allowed direct across-age comparison of multiple cognitive domains. Exponential decreases in reaction time and linear increases in accuracy were observed across adolescent development in a cross-sectional sample of 38,778 individuals and confirmed in a 5788 individual longitudinal sample with 1-year repeat assessments. These results have important implications for the repeated assessment of cognition during development where expected maturational changes in cognition must be accounted for during cognitive testing.

The development of associate learning in school age children.

Associate learning is fundamental to the acquisition of knowledge and plays a critical role in the everyday functioning of the developing child, though the developmental course is still unclear. This study investigated the development of visual associate learning in 125 school age children using the Continuous Paired Associate Learning task. As hypothesized, younger children made more errors than older children across all memory loads and evidenced decreased learning efficiency as memory load increased. Results suggest that age-related differences in performance largely reflect continued development of executive function in the context of relatively developed memory processes.

Subjective memory complaints, cognitive performance, and psychological factors in healthy older adults.

OBJECTIVE: To determine whether subjective memory complaints (SMCs) are associated with performance on objective cognitive measures and psychological factors in healthy, community-dwelling older adults. METHOD: The cohort was composed of adults, 65 years and older with no clinical evidence of cognitive impairment (n = 125). Participants were administered: CogState computerized neurocognitive battery, Prospective Retrospective Memory Questionnaire, personality and meaning-in-life measures. RESULTS: SMCs were associated with poorer performance on measures of executive function (p = 0.001). SMCs were also associated with impaired delayed recall (p = 0.006) but this did not remain significant after statistical adjustment for multiple comparisons. SMCs were inversely associated with conscientiousness (p = 0.004) and directly associated with neuroticism (p < 0.001). Higher scores on SMCs were associated with higher perceived stress (p = 0.001), and ineffective coping styles (p = 0.001). Factors contributing to meaning-in-life were associated with fewer SMCs (p < 0.05). CONCLUSIONS: SMCs may reflect early, subtle cognitive changes and are associated with personality traits and meaning-in-life in healthy, older adults.

Effect of cholinergic neurotransmission modulation on visual spatial paired associate learning in healthy human adults.

RATIONALE: Use of cross-species neuropsychological paradigms such as visual-spatial paired associate learning (PAL) may allow for a better understanding of underlying neural substrates of memory. Such paradigms, which are often used to guide models of memory in animals, can then be carried forward into humans to provide a basis for evaluation of pharmacologic compounds designed to ameliorate learning and memory impairments in neurologic and psychiatric morbidities. OBJECTIVES: This double-blind, randomized, crossover trial investigated effects of donepezil, an acetylcholinesterase (AChE) inhibitor, in attenuating scopolamine-induced cognitive impairment using a novel, "process-based" computerized measure of visual-spatial PAL. RESULTS: In healthy male volunteers, scopolamine (0.6 mg) induced a time-dependent reduction in visual-spatial PAL, with the greatest impairment (Cohen's d = 1.37) observed 2 h after dosing. Cotreatment with donepezil (10 mg) significantly ameliorated scopolamine-induced impairment at the 2-h time point (Cohen's d = 0.66). Process-based analyses revealed a significant impairment in both memory (Cohen's d = 1.37 to 0.50) and executive (Cohen's d = 1 .21 to 0.62) aspects of visual-spatial PAL performance following acute scopolamine challenge, and these reductions were ameliorated by donepezil. CONCLUSIONS: Acute scopolamine challenge can produce large and robust deficits in visual-spatial PAL, which reflect impairments in both memory and executive processes. Coadministration of a single dose of donepezil can ameliorate these deficits. These results provide support for the use of a visual-spatial PAL test as a pharmacodynamic cognitive marker of central nervous system (CNS)-mediating compounds in humans.

A process-based approach to characterizing the effect of acute alprazolam challenge on visual paired associate learning and memory in healthy older adults.

OBJECTIVE: Alprazolam is a benzodiazepine that, when administered acutely, results in impairments in several aspects of cognition, including attention, learning, and memory. However, the profile (i.e., component processes) that underlie alprazolam-related decrements in visual paired associate learning has not been fully explored. METHODS: In this double-blind, placebo-controlled, randomized cross-over study of healthy older adults, we used a novel, "process-based" computerized measure of visual paired associate learning to examine the effect of a single, acute 1-mg dose of alprazolam on component processes of visual paired associate learning and memory. RESULTS: Acute alprazolam challenge was associated with a large magnitude reduction in visual paired associate learning and memory performance (d = 1.05). Process-based analyses revealed significant increases in distractor, exploratory, between-search, and within-search error types. Analyses of percentages of each error type suggested that, relative to placebo, alprazolam challenge resulted in a decrease in the percentage of exploratory errors and an increase in the percentage of distractor errors, both of which reflect memory processes. CONCLUSIONS: Results of this study suggest that acute alprazolam challenge decreases visual paired associate learning and memory performance by reducing the strength of the association between pattern and location, which may reflect a general breakdown in memory consolidation, with less evidence of reductions in executive processes (e.g., working memory) that facilitate visual paired associate learning and memory.

Examining the nature of impairment in visual paired associate learning in amnestic mild cognitive impairment.

OBJECTIVE: Visual spatial learning is impaired in mild cognitive impairment (MCI) although the nature of this impairment is not clear. This study investigated the nature and magnitude of errors made by adults with amnestic MCI (aMCI) when learning pattern-location paired associations in a continuous manner. METHOD: Visual associate learning was measured using the Continuous Paired Associate Learning (CPAL) task in which 30 adults who met clinical criteria for aMCI and 30 matched controls were required to learn a set of associations between patterns and locations across increasing memory loads (two, four, six, and eight). RESULTS: As hypothesized, the aMCI group made more total errors than controls for all memory loads above two. However, the rate of increase in errors with memory load in the aMCI group was approximately twice that for controls. CONCLUSIONS: In controls, errors on the CPAL task reflected almost exclusively difficulty in memory. In the aMCI group, errors on the CPAL reflected limitations in associative learning but also in short-term memory and response monitoring. These results suggest that impairments in specific aspects of executive function and working memory might contribute to poor performance on visual paired associate learning in aMCI.

It takes nine days to iron a shirt: the development of cognitive estimation skills in school age children.

Data are presented for 315 elementary school-aged children (K-11) who took the Biber Cognitive Estimation Test, a 20-item test with five estimation questions in each of four domains: quantity, time/duration, weight, and distance/length. Performance showed significant development yearly until around the age of nine years, with much slower development subsequently. No gender effects were found. Age and fund of knowledge correlated with overall test performance. Fund of information accounted for a large proportion of the variance in estimation skills for children 8 years and under, but not for children 9 years and older. Since estimation skills require retrieval and manipulation of relevant knowledge and inhibition of impulsive responding and are necessary in many everyday tasks, it was anticipated that this test may provide a useful measure of judgment and estimations and may correlate with other executive skills in school-aged children.

Feigned depression and feigned sleepiness: a voice acoustical analysis.

We sought to profile the voice acoustical correlates of simulated, or feigned depression by neurologically and psychiatrically healthy control subjects. We also sought to identify the voice acoustical correlates of feigned sleepiness for these same subjects. Twenty-two participants were asked to speak freely about a cartoon, to count from 1 to 10, and to sustain an "a" sound for approximately 5s. These exercises were completed three times (within the same testing session) with three differing sets of instructions to the participants. These three conditions were presented in pseudo-random order to control for any order effects, and all subjects were naïve to the intended purpose of this study. For all three conditions, mean speaking rates and pitch ranges were calculated. A series of paired t tests showed significant differences in the speaking rates (counting numbers and free-speech exercises) between the 'normal' and feigned sleepy conditions, and between the normal and feigned depression conditions, but not between the 'sleepy' and 'depressed' conditions. The results for pitch range, for all speech exercises, were not different between the normal and either the feigned depression or feigned sleepiness conditions. These results indicate that persons feigning depression and sleepiness demonstrate some level of conscious control of their speech rate, but they did not convincingly alter their pitch ranges while feigning depression or sleepiness.