Evolocumab in paediatric heterozygous familial hypercholesterolaemia: cognitive function during 80 weeks of open-label extension treatment.

AIMS: PCSK9 inhibition intensively lowers low density lipoprotein cholesterol and is well tolerated in adults and paediatric patients with familial hypercholesterolaemia (FH). HAUSER-RCT showed that 24 weeks of treatment with evolocumab in paediatric patients did not affect cognitive function. This study determined the effects of 80 additional weeks of evolocumab treatment on cognitive function in paediatric patients with heterozygous FH. METHODS AND RESULTS: HAUSER-OLE was an 80-week open-label extension of HAUSER-RCT, a randomized, double-blind, 24-week trial evaluating the efficacy and safety of evolocumab in paediatric patients (ages 10-17 years) with FH. During the OLE, all patients received monthly 420 mg subcutaneous evolocumab injections. Tests of psychomotor function, attention, visual learning, and executive function were administered at baseline and Weeks 24 and 80 of the OLE. Changes over time were analysed descriptively and using analysis of covariance. Cohen's d statistic was used to evaluate the magnitude of treatment effects. Analysis of covariance results indicated no decrease in performance across visits during 80 weeks of evolocumab treatment for Groton Maze Learning, One Card Learning accuracy, Identification speed, or Detection speed (all P > 0.05). Performance on all tasks was similar for those who received placebo or evolocumab in the RCT (all P > 0.05). For all tests, the least square mean differences between patients who received placebo vs. evolocumab in the parent study were trivial (all Cohen's d magnitude < 0.2). CONCLUSION: In paediatric patients with FH, 80 weeks of open-label evolocumab treatment had no negative impact on cognitive function. REGISTRATION: ClinicalTrials.gov identifier: NCT02624869.

Some children are born with a genetic disorder that causes high cholesterol, which leads to heart disease. Children with high cholesterol can be treated with evolocumab, a medication that lowers blood cholesterol. Because cholesterol is important for development and adequate function of the brain, there is a concern that lowering cholesterol in children may affect mental ability. In this study, we tested whether treating children with evolocumab for 80 weeks affected mental ability in performing several tasks. A battery of tests that measure executive function (Groton Maze Learning Test), visual learning (One Card Learning Test), visual attention (Identification Test), and psychomotor function (Detection Test) showed no decrease in performance across visits during 80 weeks of evolocumab treatment. Performance on all tasks was similar for the children who received placebo for the first 24 weeks then received evolocumab for an additional 80 weeks (placebo/evolocumab) and those who received evolocumab for 24 weeks then received evolocumab for an additional 80 weeks (evolocumab/evolocumab).

Sensitivity of Individual and Composite Test Scores from the Cogstate Brief Battery to Mild Cognitive Impairment and Dementia Due to Alzheimer's Disease.

BACKGROUND: The Cogstate Brief Battery (CBB) is a computerized cognitive test battery used commonly to identify cognitive deficits related to Alzheimer's disease (AD). However, AD and normative samples used to understand the sensitivity of the CBB to AD in the clinic have been limited, as have the outcome measures studied. OBJECTIVE: This study investigated the sensitivity of CBB outcomes, including potential composite scores, to cognitive impairment in mild cognitive impairment (MCI) and dementia due to AD, in carefully selected samples. METHODS: Samples consisted of 4,871 cognitively unimpaired adults and 184 adults who met clinical criteria for MCI (Clinical Dementia Rating (CDR) = 0.5) or dementia (CDR > 0.5) due to AD and CBB naive. Speed and accuracy measures from each test were examined, and theoretically- and statistically-derived composites were created. Sensitivity and specificity of classification of cognitive impairment were compared between outcomes. RESULTS: Individual CBB measures of learning and working memory showed high discriminability for AD-related cognitive impairment for CDR 0.5 (AUCs ∼ 0.79-0.88), and CDR > 0.5 (AUCs ∼ 0.89-0.96) groups. Discrimination ability for theoretically derived CBB composite measures was high, particularly for the Learning and Working Memory (LWM) composite (CDR 0.5 AUC = 0.90, CDR > 0.5 AUC = 0.97). As expected, statistically optimized linear composite measures showed strong discrimination abilities albeit similar to the LWM composite. CONCLUSIONS: In older adults, the CBB is effective for discriminating cognitive impairment due to MCI or AD-dementia from unimpaired cognition with the LWM composite providing the strongest sensitivity.

Feasibility of serial neurocognitive assessment using Cogstate during and after therapy for childhood leukemia.

PURPOSE: Neurocognitive impairment is frequently observed among survivors of childhood acute lymphoblastic leukemia (ALL) within the domains of attention, working memory, processing speed, executive functioning, and learning and memory. However, few studies have characterized the trajectory of treatment-induced changes in neurocognitive function beginning in the first months of treatment, to test whether early changes predict impairment among survivors. If correct, we hypothesize that those children who are most susceptible to early impairment would be ideal subjects for clinical trials testing interventions designed to protect against treatment-related neurocognitive decline. METHODS: In this pilot study, we prospectively assessed neurocognitive functioning (attention, working memory, executive function, visual learning, and processing speed), using the Cogstate computerized battery at six time points during the 2 years of chemotherapy treatment and 1-year post-treatment (Dana-Farber Cancer Institute ALL Consortium protocol 11-001; NCT01574274). RESULTS: Forty-three patients with ALL consented to serial neurocognitive testing. Of the 31 participants who remained on study through the final time point, 1 year after completion of chemotherapy, 28 (90%) completed at least five of six planned Cogstate testing time points. Performance and completion checks indicated a high tolerability (≥ 88%) for all subtests. One year after completion of treatment, 10 of 29 patients (34%) exhibited neurocognitive function more than 2 standard deviations below age-matched norms on one or more Cogstate subtests. CONCLUSIONS: Serial collection of neurocognitive data (within a month of diagnosis with ALL, during therapy, and 1-year post-treatment) is feasible and can be informative for evaluating treatment-related neurocognitive impairment.

ENHANCE: a comparative prospective longitudinal study of cognitive outcomes after 3 years of hearing aid use in older adults.

Background: With an aging population, the prevalence of hearing loss and dementia are increasing rapidly. Hearing loss is currently considered the largest potentially modifiable risk factor for dementia. The effect of hearing interventions on cognitive function should therefore be investigated, as if effective, these may be successfully implemented to modify cognitive outcomes for older adults with hearing loss. Methods: This prospective longitudinal observational cohort study compared outcomes of a convenience sample of prospectively recruited first-time hearing aid users without dementia from an audiology center with those of community-living older adults participating in a large prospective longitudinal cohort study with/without hearing loss and/or hearing aids. All participants were assessed at baseline, 18 months, and 36 months using the same measures. Results: Participants were 160 audiology clinic patients (48.8% female patient; mean age 73.5 years) with mild-severe hearing loss, fitted with hearing aids at baseline, and 102 participants of the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Aging (AIBL) (55.9% female patient; mean age 74.5 years). 18- and 36-month outcomes of subsets of the first participants to reach these points and complete the cognition assessment to date are compared. Primary comparative analysis showed cognitive stability for the hearing aid group while the AIBL group declined on working memory, visual attention, and psychomotor function. There was a non-significant trend for decline in visual learning for the AIBL group versus no decline for the hearing aid group. The hearing aid group showed significant decline on only 1 subtest and at a significantly slower rate than for the AIBL participants (p < 0.05). When education effects on cognitive trajectory were controlled, the HA group still performed significantly better on visual attention and psychomotor function (lower educated participants only) compared to the AIBL group but not on working memory or visual learning. Physical activity had no effect on cognitive performance trajectory. Conclusion: Hearing aid users demonstrated significantly better cognitive performance to 3 years post-fitting, suggesting that hearing intervention may delay cognitive decline/dementia onset in older adults. Further studies using appropriate measures of cognition, hearing, and device use, with longer follow-up, are required.

Cognitive function with evolocumab in pediatric heterozygous familial hypercholesterolemia.

BACKGROUND: Evolocumab is a fully human monoclonal antibody inhibitor of PCSK9 approved for lowering low-density lipoprotein cholesterol in adults and pediatric patients with familial hypercholesterolemia (FH). The cognitive safety of evolocumab has been established in adults but has not yet been described in pediatric patients. OBJECTIVE: To determine the effects of evolocumab on cognitive function in pediatric heterozygous FH. METHODS: Cognitive function was assessed during a 24-week, randomized, double-blind, placebo-controlled study (HAUSER-RCT) evaluating the efficacy, safety, and tolerability of 24 weeks of monthly subcutaneous injections of evolocumab in pediatric patients with FH. Cognitive safety endpoints included changes from baseline to week 24 in test scores in domains of psychomotor function, attention, visual learning, and executive function. Between-group differences in age-standardized mean test score changes were analyzed using analysis of covariance models and point estimates with 95% confidence interval (CI). Magnitudes of difference between treatment groups (Cohen's d) and reliable change indices were calculated for each cognitive function test. RESULTS: At week 24, changes from baseline in age-standardized cognitive test scores were similar between the treatment groups. Differences (95% CI) between the evolocumab and placebo groups in mean test score changes for the Groton Maze Learning, One-Card Learning, Identification, and Detection tests were 0.1 (-0.2, 0.4), -0.1 (-0.5, 0.4), 0.3 (0.0, 0.7), 0.3 (-0.1, 0.8), respectively. For all tests, abnormal and clinically important cognitive decline occurred with lesser frequency in the evolocumab group. CONCLUSION: In pediatric patients with FH, 24-week treatment with evolocumab did not negatively influence cognition. FUNDING: This study was funded and designed by Amgen.

Validation of a digit symbol substitution test for use in supervised and unsupervised assessment in mild Alzheimer's disease.

INTRODUCTION: The Digit-Symbol-Substitution Test (DSST) is used widely in neuropsychological investigations of Alzheimer's Disease (AD). A computerized version of this paradigm, the DSST-Meds, utilizes medicine-date pairings and has been developed for administration in both supervised and unsupervised environments. This study determined the utility and validity of the DSST-Meds for measuring cognitive dysfunction in early AD. METHOD: Performance on the DSST-Meds was compared to performance on the WAIS Coding test, and a computerized digit symbol coding test (DSST-Symbols). The first study compared supervised performance on the three DSSTs versions in cognitively unimpaired (CU) adults (n = 104). The second compared supervised DSST performance between CU (n = 60) and mild-symptomatic AD (mild-AD, n = 79) groups. The third study compared performance on the DSST-Meds between unsupervised (n= 621) and supervised settings. RESULTS: In Study 1, DSST-Meds accuracy showed high correlations with the DSST-Symbols accuracy (r = 0.81) and WAIS-Coding accuracy (r = 0.68). In Study 2, when compared to CU adults, the mild-AD group showed lower accuracy on all three DSSTs (Cohen's d ranging between 1.39 and 2.56) and DSST-Meds accuracy was correlated moderately with Mini-Mental State Examination scores (r = 0.44, p < .001). Study 3 observed no difference in DSST-meds accuracy between supervised and unsupervised administrations. CONCLUSION: The DSST-Meds showed good construct and criterion validity when used in both supervised and unsupervised contexts and provided a strong foundation to investigate the utility of the DSST in groups with low familiarity to neuropsychological assessment.

A Paradox in Digital Memory Assessment: Increased Sensitivity With Reduced Difficulty.

The One Card Learning Test (OCL80) from the Cogstate Brief Battery-a digital cognitive test used both in-person and remotely in clinical trials and in healthcare contexts to inform health decisions-has shown high sensitivity to changes in memory in early Alzheimer's disease (AD). However, recent studies suggest that OCL sensitivity to memory impairment in symptomatic AD is not as strong as that for other standardized assessments of memory. This study aimed to improve the sensitivity of the OCL80 to AD-related memory impairment by reducing the test difficultly (i.e., OCL48). Experiment 1 showed performance in healthy adults improved on the OCL48 while the pattern separation operations that constrain performance on the OCL80 were retained. Experiment 2 showed repeated administration of the OCL48 at short retest intervals did not induce ceiling or practice effects. Experiment 3 showed that the sensitivity of the OCL48 to AD-related memory impairment (Glass's Δ = 3.11) was much greater than the sensitivity of the OCL80 (Glass's Δ = 1.94). Experiment 4 used data from a large group of cognitively normal older adults to calibrate performance scores between the OCL80 and OCL48 using equipercentile equating. Together these results showed the OCL48 to be a valid and reliable test of learning with greater sensitivity to memory impairment in AD than the OCL80.

Neurocognitive Dysfunction and Smaller Brain Volumes in Adolescents and Adults With a Fontan Circulation.

BACKGROUND: Neurocognitive outcomes beyond childhood in people with a Fontan circulation are not well defined. This study aimed to investigate neurocognitive functioning in adolescents and adults with a Fontan circulation and associations with structural brain injury, brain volumetry, and postnatal clinical factors. METHODS: In a binational study, participants with a Fontan circulation without a preexisting major neurological disability were prospectively recruited from the Australia and New Zealand Fontan Registry. Neurocognitive function was assessed by using Cogstate software in 107 participants with a Fontan circulation and compared with control groups with transposition of the great arteries (n=50) and a normal circulation (n=41). Brain MRI with volumetric analysis was performed in the participants with a Fontan circulation and compared with healthy control data from the ABIDE I and II (Autism Brain Imaging Data Exchange) and PING (Pediatric Imaging, Neurocognition, and Genetics) data repositories. Clinical data were retrospectively collected. RESULTS: Of the participants with a Fontan circulation who had a neurocognitive assessment, 55% were male and the mean age was 22.6 years (SD 7.8). Participants with a Fontan circulation performed worse in several areas of neurocognitive function compared with those with transposition of the great arteries and healthy controls (P<0.05). Clinical factors associated with worse neurocognitive outcomes included more inpatient days during childhood, younger age at Fontan surgery, and longer time since Fontan procedure (P<0.05). Adults with a Fontan circulation had more marked neurocognitive dysfunction than adolescents with a Fontan circulation in 2 domains (psychomotor function, P=0.01 and working memory, P=0.02). Structural brain injury was present in the entire Fontan cohort; the presence of white matter injury was associated with worse paired associate learning (P<0.001), but neither the presence nor severity of infarct, subcortical gray matter injury, and microhemorrhage was associated with neurocognitive outcomes. Compared with healthy controls, people with a Fontan circulation had smaller global brain volumes (P<0.001 in all regions) and smaller regional brain volumes in most cerebral cortical regions (P<0.05). Smaller global brain volumes were associated with worse neurocognitive functioning in several domains (P<0.05). A significant positive association was also identified between global brain volumes and resting oxygen saturations (P≤0.04). CONCLUSIONS: Neurocognitive impairment is common in adolescents and adults with a Fontan circulation and is associated with smaller gray and white matter brain volume. Understanding modifiable factors that contribute to brain injury to optimize neurocognitive function is paramount.

Neurocognitive Function, Psychosocial Outcome, and Health-Related Quality of Life of the First-Generation Metastatic Melanoma Survivors Treated with Ipilimumab.

PURPOSE: To assess neurocognitive function (NCF), psychosocial outcome, health-related quality of life (HRQoL), and long-term effects of immune-related adverse events (irAE) on metastatic melanoma survivors treated with ipilimumab (IPI). METHODS: Melanoma survivors were identified within two study populations (N = 104), at a single-center university hospital, and defined as patients who were disease-free for at least 2 years after initiating IPI. Data were collected using 4 patient-reported outcome measures, computerized NCF testing, and a semistructured interview at the start and 1-year follow-up. RESULTS: Out of 18 eligible survivors, 17 were recruited (5F/12M); median age is 57 years (range 33-86); and median time since initiating IPI was 5.6 years (range 2.1-9.3). The clinical interview revealed that survivors suffered from cancer-related emotional distress such as fear of recurrence (N = 8), existential problems (N = 2), survivor guilt (N = 2), and posttraumatic stress disorder (N = 6). The mean EORTC QLQ-C30 Global Score was not significantly different from the European mean of the healthy population. Nine survivors reported anxiety and/or depression (Hospitalization Depression Scale) during the survey. Seven survivors (41%) reported fatigue (Fatigue Severity Scale). Seven patients (41%) had impairment in NCF; only three out of seven survivors had impairment in subjective cognition (Cognitive Failure Questionnaire). Anxiety, depression, fatigue, and neurocognitive symptoms remained stable at the 1-year follow-up. All cases of skin toxicity (N = 8), hepatitis (N = 1), colitis (N = 3), and sarcoidosis (N = 1) resolved without impact on HRQoL. Three survivors experienced hypophysitis; all suffered from persistent fatigue and cognitive complaints 5 years after onset. One survivor who experienced a Guillain-Barré-like syndrome suffered from persisting depression, fatigue, and impairment in NCF. CONCLUSION: A majority of melanoma survivors treated with IPI continue to suffer from emotional distress and impairment in NCF. Timely detection in order to offer tailored care is imperative, with special attention for survivors with a history of neuroendocrine or neurological irAE. The trial is registered with B.U.N. 143201421920.

Unsupervised assessment of cognition in the Healthy Brain Project: Implications for web-based registries of individuals at risk for Alzheimer's disease.

INTRODUCTION: Web-based platforms are used increasingly to assess cognitive function in unsupervised settings. The utility of cognitive data arising from unsupervised assessments remains unclear. We examined the acceptability, usability, and validity of unsupervised cognitive testing in middle-aged adults enrolled in the Healthy Brain Project. METHODS: A total of 1594 participants completed unsupervised assessments of the Cogstate Brief Battery. Acceptability was defined by the amount of missing data, and usability by examining error of test performance and the time taken to read task instructions and complete tests (learnability). RESULTS: Overall, we observed high acceptability (98% complete data) and high usability (95% met criteria for low error rates and high learnability). Test validity was confirmed by observation of expected inverse relationships between performance and increasing test difficulty and age. CONCLUSION: Consideration of test design paired with acceptability and usability criteria can provide valid indices of cognition in the unsupervised settings used to develop registries of individuals at risk for Alzheimer's disease.

The Effect of Hearing Aid Use on Cognition in Older Adults: Can We Delay Decline or Even Improve Cognitive Function?

Hearing loss is a modifiable risk factor for dementia in older adults. Whether hearing aid use can delay the onset of cognitive decline is unknown. Participants in this study (aged 62-82 years) were assessed before and 18 months after hearing aid fitting on hearing, cognitive function, speech perception, quality of life, physical activity, loneliness, isolation, mood, and medical health. At baseline, multiple linear regression showed hearing loss and age predicted significantly poorer executive function performance, while tertiary education predicted significantly higher executive function and visual learning performance. At 18 months after hearing aid fitting, speech perception in quiet, self-reported listening disability and quality of life had significantly improved. Group mean scores across the cognitive test battery showed no significant decline, and executive function significantly improved. Reliable Change Index scores also showed either clinically significant improvement or stability in executive function for 97.3% of participants, and for females for working memory, visual attention and visual learning. Relative stability and clinically and statistically significant improvement in cognition were seen in this participant group after 18 months of hearing aid use, suggesting that treatment of hearing loss with hearing aids may delay cognitive decline. Given the small sample size, further follow up is required.

Necessity of technicians for computerized neuropsychological assessment devices in multiple sclerosis.

OBJECTIVE: Determine the influence of technician supervision on computer-administered cognitive tests in multiple sclerosis (MS). METHODS: Eighty MS patients underwent assessment using the CogState Brief Battery (CSBB) and the Cleveland Clinic Cognitive Battery (C3B). Each was administered twice, once with a technician guiding assessment, and once with technician-absent. Twenty-eight healthy controls were also evaluated. RESULTS: The influence of technician guidance was not statistically significant for group means on either test. For CSBB, administration problems were more common in the technician-absent condition. CONCLUSION: In this MS sample, reliable and valid test results were obtained from computer-assisted cognitive testing without technician guidance.

The impact of chemotherapy on cognitive function: a multicentre prospective cohort study in testicular cancer.

PURPOSE: The causal link between chemotherapy and cognitive impairment is unclear. We studied testicular cancer patients' objective and subjective cognitive function longitudinally, comparing a surgery group with a surgery + chemotherapy group, addressing prior methodological issues using a computerized test to limit assessment issues, and controlling for confounding variables. METHODS: Prospectively, of 145 patients from 16 centres with sufficient data, n = 61 receiving surgery + chemotherapy (etoposide and cisplatin ± bleomycin, BEP/EP; or single agent carboplatin) were compared to n = 41 receiving surgery alone. CogHealth assessed six objective cognitive tasks. The Cognitive Failures Questionnaire assessed self-perceived cognitive dysfunction. The Functional Assessment of Chronic Illness Therapy-Fatigue and the Hospital Anxiety and Depression Scale assessed psychological influences. Linear mixed models compared changes from baseline (< 6 months post-surgery/pre-chemotherapy) to follow-up (12-18 months post-baseline), controlling covariates. RESULTS: There were no significant interaction effects for five objective cognitive function tasks suggesting that changes over time were not due to group membership. However, psychomotor function (controlling for age) and physical well-being were significantly worse for the chemotherapy versus the surgery group at baseline, with groups converging by follow-up. Groups showed no differences in subjective cognitive dysfunction. The chemotherapy group showed higher anxiety, poorer functional well-being and worse fatigue compared to the surgery-only group at baseline, but not by follow-up. For both groups, emotional well-being, functional well-being and anxiety significantly improved over time. CONCLUSION: No substantive differences in objective or subjective cognitive dysfunction in either group persisted 12-18 months post-baseline. Patients undergoing chemotherapy for testicular cancer differ from findings in breast cancer populations. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: ACTRN12609000545268.

The Effect of Cochlear Implants on Cognitive Function in Older Adults: Initial Baseline and 18-Month Follow Up Results for a Prospective International Longitudinal Study.

In older adults, hearing loss is independently associated with an increased rate of cognitive decline, and has been identified to be a modifiable risk factor for dementia. The mechanism underlying the cognitive decline associated with hearing loss is not understood, but it is known that the greater the hearing loss, the faster the rate of decline. It is unknown whether remediation of hearing loss with hearing devices can delay cognitive decline. This 5-year international longitudinal study is investigating the impact of cochlear implants on cognitive function in older people with severe-profound hearing loss, and whether remediation of hearing loss could delay the onset of cognitive impairment. This is the first study to examine the major primary risk factors associated with dementia in the same cohort. Participants were assessed before cochlear implantation and 18 months later using an identical battery including a visually presented cognitive assessment tool (Cogstate battery) that is highly sensitive to small changes in cognition and suitable for use with people with hearing loss. Hearing and speech perception ability were assessed in sound-treated conditions by an audiologist, and a range of questionnaire tools was administered to assess self-perceived ease of listening, quality of life, physical activity, diet, social and emotional loneliness, isolation, anxiety, and depression. A detailed medical health history was taken. Pre-operatively, despite the small initial sample size (n = 59), increased hearing loss and age predicted significantly poorer executive function and visual attention, while tertiary education predicted better executive function. Better self-reported quality of life was correlated with better visual learning performance, and engaging in frequent vigorous physical activity was correlated with poorer visual learning performance. At 18 months, for the first 20 participants, significant benefits of cochlear implants were seen in terms of speech perception, communication ability, and quality of life. Multiple linear regression modeling showed executive function improved significantly for non-tertiary educated males, while cognitive function remained stable for other participants. Further follow-up at 18 month intervals with a larger sample will reveal the effects of cochlear implant intervention on all outcomes, and whether this can delay cognitive decline.

Exercise effects on cognitive functioning in young adults with first-episode psychosis: FitForLife.

BACKGROUND: Exercise has mood-enhancing effects and can improve cognitive functioning, but the effects in first-episode psychosis (FEP) remain understudied. We examined the feasibility and cognitive effects of exercise in FEP. METHOD: Multi-center, open-label intervention study. Ninety-one outpatients with FEP (mean age = 30 years, 65% male) received usual care plus a 12-week supervised circuit-training program, consisting of high-volume resistance exercises, aerobic training, and stretching. Primary study outcome was cognitive functioning assessed by Cogstate Brief Battery (processing speed, attention, visual learning, working memory) and Trailmaking A and B tasks (visual attention and task shifting). Within-group changes in cognition were assessed using paired sample t tests with effect sizes (Hedges' g) reported for significant values. Relationships between exercise frequency and cognitive improvement were assessed using analysis of covariance. Moderating effects of gender were explored with stratified analyses. RESULTS: Participants exercised on average 13.5 (s.d. = 11.7) times. Forty-eight percent completed 12 or more sessions. Significant post-intervention improvements were seen for processing speed, visual learning, and visual attention; all with moderate effect sizes (g = 0.47-0.49, p < 0.05). Exercise participation was also associated with a positive non-significant trend for working memory (p < 0.07). Stratified analyses indicated a moderating effect of gender. Positive changes were seen among females only for processing speed, visual learning, working memory, and visual attention (g = 0.43-0.69). A significant bivariate correlation was found between total training frequency and improvements in visual attention among males (r = 0.40, p < 0.05). CONCLUSION: Supported physical exercise is a feasible and safe adjunct treatment for FEP with potential cognitive benefits, especially among females.

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.

A Videogame-Based Digital Therapeutic to Improve Processing Speed in People with Multiple Sclerosis: A Feasibility Study.

INTRODUCTION: Self-administered in-home digital therapeutics could expand access to cognitive rehabilitation for individuals with multiple sclerosis (MS), over half of whom experience cognitive impairment (CI). However, feasibility in an MS population must be clarified. This study was conducted to assess the feasibility of deploying a videogame-like digital treatment for CI in MS, including initial efficacy and barriers to adherence. METHODS: In this pilot study, 21 participants with MS completed an in-clinic baseline neurological evaluation. Cognitive tests included paper-and-pencil Brief International Cognitive Assessment for Multiple Sclerosis [BICAMS-which included the Symbol Digit Modalities Test (SDMT)] and other unsupervised tablet-based tests (including Match: an unsupervised test of executive functions and processing speed, developed at UCSF; and the Cogstate MS Battery). Participants then completed an in-home, tablet-based, videogame-like investigational digital treatment (Project: EVO™) for 25 min daily, 5 days weekly, for 4 weeks. This was followed by a repeat in-clinic evaluation. RESULTS: Of the 21 participants (mean [standard deviation, SD] age 53.8 [11.6] years, median Expanded Disability Status Scale (EDSS) 2.5 [SD 2.0, IQR [2-3.5]]) enrolled to use the digital therapeutic at home (mean [SD] SDMT z score: - 0.21 [1.16]), 18 completed the study, during which they completed an average of 19.7 days (median [SD]: 20.5 [8.4]). Overall, 78% of these 18 participants completed 75% of prescribed days (i.e., at least 15), and 50% completed all 20 days or more. Over the 4-week period, scores of processing speed improved significantly (based on one-sided t test), including SDMT (p = 0.003) and Match (p = 0.006). The Cogstate DET test (psychomotor function) also increased (p = 0.006). Mean increase in SDMT was 3.6 points. Male sex, not being employed, and higher baseline anxiety all were significantly associated with greater improvement in SDMT over the 4-week period. Interestingly, lower baseline cognitive scores were associated with greater number of sessions completed (e.g., SDMT: p = 0.003, R2 = 0.44). Adjusting for employment, a proxy for time available, did not significantly improve the model fit. DISCUSSION: Deploying an in-home digital tool to improve processing speed in MS is feasible, and shows preliminary efficacy. A larger, randomized controlled clinical trial is ongoing.

Estimates of age-related memory decline are inflated by unrecognized Alzheimer's disease.

Cognitive decline is considered an inevitable consequence of aging; however, estimates of cognitive aging may be influenced negatively by undetected preclinical Alzheimer's disease (AD). This study aimed to determine the extent to which estimates of cognitive aging were biased by preclinical AD. Cognitively normal older adults (n = 494) with amyloid-ß status determined from positron emission tomography neuroimaging underwent serial neuropsychological assessment at 18-month intervals over 72 months. Estimates of the effects of age on verbal memory, working memory, executive function, and processing speed were derived using linear mixed models. The presence of preclinical AD and clinical progression to mild cognitive impairment or dementia during the study were then added to these models as covariates. Initially, age was associated with decline across all 4 cognitive domains. With the effects of elevated amyloid-ß and clinical progression controlled, age was no longer associated with decline in verbal or working memory. However, the magnitude of decline was reduced only slightly for executive function and was unchanged for processing speed. Thus, considered together, the results of the study indicate that undetected preclinical AD negatively biases estimates of age-related cognitive decline for verbal and working memory.

Prolonged-Release Fampridine as Adjunct Therapy to Active Motor Training in MS Patients: A Pilot, Double-Blind, Randomized, Placebo-Controlled Study.

BACKGROUND: Both prolonged-release fampridine (PRF) and enabling active motor training (EAMT) are beneficial in multiple sclerosis (MS) patients. Their combined effect is, however, understudied. OBJECTIVE: The objective of this paper is to determine if PRF augments the beneficial effect of EAMT in MS patients as opposed to placebo. METHOD: This is a pilot, randomized, placebo-controlled, double-blind 14-week study. Participants were randomly assigned to receive PRF 10 mg BID (n = 21) or placebo (n = 20). All patients underwent EAMT during the first six weeks. Patients were assessed at -4, 0, 6 and 14 weeks. RESULTS: Both groups remained stable between -4 to 0 weeks and showed statistically significant improvements for the six-minute walk and the five-times-sit-to-stand test at weeks 6 and 14. The PRF-treated group achieved a greater mean percentage improvement and a higher incidence of responders in all three tasks at both time points. The study was, however, underpowered to reach statistical significance. CONCLUSION: Our results confirm previous studies demonstrating that MS patients, despite significant disability, do benefit from a rehabilitation program. Our study is the first to show a trend suggesting that PRF in MS patients appears to enhance the benefit of EAMT. Further studies are required to confirm this.Clinical trial registration number with Clinicaltrial.gov: NCT02146534.

Amyloid burden and incident depressive symptoms in preclinical Alzheimer's disease.

BACKGROUND: Relationships between depression and Alzheimer's disease (AD) may become clearer if studied in preclinical AD where dementia is not present. METHOD: The aim of this study was to evaluate prospectively, relationships between brain amyloid-ß (Aß), depressive symptoms and screen positive depression in cognitively normal (CN) older adults. Depressive symptoms were measured with the Geriatric Depression Inventory (GDS-15) in CN adults from the Australian Imaging Biomarkers and Lifestyle (AIBL) study without depression at baseline and classified as having abnormally high (Aß+; n = 136) or low (Aß-; n = 449) Aß according to positron emission tomography at 18-month intervals over 72 months. RESULTS: Incident cases of screen positive depression were not increased in Aß+ CN adults although small increases in overall depressive symptoms severity (d = - 0.25; 95% CI, - 0.45, - 0.05) and apathy-anxiety symptoms (d = - 0.28; 95% CI - 0.48, - 0.08) were. LIMITATIONS: As the AIBL sample is an experimental sample, no individuals had severe medical illnesses or significant psychiatric disorders. Additionally, individuals who had evidence of screen-positive depression at screening were excluded from enrolment in the AIBL study. Thus, the current data can be considered only as providing a foundation for understanding relationships between Aß and depression in preclinical AD. CONCLUSIONS: These results suggest that the presence of a depressive disorder or even increased depressive symptoms are themselves unlikely to be a direct consequence of increasing Aß. New depressive disorders presenting in CN older adults could therefore be investigated for aetiologies beyond AD.