The Neurocognitive Effects of Bacopa monnieri and Cognitive Training on Markers of Brain Microstructure in Healthy Older Adults.

Bacopa monnieri (BM) is a herbal supplement that increases signaling molecules implicated in synaptogenesis. Combined with cognitive stimulation, it may be a viable supplement to enhance long-term potentiation (LTP) and improve cognitive health in older adults. This randomized, double-blind, placebo-controlled trial asked 28 healthy adults aged over 55 years to complete cognitive training (CT) 3 hours weekly for 12 weeks. Fifteen consumed a standardized extract of BM and 13 consumed a placebo daily. Cognitive tasks, life-satisfaction, memory complaints and mood were assessed, and bloods analyzed for serum brain-derived neurotrophic factor (BDNF) before and after 12-weeks of the intervention. Diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) in gray (GM) and white matter (WM) were also analyzed. Results demonstrated slower reaction time in an image discrimination task in the BM group and faster reaction time in a spatial working memory task (SWM-O RT) in the placebo group. Mean accuracy was higher in the BM group for these tasks, suggesting a change in the speed accuracy trade-off. Exploratory neuroimaging analysis showed increased WM mean diffusivity (MD) and GM dispersion of neurites (orientation dispersion index, ODI) and decreased WM fractional anisotropy (FA) and GM neurite density (ND) in the BM group. No other outcomes reached statistical significance. An increase in ODI with a decrease in MD and ND in the BM group may indicate an increase in network complexity (through higher dendritic branching) accompanied by dendritic pruning to enhance network efficiency. These neuroimaging outcomes conflict with the behavioral results, which showed poorer reaction time in the BM group. Given the exploratory outcomes and inconsistent findings between the behavioral and neuroimaging data, a larger study is needed to confirm the synaptogenic mechanisms of BM.

Effects of Purified Anthocyanins in People at Risk for Dementia: Study Protocol for a Phase II Randomized Controlled Trial.

Background: The number of people with dementia is increasing, with huge challenges for society and health-care systems. There are no disease-modifying therapies available. There is, therefore, an urgent need to identify strategies to reduce the risk of developing dementia. Anthocyanins are a class of compounds found in dark berries and fruits with some effects that might reduce the risk for cognitive decline and the development of dementia in older people. Aim: This phase II three-center, randomized, 24-week, placebo-controlled study, ongoing in Norway, aims to evaluate the safety, and efficacy of anthocyanins in modifying key dementia-related mechanisms and maintain cognitive functioning in older people at risk for dementia. Methods: Participants (220 individuals aged 60-80 years) who meet the inclusion criteria (either mild cognitive impairment or two or more cardiometabolic disorders) are being enrolled in this study at three different centers in Norway. Participants are block randomized to identically appearing capsules containing 80 mg of naturally purified anthocyanins or placebo 1:1. Dosage is 2 + 2 capsules per day for 24 weeks. The primary outcome will be the quality of episodic memory score, a composite measure from the extensively validated online cognitive test battery CogTrack®, which is administered at baseline and monthly for the next 6 months. Secondary outcomes include other major scores from CogTrack, as well as a range of neuroimaging and other biomarkers. Anthocyanin metabolites will be measured in blood and cerebrospinal fluid. The change from baseline scores will be subject to a mixed model for repeated measures analysis of covariance. The primary comparison will be the contrast (difference in the least-square means) between active and placebo at the end of the study (week 24). The primary study population will be a modified intention-to-treat population (ClinicalTrials.gov, NCT03419039). Discussion: This study aims to demonstrate whether there are beneficial effects of purified anthocyanins on cognition and relevant biological functions in people at increased risk for dementia. Forthcoming results may contribute to further improvement of intervention strategies to prevent or delay the onset of dementia, including a potential decision to take anthocyanins toward phase III trials.

Cognitive profiles in obstructive sleep apnea: a cluster analysis in sleep clinic and community samples.

STUDY OBJECTIVES: Although cognitive dysfunction is a recognized consequence of untreated obstructive sleep apnea (OSA), the deficit pattern is heterogeneous. Understanding this heterogeneity may identify those at risk of cognitive deficits and guide intervention strategies. To facilitate understanding, we examined whether distinct profiles of neuropsychological performance were present in OSA and, if so, how they are related to other OSA features. METHODS: We studied sleep clinic (n = 121) and community (n = 398) samples with moderate-severe OSA (apnea-hypopnea index ≥ 15 events/h). Attention and memory were assessed using the Cognitive Drug Research system. Sleep was assessed using polysomnography in the clinic sample and dual channel (flow, oximetry) portable monitoring in the community sample. Latent profile analysis was used to determine structure of cognitive clusters. Discriminant function analysis was used to examine associations between nocturnal and diurnal features of OSA and profile membership. RESULTS: Both samples were best characterized by a 3-profile solution: (1) strong thinkers (performed well across most domains and showed greater cognitive reserve); (2) inattentive fast thinkers (strong processing speed but poor ability to maintain attention); and (3) accurate slow thinkers (strengths in maintaining attention but poor processing speed). Profile membership was associated with mean overnight oxygen saturation and cognitive reserve in the clinic sample and the presence of cardiovascular disease and/or diabetes in the community sample. CONCLUSIONS: These findings help explain the diversity of outcomes in previous studies of cognitive dysfunction in OSA by demonstrating that individual differences in cognitive reserve, nocturnal oxygen saturation, and comorbidities affect how cognition is impacted by OSA.

D-Cycloserine Improves Difficult Discriminations in a Pattern Separation Task in Alzheimer's Disease Patients with Dementia.

Recent fMRI studies in human identified that pattern separation ability is associated with increased activity in the hippocampal dentate gyrus (DG), whereas no such DG changes are seen during pattern completion. Disruption to neurogenesis in the DG has been associated with Alzheimer's disease (AD). In a post-hoc analysis of two large unsuccessful AD clinical trials, we examined the effect of D-cycloserine (DCS) on a specific object pattern separation measure, a component of the picture recognition task from the Cognitive Drug Research (CDR) system. This task yields a measure of pattern separation and a measure of pattern completion. Study data were available for 756 AD patients with dementia, randomized to several doses of DCS. Data were available at week 2, 6, 14, and 26 for 732, 707, 653, and 559 patients, respectively. None of the DCS doses had a statistically significant benefit over placebo on pattern completion. However, the DCS 15 mg BID dose significantly increased accuracy over placebo on the pattern separation measure by 5.1%. Further, the magnitude of the benefit of DCS 15 mg BID over placebo was almost doubled relative to the whole study population in a subset of patients whose pattern separation scores were≥2 standard deviations poorer than the CDR norm of age-matched healthy individuals at baseline. These post-hoc analyses suggest a potential value of the pattern separation task for evaluating compounds promoting neurogenesis. Further, the use of a restrictive pattern separation eligibility criterion might facilitate signal detection.

Mild Behavioral Impairment as a Marker of Cognitive Decline in Cognitively Normal Older Adults.

OBJECTIVE: Mild behavioral impairment (MBI) is a neurobehavioral syndrome characterized by later life emergent neuropsychiatric symptoms (NPS) that represent an at-risk state for incident cognitive decline and dementia in people with mild cognitive impairment (MCI). We undertook a study to determine whether MBI was associated with progressive changes in neuropsychological performance in people without significant cognitive impairment. METHODS: A total of 9,931 older adults enrolled in the PROTECT study who did not have MCI or dementia undertook a comprehensive neuropsychological battery measuring attention, reasoning, executive function, and working memory at baseline and 1 year. MBI was ascertained using self-administration of the Mild Behavioral Impairment Checklist at 1 year, and participants were grouped according to MBI status: No Symptoms, Intermediate NPS and MBI. All assessments were completed online, and data analyzed using mixed-effects model repeated measures analysis of covariance. RESULTS: A total of 949 (10%) people had MBI. These individuals had significantly worse cognitive performance at baseline and significantly greater decline over 1 year in the four composite cognitive scores measuring attentional intensity (F [2,8578] = 3.97; p = 0.019), sustained attention (F [2,8578] = 18.63; p <0.0001), attentional fluctuation (F [2,8578] = 10.13; p <0.0001) and working memory (F [2,9895] = 13.1; p <0.0001). CONCLUSION: Our novel findings show that MBI is associated with faster decline in attention and working memory in this cognitively normal sample. MBI may be an earlier marker of neurodegenerative disease than MCI, captured at the stage of subjective cognitive decline or before, raising the possibility that MBI represents a novel target for dementia clinical trials or prevention strategies.

The relationship between the frequency of number-puzzle use and baseline cognitive function in a large online sample of adults aged 50 and over.

OBJECTIVE: Establishing affordable lifestyle interventions that might preserve cognitive function in the aging population and subsequent generations is a growing area of research focus. Data from the PROTECT study has been utilised to examine whether number-puzzle use is related to cognitive function in older adults. METHODS: Data from 19 078 healthy volunteers aged 50 to 93 years old enrolled on the online PROTECT study were evaluated for self-reported frequency of performing number puzzles. Two cognitive-test batteries were employed to assess core aspects of cognitive function including reasoning, focussed and sustained attention, information processing, executive function, working memory, and episodic memory. Analysis of covariance was used to establish the differences between the six frequency groups. RESULTS: Highly statistically significant main effects of the frequency of performing number puzzles were seen on all 14 cognitive measures, with P values of less than 0.0004. Interestingly, participants who reported engaging in number puzzles more than once a day had superior cognitive performance on 10 core measures compared with all other frequency groups, although not all were statistically significant. CONCLUSIONS: This study has identified a close relationship between frequency of number-puzzle use and the quality of cognitive function in adults aged 50 to 93 years old. In order to determine the value of these findings as a potential intervention, further research should explore the type and difficulty of the number puzzles. These findings further contribute to the growing evidence that engaging in mentally stimulating activities could benefit the brain function of the ageing population.

An online investigation of the relationship between the frequency of word puzzle use and cognitive function in a large sample of older adults.

OBJECTIVE: The identification of modifiable lifestyle factors to preserve cognitive function in older individuals becomes increasingly of importance. This study examines whether word puzzle use is related to cognitive function in older adults. METHODS: Cognitive data from 19 078 cognitively healthy individuals aged 50 to 93 years enrolled into the online PROTECT study were evaluated for self-reported frequency of performing word puzzles on a six-point scale, ranging from "more than once per day" to "never". Nine cognitive tests covered a range of domains including focussed and sustained attention, information processing, executive function, working memory, and episodic memory. Analyses of covariance were used to determine any differences between the six response groups. RESULTS: Each of the 14 cognitive measures analysed showed highly statistically significant main effects of the frequency of performing word puzzles. For each measure, the group who never performed word puzzles performed most poorly, with the group who reported occasional puzzle use also performing more poorly than virtually every other group. Measures of speed provided the greatest discriminations, with a grammatical reasoning score differentiating the two highest frequency groups, performing word puzzles daily or more than once daily. CONCLUSIONS: The frequency of word puzzle use is directly related to cognitive function in adults aged 50 and over. Future work needs to determine whether engaging in such puzzles can favourably influence cognitive trajectory with age.

The Cognitive Ageing, Nutrition and Neurogenesis (CANN) trial: Design and progress.

INTRODUCTION: The Cognitive Ageing, Nutrition and Neurogenesis trial hypothesizes that a combined intervention with long-chain n-3 polyunsaturated fatty acids (n-3) and cocoa flavan-3-ols (FLAV) will mitigate the cognitive decline anticipated to naturally occur over 1 year in older adults. METHODS: In a double-blinded, placebo-controlled parallel design, 259 individuals with mild cognitive impairment or subjective memory impairment were randomized to a control or n-3 FLAV group (1.5 g docosahexaenoic acid + eicosapentaenoic acid and 500 mg n-3 FLAV daily) for 12 months. Cognition was measured at 0, 3, and 12 months. The primary end-point is hippocampus-sensitive cognitive function (e.g., number of false-positives on the Picture Recognition Task of the Cognitive Drug Research test battery). Secondary outcomes include additional cognitive measures, brain atrophy and blood flow (assessed by magnetic resonance imaging), vascular function, circulating biomarkers of cardiovascular and cognitive health, gut microflora, red blood cell fatty acid status, and urine flavan-3-ol metabolites. RESULTS: Screening began in 2015, with all baseline visits completed in March 2017. The intervention was finished in March 2018. DISCUSSION: Cognitive Ageing, Nutrition and Neurogenesis aims to identify an effective diet-based intervention to prevent or delay cognitive impairment in cognitively at-risk individuals, which could ultimately contribute to a reduced population burden of dementia. CLINICALTRIALSGOV: NCT02525198.

The effects of the selective muscarinic M3 receptor antagonist darifenacin, and of hyoscine (scopolamine), on motion sickness, skin conductance & cognitive function.

AIMS: The aim of this study was to compare the effects of the selective M3 muscarinic acetylcholine receptor antagonist darifenacin, oral hyoscine hydrobromide and placebo on motion sickness induced by cross-coupled stimulation. METHODS: The effects of darifenacin 10 mg or 20 mg, hyoscine hydrobromide 0.6 mg and placebo were assessed in a randomized, double-blind, four-way cross over trial of 16 healthy subjects. Motion sickness, skin conductance (a measure of sweating) and psychomotor cognitive function tests were investigated. RESULTS: Hyoscine hydrobromide produced significantly increased tolerance to motion versus placebo (P < 0.05 to P < 0.01). The motion protection effect of darifenacin (10 or 20 mg) was approximately one third that of hyoscine hydrobromide but was not significant versus placebo. Darifenacin and hyoscine hydrobromide both significantly reduced skin conductance versus placebo. Darifenacin produced either no effect or an enhanced effect on cognitive function in contrast to hyoscine hydrobromide, where there was significant impairment of psychomotor performance. CONCLUSION: The results suggest that selective antagonism of the M3 receptor may not be important in the prevention of motion sickness. However, selective M3 antagonism does not impair cognitive function. These observations may be important given that long-term treatment with non-selective anti-muscarinic agents such as oxybutynin may lead to an increased incidence of dementia.

Impaired verbal episodic memory in healthy older adults is marked by increased F2-Isoprostanes.

Age-associated cognitive decline amongst otherwise healthy older individuals is a multifaceted characteristic of ageing. The role of oxidative stress biomarkers has been increasingly examined in the context of pathological aging conditions that affect cognition. Plasma F2-Isoprostane levels are a reliable index of systemic oxidative stress (specifically lipid peroxidation) and are elevated in dementia patients. Less is known about their role in healthy cognitive ageing. This study evaluated the relationship between F2-Isoprostanes and cognitive functioning in a cohort of 211 healthy elderly adults (60-75 years: Male; 88, Female; 123). Cognitive assessment included the Cognitive Drug Research (CDR) computerised assessment battery, which produces five validated factor scores (corresponding to 'Quality of Episodic Memory', 'Speed of Memory', Quality of Working Memory', Power of Attention' and 'Continuity of Attention'). Participants with higher F2-Isoprostane levels had significantly lower Quality of Episodic Memory scores (suggesting inferior abilities in retaining and retrieving verbal information in episodic memory). This is, to our knowledge, the first report of compromised verbal episodic memory in healthy ageing humans being linked to increased levels of F2-Isoprostanes. These results have relevance for interventions aimed at improving cognitive performance in the healthy elderly.

Spearmint Extract Improves Working Memory in Men and Women with Age-Associated Memory Impairment.

OBJECTIVE: The purpose of this study was to investigate the effects of supplementation with a spearmint (Mentha spicata L.) extract, high in polyphenols including rosmarinic acid, on cognitive performance, sleep, and mood in individuals with age-associated memory impairment (AAMI). DESIGN: Subjects with AAMI (N = 90; 67% female; age = 59.4 ± 0.6 years) were randomly assigned (n = 30/group) to consume 900, 600, or 0 mg/day (two capsules, once daily) spearmint extract for 90 days, in this double-blind, placebo-controlled trial. Assessments were completed for cognition (days 0, 45, and 90), sleep (days 0 and 90), and mood (days 0 and 90) by using the Cognitive Drug Research (CDR) System™, Leeds Sleep Evaluation Questionnaire (LSEQ), and Profile of Mood States (POMS™), respectively. RESULTS: Quality of working memory and spatial working memory accuracy improved after supplementation with 900 mg/day spearmint extract by 15% (p = 0.0469) and 9% (p = 0.0456), respectively, versus placebo. Subjects consuming 900 mg/day spearmint extract reported improvement in their ability to fall asleep, relative to subjects consuming placebo (p = 0.0046). Overall treatment effects were evident for vigor-activity (p = 0.0399), total mood disturbance (p = 0.0374), and alertness and behavior following wakefulness (p = 0.0415), with trends observed for improvements after spearmint supplementation relative to placebo. CONCLUSIONS: These results suggest that the distinct spearmint extract may be a beneficial nutritional intervention for cognitive health in older subjects with AAMI.

Longitudinal changes in global and domain specific cognitive function in the very-old: findings from the Newcastle 85+ Study.

OBJECTIVE: Ageing is associated with changes in cognition in some, but not all domains. In young-old adults, defined as persons aged 65-84 years, baseline cognitive function has been shown to impact on cognitive trajectories. Whether similar patterns occur in the very-old, defined as persons aged 85 years and over, is not known. METHODS: Longitudinal changes (5 years' follow-up) in global and domain specific cognitive function including memory, attention and speed were investigated in participants from the Newcastle 85+ Study (n = 845). At baseline, participants were grouped using Mini-Mental State Examination cut-off scores and dementia status into the following: not impaired, mildly impaired or severely impaired/dementia groups. RESULTS: Only a limited number of cognitive measures showed significant decline in performance over time. Where observed, change generally occurred only in the severely impaired group. In the severely impaired group, small differences in baseline age were associated with poorer performance over time on most measures. Education was not protective against cognitive decline in any group. CONCLUSIONS: There are individuals who maintain a high level of cognitive function or only show mild impairments even into their ninth decade of life. This group of successful cognitive agers may provide insight for identifying predictors of cognitive integrity in later life. In individuals with severe impairment, cognitive performance shows significant decline over time, especially in measures of attention and speed. Further work to identify those individuals at highest risk of cognitive decline is necessary to implement early support and intervention strategies in this rapidly expanding age group. © 2017 The Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons Ltd.

Does attentional dysfunction and thalamic atrophy predict decline in dementia with Lewy bodies?

INTRODUCTION: To evaluate the clinical characteristics of DLB subjects who died within 1 year of assessment compared to those who survived and investigate their patterns of in vivo regional thalamic atrophy using structural MRI. METHODS: Seventy subjects (35 DLB, 35 aged controls) underwent 3 T T1-weighted MR scanning as well as clinical and cognitive assessments, including a computerised assessment of attention. All subjects were contacted after 12 months for reassessment. For both hemispheres, using FSL FIRST, the thalamus was automatically segmented followed by inter-subject vertex-wise analyses involving group comparisons and behavioural correlates. RESULTS: There was significant bilateral atrophy in the ventral-dorsal and pulvinar regions in DLB relative to controls (pcorrected < 0.05). The DLB group was then re-categorised based on 12-month mortality data: DLB-a (n = 26) and DLB-d (n = 9) (a = alive, d = death within 12 months of study assessment). Compared to controls, significant attentional dysfunction and bilateral atrophy of the pulvinar, ventral and dorsal nuclei were observed in DLB-d (pcorrected < 0.05), whereas in DLB-a, atrophy was far less extensive. CONCLUSIONS: Distinct patterns of thalamic atrophy occur in DLB that may relate to the attentional dysfunction and cognitive fluctuations that characterise this disorder. Relative to controls, the extent of attentional impairment and pattern of thalamic degeneration differ in those patients who died within 12 months of assessment, despite having an otherwise similar level of dementia severity. These findings may provide insight into the neurobiological changes underpinning important clinical characteristics and disease heterogeneity.

One-Carbon Metabolism Biomarkers and Cognitive Decline in the Very Old: The Newcastle 85+ Study.

OBJECTIVES: Although the biological rationale for the association between folate, vitamin B12, and homocysteine with cognitive function seems plausible, conflicting results have been reported. This study aimed to determine the associations between 1-carbon (1-C) metabolism biomarkers (folate, vitamin B12, and homocysteine), and cognitive impairment at baseline and the rate of cognitive decline over 5 years in the very old. DESIGN: The Newcastle 85+ Study was a prospective longitudinal study of people 85 years old and followed over 5 years in Northeast England. SETTING: Community-dwelling and institutionalized. PARTICIPANTS: The analytical sample included 765 very old participants with 1-C metabolism biomarkers and cognitive measures. MEASUREMENTS: Global cognition was measured by the Standardized Mini-Mental State Examination (SMMSE) at baseline, and at 3 and 5 years of follow-up and, attention-specific cognition with the Cognitive Drug Research (CDR) System at baseline, and at 1.5 and 3.0 years of follow-up. Baseline red blood cell folate (RBC folate), plasma vitamin B12, and total homocysteine (tHcy) concentrations were determined by immunoassay. Linear mixed models were used to estimate the associations between quartiles of 1-C metabolism biomarkers and cognition over 3 (CDR) and 5 years (SMMSE). RESULTS: Compared with participants in the lowest quartile of RBC folate concentrations (<612 nmol/L), those in the highest quartile of RBC folate concentrations (>1280 nmol/L) had 1 more point on the SMMSE at baseline (ß = +1.02, SE = 0.43, P = .02). Those in quartile 4 of tHcy (>21.4 µmol/L) had 1 point less in the SMMSE at baseline than those in the lowest quartile (<13.5 µmol/L) (ß = -1.05, SE = 0.46, P = .02). Plasma vitamin B12 was not predictive of global or attention-specific cognition at baseline and at follow-up. None of the 1-C metabolism biomarkers except tHcy was associated with the rate of decline in attention scores over 3 years. CONCLUSION: RBC folate and tHcy, but not plasma vitamin B12, were associated with better global cognition in the very old at baseline but were not predictive of rate of decline over 5 years.

Effects of the Red Bull energy drink on cognitive function and mood in healthy young volunteers.

The present study compared the cognitive and mood effects of two commercially available products, Red Bull energy drink 250 mL and Red Bull Sugarfree energy drink 250 mL, together with a matching placebo 250 mL. Twenty-four healthy young volunteers took part in a randomised, placebo controlled, double-blind, three-way cross-over study. Cognitive function was assessed using an integrated set of nine computerised tests of attention, working and episodic memory. On each study day the volunteers received a standardised breakfast prior to completing a baseline performance on cognitive tests and mood scales, followed by the consumption of the study drink. The cognitive tests and scales were then re-administered at 30, 60 and 90 min post-dose. Red Bull was found to produce significant improvements over both the Sugarfree version and the placebo drink on two composite scores from the six working and episodic memory tests; one combining the 12 accuracy measures from the six tasks and the other the average speed of correct responses from the working memory and episodic recognition memory tasks. These improvements were in the range of a medium effect size, which reflects a substantial enhancement to memory in young volunteers.

Utility, reliability, sensitivity and validity of an online test system designed to monitor changes in cognitive function in clinical trials.

OBJECTIVE: The advent of long-term remotely conducted clinical trials requires assessments which can be administered online. This paper considers the utility, reliability, sensitivity and validity of an internet-based system for measuring changes in cognitive function which is being used in one such trial. METHODS: The Platform for Research Online to investigate Genetics and Cognition in Ageing is a 10-year longitudinal and entirely remote study launched in November 2015. The CogTrackTM System is being used to monitor changes in important aspects of cognitive function using tests of attention, information processing and episodic memory. On study entry, the participants performed CogTrackTM up to three times over seven days, and these data are evaluated in this paper. RESULTS: During the first six months of the study, 14 531 individuals aged 50 to 94 years enrolled and performed the CogTrackTM System, 8627 of whom completed three test sessions. On the first administration, 99.4% of the study tasks were successfully completed. Repeated testing showed training/familiarisation effects on four of the ten measures which had largely stabilised by the third test session. The factor structure of the various measures was found to be robust. Evaluation of the influence of age identified clinically relevant declines over the age range of the population on one or more measures from all tasks. CONCLUSIONS: The results of these analyses identify CogTrackTM to be a practical and valid method to reliably, sensitively, remotely and repeatedly collect cognitive data from large samples of individuals aged 50 and over. Copyright © 2017 John Wiley & Sons, Ltd.

Effects of levomilnacipran extended-release on major depressive disorder patients with cognitive impairments: post-hoc analysis of a phase III study.

Performance-based cognitive data were collected using the Cognitive Drug Research System in a study of levomilnacipran extended-release (ER) 40-120 mg/day (NCT01034462) in adults with major depressive disorder. These data were analyzed post-hoc to explore the relationship between cognitive measures, depression symptoms (Montgomery-Åsberg Depression Rating Scale, MADRS), and self-reported psychosocial functioning (Sheehan Disability Scale; SDS). Changes from baseline were analyzed in the intent-to-treat population and subgroups with impaired attention, as indicated by baseline Cognitive Drug Research System scores for Power of Attention and Continuity of Attention. Path analyses evaluated the direct and indirect effects of levomilnacipran ER on SDS total score change. Significantly greater improvements were observed for levomilnacipran ER versus placebo for Power of Attention, Continuity of Attention, MADRS, and SDS score changes; the mean differences were larger in the impaired subgroups than in the overall intent-to-treat population. Path analyses showed that the majority of SDS total score improvement (≥50%) was attributable to an indirect treatment effect through MADRS total score change; some direct effect of levomilnacipran ER on SDS total score improvement was also observed. In adults with major depressive disorder, levomilnacipran ER effectively improved measures of depression and cognition, which contributed toward reductions in self-reported functional impairment.

Predicting Risk of Cognitive Decline in Very Old Adults Using Three Models: The Framingham Stroke Risk Profile; the Cardiovascular Risk Factors, Aging, and Dementia Model; and Oxi-Inflammatory Biomarkers.

OBJECTIVES: To examine the Framingham Stroke Risk Profile (FSRP); the Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) risk score, and oxi-inflammatory load (cumulative risk score of three blood biomarkers-homocysteine, interleukin-6, C-reactive protein) for associations with cognitive decline using three cohort studies of very old adults and to examine whether incorporating these biomarkers with the risk scores can affect the association with cognitive decline. DESIGN: Three longitudinal, population-based cohort studies. SETTING: Newcastle-upon-Tyne, United Kingdom; Leiden, the Netherlands; and Lakes and Bay of Plenty District Health Board areas, New Zealand. PARTICIPANTS: Newcastle 85+ Study participants (n = 616), Leiden 85-plus Study participants (n = 444), and Life and Living in Advanced Age, a Cohort Study in New Zealand (LiLACS NZ Study) participants (n = 396). MEASUREMENTS: FSRP, CAIDE risk score, oxi-inflammatory load, FSRP incorporating oxi-inflammatory load, and CAIDE risk score incorporating oxi-inflammatory load. Oxi-inflammatory load could be calculated only in the Newcastle 85+ and the Leiden 85-plus studies. Measures of global cognitive function were available for all three data sets. Domain-specific measures were available for the Newcastle 85+ and the Leiden 85-plus studies. RESULTS: Meta-analysis of pooled results showed greater risk of incident global cognitive impairment with higher FSRP (hazard ratio (HR) = 1.46, 95% confidence interval (CI) = 1.08-1.98), CAIDE (HR = 1.53, 95% CI = 1.09-2.14), and oxi-inflammatory load (HR = 1.73, 95% CI = 1.04-2.88) scores. Adding oxi-inflammatory load to the risk scores increased the risk of cognitive impairment for the FSRP (HR = 1.65, 95% CI = 1.17-2.33) and the CAIDE model (HR = 1.93, 95% CI = 1.39-2.67). CONCLUSION: Adding oxi-inflammatory load to cardiovascular risk scores may be useful for determining risk of cognitive impairment in very old adults.

Single-Dose Interaction Study of the Arginine Vasopressin Type 1B Receptor Antagonist ABT-436 and Alcohol in Moderate Alcohol Drinkers.

BACKGROUND: ABT-436, a potent and selective arginine vasopressin (AVP) type 1B receptor (V1B ) antagonist, has previously demonstrated basal hypothalamic-pituitary-adrenal (HPA) axis attenuation in man. A V1B antagonist is hypothesized as an alcohol-dependent treatment based on the role of the V1B receptor in stress regulation and the finding that stress is a trigger for relapse in alcoholics. A V1B antagonist has shown favorable effects in rat models of alcohol dependence. A single-dose clinical study was conducted to assess the potential for pharmacokinetic or pharmacodynamic interaction between ABT-436 and alcohol. METHODS: Twenty moderate alcohol drinkers each received the 4 possible combinations of a single 1,000 mg ABT-436 dose (or matching placebo) and a single 0.5 g/kg alcohol dose (or placebo for alcohol) in a double-blind, randomized, 4-period crossover study. Plasma ABT-436 and blood alcohol levels were measured to assess pharmacokinetic interactions. A computerized cognitive test battery (CDR System), Bond-Lader Visual Analog Scales scales, and a postural stability test were used to measure the effects of alcohol and the potential interaction with ABT-436. The pharmacologic effect of ABT-436 was assessed by measuring serum cortisol. RESULTS: Neither ABT-436 nor alcohol affected the blood levels of the other. Alcohol reduced performance on 2 of 5 CDR System composite variables (power of attention, p = 0.002; quality of secondary episodic memory, p < 0.001), and decreased postural stability (p = 0.043). ABT-436 did not exacerbate those deleterious effects. ABT-436 reduced serum cortisol (p < 0.001), and alcohol did not significantly diminish this expected effect on the HPA axis. CONCLUSIONS: No pharmacokinetic or pharmacodynamic interaction between ABT-436 and alcohol was observed.