Cognitive Function in Adults with Enduring Anorexia Nervosa.

Anorexia Nervosa (AN) is a severe and often enduring disorder characterized by restriction of food intake, low body weight, fear of weight gain, and distorted body image. Investigations on cognition performance in AN patients have yielded conflicting results. Using an established and sensitive computerized cognitive test battery, we aimed to assess core aspects of cognitive function, including attention span, information processing, reasoning, working and episodic memory, in AN patients and controls. Patients were recruited from the Danish Prospective Longitudinal all-comer inclusion study in Eating Disorders (PROLED). Included were 26 individuals with AN and 36 healthy volunteers (HV). All were tested with CogTrack (an online cognitive assessment system) at baseline, and AN patients were tested again at a follow-up time point after weight increase (n = 13). At baseline, AN patients showed faster reaction times in the attention tasks, as well as increased accuracy in grammatical reasoning compared to HV. There were no differences in cognitive function between AN patients and HV in the other cognitive domains measured (sustained attention, working and episodic memory, speed of retrieval, and speed of grammatical reasoning). No differences were visible in the AN sample between baseline and follow-up. Performance did not correlate with any clinical variables in the AN sample. These findings supplement results from other studies suggesting increased concentration and reasoning accuracy in patients suffering from AN, who showed increased performance in cognitive tasks despite their illness.

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.

FLAME: A computerized neuropsychological composite for trials in early dementia.

INTRODUCTION: Sensitive neuropsychological tests are needed to improve power for clinical trials in early Alzheimer's disease (AD). METHODS: To develop a neuropsychological composite (FLAME - Factors of Longitudinal Attention, Memory and Executive Function), we assessed, 10,714 participants over the age of 50 from PROTECT with validated computerized assessments for 2 years. A factorial analysis was completed to identify the key cognitive factors in all participants, and further analyses examined sensitivity to change in people with stage 2/3 early Alzheimer's disease (AD) according to the US Food and Drug Administration (FDA) framework. RESULTS: The FLAME composite score (speed of attention, accuracy of attention, memory, and executive function) distinguished between normal cognition and stage 2/3 early AD at baseline, and was sensitive to cognitive and global/functional decline over 2 years, with the potential to improve power for clinical trials. DISCUSSION: FLAME is sensitive to change, providing a straightforward approach to reduce sample size for RCTs in early AD. CONCLUSION: FLAME is a useful computerized neuropsychology composite with utility for clinical trials focusing on cognition.

Tea consumption and measures of attention and psychomotor speed in the very old: the Newcastle 85+ longitudinal study.

BACKGROUND: A number of studies have indicated a beneficial effect of tea consumption on the reduction of risk of cognitive impairment and dementia in older aged populations. However, there is a paucity of data on these associations in the very old, defined as individuals aged 85 years and over. We investigated the relationship between tea consumption in the very old and measures of global cognitive function, memory, attention and psychomotor speed. METHOD: Longitudinal (5-years), population-based cohort study of individuals aged 85+ years in the North East of England, United Kingdom. Participants were community-dwelling and institutionalized men and women recruited through general medical practices (n = 676). Baseline tea consumption and longitudinal measures of global and domain specific (memory, speed and attention) cognitive function were assessed. Linear mixed models, controlling for demographic (e.g. age, sex and education) and health variables were used to determine whether tea consumption was protective against cognitive decline. RESULTS: Tea consumption was not associated with cognitive function at baseline on any measure (unadjusted and adjusted analyses). In the linear mixed effects models adjusted for age, sex, education and disease co-morbidity, higher tea consumption was associated with significantly better attention (focused and sustained attention), and psychomotor speed (complex tasks only) over five-years follow-up. However, there was no association between tea consumption and global cognitive function, memory or performance on simple speed tasks over time. CONCLUSIONS: In this cohort study of non-demented very old adults we found that higher (vs. lower) tea consumption was associated with better performance over time on measures of focused and sustained attention and some psychomotor speed tasks. No associations with global cognition, memory or easy speed tasks (simple Reaction Time or Word Recognition) were detected. The results have implications for the development of possible diet-based interventions focused on improving cognitive function in the very old age group. These findings need to be confirmed in a sufficiently powered and well-designed RCT with non-demented very old adults.

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.

CoQ10 and Cognition a Review and Study Protocol for a 90-Day Randomized Controlled Trial Investigating the Cognitive Effects of Ubiquinol in the Healthy Elderly.

Introduction: With an aging population there is an important need for the development of effective treatments for the amelioration of cognitive decline. Multiple mechanisms underlie age-related cognitive decline including cerebrovascular disease, oxidative stress, reduced antioxidant capacity and mitochondrial dysfunction. CoQ10 is a novel treatment which has the potential to improve brain function in healthy elderly populations due to established beneficial effects on mitochondrial function, vascular function and oxidative stress. Methods and Analysis: We describe the protocol for a 90-day randomized controlled trial which examines the efficacy of Ubiquinol (200 mg/day) vs. placebo for the amelioration of cognitive decline in a healthy (non-demented) elderly sample, aged 60 years and over. The primary outcome is the effect of Ubiquinol at 90 days compared to baseline on CogTrack composite measures of cognition. Additional cognitive measures, as well as measures of cardiovascular function, oxidative stress, liver function and mood will also be monitored across 30-, 60- and 90- day time points. Data analyses will involve repeated measures analysis of variance (ANOVA). Discussion: This study will be the first of its kind to provide important clinical and mechanistic data regarding the efficacy of Ubiquinol as a treatment for age-related cognitive decline in the healthy elderly with important implications for productivity and quality of life within this age group. Clinical Trial Registration: The trial has been registered with the Australian and New Zealand Clinical Trials Registry (ANZCTRN12618001841268).

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.

Investigating the relationship between age of onset of depressive disorder and cognitive function.

OBJECTIVES: Depressive disorder is commonly associated with impaired cognitive function; however, it is unclear whether the age of onset of the first episode of depression, current depression severity, or historical severity of depressive episodes are associated with cognitive performance. METHODS: This study examined baseline cross-sectional data from the ongoing online PROTECT study. A total of 7344 participants, 50 years or older, with a history of depression and no diagnosis of dementia were divided into three groups according to age of onset of their first depressive episode: early-onset, midlife-onset, and late-onset. Performance on measures of visuospatial episodic memory, executive function, verbal working, and visual working memory were evaluated. Demographic and clinical characteristics such as age, education, and severity of symptoms during their worst previous depressive episode and current depression severity were included in multivariate regression models. RESULTS: The late-onset depression group scored significantly lower on the verbal reasoning task than the early-onset group while there were no significant differences found on the other tasks. Midlife-onset depression participants performed better in the visual episodic memory task, but worse on the verbal reasoning task, than early-onset depression participants. Current depression severity was negatively correlated with all four cognitive domains, while historical severity score was found to be significantly associated with cognitive performance on the verbal reasoning and spatial working memory tasks. CONCLUSIONS: The most important indicator of cognitive performance in depression appears to be current, rather than historic depression severity; however, late-onset depression may be associated with more executive impairment than an early-onset depression.

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.

Poor cognitive ageing: Vulnerabilities, mechanisms and the impact of nutritional interventions.

BACKGROUND: Ageing is a highly complex process marked by a temporal cascade of events, which promote alterations in the normal functioning of an individual organism. The triggers of normal brain ageing are not well understood, even less so the factors which initiate and steer the neuronal degeneration, which underpin disorders such as dementia. A wealth of data on how nutrients and diets may support cognitive function and preserve brain health are available, yet the molecular mechanisms underlying their biological action in both normal ageing, age-related cognitive decline, and in the development of neurodegenerative disorders have not been clearly elucidated. OBJECTIVES: This review aims to summarise the current state of knowledge of vulnerabilities that predispose towards dysfunctional brain ageing, highlight potential protective mechanisms, and discuss dietary interventions that may be used as therapies. A special focus of this paper is on the impact of nutrition on neuroprotection and the underlying molecular mechanisms, and this focus reflects the discussions held during the 2nd workshop 'Nutrition for the Ageing Brain: Functional Aspects and Mechanisms' in Copenhagen in June 2016. The present review is the most recent in a series produced by the Nutrition and Mental Performance Task Force under the auspice of the International Life Sciences Institute Europe (ILSI Europe). CONCLUSION: Coupling studies of cognitive ageing with studies investigating the effect of nutrition and dietary interventions as strategies targeting specific mechanisms, such as neurogenesis, protein clearance, inflammation, and non-coding and microRNAs is of high value. Future research on the impact of nutrition on cognitive ageing will need to adopt a longitudinal approach and multimodal nutritional interventions will likely need to be imposed in early-life to observe significant impact in older age.

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.

Tolerability of ORM-12741 and effects on episodic memory in patients with Alzheimer's disease.

INTRODUCTION: ORM-12741 is a novel selective antagonist of alpha-2C adrenoceptors. This trial evaluated the safety and efficacy of ORM-12741 in patients with Alzheimer's disease (AD). METHODS: A randomized, double-blind, placebo-controlled, exploratory phase 2a trial was conducted in 100 subjects with AD and neuropsychiatric symptoms. Participants were randomized to receive one of two flexible doses of ORM-12741 (30-60 mg or 100-200 mg) or placebo b.i.d. for 12 weeks in addition to standard therapy with cholinesterase inhibitors. Efficacy was assessed primarily with the Cognitive Drug Research (CDR) computerized assessment system and secondarily with the Neuropsychiatric Inventory (NPI). RESULTS: A statistically significant treatment effect was seen in one of the four primary CDR system end points, Quality of Episodic Memory (P = .030; not adjusted for multiple comparisons), favoring ORM-12741 over placebo. NPI caregiver distress scores also favored ORM-12741 (P = .034). ORM-12741 was well tolerated. DISCUSSION: This is the first clinical trial providing evidence on an acceptable safety profile for ORM-12741 in patients with AD and neuropsychiatric symptoms. In addition, the trial provided hints of potential therapeutic benefit, primarily on episodic memory, in this patient population.