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IntroductionThe development of high-quality stated preference (SP) surveys requires a rigorous design process involving engagement with representatives from the target population. However, while transparency in the reporting of the development of SP surveys is encouraged, few studies report on this process and the outcomes. Recommended stages of instrument development includes both steps for stakeholder/end-user engagement and pretesting. Pretesting typically involves interviews, often across multiple waves, with improvements made at each wave; pretesting is therefore resource intensive. The aims of this paper are to report on the outcomes of collaboration with a Lewy body dementia research advisory group during the design phase of a SP survey. We also evaluate an alternative approach to instrument development, necessitated by a resource constrained context.MethodThe approach involved conducting the stages of end-user engagement and pretesting together during a public involvement event. A hybrid approach involving a focus group with breakout interviews was employed. Feedback from contributors informed the evolution of the survey instrument.ResultsChanges to the survey instrument were organized into four categories: attribute modifications; choice task presentation and understanding; information presentation, clarity and content; and best-best scaling presentation. The hybrid approach facilitated group brainstorming while still allowing the researcher to assess the feasibility of choice tasks in an interview setting. However, greater individual exploration and the opportunity to trial iterative improvements across waves was not feasible with this approach.DiscussionInvolvement of the research advisory group resulted in a more person-centered survey design. In a context constrained by time and budget, and with consideration of the capacity and vulnerability of the target population, the approach taken was a feasible and pragmatic mechanism for improving the design of a SP survey.

Post-mortem brain tissue from patients with Dementia with Lewy bodies shows differentially methylated CpG sites and potential epigenetic associations with other conditions such as mood disorders and Parkinson’s Disease.

Abstract Delirium is an acute change in attention and cognition occurring in ~ 65% of severe SARS-CoV-2 cases. It is also common following surgery and an indicator of brain vulnerability and risk for the development of dementia. In this work we analyzed the underlying role of metabolism in delirium-susceptibility in the postoperative setting using metabolomic profiling of cerebrospinal fluid and blood taken from the same patients prior to planned orthopaedic surgery. Distance correlation analysis and Random Forest (RF) feature selection were used to determine changes in metabolic networks. We found significant concentration differences in several amino acids, acylcarnitines and polyamines linking delirium-prone patients to known factors in Alzheimer’s disease such as monoamine oxidase B (MAOB) protein. Subsequent computational structural comparison between MAOB and angiotensin converting enzyme 2 as well as protein–protein docking analysis showed that there potentially is strong binding of SARS-CoV-2 spike protein to MAOB. The possibility that SARS-CoV-2 influences MAOB activity leading to the observed neurological and platelet-based complications of SARS-CoV-2 infection requires further investigation.

Abstract Background Type 2 diabetes is a risk factor for Alzheimer’s disease (AD), and AD brain shows impaired insulin signalling. The role of peripheral insulin resistance on AD aetiopathogenesis in non-diabetic patients is still debated. Here we evaluated the influence of insulin resistance on brain glucose metabolism, grey matter volume and white matter lesions (WMLs) in non-diabetic AD subjects. Methods In total, 130 non-diabetic AD subjects underwent MRI and [18F]FDG PET scans with arterial cannula insertion for radioactivity measurement. T1 Volumetric and FLAIR sequences were acquired on a 3-T MRI scanner. These subjects also had measurement of glucose and insulin levels after a 4-h fast on the same day of the scan. Insulin resistance was calculated by the updated homeostatic model assessment (HOMA2). For [18F]FDG analysis, cerebral glucose metabolic rate (rCMRGlc) parametric images were generated using spectral analysis with arterial plasma input function. Results In this non-diabetic AD population, HOMA2 was negatively associated with hippocampal rCMRGlc, along with total grey matter volumes. No significant correlation was observed between HOMA2, hippocampal volume and WMLs. Conclusions In non-diabetic AD, peripheral insulin resistance is independently associated with reduced hippocampal glucose metabolism and with lower grey matter volume, suggesting that peripheral insulin resistance might influence AD pathology by its action on cerebral glucose metabolism and on neurodegeneration.

Abstract Background People with dementia (PwD) face unique challenges with medicines management, yet little is known about these challenges from the perspectives of primary healthcare professionals, particularly general practitioners (GPs) and community pharmacists. Few medicines management interventions have been developed which are aimed at community-dwelling PwD. This study sought to develop an intervention to improve medicines management for PwD in primary care using a theory-informed approach. Methods Semi-structured interviews were conducted with GPs (n = 15) and community pharmacists (n = 15) to explore participants’ views and experiences of medicines management for PwD, and their perceptions of barriers and facilitators to successful medicines management for PwD. The 14-domain Theoretical Domains Framework was the underpinning theoretical guide, allowing key theoretical domains to be identified and mapped to behaviour change techniques (BCTs) which are considered the ‘active ingredients’ of an intervention. Draft interventions were developed to operationalise selected BCTs and were presented to GPs and community pharmacists during task groups. Final selection of an intervention for feasibility testing was guided by feedback provided during these task groups and through application of the APEASE (Affordability, Practicability, Effectiveness/cost-effectiveness, Acceptability, Side-effects/safety, Equity) criteria. Results Participants expressed a number of concerns about medicines management for PwD, particularly monitoring adherence to medication regimens and conducting medication review. Two draft interventions comprising selected BCTs (‘Modelling or demonstration of behaviour’; ‘Salience of consequences’; ‘Health consequences’; ‘Social and environmental consequences’; ‘Action planning’; Social support or encouragement’, ‘Self-monitoring of behaviour’) were developed, each targeting GPs and community pharmacists. Following the task groups and discussions within the research team, the community pharmacy-based intervention was selected for future feasibility testing. The intervention will target community pharmacists to conduct a medication review (incorporating an adherence check) with a PwD, delivered as an online video demonstrating key behaviours. The video will include feedback emphasising positive outcomes of performing the behaviours. Action planning and a quick reference guide will be used as complementary intervention components. Conclusions A community pharmacist-based intervention has been developed targeting medicines management for PwD in primary care using a systematic, theory-informed approach. Future work will determine the usability and acceptability of implementing this intervention in clinical practice.

Background: Medications that modify the renin–angiotensin system may reduce Alzheimer’s disease pathology and reduce the rate of disease progression. Objective: This study investigated whether taking the antihypertensive drug losartan, in addition to normal care, would slow the progression of Alzheimer’s disease when compared with a placebo. Design: A double-blind multicentre randomised controlled trial, after a 4-week open-label phase, with follow-up at 14 days and at 3, 6, 9 and 12 months. The primary outcome was based on measured imaging differences in brain volume between baseline and 12 months. Setting: Twenty-three NHS hospital trusts across England, Scotland and Northern Ireland. Participants: Patients diagnosed with mild-to-moderate Alzheimer’s disease were eligible to participate if they met the following criteria: (1) aged ≥ 55 years; (2) a Mini Mental State Examination score of 15–28; (3) a modified Hachinski Ischaemic Score of ≤ 5; (4) a previous computerised tomography, single-photon emission computed tomography or magnetic resonance imaging scan consistent with a diagnosis of Alzheimer’s disease; (5) a study companion who was willing to participate in the study; and (6) capacity to consent for themselves. Patients were ineligible if they were (1) taking or intolerant to renin–angiotensin system-related medications, (2) unlikely to undergo magnetic resonance imaging or (3) unlikely to complete the trial protocol. People who had blood pressure outside the normal ranges, defined cardiovascular issues, impaired liver or renal function, or a primary neurodegenerative disease that was not Alzheimer’s disease were also excluded, as were women who had not reached menopause and were unwilling to take relevant protocol-specific safety precautions. Intervention: The intervention was either 100 mg of overencapsulated losartan (Teva Pharmaceuticals Industries Ltd, Petah Tikva, Israel) daily or a matched placebo for 12 months. Main outcome measures: Difference in brain atrophy, represented by measurement of whole-brain volume before and following 12 months of treatment post randomisation, was measured using volumetric MRI and determined by boundary shift interval analysis. Secondary outcomes included changes in rates of Alzheimer’s disease progression (as assessed using the ADAS-Cog, Mini Mental State Examination and Neuropsychiatric Inventory), the volume of white matter hyperintensities, cerebral blood flow (assessed by magnetic resonance imaging), blood pressure, magnetic resonance imaging measures of atrophy and association with measures of cognitive decline, and drug compliance and tolerability. Results: A total of 261 participants entered the open-label phase, of whom 211 were randomised to the intervention (n = 105) or placebo (n = 106) arms. Of the 197 people (93%) who completed the study, 81% (n = 171) had a valid primary outcome. The difference in brain volume between arms was consistent with chance (–2.79 ml, 95% confidence interval –6.46 to 0.89 ml; p = 0.19), and there was no evidence of benefit for any of the secondary outcome measures. Limitations: Our study had 82% power to detect treatment-based changes and, as a result, may have been underpowered or, more likely, the intervention, which may not have crossed the blood–brain barrier as much as expected, may have been given too late or for an insufficient amount of time in the disease process to influence the outcomes. Conclusions: Losartan administered over 12 months did not alter brain atrophy in Alzheimer’s disease. Future work: Other related ‘sartans’ could be tested in patient groups with mild cognitive impairment and for longer to fully test this hypothesis. Trial registration: Current Controlled Trials ISRCTN93682878 and EudraCT 2012-003641-15. Funding: This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 8, No. 19. See the NIHR Journals Library website for further project information.

Abstract Background Mild cognitive impairment (MCI) among an aging global population is a growing challenge for healthcare providers and payers. In many cases, MCI is an ominous portent for dementia. Early and accurate diagnosis of MCI provides a window of opportunity to improve the outcomes using a personalized care plan including lifestyle modifications to reduce the impact of modifiable risk factors (for example, blood pressure control and increased physical activity), cognitive training, dietary advice, and nutritional support. Souvenaid is a once-daily drink containing a mixture of precursors and cofactors (long-chain omega-3 fatty acids, uridine, choline, B vitamins, vitamin C, vitamin E, and selenium), which was developed to support the formation and function of neuronal membranes and synapses. Healthcare providers, patients, and carers require expert advice about the use of Souvenaid. Methods An international panel of experts was convened to review the evidence and to make recommendations about the diagnosis and management of MCI, identification of candidates for Souvenaid, and use of Souvenaid in real-world practice. This article provides a summary of the expert opinions and makes recommendations for clinical practice and future research. Summary of opinion Early diagnosis of MCI requires the use of suitable neuropsychological tests combined with a careful clinical history. A multimodal approach is recommended; dietary and nutritional interventions should be considered alongside individualized lifestyle modifications. Although single-agent nutritional supplements have failed to produce cognitive benefits for patients with MCI, a broader nutritional approach warrants consideration. Evidence from randomized controlled trials suggests that Souvenaid should be considered as an option for some patients with early Alzheimer’s disease (AD), including those with MCI due to AD (prodromal AD). Conclusion Early and accurate diagnosis of MCI provides a window of opportunity to improve the outcomes using a multimodal management approach including lifestyle risk factor modification and consideration of the multinutrient Souvenaid.

Abstract Background Liraglutide is a glucagon-like peptide-1 (GLP-1) analogue currently approved for type 2 diabetes and obesity. Preclinical evidence in transgenic models of Alzheimer’s disease suggests that liraglutide exerts neuroprotective effects by reducing amyloid oligomers, normalising synaptic plasticity and cerebral glucose uptake, and increasing the proliferation of neuronal progenitor cells. The primary objective of the study is to evaluate the change in cerebral glucose metabolic rate after 12 months of treatment with liraglutide in participants with Alzheimer’s disease compared to those who are receiving placebo. Methods/design ELAD is a 12-month, multi-centre, randomised, double-blind, placebo-controlled, phase IIb trial of liraglutide in participants with mild Alzheimer’s dementia. A total of 206 participants will be randomised to receive either liraglutide or placebo as a daily injection for a year. The primary outcome will be the change in cerebral glucose metabolic rate in the cortical regions (hippocampus, medial temporal lobe, and posterior cingulate) from baseline to follow-up in the treatment group compared with the placebo group. The key secondary outcomes are the change from baseline to 12 months in z scores for clinical and cognitive measures (Alzheimer’s Disease Assessment Scale—Cognitive Subscale and Executive domain scores of the Neuropsychological Test Battery, Clinical Dementia Rating Sum of Boxes, and Alzheimer’s Disease Cooperative Study—Activities of Daily Living) and the incidence and severity of treatment-emergent adverse events or clinically important changes in safety assessments. Other secondary outcomes are 12-month change in magnetic resonance imaging volume, diffusion tensor imaging parameters, reduction in microglial activation in a subgroup of participants, reduction in tau formation and change in amyloid levels in a subgroup of participants measured by tau and amyloid imaging, and changes in composite scores using support machine vector analysis in the treatment group compared with the placebo group. Discussion Alzheimer’s disease is a leading cause of morbidity worldwide. As available treatments are only symptomatic, the search for disease-modifying therapies is a priority. If the ELAD trial is successful, liraglutide and GLP-1 analogues will represent an important class of compounds to be further evaluated in clinical trials for Alzheimer’s treatment. Trial registration ClinicalTrials.gov, NCT01843075. Registration 30 April 2013.

Access to affordable, objective and scalable biomarkers of brain function is needed to transform the healthcare burden of neuropsychiatric and neurodegenerative disease. Electroencephalography (EEG) recordings, both resting and in combination with targeted cognitive tasks, have demonstrated utility in tracking disease state and therapy response in a range of conditions from schizophrenia to Alzheimer's disease. But conventional methods of recording this data involve burdensome clinic visits, and behavioural tasks that are not effective in frequent repeated use. This paper aims to evaluate the technical and human-factors feasibility of gathering large-scale EEG using novel technology in the home environment with healthy adult users. In a large field study, 89 healthy adults aged 40–79 years volunteered to use the system at home for 12 weeks, 5 times/week, for 30 min/session. A 16-channel, dry-sensor, portable wireless headset recorded EEG while users played gamified cognitive and passive tasks through a tablet application, including tests of decision making, executive function and memory. Data was uploaded to cloud servers and remotely monitored via web-based dashboards. Seventy-eight participants completed the study, and high levels of adherence were maintained throughout across all age groups, with mean compliance over the 12-week period of 82% (4.1 sessions per week). Reported ease of use was also high with mean System Usability Scale scores of 78.7. Behavioural response measures (reaction time and accuracy) and EEG components elicited by gamified stimuli (P300, ERN, Pe and changes in power spectral density) were extracted from the data collected in home, across a wide range of ages, including older adult participants. Findings replicated well-known patterns of age-related change and demonstrated the feasibility of using low-burden, large-scale, longitudinal EEG measurement in community-based cohorts. This technology enables clinically relevant data to be recorded outside the lab/clinic, from which metrics underlying cognitive ageing could be extracted, opening the door to potential new ways of developing digital cognitive biomarkers for disorders affecting the brain.

Abstract Introduction The increasing number of people with dementia (PwD) is a significant health and financial challenge for countries. PwD often transition to a care home. This study explored factors predicting transition to care homes for PwD and the place and causes of death. Methods Data about dementia medication, care home transitions, demographic characteristics, deaths, and hospital admissions were extracted from national databases from 2010 to 2016. Results PwD (n = 25,418) were identified through prescriptions of dementia medication, from which 11,930 transitioned to care homes. A logistic regression showed that increased age, female sex, living in less deprived and urban areas, and hospital admissions predicted this transition. PwD who transition to care homes are more likely to die there. The most common cause of death was dementia. Discussion Certain demographic characteristics are significant predictors for care home transitions and they should be considered in the development of early community‐based care services to delay transitions. In the last decades, dementia has been reported more frequently in death certificates.

Abstract Background Pain assessment and management in advanced and end-stage dementia are challenging; patients are at risk of under-diagnosis, under-assessment and under-treatment. Previous research has highlighted the importance of needs-driven training and development in this area for physicians, nurses and healthcare assistants (HCAs) across specialties, disciplines and care settings. This study used teleconferencing technology to connect healthcare professionals across multiple settings and disciplines in real-time clinics, based on the Project ECHO© model. This paper reports the evaluation of the clinics by physicians, nurses and HCAs, including their knowledge and self-efficacy in pain assessment and management for patients with advanced and end-stage dementia. Methods A mixed method evaluation comprising quantitative survey of self-reported knowledge and self-efficacy pre- and post-ECHO clinic participation, and qualitative exploration of experiences of the clinics using focus group interviews. A census approach to sampling was undertaken. Pre- and post-ECHO evaluations were administered electronically using Survey Monkey software. Mann-Whitney U tests were used to explore differences in knowledge and self-efficacy scores pre- and post-ECHO clinic participation. Statistical significance was set a-priori at p = 0.05. Focus groups were video- and audio-recorded, transcribed verbatim and analysed using Braun & Clarke’s model of thematic analysis. Results Eighteen healthcare professionals [HCPs] (physicians [n = 7], nurses [n = 10], HCA [n = 1]) and twenty HCPs (physicians [n = 10], nurses [n = 10]) completed pre- and post-ECHO evaluations respectively, reporting improvements in knowledge and self-efficacy on participation in ECHO clinics and perceived utility of the clinics. Seven HCPs (physicians [n = 2], nurses [n = 5]) participated in two focus groups. Four themes emerged: knowledge and skills development and dissemination; protected time; areas for improvement; and the future of ECHO. Conclusions Telementoring clinics for HCP education and training in pain assessment and management in advanced and end-stage dementia demonstrate a positive impact on knowledge and self-efficacy of HCPs and highlight the value of a cross-specialty network of practice which spans across disciplines/HCP types, care settings and geographical areas. Further development of ECHO services in this and in other clinical areas, shows significant potential to support delivery of high-quality care to complex patient populations.

Alzheimer’s disease (AD) is reported to be closely linked with abnormal lipid metabolism. To gain a more comprehensive understanding of what causes AD and its subsequent development, we profiled the lipidome of postmortem (PM) human brains (neocortex) of people with a range of AD pathology (Braak 0–6). Using high-resolution mass spectrometry, we employed a semi-targeted, fully quantitative lipidomics profiling method (Lipidyzer) to compare the biochemical profiles of brain tissues from persons with mild AD (n = 15) and severe AD (AD; n = 16), and compared them with age-matched, cognitively normal controls (n = 16). Univariate analysis revealed that the concentrations of 420 lipid metabolites significantly (p < 0.05; q < 0.05) differed between AD and controls. A total of 49 lipid metabolites differed between mild AD and controls, and 439 differed between severe AD and mild AD. Interestingly, 13 different subclasses of lipids were significantly perturbed, including neutral lipids, glycerolipids, glycerophospholipids, and sphingolipids. Diacylglycerol (DAG) (14:0/14:0), triacylglycerol (TAG) (58:10/FA20:5), and TAG (48:4/FA18:3) were the most notably altered lipids when AD and control brains were compared (p < 0.05). When we compare mild AD and control brains, phosphatidylethanolamine (PE) (p-18:0/18:1), phosphatidylserine (PS) (18:1/18:2), and PS (14:0/22:6) differed the most (p < 0.05). PE (p-18:0/18:1), DAG (14:0/14:0), and PS (18:1/20:4) were identified as the most significantly perturbed lipids when AD and mild AD brains were compared (p < 0.05). Our analysis provides the most extensive lipid profiling yet undertaken in AD brain tissue and reveals the cumulative perturbation of several lipid pathways with progressive disease pathology. Lipidomics has considerable potential for studying AD etiology and identifying early diagnostic biomarkers.

Abstract Background A general practitioner (GP)-targeted intervention aimed at improving the prescribing of appropriate polypharmacy for older people was previously developed using a systematic, theory-based approach based on the UK Medical Research Council’s complex intervention framework. The primary intervention component comprised a video demonstration of a GP prescribing appropriate polypharmacy during a consultation with an older patient. The video was delivered to GPs online and included feedback emphasising the positive outcomes of performing the behaviour. As a complementary intervention component, patients were invited to scheduled medication review consultations with GPs. This study aimed to test the feasibility of the intervention and study procedures (recruitment, data collection). Methods GPs from two general practices were given access to the video, and reception staff scheduled consultations with older patients receiving polypharmacy (≥4 medicines). Primary feasibility study outcomes were the usability and acceptability of the intervention to GPs. Feedback was collected from GP and patient participants using structured questionnaires. Clinical data were also extracted from recruited patients’ medical records (baseline and 1 month post-consultation). The feasibility of applying validated assessment of prescribing appropriateness (STOPP/START criteria, Medication Appropriateness Index) and medication regimen complexity (Medication Regimen Complexity Index) to these data was investigated. Data analysis was descriptive, providing an overview of participants’ feedback and clinical assessment findings. Results Four GPs and ten patients were recruited across two practices. The intervention was considered usable and acceptable by GPs. Some reservations were expressed by GPs as to whether the video truly reflected resource and time pressures encountered in the general practice working environment. Patient feedback on the scheduled consultations was positive. Patients welcomed the opportunity to have their medications reviewed. Due to the short time to follow-up and a lack of detailed clinical information in patient records, it was not feasible to detect any prescribing changes or to apply the assessment tools to patients’ clinical data. Conclusion The findings will help to further refine the intervention and study procedures (including time to follow-up) which will be tested in a randomised pilot study that will inform the design of a definitive trial to evaluate the intervention’s effectiveness. Trial registration ISRCTN18176245

Late onset Alzheimer's disease is the most common form of dementia for which about 30 susceptibility loci have been reported. The aim of the current study is to identify novel genes associated with Alzheimer's disease using the largest up-to-date reference single nucleotide polymorphism (SNP) panel, the most accurate imputation software and a novel gene-based analysis approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 million genotypes from 17,008 Alzheimer's cases and 37,154 controls. In addition to earlier reported genes, we detected three novel gene-wide significant loci PPARGC1A (p = 2.2 × 10-6), RORA (p = 7.4 × 10-7) and ZNF423 (p = 2.1 × 10-6). PPARGC1A and RORA are involved in circadian rhythm; circadian disturbances are one of the earliest symptoms of Alzheimer's disease. PPARGC1A is additionally linked to energy metabolism and the generation of amyloid beta plaques. RORA is involved in a variety of functions apart from circadian rhythm, such as cholesterol metabolism and inflammation. The ZNF423 gene resides in an Alzheimer's disease-specific protein network and is likely involved with centrosomes and DNA damage repair.

Abstract Background It is advocated that interventions to improve clinical practice should be developed using a systematic approach and intervention development methods should be reported. However, previous interventions aimed at ensuring that older people receive appropriate polypharmacy have lacked details on their development. This study formed part of a multiphase research project which aimed to develop an intervention to improve appropriate polypharmacy in older people in primary care. Methods The target behaviours for the intervention were prescribing and dispensing of appropriate polypharmacy to older patients by general practitioners (GPs) and community pharmacists. Intervention development followed a systematic approach, including previous mapping of behaviour change techniques (BCTs) to key domains from the Theoretical Domains Framework that were perceived by GPs and pharmacists to influence the target behaviours. Draft interventions were developed to operationalise selected BCTs through team discussion. Selection of an intervention for feasibility testing was guided by a subset of the APEASE (Affordability, Practicability, Effectiveness/cost-effectiveness, Acceptability, Side-effects/safety, Equity) criteria. Results Three draft interventions comprising selected BCTs were developed, targeting patients, pharmacists and GPs, respectively. Following assessment of each intervention using a subset of the APEASE criteria (affordability, practicability, acceptability), the GP-targeted intervention was selected for feasibility testing. This intervention will involve a demonstration of the behaviour and will be delivered as an online video. The video demonstrating how GPs can prescribe appropriate polypharmacy during a typical consultation with an older patient will also demonstrate salience of consequences (feedback emphasising the positive outcomes of performing the behaviour). Action plans and prompts/cues will be used as complementary intervention components. The intervention is designed to facilitate the prescribing of appropriate polypharmacy in routine practice. Conclusion A GP-targeted intervention to improve appropriate polypharmacy in older people has been developed using a systematic approach. Intervention content has been specified using an established taxonomy of BCTs and selected to maximise feasibility. The results of a future feasibility study will help to determine if the theory-based intervention requires further refinement before progressing to a larger scale randomised evaluation.

An amendment to this paper has been published and can be accessed via the original article.

Abstract Introduction Cerebral small‐vessel disease has been implicated in the development of Alzheimer's disease (AD). The retinal microvasculature enables the noninvasive visualization and evaluation of the systemic microcirculation. We evaluated retinal microvascular parameters in a case‐control study of AD patients and cognitively normal controls. Methods Retinal images were computationally analyzed and quantitative retinal parameters (caliber, fractal dimension, tortuosity, and bifurcation) measured. Regression models were used to compute odds ratios (OR) and confidence intervals (CI) for AD with adjustment for confounders. Results Retinal images were available in 213 AD participants and 294 cognitively normal controls. Persons with lower venular fractal dimension (OR per standard deviation [SD] increase, 0.77 [CI: 0.62–0.97]) and lower arteriolar tortuosity (OR per SD increase, 0.78 [CI: 0.63–0.97]) were more likely to have AD after appropriate adjustment. Discussion Patients with AD have a sparser retinal microvascular network and retinal microvascular variation may represent similar pathophysiological events within the cerebral microvasculature of patients with AD.

Background: There is currently no disease-modifying treatment available to halt or delay the progression of the disease pathology in dementia. An agreed core set of the best-available and most appropriate outcomes for disease modification would facilitate the design of trials and ensure consistency across disease modification trials, as well as making results comparable and meta-analysable in future trials. Objectives: To agree a set of core outcomes for disease modification trials for mild to moderate dementia with the UK dementia research community and patient and public involvement (PPI). Data sources: We included disease modification trials with quantitative outcomes of efficacy from (1) references from related systematic reviews in workstream 1; (2) searches of the Cochrane Dementia and Cognitive Improvement Group study register, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature, EMBASE, Latin American and Caribbean Health Sciences Literature and PsycINFO on 11 December 2015, and clinical trial registries [International Standard Randomised Controlled Trial Number (ISRCTN) and clinicaltrials.gov] on 22 and 29 January 2016; and (3) hand-searches of reference lists of relevant systematic reviews from database searches. Review methods: The project consisted of four workstreams. (1) We obtained related core outcome sets and work from co-applicants. (2) We systematically reviewed published and ongoing disease modification trials to identify the outcomes used in different domains. We extracted outcomes used in each trial, recording how many used each outcome and with how many participants. We divided outcomes into the domains measured and searched for validation data. (3) We consulted with PPI participants about recommended outcomes. (4) We presented all the synthesised information at a conference attended by the wider body of National Institute for Health Research (NIHR) dementia researchers to reach consensus on a core set of outcomes. Results: We included 149 papers from the 22,918 papers screened, referring to 125 individual trials. Eighty-one outcomes were used across trials, including 72 scales [31 cognitive, 12 activities of daily living (ADLs), 10 global, 16 neuropsychiatric and three quality of life] and nine biological techniques. We consulted with 18 people for PPI. The conference decided that only cognition and biological markers are core measures of disease modification. Cognition should be measured by the Mini Mental State Examination (MMSE) or the Alzheimer’s Disease Assessment Scale – Cognitive subscale (ADAS-Cog), and brain changes through structural magnetic resonance imaging (MRI) in a subset of participants. All other domains are important but not core. We recommend using the Neuropsychiatric Inventory for neuropsychiatric symptoms: the Disability Assessment for Dementia for ADLs, the Dementia Quality of Life Measure for quality of life and the Clinical Dementia Rating scale to measure dementia globally. Limitations: Most of the trials included participants with Alzheimer’s disease, so recommendations may not apply to other types of dementia. We did not conduct economic analyses. The PPI consultation was limited to members of the Alzheimer’s Society Research Network. Conclusions: Cognitive outcomes and biological markers form the core outcome set for future disease modification trials, measured by the MMSE or ADAS-Cog, and structural MRI in a subset of participants. Future work: We envisage that the core set may be superseded in the future, particularly for other types of dementia. There is a need to develop an algorithm to compare scores on the MMSE and ADAS-Cog. Study registration: The project was registered with Core Outcome Measures in Effectiveness Trials [www.comet-initiative.org/studies/details/819?result=true (accessed 7 April 2016)]. The systematic review protocol is registered as PROSPERO CRD42015027346. Funding: The National Institute for Health Research Health Technology Assessment programme.

BackgroundThere are no disease-modifying treatments for dementia. There is also no consensus on disease modifying outcomes. We aimed to produce the first evidence-based consensus on core outcome measures for trials of disease modification in mild-to-moderate dementia.Methods and findingsWe defined disease-modification interventions as those aiming to change the underlying pathology. We systematically searched electronic databases and previous systematic reviews for published and ongoing trials of disease-modifying treatments in mild-to-moderate dementia. We included 149/22,918 of the references found; with 81 outcome measures from 125 trials. Trials involved participants with Alzheimer's disease (AD) alone (n = 111), or AD and mild cognitive impairment (n = 8) and three vascular dementia. We divided outcomes by the domain measured (cognition, activities of daily living, biological markers, neuropsychiatric symptoms, quality of life, global). We calculated the number of trials and of participants using each outcome. We detailed psychometric properties of each outcome. We sought the views of people living with dementia and family carers in three cities through Alzheimer's society focus groups. Attendees at a consensus conference (experts in dementia research, disease-modification and harmonisation measures) decided on the core set of outcomes using these results. Recommended core outcomes were cognition as the fundamental deficit in dementia and to indicate disease modification, serial structural MRIs. Cognition should be measured by Mini Mental State Examination or Alzheimer's Disease Assessment Scale-Cognitive Subscale. MRIs would be optional for patients. We also made recommendations for measuring important, but non-core domains which may not change despite disease modification.LimitationsMost trials were about AD. Specific instruments may be superseded. We searched one database for psychometric properties.InterpretationThis is the first review to identify the 81 outcome measures the research community uses for disease-modifying trials in mild-to-moderate dementia. Our recommendations will facilitate designing, comparing and meta-analysing disease modification trials in mild-to-moderate dementia, increasing their value.Trial registrationPROSPERO no. CRD42015027346.

BACKGROUND:Stroke is associated with the development of cognitive impairment and dementia. We assessed the effect of intensive blood pressure (BP) and/or lipid lowering on cognitive outcomes in patients with recent stroke in a pilot trial. METHODS:In a multicentre, partial-factorial trial, patients with recent stroke, absence of dementia, and systolic BP (SBP) 125-170 mmHg were assigned randomly to at least 6 months of intensive (target SBP

Brain is a lipid-rich tissue, and fatty acids (FAs) play a crucial role in brain function, including neuronal cell growth and development. This study used GC-MS to survey all detectable FAs in the human parietal cortex (Brodmann area 7). These FAs were accurately quantified in 27 cognitively normal age-matched controls, 16 cases of moderate Alzheimer’s disease (AD), 30 severe AD, and 14 dementia with Lewy bodies (DLB). A total of 24 FA species were identified. Multiple comparison procedures, using stepdown permutation tests, noted higher levels of 13 FAs but the majority of changes were in moderate AD and DLB, rather than severe AD. Subjects with moderate AD and DLB pathology exhibited significantly higher levels of a number of FAs (13 FAs and 12 FAs, respectively). These included nervonic, lignoceric, cis-13,16-docosadienoic, arachidonic, cis-11,14,17-eicosatrienoic, erucic, behenic, α-linolenic, stearic, oleic, cis-10-heptanoic, and palmitic acids. The similarities between moderate AD and DLB were quite striking—arachidic acid was the only FA which was higher in moderate AD than control, and was not similarly affected in DLB. Furthermore, there were no significant differences between moderate AD and DLB. The associations between each FA and a number of variables, including diagnosis, age, gender, Aβ plaque load, tau load, and frontal tissue pH, were also investigated. To conclude, the development of AD or DLB pathology affects brain FA composition but, intriguingly, moderate AD neuropathology impacts this to a much greater extent. Post-mortem delay is a potential confounding factor, but the findings here suggest that there could be a more dynamic metabolic response in the earlier stages of the disease pathology.

The presenilins (PSs) were identified as causative genes in cases of early-onset familial Alzheimer’s disease (AD) and current evidence indicates that PSs are part of the γ-secretase complex responsible for proteolytic processing of type I membrane proteins. p75NTR, a common neurotrophin receptor, was shown to be subject to γ-secretase processing. However, it is not clear if the p75NTR downstream signal is altered in response to γ-secretase cleavage, and further there is a possibility that AD-related PS mutations may affect this cleavage, resulting in pathogenic alterations in signal transduction. In this study, we confirmed that p75NTR downstream signalling is altered by PS2 mutation or γ-secretase inhibition in SHSY-5Y cells. The activity of the small GTPase RhoA is strongly affected by these treatments. This study demonstrates that γ-secretase and PS2 play an important role in regulating neurotrophin signal transduction and either mutation of PS2 or inhibition of γ-secretase disturbs this function.

This study combined high resolution mass spectrometry (HRMS), advanced chemometrics and pathway enrichment analysis to analyse the blood metabolome of patients attending the memory clinic: cases of mild cognitive impairment (MCI; n = 16), cases of MCI who upon subsequent follow-up developed Alzheimer's disease (MCI_AD; n = 19), and healthy age-matched controls (Ctrl; n = 37). Plasma was extracted in acetonitrile and applied to an Acquity UPLC HILIC (1.7μm x 2.1 x 100 mm) column coupled to a Xevo G2 QTof mass spectrometer using a previously optimised method. Data comprising 6751 spectral features were used to build an OPLS-DA statistical model capable of accurately distinguishing Ctrl, MCI and MCI_AD. The model accurately distinguished (R2 = 99.1%; Q2 = 97%) those MCI patients who later went on to develop AD. S-plots were used to shortlist ions of interest which were responsible for explaining the maximum amount of variation between patient groups. Metabolite database searching and pathway enrichment analysis indicated disturbances in 22 biochemical pathways, and excitingly it discovered two interlinked areas of metabolism (polyamine metabolism and L-Arginine metabolism) were differentially disrupted in this well-defined clinical cohort. The optimised untargeted HRMS methods described herein not only demonstrate that it is possible to distinguish these pathologies in human blood but also that MCI patients 'at risk' from AD could be predicted up to 2 years earlier than conventional clinical diagnosis. Blood-based metabolite profiling of plasma from memory clinic patients is a novel and feasible approach in improving MCI and AD diagnosis and, refining clinical trials through better patient stratification.

BACKGROUND:Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls. PRINCIPAL FINDINGS:In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10-6) and 14 (IGHV1-67 p = 7.9×10-8) which indexed novel susceptibility loci. SIGNIFICANCE:The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.

BACKGROUND:The insulin-degrading enzyme gene (IDE) is a strong functional and positional candidate for late onset Alzheimer's disease (LOAD). METHODOLOGY/PRINCIPAL FINDINGS:We examined conserved regions of IDE and its 10 kb flanks in 269 AD cases and 252 controls thereby identifying 17 putative functional polymorphisms. These variants formed eleven haplotypes that were tagged with ten variants. Four of these showed significant association with IDE transcript levels in samples from 194 LOAD cerebella. The strongest, rs6583817, which has not previously been reported, showed unequivocal association (p = 1.5x10(-8), fold-increase = 2.12,); the eleven haplotypes were also significantly associated with transcript levels (global p = 0.003). Using an in vitro dual luciferase reporter assay, we found that rs6583817 increases reporter gene expression in Be(2)-C (p = 0.006) and HepG2 (p = 0.02) cell lines. Furthermore, using data from a recent genome-wide association study of two Croatian isolated populations (n = 1,879), we identified a proxy for rs6583817 that associated significantly with decreased plasma Abeta40 levels (ss = -0.124, p = 0.011) and total measured plasma Abeta levels (b = -0.130, p = 0.009). Finally, rs6583817 was associated with decreased risk of LOAD in 3,891 AD cases and 3,605 controls. (OR = 0.87, p = 0.03), and the eleven IDE haplotypes (global p = 0.02) also showed significant association. CONCLUSIONS:Thus, a previously unreported variant unequivocally associated with increased IDE expression was also associated with reduced plasma Abeta40 and decreased LOAD susceptibility. Genetic association between LOAD and IDE has been difficult to replicate. Our findings suggest that targeted testing of expression SNPs (eSNPs) strongly associated with altered transcript levels in autopsy brain samples may be a powerful way to identify genetic associations with LOAD that would otherwise be difficult to detect.

This paper presents a new approach to segment traffic signs from the rest of a scene via CIECAM, a colour appearance model. This approach not only takes CIECAM into practical application for the first time since it was standardised in 1998, but also introduces a new way of segmenting traffic signs in order to improve the accuracy of colour-based approach. Comparison with the other CIE spaces, including CIELUV and CIELAB, and RGB colour space is also carried out. The results show that CIECAM performs better than the other three spaces with 94%, 90%, and 85% accurate rates for sunny, cloudy, and rainy days, respectively. The results also confirm that CIECAM does predict the colour appearance similar to average observers.

Background The aims of this study were to explore the knowledge, attitudes and beliefs that nursing home managers hold with regard to the assessment and management of pain in residents with dementia and to determine how these may be affected by the demographic characteristics of the respondents. Methods A questionnaire comprising six sections was mailed, on two occasions during March and April 2010, to 244 nursing home managers in Northern Ireland (representing 96% of the nursing homes in Northern Ireland). Results The response rate was 39%. Nearly all respondents (96%) provided care to residents with dementia, yet only 60% of managers claimed to use pain treatment guidelines within their nursing home. Respondents demonstrated good knowledge about pain in residents with dementia and acknowledged the difficulties surrounding accurate pain assessment. Nursing home managers were uncertain about how to manage pain in residents with dementia, demonstrating similar concerns about the use of opioid analgesics to those reported in previous studies about pain in older people. Managers who had received recent training ( p = 0.044) were less likely to have concerns about the use of opioid analgesia than those who had not received training. Respondents' beliefs about painkillers were largely ambivalent and were influenced by the country in which they had received their nursing education. Conclusions The study has revealed that accurate pain assessment, training of nursing staff and a standardised approach to pain management (the use of pain management guidelines) within nursing homes all have a significant part to play in the successful management of pain in residents with dementia. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Research into the cause of Alzheimer’s disease (AD) has identified strong connections to cholesterol. Cholesterol and cholesterol esters can modulate amyloid precursor protein (APP) processing, thus altering production of the Aβ peptides that deposit in cortical amyloid plaques. Processing depends on the encounter between APP and cellular secretases, and is thus subject to the influence of cholesterol-dependent factors including protein trafficking, and distribution between membrane subdomains. We have directly investigated endogenous membrane β-secretase activity in the presence of a range of membrane cholesterol levels in SH-SY5Y human neuroblastoma cells and human platelets. Membrane cholesterol significantly influenced membrane β-secretase activity in a biphasic manner, with positive correlations at higher membrane cholesterol levels, and negative correlations at lower membrane cholesterol levels. Platelets from individuals with AD or mild cognitive impairment ( n = 172) were significantly more likely to lie within the negative correlation zone than control platelets ( n = 171). Pharmacological inhibition of SH-SY5Y β-secretase activity resulted in increased membrane cholesterol levels. Our findings are consistent with the existence of a homeostatic feedback loop between membrane cholesterol level and membrane β-secretase activity, and suggest that this regulatory mechanism is disrupted in platelets from individuals with cognitive impairment. [ABSTRACT FROM AUTHOR]

Factors influencing the use of neuroleptic and other CNS-acting medications (‘antidepressants’ and ‘hypnotics/anxiolytics’) were examined in different elderly populations (>65 years): long-stay care hospital subjects (n = 381), nursing home subjects (n = 1247), private residential home subjects (n = 321), statutory residential home subjects (n = 525), old age psychiatry facility subjects (n = 48), community dwellers (n = 97), in different geographical areas (urban n = 1223 and rural n = 1396). Neuroleptics were prescribed in 28% of the individuals, hypnotics/anxiolytics in 33% and antidepressants in 12%. Prescription of neuroleptics was significantly predicted by institutional placement (other than long-stay care hospital facility), lower cognitive function and rural geographical area. Age greater than 75 years and lower functional score (lower dependency) significantly decreased the likelihood of receipt of neuroleptics. Antidepressant use was significantly less likely in male subjects, patients with cognitive impairment and patients greater than 85 years. Institutional placement (other than long-stay care hospital facility and old age psychiatry facility) and rural locality predicted increased likelihood of antidepressant prescription. Institutional placement (other than long-stay care hospital facility) and geographical (rural) location were significant independent predictors of hypnotic/anxiolytic use. Prescription of hypnotic/anxiolytic drug class was significantly less likely in those individuals with lower cognitive status. In this representative elderly cohort, patient characteristics: age, sex, cognitive score, functional score, place of residence and geographical location markedly influenced drug utilisation. Copyright © 2003 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]