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Objectives:To examine the costs and cost-effectiveness of mirtazapine compared to placebo over 12-week follow-up.Design:Economic evaluation in a double-blind randomized controlled trial of mirtazapine vs. placebo.Setting:Community settings and care homes in 26 UK centers.Participants:People with probable or possible Alzheimer’s disease and agitation.Measurements:Primary outcome included incremental cost of participants’ health and social care per 6-point difference in CMAI score at 12 weeks. Secondary cost-utility analyses examined participants’ and unpaid carers’ gain in quality-adjusted life years (derived from EQ-5D-5L, DEMQOL-Proxy-U, and DEMQOL-U) from the health and social care and societal perspectives.Results:One hundred and two participants were allocated to each group; 81 mirtazapine and 90 placebo participants completed a 12-week assessment (87 and 95, respectively, completed a 6-week assessment). Mirtazapine and placebo groups did not differ on mean CMAI scores or health and social care costs over the study period, before or after adjustment for center and living arrangement (independent living/care home). On the primary outcome, neither mirtazapine nor placebo could be considered a cost-effective strategy with a high level of confidence. Groups did not differ in terms of participant self- or proxy-rated or carer self-rated quality of life scores, health and social care or societal costs, before or after adjustment.Conclusions:On cost-effectiveness grounds, the use of mirtazapine cannot be recommended for agitated behaviors in people living with dementia. Effective and cost-effective medications for agitation in dementia remain to be identified in cases where non-pharmacological strategies for managing agitation have been unsuccessful.

One of the mutations in the microtubule-associated protein tau, P301S, is causative for dominantly inherited frontotemporal dementia characterized by extensive tau pathology for which no licensed treatment is available. Hydromethylthionine is a potent tau aggregation inhibitor. We report treatment of an asymptomatic carrier of the P301S mutation using hydromethylthionine over a 5-year period beginning at the mean age of onset of clinical decline in the family. During the period of treatment, the rates of progression of cerebral atrophy were reduced by 61%–66% in frontal and temporal lobes, and the patient remained clinically asymptomatic.

In the transitional period following registration, newly qualified nurses may feel socially isolated and easily overwhelmed by increases in accountability, workplace pressures and the psychological demands of the role. Such experiences place them at risk of burnout and leaving the profession.To explore newly qualified nurses' support needs and their experiences of an online peer support intervention.Eighteen newly qualified nurses participated in online peer support groups. After 3 months participants took part in interviews exploring their support needs and experiences of the groups. Eight one-to one interviews were conducted between October 2019 and January 2020. Qualitative thematic analysis was used.Two themes identified were; "The Support needs of newly qualified nurses" with two subthemes, "The role of the newly qualified nurse" and "Unmet support needs"; "The online experience" with three subthemes, "Barriers to participation", "Anticipated benefits" and "Unmet expectations".Our findings suggested that there is insufficient support for newly qualified nurses. The newly qualified nurses wanted to use online support to help manage their stress. However, the organisation of online peer support needs careful consideration to ensure participation can be beneficial.Online support requires careful design and clear support from employing organisations to promote improved transition experiences. Further research should focus on evaluating adjusted online support interventions.

Aims: To explore newly qualified nurses’ support needs and their perceptions of online peer support Background: The experience of being a newly qualified nurse is stressful and isolating. Support from colleagues and peers can enhance perceptions of competence and confidence in newly qualified nurses, improve well-being and aid retention. However, despite initiatives such as preceptorship, support needs may remain unmet in busy clinical environments. Online support has potential to offer a partial solution to professional isolation, but there is a lack of research into how technology can support nurses’ emotional and social wellbeing. Design: A qualitative exploratory study was designed, employing semi-structured focus groups, analysed using thematic analysis. The study is reported in accordance with the COnsolidated criteria for REporting Qualitative research checklist. Methods: Eight focus groups, supplemented by one individual interview, were conducted with newly qualified nurses between June 2018 and January 2019. Findings: Two main themes arose. The first was Drowning, a lot of the time with two sub-themes: (i) Feelings and emotions about being a Newly Qualified Nurse: ‘Absolutely terrified’ and (ii) Support within the role: ‘Somebody you can count on’. The second was Potential advantages and disadvantages of online modality: ‘Somebody is going to get in that phone!’ which included three sub-themes (i) Potential advantages, (ii) Potential disadvantages and (iii) Preferences and recommendations. Conclusions: This study demonstrates that if barriers can be overcome, then online support has potential to contribute to newly qualified nurses’ well-being. Further research is needed to explore technical and ethical issues around online support and evaluate its effectiveness for newly qualified nurses. Relevance to clinical practice: Online support has the potential to add to existing strategies to support nurses during stressful times. This may be particularly relevant when many staff are working under increased pressure due to the Covid-19 pandemic.

Background Minocycline is an anti-inflammatory drug and protects against the toxic effects of β-amyloid in vitro and in animal models of Alzheimer’s disease. To the best of our knowledge, no randomised placebo-controlled clinical trials in patients with Alzheimer’s disease looking at the efficacy and tolerability of minocycline have been carried out. Objectives The trial investigated whether or not minocycline was superior to placebo in slowing down the rate of decline in cognitive and functional ability over 2 years. The safety and tolerability of minocycline were also assessed. Design A Phase II, three-arm, randomised, double-blind, multicentre trial with a semifactorial design. Participants continued on trial treatment for up to 24 months. Setting Patients were identified from memory services, both within the 32 participating NHS trusts and within the network of memory services supported by the Dementias and Neurodegenerative Diseases Research Network (also known as DeNDRoN). Participants Patients with standardised Mini Mental State Examination scores of > 23 points and with Alzheimer’s disease assessed by the National Institute on Aging–Alzheimer’s Association’s criteria were identified from memory services. Intervention Patients with mild Alzheimer’s disease were randomly allocated 1 : 1 : 1 to receive one of three treatments: arm 1 – 400 mg per day of minocycline; arm 2 – 200 mg per day of minocycline; or arm 3 – placebo. Patients continued treatment for 24 months. Participants, investigators and outcome assessors were blind to treatment allocation. Main outcome measures Primary outcome measures were decline in standardised Mini Mental State Examination and Bristol Activities of Daily Living Scale scores of combined minocycline treatment arms versus placebo, as analysed by intention-to-treat repeated measures regression. Results Between 23 May 2014 and 14 April 2016, 554 participants were randomised. Of the 544 eligible participants, the mean age was 74.3 years and the average standardised Mini Mental State Examination score was 26.4 points. A total of 252 serious adverse events were reported, with the most common categories being neuropsychiatric and cardiocirculatory. Significantly fewer participants completed treatment with 400 mg of minocycline [29% (53/184)] than 200 mg [62% (112/181)] or placebo [64% (114/179)] (p p = 0.0008), dermatological side effects (p = 0.02) and dizziness (p = 0.01). Assessment rates were also lower in the 400-mg treatment arm: 68% (119 of 174 expected) for standardised Mini Mental State Examination scores at 24 months, compared with 82% (144/176) for the 200-mg treatment arm and 84% (140/167) for the placebo arm. Decline in standardised Mini Mental State Examination scores over the 24-month study period in the combined minocycline arms was similar to that in the placebo arm (4.1- vs. 4.3-point reduction; p = 0.9), as was the decline in the 400- and 200-mg treatment arms (3.3 vs. 4.7 points; p = 0.08). Likewise, worsening of Bristol Activities of Daily Living Scale scores over 24 months was similar in all trial arms (5.7, 6.6 and 6.2 points in the 400-mg treatment arm, 200-mg treatment arm and placebo arm, respectively; a p-value of 0.57 for minocycline vs. placebo and a p-value of 0.77 for 400 vs. 200 mg of minocycline). Results were similar in different patient subgroups and in sensitivity analyses adjusting for missing data. Limitations Potential limitations of the study include that biomarkers were not used to confirm the diagnosis of Alzheimer’s disease, as these and apolipoprotein E (APOE) genotyping are not routinely available within the NHS. Compliance was also worse than expected and differential follow-up rates were observed, with fewer assessments obtained for the 400-mg treatment arm than for the 200-mg treatment and placebo arms. Conclusions Minocycline does not delay the progress of cognitive or functional impairment in people with mild Alzheimer’s disease over a 2-year period. Minocycline at a dose of 400 mg is poorly tolerated in this population. Future work The Minocycline in mild Alzheimer’s DiseasE (MADE) study provides a framework for a streamlined trial design that can be usefully applied to test other disease-modifying therapies. Trial registration Current Controlled Trials ISRCTN16105064 and EudraCT 2013-000397-30. Funding This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership, and will be published in full in Efficacy and Mechanism Evaluation; Vol. 7, No. 2. See the NIHR Journals Library website for further project information.

Background\ud Agitation is common in people with dementia and negatively affects the quality of life of both people with dementia and carers. Non-drug patient-centred care is the first-line treatment, but there is a need for other treatment when this care is not effective. Current evidence is sparse on safer and effective alternatives to antipsychotics. We assessed the efficacy and safety of mirtazapine, an antidepressant prescribed for agitation in dementia.\ud \ud Methods\ud This parallel-group, double-blind, placebo-controlled trial—the Study of Mirtazapine for Agitated Behaviours in Dementia trial (SYMBAD)—was done in 26 UK centres. Participants had probable or possible Alzheimer's disease, agitation unresponsive to non-drug treatment, and a Cohen-Mansfield Agitation Inventory (CMAI) score of 45 or more. They were randomly assigned (1:1) to receive either mirtazapine (titrated to 45 mg) or placebo. The primary outcome was reduction in CMAI score at 12 weeks. This trial is registered with ClinicalTrials.gov, NCT03031184, and ISRCTN17411897.\ud \ud Findings\ud Between Jan 26, 2017, and March 6, 2020, 204 participants were recruited and randomised. Mean CMAI scores at 12 weeks were not significantly different between participants receiving mirtazapine and participants receiving placebo (adjusted mean difference –1·74, 95% CI –7·17 to 3·69; p=0·53). The number of controls with adverse events (65 [64%] of 102 controls) was similar to that in the mirtazapine group (67 [66%] of 102 participants receiving mirtazapine). However, there were more deaths in the mirtazapine group (n=7) by week 16 than in the control group (n=1), with post-hoc analysis suggesting this difference was of marginal statistical significance (p=0·065).\ud \ud Interpretation\ud This trial found no benefit of mirtazapine compared with placebo, and we observed a potentially higher mortality with use of mirtazapine. The data from this study do not support using mirtazapine as a treatment for agitation in dementia.\ud \ud Funding\ud UK National Institute for Health Research Health Technology Assessment Programme.

The behavioural variant of frontotemporal dementia is a clinical syndrome characterized by changes in behaviour, cognition and functional ability. Although atrophy in frontal and temporal regions would appear to be a defining feature, neuroimaging studies have identified volumetric differences distributed across large parts of the cortex, giving rise to a classification into distinct neuroanatomical subtypes. Here, we extended these neuroimaging studies to examine how distributed patterns of cortical atrophy map onto brain network hubs. We used baseline structural magnetic resonance imaging data collected from 213 behavioural variant of frontotemporal dementia patients meeting consensus diagnostic criteria and having definite evidence of frontal and/or temporal lobe atrophy from a global clinical trial conducted in 70 sites in Canada, United States of America, Australia, Asia and Europe. These were compared with data from 244 healthy elderly subjects from a well-characterized cohort study. We have used statistical methods of hierarchical agglomerative clustering of 68 regional cortical and subcortical volumes (34 in each hemisphere) to determine the reproducibility of previously described neuroanatomical subtypes in a global study. We have also attempted to link the structural findings to clinical features defined systematically using well-validated clinical scales (Addenbrooke’s Cognitive Examination Revised, the Mini-Mental Status Examination, the Frontotemporal Dementia Rating Scale and the Functional Assessment Questionnaire) and subscales derived from them. Whilst we can confirm that the subtypes are robust, they have limited value in explaining the clinical heterogeneity of the syndrome. We have found that a common pattern of degeneration affecting a small number of subcortical, limbic and frontal nodes within highly connected networks (most previously identified as rich club members or functional binding nodes) is shared by all the anatomical subtypes. Degeneration in these core regions is correlated with cognitive and functional impairment, but less so with behavioural impairment. These findings suggest that degeneration in highly connected basal, limbic and frontal networks is a core feature of the behavioural variant of frontotemporal dementia phenotype irrespective of neuroanatomical and clinical heterogeneity, and may underly the impairment of integration in cognition, function and behaviour responsible for the loss of insight that characterizes the syndrome., Using trial baseline MRI scans from 213 behavioural variant frontotemoporal dementia patients, Vuksanovic et al. report that the four known cortical atrophy subtypes all share degeneration in core basal, limbic and frontal network hubs that correlates with cognitive and functional impairment irrespective of subtype., Graphical Abstract Graphical Abstract

Purpose: To assess the similarities and differences in retinal microvascular function between mild Alzheimer’s disease (AD) patients, early-stage primary open angle glaucoma (POAG) patients and healthy controls. Methods: Retinal vessel reactivity to flickering light was assessed in 10 AD, 19 POAG and 20 healthy age matched control patients by means of dynamic retinal vessel analysis (DVA, IMEDOS, GmbH, Jena, Germany) according to an established protocol. All patients additionally underwent BP measurements and blood analysis for glucose and lipid metabolism markers. Results: AD and POAG patients demonstrated comparable alterations in retinal artery reactivity, in the form of an increased arterial reaction time (RT) to flicker light on the final flicker cycle (p = 0.009), which was not replicated by healthy controls (p > 0.05). Furthermore, the sequential changes in RT on progressing from flicker one to flicker three were found to differ between healthy controls and the two disease groups (p = 0.001). Conclusion: AD and POAG patients demonstrate comparable signs of vascular dysfunction in their retinal arteries at the early stages of their disease process. This provides support for the concept of a common underlying vascular aetiology in these two neurodegenerative diseases.

To explore experiences of online peer support for newly qualified nurses.Qualitative study using semi-structured interviews and thematic analysis.Phase one involves conducting focus groups with newly qualified nurses in the West Midlands area to refine the online peer support environment. Phase two involves 30-40 new nurses joining an online peer group for 3 months; participants will be able to access a general chat community alongside a more structured discussion board. Phase 3 will collect written interview data from all participants about their experiences of online peer support. Face-to-face interviews with 10-12 participants will also be undertaken. The study will run from May 2018-October 2019.Data from focus groups, written and verbal interviews will be analysed using thematic analysis with the aid of NVivo software. Findings will be disseminated to participants and key stakeholders involved in the study and also via publication and networking events.If online peer support is found to be beneficial to new nurses, it may be adopted by local NHS trusts as part of an innovation scheme.It is important that the psychological well-being of nurses is addressed as more nurses are now leaving than joining the profession; this is an international concern. Online peer support may offer a sustainable and accessible means of promoting psychological well-being in the nursing workforce. In such a way, contributory factors to low retention rates such as burnout, stress and job dissatisfaction may also be reduced.目的: 探索支持护士新手的在线同伴经验。 设计: 采用半结构化访谈与主题分析的实证研究 方法: 第一阶段包括在西米德兰兹地区与护士新手建立重点小组,以完善在线同伴支持环境。第二阶段包括让30-40名新护士加入一个在线同伴小组,加入时间为3个月;加入的护士新手将能通过一个更结构化的讨论板来对普通的聊天社区进行访问。第三阶段将对所有参与的护士新手就在线同伴支持经验进行书面访谈的数据收集。还将对10-12名参与的护士新手进行面谈。本研究将于2018年5月至2019年10月进行。 发现: 通过NVivo软件对重点小组、书面访谈和面谈的数据进行主题分析。研究发现将告知以及通过出版提供给研究的参与者和主要利益相关者。 结论: 如果在线同伴支持被证明对护士新手是有用的,当地的国家医疗服务信托机构将会对其进行采纳,从而成为创新计划的一部分。 影响: 重要的是,随着越来越多的护士选择离职而不是入职,护士的心理健康问题需要解决,这是一个国际问题。在线同伴支持可以提供一种持续、容易的方式来促进护士的心理健康。这种方式将会减少导致低员工留存率的因素(倦怠、压力和工作不满等)。.

Objectives The use of assistive technology and telecare (ATT) has been promoted to manage risks associated with independent living in people with dementia but with little evidence for effectiveness. Methods Participants were randomly assigned to receive an ATT assessment followed by installation of all appropriate ATT devices or limited control of appropriate ATT. The primary outcomes were time to institutionalisation and cost-effectiveness. Key secondary outcomes were number of incidents involving risks to safety, burden and stress in family caregivers and quality of life. Results Participants were assigned to receive full ATT (248 participants) or the limited control (247 participants). After adjusting for baseline imbalance of activities of daily living score, HR for median pre-institutionalisation survival was 0.84; 95% CI, 0.63 to 1.12; P = 0.20. There were no significant differences between arms in health and social care (mean -£909; 95% CI, -£5,336 to £3,345, P = 0.678) and societal costs (mean -£3,545; 95% CI, -£13,914 to £6,581, P = 0.499). ATT group members had reduced participant-rated quality-adjusted life years (QALYs) at 104 weeks (mean − 0.105; 95% CI, −0.204 to −0.007, P = 0.037) but did not differ in QALYs derived from proxy-reported EQ-5D. Discussion Fidelity of the intervention was low in terms of matching ATT assessment, recommendations and installation. This, however, reflects current practice within adult social care in England. Conclusions Time living independently outside a care home was not significantly longer in participants who received full ATT and ATT was not cost-effective. Participants with full ATT attained fewer QALYs based on participant-reported EQ-5D than controls at 104 weeks.

Introduction There is increasing emphasis on the importance of optimizing and standardizing clinical trials of agitation in Alzheimer's disease (AD), but the risks of bias arising from published trials and the number and design of unpublished studies are poorly understood. Methods Using the ClinicalTrials.gov database, we systematically reviewed all registered investigational clinical trials for agitation in AD to describe the landscape of agitation drug treatment trials and to assess their quality and generalizability. Results We included 52 clinical studies registered over the past 25 years. Within published randomized controlled trials (RCTs), there was a high rate of participant dropout, poor reporting of randomization procedures, and inconsistent definitions of the sample included for analysis. There was also evidence of publication and funder bias. Discussion We discuss factors that limit the internal and external validity of published RCTs and make additional recommendations for the conduct and reporting of future clinical trials of agitation in AD.

BackgroundAssistive technology and telecare have been promoted to manage the risks associated with independent living for people with dementia, but there is limited evidence of their effectiveness.ObjectivesThis trial aimed to establish whether or not assistive technology and telecare assessments and interventions extend the time that people with dementia can continue to live independently at home and whether or not they are cost-effective. Caregiver burden, the quality of life of caregivers and of people with dementia and whether or not assistive technology and telecare reduce safety risks were also investigated.DesignThis was a pragmatic, randomised controlled trial. Blinding was not undertaken as it was not feasible to do so. All consenting participants were included in an intention-to-treat analysis.SettingThis trial was set in 12 councils in England with adult social services responsibilities.ParticipantsParticipants were people with dementia living in the community who had an identified need that might benefit from assistive technology and telecare.InterventionsParticipants were randomly assigned to receive either assistive technology and telecare recommended by a health or social care professional to meet their assessed needs (a full assistive technology and telecare package) or a pendant alarm, non-monitored smoke and carbon monoxide detectors and a key safe (a basic assistive technology and telecare package).Main outcome measuresThe primary outcomes were time to admission to care and cost-effectiveness. Secondary outcomes assessed caregivers using the 10-item Center for Epidemiological Studies Depression Scale, the State–Trait Anxiety Inventory 6-item scale and the Zarit Burden Interview.ResultsOf 495 participants, 248 were randomised to receive full assistive technology and telecare and 247 received the limited control. Comparing the assistive technology and telecare group with the control group, the hazard ratio for institutionalisation was 0.76 (95% confidence interval 0.58 to 1.01;p = 0.054). After adjusting for an imbalance in the baseline activities of daily living score between trial arms, the hazard ratio was 0.84 (95% confidence interval 0.63 to 1.12;p = 0.20). At 104 weeks, there were no significant differences between groups in health and social care resource use costs (intervention group – control group difference: mean –£909, 95% confidence interval –£5336 to £3345) or in societal costs (intervention group – control group difference: mean –£3545; 95% confidence interval –£13,914 to £6581). At 104 weeks, based on quality-adjusted life-years derived from the participant-rated EuroQol-5 Dimensions questionnaire, the intervention group had 0.105 (95% confidence interval –0.204 to –0.007) fewer quality-adjusted life-years than the control group. The number of quality-adjusted life-years derived from the proxy-rated EuroQol-5 Dimensions questionnaire did not differ between groups. Caregiver outcomes did not differ between groups over 24 weeks.LimitationsCompliance with the assigned trial arm was variable, as was the quality of assistive technology and telecare needs assessments. Attrition from assessments led to data loss additional to that attributable to care home admission and censoring events.ConclusionsA full package of assistive technology and telecare did not increase the length of time that participants with dementia remained in the community, and nor did it decrease caregiver burden, depression or anxiety, relative to a basic package of assistive technology and telecare. Use of the full assistive technology and telecare package did not increase participants’ health and social care or societal costs. Quality-adjusted life-years based on participants’ EuroQol-5 Dimensions questionnaire responses were reduced in the intervention group compared with the control group; groups did not differ in the number of quality-adjusted life-years based on the proxy-rated EuroQol-5 Dimensions questionnaire.Future workFuture work could examine whether or not improved assessment that is more personalised to an individual is beneficial.Trial registrationCurrent Controlled Trials ISRCTN86537017.FundingThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 25, No. 19. See the NIHR Journals Library website for further project information.

Background Hydromethylthionine is a potent inhibitor of pathological aggregation of tau and TDP-43 proteins. Objective To compare hydromethylthionine treatment effects at two doses and to determine how drug exposure is related to treatment response in bvFTD. Methods We undertook a 52-week Phase III study in 220 bvFTD patients randomized to compare hydromethylthionine at 200 mg/day and 8 mg/day (intended as a control). The principal outcomes were change on the Addenbrookes Cognitive Examination - Revised (ACE-R), the Functional Activities Questionnaire (FAQ), and whole brain volume. Secondary outcomes included Modified Clinical Global Impression of Change (Modified-CGIC). A population pharmacokinetic exposure-response analysis was undertaken in 175 of the patients with available blood samples and outcome data using a discriminatory plasma assay for the parent drug. Results There were no significant differences between the two doses as randomized. There were steep concentration-response relationships for plasma levels in the range 0.3-0.6 ng/ml at the 8 mg/day dose on clinical and MRI outcomes. There were significant exposure-dependent differences at 8 mg/day for FAQ, Modified-CGIC, and whole brain atrophy comparing patients with plasma levels greater than 0.346 ng/ml with having minimal drug exposure. The exposure-response is biphasic with worse outcomes at the high concentrations produced by 200 mg/day. Conclusions Hydromethylthionine has a similar concentration-response profile for effects on clinical decline and brain atrophy at the 8 mg/day dose in bvFTD as recently reported in AD. Treatment responses in bvFTD are predicted to be maximal at doses in the range 20-60 mg/day. A confirmatory placebo-controlled trial is now planned.

Background: LMTM is being developed as a treatment for AD based on inhibition of tau aggregation. Objectives: To examine the efficacy of LMTM as monotherapy in non-randomized cohort analyses as modified primary outcomes in an 18-month Phase III trial in mild AD. Methods: Mild AD patients (n = 800) were randomly assigned to 100 mg twice a day or 4 mg twice a day. Prior to unblinding, the Statistical Analysis Plan was revised to compare the 100 mg twice a day as monotherapy subgroup (n = 79) versus 4 mg twice a day as randomized (n = 396), and 4 mg twice a day as monotherapy (n = 76) versus 4 mg twice a day as add-on therapy (n = 297), with strong control of family-wise type I error. Results: The revised analyses were statistically significant at the required threshold of p

Introduction: The objective of this study was to define current assistive technology and telecare (ATT) practice for people with dementia living at home.Methods: This is a randomized controlled trial (N = 495) of ATT assessment and ATT installation intervention, compared with control (restricted ATT package). ATT assessment and installation data were collected. Qualitative work identified value networks delivering ATT, established an ATT assessment standard.Results: ATT was delivered by public and not-for-profit telecare networks. ATT assessments showed 52% fidelity to the ATT assessment standard. Areas of assessment most frequently leading to identifying ATT need were daily activities (93%), memory (89%), and problem-solving (83%). ATT needs and recommendations were weakly correlated (τ = 0.242; P < .000), with ATT recommendations and installations moderately correlated (τ = -0.470; P < .000). Half (53%) of recommended technology was not installed. Safety concerns motivated 38% of installations.Discussion: Assessment recommendations were routinely disregarded at the point of installation. ATT was commonly recommended for safety and seldom for supporting leisure.

TAR DNA-binding protein of 43 kDa (TDP-43) and fused in sarcoma (FUS) are RNA binding proteins (RBPs) primarily located in the nucleus, and involved in numerous aspects of RNA metabolism. Both proteins can be found to be depleted from the nucleus and accumulated in cytoplasmic inclusions in two major neurodegenerative conditions, amyotrophic lateral sclerosis and frontotemporal dementia. Recent evidences suggest that, in addition to their nuclear functions, both TDP-43 and FUS are involved in multiple processes in the cytoplasm, including mRNA stability and transport, translation, the stress response, mitochondrial function and autophagy regulation. Here, we review the most recent advances in understanding their functions in the cytoplasm and how these are affected in disease.

Background Although hydromethylthionine is a potent tau aggregation inhibitor, no difference was found in either of two Phase III trials in mild to moderate Alzheimer's disease (AD) comparing doses in the range 150-250 mg/day with 8 mg/day intended as a control. Objective To determine how drug exposure is related to treatment response. Methods A sensitive plasma assay for the drug was used in a population pharmacokinetic analysis of samples from 1,162 of the 1,686 patients who participated in either of the Phase III trials with available samples and efficacy outcome data. Results There are steep concentration-response relationships for steady state plasma levels in the range 0.3-0.8 ng/ml at the 8 mg/day dose. Using a threshold based on the lower limit of quantitation of the assay on Day 1, there are highly significant differences in cognitive decline and brain atrophy in patients with above threshold plasma levels, both for monotherapy and add-on therapy, but with effect sizes reduced by half as add-on. Plasma concentrations in the range 4-21 ng/ml produced by the high doses are not associated with any additional benefit. Conclusions Hydromethylthionine has pharmacological activity on brain structure and function at the 8 mg/day dose as monotherapy or as add-on to symptomatic treatments. This combined with a plateau at higher doses is consistent with the lack of dose-response seen in the Phase III trials. Treatment benefit is predicted to be maximal at 16 mg/day as monotherapy. A placebo-controlled trial in mild/moderate AD is now ongoing to confirm efficacy at this dose.

In the UK, one third of the 850,000 people with dementia live in care homes. This article explores the process of carrying out research in nursing homes, identifying barriers and enabling factors, and making recommendations for researchers. The authors' experiences derive from an ongoing study investigating the effect of educational interventions to promote and embed person-centred care, designed for nurses caring for the people with dementia in nursing homes. Design issues arose from the need to use cluster randomisation which requires a large sample size, implementation fidelity, poor compliance and high numbers of participants lost to follow up. Further difficulties included gaining ethical approval, recruitment, raising concerns and the practicalities of participant retention. There are many benefits of conducting research in care homes, for the homes themselves, their staff and residents. These include training and education, networking and empowerment of staff and subsequent improved standards of care. For the research team, benefits include opportunities to contribute to an underserved setting, to advance care standards and improve nurses' working lives.

Background Very late (aged ≥60 years) onset schizophrenia-like psychosis occurs frequently but no placebo-controlled, randomised trials have assessed the efficacy and risks of antipsychotic treatment. We investigated whether low-dose amisulpride (100 mg daily) is superior to placebo in reducing psychosis symptoms over 12 weeks and whether any benefit is maintained by continuing treatment after 12 weeks. Methods The ATLAS double-blind controlled trial enrolled participants from 25 old age psychiatry services in the UK. Eligible participants (ie, those with a diagnosis of very late-onset schizophrenia-like psychosis and a Brief Psychiatric Rating Scale [BPRS] score of ≥30, without cognitive impairment) were randomly assigned (1:1:1) to one of three groups in a two-stage trial: amisulpride in stage 1 and 2 (group A), amisulpride then placebo (group B), or placebo then amisulpride (group C). Treatment (100 mg oral amisulpride daily vs placebo) was given for 12 weeks in stage 1 and, initially, 24 weeks then reduced to 12 weeks in stage 2. Participants, investigators, and outcome assessors were masked to treatment allocation. Primary outcomes were psychosis symptoms assessed by the BPRS at 4, 12, and 24, or 36 weeks, and trial treatment discontinuation for non-efficacy. The primary, secondary, and safety endpoints were all analysed in participants given at least one dose of study treatment in modified intention-to-treat analyses. This study is registered with EudraCT, number 2010-022184-35, and ISRCTN, number ISRCTN45593573. Findings Between Sept 27, 2012, and June 28, 2016, we recruited 101 participants. 92 (91%) of 101 participants took trial medication, of whom 59 (64%) completed stage 1 and 34 (58%) of these 59 participants completed stage 2 treatment. Despite suboptimal compliance, improvements in BPRS scores at 12 weeks were 7·7 points (95% CI 3·8–11·5, p=0·0002) greater with amisulpride (mean 11·9 points [SE 1·3]) than with placebo (4·2 points [1·0]). In stage 2, BPRS scores improved by a mean of 1·1 points (1·6) from 12 weeks to the final assessment in those who continued amisulpride but deteriorated by 5·2 points (2·0) in those who switched from amisulpride to placebo (difference 6·3 points [95% CI 0·9–11·7], p=0·024). Fewer participants who were allocated amisulpride than placebo stopped treatment because of non-efficacy in stage 1 (p=0·010) and stage 2 (p=0·031). Serious adverse events were reported more frequently in the amisulpride group than in the placebo group in stage 1 (p=0·057) and stage 2 (p=0·19). The most common serious adverse events were infection (five patients in the amisulpride group, three in the placebo group) and extrapyrimidal side-effects (three patients in the amisulpride group, none in the placebo group). Five patients died during the study, one from a gastric ulcer bleed before treatment started (group B), two while taking stage 2 treatment (one in group A and one in group C), and two who stopped trial treatment in stage 1 and died many weeks later (one in group B and one in group C). No deaths were related to treatment. Interpretation Low-dose amisulpride is effective and well tolerated as a treatment for very late-onset schizophrenia-like psychosis, with benefits maintained by prolonging treatment. Funding UK National Institute for Health Research.

Training is known to improve performance in a variety of perceptual and cognitive skills. However, there is accumulating evidence that mere exposure (i.e. without supervised training) to regularities (i.e. patterns that co-occur in the environment) facilitates our ability to learn contingencies that allow us to interpret the current scene and make predictions about future events. Recent neuroimaging studies have implicated fronto-striatal and medial temporal lobe brain regions in the learning of spatial and temporal statistics. Here, we ask whether patients with mild cognitive impairment due to Alzheimer′s disease (MCI-AD) that are characterized by hippocampal dysfunction are able to learn temporal regularities and predict upcoming events. We tested the ability of MCI-AD patients and age-matched controls to predict the orientation of a test stimulus following exposure to sequences of leftwards or rightwards orientated gratings. Our results demonstrate that exposure to temporal sequences without feedback facilitates the ability to predict an upcoming stimulus in both MCI-AD patients and controls. However, our fMRI results demonstrate that MCI-AD patients recruit an alternate circuit to hippocampus to succeed in learning of predictive structures. In particular, we observed stronger learning-dependent activations for structured sequences in frontal, subcortical and cerebellar regions for patients compared to age-matched controls. Thus, our findings suggest a cortico-striatal–cerebellar network that may mediate the ability for predictive learning despite hippocampal dysfunction in MCI-AD.

Learning the statistics of the environment is critical for predicting upcoming events. However, little is known about how we translate previous knowledge about scene regularities to sensory predictions. Here, we ask whether patients with mild cognitive impairment due to Alzheimer's disease (MCI-AD) that are known to have spared implicit but impaired explicit recognition memory are able to learn temporal regularities and predict upcoming events. We tested the ability of MCI-AD patients and age-matched controls to predict the orientation of a test stimulus following exposure to sequences of leftwards or rightwards oriented gratings. Our results demonstrate that exposure to temporal sequences without feedback facilitates the ability to predict an upcoming stimulus in both MCI-AD patients and controls. Further, we show that executive cognitive control may account for individual variability in predictive learning. That is, we observed significant positive correlations of performance in attentional and working memory tasks with post-training performance in the prediction task. Taken together, these results suggest a mediating role of circuits involved in cognitive control (i.e. frontal circuits) that may support the ability for predictive learning in MCI-AD.

This study aimed to explore experiences of a training and supervision intervention for nurses in nursing homes. This paper reports on the qualitative findings of a larger mixed-methods study. Few studies have explored reactions to training on burnout in nurses working in nursing homes and whether outcomes are sustained. The training consisted of a combination of classroom-based and workplace training, which involved the trainer working alongside the nurses. Interviews were carried out in 2015, exploring how the nurses implemented the knowledge and skills they had been taught and whether burnout was affected by the training intervention. Interviews were conducted with eight nurses who received training followed by supervision (T+S) and five nurses who received training only (TO). The interviews were recorded and transcribed verbatim and analysed using Template Analysis. Findings are presented under three themes: Experiences of Burnout, Reactions to Training and Experiences of Supervision. The findings indicated the training and supervision interventions empowered nurses to change their practice. Active learning strategies and a person-centred approach to learning empowered the nurses, while clinical supervision aided implementation and adjustment of strategies, leading to an increased sense of job control and job satisfaction.

The development, pilot and evaluation of a brief psychosocial training intervention (BPTI) for staff working with people with dementia in an acute hospital setting are described. The project had two phases. Phase one involved adapting an existing competency framework and developing the BPTI using focus groups. For the pilot and evaluation, in phase two, a mixed methods approach was adopted using self-administered standardised questionnaires and qualitative interviews. Qualitative analysis suggested that delivering skillsbased training can develop communication, problemsolving and self-directed learning skills; benefit staff in terms of increased knowledge, skills and confidence; and be problematic in the clinical area in terms of time, organisation and the physical environment. These factors must be taken into consideration when delivering training. These changes were not reflected in the quantitative results and measures were not always sensitive to changes in this setting. Definitive conclusions cannot be drawn about the efficacy of the intervention, due to the contradictory outcomes between the quantitative and qualitative data. Further developments and research are required to explore how staff and organisations can be supported to deliver the best possible care. © 2013 RCN Publishing Ltd.

Early diagnosis of dementia is critical for assessing disease progression and potential treatment. State-or-the-art machine learning techniques have been increasingly employed to take on this diagnostic task. In this study, we employed Generalised Matrix Learning Vector Quantization (GMLVQ) classifiers to discriminate patients with Mild Cognitive Impairment (MCI) from healthy controls based on their cognitive skills. Further, we adopted a ``Learning with privileged information'' approach to combine cognitive and fMRI data for the classification task. The resulting classifier operates solely on the cognitive data while it incorporates the fMRI data as privileged information (PI) during training. This novel classifier is of practical use as the collection of brain imaging data is not always possible with patients and older participants. MCI patients and healthy age-matched controls were trained to extract structure from temporal sequences. We ask whether machine learning classifiers can be used to discriminate patients from controls based on the learning performance and whether differences between these groups relate to individual cognitive profiles. To this end, we tested participants in four cognitive tasks: working memory, cognitive inhibition, divided attention, and selective attention. We also collected fMRI data before and after training on the learning task and extracted fMRI responses and connectivity as features for machine learning classifiers. Our results show that the PI guided GMLVQ classifiers outperform the baseline classifier that only used the cognitive data. In addition, we found that for the baseline classifier, “divided attention” is the only relevant cognitive feature. When PI was incorporated, divided attention remained the most relevant feature while cognitive inhibition became also relevant for the task. Interestingly, this analysis for the fMRI GMLVQ classifier suggests that (1) when overall fMRI signal for structured stimuli is used as inputs to the classifier, the post-training session is most relevant; and (2) when the graph feature reflecting underlying spatiotemporal fMRI pattern is used, the pre-training session is most relevant. Taken together these results suggest that brain connectivity before training and overall fMRI signal after training are both diagnostic of cognitive skills in MCI.

Background The care home workforce (over half a million people in the UK) has a pivotal role in the quality of care provided to the residents. Much care in this setting is inadequate, lacks a person-centred focus and neglects the dignity of residents. A combination of factors leads to burnout in nurses working in nursing homes, contributing to poor quality care. Recent reports have indicated that cultures of care need to be addressed through training, improved workforce support and supervision and that improving the quality of care for people with dementia can be achieved by the development of leadership in nursing and clarifying professional values. Addressing burnout through an educational intervention should improve quality of care and nurses' experiences. Objectives The study aimed to explore the training needs of nurses working with people with dementia in nursing homes with a view to developing an educational intervention to reduce nurses' burnout and improve person-centred care. Design Four focus groups were conducted with 11 qualified nurses working in nursing homes; data was analysed using thematic analysis. Results Four themes emerged through the analysis of the transcripts. Participants reported that their work responsibilities revolved mainly around directing others, day to day care, paper work and supporting family carers. Nurses identified the importance of person-centred ways of being, communication and clinical skills when working in nursing home setting. They expressed their frustrations associated with managing staff levels, responding to behaviour that challenges and lack of time. Conclusions The barriers to learning, experience of previous training and gaps in knowledge identified could inform the design of future training and support programmes.

A b s t r ac t Background Clinical trials have shown the benefits of cholinesterase inhibitors for the treatment of mild-to-moderate Alzheimer’s disease. It is not known whether treatment benefits continue after the progression to moderate-to-severe disease. Methods We assigned 295 community-dwelling patients who had been treated with donepezil for at least 3 months and who had moderate or severe Alzheimer’s disease (a score of 5 to 13 on the Standardized Mini–Mental State Examination [SMMSE, on which scores range from 0 to 30, with higher scores indicating better cognitive function]) to continue donepezil, discontinue donepezil, discontinue donepezil and start memantine, or continue donepezil and start memantine. Patients received the study treatment for 52 weeks. The coprimary outcomes were scores on the SMMSE and on the Bristol Activities of Daily Living Scale (BADLS, on which scores range from 0 to 60, with higher scores indicating greater impairment). The minimum clinically important differences were 1.4 points on the SMMSE and 3.5 points on the BADLS. Results Patients assigned to continue donepezil, as compared with those assigned to discontinue donepezil, had a score on the SMMSE that was higher by an average of 1.9 points (95% confidence interval [CI], 1.3 to 2.5) and a score on the BADLS that was lower (indicating less impairment) by 3.0 points (95% CI, 1.8 to 4.3) (P

BACKGROUND: Agitation is a common and distressing symptom in patients with Alzheimer's disease. Cholinesterase inhibitors improve cognitive outcomes in such patients, but the benefits of these drugs for behavioral disturbances are unclear. METHODS: We randomly assigned 272 patients with Alzheimer's disease who had clinically significant agitation and no response to a brief psychosocial treatment program to receive 10 mg of donepezil per day (128 patients) or placebo (131 patients) for 12 weeks. The primary outcome was a change in the score on the Cohen-Mansfield Agitation Inventory (CMAI) (on a scale of 29 to 203, with higher scores indicating more agitation) at 12 weeks. RESULTS: There was no significant difference between the effects of donepezil and those of placebo on the basis of the change in CMAI scores from baseline to 12 weeks (estimated mean difference in change [the value for donepezil minus that for placebo], -0.06; 95% confidence interval [CI], -4.35 to 4.22). Twenty-two of 108 patients (20.4%) in the placebo group and 22 of 113 (19.5%) in the donepezil group had a reduction of 30% or greater in the CMAI score (the value for donepezil minus that for placebo, -0.9 percentage point; 95% CI, -11.4 to 9.6). There were also no significant differences between the placebo and donepezil groups in scores for the Neuropsychiatric Inventory, the Neuropsychiatric Inventory Caregiver Distress Scale, or the Clinician's Global Impression of Change. CONCLUSIONS: In this 12-week trial, donepezil was not more effective than placebo in treating agitation in patients with Alzheimer's disease. (ClinicalTrials.gov number, NCT00142324 [ClinicalTrials.gov].).

Aberrant motor behaviour (AMB) in Alzheimer's disease shares behavioural correlates with obsessive compulsive disorder (OCD). We investigated whether AMB was also comparable in terms of metabolic activity in the orbitofrontal cortex (OFC), an area shown to be hyperactive in OCD. In this study 135 patients meeting research criteria for Alzheimer's disease were identified from a database of patients recruited as part of a phase II drug trial. These patients were assessed using the Neuropsychiatric Inventory, the Alzheimer's disease assessment scale, cognitive subscale and perfusion SPECT performed with 99Tc(m) hexamethylpropyleneamine oxime. Regions of interest were created for orbitofrontal cortices and basal ganglia. In 35 patients with AMB, adjusted tracer uptake was greater in the OFC. This reached statistical significance in right superior, left superior, right medial and left medial orbital gyri (p0.05). The association between AMB and hyperactivity in the OFC remained significant after adjusting for the presence of anxiety. These results parallel the OFC hypermetabolism consistently seen in OCD. One model of OCD, proposes that dysfunctional interactions between frontal regions, including the OFC, produce the characteristic symptoms of OCD. The behaviour is though to be brought about by a perceived incompleteness of performing a task and is caused by an error in normal reward signals initiated upon task completion. These finding indicate that AMB in Alzheimer's disease are brought about by the same mechanistic failure.

Summary Background Depression is common in dementia but the evidence base for appropriate drug treatment is sparse and equivocal. We aimed to assess efficacy and safety of two of the most commonly prescribed drugs, sertraline and mirtazapine, compared with placebo. Methods We undertook the parallel-group, double-blind, placebo-controlled, Health Technology Assessment Study of the Use of Antidepressants for Depression in Dementia (HTA-SADD) trial in participants from old-age psychiatry services in nine centres in England. Participants were eligible if they had probable or possible Alzheimer's disease, depression (lasting ≥4 weeks), and a Cornell scale for depression in dementia (CSDD) score of 8 or more. Participants were ineligible if they were clinically critical (eg, suicide risk), contraindicated to study drugs, on antidepressants, in another trial, or had no carer. The clinical trials unit at King's College London (UK) randomly allocated participants with a computer-generated block randomisation sequence, stratified by centre, with varying block sizes, in a 1:1:1 ratio to receive sertraline (target dose 150 mg per day), mirtazapine (45 mg), or placebo (control group), all with standard care. The primary outcome was reduction in depression (CSDD score) at 13 weeks (outcomes to 39 weeks were also assessed), assessed with a mixed linear-regression model adjusted for baseline CSDD, time, and treatment centre. This study is registered, number ISRCTN88882979 and EudraCT 2006-000105-38. Findings Decreases in depression scores at 13 weeks did not differ between 111 controls and 107 participants allocated to receive sertraline (mean difference 1·17, 95% CI −0·23 to 2·58; p=0·10) or mirtazapine (0·01, −1·37 to 1·38; p=0·99), or between participants in the mirtazapine and sertraline groups (1·16, −0·25 to 2·57; p=0·11); these findings persisted to 39 weeks. Fewer controls had adverse reactions (29 of 111 [26%]) than did participants in the sertraline group (46 of 107, 43%; p=0·010) or mirtazapine group (44 of 108, 41%; p=0·031), and fewer serious adverse events rated as severe (p=0·003). Five patients in every group died by week 39. Interpretation Because of the absence of benefit compared with placebo and increased risk of adverse events, the present practice of use of these antidepressants, with usual care, for first-line treatment of depression in Alzheimer's disease should be reconsidered. Funding UK National Institute of Health Research HTA Programme.

Performance on neuropsychological tests can be influenced by non-cognitive factors, including deliberate underperformance, stress, the need to fulfil a sick role, depression, un-cooperativeness, fatigue and unhappiness with the evaluative situation. Tests to detect suboptimal effort are becoming widely used in clinical practice and are based on their reported insensitivity to cognitive dysfunction. A diagnosis of dementia has life-changing implications for an individual of working age. It is therefore crucial that clinicians can be confident they have obtained a valid estimate of current cognitive functioning. This study aimed to establish whether mood or cognitive functioning adversely influenced performance on symptom validity tests (SVTs) in individuals with working age dementia, who were judged to be using full effort.Forty-two participants with dementia diagnosed before the age of 65 completed measures of emotional and cognitive functioning and six SVTs.There were no significant correlations between emotional functioning and measures of effort. However, cognitive functioning, in particular new learning, was significantly related to SVT performance. Participants with mild dementia performed significantly better on all six SVTs than those with moderate/severe dementia. The results also suggest that the SVTs are not equally sensitive to cognitive dysfunction. Rey's Dot Counting Test (DCT) (times criterion) achieved 100% specificity, and was the only test passed by every participant.Rey's DCT is the only SVT that can be recommended for use in those under 65 years with possible dementia at this time until further validation studies are undertaken.

BACKGROUND Although less likely to be reported in clinical trials than expressions of the statistical significance of differences in outcomes, whether or not a treatment has delivered a specified minimum clinically important difference (MCID) is also relevant to patients and their caregivers and doctors. Many dementia treatment randomised controlled trials (RCTs) have not reported MCIDs and, where they have been done, observed differences have not reached these. METHODS As part of the development of the Statistical Analysis Plan for the DOMINO trial, investigators met to consider expert opinion- and distribution-based values for the MCID and triangulated these to provide appropriate values for three outcome measures, the Standardised Mini-mental State Examination (sMMSE), Bristol Activities of Daily Living Scale (BADLS) and Neuropsychiatric Inventory (NPI). Only standard deviations (SD) were presented to investigators who remained blind to treatment allocation. RESULTS Adoption of values for MCIDs based upon 0.4 of the SD of the change in score from baseline on the sMMSE, BADLS and NPI in the first 127 participants to complete DOMINO yielded MCIDs of 1.4 points for sMMSE, 3.5 for BADLS and 8.0 for NPI. CONCLUSIONS Reference to MCIDs is important for the full interpretation of the results of dementia trials and those conducting such trials should be open about the way in which they have determined and chosen their values for the MCIDs

Mechanical compaction of sand-rich reservoirs usually occurs during shallow burial and involves the rearrangement of framework grains and the ductile deformation of soft lithoclasts. The reservoir quality (porosity and permeability) of some Neogene sandstones of the South Caspian Basin has, however, been dramatically reduced by mechanical compaction involving extensive grain-fracturing (i.e. porosity collapse). These sandstones were probably susceptible to pervasive grain-fracturing because they were buried rapidly and experienced compressional deformation prior to reaching 80 °C. Consequently, they did not undergo quartz cementation and were therefore exposed to high stresses while they were extremely weak. Grain-size and structural position are also important controls on the distribution of grain fracturing in the onshore analogue in the Apsheron Peninsula. Microstructural analysis confirms that susceptibility to distributed grain-fracturing increases with increasing grain-size. Structural position has also an important impact on the distribution of porosity collapse. In particular, sandstones within the hinges of folded sections have undergone much more extensive grain-fracturing than within the surrounding area; the increased stresses in this structural position have enhanced distributed grain-fracturing and subsequent deformation band development.

Aims and methodClinical audit methodology was used to compare the treatment of alcohol misusers at risk of Wernicke's encephalopathy in an acute medical setting, and to assess the impact of providing information about best practice to prescribing doctors. All patients prescribed thiamine during an admission to an acute hospital trust over a 6-month period were identified, and data about their treatment episode were collected retrospectively. Hospital pharmacists then provided all prescribers with a flowchart summarising current prescribing guidelines, and prescribing patterns were re-audited 6 months later.ResultsOver two audit periods, half of the patients prescribed thiamine whose case notes we examined had symptoms suggestive of Wernicke's encephalopathy, and another 30% were at high risk. Prescribing adhered to hospital guidelines only in 14% of cases, with the pharmacy-led intervention associated with a small but significant increase in the number of patients receiving adequate treatment for Wernicke's encephalopathy.Clinical implicationsWernicke's encephalopathy is relatively common in alcohol-dependent individuals admitted to hospital, and it is easily and cheaply managed. However, even when potential cases are identified, prescribing guidelines are followed in a minority of cases, even with prompting by a hospital pharmacist. This may be related to the limited research base concerning the optimum dosing schedule of thiamine, or fears about possible anaphylaxis when using parenteral preparations.

Alzheimer's disease (AD) patients commonly suffer from behavioral and psychological symptoms of dementia (BPSD). Variants within the neuregulin-1 (NRG1) gene have been investigated both in early onset psychiatric disorders, such as schizophrenia and recently in AD patients with psychosis. In this study, we analyzed NRG1 variants in AD patients with and without psychosis. Our large cohort of 399 probable AD patients had longitudinal information on the BPSD, which was used to dichotomize patients into whether they had ever suffered from psychotic symptoms within the study period. The NRG1 single nucleotide polymorphisms rs3924999, rs35753505 (SNP8NRG221533) and the microsatellites 478B14-848 and 420M9-1395 were investigated for association with psychosis using genotype, allele, and haplotype analyses. No associations were found between any of these variants or haplotypic combinations with delusions, hallucinations, psychosis, or elation/mania in our cohort. Positive associations with polymorphisms and haplotype combinations of NRG1 have been reported in psychiatric disorders. One previous study found an association with psychosis in AD, with a SNP outside the haplotype block first reported for association with schizophrenia. We found no association with any of these variants in our cohort. Further investigations of this region on chromosome 8 are clearly required, with replication in different large longitudinal cohorts. © 2010 - IOS Press and the authors. All rights reserved.

BACKGROUND: Good practice guidelines state that a psychological intervention should usually precede pharmacotherapy, but there are no data evaluating the feasibility of psychological interventions used in this way. METHODS: At the first stage of a randomized blinded placebo-controlled trial, 318 patients with Alzheimer disease (AD) with clinically significant agitated behavior were treated in an open design with a psychological intervention (brief psychosocial therapy [BPST]) for 4 weeks, preceding randomization to pharmacotherapy. The therapy involved social interaction, personalized music, or removal of environmental triggers. RESULTS: Overall, 318 patients with AD completed BPST with an improvement of 5.6 points on the total Cohen-Mansfield Agitation Inventory (CMAI; mean [SD], 63.3 [16.0] to 57.7 [18.4], t = 4.8, df = 317, p < 0.0001). Therapy worksheets were completed in six of the eight centers, with the key elements of the intervention delivered according to the manual for >95% of patients. More detailed evaluation of outcome was completed for the 198 patients with AD from these centers, who experienced a mean improvement of 6.6 points on the total CMAI (mean [SD], 62.2 [14.3] to 55.6 [15.8], t = 6.5, df = 197, p < 0.0001). Overall, 43% of participants achieved a 30% improvement in their level of agitation. CONCLUSION: The specific attributable benefits of BPST cannot be determined from an open trial. However, the BPST therapy was feasible and was successfully delivered according to an operationalized manual. The encouraging outcome indicates the need for a randomized controlled trial of BPST.

Background/Aims: Alzheimer’s disease patients commonly suffer from behavioural and psychological symptoms of dementia (BPSD); a genetic component to the development of BPSD has been demonstrated. Genetic risk factors for other psychiatric disorders have been implicated in BPSD; however, this is the first known investigation of the dopamine transporter (DAT1) gene in BPSD. Methods: Our large cohort of 395 patients with probable Alzheimer’s disease was dichotomised into whether they had ever suffered from a given symptom over the study period or not, based on longitudinal data using the BPSD (Neuropsychiatric Inventory). These measures were related to the DAT1 3′-untranslated region (UTR) variable number tandem repeat (VNTR) polymorphism. Results: Potential associations were revealed between the 9-repeat allele and presence of irritability and between the 10-repeat allele and aberrant motor behaviour (AMB); however, these do not remain significant after correction for multiple testing. No associations were observed with delusions, hallucinations, depression, agitation/aggression or elation. Conclusion: Our data suggest that the DAT1 3′-UTR VNTR could play a role in susceptibility to irritability and AMB. The findings presented here require replication in large well-characterised cohorts.

Background Cardiovascular risk factors and a history of vascular disease can increase the risk of Alzheimer's disease (AD). AD is less common in aspirin users than non-users, and there are plausible biological mechanisms whereby aspirin might slow the progression of either vascular or Alzheimer-type pathology. We assessed the benefits of aspirin in patients with AD. Methods 310 community-resident patients who had AD and who had no potential indication or definite contraindication for aspirin were randomly assigned to receive open-label aspirin (n=156; one 75-mg enteric-coated tablet per day, to continue indefinitely) or to avoid aspirin (n=154). Primary outcome measures were cognition (assessed with the mini-mental state examination [MMSE]) and functional ability (assessed with the Bristol activities of daily living scale [BADLS]). Secondary outcomes were time to formal domiciliary or institutional care, progress of disability, behavioural symptoms, caregiver wellbeing, and care time. Patients were assessed at 12-week intervals in the first year and once each year thereafter. Analysis of the primary outcome measures was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN96337233. Findings Patients had a median age of 75 years; 156 patients had mild AD, 154 had moderate AD, and 18 had concomitant vascular dementia. Over the 3 years after randomisation, in patients who took aspirin, mean MMSE score was 0·10 points higher (95% CI −0·37 to 0·57; p=0·7) and mean BADLS score was 0·62 points lower (−1·37 to 0·13; p=0·11) than in patients assigned to aspirin avoidance. There were no obvious differences between the groups in any other outcome measurements. 13 (8%) patients on aspirin and two (1%) patients in the control group had bleeds that led to admission to hospital (relative risk=4·4, 95% CI 1·5–12·8; p=0·007); three (2%) patients in the aspirin group had fatal cerebral bleeds. Interpretation Although aspirin is commonly used in dementia, in patients with typical AD 2 years of treatment with low-dose aspirin has no worthwhile benefit and increases the risk of serious bleeds.

Background: Patients with Alzheimer’s disease and dementia commonly suffer from behavioural and psychological symptoms of dementia (BPSD). A genetic component to BPSD development in Alzheimer’s disease has been demonstrated. Several studies have investigated whether the exon 4 e2/e3/e4 haplotype of the apolipoprotein E ( APOE ) gene is associated with BPSD, with variable results. Objective: We investigated the exon 4 polymorphisms and extended this study to include promoter polymorphisms and the resultant haplotypes across the gene. Methods: Our large independent cohort of 388 patients with longitudinal measures of BPSD assessed by the Neuropsychiatric Inventory was used to analyse whether any of these variants were associated with the presence of BPSD. Results: We revealed several significant relationships before correction for multiple testing. The exon 4 haplotype was associated with hallucinations and anxiety, A-491T with irritability, T-427C with agitation/aggression and appetite disturbances, and T-219C with depression. Haplotype analyses of all variants did not reveal any statistically significant findings. Conclusions: Our data and a review of previous studies showed a diversity of relationships, suggesting that these findings might be due to chance and so collectively do not support a role for the APOE gene in BPSD.

Background/Aims: Alzheimer disease (AD) patients commonly suffer from behavioural and psychological symptoms of dementia (BPSD). A genetic component to BPSD development in AD has been demonstrated. This is an investigation of whether the linked polymorphic region and variable number tandem repeat variants of the serotonin transporter (SERT) are associated with BPSD. Methods: The longitudinal measures of BPSD of our large cohort of 367 AD patients were assessed by the Neuropsychiatric Inventory. Measures with good evidence of serotonergic involvement (delusions, hallucinations, depression, anxiety, agitation/aggression and irritability) were related to genotype and allele frequencies of the linked polymorphic region and variable number tandem repeat variants. Results: Analysis revealed significant relationships between the linked polymorphic region variant long allele with irritability and the variable number tandem repeat 10-repeat allele with psychosis, but no associations were found with depression, anxiety or agitation/aggression. Conclusion: Our data and review of previous studies suggest SERT could play a minor role in development of psychosis and aggressive/irritable tendencies; however, further investigations are required in large, well-characterized cohorts.

Background: As tau aggregation pathology correlates with clinical dementia in Alzheimer’s disease (AD), a tau aggregation inhibitor (TAI) could have therapeutic utility. Methylthioninium (MT) acts as a selective TAI in vitro and reduces tau pathology in transgenic mouse models. Objective: To determine the minimum safe and effective dose of MT required to prevent disease progression on clinical and functional molecular imaging outcomes. Methods: An exploratory double-blind, randomized, placebo-controlled, dose-finding trial of MT (69, 138, and 228 mg/day) was conducted in 321 mild/moderate AD subjects. The primary outcome was change on the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) at 24 weeks relative to baseline severity. Effect of treatment on regional cerebral blood flow decline was determined in a sub-study in 135 subjects. After 24 weeks, subjects were re-consented to enter sequential 6- and 12-month blinded extension phases. Registered with ClinicalTrials.gov (NCT00515333). Results: At 24 weeks, there were significant treatment benefits in two independent populations at the 138 mg/day dose: in moderate subjects on the ADAS-cog scale (treatment effect: −5.42 units, corrected p = 0.047) and two other clinical scales; in mild subjects on the more sensitive regional cerebral blood flow measure (treatment effect: 1.97%, corrected p < 0.001). With continued treatment for 50 weeks, benefit was seen on the ADAS-cog scale in both mild and moderate subjects. The delivery of the highest dose was impaired due to dose-dependent dissolution and absorption limitations. Conclusion: The minimum safe and effective daily MT dose is 138 mg and suggests that further study of MT is warranted in AD.

Summary Background Findings from observational studies have suggested a delay in nursing home placement with dementia drug treatment, but findings from a previous randomised trial of patients with mild-to-moderate Alzheimer's disease showed no effect. We investigated the effects of continuation or discontinuation of donepezil and starting of memantine on subsequent nursing home placement in patients with moderate-to-severe Alzheimer's disease. Methods In the randomised, double-blind, placebo-controlled Donepezil and Memantine in Moderate to Severe Alzheimer's Disease (DOMINO-AD) trial, community-living patients with moderate-to-severe Alzheimer's disease (who had been prescribed donepezil continuously for at least 3 months at a dose of 10 mg for at least the previous 6 weeks and had a score of between 5 and 13 on the Standardised Mini-Mental State Examination) were recruited from 15 secondary care memory centres in England and Scotland and randomly allocated to continue donepezil 10 mg per day without memantine, discontinue donepezil without memantine, discontinue donepezil and start memantine 20 mg per day, or continue donepezil 10 mg per day and start memantine 20 mg per day, for 52 weeks. After 52 weeks, choice of treatment was left to participants and their physicians. Place of residence was recorded during the first 52 weeks of the trial and then every 26 weeks for a further 3 years. A secondary outcome of the trial, reported in this study, was nursing home placement: an irreversible move from independent accommodation to a residential caring facility. Analyses restricted to risk of placement in the first year of follow-up after the patients had completed the double-blind phase of the trial were post-hoc. The DOMINO-AD trial is registered with the ISRCTN Registry, number ISRCTN49545035. Findings Between Feb 11, 2008, and March 5, 2010, 73 (25%) patients were randomly assigned to continue donepezil without memantine, 73 (25%) to discontinue donepezil without memantine, 76 (26%) to discontinue donepezil and start memantine, and 73 (25%) to continue donepezil and start memantine. 162 (55%) patients underwent nursing home placement within 4 years of randomisation, with similar numbers for all groups (36 [49%] in patients who continued donepezil without memantine, 42 [58%] who discontinued donepezil without memantine, 41 [54%] who discontinued donepezil and started memantine, and 43 [59%] who continued donepezil and started memantine). We noted significant (p=0·010) heterogeneity of treatment effect over time, with significantly more nursing home placements in the combined donepezil discontinuation groups during the first year (hazard ratio 2·09 [95% CI 1·29–3·39]) than in the combined donepezil continuation groups, and no difference during the next 3 years (0·89 [0·58–1·35]). We noted no effect of patients starting memantine compared with not starting memantine during the first year (0·92 [0·58–1·45]) or the next 3 years (1·23 [0·81–1·87]). Interpretation Withdrawal of donepezil in patients with moderate-to-severe Alzheimer's disease increased the risk of nursing home placement during 12 months of treatment, but made no difference during the following 3 years of follow-up. Decisions to stop or continue donepezil treatment should be informed by potential risks of withdrawal, even if the perceived benefits of continued treatment are not clear. Funding Medical Research Council and UK Alzheimer's Society.

Approximately 18,500 younger people suffer from dementia in the UK. In many ways the needs of these individuals and their carers differ significantly from those of older people with the disorder. Accurate timely diagnosis, provision of information, effective treatment, rehabilitation, maintenance of valued occupation, support of the patient, their carers and family, and the provision of longer-term care all pose considerable challenges to health and social care services. Specialist multidisciplinary provision for this group is recommended as being essential to maximize their potential for health-related quality of life.

Background Cholinesterase inhibitors produce small improvements in cognitive and global assessments in Alzheimer's disease. We aimed to determine whether donepezil produces worthwhile improvements in disability, dependency, behavioural and psychological symptoms, carers' psychological wellbeing, or delay in institutionalisation. If so, which patients benefit, from what dose, and for how long? Methods 565 community-resident patients with mild to moderate Alzheimer's disease entered a 12-week run-in period in which they were randomly allocated donepezil (5 mg/day) or placebo. 486 who completed this period were rerandomised to either donepezil (5 or 10 mg/day) or placebo, with double-blind treatment continuing as long as judged appropriate. Primary endpoints were entry to institutional care and progression of disability, defined by loss of either two of four basic, or six of 11 instrumental, activities on the Bristol activities of daily living scale (BADLS). Outcome assessments were sought for all patients and analysed by logrank and multilevel models. Findings Cognition averaged 0·8 MMSE (mini-mental state examination) points better (95% Cl 0·5–1·2; p