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Background: Agitation is common and impacts negatively on people with dementia and carers. Non-drug patient-centred care is first-line treatment, but we need other treatment when this fails. Current evidence is sparse on safer and effective alternatives to antipsychotics., Objectives: To assess clinical and cost-effectiveness and safety of mirtazapine and carbamazepine in treating agitation in dementia., Design: Pragmatic, phase III, multicentre, double-blind, superiority, randomised, placebo-controlled trial of the clinical effectiveness of mirtazapine over 12 weeks (carbamazepine arm discontinued)., Setting: Twenty-six UK secondary care centres., Participants: Eligibility: probable or possible Alzheimer's disease, agitation unresponsive to non-drug treatment, Cohen-Mansfield Agitation Inventory score ≥ 45., Interventions: Mirtazapine (target 45 mg), carbamazepine (target 300 mg) and placebo., Outcome Measures: Primary: Cohen-Mansfield Agitation Inventory score 12 weeks post randomisation. Main economic outcome evaluation: incremental cost per six-point difference in Cohen-Mansfield Agitation Inventory score at 12 weeks, from health and social care system perspective. Data from participants and informants at baseline, 6 and 12 weeks. Long-term follow-up Cohen-Mansfield Agitation Inventory data collected by telephone from informants at 6 and 12 months., Randomisation and Blinding: Participants allocated 1 : 1 : 1 ratio (to discontinuation of the carbamazepine arm, 1 : 1 thereafter) to receive placebo or carbamazepine or mirtazapine, with treatment as usual. Random allocation was block stratified by centre and residence type with random block lengths of three or six (after discontinuation of carbamazepine, two or four). Double-blind, with drug and placebo identically encapsulated. Referring clinicians, participants, trial management team and research workers who did assessments were masked to group allocation., Results: Two hundred and forty-four participants recruited and randomised (102 mirtazapine, 102 placebo, 40 carbamazepine). The carbamazepine arm was discontinued due to slow overall recruitment; carbamazepine/placebo analyses are therefore statistically underpowered and not detailed in the abstract. Mean difference placebo-mirtazapine (-1.74, 95% confidence interval -7.17 to 3.69; p  = 0.53). Harms: The number of controls with adverse events (65/102, 64%) was similar to the mirtazapine group (67/102, 66%). However, there were more deaths in the mirtazapine group ( n  = 7) by week 16 than in the control group ( n  = 1). Post hoc analysis suggests this was of marginal statistical significance ( p  = 0.065); this difference did not persist at 6- and 12-month assessments. At 12 weeks, the costs of unpaid care by the dyadic carer were significantly higher in the mirtazapine than placebo group [difference: £1120 (95% confidence interval £56 to £2184)]. In the cost-effectiveness analyses, mean raw and adjusted outcome scores and costs of the complete cases samples showed no differences between groups., Limitations: Our study has four important potential limitations: (1) we dropped the proposed carbamazepine group; (2) the trial was not powered to investigate a mortality difference between the groups; (3) recruitment beyond February 2020, was constrained by the COVID-19 pandemic; and (4) generalisability is limited by recruitment of participants from old-age psychiatry services and care homes., Conclusions: The data suggest mirtazapine is not clinically or cost-effective (compared to placebo) for agitation in dementia. There is little reason to recommend mirtazapine for people with dementia with agitation., Future Work: Effective and cost-effective management strategies for agitation in dementia are needed where non-pharmacological approaches are unsuccessful., Study Registration: This trial is registered as ISRCTN17411897/NCT03031184., Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 27, No. 23. See the NIHR Journals Library website for further project information.

Identification of shared causal genes between dementia and its related clinical outcomes can help understand shared aetiology and multimorbidity surrounding dementia. We performed the HyPrColoc colocalization analysis to detect possible shared causal genes between dementia or Alzheimer's disease (AD) and 5 selected traits: stroke, diabetes, atherosclerosis, cholesterol level, and alcohol consumption within 601 dementia or AD associated genetic regions using summary results of the UK Biobank genome-wide association studies. Functional analysis was performed on the candidate causal genes to explore potential biological pathways. Rs150562240 in the LPIN3 gene was identified as a candidate shared causal variant across dementia, AD and atherosclerosis. Evidence for pairwise colocalization between dementia and stroke, dementia (or AD) and atherosclerosis, and dementia (or AD) and diabetes was found in 2, 6 and 2 genetic regions respectively. Colocalization signals between diabetes and the other 3 non-dementia/AD traits were detected in 5 regions. The colocalization evidence shown in our study suggested shared aetiology between dementia and related diseases such as stroke, atherosclerosis, and diabetes., (Copyright © 2022. Published by Elsevier Inc.)

Given considerable variation in diagnostic and therapeutic practice, there is a need for national guidance on the use of neuroimaging, fluid biomarkers, cognitive testing, follow-up and diagnostic terminology in mild cognitive impairment (MCI). MCI is a heterogenous clinical syndrome reflecting a change in cognitive function and deficits on neuropsychological testing but relatively intact activities of daily living. MCI is a risk state for further cognitive and functional decline with 5-15% of people developing dementia per year. However, ~50% remain stable at 5 years and in a minority, symptoms resolve over time. There is considerable debate about whether MCI is a useful clinical diagnosis, or whether the use of the term prevents proper inquiry (by history, examination and investigations) into underlying causes of cognitive symptoms, which can include prodromal neurodegenerative disease, other physical or psychiatric illness, or combinations thereof. Cognitive testing, neuroimaging and fluid biomarkers can improve the sensitivity and specificity of aetiological diagnosis, with growing evidence that these may also help guide prognosis. Diagnostic criteria allow for a diagnosis of Alzheimer's disease to be made where MCI is accompanied by appropriate biomarker changes, but in practice, such biomarkers are not available in routine clinical practice in the UK. This would change if disease-modifying therapies became available and required a definitive diagnosis but would present major challenges to the National Health Service and similar health systems. Significantly increased investment would be required in training, infrastructure and provision of fluid biomarkers and neuroimaging. Statistical techniques combining markers may provide greater sensitivity and specificity than any single disease marker but their practical usefulness will depend on large-scale studies to ensure ecological validity and that multiple measures, e.g. both cognitive tests and biomarkers, are widely available for clinical use. To perform such large studies, we must increase research participation amongst those with MCI., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Geriatrics Society.)

Importance: There are no disease-modifying treatments for Alzheimer disease (AD), the most common cause of dementia. Minocycline is anti-inflammatory, protects against the toxic effects of β-amyloid in vitro and in animal models of AD, and is a credible repurposed treatment candidate., Objective: To determine whether 24 months of minocycline treatment can modify cognitive and functional decline in patients with mild AD., Design, Setting, and Participants: Participants were recruited into a double-blind randomized clinical trial from May 23, 2014, to April 14, 2016, with 24 months of treatment and follow-up. This multicenter study in England and Scotland involved 32 National Health Service memory clinics within secondary specialist services for people with dementia. From 886 screened patients, 554 patients with a diagnosis of mild AD (Standardised Mini-Mental State Examination [sMMSE] score ≥24) were randomized., Interventions: Participants were randomly allocated 1:1:1 in a semifactorial design to receive minocycline (400 mg/d or 200 mg/d) or placebo for 24 months., Main Outcomes and Measures: Primary outcome measures were decrease in sMMSE score and Bristol Activities of Daily Living Scale (BADLS), analyzed by intention-to-treat repeated-measures regression., Results: Of 544 eligible participants (241 women and 303 men), the mean (SD) age was 74.3 (8.2) years, and the mean (SD) sMMSE score was 26.4 (1.9). Fewer participants completed 400-mg minocycline hydrochloride treatment (28.8% [53 of 184]) than 200-mg minocycline treatment (61.9% [112 of 181]) or placebo (63.7% [114 of 179]; P < .001), mainly because of gastrointestinal symptoms (42 in the 400-mg group, 15 in the 200-mg group, and 10 in the placebo group; P < .001), dermatologic adverse effects (10 in the 400-mg group, 5 in the 200-mg group, and 1 in the placebo group; P = .02), and dizziness (14 in the 400-mg group, 3 in the 200-mg group, and 1 in the placebo group; P = .01). Assessment rates were lower in the 400-mg group: 68.4% (119 of 174 expected) for sMMSE at 24 months compared with 81.8% (144 of 176) for the 200-mg group and 83.8% (140 of 167) for the placebo group. Decrease in sMMSE scores over 24 months in the combined minocycline group was similar to that in the placebo group (4.1 vs 4.3 points). The combined minocycline group had mean sMMSE scores 0.1 points higher than the placebo group (95% CI, -1.1 to 1.2; P = .90). The decrease in mean sMMSE scores was less in the 400-mg group than in the 200-mg group (3.3 vs 4.7 points; treatment effect = 1.2; 95% CI, -0.1 to 2.5; P = .08). Worsening of BADLS scores over 24 months was similar in all groups: 5.7 in the 400-mg group, 6.6 in the 200-mg group, and 6.2 in the placebo groups (treatment effect for minocycline vs placebo = -0.53; 95% CI, -2.4 to 1.3; P = .57; treatment effect for 400 mg vs 200 mg of minocycline = -0.31; 95% CI, -0.2 to 1.8; P = .77). Results were similar in different patient subgroups and in sensitivity analyses adjusting for missing data., Conclusions and Relevance: Minocycline did not delay the progress of cognitive or functional impairment in people with mild AD during a 2-year period. This study also found that 400 mg of minocycline is poorly tolerated in this population., Trial Registration: isrctn.org Identifier: ISRCTN16105064.

Objective: Most investigations of pharmacotherapy for treating Alzheimer's disease focus on patients with mild-to-moderate symptoms, with little evidence to guide clinical decisions when symptoms become severe. We examined whether continuing donepezil, or commencing memantine, is cost-effective for community-dwelling, moderate-to-severe Alzheimer's disease patients., Methods: Cost-effectiveness analysis was based on a 52-week, multicentre, double-blind, placebo-controlled, factorial clinical trial. A total of 295 community-dwelling patients with moderate/severe Alzheimer's disease, already treated with donepezil, were randomised to: (i) continue donepezil; (ii) discontinue donepezil; (iii) discontinue donepezil and start memantine; or (iv) continue donepezil and start memantine., Results: Continuing donepezil for 52 weeks was more cost-effective than discontinuation, considering cognition, activities of daily living and health-related quality of life. Starting memantine was more cost-effective than donepezil discontinuation. Donepezil-memantine combined is not more cost-effective than donepezil alone., Conclusions: Robust evidence is now available to inform clinical decisions and commissioning strategies so as to improve patients' lives whilst making efficient use of available resources. Clinical guidelines for treating moderate/severe Alzheimer's disease, such as those issued by NICE in England and Wales, should be revisited. © 2016 The Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons Ltd., (© 2016 The Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons Ltd.)

Context: This commentary discusses the implications of disease-modifying treatments for Alzheimer's disease which seem likely to appear in the next few years and results from a meeting of British experts in neurodegenerative diseases in Edinburgh. The availability of such treatments would help change public and professional attitudes and accelerate engagement with the prodromal and preclinical populations who might benefit from them. However, this would require an updated understanding of Alzheimer's disease, namely the important distinction between Alzheimer's disease and Alzheimer's dementia., Consensus: Since treatments are likely to be most effective in the early stages, identification of clinically relevant brain changes (for example, amyloid burden using imaging or cerebrospinal fluid biomarkers) will be crucial. While current biomarkers could be useful in identifying eligibility for new therapies, trial data are not available to aid decisions about stopping or continuing treatment in clinical practice. Therefore, effective monitoring of safety and effectiveness when these treatments are introduced into clinical practice will be necessary to inform wide-scale use. Equity of access is key but there is a tension between universal access for everyone with a diagnosis of Alzheimer's disease and specifying an eligible population most likely to respond. We propose the resources necessary for an optimal care pathway as well as the necessary education and training for primary and secondary care., Conclusion: The majority of current services in the UK and elsewhere would not be able to accommodate the specialist investigations required to select patients and prescribe these therapies. Therefore, a stepped approach would be necessary: from innovating sentinel clinical-academic centres that already have capacity to deliver the necessary phase IV trials, through early adoption in a hub and spoke model, to nationwide adoption for true equity of access. The optimism generated by recent and anticipated developments in the understanding and treatment of Alzheimer's disease presents a great opportunity to innovate and adapt our services to incorporate the next exciting development in the field of dementia.

Objectives: The literature commonly evaluates those daily activities which are impaired in dementia. However, in the mild stages, people with dementia (PwD) are still able to initiate and perform many of those tasks. With a lack of research exploring variations between different dementia diagnoses, this study sought to investigate those daily activities with modest impairments in the mild stages and how these compare between Alzheimer's disease (AD), vascular dementia (VaD) and mixed dementia., Methods: Staff from memory assessment services from nine National Health Service trusts across England identified and approached informal carers of people with mild dementia. Carers completed the newly revised Interview for Deteriorations in Daily Living Activities in Dementia 2 assessing the PwD's initiative and performance of instrumental activities of daily living (IADLs). Data were analysed using analysis of variance and Chi-square tests to compare the maintenance of IADL functioning across AD, VaD, and mixed dementia., Results: A total of 160 carers returned the Interview for Deteriorations in Daily Living Activities in Dementia 2, of which 109, 21, and 30 cared for someone with AD, VaD, and mixed dementia, respectively. There were significant variations across subtypes, with AD showing better preserved initiative and performance than VaD for several IADLs. Overall, PwD showed greater preservation of performance than initiative, with tasks such as preparing a hot drink and dressing being best maintained., Conclusion: Findings can help classify dementia better into subtypes in order to receive bespoke support. It suggests that interventions should primarily address initiative to improve overall functioning. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

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., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Executive control is impaired from the early stages of Alzheimer's Disease (AD) and this produces deregulated semantic cognition (Corbett, Jefferies, Burns, & Lambon Ralph, ; Perry, Watson, & Hodges, ). While control deficits should affect semantic retrieval across all modalities, previous studies have typically focused on verbal semantic tasks. Even when non-verbal semantic tasks have been used, these have typically employed simple picture-matching tasks, which may be influenced by abnormalities in covert naming. Therefore, in the present study, we examined 10 patients with AD on a battery of object-use tasks, in order to advance our understanding of the origins of non-verbal semantic deficits in this population. The AD patients' deficits were contrasted with previously published performance on the same tasks within two additional groups of patients, displaying either semantic degradation (semantic dementia) or deregulation of semantic retrieval (semantic aphasia; Corbett, Jefferies, Ehsan, & Lambon Ralph, ). While overall accuracy was comparable to the scores in both other groups, the AD patients' object-use impairment most closely resembled that observed in SA; they exhibited poorer performance on comprehension tasks that placed strong demands on executive control. A similar pattern was observed in the expressive domain: the AD and SA groups were relatively good at straightforward object use compared to executively demanding, mechanical puzzles. Error types also differed: while all patients omitted essential actions, the SA and AD groups' demonstrations also featured unrelated intrusions. An association between AD patients' object use and their scores on standard executive measures suggested that control deficits contributed to their non-verbal semantic deficits. Moreover, in a task specifically designed to manipulate executive demand, patients with AD (and SA) exhibited difficulty in thinking flexibly about the non-canonical uses of everyday objects, especially when distracted by semantically related objects. This study provides converging evidence for the notion that a failure of regulatory control contributes to multimodal semantic impairment in AD and uniquely demonstrates this pattern for the highly non-verbal domain of object use., (© 2014 The Authors Journal of Neuropsychology published by John Wiley & Sons Ltd on behalf of British Psychological Society.)

Background: Neuropsychiatric symptoms in Alzheimer disease (AD) cause significant distress and present a complex clinical challenge for treatment. Pharmacological treatment options are limited to antipsychotics, which carry extensive safety issues. There is emerging evidence to support the potential benefits of memantine, currently licensed for moderate to severe AD, in the prophylaxis of neuropsychiatric symptoms., Methods: The MAIN-AD study is a double-blind randomized placebo-controlled withdrawal trial comparing memantine with antipsychotics for the treatment of neuropsychiatric symptoms over 24 weeks. A total of 199 people with probable AD living in care homes already receiving an antipsychotic were randomized to receive either memantine or to continue an antipsychotic. The primary outcomes were function (Bristol Activities of Daily Living Scale [BADLS]) and agitation (Cohen-Mansfield Agitation Inventory [CMAI]). Secondary outcomes were Neuropsychiatric Inventory (NPI), Mini-Mental State Examination (MMSE), and mortality., Results: There was no significant difference between groups on the BADLS or CMAI. At 24 weeks, there was a nonsignificant adjusted difference in favor of memantine on the BADLS of 0.23 (95% CI -1.80-2.27; P = .82) and in favor of antipsychotic on the CMAI of 0.09 (95% CI -0.35-8.53; P = .07). Although there were no significant differences in total NPI, there were 5.01 (95% CI -1.68-11.70; P = .05) and 3.63 (95% CI -1.40-8.67; P = .16) point advantages favoring antipsychotics at weeks 12 and 24, respectively. In addition, in an exploratory analysis, individuals allocated to antipsychotics were significantly less likely to experience relapse of neuropsychiatric symptoms at all time points. The group receiving memantine had a nonsignificant 1.3-point advantage on the MMSE at 24 weeks., Discussion: This study indicates no benefits for memantine in the long-term treatment and prophylaxis of clinically significant neuropsychiatric symptoms. The results did indicate some benefits for antipsychotic medications in reducing the relapse of neuropsychiatric symptoms, but this must be balanced against increased mortality risk., (Copyright © 2015 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Existing drugs for Alzheimer's disease provide symptomatic benefit for up to 12 months, but there are no approved disease-modifying therapies. Given the recent failures of various novel disease-modifying therapies in clinical trials, a complementary strategy based on repositioning drugs that are approved for other indications could be attractive. Indeed, a substantial body of preclinical work indicates that several classes of such drugs have potentially beneficial effects on Alzheimer's-like brain pathology, and for some drugs the evidence is also supported by epidemiological data or preliminary clinical trials. Here, we present a formal consensus evaluation of these opportunities, based on a systematic review of published literature. We highlight several compounds for which sufficient evidence is available to encourage further investigation to clarify an optimal dose and consider progression to clinical trials in patients with Alzheimer's disease.

Purpose of Review: In this article, we discuss new data on currently licensed drugs for dementia and novel developments in the management of neuropsychiatric symptoms in patients with dementia., Recent Findings: During the last years, a large body of evidence has been accumulated to support the use of antidementia medication in patients with severe Alzheimer's disease. Combination therapy with acetylcholinesterase inhibitors and memantine for Alzheimer's disease remains controversial, as controlled trials have yielded conflicting results. Memantine is not indicated in patients with mild Alzheimer's disease. Studies on memantine for Parkinson's disease dementia and dementia with Lewy bodies were inconclusive. In adult patients with dementia in the context of Down syndrome, memantine is not effective, and further studies on acetylcholinesterase inhibitors are warranted. There is still no treatment established for patients with vascular or frontotemporal dementia. The efficacy of antidepressants to treat depression associated with dementia is not proven. Treatment of agitation and psychosis in patients with dementia remains a challenge., Summary: Recent systematic clinical reviews and new research on currently available treatment options provide valuable assistance for clinicians to deal with frequent clinical problems in the context of dementia.

Objective: The decline of episodic memory in Alzheimer's disease (AD) is well established, but the exact appearance and staging of deficits in other cognitive domains is sometimes contentious. The current investigation attempted to elucidate the appearance of additional cognitive deficits in the non-episodic domains and to understand these deficits with respect to the known pathological staging of AD., Methods: A cross-sectional investigation compared cognitively normal age-matched controls with patients with mild AD and mild cognitive impairment (MCI) using a detailed neuropsychological assessment., Results: The systematic investigation of cognitive performance across the major cognitive domains demonstrates that the appearance of additional cognitive deficits in MCI and AD can be predicted, with impaired semantic cognition performance pre-empting the appearance of attention/executive dysfunction and visuospatial deficits in the majority of patients with MCI., Conclusions: This progressive pattern of cognitive deficits fits with the known pathological staging of AD, and the data further highlight the relative rarity of pure amnestic MCI. These results indicate that any neuropsychological test battery used to assess patients with MCI should include language and semantic memory tests in addition to typical episodic memory tests, as changes within this domain might be a sensitive indication of incipient AD., (Copyright © 2011 John Wiley & Sons, Ltd.)

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<0.001 for both comparisons). Patients assigned to receive memantine, as compared with those assigned to receive memantine placebo, had a score on the SMMSE that was an average of 1.2 points higher (95% CI, 0.6 to 1.8; P<0.001) and a score on the BADLS that was 1.5 points lower (95% CI, 0.3 to 2.8; P=0.02). The efficacy of donepezil and of memantine did not differ significantly in the presence or absence of the other. There were no significant benefits of the combination of donepezil and memantine over donepezil alone., Conclusions: In patients with moderate or severe Alzheimer's disease, continued treatment with donepezil was associated with cognitive benefits that exceeded the minimum clinically important difference and with significant functional benefits over the course of 12 months. (Funded by the U.K. Medical Research Council and the U.K. Alzheimer's Society; Current Controlled Trials number, ISRCTN49545035.).

Objective: Spontaneous cerebral emboli occur frequently in patients with Alzheimer's disease and vascular dementia. The authors investigated the effect of cerebral emboli on cognitive and functional decline in both Alzheimer's disease and vascular dementia patients over a 2-year period., Method: Cerebral emboli entering the middle cerebral arteries were counted at baseline and every 6 months over the following 18 months using transcranial Doppler ultrasonography in 144 patients with dementia (Alzheimer's disease, N=84; vascular dementia, N=60). Deterioration in cognition was measured every 6 months over 2 years using the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog), the Mini-Mental State Examination (to assess cognition), the Interview for Deterioration in Daily Living Activities in Dementia (to assess function), and the Neuropsychiatric Inventory (to assess behavioral and psychological symptoms). The relationship between cerebral emboli and progression of dementia was analyzed using longitudinal regression modeling, adjusted for age, sex, diagnostic subtype, age at onset of dementia, and significant vascular risk factors., Results: Spontaneous cerebral emboli were detected in 63 (44%) dementia patients, 36 (43%) Alzheimer's disease patients, and 27 (45%) vascular dementia patients. ADAS-Cog scores revealed faster deterioration in cognitive functioning in patients with cerebral emboli over 2 years, with a mean increase in score of 15.4 in these patients, compared with only 6.0 for those without cerebral emboli. Similarly, Interview for Deterioration in Daily Living Activities in Dementia scores revealed more rapid deterioration in those with cerebral emboli, with a mean increase in score of 59.0 in these patients, compared with 17.9 for those without cerebral emboli. Neuropsychiatric Inventory scores also indicated faster decline in patients with cerebral emboli, with a mean increase in score of 12.0 in these patients, compared with a mean decrease in score of -3.8 for patients in whom no emboli were detected., Conclusions: Spontaneous cerebral emboli predict more rapid progression of dementia over 2 years in both Alzheimer's disease and vascular dementia. Clinical trials on the inhibition of cerebral emboli in the prevention and treatment of dementia are needed.

Despite a vast literature examining semantic impairment in Alzheimer's disease (AD), consensus regarding the nature of the deficit remains elusive. We re-considered this issue in the context of a framework that assumes semantic cognition can break down in two ways: (1) core semantic representations can degrade or (2) cognitive control mechanisms can become impaired. We hypothesised and confirmed that the nature of semantic impairment in AD changes with disease severity. Patients at mild or severe stages of the disorder exhibited impairment across various semantic tasks but the nature of those deficits differed qualitatively for the two groups. Commensurate with early dysfunction of the cognitive control, temporoparietal-frontal-cingulate network, characteristics of deregulated semantic cognition were exhibited by the mild AD cases. In contrast, the severe AD group reproduced features of additional degradation of core semantic representations. These results suggest that spread of pathology into lateral anterior temporal lobes in later stage AD produces degradation of semantic representations, exacerbating the already deregulated system. Moreover, the dual nature of severe patients' impairment was highlighted by disproportionately poor performance on tasks placing high demand on both conceptual knowledge and control processes--e.g., category fluency.

Developing rehabilitation techniques to combat cognitive decline is a key goal of healthcare strategies aimed at promoting increased longevity and better quality of life for individuals with Alzheimer's disease (AD). In AD, problems with episodic memory and word-finding greatly affect everyday life and, as such, these symptoms provide a clear clinical target for therapeutic interventions. Errorless learning (EL) has been proposed as a particularly effective technique for relearning in individuals with memory dysfunction, including AD. However, EL learning has rarely been directly contrasted with other more traditional trial-and-error techniques (errorful learning or EF) in individuals with AD, especially in the context of alleviating word-finding problems. In the current study, we directly contrasted the therapeutic gains of an EL learning paradigm (consisting of reading/repetition of object names) with an EF learning technique (comprised of phonemic/orthographic cueing) in eight mild to moderate AD patients with pronounced anomia. Both techniques were administered concurrently in sessions run twice a week over a five-week period. Therapeutic gains were assessed at one week and five weeks post-intervention using confrontation naming. Our results suggest that, both at the group and individual patient level, EL and EF techniques were equally effective. Correlational analyses of overall therapy gains and background assessments of patient neuropsychology revealed that individuals with better scores on measures of semantic memory, pre-intervention naming, and recognition memory demonstrated larger therapy gains. No individual patient showed a significant advantage for EL over EF learning, however, for patients that showed a numerical advantage in this direction. These results suggest that either EL or EF therapy can be used to alleviate word-finding problems in AD.

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., (Copyright © 2010 John Wiley & Sons, Ltd.)

The British Association for Psychopharmacology (BAP) coordinated a meeting of experts to review and revise its first (2006) Guidelines for clinical practice with anti-dementia drugs. As before, levels of evidence were rated using accepted standards which were then translated into grades of recommendation A to D, with A having the strongest evidence base (from randomized controlled trials) and D the weakest (case studies or expert opinion). Current clinical diagnostic criteria for dementia have sufficient accuracy to be applied in clinical practice (B) and brain imaging can improve diagnostic accuracy (B). Cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) are effective for mild to moderate Alzheimer's disease (A) and memantine for moderate to severe Alzheimer's disease (A). Until further evidence is available other drugs, including statins, anti-inflammatory drugs, vitamin E and Ginkgo biloba, cannot be recommended either for the treatment or prevention of Alzheimer's disease (A). Neither cholinesterase inhibitors nor memantine are effective in those with mild cognitive impairment (A). Cholinesterase inhibitors are not effective in frontotemporal dementia and may cause agitation (A), though selective serotonin reuptake inhibitors may help behavioural (but not cognitive) features (B). Cholinesterase inhibitors should be used for the treatment of people with Lewy body dementias (Parkinson's disease dementia and dementia with Lewy bodies (DLB)), especially for neuropsychiatric symptoms (A). Cholinesterase inhibitors and memantine can produce cognitive improvements in DLB (A). There is no clear evidence that any intervention can prevent or delay the onset of dementia. Although the consensus statement focuses on medication, psychological interventions can be effective in addition to pharmacotherapy, both for cognitive and non-cognitive symptoms. Many novel pharmacological approaches involving strategies to reduce amyloid and/or tau deposition are in progress. Although results of pivotal studies are awaited, results to date have been equivocal and no disease-modifying agents are either licensed or can be currently recommended for clinical use.

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., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Objective: This paper presents the results of a trans-cultural study looking at the possible differences in the symptomatology of Alzheimer's disease (AD) in people from Manchester, UK and Rawalpindi, Pakistan., Methods: Two groups of people with AD (45 in each group) were recruited at the two sites. The participants and their carers were interviewed to investigate possible differences in demographics and symptomatology including cognition, depression, personality change and every day activities. The instrument used included the Mini Mental State Examination (MMSE), Geriatric Depression Scale (GDS), Cornell Scale for Depression in Dementia (CSDD), The Brooks and McKinlay Personality Inventory and Informant Questionnaire on Cognitive Decline in the Elderly (IQ CODE)., Results: The data analysis showed that compared to people from Manchester the Pakistanis had lower literacy levels but similar cognitive deficits when MMSE scores were adjusted for education. They were however more depressed; they had a different profile of personality change since the onset of illness and their reported changes in activities of daily living were more severe., Conclusion: The study has shown a number of possible cultural differences in affective symptoms, personality changes and every day activities. It highlights the need for developing mental health services for older people in Pakistan and making UK services more accessible for this growing community. Further research on service and care needs along with developing culturally sensitive instruments for assessing cognition, psychiatric symptoms, personality changes and daily activities is needed., (Copyright © 2010 John Wiley & Sons, Ltd.)

Objectives: To define a practice guideline for biological treatment of dementia and to make transparent the development of the guideline connecting the original data with the resulting recommendations., Methods: This guideline includes pharmacologic treatment considerations for patients with Alzheimer's disease, vascular dementia, DLB, and fronto-temporal dementia. Studies were selected that represent double-blind placebo-controlled trials of at least 3 months duration in patients with a diagnosis of dementia according to accepted international diagnostic criteria (for example the NINCDS/ADRDA or NINDS/AIREN criteria). Moreover, to be included studies had to fulfill a restrictive set of methodological criteria. Original studies and not meta-analyses determined the evaluation and the development of recommendations., Results: Antidementia pharmaceuticals neither cure nor arrest the disease. A modest effect of improvement of symptoms compared with placebo can be observed. Antidementia pharmaceuticals show different efficacy and side effect profiles. The type of dementia, the individual symptom constellation and the tolerability should determine what medication should be used. There are hints that combination therapy of drugs with different therapeutic mechanisms might improve the efficacy. In treating neuropsychiatric symptoms (NPS), psychosocial intervention should be the treatment of first choice. Pharmaceuticals can only be recommended when psychosocial interventions is not adequate. However, even then the side effects of pharmaceuticals limit their use., Conclusions: Depending on the diagnostic entity and the pathology treated different anti-dementia drugs can be recommended to improve symptoms. In the management of NPS, side effects limit the use of medications even when psychosocial interventions have failed. Thus, there is an urgent need to develop more efficacious medications for the treatment of dementia.

Background/aims: Behavioural and psychological symptoms (BPSD) are frequent in people with Alzheimer's disease and cause considerable stress to patients and their carers. Antipsychotics have been widely used as a first-line treatment, resulting in an estimated 1,800 excess strokes and 1,600 excess deaths in the UK alone. Safe and effective alternatives are urgently needed. Based upon preliminary evidence from clinical trials, aromatherapy with melissa oil may be such an alternative, but initial studies have been modest in size, and adequate blinding has been problematic. Our objective was to assess the efficacy of melissa aromatherapy in the treatment of agitation in people with Alzheimer's disease in an adequately powered and robustly blinded randomized controlled trial comparing it with donepezil, an anticholinesterase drug used with some benefit to treat BPSD., Methods and Findings: The study was a double-blind parallel-group placebo-controlled randomized trial across 3 specialist old age psychiatry centres in England. Participants had probable or possible Alzheimer's disease, were resident in a care home, had clinically significant agitation (defined as a score of 39 or above on the Cohen Mansfield Agitation Inventory) and were free of antipsychotics and/or anticholinesterase for at least 2 weeks. Participants were allocated to 1 of 3 groups: placebo medication and active aromatherapy; active medication and placebo aromatherapy or placebo of both., Main Outcome: The primary outcome measure was reduction in agitation as assessed by the Pittsburgh Agitation Scale (PAS) at 4 weeks. This is an observational scale, and raters were required to wear nose clips to ensure that full blinding was maintained. The PAS, Neuropsychiatric Inventory (NPI; another measure of BPSD) and other outcome measures were completed at baseline, 4-week and 12-week follow-ups. 114 participants were randomized, of whom 94 completed the week 4 assessment and 81 completed the week 12 assessment. Aromatherapy and donepezil were well tolerated. There were no significant differences between aromatherapy, donepezil and placebo at week 4 and week 12, but importantly there were substantial improvements in all 3 groups with an 18% improvement in the PAS and a 37% improvement in the NPI over 12 weeks., Conclusion: When assessed using a rigorous design which ensures blinding of treatment arms, there is no evidence that melissa aromatherapy is superior to placebo or donepezil, in the treatment of agitation in people with Alzheimer's disease. However, the sizeable improvement in the placebo group emphasizes the potential non-specific benefits of touch and interaction in the treatment of agitation in people with Alzheimer's disease., (Copyright © 2011 S. Karger AG, Basel.)

Objective: Does psychosocial intervention for caregivers whose spouses with Alzheimer disease (AD) are taking donepezil delay nursing home (NH) placement or death of patients?, Design: Randomized controlled trial with 2 years of active treatment and up to 8.5 years of follow-up (mean: 5.4 years, SD: 2.4)., Setting: Outpatients of research clinics in Australia, the United Kingdom, and the United States., Participants: One hundred and fifty-five persons with AD and their spouses., Intervention: Five sessions of individual and family counseling (+ prn ad hoc counseling) or usual care., Measurements: Time to institutionalization and death using Cox proportional hazards methods., Results: Over a mean of 5.4 years (SD: 2.4), there were no differences in NH placement or mortality by intervention group, but there were by country, with Australian patients admitted to NHs earlier than U.S. than U.K. patients., Conclusion: Earlier NH admission of Australian compared to U.K. and U.S. subjects may be due to differences in health care, NH systems, availability, and affordability.

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.

Alzheimer's disease (AD) and vascular dementia (VaD) are the two commonest forms of dementia, with evidence of a considerable overlap between them. Vascular risk factors are important in the genesis of both dementias but underlying mechanisms need further exploration. In this respect, asymptomatic spontaneous cerebral emboli (SCE) may be of interest. Such emboli are common in patients at risk of stroke, for example those with symptomatic or severe carotid artery disease, and predict the future risk of strokes. Here we summarise our research which shows that asymptomatic SCE may be involved in the aetiology, symptomatology and progression of both AD and VaD. In just 1 h of transcranial Doppler (TCD) monitoring SCE were detected in 40% of AD and 37% of VaD patients compared to 15% and 14% of their respective controls. The odds ratio for SCE was 2.70 (1.18-6.21) for AD and 5.36 (1.24-23.18) for VaD, adjusted for cardiovascular risk factors. The presence of SCE was associated with the concurrent presence of clinically relevant depressive symptoms and the future rapid rates of decline in cognition and daily function. SCE may represent a potentially treatable target to slow and possibly prevent dementia, both AD and VaD.

Background: Agitation is common in people with dementia, is distressing to patients and stressful to their carers. Drugs used to treat the condition have the potential to cause particularly severe side effects in older people with dementia and have been associated with an increased death rate. Alternatives to drug treatment for agitation should be sought. The study aimed to assess the effects of bright light therapy on agitation and sleep in people with dementia., Methods: A single center randomized controlled trial of bright light therapy versus standard light was carried out. The study was completed prior to the mandatory registration of randomized controls on the clinical trials registry database and, owing to delays in writing up, retrospective registration was not completed., Results: There was limited evidence of reduction in agitation in people on active treatment, sleep was improved and a suggestion of greater efficacy in the winter months., Conclusions: Bright light therapy is a potential alternative to drug treatment in people with dementia who are agitated.

Background: Alzheimer's disease (AD) is the commonest cause of dementia. Cholinesterase inhibitors, such as donepezil, are the drug class with the best evidence of efficacy, licensed for mild to moderate AD, while the glutamate antagonist memantine has been widely prescribed, often in the later stages of AD. Memantine is licensed for moderate to severe dementia in AD but is not recommended by the England and Wales National Institute for Health and Clinical Excellence. However, there is little evidence to guide clinicians as to what to prescribe as AD advances; in particular, what to do as the condition progresses from moderate to severe. Options include continuing cholinesterase inhibitors irrespective of decline, adding memantine to cholinesterase inhibitors, or prescribing memantine instead of cholinesterase inhibitors. The aim of this trial is to establish the most effective drug option for people with AD who are progressing from moderate to severe dementia despite treatment with donepezil., Method: DOMINO-AD is a pragmatic, 15 centre, double-blind, randomized, placebo controlled trial. Patients with AD, currently living at home, receiving donepezil 10 mg daily, and with Standardized Mini-Mental State Examination (SMMSE) scores between 5 and 13 are being recruited. Each is randomized to one of four treatment options: continuation of donepezil with memantine placebo added; switch to memantine with donepezil placebo added; donepezil and memantine together; or donepezil placebo with memantine placebo. 800 participants are being recruited and treatment continues for one year. Primary outcome measures are cognition (SMMSE) and activities of daily living (Bristol Activities of Daily Living Scale). Secondary outcomes are non-cognitive dementia symptoms (Neuropsychiatric Inventory), health related quality of life (EQ-5D and DEMQOL-proxy), carer burden (General Health Questionnaire-12), cost effectiveness (using Client Service Receipt Inventory) and institutionalization. These outcomes are assessed at baseline, 6, 18, 30 and 52 weeks. All participants will be subsequently followed for 3 years by telephone interview to record institutionalization., Discussion: There is considerable debate about the clinical and cost effectiveness of anti-dementia drugs. DOMINO-AD seeks to provide clear evidence on the best treatment strategies for those managing patients at a particularly important clinical transition point., Trial Registration: Current controlled trials ISRCTN49545035.

Investigators in Germany have solicited the views of neurologists and psychiatrists on the effectiveness of antidementia drug treatments. The study concludes that clinicians generally consider these treatments to be beneficial, and that the provision of support to caregivers seems to further enhance the perceived benefits.

Background: The efficacy of galantamine has been shown in patients with mild, moderate, and advanced moderate Alzheimer's disease (AD). Here we report its efficacy in patients with severe AD., Methods: Between December, 2003, and March, 2007, patients aged 84 (SD 6) years with severe AD (mini-mental state examination [MMSE] score 5-12 points), in a nursing home setting were randomly assigned to receive galantamine (n=207), titrated initially to 24 mg/day, or placebo (n=200). Co-primary efficacy measures for cognitive function and ability to undertake normal daily activities were the severe impairment battery (SIB) and the seven-item minimum data set-activities of daily living (MDS-ADL), respectively. Adverse events, vital signs, laboratory parameters, and electrocardiograms were monitored. This trial is registered with ClinicalTrials.gov, number NCT00216593., Findings: 168 of 207 (81%) patients in the galantamine group and 161 of 200 (81%) in the placebo group completed the study. Mean SIB scores increased (improved) by 1.9 (95% CI -0.1 to 3.9) points with galantamine and decreased (worsened) by 3.0 (-5.6 to -0.5) points with placebo (between-group least squares mean difference 4.36, 1.3 to 7.5; p=0.006). Mean MDS-ADL self-performance score worsened by 1.2 (0.6 to 1.8) points and 1.6 (0.8 to 2.3) points, respectively (between-group least squares mean difference -0.41, -1.3 to 0.5; p=0.383). Nominally significant between-group differences in favour of galantamine occurred for the SIB domains of memory (p=0.006), praxis (p=0.010), and visuospatial ability (p=0.002), and for the MDS-ADL subitem locomotion on unit (p=0.021). 183 of 207 patients (88%) who received galantamine and 177 of 200 (89%) who received placebo had adverse events, which were mostly mild to moderate. Eight patients (4%) in the galantamine group and 21 patients (11%) in the placebo group died. ECG abnormalities were similar between the two groups., Interpretation: Galantamine can be started and used safely in elderly patients with severe AD. Galantamine improved cognitive function but failed to significantly improve the co-primary parameter of overall activities of daily living.

Objective: To evaluate the effectiveness of a combination of cholinesterase inhibitor therapy for patients with Alzheimer disease (AD) and psychosocial intervention, for their spouse caregivers compared with drug treatment alone in three countries simultaneously., Design: Randomized controlled trial. Structured questionnaires were administered at baseline and at regular follow-up intervals for 24 months by independent raters blind to group assignment., Setting: Outpatient research clinics in New York City, U.S., Manchester, U.K. and Sydney, Australia., Participants: Volunteer sample of 158 spouse caregivers of community dwelling patients with AD., Interventions: Five sessions of individual and family counseling within 3 months of enrollment and continuous availability of ad hoc telephone counseling were provided for half the caregivers. Donepezil was prescribed for all patients., Main Outcome Measure: Depressive symptoms of spouse caregivers measured at intake and follow-up assessments for 24 months using Beck Depression Inventory (revised)., Results: Depression scores of caregivers who received counseling decreased over time, whereas the depression scores for caregivers who did not receive counseling increased. The benefit of the psychosocial intervention was significant after controlling for site, gender and country was not accounted for by antidepressant use and increased over 2 years even though the individual and family counseling sessions occurred in the first 3 months., Conclusion: Effective counseling and support interventions can reduce symptoms of depression in caregivers when patients are taking donepezil. Harmonized multinational psychosocial interventions are feasible. Combined drug and supportive care approaches to the management of people with AD should be a priority.

In this article, the authors describe how the European Dementia Consensus Network developed a consensus on research ethics in dementia, taking into account the questions posed by the era of genetic research and its new research methods. The consensus process started with a Delphi procedure to analyze relevant stakeholders' positions by describing their statements on the possibilities and limitations of research into genetic determinants of Alzheimer disease and to describe and analyze the moral desirability of genetic research on Alzheimer disease. The conclusions drawn from the Delphi procedure fuelled the development of the consensus statement, which is presented in this paper. The consensus statement aims to stimulate ethically acceptable research in the field of dementia and the protection of vulnerable elderly patients with dementia from application of inadequate research methods or designs.

Background/aims: Behavioural and psychological symptoms have a high prevalence amongst patients with dementia and can be a significant source of distress to both patients and carers. The present study explored the relationships between quality of life and behavioural and psychological symptoms in dementia (BPSD) from both patient and carer perspectives. Contextual factors surrounding the occurrence of BPSD were explored., Methods: Forty-six patients and 116 carers completed questionnaire measures of BPSD and quality of life., Results: BPSD were negatively associated with both patient and carer ratings of patient quality of life. The symptoms related to lower quality of life differed between patient and carer ratings: depression and irritability were found to predict lower carer ratings of quality of life, whilst delusions and apathy indicated lower patient ratings. Carers were found to be poor at identifying antecedents and consequences of BPSD., Conclusions: The presence of BPSD is associated with lower quality of life in dementia. Interventions designed to improve the quality of life for patients should focus on the BPSD specifically associated with the patient's rating of quality of life. Information regarding the role of contextual factors in behaviour management should be made available to carers., (Copyright 2008 S. Karger AG, Basel.)

Background: Defining treatment success in progressive diseases, such as Alzheimer's disease (AD), can be challenging., Objective: To explore the impact of employing different criteria to define a treatment 'responder' using analyses of patient-level data from randomized, placebo-controlled studies of donepezil in AD., Methods: Trials were included in the analysis if they met several criteria, including the following: randomized, placebo-controlled trial of donepezil 10 mg/day in mild-to-moderate AD; cognition measured by the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) or Mini-Mental State Examination (MMSE); and a 24-week endpoint and outcomes that included global assessments. Definitions of response were: improvements in cognition plus one other domain; improvement in cognition only; improvement or improvement/no change in global response; and improvement/stabilization/less than expected decline by < or = 2 or < or = 4 or < or = 6 points on the ADAS-cog., Results: Five studies identified from the literature search met the specified criteria for inclusion. The response to donepezil measured by ADAS-cog varied from 26% to 63% and that of placebo from 14% to 47%, depending on the definition of improvement used. For definitions that included a less than expected decline on ADAS-cog, the more modest the effect defined, the less the drug versus placebo difference and the higher the percentage of patients meeting this definition., Conclusions: The definition of treatment 'response' in a progressive neurodegenerative disease can encompass a variety of outcomes, including short-term improvement, longer-term stabilization and a slowed decline in one or more clinically relevant symptoms or symptom domains. The ability to identify groups of people who respond to donepezil underscores the clinical utility of the medication and may contribute to more focused assessments of the cost effectiveness of cholinesterase inhibitors.

Background: The study aims to quantify the population impact of prescribing cholinesterase inhibitors to slow the cognitive decline in Alzheimer's disease (AD), and to compare with the benefit of treating hypertension to prevent the onset of AD., Methods: Literature review to ascertain the prevalence of AD, benefits of interventions, analysis of local and national surveys to measure the current use of interventions in the relevant population and application of the relevant findings to calculate Population Impact Measures. The Number of Events Prevented in a Population (NEPP) by the intervention over a defined time period is calculated for a UK urban population in one Local Authority (population size 217,000)., Results: Treatment of all eligible patients with mild to moderate AD with Cholinesterase Inhibitors would prevent cognitive deterioration (measured by ADAS - cog scale) in 123.6 (95% Confidence Intervals (CI) 82.3, 169.1), 16.4 (95% CI 2.1, 31.2) would show a mild improvement (4 points or more on the ADAS - cog scale) and 2.6 (95% CI 0.2, 5.8) would show an improvement of 7 points or more over a period of 6 months. This would require the treatment of 406 patients with Cholinesterase Inhibitors. Increasing from the current treatment rate of 46% of eligible patients to 'best practice' level would prevent cognitive deterioration in 66.8 (95% CI 44.0, 92.6), 8.99 (95% CI 1.2, 16.8) and 1.4 (95% CI 0.11, 3.2) would improve by 4 and 7 points respectively on the ADAS - cog scale over 6 months. This would require the treatment of an extra 187 patients with Cholinesterase Inhibitors beyond current practice, at an additional annual direct drug cost of pound187,000. Improving the treatment of hypertension from current practice by 20% could prevent 8.2 (95% CI 2.3, 16.8) incident cases of AD in the next year. This would require the treatment of an extra 2711 patients with antihypertensive drugs., Conclusion: Population Impact Measures are a new method to allow a demonstration of the magnitude of the benefit for the whole population following interventions. The use of drugs to slow cognitive decline, or to prevent AD by treating hypertension, can thus be assessed in a prioritisation exercise in competition with alternative use of resources.

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].)., (Copyright 2007 Massachusetts Medical Society.)

Donepezil is the most widely prescribed of the cholinesterase inhibitors that has been licensed for the treatment of mild-to-moderate Alzheimer's disease. Evidence from a number of clinical trials suggests that it improves cognitive performance and stabilizes the functional abilities in people with mild-to-moderate Alzheimer's disease. Donepezil increases the amount of the neurotransmitter acetylcholine in the brain, the deficit of which is thought to play a major role in the clinical presentation of Alzheimer's disease. Studies show good safety and long-term tolerability. In addition, donepezil's pharmacokinetic properties make it convenient to prescribe. There are a number of newer drug therapies in various stages of pharmacological development, but donepezil should continue to play a major role in the treatment of Alzheimer's disease for the next few years.

Background: Spontaneous cerebral emboli (SCE) are frequent in Alzheimer's disease (AD) and vascular dementia (VaD). We investigated the effect of SCE on the rates of cognitive and functional decline in AD and VaD., Methods: One hundred thirty-two patients with dementia (74 AD, National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association [NINCDS/ADRDA] criteria; 58 VaD, National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche et l'Enseignement en Neurosciences [NINDS/AIREN] criteria) underwent 1-hour transcranial Doppler for detection of SCE (mean [SD] age 75.5 (7.4) years; 46% female). Neuropsychological tests (Mini-Mental State Examination [MMSE], Alzheimer's Disease Assessment Scale-Cognitive subscale [ADAS-Cog], and Neuropsychiatric Inventory [NPI]) and assessment of activities of daily living (Interview for Deterioration in Daily Living Activities in Dementia [IDDD]) were performed initially and 6 months later. SCE positive (SCE+ve, n = 47) and SCE negative (SCE-ve, n = 85) patients were compared using repeated measures analyses of variance (ANOVAs) adjusted for age, gender, and cardiovascular risk factors., Results: SCE+ve patients with dementia, both AD and VaD, suffered a more rapid decline in cognitive functioning over 6 months (ADAS-cog, mean increase 7.1 for SCE+ve compared with 3.3 for SCE-ve, p = .006) and activities of daily living (IDDD, mean increase 24.4 for SCE+ve compared with 10.8 for SCE-ve, p = .014)., Conclusions: Asymptomatic SCE are associated with an accelerated cognitive and functional decline in dementia. SCE may be a potentially treatable cause of disease progression in dementia.

Objective: To investigate psychiatric morbidity, cognitive impairment, dependency, and survival in residents newly admitted to care homes., Methods: A total of 308 older people were assessed using measures of cognitive impairment and depressive symptomatology, and interviewable residents completed a quality-of-life interview. Dependency levels were assessed by interviews with staff and medication data were collected from home records. Follow-up assessments were carried out at five and nine months. A telephone follow-up approximately 12 months later augmented the survival data., Results: Of residents whose outcomes were known, 73% survived throughout the nine-month study period. Residents who died before the five-month follow-up had higher scores on the depression measure than those surviving longer. Reduced survival was predicted by greater dependency at baseline. Of 188 surviving residents, 63 (38%) were classified as depressed at baseline. Twenty-seven (43%) of the latter were still classed as depressed at five and nine months. Just 19% of residents rated as depressed at baseline were prescribed antidepressant medication, increasing to 26% at each follow-up. There was significant coexistence of cognitive impairment and depressive symptomatology., Conclusion: High levels of mortality, psychiatric morbidity, and chronicity of depressed mood among residents requires care homes to improve access to specialist resources such as geriatric consultation, old-age psychiatry, occupational therapy, and physiotherapy. Findings suggest that future care standards should include external factors, such as the extent of access to relevant specialist services for vulnerable older people.

Objectives: The aim of this study was to examine knowledge of dementia in South Asian older people, as compared with Caucasian older people., Methods: Attendees, not known to suffer from dementia, of one South Asian and two predominantly Caucasian day centres for older people in Manchester (UK) were asked to complete the Dementia Knowledge Questionnaire (DKQ). The DKQ was translated into Gujarathi and Urdu by the professional translators., Results: One hundred and ninety-one DKQs from Indian and 55 DKQs from Caucasian (white UK/Irish/European) older people were included in the analyses. Knowledge of dementia was poor in both Indian and Caucasian older people, especially so in the former. The median (25th-75th percentile) total DKQ scores were 3 (2-5) in Indians and 6 (3.5-9) in Caucasians (p < 0.001). Indian older people showed significantly less knowledge about basic aspects (p < 0.001) and epidemiology (p < 0.001) of dementia when compared to Caucasian older people. Both groups faired equally badly on questions about aetiology (p = 0.91) and symptomatology (p = 0.66). Indian older people were less aware of personality, reasoning, and speech being the affected in dementia (p < 0.001, p < 0.001 and p = 0.04, respectively)., Conclusion: Indian older people in Manchester (UK) do not seem to have sufficient knowledge about dementia, which may be one of the reasons for their relative absence in the local dementia treatment clinics.

Objective: To assess the effect of rivastigmine in patients with mild cognitive impairment (MCI) on the time to clinical diagnosis of Alzheimer's disease (AD) and the rate of cognitive decline., Methods: The study was a double-blind, randomised, placebo-controlled trial of up to 48 months. All patients had MCI operationally defined by having cognitive symptoms, a global clinical dementia rating stage of 0.5, a score of less than 9 on the New York University delayed paragraph recall test, and by not meeting the diagnostic criteria for AD. Primary efficacy variables were time to clinical diagnosis of AD, and change in performance on a cognitive test battery. This study is registered with the US National Institutes of Health clinical trials database (ClinicalTrials.gov), number NCT00000174., Findings: Of 1018 study patients enrolled, 508 were randomly assigned to rivastigmine and 510 to placebo; 17.3% of patients on rivastigmine and 21.4% on placebo progressed to AD (hazard ratio 0.85 [95% CI 0.64-1.12]; p=0.225). There was no significant difference between the rivastigmine and placebo groups on the standardised Z score for the cognitive test battery measured as mean change from baseline to endpoint (-0.10 [95% CI -0.63 to 0.44], p=0.726). Serious adverse events were reported by 141 (27.9%) rivastigmine-treated patients and 155 (30.5%) patients on placebo; adverse events of all types were reported by 483 (95.6%) rivastigmine-treated patients and 472 (92.7%) placebo-treated patients. The predominant adverse events were cholinergic: the frequencies of nausea, vomiting, diarrhoea, and dizziness were two to four times higher in the rivastigmine group than in the placebo group., Interpretation: There was no significant benefit of rivastigmine on the progression rate to AD or on cognitive function over 4 years. The overall rate of progression from MCI to AD in this randomised clinical trial was much lower than predicted. Rivastigmine treatment was not associated with any significant safety concerns.

The age distribution of the epsilon4 allelic form of the apolipoprotein E gene (APOE) was investigated in 630 patients with Alzheimer's disease (AD) with onset age ranging from 35 to 90 years. Overall, mean age at onset in APOE epsilon4 allele bearers was significantly later than that in nonbearers. However, when stratified into early onset AD (EOAD) and late onset (LOAD) groups, mean age at onset in EOAD cases bearing APOE epsilon4 allele was later than that in those EOAD cases without epsilon4 allele, whereas in LOAD mean age at onset in cases bearing APOE epsilon4 allele was earlier than in those without epsilon4 allele. When analysed by decade, it was observed that 37% of the total number of APOE epsilon4 allele bearers, and 43% of total number of cases with APOE epsilon4/epsilon4 genotype fell into the 60-69 years age class. Hence, APOE epsilon4 allele frequency, at 0.44, was highest in the 60-69 years age class, progressively decreasing either side of this age group. APOE epsilon4 allele therefore has its maximum impact between onset ages of between 60 and 70 years., (Copyright 2007 S. Karger AG, Basel)

Background: In the UK, the National Institute for Health and Clinical Excellence (NICE) is currently reviewing cost-effectiveness of cholinesterase inhibitors (ChEIs) for Alzheimer's disease (AD) in the NHS. The implementation of the original NICE (2001) guidance that made these drugs available in the UK was not examined in this review process, and was the objective of this study., Method: Ten hospitals in and around Manchester participated in the audit. Case records of all patients who were started on ChEIs between January 2002 and the date of the audit (November 2003 to December 2004) were examined to assess adherence to the NICE (2001) guidance. Information about available resources was gathered from lead clinicians of each hospital., Results: A total of 1,092 case records were examined. The treatment of AD with ChEIs varied considerably with regard to pre-treatment investigations, waiting period for treatment, scales used to assess efficacy, adherence to the NICE (2001) guidance, and available resources. The actual number of patients with mild to moderate AD receiving ChEIs was much lower than that expected from known prevalence rates. Non-uniformity of clinical practice and missing data were the main limitations of the audit., Conclusion: There is a need to harmonise the use and monitoring of ChEIs for AD in the NHS so that the data from routine clinical practice could feed into future clinical and cost-effectiveness analyses., (Copyright (c) 2006 John Wiley & Sons, Ltd.)

Background: The vascular depression hypothesis and our recent findings of increased frequency of spontaneous cerebral emboli in dementia suggest that such emboli may be involved in the causation of depressive symptoms in dementia., Aims: To evaluate the association between spontaneous cerebral emboli and depressive symptoms in Alzheimer's disease and vascular dementia., Method: In a cohort of 142 patients with dementia (72 with Alzheimer's disease and 70 with vascular dementia), the association between spontaneous cerebral emboli and clinically relevant depressive symptoms was examined using multiple logistic regression analyses., Results: Spontaneous cerebral emboli were significantly more frequent in the patients with clinically relevant depressive symptoms (66 v. 37%, P=0.03). After adjustment for age, gender, Mini-Mental State Examination score, type of dementia and significant cardiovascular risk factors, the relationship remained significant (OR=3.47, 95% CI 1.10-10.97)., Conclusions: Spontaneous cerebral emboli are associated with clinically relevant depressive symptoms in dementia, and further research is needed to explore the nature of this relationship.

Objectives: To examine the association between the angiotensin-converting enzyme (ACE) deletion/insertion (D/I) polymorphism and white matter hyperintensities (WMHs) in patients with dementia., Design: Observational pilot study with adjustment for potential confounders using analysis of covariance., Setting: Secondary care old-age psychiatry services in greater Manchester, United Kingdom., Participants: Ninety-seven patients with dementia: 49 with Alzheimer's disease (AD, National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association criteria) and 48 with vascular dementia (VaD, National Institute of Neurological Disorders and Stroke/Association Internationale pour la Recherche et l'Enseignement en Neurosciences criteria)., Measurements: The ACE D/I polymorphism, WMHs (deep WMHs (DWMHs) and periventricular hyperintensities (PVHs)) on T2-weighted magnetic resonance imaging, and potential cardiovascular confounders., Results: The D/D polymorphism of the ACE genotype was associated with severity of DWMH (P = .005) but not PVH (P = .34), corrected for age, cardiovascular risk factors, and type of dementia. Post hoc analyses were limited by statistical power but suggested an interaction with the apolipoprotein E epsilon4 allele., Conclusion: The results support previous observations that genetic factors influence the development of WMHs in dementia. The involvement of the ACE D/I polymorphism in the pathogenesis of DWMHs in dementia (AD and VaD), by a mechanism that is independent of its association with cardiovascular risk factors, should be confirmed in a large population-based sample.

Objective: To compare the occurrence of spontaneous cerebral emboli and venous to arterial circulation shunts in patients with Alzheimer's disease or vascular dementia and controls without dementia., Design: Cross sectional case-control study., Setting: Secondary care old age psychiatry services, Manchester., Participants: 170 patients with dementia (85 with Alzheimer's disease, 85 with vascular dementia) and 150 age and sex matched controls. Patients on anticoagulant treatment, patients with severe dementia, and controls with marked cognitive impairment were excluded., Main Outcome Measures: Frequencies of detection of spontaneous cerebral emboli during one hour monitoring of the middle cerebral arteries with transcranial Doppler and venous to arterial circulation shunts by a transcranial Doppler technique using intravenous microbubbles as an ultrasound contrast., Results: Spontaneous cerebral emboli were detected in 32 (40%) of patients with Alzheimer's disease and 31 (37%) of those with vascular dementia compared with just 12 each (15% and 14%) of their controls, giving significant odds ratios adjusted for vascular risk factors of 2.70 (95% confidence interval 1.18 to 6.21) for Alzheimer's disease and 5.36 (1.24 to 23.18) for vascular dementia. These spontaneous cerebral emboli were not caused by carotid disease, which was equally frequent in dementia patients and their controls. A venous to arterial circulation shunt indicative of patent foramen ovale was found in 27 (32%) Alzheimer's disease patients and 25 (29%) vascular dementia patients compared with 19 (22%) and 17 (20%) controls, giving non-significant odds ratios of 1.57 (0.80 to 3.07) and 1.67 (0.81 to 3.41)., Conclusion: Spontaneous cerebral emboli were significantly associated with both Alzheimer's disease and vascular dementia. They may represent a potentially preventable or treatable cause of dementia.