AbstractSenile plaques are a hallmark of Alzheimer’s disease (AD) that develop in its earliest stages. Thus, non-invasive detection of these plaques would be invaluable for diagnosis and the development and monitoring of treatments, but this remains a challenge due to their small size. Here, we investigated the utility of manganese-enhanced MRI (MEMRI) for visualizing plaques in transgenic rodent models of AD across two species: 5xFAD mice and TgF344-AD rats.Fourteen mice (eight transgenic, six wild-type) and eight rats (four transgenic, four wild-type) were given subcutaneous injections of MnCl2 and imaged in vivo using a 9.4T Bruker scanner. Susceptibility-weighted images, transverse relaxation rate (R2*) maps, and quantitative susceptibility maps were derived from high-resolution 3D multi-gradient-echo (MGE) data to directly visualize plaques. Longitudinal relaxation rate (R1) maps were derived from MP2RAGE data to measure regional manganese uptake. After scanning, the brains were processed for histology and stained for beta-amyloid (4G8 antibody), iron (Perl’s), and calcium/manganese (Alizarin Red).MnCl2 improved signal-to-noise ratio (1.55±0.39-fold increase in MGE images) as expected, although this was not necessary for detection of plaques in the high-resolution images. Plaques were visible in susceptibility-weighted images, R2. maps, and quantitative susceptibility maps, with increased R2. and more positive magnetic susceptibility compared to surrounding tissue.In the 5xFAD mice, most MR-visible plaques were in the hippocampus, though histology confirmed plaques in the cortex and thalamus as well. In the TgF344-AD rats, many more plaques were MR-visible throughout the hippocampus and cortex. Beta-amyloid and iron staining indicate that, in both models, MR visibility was driven by plaque size and iron load.Voxel-wise comparison of R1 maps revealed increased manganese uptake in brain regions of high plaque burden in transgenic animals compared to their wild-type littermates. Interestingly, in contrast to plaque visibility in the high-resolution images, the increased manganese uptake was limited to the rhinencephalon in the TgF344-AD rats (family-wise error (FWE)-corrected p < 0.05) while it was most significantly increased in the cortex of the 5xFAD mice (FWE-corrected p < 0.3). Alizarin Red staining suggests that manganese bound to plaques in 5xFAD mice but not in TgF344-AD rats.Multi-parametric MEMRI is a simple, viable method for detecting senile plaques in rodent models of AD. Manganese-induced signal enhancement can enable higher-resolution imaging, which is key to visualizing these small amyloid deposits. We also present in vivo evidence of manganese as a potential targeted contrast agent for imaging plaques in the 5xFAD model of AD.HighlightsThis is the first study to use manganese-enhanced MRI (MEMRI) for direct visualization of senile plaques in rodent models of Alzheimer’s disease, in vivo.Manganese enhancement is not necessary to detect plaques but improves image contrast and signal-to-noise ratio.Manganese binds to plaques in 5xFAD mice but not in TgF344-AD rats, demonstrating potential as a targeted contrast agent for imaging plaques in certain models of AD.

AbstractBackgroundPsychosis (delusions and hallucinations) is common in Alzheimer’s disease (AD) and associated with worse clinical outcomes including accelerated cognitive decline and shorter time to nursing home admission. Atypical antipsychotics have limited efficacy which, along with emerging genomic research, suggests some overlapping mechanisms with other disorders characterized by psychosis, like schizophrenia. In this study, we tested whether polygenic risk score (PRS) for schizophrenia was associated with psychotic symptoms in AD.MethodsSchizophrenia PRS was calculated using Psychiatric Genomics Consortium data at 10 GWAS p-value thresholds (PT) in 3,173 AD cases from 11 cohort studies. Association between PRS and AD psychosis status was tested by logistic regression in each cohort individually and the results meta-analyzed.ResultsThe schizophrenia PRS was associated with psychosis in AD at an optimumPTof the strongest association was for delusions where a one standard deviation increase in PRS was associated with a 1.17-fold increased risk (95% CI: 1.07-1.3; p=0.001).ConclusionThese new findings point towards psychosis in AD – and particularly delusions – sharing some genetic liability with schizophrenia, and support a transdiagnostic view of psychotic symptoms across the lifespan.

Abstract
. Background: it is unclear whether people with dementia (PwD) have more negative attitudes toward own aging (ATOA) than people without dementia and what factors influence ATOA among PwD. We investigated whether PwD have more negative ATOA than individuals without dementia and whether cognition and dementia subtype are associated with ATOA in PwD.Methods: Data from the IDEAL and PROTECT studies were used to compare ATOA between 1,502 PwD (mean (SD) age = 76.3 (8.5)) and 6,377 individuals without dementia (mean (SD) age = 66.1 (7.1)). Linear regressions and ANOVA were used.Results: PwD reported slightly more negative ATOA than people without dementia; this relationship disappeared after controlling for depression and self-rated health. In PwD more positive ATOA showed negligible associations with better general cognition, memory performance, verbal fluency, and visuospatial ability. However, after adjusting for covariates only better visuospatial ability predicted more positive ATOA. Additional analyses showed that before and after controlling for covariates, individuals with poorer self-reported visual acuity have more negative ATOA. Amongst dementia subtypes, people with Parkinson’s disease dementia and dementia with Lewy bodies reported most negative ATOA. Conclusions: ATOA between PwD and people without dementia do not differ. ATOA in PwD appear to be affected not by cognitive impairment but by other characteristics that vary across dementia subtypes. Among PwD, those with Parkinson’s disease dementia and dementia with Lewy bodies may have higher risk of experiencing negative ATOA due to the motor and visual impairments that they experience.

Abstract
. Higher awareness of positive age-related changes (AARC gains) is related to better mental health, whereas higher awareness of negative age-related changes (AARC losses) is related to poorer mental and physical health. So far perceived gains and losses have been explored separately, but people report gains and losses concurrently in varying degrees, and different profiles of gains and losses may be differentially associated with health. We identified profiles of gains and losses and explored whether different profiles differed in physical, mental, and cognitive health. We used cross-sectional data from the PROTECT study (N= 6,192; mean(SD) age= 66.1(7.0)). Using latent profile analysis, a four-class solution showed the best model fit. We found that 45% of people perceived many gains and few losses (Class 1); 24% perceived moderate gains and few losses (Class 2); 24% perceived many gains and moderate losses (Class 3); 7% perceived many gains and many losses (Class 4). Analysis of variance and Chi-square tests showed that Class 1 had relatively better physical, mental, and cognitive health, followed by Classes 2, 3, and 4. Experiencing one’s ageing to a high degree as gain may be related to better health only when individuals interpret ageing as involving low levels of loss across several life domains. Risk in terms of poorer health emerged in those who perceived high losses. Considering gains and losses in parallel, rather than separately, may lead to a more fine-tuned understanding of relations with health.

Higher awareness of positive age-related changes (AARC gains) is related to better mental health, whereas higher awareness of negative age-related changes (AARC losses) is related to poorer mental and physical health. So far perceived gains and losses have been explored separately, but people report gains and losses concurrently in varying degrees, and different profiles of gains and losses may be differentially associated with health. We identified profiles of gains and losses and explored whether different profiles differed in physical, mental, and cognitive health.
We used cross-sectional data from the PROTECT study (N= 6,192; mean (SD) age= 66.1(7.0)).
Using latent profile analysis, a four-class solution showed the best model fit. We found that 45% of people perceived many gains and few losses (Class 1); 24% perceived moderate gains and few losses (Class 2); 24% perceived many gains and moderate losses (Class 3); 7% perceived many gains and many losses (Class 4). Analysis of variance and Chi-squared tests showed that Class 1 had relatively better physical, mental, and cognitive health, followed by Classes 2, 3, and 4.
Experiencing one’s ageing to a high degree as gain may be related to better health only when individuals interpret ageing as involving low levels of loss across several life domains. Risk in terms of poorer health emerged in those who perceived high losses. Considering gains and losses in parallel, rather than separately, may lead to a more fine-tuned understanding of relations with health.

AbstractRapid eye movement (REM) sleep behaviour disorder (RBD) is a rare parasomnia that may predict the later occurrence of alpha-synucleinopathies. Variants in the gene encoding for the lysosomal enzyme glucocerebrosidase, GBA, strongly increase the risk of RBD. In a GBA1-mouse model recently shown to mimic prodromal stages of α-synucleinopathy, we now demonstrate striking REM and NREM sleep abnormalities accompanied by distinct structural changes in the more widespread sleep neurocircuitry.

BACKGROUND: Mild Behavioral Impairment (MBI) is a neuropsychiatric syndrome describing later-life emergent apathy, mood/anxiety symptoms, impulse dyscontrol, social inappropriateness and psychosis that are not attributable to psychiatric diagnoses. MBI is an at-risk state for incident cognitive decline and dementia, and is associated with dementia biomarkers including amyloid beta; and neurofilament light. Thus, MBI may be an early clinical marker of neurodegenerative disease. In this study, we hypothesized that stratification by MBI in a cognitively normal sample would moderate the signal between Alzheimer disease (AD) genetic risk and cognition.
METHODS: Genetic, cognitive and MBI data was available for 3,126 PROTECT study participants over 50 without dementia. A general cognitive composite score was constructed based on scores on paired associates learning, digit span, self-ordered search and verbal reasoning. MBI was assessed using the MBI Checklist. Polygenic scores for AD were split by tertile (representing low, medium and high risk) and the sample was stratified by MBI into those with no symptoms and those with any symptoms.
RESULTS: AD genetic risk was associated with poorer cognition in the MBI strata only (MBI: F(2,1746)=4.95, p=0.007; no MBI: F(2,1366)=0.72, p=0.49). The mean difference between low and high genetic risk groups was significant (p=0.005) and the standardised effect size in the MBI sample was higher than in the whole sample.
CONCLUSIONS: These findings justify MBI screening to enrich samples with at-risk individuals, and underscore the importance of late-life neuropsychiatric symptoms in cognitive ageing.

AbstractPsychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer disease (AD with psychosis, AD+P). AD+P affects ∼50% of individuals with AD, identifies a subgroup with poor outcomes, and is associated with a greater degree of cognitive impairment and depressive symptoms, compared to subjects without psychosis (AD-P). Although the estimated heritability of AD+P is 61%, genetic sources of risk are unknown. We report a genome-wide meta-analysis of 12,317 AD subjects, 5,445 AD+P. Results showed common genetic variation accounted for a significant portion of heritability. Two loci, one in ENPP6 (rs9994623, O.R. (95%CI) 1.16 (1.10, 1.22), p=1.26×10−8) and one spanning the 3’-UTR of an alternatively spliced transcript of SUMF1 (rs201109606, O.R. 0.65 (0.56-0.76), p=3.24×10−8), had genome-wide significant associations with AD+P. Gene-based analysis identified a significant association with APOE, due to the APOE risk haplotype ε4. AD+P demonstrated negative genetic correlations with cognitive and educational attainment and positive genetic correlation with depressive symptoms. We previously observed a negative genetic correlation with schizophrenia; instead, we now found a stronger negative correlation with the related phenotype of bipolar disorder. Analysis of polygenic risk scores supported this genetic correlation and documented a positive genetic correlation with risk variation for AD, beyond the effect of ε4. We also document a small set of SNPs likely to affect risk for AD+P and AD or schizophrenia. These findings provide the first unbiased identification of the association of psychosis in AD with common genetic variation and provide insights into its genetic architecture.

AbstractIntroductionNon-verbal communication remains a relatively unexplored area in dementia care with a lack of validated assessment tools available to measure non-verbal communication function in dementia.MethodsThis scoping review identifies assessment scales of nonverbal communication in dementia and evaluates the psychometric properties and clinical utility of these instruments. Relevant publications in English, from 1947 to 2017, were identified through an extensive search strategy in Medline, Psychinfo and the Cumulative Index to Nursing and Allied Health Literature (CINAHL), EMBASE, Cochrane and generic search engines (Google) and available off-line resources. Quality judgement criteria was formulated and used to evaluate the psychometric aspects of the scales.ResultsForty-one tools were identified measuring various communication channels including verbal, nonverbal (e.g. facial expressions, gestures, eye contact) and functional, communication means; within various settings and populations, for instance, those assessing cognition and verbal language difficulties secondary to stroke, aphasia and nonverbal cues associated with pain. A number of tools presented psychometrics qualities; only nine of the forty-one tools specifically focussed on nonverbal communication, however, comprehensive assessment of nonverbal communication function was not presented in majority of the identified tools. Two tools provided a detailed assessment of nonverbal communication, the Emory dyssemia Index (EDI) and the Threadgold Communication Tool (TCT).ConclusionBased on the psychometric qualities and criteria regarding sensitivity and clinical utility, we concluded that although it is difficult to recommend one particular tool, the EDI and TCT are the most appropriate scales currently available. Further research should focus on improving these scales by further testing their validity, reliability and clinical utility in dementia.

AbstractThe current paper describes the identification of novel candidate compounds for repositioning as treatments for Alzheimer’s disease (AD) from the CMAP library. Candidate compounds were identified based on inverse correlation with transcriptome signatures developed from meta-analyses of Alzheimer RNA expression studies using the SPIED platform. The 78 compounds with a significant inverse correlation were taken forward into an in vitro programme using 6 well validated screening assays relevant to potential treatment targets in AD. Nineteen pf the compounds were hits in at least 2 of these assays. A description of each of these compounds is presented.

Abstract
. Background: a questionnaire assessing awareness of positive and negative age-related changes (AARC gains and losses) was developed in the US and Germany. We validated the short form of the measure (AARC-10 SF) and the cognitive functioning subscale from the 50-item version of the AARC (AARC-50) questionnaire in the UK population aged 50 and over.Methods: Data from 14,797 participants in the “blind for review” cohort were used to explore and confirm the psychometric properties of the AARC measures including: validity of the factor structure; reliability; measurement invariance across males and females and across individuals with and without a university degree; and convergent validity with measures of self-perception of aging and mental, physical, and cognitive health. We also explored the relationship between demographic variables and AARC.Results: We confirmed the two-factor structure (gains and losses) of the AARC-10 SF and the AARC-50 cognitive functioning subscale. Both scales showed good reliability and convergent validity. The meaning of AARC gains and losses was the same across males and females and across individuals with and without a university degree. Items composing AARC scales had the same meaning across individuals with and without a university degree. Items composing the AARC-50 cognitive functioning subscale had the same meaning across males and females. Two items in the AARC-10 SF had different meaning across males and females. Demographic variables significantly predicted AARC gains and losses.Conclusions: the AARC-10 SF and AARC-50 cognitive functioning subscale can help to identify UK individuals who perceive age-related changes in their mental, physical, and cognitive health.

Abstract
. Background: a questionnaire assessing awareness of positive and negative age-related changes (AARC gains and losses) was developed in the US and Germany. We validated the short form of the measure (AARC-10 SF) and the cognitive functioning subscale from the 50-item version of the AARC (AARC-50) questionnaire in the UK population aged 50 and over. Methods: Data from 9,410 participants (Mean (SD) age= 65.9 (7.1)) in the PROTECT cohort were used to explore and confirm the psychometric properties of the AARC measures including: validity of the factor structure; reliability; measurement invariance across men and women, individuals with and without a university degree, and in middle age, early old age, and advanced old age; and convergent validity with measures of self-perception of aging and mental, physical, and cognitive health. We explored the relationship between demographic variables (age, sex, marital status, employment, and university education) and AARC. Results: We confirmed the two-factor structure (gains and losses) of the AARC-10 SF and the AARC-50 cognitive functioning subscale. Both scales showed good reliability and good convergent validity for AARC losses, but weak convergent validity for AARC gains. For both scales metric invariance was held for the two subgroups defined by education level and age. For the AARC-50 subscale, but not for the AARC-10 SF, strong invariance was also held for the two subgroups defined by sex. Age, sex, marital status, employment, and university education predicted AARC gains and losses. Conclusions: the AARC-10 SF and AARC-50 cognitive functioning subscale identify UK individuals who perceive age-related changes in their mental, physical, and cognitive health.

AbstractBackgroundEpisodic changes in mood characterise disorders such as bipolar disorder, which includes distinct periods of manic excitability or irritability, along with additional symptoms experienced during these periods. Common clinical understanding informs diagnostic criteria and epidemiological studies reflect clinical thresholds.AimsTo use a data-driven approach to defining groupings of symptoms experienced during periods of manic or irritable mood, which could inform understanding of mood disorders and guide case classification by identifying subgroups with homogeneous clinical/functional outcomes.MethodsWe used latent class analysis (LCA) to conduct an exploration of the latent structure in symptom responses in the UK Biobank and PROTECT studies, by investigating how symptoms, experienced during periods of manic or irritable mood, formed latent subgroups. We tested associations of latent subgroups with sociodemographic characteristics, diagnoses of psychiatric disorders and polygenic risk scores (PRS).ResultsFive latent classes were identified that captured patterns of symptoms experienced during periods of manic or irritable mood (N=42,183) in UK Biobank. We identified one class that experienced disruptive episodes of mostly irritable mood that was largely comprised of cases of depression/anxiety, and a class of individuals with increased confidence/creativity that reported lower disruptiveness and lower functional impairment. The five latent classes were replicated in an independent cohort, the PROTECT study (N=4,445), with similar distinctions between classes.ConclusionOur data-driven approach to grouping individuals identified distinct latent classes. A dimensional classification of mood disorders informed by our findings will be able to better assess or subtype these disorders in future studies.

ABSTRACTINTRODUCTIONWe aimed to explore sex differences in the association of mild behavioral impairment (MBI) with the level of cognitive performance and its rate of decline in a cohort of people without dementia with the longest term follow up of cognition.METHODSWe studied 8,181 older adults enrolled in the online PROTECT UK Study. MBI was assessed using the MBI Checklist and cognition was measured by digit span, paired associate learning, spatial working memory and verbal reasoning. Statistical analysis was conducted using linear regression models and linear mixed-effects models.RESULTSMales exhibited more often symptoms of decreased motivation, impulse dyscontrol and social inappropriateness, while less often symptoms of emotional dysregulation. The associations of MBI domains with some measures of cognitive performance and decline was stronger in males than females, with the exception of emotional dysregulation.DISCUSSIONMBI may influence cognition to a greater extent in males than in females.

Abstract
. Background: a questionnaire assessing awareness of positive and negative age-related changes (AARC gains and losses) was developed in the US and Germany. We validated the short form of the measure (AARC-10 SF) and the cognitive functioning subscale from the 50-item version of the AARC (AARC-50) questionnaire in the UK population aged 50 and over. Methods: Data from 14,797 participants in the PROTECT cohort were used to explore and confirm the psychometric properties of the AARC measures including: validity of the factor structure; reliability; measurement invariance across males and females and across individuals with and without a university degree; and convergent validity with measures of self-perception of aging and mental, physical, and cognitive health. We also explored the relationship between demographic variables and AARC. Results: We confirmed the two-factor structure (gains and losses) of the AARC-10 SF and the AARC-50 cognitive functioning subscale. Both scales showed good reliability and convergent validity. The meaning of AARC gains and losses was the same across males and females and across individuals with and without a university degree. Items composing AARC scales had the same meaning across individuals with and without a university degree. Items composing the AARC-50 cognitive functioning subscale had the same meaning across males and females. Two items in the AARC-10 SF had different meaning across males and females. Demographic variables significantly predicted AARC gains and losses. Conclusions: the AARC-10 SF and AARC-50 cognitive functioning subscale can help to identify UK individuals who perceive age-related changes in their mental, physical, and cognitive health.

Gene expression data associated with viral infection of human cell lines is harnessed to define a conserved viral response signature. Drugs that tend to drive gene expression in the direction of the cellular viral response are significantly enriched for those with established antiviral activity. Transcription therefore facilitates a simple and effective filtering of candidate drugs to be put forward for bioassay validation.

AbstractINTRODUCTIONStroke/thromboembolic events, infections and death are all significantly increased by antipsychotics in dementia but little is known about why they can be harmful. Using a novel application of a drug repurposing paradigm, we aimed to identify potential mechanisms underlying adverse events.METHODWhole transcriptome signatures were generated for SH-SY5Y cells treated with amisulpride, risperidone and volinanserin using RNA-sequencing. Bioinformatic analysis was performed which scored the association between antipsychotic signatures and expression data from 415,252 samples in the NCBI GEO repository.RESULTSAtherosclerosis, venous thromboembolism and influenza NCBI GEO-derived samples scored positively against antipsychotic signatures. Pathways enriched in antipsychotic signatures were linked to the cardiovascular and immune systems (e.g. BDNF, PDGFR-beta, TNF, TGF-beta, selenoamino acid metabolism and influenza infection).CONCLUSIONThese findings for the first time mechanistically link antipsychotics to specific cardiovascular and infectious diseases which are known side effects of their use in dementia, providing new information to explain related adverse events.COMPETING INTERESTSCB has received grants and personal fees from ACADIA Pharmaceuticals and Lundbeck, and personal fees from Heptares, Roche, Lilly, Otsuka, Orion, GlaxoSmithKline and Pfizer. DAC is an employee of Eli Lilly and Company Ltd.

Abstract
. BACKGROUND
Stroke/thromboembolic events, infections and death are all significantly increased by antipsychotics in dementia but little is known about why they can be harmful. Using a novel application of a drug repurposing paradigm, we aimed to identify potential mechanisms underlying adverse events.
METHODS
Whole transcriptome signatures were generated for SH-SY5Y cells treated with amisulpride, risperidone and volinanserin using RNA-sequencing. Bioinformatic analysis was performed which scored the association between antipsychotic signatures and expression data from 415,252 samples in the NCBI GEO repository.
RESULTS
Atherosclerosis, venous thromboembolism and influenza NCBI GEO-derived samples scored positively against antipsychotic signatures. Pathways enriched in antipsychotic signatures were linked to the cardiovascular and immune systems (e.g. BDNF, PDGFR-beta, TNF, TGF-beta, selenoamino acid metabolism and influenza infection).
CONCLUSIONS
These findings for the first time mechanistically link antipsychotics to specific cardiovascular and infectious diseases which are known side effects of their use in dementia, providing new information to explain related adverse events.

OBJECTIVES: This study aimed to determine the impact of the Covid-19 pandemic on neuropsychiatric symptoms and antipsychotic use in people with dementia living in nursing homes. METHODS: This was a comparative analysis of baseline data from two large nursing home studies, one conducted during (COVID-iWHELD study) and one prior (WHELD study) to the pandemic. It involves data from 69 and 149 nursing homes, and 1006 and 666 participants respectively. Participants were people with established dementia (score >1 on Clinical Dementia Rating Scale). Resident data included demographics, antipsychotic prescriptions and neuropsychiatric symptoms using the Neuropsychiatric Inventory Nursing Home version. Nursing home data collected were nursing home size and staffing information. RESULTS: Overall prevalence of neuropsychiatric symptoms was unchanged from pre-pandemic prevalence. Mean antipsychotic use across the sample was 32.0%, increased from 18% pre-pandemic (Fisher's exact test p 

Neuropsychiatric symptoms affect most patients with dementia over the course of the disease. They include a wide variety of symptoms from apathy and depression to psychosis, irritability, impulsivity and agitation. These symptoms are associated with significant distress to the patient and caregivers, as well as more rapid progression of dementia, institutionalisation and higher mortality. The first-line management of the neuropsychiatric symptoms of dementia should be non-pharmacological. If medications are required, antipsychotics are commonly chosen. Second-generation antipsychotics such as risperidone, olanzapine, quetiapine and aripiprazole are prescribed more often than first-generation antipsychotics, such as haloperidol. The aim of this review is to provide an update on findings on adverse outcomes and clinical implications of antipsychotic use in dementia. These medications may increase mortality and can be associated with adverse events including pneumonia, cerebrovascular events, parkinsonian symptoms or higher rates of venous thromboembolism. Risks related to antipsychotic use in dementia are moderated by a number of modifiable and non-modifiable factors such as co-prescribing of other medications, medical and psychiatric co-morbidities, and demographics such as age and sex, making individualised treatment decisions challenging. Antipsychotics have further been associated with an increased risk of reliance on long-term care and institutionalisation, and they might not be cost-effective for healthcare systems. Many of these risks can potentially be mitigated by close physical health monitoring of antipsychotic treatment, as well as early withdrawal of pharmacotherapy when clinically possible.

BACKGROUND: Alzheimer's disease (AD) is the most common type of dementia, causing progressive decline of memory, thinking, and behavior, impairing daily functioning. Early AD (eAD) includes mild cognitive impairment (MCI) due to AD and mild AD dementia. OBJECTIVE: the aim of this study was to investigate symptomatic treatment prevalence and treatment patterns in eAD. METHODS: Embase, MEDLINE, and EBM Reviews were searched in November 2021 for observational studies reporting symptomatic treatment patterns in eAD. The range of patients receiving treatment was collated. Risk of bias was assessed using the Joanna Briggs Institute (JBI) prevalence tool. Two independent reviewers screened the records, one performed data extraction and quality assessment while a second checked. RESULTS: Twenty-one studies (prospective and retrospective cohorts, cross-sectional studies, and a survey) were included. Population size ranged from 23 to 2,028. Worldwide, 18 to 35% of patients diagnosed with MCI due to AD received any AChE inhibitor (three studies; n = 631), 7 to 8% memantine (two studies; n = 229), and 9% combination therapy (one study; n = 402). Patients receiving no treatment ranged from 41 to 54% (two studies; n = 733). Worldwide, in mild AD dementia patients, 13 to 89% received any AChE inhibitor (six studies; n = 3,715), 1 to 21% memantine (five studies, n = 3,527), and 0.4 to 39% combination therapy (four studies, n = 3,018). Patients receiving no treatment ranged from 9 to 26% (five studies, n = 4,073). CONCLUSION: Limitations in reporting led to unclear risk of bias. The results reveal a pattern of use of symptomatic treatment in eAD beyond approved labels and highlights the opportunity for new consensus guidelines to inform clinical practice.

OBJECTIVE: Lower awareness of age-related gains (AARC-gains) and higher awareness of age-related losses (AARC-losses) may be risk factors for depressive and anxiety symptoms. We explored whether: (1) Baseline AARC-gains and AARC-losses predict depressive and anxiety symptoms at one-year follow-up; (2) age and rumination moderate these associations; (3) levels of AARC-gains and AARC-losses differ among individuals with different combinations of current and past depression and/or with different combinations of current and past anxiety. METHODS: in this one-year longitudinal cohort study participants (N = 3386; mean age = 66.0; SD = 6.93) completed measures of AARC-gains, AARC-losses, rumination, depression, anxiety, and lifetime diagnosis of depression and anxiety in 2019 and 2020. Regression models with tests of interaction were used. RESULTS: Higher AARC-losses, but not lower AARC-gains, predicted more depressive and anxiety symptoms. Age did not moderate these associations. Associations of lower AARC-gains and higher AARC-losses with more depressive symptoms and of higher AARC-losses with more anxiety symptoms were stronger in those with higher rumination. Individuals with both current and past depression reported highest AARC-losses and lowest AARC-gains. Those with current, but not past anxiety, reported highest AARC-losses. CONCLUSION: Perceiving many age-related losses may place individuals at risk of depressive and anxiety symptoms, especially those who frequently ruminate.

OBJECTIVE: Digital approaches to delivering person-centered care training to nursing home staff have the potential to enable widespread affordable implementation, but there is very limited evidence and no randomized controlled trials (RCTs) evaluating digital training in the nursing home setting. The objective was to evaluate a digital person-centered care training intervention in a robust RCT. DESIGN: We conducted a 2-month cluster RCT in 16 nursing homes in the United Kingdom, randomized equally to receive a digitally adapted version of the WHELD person-centered care home training program with virtual coaching compared to the digital training program alone. SETTING AND PARTICIPANTS: the study was conducted in UK nursing homes. There were 175 participants (45 nursing home staff and 130 residents with dementia). METHODS: the key outcomes were the well-being and quality of life (QoL) of residents with dementia and the attitudes and knowledge of nursing home staff. RESULTS: There were significant benefits in well-being (t = 2.76, P =. 007) and engagement in positive activities (t = 2.34, P =. 02) for residents with dementia and in attitudes (t = 3.49, P =. 001), including hope (t = 2.62, P =. 013) and personhood (t = 2.26, P =. 029), for staff in the group receiving digital eWHELD with virtual coaching compared to the group receiving digital learning alone. There was no improvement in staff knowledge about dementia. CONCLUSION AND IMPLICATIONS: the study provides encouraging initial clinical trial evidence that a digital version of the WHELD program supported by virtual coaching confers significant benefits for care staff and residents with dementia. Evidence-based digital interventions with remote coaching may also have particular utility in supporting institutional recovery of nursing homes from the COVID-19 pandemic.

BACKGROUND: in the absence of disease-modifying treatments, identifying potential psychosocial risk factors for dementia is paramount. Depression and anxiety have been identified as potential risk factors. Studies however have yielded mixed findings, lending possibility to the fact that potential constellations of co-occurring depression and anxiety symptoms may better explain the link between affective symptoms and cognitive decline. METHODS: Data from participants (aged 50 and above) of the PROTECT study was used. Latent Class Analysis (LCA) was conducted on 21,684 participants with baseline anxiety and depression measures. Multiple linear regressions models, using a subset of these participants (N = 6136) who had complete cognition data at baseline and at 2-year follow-up, were conducted to assess for associations between class membership and longitudinal changes in cognition. RESULTS: the LCA identified a 5-class solution: "No Symptoms", "Sleep", "Sleep and Worry", "Sleep and Anhedonia", and "Co-morbid Depression and Anxiety". Class membership was significantly associated with longitudinal change in cognition. Furthermore, this association differed across different cognitive measures. LIMITATIONS: Limitations included significant attrition and a generally healthy sample which may impact generalisability. CONCLUSIONS: Substantial heterogeneity in affective symptoms could explain previous inconsistent findings concerning the association between affective symptoms and cognition. Clinicians should not focus solely on total symptom scores on a single affective domain, but instead on the presence and patterns of symptoms (even if sub-clinical) on measures across multiple affective domains. Identifying particular subgroups that are at greater risk of poor cognitive outcomes may support targeted prevention work.

Abstract
. Background
. It is unclear whether people with dementia (PwD) have more negative attitudes toward own aging (ATOA) than people without dementia and what factors influence ATOA among PwD. We investigated whether PwD have more negative ATOA than individuals without dementia and whether cognition and dementia subtype are associated with ATOA in PwD.
.
. Methods
. Data from the IDEAL and PROTECT studies were used to compare ATOA between 1502 PwD (mean (SD) age = 76.3 (8.5)) and 6377 individuals without dementia (mean (SD) age = 66.1 (7.1)). Linear regressions and ANOVA were used.
.
. Results
. PwD reported slightly more negative ATOA than people without dementia; this relationship disappeared after controlling for depression and self-rated health. In PwD more positive ATOA showed negligible associations with better general cognition, memory performance, verbal fluency, and visuospatial ability. However, after adjusting for covariates only better visuospatial ability predicted more positive ATOA. Additional analyses showed that before and after controlling for covariates, individuals with poorer self-reported visual acuity have more negative ATOA. Amongst dementia subtypes, people with Parkinson’s disease dementia and dementia with Lewy bodies reported most negative ATOA.
.
. Conclusions
. ATOA between PwD and people without dementia do not differ. ATOA in PwD appear to be affected not by cognitive impairment but by other characteristics that vary across dementia subtypes. Among PwD, those with Parkinson’s disease dementia and dementia with Lewy bodies may have higher risk of experiencing negative ATOA due to the motor and visual impairments that they experience.
.

BACKGROUND: Higher continuity of GP care (CGPC), that is, consulting the same doctor consistently, can improve doctor-patient relationships and increase quality of care; however, its effects on patients with dementia are mostly unknown. AIM: to estimate the associations between CGPC and potentially inappropriate prescribing (PIP), and with the incidence of adverse health outcomes (AHOs) in patients with dementia. DESIGN AND SETTING: a retrospective cohort study with 1 year of follow-up anonymised medical records from 9324 patients with dementia, aged ≥65 years living in England in 2016. METHOD: CGPC measures include the Usual Provider of Care (UPC), Bice-Boxerman Continuity of Care (BB), and Sequential Continuity (SECON) indices. Regression models estimated associations with PIPs and survival analysis with incidence of AHOs during the follow-up adjusted for age, sex, deprivation level, 14 comorbidities, and frailty. RESULTS: the highest quartile (HQ) of UPC (highest continuity) had 34.8% less risk of delirium (odds ratio [OR] 0.65, 95% confidence interval [CI] = 0.51 to 0.84), 57.9% less risk of incontinence (OR 0.42, 95% CI = 0.31 to 0.58), and 9.7% less risk of emergency admissions to hospital (OR 0.90, 95% CI = 0.82 to 0.99) compared with the lowest quartile. Polypharmacy and PIP were identified in 81.6% (n = 7612) and 75.4% (n = 7027) of patients, respectively. The HQ had fewer prescribed medications (HQ: mean 8.5, lowest quartile (LQ): mean 9.7, P

ABSTRACTObjectives: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.

Higher awareness of positive age-related changes (AARC gains) is related to better mental health, whereas higher awareness of negative age-related changes (AARC losses) is related to poorer mental and physical health. So far perceived gains and losses have been explored separately, but people report gains and losses concurrently in varying degrees, and different profiles of gains and losses may be differentially associated with health. We identified profiles of gains and losses and explored whether different profiles differed in physical, mental, and cognitive health. We used cross-sectional data from the PROTECT study (N = 6192; mean (SD) age = 66.1 (7.0)). Using latent profile analysis, a four-class solution showed the best model fit. We found that 45% of people perceived many gains and few losses (Class 1); 24% perceived moderate gains and few losses (Class 2); 24% perceived many gains and moderate losses (Class 3); 7% perceived many gains and many losses (Class 4). Analysis of variance and Chi-squared tests showed that Class 1 had relatively better physical, mental, and cognitive health, followed by Classes 2, 3, and 4. Experiencing one's ageing to a high degree as gain may be related to better health only when individuals interpret ageing as involving low levels of loss across several life domains. Risk in terms of poorer health emerged in those who perceived high losses. Considering gains and losses in parallel, rather than separately, may lead to a more fine-tuned understanding of relations with health.

Inflammation is usually a tightly regulated process whose termination by mediators including Annexin A1 (AnxA1) results in the resolution of inflammatory responses. In neurodegenerative dementias, chronic neuroinflammation, along with accumulation of aggregated β-amyloid (Aβ) peptides and apoptosis, has long been recognized to be a pathological hallmark; but it is unclear whether a failure of inflammation resolution contributes to this pathophysiological process. In this study, we measured AnxA1 immunoreactivities in postmortem neocortex (Brodmann areas BA9 and BA40) of well characterized Alzheimer's disease (AD), Parkinson disease dementia (PDD) and dementia with Lewy bodies (DLB) patients as well as aged controls. Inactive cleaved AnxA1 was found to be elevated in AD and DLB in BA40. Levels of cleaved AnxA1 also positively correlated with amyloidogenic brain Aβ, anti-inflammatory markers such as IL10 and IL13, as well as with the pro-apoptotic marker cleaved caspase-3 in BA40. Our findings suggest that elevated cleaved AnxA1 in neurodegenerative dementias may reflect a failure of inflammation resolution in certain regions of the diseased brain, and also support a mechanistic link between AnxA1 and amyloid pathology, neuroinflammation and apoptosis.

OBJECTIVES: Older people describe positive and negative age-related changes, but we do not know much about what contributes to make them aware of these changes. We used content analysis to categorize participants' written comments and explored the extent to which the identified categories mapped onto theoretical conceptualizations of influences on awareness of age-related change (AARC). DESIGN: Cross-sectional observational study. PARTICIPANTS: the study sample comprised 609 UK individuals aged 50 years or over (mean (SD) age = 67.9 (7.6) years), enrolled in the PROTECT study. MEASUREMENTS: Between January and March 2019, participants provided demographic information, completed a questionnaire assessing awareness of age-related change (AARC-10 SF), and responded to an open-ended question asking them to comment on their responses. RESULTS: While some of the emerging categories were in line with the existing conceptual framework of AARC (e.g. experiencing negative changes and attitudes toward aging), others were novel (e.g. engagement in purposeful activities or in activities that distract from age-related thoughts). Analysis revealed some of the thought processes involved in selecting responses to the questionnaire items, demonstrating different ways in which people make sense of specific items. CONCLUSIONS: Results support the ability of the AARC questionnaire to capture perceived age-related changes in cognitive functioning, physical and mental health, and engagement in social activities and in healthy and adaptive behaviors. However, findings also suggest ways of enriching the theoretical conceptualization of how AARC develops and offer insights into interpretation of responses to measures of AARC.

OBJECTIVES: the aim of the present study was to determine whether psychotic symptoms in people with dementia (PwD) living in nursing homes were associated with reduced quality of life and to understand the additional impact of other concurrent neuropsychiatric symptoms on QoL. DESIGN: Cross-sectional cohort study (using data from WHELD cohort). SETTINGS AND PARTICIPANTS: 971 PwD living in nursing homes participating in the WHELD study. METHODS: the Neuropsychiatric Inventory-Nursing Home (NPI-NH) version was completed by informant interview. We compared mean differences in proxy-rated QoL scores (DEMQOL-Proxy) for PwD experiencing or not experiencing delusions and for PwD experiencing or not experiencing hallucinations. Backward multiple regression was used to determine the added contributions of agitation (Cohen-Mansfield Agitation Inventory), anxiety (NPI-NH-Anxiety), depression (Cornell Scale for Depression in Dementia), dementia severity (Clinical Dementia Rating-sum of boxes score), pain (Abbey Pain Scale), and antipsychotic prescription. Mediation analysis was conducted for agitation, anxiety, and depression. RESULTS: Presence of both delusions (P <. 001, B = -8.39) and hallucinations (P <. 001, B = -7.78) was associated with poorer QoL. Both associations remained significant after controlling for other factors. Agitation, anxiety, and depression partially mediated the relationship between each psychotic symptom and QoL. CONCLUSIONS AND IMPLICATIONS: Delusions and hallucinations in PwD are associated with poorer QoL among PwD living in nursing homes. The effects remain significant after adjusting for confounding variables. Direct effects of each symptom maintained significance despite significant mediation by concurrent neuropsychiatric symptoms.

Objectives Assess feasibility of a cluster randomised controlled trial (RCT) to measure clinical and cost-effectiveness of an enhanced recovery pathway for people with hip fracture and cognitive impairment (CI). Design Feasibility trial undertaken between 2016 and 2018. Setting Eleven acute hospitals from three UK regions. Participants 284 participants (208 female:69 male). Inclusion criteria: aged >60 years, confirmed proximal hip fracture requiring surgical fixation and CI; preoperative AMTS ≤8 in England or a 4AT score ≥1 in Scotland; minimum of 5 days on study ward; a € suitable informant' able to provide proxy measures, recruited within 7 days of hip fracture surgery. Exclusion criteria: no hip surgery; not expected to survive beyond 4 weeks; already enrolled in a clinical trial. Intervention PERFECT-ER, an enhanced recovery pathway with 15 quality targets supported by a checklist and manual, a service improvement lead a process lead and implemented using a plan-do-study-act model. Primary and secondary outcome measures Feasibility outcomes: recruitment and attrition, intervention acceptability, completion of participant reported outcome measures, preliminary estimates of potential effectiveness using mortality, EQ-5D-5L, economic and clinical outcome scores. Results 282 participants were consented and recruited (132, intervention) from a target of 400. Mean recruitment rates were the same in intervention and control sites, (range: 1.2 and 2.7 participants/month). Retention was 230 (86%) at 1 month and 54%(144) at 6 months. At 3 months a relatively small effect (one quarter of an SD) was observed on health-related quality of life of the patient measured with EQ-5D-5L proxy in the intervention group. Conclusion This trial design was feasible with modifications to recruitment. Mechanisms for delivering consistency in the PERFECT-ER intervention and participant retention need to be addressed. However, an RCT may be a suboptimal research design to evaluate this intervention due to the complexity of caring for people with CI after hip fracture. Trial registration number ISRCTN99336264.

INTRODUCTION: Multidomain interventions to address modifiable risk factors for dementia are promising, but require more cost-effective, scalable delivery. This study investigated the feasibility of the "Active Brains" digital behavior change intervention and its trial procedures. MATERIALS AND METHODS: Active Brains aims to reduce cognitive decline by promoting physical activity, healthy eating, and online cognitive training. We conducted 12-month parallel-design randomized controlled feasibility trials of "Active Brains" amongst "lower cognitive scoring" (n = 180) and "higher cognitive scoring" (n = 180) adults aged 60-85. RESULTS: We collected 67.2 and 76.1% of our 12-month primary outcome (Baddeley verbal reasoning task) data for the "lower cognitive score" and "higher cognitive score" groups, respectively. Usage of "Active Brains" indicated overall feasibility and satisfactory engagement with the physical activity intervention content (which did not require sustained online engagement), but engagement with online cognitive training was limited. Uptake of the additional brief telephone support appeared to be higher in the "lower cognitive score" trial. Preliminary descriptive trends in the primary outcome data might indicate a protective effect of Active Brains against cognitive decline, but further investigation in fully-powered trials is required to answer this definitively. DISCUSSION: Whilst initial uptake and engagement with the online intervention was modest, it was in line with typical usage of other digital behavior change interventions, and early indications from the descriptive analysis of the primary outcome and behavioral data suggest that further exploration of the potential protective benefits of Active Brains are warranted. The study also identified minor modifications to procedures, particularly to improve online primary-outcome completion. Further investigation of Active Brains will now seek to determine its efficacy in protecting cognitive performance amongst adults aged 60-85 with varied levels of existing cognitive performance.

OBJECTIVES: the effects of masupirdine on the neuropsychiatric symptoms were explored. METHODS: Masupirdine (SUVN-502) was evaluated for its effects on cognition in patients with moderate AD. The prespecified primary outcome showed no drug-placebo difference. Post hoc analyses of domains of the 12-item neuropsychiatric inventory scale were carried out. RESULTS: in a subgroup of patients (placebo, n = 57; masupirdine 50 mg, n = 53; masupirdine 100 mg, n = 48) with baseline agitation/aggression symptoms ≥1, a statistically significant reduction in agitation/aggression scores was observed in masupirdine 50 mg (95% confidence interval (CI), -1.9 to -0.5, p 

Psychosis is a common and distressing symptom in people with Alzheimer disease, and few safe and effective treatments are available. However, new approaches to symptom assessment and treatment are beginning to drive the field forward. New nosological perspectives have been provided by incorporating the emergence of psychotic symptoms in older adults - even in advance of dementia - into epidemiological and neurobiological frameworks as well as into diagnostic and research criteria such as the International Psychogeriatric Association criteria for psychosis in neurocognitive disorders, the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART) research criteria for psychosis in neurodegenerative disease, and the ISTAART criteria for mild behavioural impairment. Here, we highlight the latest findings in genomics, neuroimaging and neurobiology that are informing approaches to drug discovery and repurposing. Current pharmacological and non-pharmacological treatment options are discussed, with a focus on safety and precision medicine. We also explore trial data for pimavanserin, a novel agent that shows promise for the treatment of psychosis in people with dementia, and discuss existing agents that might be useful but need further exploration such as escitalopram, lithium, cholinesterase inhibitors and vitamin D. Although the assessment and management of psychosis in people with dementia remain challenging, new opportunities are providing direction and hope to the field.

AbstractRapid eye movement (REM) sleep behaviour disorder (RBD) is a REM parasomnia that often predicts the later occurrence of alpha-synucleinopathies. Variants in the gene encoding for the lysosomal enzyme glucocerebrosidase, GBA, strongly increase the risk of RBD. In a GBA1-mouse model recently shown to mimic prodromal stages of α-synucleinopathy, we now demonstrate striking REM and NREM electroencephalographic sleep abnormalities accompanied by distinct structural changes in the more widespread sleep neurocircuitry.

Suicide has been identified as a leading cause of premature death in autistic populations. Elevated autistic traits have also been associated with higher rates of self-harm, suicidal ideation, and suicidal self-harm in the general population, but this has yet to be examined in older age. Using baseline cross-sectional data from the PROTECT study, middle-age and older adults with high autistic traits (n = 276) had significantly higher rates of suicidal ideation, deliberate self-harm, and suicidal self-harm than an age/sex-matched comparison group (n = 10,495). These differences represented a 5- to 6-fold increase in likelihood for self-harming and suicidality. These findings, which remained when controlling for depression symptoms, suggest that middle-age and older adults with high autistic traits may be particularly at risk of self-harm and suicidal behaviours.

BACKGROUND: the increasing availability of large high-dimensional data from experimental medicine, population-based and clinical cohorts, clinical trials, and electronic health records has the potential to transform dementia research. Our ability to make best use of this rich data will depend on utilisation of advanced machine learning and artificial intelligence (AI) techniques and collaboration across disciplinary and geographic boundaries. METHOD: the Deep Dementia Phenotyping (DEMON) Network launched in 20191 to support the growing interest in machine learning and AI. Led by Director Prof David Llewellyn and Deputy Director Dr Janice Ranson, the leadership team additionally includes 5 Theme Leads and 14 Working Group Leads, supported by an international Steering Committee of world-leading academics. Core funding is provided by Alzheimer's Research UK, the Alan Turing Institute and the University of Exeter, with additional support from strategic partners including the UK Dementia Research Institute and the Alzheimer's Society. Grand Challenges were established at a National Strategy Workshop in June 2020. Multidisciplinary Working Groups were formed to coordinate practical activities in seven key areas: Genetics and omics, experimental medicine, drug discovery and trials optimisation, biomarkers, imaging, dementia prevention, and applied models and digital health. Additional Special Interest Groups coordinate topic specific collaborations. RESULT: Membership on 4th February 2022 comprised 1,321 individuals from 61 countries across 6 continents (see Figure). Areas of expertise include dementia research (904; 68%), data science (692; 52%), clinical practice (244; 18%), industry (162; 12%), and regulation (26; 2%). Individual membership is free, and regular knowledge transfer events are provided including a monthly seminar series, talks and workshops, training, networking, and early career development. Each Working Group meets monthly, with multiple grants, reviews, and original research articles in progress. Eight state of the science position papers are in preparation, resulting from a Symposium held in April 2021. In January 2022, 110 early career researchers participated in the Network's flagship event 'NEUROHACK', a 4-day competitive global hackathon, with pilot grants awarded to those generating the most innovative solutions. CONCLUSION: the DEMON Network is a rapidly growing global platform for innovation that is supporting the global dementia research community to collaborate. Find out more at demondementia.com.

Stroke events increase the risk of developing dementia, 10% for a first-ever stroke and 30% for recurrent strokes. However, the effects of stroke on global cognition, leading up to dementia, remain poorly understood. We investigated: (i) post-stroke trajectories of cognitive change, (ii) trajectories of cognitive decline in those who develop dementia over periods of follow-up length and (iii) risk factors precipitating the onset of dementia. Prospective cohort of hospital-based stroke survivors in North-East England was followed for up to 12 years. In this study, we included 355 stroke survivors of ≥75 years of age, not demented 3 months post-stroke, who had had annual assessments during follow-up. Global cognition was measured annually and characterized using standardized tests: Cambridge Cognition Examination-Revised and Mini-Mental State Examination. Demographic data and risk factors were recorded at baseline. Mixed-effects models were used to study trajectories in global cognition, and logistic models to test associations between the onset of dementia and key risk factors, adjusted for age and sex. of the 355 participants, 91 (25.6%) developed dementia during follow-up. The dementia group had a sharper decline in Cambridge Cognition Examination-Revised (coeff. = -1.91, 95% confidence interval = -2.23 to -1.59, P 

INTRODUCTION: the increasingly ageing population is associated with greater numbers of people living with dementia (PLwD) and mild cognitive impairment (MCI). There are an estimated 55 million PLwD and approximately 6% of people over 60 years of age are living with MCI, with the figure rising to 25% for those aged between 80 and 84 years. Sleep disturbances are common for this population, but there is currently no standardised approach within UK primary care to manage this. Coined as a 'wicked design problem', sleep disturbances in this population are complex, with interventions supporting best management in context. METHODS AND ANALYSIS: the aim of this realist review is to deepen our understanding of what is considered 'sleep disturbance' in PLwD or MCI within primary care. Specifically, we endeavour to better understand how sleep disturbance is assessed, diagnosed and managed. To co-produce this protocol and review, we have recruited a stakeholder group comprising individuals with lived experience of dementia or MCI, primary healthcare staff and sleep experts. This review will be conducted in line with Pawson's five stages including the development of our initial programme theory, literature searches and the refinement of theory. The Realist and Meta-narrative Evidence Syntheses: Evolving Standards (RAMESES) quality and reporting standards will also be followed. The realist review will be an iterative process and our initial realist programme theory will be tested and refined in response to our data searches and stakeholder discussions. ETHICS AND DISSEMINATION: Ethical approval is not required for this review. We will follow the RAMESES standards to ensure we produce a complete and transparent report. Our final programme theory will help us to devise a tailored sleep management tool for primary healthcare professionals, PLwD and their carers. Our dissemination strategy will include lay summaries via email and our research website, peer-reviewed publications and social media posts. PROSPERO REGISTRATION NUMBER: CRD42022304679.

Background: Implementation of evidence-based training into real world practice in nursing home settings is a major challenge. Digital approaches provide real potential to addressing the barriers, particularly over the difficult period of the COVID-19 pandemic. Method: iWHELD is a first-of-its-kind digital programme evolving the principles of the WHELD intervention combining person centred care, social interaction, and antipsychotic review, combining virtual coaching with a digital resource for nursing homes. The intervention utilising a Dementia Champion model supported by live virtual coaching set within a digital resource hub and peer networking platform was compared to usual care in a 16-week randomised control cluster study of 741 people with dementia across 149 nursing homes in the UK. The initial outcomes evaluated are the use of antipsychotic drugs and neuropsychiatric symptoms (using the Neuropsychiatric Inventory NH). Result: 36/72 (53%) of nursing homes allocated to the active treatment arm engaged successfully with the digital intervention, with 563 residents completing the treatment period. The average age of residents was 84.5 years, 71% were female, and there were no significant differences between treatment arms. There was a significant reduction in antipsychotic use in the digital iWHELD treatment group from 49% to 31% compared to no change in the group receiving usual care (p = 0.046). Initial analysis of neuropsychiatric symptoms indicates a non-significant improvement in the intervention group compared to those receiving usual care. Conclusion: the current RCT using an online programme with live virtual coaching delivered through a Dementia Champion achieved better than 50% engagement, which compares favourably with previous studies of digital interventions in other therapeutic areas. The intervention also achieved significant reductions in antipsychotic use without any worsening of neuropsychiatric symptoms, and provides an important potential approach to safely reducing the rise in antipsychotic use in nursing home residents with dementia that has become a major challenge during the COVID-19 pandemic.

BACKGROUND: the Lewy body diseases, Dementia with Lewy bodies (DLB), Parkinson's disease (PD) and Parkinson's disease dementia (PDD) are all neurodegenerative diseases classified by the accumulation of alpha-synuclein in neurons, forming Lewy bodies (LB). We hypothesise that these LBs cause epigenetic changes within neurons and surrounding cells and that these changes can be used to distinguish the different LB diseases from one another. METHOD: Bulk tissue from the cingulate gyrus and prefrontal cortex will be as analysed for DNA methylation levels using the Illumina Infinium Methylation EPIC array to generate quantitative methylation data for over 850,000 CpG sites across the genome (n=∼100/disease group). Linear regression and pathway analyses will be used to identify loci that are significantly different or specific to each disease. Following this we will validate loci and determine their cellular specificity using a subset of samples (15 DLB, 15 PDD, 15 PD only, 15 controls) using fluorescence activated cell sorting (FACS). In each sample we will isolate various different cellular populations, including neurons, microglia, oligodendrocytes and astrocytes before profiling these using the EPIC array. RESULT: Study groups have been sourced consisting of cases with PD, PDD and DLB based on LB deposition and clinical symptom staging. Control cases have been selected for matched age and levels of concomitant AD pathology. Cases for FACS (n=15/group) have been selected to allow where possible a high base RIN, pH and minimal post-mortem interval. CONCLUSION: We are collating a well powered study cohort to interrogate the epigenetic basis of neuropathological progression and clinical staging of LB disease, controlling for levels of concomitant AD pathology. Follow up FACS sorting and analysis will allow for the cell specific methylation changes occurring in each of the LB diseases.

BACKGROUND: Hallucinations and delusions associated with dementia-related psychosis (DRP) can occur in persons with dementia-however, quickly screening for these symptoms in busy clinical settings can be challenging. We developed the DRP3 Screen, a novel tool to screen for psychosis in clinical settings; performed an Alignment Exercise to determine association of the DRP3 Screen with established psychosis/DRP reference assessments; and retrospectively assessed the ability of the DRP3 Screen to detect patients with DRP enrolled in a clinical trial (HARMONY, NCT03325556). METHODS: the DRP3 Screen comprises 3 yes/no questions and was developed by Acadia Pharmaceuticals Inc. in collaboration with an international team of six subject matter experts (SMEs). Through facilitated discussions, the panel developed questions addressing key aspects of psychosis in dementia. SMEs independently rated level of alignment (Table) of the questions with current reference assessments (SAPS-H+D, NPI-Q, IPA Criteria) to determine if the symptoms itemized in those assessments would be captured by ≥1 DRP3 Screen question. Criteria for association with a reference assessment item was mean rating ≥2.0 for at least one DRP3 Screen question (95% CI, lower limit ≥1.3). Inter-rater reliability of the Alignment Exercise for individual reference assessments was assessed using Fleiss' kappa statistic. For retrospective application of the DRP3 Screen to HARMONY, patients were considered likely to have been identified by the DRP3 Screen if they were positive (score ≥2) on ≥1 SAPS-H+D items that were positively associated with the DRP3 Screen. RESULTS: all items across 3 reference assessments (except SAPS-H+D D6, somatic delusions) were associated with the DRP3 Screen. Mean level of alignment segregated to none/some (0.3-1.8) and most/all (2.3-3.0) with significant inter-rater agreement of the DRP3 Screen with the SAPS-H+D, NPI-Q and IPA Criteria, (kappa values: 0.37, 0.26, and 0.45, respectively; p

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

Amyloid plaques are a hallmark of Alzheimer’s disease (AD) that develop in its earliest stages. Thus, non-invasive detection of these plaques would be invaluable for diagnosis and the development and monitoring of treatments, but this remains a challenge due to their small size. Here, we investigated the utility of manganese-enhanced MRI (MEMRI) for visualizing plaques in transgenic rodent models of AD across two species: 5xFAD mice and TgF344-AD rats. Animals were given subcutaneous injections of MnCl2 and imaged in vivo using a 9.4 T Bruker scanner. MnCl2 improved signal-to-noise ratio but was not necessary to detect plaques in high-resolution images. Plaques were visible in all transgenic animals and no wild-types, and quantitative susceptibility mapping showed that they were more paramagnetic than the surrounding tissue. This, combined with beta-amyloid and iron staining, indicate that plaque MR visibility in both animal models was driven by plaque size and iron load. Longitudinal relaxation rate mapping revealed increased manganese uptake in brain regions of high plaque burden in transgenic animals compared to their wild-type littermates. This was limited to the rhinencephalon in the TgF344-AD rats, while it was most significantly increased in the cortex of the 5xFAD mice. Alizarin Red staining suggests that manganese bound to plaques in 5xFAD mice but not in TgF344-AD rats. Multi-parametric MEMRI is a simple, viable method for detecting amyloid plaques in rodent models of AD. Manganese-induced signal enhancement can enable higher-resolution imaging, which is key to visualizing these small amyloid deposits. We also present the first in vivo evidence of manganese as a potential targeted contrast agent for imaging plaques in the 5xFAD model of AD.

INTRODUCTION: People living with dementia in nursing homes have complex needs; impairments in cognition, communication, and daily function; neuropsychiatric symptoms (NPS); and poor quality of life (QoL). The current study examines impairments in non-verbal communication as a potential driver of NPS and QoL. METHODS: One hundred nursing home residents with dementia were assessed using the Emory Dyssemia Index (EDI), Neuropsychiatric Inventory Nursing Home version (NPI-NH), Quality of Life in Alzheimer's Disease (QoL-AD) at baseline, 12-, and 24-week follow-up. RESULTS: the quantile regression (0.5) model indicated that impairment of non-verbal communication was independently associated with the severity of NPS (P = .001) and proxy reported QoL (P 

Objective: There is an urgent clinical need for identifying blood-based diagnostic biomarkers for Dementia with Lewy Bodies (DLB). Transcriptomic studies have reported unique RNA changes in postmortem DLB brains. Small extracellular vesicles (SEV) that transport RNA between brain and peripheral circulation enable identifying molecular changes in living human brain. Hence, we aimed to identify differentially expressed RNA in serum SEVs from people with DLB. Methods: We investigated serum SEV total RNA profiles in people with DLB (n = 10) and age and gender matched comparisons (n = 10) using next-generation RNA-sequencing. SEVs were separated by ultracentrifugation with density gradient and were characterized by nanoparticle analysis and western blotting. We verified the differential expression levels of identified differentially expressed genes (DEG) using high-throughput qPCR. Functional implications of identified DEG were evaluated using Ingenuity pathway analyses. Results: We identified 846 nominally significant DEG including 30 miRNAs in DLB serum SEVs. We identified significant downregulation of proinflammatory genes, IL1B, CXCL8, and IKBKB. Previously reported postmortem DLB brain DEGs were significantly enriched (χ2=4.99; df=1; p = 0.03) among the identified DEGs, and the differential expression of 40 postmortem DLB brain DEGs could be detected in serum SEVs of people living with DLB. Functional pathway and network analyses highlighted the importance of immunosenescence, ubiquitin proteasome system (UPS) dysfunction, DNA repair, and RNA post-transcriptional modification deficits in DLB pathology. Conclusion: Identified DEGs, especially reduced expression levels of inflammation, and UPS-associated RNA, may aid diagnosing DLB, and their biomarker potential warrants further investigation in larger clinical cohorts. Our findings corroborate the absence of chronic neuroinflammation in DLB.

BACKGROUND: Sleep disturbance affects around 60% of people living with dementia and can negatively affect their quality of life and that of their carers. Hypnotic Z-drugs (zolpidem, zopiclone and zaleplon) are commonly used to treat insomnia, but their safety and efficacy have not been evaluated for people living with dementia. OBJECTIVES: to estimate the benefits and harms of Z-drugs in people living with dementia with sleep disturbance. DESIGN: a series of observational cohort studies using existing data from (1) primary care linked to hospital admission data and (2) clinical cohort studies of people living with dementia. DATA SOURCES: Primary care study - Clinical Practice Research Datalink linked to Hospital Episode Statistics and Office for National Statistics mortality data. Clinical cohort studies - the Resource Use and Disease Course in Dementia - Nursing Homes (REDIC) study, National Alzheimer's Coordinating Centre (NACC) clinical data set and the Improving Well-being and Health for People with Dementia (WHELD) in nursing homes randomised controlled trial. SETTING: Primary care study - 371 primary care practices in England. Clinical cohort studies - 47 nursing homes in Norway, 34 Alzheimer's disease centres in the USA and 69 care homes in England. PARTICIPANTS: Primary care study - NHS England primary care patients diagnosed with dementia and aged > 55 years, with sleep disturbance or prescribed Z-drugs or low-dose tricyclic antidepressants, followed over 2 years. Clinical cohort studies - people living with dementia consenting to participate, followed over 3 years, 12 years and 9 months, for REDIC, NACC and WHELD, respectively. INTERVENTIONS: the primary exposure was prescription or use of Z-drugs. Secondary exposures included prescription or use of benzodiazepines, low-dose tricyclic antidepressants and antipsychotics. MAIN OUTCOME MEASURES: Falls, fractures, infection, stroke, venous thromboembolism, mortality, cognitive function and quality of life. There were insufficient data to investigate sleep disturbance. RESULTS: the primary care study and combined clinical cohort studies included 6809 and 18,659 people living with dementia, with 3089 and 914 taking Z-drugs, respectively. New Z-drug use was associated with a greater risk of fractures (hazard ratio 1.40, 95% confidence interval 1.01 to 1.94), with risk increasing with greater cumulative dose (p = 0.002). The hazard ratio for Z-drug use and hip fracture was 1.59 (95% confidence interval 1.00 to 2.53) and for mortality was 1.34 (95% confidence interval 1.10 to 1.64). No excess risks of falls, infections, stroke or venous thromboembolism were detected. Z-drug use also did not have an impact on cognition, neuropsychiatric symptoms, disability or quality of life. LIMITATIONS: Primary care study - possible residual confounding because of difficulties in identifying patients with sleep disturbance and by dementia severity. Clinical cohort studies - the small numbers of people living with dementia taking Z-drugs and outcomes not necessarily being measured before Z-drug initiation restricted analyses. CONCLUSIONS: We observed a dose-dependent increase in fracture risk, but no other harms, with Z-drug use in dementia. However, multiple outcomes were examined, increasing the risk of false-positive findings. The mortality association was unlikely to be causal. Further research is needed to confirm the increased fracture risk. Decisions to prescribe Z-drugs may need to consider the risk of fractures, balanced against the impact of improved sleep for people living with dementia and that of their carers. Our findings suggest that when Z-drugs are prescribed, falls prevention strategies may be needed, and that the prescription should be regularly reviewed. FUTURE WORK: More research is needed on safe and effective management strategies for sleep disturbance in people living with dementia. STUDY REGISTRATION: This study is registered as European Union electronic Register of Post-Authorisation Studies (EU PAS) 18006. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 1. See the NIHR Journals Library website for further project information.

OBJECTIVES: to compare online cognitive-behavioral therapy (CBT) with and without telephone support respectively to online psychoeducation in a randomized controlled trial (RCT) in caregivers of people with dementia with mild anxiety or depression. DESIGN: Three-arm parallel-group RCT comparing online CBT with and without telephone support respectively to online psychoeducation. SETTING AND PARTICIPANTS: Online study with caregivers of people with dementia. MEASURES: the primary outcome measure was mental health measured by General Health Questionnaire-12 (GHQ-12) at 26 weeks. Secondary outcomes included the Hospital Anxiety and Depression Scale (HADS); the Relative Stress Scale (RSS) and the Short Sense of Competency Questionnaire. The primary analysis focused on people completing GHQ-12 at both baseline and 26 weeks, evaluated using analysis of covariance. RESULTS: 638 people were randomized to the 3 treatment arms, of whom 208 were included in the analysis population. There were significant improvements in GHQ-12 in all treatment arms compared to baseline (P 

Parkinson disease (PD) is the second most common neurodegenerative disorder, affecting >1% of the population ≥65 years of age and with a prevalence set to double by 2030. In addition to the defining motor symptoms of PD, multiple non-motor symptoms occur; among them, cognitive impairment is common and can potentially occur at any disease stage. Cognitive decline is usually slow and insidious, but rapid in some cases. Recently, the focus has been on the early cognitive changes, where executive and visuospatial impairments are typical and can be accompanied by memory impairment, increasing the risk for early progression to dementia. Other risk factors for early progression to dementia include visual hallucinations, older age and biomarker changes such as cortical atrophy, as well as Alzheimer-type changes on functional imaging and in cerebrospinal fluid, and slowing and frequency variation on EEG. However, the mechanisms underlying cognitive decline in PD remain largely unclear. Cortical involvement of Lewy body and Alzheimer-type pathologies are key features, but multiple mechanisms are likely involved. Cholinesterase inhibition is the only high-level evidence-based treatment available, but other pharmacological and non-pharmacological strategies are being tested. Challenges include the identification of disease-modifying therapies as well as finding biomarkers to better predict cognitive decline and identify patients at high risk for early and rapid cognitive impairment.

IMPORTANCE: treatment of dementia in individuals with comorbidities is complex, leading to potentially inappropriate prescribing (PIP). The impact of PIP in this population is unknown. OBJECTIVE: to estimate the rate of PIP and its effect on adverse health outcomes (AHO). DESIGN: retrospective cohort. SETTING: primary care electronic health records linked to hospital discharge data from England. SUBJECTS: 11,175 individuals with dementia aged over 65 years in 2016 and 43,463 age- and sex-matched controls. METHODS: Screening Tool of Older Persons' Prescriptions V2 defined PIP. Logistic regression tested associations with comorbidities at baseline, and survival analyses risk of incident AHO, adjusted for age, gender, deprivation and 14 comorbidities. RESULTS: the dementia group had increased risk of PIP (73% prevalence; odds ratio [OR]: 1.92; confidence interval [CI]: 83-103%; P 

OBJECTIVES: to investigate the course of activities of daily living (IADL) functioning and possible predictors of performance changes in healthy older adults conducting either a General Cognitive Training (GCT) or a Reasoning Cognitive Training (ReaCT) or no training (control group, CG) over a period of 6 weeks, 3 months, and 6 months. SETTING AND PARTICIPANTS: an online, home-based GCT and ReaCT including n = 2913 healthy participants (GCT: n = 1096; ReaCT: n = 1022; CG: n = 794) aged 60 years and older. METHODS: Multilevel analysis were calculated to explore the nature of our outcome variables of IADL part a (independence) and part B (difficulty of tasks), and to detect possible predictors for participants' performance on IADL after CT. RESULTS: the random slopes models fitted better for the outcomes IADL Part B in the GCT group (χ2 (2) =  18.78, p 

Background: the identification of people at risk of cognitive impairment is essential for improving recruitment in secondary prevention trials of Alzheimer's disease. We aimed to test and qualify a biomarker risk assignment algorithm (BRAA) to identify participants at risk of developing mild cognitive impairment due to Alzheimer's disease within 5 years, and to evaluate the safety and efficacy of low-dose pioglitazone to delay onset of mild cognitive impairment in these at-risk participants. Methods: in this phase 3, multicentre, randomised, double-blind, placebo-controlled, parallel-group study, we enrolled cognitively healthy, community living participants aged 65–83 years from 57 academic affiliated and private research clinics in Australia, Germany, Switzerland, the UK, and the USA. By use of the BRAA, participants were grouped as high risk or low risk. Participants at high risk were randomly assigned 1:1 to receive oral pioglitazone (0·8 mg/day sustained release) or placebo, and all low-risk participants received placebo. Study investigators, site staff, sponsor personnel, and study participants were masked to genotype, risk assignment, and treatment assignment. The planned study duration was the time to accumulate 202 events of mild cognitive impairment due to Alzheimer's disease in White participants who were at high risk (the population on whom the genetic analyses that informed the BRAA development was done). Primary endpoints were time-to-event comparisons between participants at high risk and low risk given placebo (for the BRAA objective), and between participants at high risk given pioglitazone or placebo (for the efficacy objective). The primary analysis included all participants who were randomly assigned, received at least one dose of study drug, and had at least one valid post-baseline visit, with significance set at p=0·01. The safety analysis included all participants who were randomly assigned and received at least one dose of study medication. An efficacy futility analysis was planned for when approximately 33% of the anticipated events occurred in the high-risk, White, non-Hispanic or Latino group. This trial is registered with ClinicalTrials.gov, NCT01931566. Findings: Between Aug 28, 2013, and Dec 21, 2015, we enrolled 3494 participants (3061 at high risk and 433 at low risk). of those participants, 1545 were randomly assigned to pioglitazone and 1516 to placebo. 1104 participants discontinued treatment (464 assigned to the pioglitazone group, 501 in the placebo high risk group, and 139 in the placebo low risk group). 3399 participants had at least one dose of study drug or placebo and at least one post-baseline follow-up visit, and were included in the efficacy analysis. 3465 participants were included in the safety analysis (1531 assigned to the pioglitazone group, 1507 in the placebo high risk group, and 427 in the placebo low risk group). In the full analysis set, 46 (3·3%) of 1406 participants at high risk given placebo had mild cognitive impairment due to Alzheimer's disease, versus four (1·0%) of 402 participants at low risk given placebo (hazard ratio 3·26, 99% CI 0·85–12·45; p=0·023). 39 (2·7%) of 1430 participants at high risk given pioglitazone had mild cognitive impairment, versus 46 (3·3%) of 1406 participants at high risk given placebo (hazard ratio 0·80, 99% CI 0·45–1·40; p=0·307). In the safety analysis set, seven (0·5%) of 1531 participants at high risk given pioglitazone died versus 21 (1·4%) of 1507 participants at high risk given placebo. There were no other notable differences in adverse events between groups. The study was terminated in January, 2018, after failing to meet the non-futility threshold. Interpretation: Pioglitazone did not delay the onset of mild cognitive impairment. The biomarker algorithm demonstrated a 3 times enrichment of events in the high risk placebo group compared with the low risk placebo group, but did not reach the pre-specified significance threshold. Because we did not complete the study as planned, findings can only be considered exploratory. The conduct of this study could prove useful to future clinical development strategies for Alzheimer's disease prevention studies. Funding: Takeda and Zinfandel.

INTRODUCTION: Idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) is increasingly recognised as an important precursor disease state of alpha-synucleinopathies. This parasomnia is characterized by a history of recurrent nocturnal dream enactment behaviour, loss of skeletal muscle atonia, and increased phasic muscle activity during REM sleep. Neuroimaging studies of striatal dopamine transporter uptake tracer signaling suggest increasing dopaminergic deficit across the continuum of the alpha-synucleinopathies, with early sleep dysfunction suggestive of early caudate dysfunction. Henceforth, we set out to investigate the relationship between early sleep changes and the striatal dopaminergic availability in iRBD. METHODS: Twelve patients with iRBD, who had undergone a video polysomnography and a neuroimaging assessment of striatal dopamine transporter (DaT) uptake tracer signaling, and 22 matched controls who had similarly undergone a video polysomnography were retrospectively identified. Data were statistically analyzed to identify altered sleep parameters and correlate them with striatal dopamine transporter uptake tracer signaling. RESULTS: the iRBD patients exhibited an increased number of periodic limb movements during sleep (P=0.001), compared to 22 age-matched healthy subjects. In addition, several significant links were found between regional DaT-uptakes and sleep architecture. Correlational analyses suggested a strong positive association between sleep fragmentation and dopamine deficiency in left caudate (r=-0.630, P=0.028), whilst an increased uptake in the whole striatum was strongly linked to the sleep efficiency, and to a lesser degree to the length of sleep duration. DISCUSSION: to the best of our knowledge, this is the first demonstration of a close relationship between dopaminergic availability in striatum and the quality of sleep in iRBD. Taken together, our exploratory findings suggest that subtle but functionally significant striatal changes in early stages of iRBD may contribute to the further shaping of sleep architecture.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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). INTERPRETATION: 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. FUNDING: UK National Institute for Health Research Health Technology Assessment Programme.

OBJECTIVES: the mental and physical health profile of autistic people has been studied in adolescence and adulthood, with elevated rates of most conditions being reported. However, this has been little studied taking a dimensional approach to autistic traits and in older age. METHODS: a total of 20,220 adults aged 50-81 years from the PROTECT study reported whether they experienced persistent sociocommunicative traits characteristic of autism. Approximately 1%, 276 individuals, were identified as endorsing elevated autistic traits in childhood and currently, henceforth the "Autism Spectrum Trait" (AST) group. An age- and gender-matched comparison group was formed of 10,495 individuals who did not endorse any autistic behavioral traits, henceforth the "Control Older Adults" (COA) group. Differences between AST and COA groups were explored in self-reported psychiatric diagnoses, self-reported symptoms of current depression and anxiety, and self-reported physical health diagnoses. Associations were also examined between autistic traits and health across the whole sample. RESULTS: the AST group reported significantly elevated rates of psychiatric diagnoses compared to the COA group. Additionally, the AST group showed significantly higher self-reported symptoms of current depression and anxiety than the COA group. However, few differences were observed in individual physical health conditions, and no differences in total co-occurring physical diagnoses between groups. Similar associations between autistic traits and health were also found taking a dimensional approach across the whole sample. DISCUSSION: These findings suggest that older adults with elevated autistic traits may be at greater risk of poorer mental, but not physical, health in later life. Future studies should incorporate polygenic scores to elucidate the possible genetic links between the propensity to autism/high autistic traits and to psychiatric conditions, and to explore whether those with elevated autistic traits experience particular barriers to mental health care.

BACKGROUND Patients with dementia due to neurodegenerative disease can have dementia-related psychosis. The effects of the oral 5-HT2A inverse agonist and antagonist pimavanserin on psychosis related to various causes of dementia are not clear. METHODS We conducted a phase 3, double-blind, randomized, placebo-controlled discontinuation trial involving patients with psychosis related to Alzheimer's disease, Parkinson's disease dementia, dementia with Lewy bodies, frontotemporal dementia, or vascular dementia. Patients received open-label pimavanserin for 12 weeks. Those who had a reduction from baseline of at least 30% in the score on the Scale for the Assessment of Positive Symptoms-Hallucinations and Delusions (SAPS-H+D, with higher scores indicating greater psychosis) and a Clinical Global Impression-Improvement (CGI-I) score of 1 (very much improved) or 2 (much improved) at weeks 8 and 12 were randomly assigned in a 1:1 ratio to continue receiving pimavanserin or to receive placebo for up to 26 weeks. The primary end point, assessed in a time-to-event analysis, was a relapse of psychosis as defined by any of the following: an increase of at least 30% in the SAPS-H+D score and a CGI-I score of 6 (much worse) or 7 (very much worse), hospitalization for dementia-related psychosis, stopping of the trial regimen or withdrawal from the trial for lack of efficacy, or use of antipsychotic agents for dementia-related psychosis. RESULTS of the 392 patients in the open-label phase, 41 were withdrawn for administrative reasons because the trial was stopped for efficacy; of the remaining 351 patients, 217 (61.8%) had a sustained response, of whom 105 were assigned to receive pimavanserin and 112 to receive placebo. A relapse occurred in 12 of 95 patients (13%) in the pimavanserin group and in 28 of 99 (28%) in the placebo group (hazard ratio, 0.35; 95% confidence interval, 0.17 to 0.73; P = 0.005). During the double-blind phase, adverse events occurred in 43 of 105 patients (41.0%) in the pimavanserin group and in 41 of 112 (36.6%) in the placebo group. Headache, constipation, urinary tract infection, and asymptomatic QT prolongation occurred with pimavanserin. CONCLUSIONS in a trial that was stopped early for efficacy, patients with dementia-related psychosis who had a response to pimavanserin had a lower risk of relapse with continuation of the drug than with discontinuation. Longer and larger trials are required to determine the effects of pimavanserin in dementia-related psychosis.

The 2020 COVID-19 pandemic has disrupted Alzheimer’s disease (AD) clinical studies worldwide. Digital technologies may help minimize disruptions by enabling remote assessment of subtle cognitive and functional changes over the course of the disease. The EU/US Clinical Trials in Alzheimer’s Disease (CTAD) Task Force met virtually in November 2020 to explore the opportunities and challenges associated with the use of digital technologies in AD clinical research. While recognizing the potential of digital tools to accelerate clinical trials, improve the engagement of diverse populations, capture clinically meaningful data, and lower costs, questions remain regarding the stability, validity, generalizability, and reproducibility of digital data. Substantial concerns also exist regarding regulatory acceptance and privacy. Nonetheless, the Task Force supported further exploration of digital technologies through collaboration and data sharing, noting the need for standardization of digital readouts. They also concluded that while it may be premature to employ remote assessments for trials of novel experimental medications, remote studies of non-invasive, multi-domain approaches may be feasible at this time.

Background: the coronavirus pandemic is having a profound impact on non-COVID-19 related research, including the delivery of clinical trials for patients with Parkinson's disease. Objectives: a preliminary investigation to explore the views of Parkinson's disease (PD) patients, with and without experience of psychosis symptoms, and carers on the resumption of clinical research and adaptations to trials in light of COVID-19. Methods: an anonymous self-administered online survey was completed by 30 PD patients and six family members/carers via the Parkinson's UK Research Support Network to explore current perceptions on taking part in PD research and how a planned clinical trial for psychosis in PD may be adapted so participants feel safe. Results: Ninety-one percent of respondents were enthusiastic about the continuation of non-COVID-19 related research as long as certain safety measures were in place. Ninety-four percent stated that they would be happy to complete assessments virtually. However, they noted that care should be taken to ensure that this does not exclude participants, particularly those with more advanced PD who may require assistance using portable electronic devices. Regular and supportive communication from the research team was also seen as important for maintaining the psychological well-being of participants while taking part in the trial. Conclusions: in the era of COVID-19 pandemic, standard approaches will have to be modified and rapid adoption of virtual assessments will be critical for the continuation of clinical research. It is important that alongside the traditional methods, new tools are developed, and older ones validated for virtual assessments, to allow safe and comprehensive assessments vital for ongoing research in people with Parkinson's.

To identify knowledge gaps regarding new-onset agitation and impulsivity prior to onset of cognitive impairment or dementia the International Society to Advance Alzheimer's Research and Treatment Neuropsychiatric Syndromes (NPS) Professional Interest Area conducted a scoping review. Extending a series of reviews exploring the pre-dementia risk syndrome Mild Behavioral Impairment (MBI), we focused on late-onset agitation and impulsivity (the MBI impulse dyscontrol domain) and risk of incident cognitive decline and dementia. This scoping review of agitation and impulsivity pre-dementia syndromes summarizes the current biomedical literature in terms of epidemiology, diagnosis and measurement, neurobiology, neuroimaging, biomarkers, course and prognosis, treatment, and ongoing clinical trials. Validations for pre-dementia scales such as the MBI Checklist, and incorporation into longitudinal and intervention trials, are needed to better understand impulse dyscontrol as a risk factor for mild cognitive impairment and dementia.

Cerebrospinal fluid analyses and neuroimaging can identify the underlying pathophysiology at the earliest stage of some neurodegenerative disorders, but do not have the scalability needed for population screening. Therefore, a blood-based marker for such pathophysiology would have greater utility in a primary care setting and in eligibility screening for clinical trials. Rapid advances in ultra-sensitive assays have enabled the levels of pathological proteins to be measured in blood samples, but research has been predominantly focused on Alzheimer disease (AD). Nonetheless, proteins that were identified as potential blood-based biomarkers for AD, for example, amyloid-β, tau, phosphorylated tau and neurofilament light chain, are likely to be relevant to other neurodegenerative disorders that involve similar pathological processes and could also be useful for the differential diagnosis of clinical symptoms. This Review outlines the neuropathological, clinical, molecular imaging and cerebrospinal fluid features of the most common neurodegenerative disorders outside the AD continuum and gives an overview of the current status of blood-based biomarkers for these disorders.

BACKGROUND AND OBJECTIVES: This systematic review aimed to synthesize and quantify the associations of awareness of age-related change (AARC) with emotional well-being, physical well-being, and cognitive functioning. RESEARCH DESIGN AND METHODS: We conducted a systematic review with a correlational random effects meta-analysis. We included quantitative studies, published from January 1, 2009 to October 3, 2018, exploring associations between AARC and one or more of the following outcomes: emotional well-being, physical well-being, and cognitive functioning. We assessed heterogeneity (I2) and publication bias. RESULTS: We included 12 studies in the review, 9 exploring the association between AARC and emotional well-being and 11 exploring the association between AARC and physical well-being. No study explored the association between AARC and cognitive functioning. Six articles were included in the meta-analysis. We found a moderate association between a higher level of AARC gains and better emotional well-being (r =. 33; 95% CI 0.18, 0.47; p

After publication of our article [1] the authors have notified us that the name of Prof. Christian Hölscher had been inadvertently forgotten when compiling the list of authors. Dr. Hölscher developed the concept of testing liraglutide in Alzheimer’s mouse model, has done the preclinical experiments, and is a co-applicant of the Alzheimer ociety UK grant that partially funds the study.

BACKGROUND: the quality of care for people with dementia in care homes is of concern. Interventions that can improve care outcomes are required. OBJECTIVE: to investigate the clinical effectiveness and cost-effectiveness of Dementia Care Mapping™ (DCM) for reducing agitation and improving care outcomes for people living with dementia in care homes, versus usual care. DESIGN: a pragmatic, cluster randomised controlled trial with an open-cohort design, follow-up at 6 and 16 months, integrated cost-effectiveness analysis and process evaluation. Clusters were not blinded to allocation. The primary end point was completed by staff proxy and independent assessors. SETTING: Stratified randomisation of 50 care homes to the intervention and control groups on a 3 : 2 ratio by type, size, staff exposure to dementia training and recruiting hub. PARTICIPANTS: Fifty care homes were randomised (intervention, n = 31; control, n = 19), with 726 residents recruited at baseline and a further 261 recruited after 16 months. Care homes were eligible if they recruited a minimum of 10 residents, were not subject to improvement notices, had not used DCM in the previous 18 months and were not participating in conflicting research. Residents were eligible if they lived there permanently, had a formal diagnosis of dementia or a score of 4+ on the Functional Assessment Staging Test of Alzheimer's Disease, were proficient in English and were not terminally ill or permanently cared for in bed. All homes were audited on the delivery of dementia and person-centred care awareness training. Those not reaching a minimum standard were provided training ahead of randomisation. Eighteen homes took part in the process evaluation. INTERVENTION: Two staff members from each intervention home were trained to use DCM and were asked to carry out three DCM cycles; the first was supported by an external expert. MAIN OUTCOME MEASURES: the primary outcome was agitation (Cohen-Mansfield Agitation Inventory), measured at 16 months. Secondary outcomes included resident behaviours and quality of life. RESULTS: There were 675 residents in the final analysis (intervention, n = 388; control, n = 287). There was no evidence of a difference in agitation levels between the treatment arms. The adjusted mean difference in Cohen-Mansfield Agitation Inventory score was -2.11 points, being lower in the intervention group than in the control (95% confidence interval -4.66 to 0.44; p = 0.104; adjusted intracluster correlation coefficient: control = 0, intervention = 0.001). The sensitivity analyses results supported the primary analysis. No differences were detected in any of the secondary outcomes. The health economic analyses indicated that DCM was not cost-effective. Intervention adherence was problematic; only 26% of homes completed more than their first DCM cycle. Impacts, barriers to and facilitators of DCM implementation were identified. LIMITATIONS: the primary completion of resident outcomes was by staff proxy, owing to self-report difficulties for residents with advanced dementia. Clusters were not blinded to allocation, although supportive analyses suggested that any reporting bias was not clinically important. CONCLUSIONS: There was no benefit of DCM over control for any outcomes. The implementation of DCM by care home staff was suboptimal compared with the protocol in the majority of homes. FUTURE WORK: Alternative models of DCM implementation should be considered that do not rely solely on leadership by care home staff. TRIAL REGISTRATION: Current Controlled Trials ISRCTN82288852. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 16. See the NIHR Journals Library website for further project information.

​​​​​​ Psychosis is common in patients with dementia; therefore, clinicians should carefully evaluate psychotic symptoms reported by patients or their caregivers. A variety of tools exist for the diagnosis of DRP, such as the Neuropsychiatric Inventory and new diagnostic criteria. It is important to talk with patients and caregivers about the impact of DRP on well-being, their level of distress (and patients' insight), the potential risks of medication to treat DRP, and the potential course of DRP because, then, it is possible for people to contribute knowledgably to discussions of the best treatment options. Certain techniques can help clinicians communicate with patients and carers about DRP symptomology and appropriate care strategies. From the University of Exeter College of Medicine and Health, UK.

INTRODUCTION: Visual hallucinations (VH) have a significant impact on quality of life for people with Parkinson's disease (PD). A major reason for this is the well-established link with cognitive impairment, but there is still a need for more longitudinal studies examining the specific cognitive domains which may be affected. The aim of this study was to profile decline in cognition associated with VH in a cohort of 69 individuals with PD over 1 year. METHOD: Visual hallucinations assessments were carried out every 3 months. Executive function and episodic memory were assessed at baseline and 1 year. All evaluations were performed via phone interviews. The presence or absence of VH was categorized based on the entirety of the year's data (i.e. no episodes and >0 episodes). We also defined a persistent VH group who had VH present at more than one time point and compared these with a no-VH group and a group with transient VH (i.e. only one episode). RESULTS: Linear mixed-effect models showed that VH were associated with more rapid overall cognitive decline (-0.26, t = -2.39, p = .02), which was driven by executive function (-0.28, t = -2.48, p = .02). Persistent VH were associated with decline in executive function (-0.33, t = -2.4, p = .02), while no relationship was found for non-persistent VH, suggesting that persistent VH be the major driver of this relationship. CONCLUSION: This finding brings greater clarity to the relationship between cognitive decline and VH in PD. Future research should examine the robustness of this phenotype for biomarkers studies and treatment interventions.

An increasing proportion of cognitive difficulties are recognized to have a functional cause, the chief clinical indicator of which is internal inconsistency. When these symptoms are impairing or distressing, and not better explained by other disorders, this can be conceptualized as a cognitive variant of functional neurological disorder, termed functional cognitive disorder (FCD). FCD is likely very common in clinical practice but may be under-diagnosed. Clinicians in many settings make liberal use of the descriptive term mild cognitive impairment (MCI) for those with cognitive difficulties not impairing enough to qualify as dementia. However, MCI is an aetiology-neutral description, which therefore includes patients with a wide range of underlying causes. Consequently, a proportion of MCI cases are due to non-neurodegenerative processes, including FCD. Indeed, significant numbers of patients diagnosed with MCI do not 'convert' to dementia. The lack of diagnostic specificity for MCI 'non-progressors' is a weakness inherent in framing MCI primarily within a deterministic neurodegenerative pathway. It is recognized that depression, anxiety and behavioural changes can represent a prodrome to neurodegeneration; empirical data are required to explore whether the same might hold for subsets of individuals with FCD. Clinicians and researchers can improve study efficacy and patient outcomes by viewing MCI as a descriptive term with a wide differential diagnosis, including potentially reversible components such as FCD. We present a preliminary definition of functional neurological disorder-cognitive subtype, explain its position in relation to other cognitive diagnoses and emerging biomarkers, highlight clinical features that can lead to positive diagnosis (as opposed to a diagnosis of exclusion), and red flags that should prompt consideration of alternative diagnoses. In the research setting, positive identifiers of FCD will enhance our recognition of individuals who are not in a neurodegenerative prodrome, while greater use of this diagnosis in clinical practice will facilitate personalized interventions.

Abstract Higher awareness of negative age-related changes (AARC-losses) is related to poorer mental and physical health whereas higher awareness of positive age-related changes (AARC-gains) is related to better mental health. Associations of health with AARC-gains and losses have been explored separately, but often people experience gains and losses concurrently. Using latent profile analysis, we identified at the cross-sectional level patterns of AARC-gains and losses and explored whether groups with distinct profiles of AARC-gains and losses differed in physical, mental, and cognitive health, and demographic characteristics. Analyses were based on the large-scale PROTECT study conducted in the UK (N= 6,192; mean age= 66.10(SD= 7.04); 76% women). A four-group solution revealed the best model fit (Akaike’s information criterion= 156,061.93; Bayesian information criterion= 156,418.67); 45% of participants perceived many AARC-gains and few losses (Group 1); 24% of participants perceived moderate AARC-gains and few losses (Group 2); 24% of participants perceived many AARC-gains and moderate losses (Group 3); and 7% of participants perceived many AARC-gains and many losses (Group 4). The four groups differed meaningfully in health; Group 1 was the most healthy, followed by Groups 2, 3 and 4. Participants in Group 1 were most likely to perceive their health as excellent, reported the lowest levels of depression and anxiety, and showed the best cognitive performance. On average participants in Group 1 were younger, and more likely to be female, employed, and married, compared to other groups. Considering the co-existence of gains and losses is important when relating awareness of age-related changes to health.

Objectives: This study aimed to develop and explore feasibility of SettleIN, a staff-led programme about healthy adjustment for people with dementia following care home placement. The main foci were intervention feasibility and the impact of the programme on resident quality of life and mood. Method: a manualised intervention developed through consultation with 47 experts was trialled using a mixed-method design. Thirteen new residents with dementia and 24 staff were recruited from six UK care homes. Outcomes were measured at baseline, intervention completion and four-week follow-up. Analysis of staff interviews and field notes is reported. Results: Most experts deemed SettleIN to be well structured, comprehensive and appropriate. However, uptake of SettleIN was low. When implemented, staff emphasised integration ease and staff benefits, but that SettleIN may not be universally suitable. High attrition, most commonly due to death and hospitalisation, and partial results from only four participants meant that there was a lack of support for the positive outcomes. Feasibility problems included a lack of staff time and dependency on families for some components. Conclusion: SettleIN is acceptable to a wide range of stakeholders though does not appear to be feasible in its current form and improvements are recommended. A second pilot phase is required, which will address the reasons for the high attrition rate in this study and amend the methodology accordingly. This is an important work, as a manualised and standardised approach to healthy adjustment in care is unique and could have huge clinical significance if effective.

Abstract Existing evidence suggests that individuals’ subjective experience of cognitive decline may be a risk state for dementia. However, whether self-awareness of positive changes confer cognitive protection is unknown. We examined the extent to which awareness of positive (AARC gains) and negative (AARC losses) age-related changes explains variability in objective cognitive performance in a sample of 6,231 UK residents (Mean age= 66.1 years, 75.9% women) without cognitive impairment. We tested a structural equation model with AARC gains and losses as predictors of cognitive performance and depressive symptoms as a mediator of the association of AARC losses with cognitive performance. The model fit the data well. The correlation between AARC gains and losses was negligible, yet higher levels of both AARC gains and losses predicted poorer cognitive scores. Hence, higher AARC gains did not confer cognitive protection. This unexpected pattern of results underscores the complexity of mapping individuals’ awareness onto objective outcomes.

Social isolation is likely to be recommended for older adults due to COVID-19, with ongoing reduced clinical contact suggested for this population. This has increased the need for remote memory clinics, we therefore review the literature, current practices and guidelines on organizing such remote memory clinics, focusing on assessment of cognition, function and other relevant measurements, proposing a novel pathway based on three levels of complexity: simple telephone or video-based interviews and testing using available tests (Level 1), digitized and validated methods based on standard pen-and-paper tests and scales (Level 2), and finally fully digitized cognitive batteries and remote measurement technologies (RMTs, Level 3). Pros and cons of these strategies are discussed. Remotely collected data negates the need for frail patients or carers to commute to clinic and offers valuable insights into progression over time, as well as treatment responses to therapeutic interventions, providing a more realistic and contextualized environment for data-collection. Notwithstanding several challenges related to internet access, computer skills, limited evidence base and regulatory and data protection issues, digital biomarkers collected remotely have significant potential for diagnosis and symptom management in older adults and we propose a framework and pathway for how technologies can be implemented to support remote memory clinics. These platforms are also well-placed for administration of digital cognitive training and other interventions. The individual, societal and public/private costs of COVID-19 are high and will continue to rise for some time but the challenges the pandemic has placed on memory services also provides an opportunity to embrace novel approaches. Remote memory clinics’ financial, logistical, clinical and practical benefits have been highlighted by COVID-19, supporting their use to not only be maintained when social distancing legislation is lifted but to be devoted extra resources and attention to fully potentiate this valuable arm of clinical assessment and care.

Social isolation is likely to be recommended for older adults due to COVID-19, with ongoing reduced clinical contact suggested for this population. This has increased the need for remote memory clinics, we therefore review the literature, current practices and guidelines on organizing such remote memory clinics, focusing on assessment of cognition, function and other relevant measurements, proposing a novel pathway based on three levels of complexity: simple telephone or video-based interviews and testing using available tests (Level 1), digitized and validated methods based on standard pen-and-paper tests and scales (Level 2), and finally fully digitized cognitive batteries and remote measurement technologies (RMTs, Level 3). Pros and cons of these strategies are discussed. Remotely collected data negates the need for frail patients or carers to commute to clinic and offers valuable insights into progression over time, as well as treatment responses to therapeutic interventions, providing a more realistic and contextualized environment for data-collection. Notwithstanding several challenges related to internet access, computer skills, limited evidence base and regulatory and data protection issues, digital biomarkers collected remotely have significant potential for diagnosis and symptom management in older adults and we propose a framework and pathway for how technologies can be implemented to support remote memory clinics. These platforms are also well-placed for administration of digital cognitive training and other interventions. The individual, societal and public/private costs of COVID-19 are high and will continue to rise for some time but the challenges the pandemic has placed on memory services also provides an opportunity to embrace novel approaches. Remote memory clinics’ financial, logistical, clinical and practical benefits have been highlighted by COVID-19, supporting their use to not only be maintained when social distancing legislation is lifted but to be devoted extra resources and attention to fully potentiate this valuable arm of clinical assessment and care.

. Background
. The effective management of agitation and other neuropsychiatric and behavioural symptoms in people with dementia is a major challenge, particularly in care home settings, where dementia severity is higher and there is limited training and support for care staff. There is evidence for the value of staff training and the use of psychosocial approaches; however, no intervention currently exists that combines these elements into an intervention that is fit for purpose and effective in these settings based on evidence from a randomised controlled trial.
.
.
. Objective
. The objective was to develop and evaluate a complex intervention to improve well-being, reduce antipsychotic use and improve quality of life in people with dementia in care homes through person-centred care, management of agitation and non-drug approaches.
.
.
. Design
. This was a 5-year programme that consisted of six work packages. Work package 1 consisted of two systematic reviews of personalised psychosocial interventions for behavioural and psychological symptoms for people with dementia in care homes. Work package 2 consisted of a metasynthesis of studies examining implementation of psychosocial interventions, in addition to developing a draft Well-being and Health for people with Dementia (WHELD) programme. Work package 3 consisted of a factorial study of elements of the draft WHELD programme in 16 care homes. Work package 4 involved optimisation of the WHELD programme based on work package 3 data. Work package 5 involved a multicentre randomised controlled trial in 69 care homes, which evaluated the impact of the optimised WHELD programme on quality of life, agitation and overall neuropsychiatric symptoms in people with dementia. Work package 6 focused on dissemination of the programme.
.
.
. Setting
. This programme was carried out in care homes in the UK.
.
.
. Participants
. Participants of this programme were people with dementia living in care homes, and the health and care professionals providing treatment and care in these settings.
.
.
. Results
. Work package 1: reviews identified randomised controlled trials and qualitative evidence supporting the use of psychosocial approaches to manage behavioural symptoms, but highlighted a concerning lack of evidence-based training manuals in current use. Work package 2: the meta-analysis identified key issues in promoting the use of interventions in care homes. The WHELD programme was developed through adaptation of published approaches. Work package 3: the factorial trial showed that antipsychotic review alone significantly reduced antipsychotic use by 50% (odds ratio 0.17, 95% confidence interval 0.05 to 0.60). Antipsychotic review plus social interaction significantly reduced mortality (odds ratio 0.36, 95% confidence interval 0.23 to 0.57), but this group showed significantly worse outcomes in behavioural and psychological symptoms of dementia than the group receiving neither antipsychotic review nor social interaction (mean difference 7.37 symptoms, 95% confidence interval 1.53 to 13.22 symptoms). This detrimental impact was reduced when combined with social interaction (mean difference –0.44 points, 95% confidence interval –4.39 to 3.52 points), but with no significant benefits for agitation. The exercise intervention significantly improved neuropsychiatric symptoms (mean difference –3.58 symptoms, 95% confidence interval –7.08 to –0.09 symptoms) but not depression (mean difference –1.21 points, 95% confidence interval –4.35 to 1.93 points). Qualitative work with care staff provided additional insights into the acceptability and feasibility of the intervention. Work package 4: optimisation of the WHELD programme led to a final version that combined person-centred care training with social interaction and pleasant activities. The intervention was adapted for delivery through a ‘champion’ model. Work package 5: a large-scale, multicentre randomised controlled trial in 69 care homes showed significant benefit to quality of life, agitation and overall neuropsychiatric symptoms, at reduced overall cost compared with treatment as usual. The intervention conferred a statistically significant improvement in quality of life (Dementia Quality of Life Scale – Proxy z-score of 2.82, mean difference 2.54, standard error of measurement 0.88, 95% confidence interval 0.81 to 4.28, Cohen’s d effect size of 0.24; p = 0.0042). There were also statistically significant benefits in agitation (Cohen-Mansfield Agitation Inventory z-score of 2.68, mean difference –4.27, standard error of measurement 1.59, 95% confidence interval –7.39 to –1.15, Cohen’s d effect size of 0.23; p = 0.0076) and overall neuropsychiatric symptoms (Neuropsychiatric Inventory – Nursing Home version z-score of 3.52, mean difference –4.55, standard error of measurement 1.28, 95% confidence interval –7.07 to –2.02, Cohen’s d of 0.30; p &lt; 0.001). The WHELD programme contributed to significantly lower health and social care costs than treatment as usual (cost difference –£4740, 95% confidence interval –£6129 to –£3156). Focus groups were conducted with 47 staff up to 12 months after the end of work package 5, which demonstrated sustained benefits. Work package 6: the outputs of the programme were translated into general practitioner workshops and a British Medical Journal e-learning module, an updated national best practice guideline and a portfolio of lay and care home outreach activities.
.
.
. Limitations
. Residents with dementia were not involved in the qualitative work.
.
.
. Conclusions
. The WHELD programme is effective in improving quality of life and reducing both agitation and overall neuropsychiatric symptoms in people with dementia in care homes. It provides a structured training and support intervention for care staff, with lower overall costs for resident care than treatment as usual.
.
.
. Future work
. It will be important to consider the long-term sustainability of the WHELD programme and cost-effective means of long-term implementation.
.
.
. Trial registration
. Current Controlled Trials ISRCTN40313497 and ISRCTN62237498.
.
.
. Funding
. This project was funded by the National Institute for Health Research (NIHR) Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research; Vol. 8, No. 6. See the NIHR Journals Library website for further project information.
.

Objectives: Does intraoperative optimization of both depth of anesthesia and regional cerebral tissue oxygenation (rScO2) in elderly patients reduce postoperative cognitive decline (primary outcome) or delirium (secondary outcome)? Design: Prospective randomized controlled single blind trial. Setting: a single major urban teaching and university hospital and tertiary referral center. Participants: Patients, 65 years of age and older, undergoing elective coronary artery bypass graft surgery on cardiopulmonary bypass. Interventions: Intraoperative depth of anesthesia bispectral index (BIS) values were targeted at 50 ± 10. Regional cerebral tissue desaturations of more than 15% of the pre-induction value, or below 50%, were avoided. Measurements and Main Results: Eighty-two patients were included, and mean depth of anesthesia values using BIS were significantly higher during surgery in the intervention group with 40.6 (7.3) versus 35.4 (6.7) in the control group, mean (standard deviation), p = 0.004. The cognitive function was similar between the treatment and control groups at 6 weeks postoperatively with a Mini Mental State Examination (MMSE) of 27 (26,29) in the intervention group and an MMSE of 29 (27,29) in the control group, median (interquartile range), with p = 0.12. The authors observed a reduction in the incidence of delirium, occurring in 2.4% (n = 1) of patients in the intervention group and in 20% (n = 8) in the control group (p = 0.01). Conclusions: This pilot trial demonstrates that noninvasive target-controlled depth of anesthesia monitoring is feasible. Cognitive function at 6 weeks showed no difference between the treatment and control groups; however, postoperative delirium was reduced in the intervention group.

Background: the global health challenge of dementia is exceptional in size, cost and impact. It is the only top ten cause of death that cannot be prevented, cured or substantially slowed, leaving disease management, caregiver support and service innovation as the main targets for reduction of disease burden. Institutionalization of persons with dementia is common in western countries, despite patients preferring to live longer at home, supported by caregivers. Such complex health challenges warrant multicomponent interventions thoroughly implemented in daily clinical practice. This article describes the rationale, development, feasibility testing and implementation process of the LIVE@Home.Path trial. Methods: the LIVE@Home.Path trial is a 2-year, multicenter, mixed-method, stepped-wedge randomized controlled trial, aiming to include 315 dyads of home-dwelling people with dementia and their caregivers, recruited from 3 municipalities in Norway. The stepped-wedge randomization implies that all dyads receive the intervention, but the timing is determined by randomization. The control group constitutes the dyads waiting for the intervention. The multicomponent intervention was developed in collaboration with user-representatives, researchers and stakeholders to meet the requirements from the national Dementia Plan 2020. During the 6-month intervention period, the participants will be allocated to a municipal coordinator, the core feature of the intervention, responsible for regular contact with the dyads to facilitate L: Learning, I: Innovation, V: Volunteering and E: Empowerment (LIVE). The primary (Continued on next page) outcome is resource utilization. This is measured by the Resource Utilization in Dementia (RUD) instrument and the Relative Stress Scale (RSS), reflecting that resource utilization is more than the actual time required for caring but also how burdensome the task is experienced by the caregiver. Discussion: We expect the implementation of LIVE to lead to a pathway for dementia treatment and care which is cost-effective, compared to treatment as usual, and will support high-quality independent living, at home. Trial registration: ClinicalTrials.gov: NCT04043364. Registered on 15 March 2019.

Introduction: Pimavanserin is a selective 5-HT2A inverse agonist/antagonist approved for treating hallucinations and delusions associated with Parkinson's disease psychosis (PDP). Results from short-term, placebo-controlled studies demonstrated a positive benefit/risk profile. This multi-year, open-label study assessed long-term safety and tolerability of pimavanserin. Methods: This was an open-label extension (OLE) study in patients previously completing a double-blind, placebo-controlled study or a previous OLE study. Safety was evaluated from adverse events (AEs), clinical laboratory results, motor symptoms, electrocardiograms (ECG), and mortality. Durability of response was assessed from the Clinical Global Impression-Severity (CGI-S) scale and Caregiver Burden Scale (CBS). Results: of 459 participants treated in this OLE study (average age 71.2 years), the median duration of treatment was 454 days. Over the entire study period (approximately 11 years), ≥1 AE occurred in 392 (85.4%) patients; the majority were of mild to moderate intensity, with fall (32.0%), urinary tract infection (19.0%), and hallucination (13.7%) most common. Serious AEs occurred in 188 (41.0%) patients, and an AE leading to study termination or dose discontinuation occurred in 133 (29.0%) patients. Sixty-one patients died, 59 (12.9%) during treatment or within 30 days after the last dose of study drug; the observed mortality rate was 6.45 per 100 patient-years of exposure. Mean scores for the CGI-S scale and CBS generally remained stable for up to 192 weeks (>3.5 years). Conclusions: Long-term treatment with pimavanserin 34 mg once daily demonstrated a favorable benefit/risk profile with no unexpected safety concerns. Mortality rates suggested no increased risk following long-term treatment.

BackgroundMinocycline 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.ObjectivesThe 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.DesignA Phase II, three-arm, randomised, double-blind, multicentre trial with a semifactorial design. Participants continued on trial treatment for up to 24 months.SettingPatients 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).ParticipantsPatients 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.InterventionPatients 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 measuresPrimary 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.ResultsBetween 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 

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

BACKGROUND/OBJECTIVES: Functional status is one of the most important markers of well-being in older adults, but the drivers of functional decline in dementia are not well known. The aim of our work was to study the association of neuropsychiatric symptoms (NPSs) with functional decline over 5 years in newly diagnosed people with Alzheimer´s disease (AD) and Lewy body dementia (LBD). DESIGN: Secondary analysis of the Dementia Study of Western Norway longitudinal cohort study. SETTING: Multicenter study conducted in memory clinics in western Norway. PARTICIPANTS: We included a total of 196 patients newly diagnosed with AD (n = 111) and LBD (n = 85), followed up annually for 5 years. MAIN OUTCOMES AND MEASURES: the outcome was the rapid disability rating scale (items 1-13). Linear mixed-effects models were used for analysis with the total score of the Norwegian Neuropsychiatric Inventory (NPI) as a predictor measured either at baseline or longitudinally, adjusted for potential confounders, including cognition. Effect modification was checked by introducing interactions with NPI score and stratifying by diagnosis. RESULTS: the total NPI score longitudinal course was associated with functional decline in both AD and LBD. At baseline, the total NPI score predicted functional decline in AD. CONCLUSION: NPSs were associated with the rate of functional decline in people with AD and LBD, independent of cognitive impairment. These results highlight the relevance of early detection and intervention of NPSs, which may also reduce functional decline. J Am Geriatr Soc 68:2257-2263, 2020.

Small vessel disease (SVD) is associated with cognitive impairment in older age and be implicated in vascular dementia. Post-mortem studies show proliferation of activated microglia in the affected white matter. However, the role of inflammation in SVD pathogenesis is incompletely understood and better biomarkers are needed. We hypothesized that expression of the 18 kDa translocator protein (TSPO), a marker of microglial activation, would be higher in SVD. Positron emission tomography (PET) was performed with the second-generation TSPO ligand [11C]PBR28 in 11 participants with SVD. TSPO binding was evaluated by a two-tissue compartment model, with and without a vascular binding component, in white matter hyperintensities (WMH) and normal-appearing white matter (NAWM). In post-mortem tissue, in a separate cohort of individuals with SVD, immunohistochemistry was performed for TSPO and a pan-microglial marker Iba1. Kinetic modeling showed reduced tracer volume and blood volume fraction in WMH compared with NAWM, but a significant increase in vascular binding. Vascular [11C]PBR28 binding was also increased compared with normal-appearing white matter of healthy participants free of SVD. Immunohistochemistry showed a diffuse increase in microglial staining (with Iba1) in sampled tissue in SVD compared with control samples, but with only a subset of microglia staining positively for TSPO. Intense TSPO staining was observed in the vicinity of damaged small blood vessels, which included perivascular macrophages. The results suggest an altered phenotype of activated microglia, with reduced TSPO expression, in the areas of greatest white matter ischemia in SVD, with implications for the interpretation of TSPO PET studies in older individuals or those with vascular risk factors.

Objective: Prevalence of Lewy body dementias (LBD) is second only to Alzheimer's disease (AD) among people with neurodegenerative dementia. LBD cause earlier mortality, more intense neuropsychiatric symptoms, more caregivers’ burden, and higher costs than AD. The molecular mechanisms underlying LBD are largely unknown. As advancing molecular level mechanistic understanding is essential for identifying reliable peripheral biomarkers and novel therapeutic targets for LBD, the authors aimed to identify differentially expressed genes (DEG), and dysfunctional molecular networks in postmortem LBD brains. Methods: the authors investigated the transcriptomics of postmortem anterior cingulate and dorsolateral prefrontal cortices of people with pathology-verified LBD using next-generation RNA-sequencing. The authors verified the identified DEG using high-throughput quantitative polymerase chain reactions. Functional implications of identified DEG and the consequent metabolic reprogramming were evaluated by Ingenuity pathway analyses, genome-scale metabolic modeling, reporter metabolite analyses, and in silico gene silencing. Results: the authors identified and verified 12 novel DEGs (MPO, SELE, CTSG, ALPI, ABCA13, GALNT6, SST, RBM3, CSF3, SLC4A1, OXTR, and RAB44) in LBD brains with genome-wide statistical significance. The authors documented statistically significant down-regulation of several cytokine genes. Identified dysfunctional molecular networks highlighted the contributions of mitochondrial dysfunction, oxidative stress, and immunosenescence toward neurodegeneration in LBD. Conclusion: Our findings support that chronic microglial activation and neuroinflammation, well-documented in AD, are notably absent in LBD. The lack of neuroinflammation in LBD brains was corroborated by statistically significant down-regulation of several inflammatory markers. Identified DEGs, especially down-regulated inflammatory markers, may aid distinguishing LBD from AD, and their biomarker potential warrant further investigation.

PURPOSE OF REVIEW: to review the incidence, treatment and genetics of psychosis in people with mild cognitive impairment (MCI) and Alzheimer's disease (AD). RECENT FINDINGS: Psychosis in Alzheimer's disease (AD) has an incidence of ~ 10% per year. There is limited evidence regarding psychological interventions. Pharmacological management has focused on atypical antipsychotics, balancing modest benefits with evidence of long-term harms. The 5HT2A inverse agonist pimavanserin appears to confer benefit in PD psychosis with initial evidence of benefit in AD. Cholinesterase inhibitors give modest benefits in DLB psychosis. The utility of muscarinic agonists, lithium, glutamatergic and noradrenergic modulators needs further study. Recent work has confirmed the importance of psychosis in MCI as well as AD. The lack of evidence regarding psychological therapies is an urgent knowledge gap, but there is encouraging evidence for emerging pharmacological treatments. Genetics will provide an opportunity for precision medicine and new treatment targets.

The prodromal phase of dementia with Lewy bodies (DLB) includes (1) mild cognitive impairment (MCI), (2) delirium-onset, and (3) psychiatric-onset presentations. The purpose of our review is to determine whether there is sufficient information yet available to justify development of diagnostic criteria for each of these. Our goal is to achieve evidence-based recommendations for the recognition of DLB at a predementia, symptomatic stage. We propose operationalized diagnostic criteria for probable and possible mild cognitive impairment with Lewy bodies, which are intended for use in research settings pending validation for use in clinical practice. They are compatible with current criteria for other prodromal neurodegenerative disorders including Alzheimer and Parkinson disease. Although there is still insufficient evidence to propose formal criteria for delirium-onset and psychiatric-onset presentations of DLB, we feel that it is important to characterize them, raising the index of diagnostic suspicion and prioritizing them for further investigation.

Background: Sleep problems and mental health difficulties are common in autistic children and young adults. However, these problems have seldom been studied in older autistic adults, or in older adults with elevated autistic traits. Method: Cross-sectional data was examined from 13,897 adults aged 50–81 years taking part in the PROTECT study, who reported whether they experienced persistent socio-communicative autistic traits. Approximately 1%, 187 individuals, were identified as endorsing high autistic traits in childhood and currently, henceforth ‘Autism Spectrum Trait’ (AST) group. An age- and gender-matched comparison group was formed of 6740 individuals who endorsed no autistic traits, henceforth ‘Control Older Adults’ (COA) group. Differences between AST and COA groups were explored in self-reported sleep behaviors, and in depression and anxiety symptoms. Results: AST and COA groups reported similar sleep duration and depth, and nighttime waking frequency. However, the AST group reported significantly more problems with falling asleep, morning drowsiness, and lower sleep quality/satisfaction than COA. More AST adults reported sleep problems past cut-off, as well as clinical levels of depression and anxiety, compared to COA. Adults in both groups who met criteria for high sleep problems experienced more mental health difficulties than those with few sleep problems. However, even amongst those without depression/anxiety, the AST group reported more sleep problems than the COA. Conclusions: These associations suggest that older adults with high autistic traits, like diagnosed autistic children/young adults, may experience poorer sleep and more mental health difficulties than those with low autistic traits. Further work is needed to see whether these results extend to older individuals meeting diagnostic criteria for autism.

Objectives: to examine the bidirectional temporal relationship between depressive symptoms and cognition in relation to risk, reaction, and prodrome. Design: Cross-lag analysis of longitudinal data collected online at baseline and 12-month follow-up. Setting and Participants: a United Kingdom population cohort of 11,855 participants aged 50 years and over. Measures: Patient Health Questionnaire-9 (depressive symptoms), cognitive measures: Paired Associate Learning, Verbal Reasoning, Spatial Working Memory, and Digit Span. Results: Depressive symptoms predicted a decline in paired associates learning [β = −.020, P =. 013, (95% confidence interval [CI], ‒.036, −.004)] and verbal reasoning [β = −.014, P =. 016, (95% CI ‒.025, −.003)] but not vice versa. Depressive symptoms predicted [β = −.043, P <. 001, (95% CI ‒.060, −.026); β = −.029, P <. 001, (95% CI ‒.043, −.015)] and were predicted by [β = −.030, P = <. 001, (95% CI ‒.047, −.014); β = −.025, P =. 003, (95% CI ‒.041, −.009)], a decline in spatial working memory and verbal digit span, respectively. Conclusions and Implications: Depressive symptoms may be either a risk factor or prodrome for cognitive decline. In addition, a decline in attention predicts depressive symptoms. Clinical implications and implications for further research are discussed.

Introduction Understanding the natural course of neuropsychiatric symptoms (NPS) in dementia is important for planning patient care and trial design, but few studies have described the long-term course of NPS in individuals.Method Primary inclusion of 223 patients with suspected mild dementia from general practice were followed by annual assessment, including the Neuropsychiatric Inventory (NPI), for up to 12 years. Total and item NPI scores were classified as stable, relapsing, single episodic or not present based on 4.96 (s.d. 2.3) observations (98% completeness of longitudinal data) for 113 patients with Alzheimer's disease and 84 patients with LBD (68 dementia with Lewy bodies and 16 Parkinson's disease dementia).Results We found that 80% had stable NPI total ≥1, 50% had stable modest NPI total ≥12 and 25% had stable NPI total ≥24 scores. Very severe NPS (≥48) were mostly single episodes, but 8% of patients with Alzheimer's disease had stable severe NPS. Patients with Alzheimer's disease and the highest 20% NPI total scores had a more stable or relapsing course of four key symptoms: aberrant motor behaviour, aggression/agitation, delusions and irritability (odds ratio 55, P < 0.001). This was not seen in LBD. Finally, 57% of patients with Alzheimer's disease and 84% of patients with LBD had reoccurring psychotic symptoms.Conclusions We observed a highly individual course of NPS, with most presenting as a single episode or relapsing; a stable course was less common, especially in LBD. These findings demonstrate the importance of an individualised approach (i.e. personalised medicine) in dementia care.

We have utilised the transcriptional response of lung epithelial cells following infection by the original Severe Acute Respiratory Syndrome coronavirus (SARS) to identify repurposable drugs for COVID-19. Drugs best able to recapitulate the infection profile are highly enriched for antiviral activity. Nine of these have been tested against SARS-2 and found to potently antagonise SARS-2 infection/replication, with a number now being considered for clinical trials. It is hoped that this approach may serve to broaden the spectrum of approved drugs that should be further assessed as potential anti-COVID-19 agents and may help elucidate how this seemingly disparate collection of drugs are able to inhibit SARS-2 infection/replication.

Visual hallucinations are common in older people and are especially associated with ophthalmological and neurological disorders, including dementia and Parkinson's disease. Uncertainties remain whether there is a single underlying mechanism for visual hallucinations or they have different disease-dependent causes. However, irrespective of mechanism, visual hallucinations are difficult to treat. The National Institute for Health Research (NIHR) funded a research programme to investigate visual hallucinations in the key and high burden areas of eye disease, dementia and Parkinson's disease, culminating in a workshop to develop a unified framework for their clinical management. Here we summarise the evidence base, current practice and consensus guidelines that emerged from the workshop.Irrespective of clinical condition, case ascertainment strategies are required to overcome reporting stigma. Once hallucinations are identified, physical, cognitive and ophthalmological health should be reviewed, with education and self-help techniques provided. Not all hallucinations require intervention but for those that are clinically significant, current evidence supports pharmacological modification of cholinergic, GABAergic, serotonergic or dopaminergic systems, or reduction of cortical excitability. A broad treatment perspective is needed, including carer support. Despite their frequency and clinical significance, there is a paucity of randomised, placebo-controlled clinical trial evidence where the primary outcome is an improvement in visual hallucinations. Key areas for future research include the development of valid and reliable assessment tools for use in mechanistic studies and clinical trials, transdiagnostic studies of shared and distinct mechanisms and when and how to treat visual hallucinations.

Heterozygous mutations in GBA1, the gene which encodes the lysosomal enzyme glucocerebrosidase (GCase), are a strong genetic risk factor for the development of Lewy body dementia (LBD). Until this point however, recapitulation of the symptoms and pathology of LBD has been limited to a homozygous GBA1 mouse model which genetically and enzymatically reflects the lysosomal storage disorder Gaucher's disease. This study reports for the first time cognitive impairment by two independent behavioural tests in heterozygous GBA1 mutant mice (D409V/WT) which demonstrate significant cognitive impairment by the age of 12 months. Furthermore, reductions in GBA1 GCase enzyme activity within the brain reflects levels seen in sporadic and GBA1 mutant LBD patients. While there is no overt deposition of Lewy bodies within the hippocampus, alterations to cholinergic machinery and glial proliferation are evident, both pathological features of LBD. Interestingly, we also describe the novel finding of significantly reduced GBA2 GCase enzyme activity specifically within the hippocampus. This suggests that reduced GBA1 GCase enzyme activity dis-equilibrates the finely balanced glycosphingolipid metabolism pathway and that reductions in GBA2 GCase enzyme could contribute to the pathological and behavioural effects seen. Overall, this study presents evidence to suggest that pathological hallmarks associated with LBD specifically affecting brain regions intrinsically linked with cognition are present in the D409V/WT mice. In the absence of Lewy body deposition, the D409V/WT mice could be considered an early pre-clinical model of LBD with potential for drug discovery. Since few robust pre-clinical models of LBD currently exist, with further characterization, the mouse model described here may contribute significantly to developments in the LBD field.

BACKGROUND: Alzheimer's disease (AD) is an incurable complex neurodegenerative condition with no new therapies licensed in the past 20 years. AD progression is characterized by the up- and downregulation of distinct biological processes that can be followed through the expression level changes of associated genes and gene networks. OBJECTIVE: Our study aims to establish a multiplex gene expression tracking platform to follow disease progression in an animal model facilitating the study of treatment paradigms. METHODS: We have established a multiplex platform covering 47 key genes related to immunological, neuronal, mitochondrial, and autophagy cell types and processes that capture disease progression in the 5×FAD mouse model. RESULTS: We show that the immunological response is the most pronounced change in aged 5×FAD mice (8 months and above), and in agreement with early stage human disease samples, observe an initial downregulation of microglial genes in one-month-old animals. The less dramatic downregulation of neuronal and mitochondrial gene sets is also reported. CONCLUSION: This study provides the basis for a quantitative multi-dimensional platform to follow AD progression and monitor the efficacy of treatments in an animal model.

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

Introduction: People with dementia may be unable to verbally express pain and suffer from untreated pain. Use of analgesics in people with dementia has increased during the last decade, in particular opioid analgesics with high potential for adverse effects. Areas covered: This article presents a systematic review of the current evidence for safety and tolerability of analgesic drugs from randomized controlled trials in people with dementia. Relevant trials were identified by a literature search in the EMBASE, MEDLINE, and Cochrane databases from inception to November 2018. The search included the main terms ‘dementia’ and ‘analgesic’ or their subterms, and was filtered to limit results to clinical trials. Expert opinion: Although pain treatment is increasingly recognized as an important clinical issue in people with advanced dementia, there is currently a lack of evidence to support safety evaluations of commonly used analgesics in this group. To inform treatment decisions and enable care providers to appropriately monitor patients at risk of adverse effects, it is necessary to conduct well-designed clinical trials to investigate the relative efficacy and safety of analgesics in people with dementia, with particular emphasis on harmful effects of long-term opioid use as well as short-term use of nonsteroidal anti-inflammatory drugs.

Introduction Recent failures of potential novel therapeutics for Alzheimer's disease (AD) have prompted a drive towards clinical studies in prodromal or preclinical states. However, carrying out clinical trials in early disease stages is extremely challenging-a key reason being the unfeasibility of using classical outcome measures of dementia trials (eg, conversion to dementia) and the lack of validated surrogate measures so early in the disease process. The Deep and Frequent Phenotyping (DFP) study aims to resolve this issue by identifying a set of markers acting as indicators of disease progression in the prodromal phase of disease that could be used as indicative outcome measures in proof-of-concept trials. Methods and analysis the DFP study is a repeated measures observational study where participants will be recruited through existing parent cohorts, research interested lists/databases, advertisements and memory clinics. Repeated measures of both established (cognition, positron emission tomography (PET) imaging or cerebrospinal fluid (CSF) markers of pathology, structural MRI markers of neurodegeneration) and experimental modalities (functional MRI, magnetoencephalography and/or electroencephalography, gait measurement, ophthalmological and continuous smartphone-based cognitive and other assessments together with experimental CSF, blood, tear and saliva biomarkers) will be performed. We will be recruiting male and female participants aged >60 years with prodromal AD, defined as absence of dementia but with evidence of cognitive impairment together with AD pathology as assessed using PET imaging or CSF biomarkers. Control participants without evidence of AD pathology will be included at a 1:4 ratio. Ethics and dissemination the study gained favourable ethical opinion from the South Central-Oxford B NHS Research Ethics Committee (REC reference 17/SC/0315; approved on 18 August 2017; amendment 13 February 2018). Data will be shared with the scientific community no more than 1 year following completion of study and data assembly.

Alzheimer's disease is a complex disorder encompassing multiple pathological features with associated genetic and molecular culprits. However, target-based therapeutic strategies have so far proved ineffective. The aim of this study is to develop a methodology harnessing the transcriptional changes associated with Alzheimer's disease to develop a high content quantitative disease phenotype that can be used to repurpose existing drugs. Firstly, the Alzheimer's disease gene expression landscape covering severe disease stage, early pathology progression, cognitive decline and animal models of the disease has been defined and used to select a set of 153 drugs tending to oppose disease-associated changes in the context of immortalised human cancer cell lines. The selected compounds have then been assayed in the more biologically relevant setting of iPSC-derived cortical neuron cultures. It is shown that 51 of the drugs drive expression changes consistently opposite to those seen in Alzheimer's disease. It is hoped that the iPSC profiles will serve as a useful resource for drug repositioning within the context of neurodegenerative disease and potentially aid in generating novel multi-targeted therapeutic strategies.

Introduction: Heterogeneity of outcomes in Alzheimer's disease (AD) clinical trials necessitates large sample sizes and contributes to study failures. This analysis determined whether mild-to-moderate AD populations could be enriched for cognitive decline based on apolipoprotein (APOE) ε4 genotype, family history of AD, and amyloid abnormalities. Methods: Modeling estimated the number of randomized patients needed to detect a 2-point treatment difference on the AD Assessment Scale–Cognitive subscale using placebo data from three randomized, double-blind trials (ClinicalTrials.gov Identifiers: NCT01955161, NCT02006641, and NCT02006654). Results: an 80% power to detect a 2-point treatment effect required the randomization of 148 amyloid-positive patients; 178 ε4 homozygous or amyloid-positive patients; and 231 ε4 homozygous, family history-positive, or amyloid-positive patients, compared with 1619 unenriched patients (per arm). Discussion: Enrichment in mild-to-moderate AD clinical trials can be achieved using combinations of biomarkers/risk factors to increase the likelihood of observing potential treatment effects.

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

Alzheimer's disease (AD) is the most common form of dementia characterized by substantial neuronal loss and progressive brain atrophy. Animal studies have suggested that the process of adult neurogenesis might be altered at the earliest phases of disease onset. The relationship between AD progression and adult neurogenesis in the human brain is, however, not well understood. Here, we present a systematic review of the postmortem studies that investigated changes in human adult neurogenesis in the AD brain. We present findings from 11 postmortem studies that were identified by a systematic search within the literature, focusing on what markers of neurogenesis were used, which stages of AD were investigated, and whether the studies had any confounding information that could potentially hinder clear interpretation of the presented data. In addition, we also review studies that examined transcriptomic changes in human AD postmortem brains and reveal upregulated expression of neural progenitor and proliferation markers and downregulated expression of later neurogenic markers in AD. Taken together, the existing literature seems to suggest that the overall level of human adult neurogenesis is reduced during the later stages of AD, potentially due to failed maturation and integration of new-born neurons. Further investigations using complementary methods such as in vitro disease modeling will be helpful to understand the exact molecular mechanisms underlying such pattern of change and to determine whether neurogenesis can be an effective therapeutic target for early intervention.

Background: Chronic pain conditions, especially osteoarthritis (OA), are as common in individuals with Alzheimer's disease (AD) as in the general elderly population, which results in detrimental impact on patient's quality of life. However, alteration in perception of pain in AD coupled with deteriorating ability to communicate pain sensations often result in under-diagnosis and inappropriate management of pain. Therefore, a better understanding of mechanisms in chronic pain processing in AD is needed. Here, we explored the development and progression of OA pain and the effect of analgesics in a transgenic mouse model of AD. Methods: Unilateral OA pain was induced chemically, via an intra-articular injection of monosodium iodoacetate (MIA) in the left knee joint of AD-mice (TASTPM) and age- and gender-matched C57BL/6J (WT). Pharmacological and biochemical assessments were conducted in plasma and spinal cord tissue. Results: MIA resulted in hind paw mechanical hypersensitivity (allodynia), initiating on day 3, in TASTPM and WT controls. However, from 14 to 28 days, TASTPM displayed partial attenuation of allodynia and diminished spinal microglial response compared to WT controls. Naloxone, an opioid antagonist, re-established allodynia levels as observed in the WT group. Morphine, an opioid agonist, induced heightened analgesia in AD-mice whilst gabapentin was devoid of efficacy. TASTPM exhibited elevated plasma level of β-endorphin post-MIA which correlated with impaired allodynia. Conclusions: These results indicate an alteration of the opioidergic system in TASTPM as possible mechanisms underlying impaired persistent pain sensitivity in AD. This work provides basis for re-evaluation of opioid analgesic use for management of pain in AD. Significance: This study shows attenuated pain-like behaviour in a transgenic mouse model of Alzheimer's disease due to alterations in the opioidergic system and central plasticity mechanisms of persistent pain.

INTRODUCTION: to examine whether an optimized intervention is a more cost-effective option than treatment as usual (TAU) for improving agitation and quality of life in nursing home residents with clinically significant agitation and dementia. METHODS: a cost-effectiveness analysis within a cluster-randomized factorial study in 69 care homes with 549 residents was conducted. Each cluster was randomized to receive either the Well-being and Health for people with Dementia (WHELD) intervention or TAU for nine months. Health and social care costs, agitation, and quality of life outcomes were evaluated. RESULTS: Improvements in agitation and quality of life were evident in residents allocated to the WHELD intervention group. The additional cost of the WHELD intervention was offset by the higher health and social care costs incurred by TAU group residents (mean difference, £2103; 95% confidence interval, -13 to 4219). DISCUSSION: the WHELD intervention has clinical and economic benefits when used in residents with clinically significant agitation.

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

Abstract
. Associations of awareness of age-related change (AARC) with emotional and physical well-being and cognitive functioning were synthesised in a systematic review with a correlational random-effects meta-analysis. Twelve studies were included in the review, nine exploring the association between AARC and emotional well-being and eleven exploring the association between AARC and physical well-being. No study explored the association between AARC and cognition. There is evidence of weak associations between higher level of AARC gains and better emotional well-being and between higher level of AARC losses and both poorer emotional well-being and poorer physical well-being. There was no association between AARC gains and physical well-being. There is some indication that AARC gains and losses can play a role in emotional well-being and that AARC losses are associated with physical well-being but these associations are weak. Due to the limited number of studies and their high heterogeneity, interpretation of these results remains unclear.

Abstract Associations of awareness of age-related change (AARC) with emotional and physical well-being and cognitive functioning were synthesised in a systematic review with a correlational random-effects meta-analysis. Twelve studies were included in the review, nine exploring the association between AARC and emotional well-being and eleven exploring the association between AARC and physical well-being. No study explored the association between AARC and cognition. There is evidence of weak associations between higher level of AARC gains and better emotional well-being and between higher level of AARC losses and both poorer emotional well-being and poorer physical well-being. There was no association between AARC gains and physical well-being. There is some indication that AARC gains and losses can play a role in emotional well-being and that AARC losses are associated with physical well-being but these associations are weak. Due to the limited number of studies and their high heterogeneity, interpretation of these results remains unclear.

Objectives: Behavioral and psychological symptoms of dementia (BPSD) are nearly universal in dementia, a condition occurring in more than 40 million people worldwide. BPSD present a considerable treatment challenge for prescribers and healthcare professionals. Our purpose was to prioritize existing and emerging treatments for BPSD in Alzheimer's disease (AD) overall, as well as specifically for agitation and psychosis. Design: International Delphi consensus process. Two rounds of feedback were conducted, followed by an in-person meeting to ratify the outcome of the electronic process. Settings: 2015 International Psychogeriatric Association meeting. Participants: Expert panel comprised of 11 international members with clinical and research expertise in BPSD management. Results: Consensus outcomes showed a clear preference for an escalating approach to the management of BPSD in AD commencing with the identification of underlying causes. For BPSD overall and for agitation, caregiver training, environmental adaptations, person-centered care, and tailored activities were identified as first-line approaches prior to any pharmacologic approaches. If pharmacologic strategies were needed, citalopram and analgesia were prioritized ahead of antipsychotics. In contrast, for psychosis, pharmacologic options, and in particular, risperidone, were prioritized following the assessment of underlying causes. Two tailored non-drug approaches (DICE and music therapy) were agreed upon as the most promising non-pharmacologic treatment approaches for BPSD overall and agitation, with dextromethorphan/quinidine as a promising potential pharmacologic candidate for agitation. Regarding future treatments for psychosis, the greatest priority was placed on pimavanserin. Conclusions: This international consensus panel provided clear suggestions for potential refinement of current treatment criteria and prioritization of emerging therapies.

Introduction: Safety warnings relating to antipsychotic-associated stroke among older persons in the UK and Italy were issued. However, the impact of these safety warnings on stroke risk has not been measured to date. Objective: the aim of this study was to measure the change in stroke incidence after two safety warnings in both the UK and Italy. Method: a cohort study was conducted using electronic medical records representative of the UK (The Health Improvement Network) and Italy (Health Search—IQVIA Health LPD), containing data on 11 million and 1 million patients, respectively. After each drug safety warning, elderly antipsychotic new initiators were propensity-score matched 1:1:1 on antipsychotic initiators before any safety warning. Stroke incidence within 6 months of antipsychotic initiation, using an intention-to-treat approach, was the main outcome. Results: in the UK and Italy, 6342 and 7587 elderly antipsychotic initiators were identified, respectively. A 42% stroke incidence reduction was seen in the UK after the first safety warning [42.3 (95% confidence interval (CI) 35.2–50.8) vs. 24.4 [95% CI 19.0–31.2] events per 1000 person-years (PYs)], while there was a 60% stroke incidence reduction after the second warning (16.9 [95% CI 12.2–23.4] events per 1000 PYs) compared to before the first warning. There was no significant reduction in stroke incidence in Italy. Conclusion: Antipsychotic safety warnings were followed by a reduction in stroke incidence among older antipsychotic users in the UK, but not Italy.

This open-label extension study evaluated the long-term safety and tolerability of idalopirdine 60 mg/day as adjunctive therapy in patients with mild-moderate Alzheimer's disease (AD). This extension study was a continuation of Studies 1 and 2 of the Phase III development program for idalopirdine and comprised a 28-week open-label treatment period ("OLEX") and a subsequent 24-week open-label treatment period with memantine ("MEMOLEX") in selected patients. The previous studies had shown no evidence of efficacy with idalopirdine as adjunctive treatment to donepezil but with good tolerability (of 1,791 patients randomized, 1,609 [90] completed the double-blind studies). of those, 1,463 patients (91) entered the open-label extension study. During the 28-week OLEX period, the percentage of patients having treatment-emergent adverse events (TEAEs) ranged between 51 and 59 across the treatment groups originating from the lead-in studies. During the subsequent 24-week MEMOLEX period, 51 of the patients had TEAEs. Increases in liver enzymes (occurring in 1-3 of trial participants) were transient and no new safety signals were observed with longer term exposure. No consistent effects demonstrating benefits with idalopirdine were observed on efficacy parameters when patients transitioned to 60 mg in the extension study. Overall, idalopirdine was safe and well tolerated when added to donepezil, and when memantine was added to a prior combination of idalopirdine and donepezil. There were no new safety signals observed with up to 18 months of exposure at the described doses to idalopirdine.

BACKGROUND: Pimavanserin is a 5-HT2A receptor inverse agonist/antagonist and is approved in the United States for the treatment of hallucinations and delusions associated with Parkinson's disease psychosis. OBJECTIVE: Evaluate the efficacy of pimavanserin on symptoms of psychosis in patients with Alzheimer's disease (AD). DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Nursing home residents. PARTICIPANTS: Patients with AD psychosis. INTERVENTIONS: Pimavanserin 34 mg or placebo daily for 12 weeks. MEASUREMENTS: the primary endpoint was mean change from baseline at Week 6 on the Neuropsychiatric Inventory-Nursing Home Version psychosis score (NPI-NH-PS). In the prespecified subgroup analysis, the mean change in NPI-NH-PS and the responder rates among those with baseline NPI-NH-PS ≥12 were evaluated. RESULTS: of 181 patients randomized (n=90 pimavanserin; n=91 placebo), 57 had baseline NPI-NH-PS ≥12 (n=27 pimavanserin; n=30 placebo). In this severe subgroup, large treatment effects were observed (delta=-4.43, Cohen's d=-0.73, p=0.011), and ≥30% improvement was 88.9% vs. 43.3% (p

ABSTRACTObjectives:In this large population study, we set out to examine the profile of mild behavioral impairment (MBI) by using the Mild Behavioral Impairment Checklist (MBI-C) and to explore its factor structure when employed as a self-reported and informant-rated tool.Design:This was a population-based cohort study.Setting:Participants were recruited from the Platform for Research Online to Investigate Genetics and Cognition in Aging study (https://www.protect-exeter.org.uk).Participants:A total of 5,742 participant-informant dyads participated in the study.Measurements:Both participants and informants completed the MBI-C. The factor structure of the MBI-C was evaluated by exploratory factor analysis.Results:The most common MBI-C items, as rated by self-reported and informants, related to affective dysregulation (mood/anxiety symptoms), being present in 34% and 38% of the sample, respectively. The least common items were those relating to abnormal thoughts and perception (psychotic symptoms) (present in 3% and 6% of the sample, respectively). Only weak correlations were observed between self-reported and informant-reported MBI-C responses. Exploratory factor analysis for both sets of respondent answers indicated that a five-factor solution for the MBI-C was appropriate, reflecting the hypothesized structure of the MBI-C.Conclusion:This is the largest and most detailed report on the frequency of MBI symptoms in a nondementia sample. The full spectrum of MBI symptoms was present in our sample, whether rated by self-reported or informant report. However, we show that the MBI-C performs differently in self-reported versus informant-reported situations, which may have important implications for the use of the questionnaire in clinic and research.

Background: Hip fracture represents a substantial acute inflammatory trauma, which may constitute a significant insult to the degenerating brain. Research suggests that an injury of this kind can affect memory and thinking in the future but it is unclear whether, and how, inflammatory trauma injures the brain. The impact of Acute SystematiC inflammation upon cerebRospinal fluId and blood BiomarkErs of brain inflammation and injury in Dementia: a study in acute hip fracture patients (ASCRIBED) explores this relationship, to understand the effect of inflammation on the progression of dementia. Methods: This protocol describes a multi-centre sample collection observational study. The study utilises the unique opportunity provided by hip fracture operations undertaken via spinal anaesthesia to collect cerebrospinal fluid (CSF) and blood, to investigate the impact of acute brain inflammation caused by hip fracture on the exacerbation of dementia. We will recruit 200 hip fracture patients with a diagnosis or evidence of dementia; and 200 hip fracture patients without dementia. We will also recruit 'Suitable informants', individuals in regular contact with the patient, to provide further proxy evidence of a patient's potential cognitive decline. We will compare these 400 samples with existing CSF and blood samples from a cohort of dementia patients who had not experienced a systemic inflammatory response due to injury. This will provide a comparison between patients with and without dementia who are suffering a systemic inflammatory response; with stable patients living with dementia. Discussion: We will test the hypothesis that hip fracture patients living with dementia show elevated markers of brain inflammation, as well as neuronal injury and Alzheimer-related plaque pathology, in comparison to (1) stable patients living with dementia and (2) hip fracture patients without dementia, as measured by biomarkers in CSF and blood. The findings will address the hypothesis that systemic inflammatory events can exacerbate underlying dementia and inform the search for new treatments targeting inflammation in dementia. Trial registration: ISRCTN43803769. Registered 11 May 2017.

OBJECTIVE: to synthesize the evidence across longitudinal studies comparing survival in dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). METHODS: We conducted a systematic review and meta-analysis of studies comparing survival in clinically diagnosed DLB to AD. Longitudinal cohort studies were identified through a systematic search of major electronic databases from inception to May 2018. A random effects meta-analysis was performed to calculate survival time and relative risk of death. RESULTS: Overall, 11 studies were identified including 22,952 patients with dementia: 2029 with DLB (mean diagnosis age 76.3; 47% female) compared with 20,923 with AD (mean diagnosis age 77.2; 65.1% female). Average survival time in DLB from diagnosis was 4.11 years (SD ± 4.10) and in AD 5.66 (SD ± 5.32) years, equating to a 1.60 (95% CI: -2.44 to -0.77) years shorter survival in DLB (p 

OBJECTIVES: to investigate if the multicomponent intervention of the COSMOS trial, combining communication, systematic pain management, medication review, and activities, improved quality of life (QoL) in nursing home patients with complex needs. DESIGN: Multicenter, cluster-randomized, single-blinded, controlled trial. SETTING: Thirty-three nursing homes with 67 units (clusters) from 8 Norwegian municipalities. PARTICIPANTS: Seven hundred twenty-three patients with and without dementia (≥65 years) were cluster randomized to usual care or intervention in which health care staff received standardized education and on-site training for 4 months with follow-up at month 9. MEASUREMENTS: Primary outcome was change in QoL as measured by QUALIDEM (QoL dementia scale); QUALID (QoL late-stage dementia scale), and EQ-VAS (European QoL-visual analog scale) from baseline to month 4. Secondary outcomes were activities of daily living (ADL), total medication, staff distress, and clinical global impressions of change (CGIC). RESULTS: During the active intervention, all 3 QoL measures worsened, 2 significantly (QUALID P = .04; QUALIDEM P = .002). However, follow-up analysis from month 4 to 9 showed an intervention effect for EQ-VAS (P = .003) and QUALIDEM total score (P = .01; care relationship P = .02; positive affect P = .04, social relations P = .01). The secondary outcomes of ADL function, reduction of medication (including psychotropics) and staff distress, improved significantly from baseline to month 4. Intervention effects were also demonstrated for CGIC at month 4 (P = .023) and 9 (P = .009), mainly because of deterioration in the control group. CONCLUSION AND IMPLICATIONS: Temporarily, the QoL decreased in the intervention group, leading to our hypothesis that health care staff may be overwhelmed by the work-intensive COSMOS intervention period. However, the decrease reversed significantly during follow-up, indicating a potential learning effect. Further, the intervention group improved in ADL function and received less medication, and staff reported less distress and judged COSMOS as able to bring about clinically relevant change. This suggests that nonpharmacologic multicomponent interventions require long follow-up to ensure uptake and beneficial effects.

OBJECTIVES: to describe the incidence of delirium recording before and after a diagnosis of dementia is established in patients with dementia with Lewy bodies (DLB) and compare findings to a matched cohort of patients with Alzheimer's disease (AD). DESIGN: Retrospective cohort study. SETTING AND PARTICIPANTS: a cohort of patients with dementia from a large mental health and dementia care database in South London, linked to hospitalization and mortality data. We identified 194 patients with DLB and 1:4 matched these with 776 patients diagnosed with AD on age, gender, and cognitive status. MEASURES: We identified delirium episodes recorded in mental health and hospital records from 1 year before to 1 year after dementia diagnosis. Using dementia diagnosis as an index date we additionally followed patients until first episode of delirium, death or a censoring point without restricting the observation period. RESULTS: Patients with DLB had significantly more episodes of delirium recorded in the year before dementia diagnosis than patients with AD (incidence rate 17.6 vs 3.2 per 100 person-years; P 

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

While it is generally understood that Alzheimer's disease (AD) and related dementias (ADRD) is one of the costliest diseases to society, there is widespread concern that researchers and policymakers are not comprehensively capturing and describing the full scope and magnitude of the socioeconomic burden of ADRD. This review aimed to 1) catalogue the different types of AD-related socioeconomic costs described in the literature; 2) assess the challenges and gaps of existing approaches to measuring these costs; and 3) analyze and discuss the implications for stakeholders including policymakers, healthcare systems, associations, advocacy groups, clinicians, and researchers looking to improve the ability to generate reliable data that can guide evidence-based decision making. A centrally emergent theme from this review is that it is challenging to gauge the true value of policies, programs, or interventions in the ADRD arena given the long-term, progressive nature of the disease, its insidious socioeconomic impact beyond the patient and the formal healthcare system, and the complexities and current deficiencies (in measures and real-world data) in accurately calculating the full costs to society. There is therefore an urgent need for all stakeholders to establish a common understanding of the challenges in evaluating the full cost of ADRD and define approaches that allow us to measure these costs more accurately, with a view to prioritizing evidence-based solutions to mitigate this looming public health crisis.

Although Alzheimer's disease (AD) is the world's leading cause of dementia and the population of patients with AD continues to grow, no new therapies have been approved in more than a decade. Many clinical trials of single-agent therapies have failed to affect disease progression or symptoms compared with placebo. The complex pathophysiology of AD may necessitate combination treatments rather than monotherapy. The goal of this narrative literature review is to describe types of combination therapy, review the current clinical evidence for combination therapy regimens (both symptomatic and disease-modifying) in the treatment of AD, describe innovative clinical trial study designs that may be effective in testing combination therapy, and discuss the regulatory and drug development landscape for combination therapy. Successful combination therapies in other complex disorders, such as human immunodeficiency virus, may provide useful examples of a potential path forward for AD treatment.

OBJECTIVES: the study aims to understand the factors that care home staff felt enabled or hindered them in continuing to use the well-being and health for people with dementia (WHELD) psychosocial approach in their care home and investigate whether there was sustained activity 9 to 12 months after the study ended. METHODS: This qualitative study is part of a wider clinical trial, which demonstrated effectiveness of a psychosocial intervention on quality of life outcomes and neuropsychiatric symptoms for residents. Forty-seven care home staff within nine care homes in the United Kingdom participated in focus groups, between 9 and 12 months after the intervention had finished. Inductive thematic analysis was used to identify themes and interpret the data. RESULTS: the findings highlighted that staff continued to use a range of activities and processes acquired through the research intervention, after the study had ended. Three overarching themes were identified as influential: "recognising the value" of the approach for residents and staff, "being well practiced" with sufficient support and opportunity to consolidate skills prior to the withdrawal of the researchers, and "taking ownership of the approach" to incorporate it as usual care. CONCLUSIONS: the WHELD approach can be sustained where the value of the approach is recognised, and sufficient support is provided during initial implementation for staff to build skills and confidence for it to become routine care. Further follow-up is required to understand longer term use and the impact for residents.

Background: Concussion (mild) and other moderate traumatic brain injury (TBI) and Alzheimer’s disease (AD) share overlapping neuropathologies, including neuronal pre-programmed cell death (PPCD), and clinical impairments and disabilities. Multiple clinical trials targeting mechanisms based on the Amyloid Hypothesis of AD have so far failed, indicating that it is prudent for new drug developments to also pursue mechanisms independent of the Amyloid Hypothesis. To address these issues, we have proposed the use of an animal model of concussion/TBI as a supplement to AD transgenic mice to provide an indication of an AD drug candidate’s potential for preventing PPCD and resulting progression towards dementia in AD. Methods: We searched PubMed/Medline and the references of identified articles for background on the neuropathological progression of AD and its implications for drug target identification, for AD clinical trial criteria used to assess disease modification outcomes, for plasma biomarkers associated with AD and concussion/TBI, neuropathologies and especially PPCD, and for methodological critiques of AD and other neuropsychiatric clinical trial methods. Results: We identified and address seven issues and highlight the Thal-Sano AD ‘Time to Onset of Impairment’ Design for possible applications in our clinical trials. Diverse and significant pathological cascades and indications of self-induced neuronal PPCD were found in concussion/TBI, anoxia, and AD animal models. To address the dearth of peripheral markers of AD and concussion/TBI brain pathologies and PPCD we evaluated Extracellular Vesicles (EVs) enriched for neuronal origin, including exosomes. In our concussion/TBI, anoxia and AD animal models we found evidence consistent with the presence of time-dependent PPCD and (-)-phenserine suppression of neuronal self-induced PPCD. We hence developed an extended controlled release formulation of (-)-phenserine to provide individualized dosing and stable therapeutic brain concentrations, to pharmacologically interrogate PPCD as a drug development target. To address the identified problems potentially putting any clinical trial at risk of failure, we developed exploratory AD and concussion/TBI clinical trial designs. Conclusions: Our findings inform the biomarker indication of progression of pathological targets in neurodegenerations and propose a novel approach to these conditions through neuronal protection against self-induced PPCD.

OBJECTIVE: National and global dementia plans have focused on the research ambition to develop a cure or disease-modifying therapy by 2025, with the initial focus on investment in drug discovery approaches. We set out to develop complementary research ambitions in the areas of prevention, diagnosis, intervention, and care and strategies for achieving them. METHODS: Alzheimer's Society facilitated a taskforce of leading UK clinicians and researchers in dementia, UK funders of dementia research, people with dementia, and carer representatives to develop, using iterative consensus methodology, goals and recommendations to advance dementia research. RESULTS: the taskforce developed 5 goals and 30 recommendations. The goals focused on preventing future cases of dementia through risk reduction, maximising the benefit of a dementia diagnosis, improving quality of life, enabling the dementia workforce to improve practice, and optimising the quality and inclusivity of health and social care systems. Recommendations addressed gaps in knowledge and limitations in research methodology or infrastructure that would facilitate research in prioritised areas. A 10-point action plan provides strategies for delivering the proposed research agenda. CONCLUSIONS: By creating complementary goals for research that mirror the need to find effective treatments, we provide a framework that enables a focus for new investment and initiatives. This will support a broader and more holistic approach to research on dementia, addressing prevention, surveillance of population changes in risk and expression of dementia, the diagnostic process, diagnosis itself, interventions, social support, and care for people with dementia and their families.

In Alzheimer's disease (AD), the canonical Wnt inhibitor Dickkopf-1 (Dkk1) is induced by β-amyloid (Aβ) and shifts the balance from canonical towards non-canonical Wnt signalling. Canonical (Wnt-β-catenin) signalling promotes synapse stability, while non-canonical (Wnt-PCP) signalling favours synapse retraction; thus Aβ-driven synapse loss is mediated by Dkk1. Here we show that the Amyloid Precursor Protein (APP) co-activates both arms of Wnt signalling through physical interactions with Wnt co-receptors LRP6 and Vangl2, to bi-directionally modulate synapse stability. Furthermore, activation of non-canonical Wnt signalling enhances Aβ production, while activation of canonical signalling suppresses Aβ production. Together, these findings identify a pathogenic-positive feedback loop in which Aβ induces Dkk1 expression, thereby activating non-canonical Wnt signalling to promote synapse loss and drive further Aβ production. The Swedish familial AD variant of APP (APPSwe) more readily co-activates non-canonical, at the expense of canonical Wnt activity, indicating that its pathogenicity likely involves direct effects on synapses, in addition to increased Aβ production. Finally, we report that pharmacological inhibition of the Aβ-Dkk1-Aβ positive feedback loop with the drug fasudil can restore the balance between Wnt pathways, prevent dendritic spine withdrawal in vitro, and reduce Aβ load in vivo in mice with advanced amyloid pathology. These results clarify a relationship between Aβ accumulation and synapse loss and provide direction for the development of potential disease-modifying treatments.

OBJECTIVE: Neuropsychiatric symptoms such as agitation and delusions occur frequently in Lewy body dementia and Alzheimer's disease and represent significant burden and unmet treatment need. The underlying aetiology remains poorly understood. METHODS: We used a multidimensional linear model to look for associations between measurements of agitation, delusions, amyloid, tau and α-synuclein pathology, and synaptic proteins (ZnT3, PSD95, synaptophysin, and β-III-tubulin) across multiple brain regions in post-mortem tissue from a cohort of 130 Lewy body dementia and Alzheimer's disease patients and non-demented controls. RESULTS: We found both agitations and delusions to be significantly associated with increased tau pathology and decreased levels of ZnT3. ZnT3 packages Zn2+ into synaptic vesicles to be released as a long-term modulator of synaptic activity. CONCLUSIONS: Our finding adds to the evidence that zinc modulating compounds are of interest for treatment or symptomatic relief in these dementias.

Objective: Neuropsychiatric symptoms (NPS) in dementia are frequent and challenging for patients, carers, and the health care system, but few long-term studies exist. We analyse the longitudinal course of NPS in patients with mild dementia. Methods: a longitudinal cohort study of 223 patients with mild dementia and annual assessments using the Neuropsychiatric Inventory (NPI) for 5 years. Results: a total 1043 NPI assessments, representing 97% of all possible measurements of living cohort members, were analysed. Neuropsychiatric symptoms were common at baseline, and only a moderate increase in total NPS score from 15 to 17 with no increase in the proportion with high NPI total scores. Ninety seven percent scored ≥16, and 49% scored ≥36 on NPI total score at least once during follow-up. Individual NPS fluctuated and often reappeared. The most common symptoms ever reported was apathy (83%), depression (63%), appetite (63%), and aberrant motor behavior (60%). Cognitive decline was associated with higher NPI total score and several NPI items, but only the frequency of apathy increased significantly with time. Lewy body dementia was associated with higher NPI total score and psychotic symptoms. Alzheimer's disease was associated with increase in apathy. Conclusions: Severe NPS are already common at time of dementia diagnosis, and the increase in overall severity over 5 years was moderate. Individual symptoms tend to fluctuate over time within patients and correspond to states rather than traits. These findings highlight the need to focus on, and plan for, NPS as part of dementia pathway, and are relevant for clinical trial design.

Background: Chronic pain and depression often co-occur, and pain may exacerbate depression in people with dementia. Objective: the objective of this study was to assess the efficacy and safety of analgesic treatment for depression in nursing home patients with advanced dementia and clinically significant depressive symptoms. Methods: We conducted a multicentre, parallel-group, double-blind, placebo-controlled trial in 47 nursing homes, including 162 nursing home patients aged ≥ 60 years with dementia (Mini-Mental State Examination ≤ 20) and depression (Cornell Scale for Depression in Dementia ≥ 8). Patients were randomised to receive active analgesic treatment (paracetamol or buprenorphine transdermal system) or identical placebo for 13 weeks. The main outcome measure was the change in depression (Cornell Scale for Depression in Dementia) from baseline to 13 weeks, assessed using linear mixed models with fixed effects for time, intervention and their interaction in the models. Secondary outcomes were to assess whether any change in depression was secondary to change in pain (Mobilisation-Observation-Behaviour-Intensity-Dementia-2 Pain Scale) and adverse events. Results: the mean depression change was − 0.66 (95% confidence interval − 2.27 to 0.94) in the active group (n = 80) and − 3.30 (− 4.68 to −1.92) in the placebo group (n = 82). The estimated treatment effect was 2.64 (0.55–4.72, p = 0.013), indicating that analgesic treatment had no effect on depressive symptoms from baseline to 13 weeks while placebo appeared to ameliorate depressive symptoms. There was no significant reduction in pain in the active treatment group (paracetamol and buprenorphine combined) vs. placebo; however, a subgroup analysis demonstrated a significant reduction in pain for paracetamol vs. placebo [by − 1.11 (− 2.16 to − 0.06, p = 0.037)] from week 6 to 13 without a change in depression. Buprenorphine did not have significant effects on depression [3.04 (− 0.11 to 6.19), p = 0.059] or pain [0.47 (− 0.77 to 1.71), p = 0.456] from 0 to 13 weeks. Thirty-five patients were withdrawn from the study because of adverse reactions, deterioration or death: 25 (31.3%) during active treatment [23 (52.3%) who received buprenorphine], and ten (12.2%) in the placebo group. The most frequently occurring adverse events were psychiatric (17 adverse reactions) and neurological (14 adverse reactions). Conclusion: Analgesic treatment did not reduce depression while placebo appeared to improve depressive symptoms significantly by comparison, possibly owing to the adverse effects of active buprenorphine. The risk of adverse events warrants caution when prescribing buprenorphine for people with advanced dementia. Trial registration: ClinicalTrials.gov NCT02267057 (registered 7 July, 2014) and Norwegian Medicines Agency EudraCT 2013-002226-23.

Background: Pimavanserin is a selective 5-HT2A receptor inverse agonist and antagonist approved in the USA for the treatment of hallucinations and delusions associated with Parkinson's disease psychosis. No safe or effective pharmacological treatment is approved for psychosis in patients with Alzheimer's disease. Therefore, we aimed to evaluate the safety, tolerability, and efficacy of pimavanserin versus placebo in patients with Alzheimer's disease psychosis. Methods: We did a phase 2, randomised, double-blind, placebo-controlled, single-centre (with multiple affiliated nursing home sites across the UK) study. We included participants of either sex who were aged 50 years or older with possible or probable Alzheimer's disease and psychotic symptoms including visual or auditory hallucinations, delusions, or both. Participants were randomly assigned (1:1) to 12 weeks of oral treatment with either pimavanserin (two 17 mg tablets daily) or placebo, with use of permuted block sizes of four and stratified by baseline Mini-Mental State Examination (MMSE) total score (

OBJECTIVES: the objective of this study was to establish the feasibility and initial effectiveness of training and support intervention for care staff to improve pain management in people with dementia living in care homes (PAIN-Dem). METHODS: PAIN-Dem training was delivered to care staff from three care homes in South London, followed by intervention support and resources to encourage improved pain management by staff over 4 weeks. Feasibility was assessed through fidelity to intervention materials and qualitative approaches. Focus group discussions with staff explored the use of the PAIN-Dem intervention, and interviews were held with six residents and family carers. Pain was assessed in all residents at baseline, 3 and 4 weeks, and goal attainment scaling was assessed at 4 weeks. RESULTS: Delivery of training was a key driver for success and feasibility of the PAIN-Dem intervention. Improvements in pain management behaviour and staff confidence were seen in homes where training was delivered in a care home setting across the care team with good manager buy-in. Family involvement in pain management was highlighted as an area for improvement. Goal attainment in residents was significantly improved across the cohort, although no significant change in pain was seen. CONCLUSIONS: This study shows good initial feasibility of the PAIN-Dem intervention and provides valuable insight into training and support paradigms that deliver successful learning and behaviour change. There is a need for a larger trial of PAIN-Dem to establish its impact on resident pain and quantifiable staff behaviour measures. Copyright © 2017 John Wiley & Sons, Ltd.

Glial cell line-derived neurotrophic factor (GDNF) is the most potent neuroprotective agent tested in cellular and animal models of Parkinson's disease (PD). However, CNS delivery of GDNF is restricted by the blood-brain barrier (BBB). Using total body irradiation as transplant preconditioning, we previously reported that hematopoietic stem cell (HSC) transplantation (HSCT)-based macrophage-mediated gene therapy could deliver GDNF to the brain to prevent degeneration of nigrostriatal dopamine (DA) neurons in an acute murine neurotoxicity model. Here, we validate this therapeutic approach in a chronic progressive PD model - the MitoPark mouse, with head shielding to avoid inducing neuroinflammation and compromising BBB integrity. Bone marrow HSCs were transduced ex vivo with a lentiviral vector expressing macrophage promoter-driven GDNF and transplanted into MitoPark mice exhibiting well developed PD-like impairments. Transgene-expressing macrophages infiltrated the midbrains of MitoPark mice, but not normal littermates, and delivered GDNF locally. Macrophage GDNF delivery markedly improved both motor and non-motor symptoms, and dramatically mitigated the loss of both DA neurons in the substantia nigra and tyrosine hydroxylase-positive axonal terminals in the striatum. Our data support further development of this HSCT-based macrophage-mediated GDNF delivery approach in order to address the unmet need for a disease-modifying therapy for PD.

Heterozygous mutations in glucocerebrosidase gene (GBA) are a major genetic risk factor for Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Recently, there has been a considerable focus on the relationship between GBA mutations and emergence of cognitive impairment and neuropsychiatric symptoms in these diseases. Here, we review the literature in this area, with a particular focus, including meta-analysis, on the key neuropsychiatric symptoms of cognitive impairment, psychosis, and depression in Parkinson's disease. Our meta-analysis demonstrated that GBA mutations are associated with a 2.4-fold increased risk of cognitive impairment. In addition, our novel meta-analyses of psychosis and depression showed a 1.8- and 2.2-fold increased risk respectively associated with GBA mutations, although due to possible bias and heterogeneity the depression findings should be interpreted with caution. While the precise mechanisms which increase susceptibility to neurodegeneration in GBA carriers are not known, evidence of greater cortical Lewy body pathology, reduced patterns of cortical activation, and hippocampal pathology in animal models are all consistent with a direct effect of GBA mutations on these symptoms. Extension of this work in DLB and individuals without neurodegeneration will be important in further characterizing how GBA mutations increase risk for PD and DLB and influence disease course.

Introduction: Increased hospitalization is a major component of dementia impact on individuals and cost, but has rarely been studied in dementia with Lewy bodies (DLB). Our aim was to describe the risk and duration of hospital admissions in patients with DLB, and compare these to those in Alzheimer's disease (AD) and the general population. Methods: a large database of mental health and dementia care in South London was used to assemble a cohort of patients diagnosed with DLB. These were 1:4 matched with patients diagnosed with AD on age, gender, and cognitive status. Results: Rates of hospital admissions in the year after dementia diagnosis were significantly higher in 194 patients with DLB than in 776 patients with AD (crude incidence rate ratio 1.50; 95% confidence interval: 1.28–1.75) or the catchment population (indirectly standardized hospitalization rate 1.22; 95% confidence interval: 1.06–1.39). Patients with DLB had on average almost four additional hospital days per person-year than patients with AD. Multivariate Poisson regression models indicated poorer physical health early in the disease course as the main driver of this increased rate of hospitalization, whereby neuropsychiatric symptoms additionally explained the higher number of hospital days. Discussion: Patients with DLB are more frequently admitted to general hospitals and utilize inpatient care to a substantially higher degree than patients with AD or the general elderly population. These data highlight an opportunity to reduce hospital days by identifying DLB earlier and providing more targeted care focused on the specific triggers for hospitalization and associations of prolonged stay.

BACKGROUND: Agitation is a common, challenging symptom affecting large numbers of people with dementia and impacting on quality of life (QoL). There is an urgent need for evidence-based, cost-effective psychosocial interventions to improve these outcomes, particularly in the absence of safe, effective pharmacological therapies. This study aimed to evaluate the efficacy of a person-centred care and psychosocial intervention incorporating an antipsychotic review, WHELD, on QoL, agitation, and antipsychotic use in people with dementia living in nursing homes, and to determine its cost. METHODS AND FINDINGS: This was a randomised controlled cluster trial conducted between 1 January 2013 and 30 September 2015 that compared the WHELD intervention with treatment as usual (TAU) in people with dementia living in 69 UK nursing homes, using an intention to treat analysis. All nursing homes allocated to the intervention received staff training in person-centred care and social interaction and education regarding antipsychotic medications (antipsychotic review), followed by ongoing delivery through a care staff champion model. The primary outcome measure was QoL (DEMQOL-Proxy). Secondary outcomes were agitation (Cohen-Mansfield Agitation Inventory [CMAI]), neuropsychiatric symptoms (Neuropsychiatric Inventory-Nursing Home Version [NPI-NH]), antipsychotic use, global deterioration (Clinical Dementia Rating), mood (Cornell Scale for Depression in Dementia), unmet needs (Camberwell Assessment of Need for the Elderly), mortality, quality of interactions (Quality of Interactions Scale [QUIS]), pain (Abbey Pain Scale), and cost. Costs were calculated using cost function figures compared with usual costs. In all, 847 people were randomised to WHELD or TAU, of whom 553 completed the 9-month randomised controlled trial. The intervention conferred a statistically significant improvement in QoL (DEMQOL-Proxy Z score 2.82, p = 0.0042; mean difference 2.54, SEM 0.88; 95% CI 0.81, 4.28; Cohen's D effect size 0.24). There were also statistically significant benefits in agitation (CMAI Z score 2.68, p = 0.0076; mean difference 4.27, SEM 1.59; 95% CI -7.39, -1.15; Cohen's D 0.23) and overall neuropsychiatric symptoms (NPI-NH Z score 3.52, p < 0.001; mean difference 4.55, SEM 1.28; 95% CI -7.07,-2.02; Cohen's D 0.30). Benefits were greatest in people with moderately severe dementia. There was a statistically significant benefit in positive care interactions as measured by QUIS (19.7% increase, SEM 8.94; 95% CI 2.12, 37.16, p = 0.03; Cohen's D 0.55). There were no statistically significant differences between WHELD and TAU for the other outcomes. A sensitivity analysis using a pre-specified imputation model confirmed statistically significant benefits in DEMQOL-Proxy, CMAI, and NPI-NH outcomes with the WHELD intervention. Antipsychotic drug use was at a low stable level in both treatment groups, and the intervention did not reduce use. The WHELD intervention reduced cost compared to TAU, and the benefits achieved were therefore associated with a cost saving. The main limitation was that antipsychotic review was based on augmenting processes within care homes to trigger medical review and did not in this study involve proactive primary care education. An additional limitation was the inherent challenge of assessing QoL in this patient group. CONCLUSIONS: These findings suggest that the WHELD intervention confers benefits in terms of QoL, agitation, and neuropsychiatric symptoms, albeit with relatively small effect sizes, as well as cost saving in a model that can readily be implemented in nursing homes. Future work should consider how to facilitate sustainability of the intervention in this setting. TRIAL REGISTRATION: ISRCTN Registry ISRCTN62237498.

Background: Globalization of clinical trials has important consequences for trial planning and interpretation. This study investigated heterogeneity in patient characteristics and outcomes among world regions in the global idalopirdine Phase 3 clinical program. Methods: Data were pooled from three 24-week randomized controlled trials in patients aged ≥ 50 years with mild-to-moderate Alzheimer's disease (AD) (n = 2506). Patients received idalopirdine (10, 30, or 60 mg/day) or placebo, added to cholinesterase inhibitor treatment. Patients were categorized into the following regions: Eastern Europe/Turkey (n = 759), Western Europe/Israel (n = 709), USA/Canada (n = 444), South America/Mexico (n = 361), Asia (n = 134), and Australia/South Africa (n = 99). For each region, operational characteristics, baseline demographic and clinical characteristics, adverse events, and mean change from baseline to week 24 in clinical rating scale scores (placebo group only) were summarized using descriptive statistics. Results: Completion rates were 0.86-0.90 in all regions. Heterogeneity among global regions was evident. Protocol deviations were twice as common in South America/Mexico as in USA/Canada (2.64 vs 1.35 per patient screened). Educational level ranged from 9.2 years in South America/Mexico to 13.4 years in USA/Canada. APOE ϵ4 carriage was 80.6% in Australia/South Africa, 63.1% in Western Europe/Israel, and < 60% in other regions. Screening Mini-Mental State Examination scores were higher in Eastern Europe/Turkey (18.0) and USA/Canada (17.5) than in other regions (16.9-17.1). Baseline AD Assessment Scale - Cognitive subscale (ADAS-Cog) scores ranged from 24.3 in USA/Canada to 27.2 in South America/Mexico. Baseline AD Cooperative Study - Activities of Daily Living, 23-item version (ADCS-ADL23) scores ranged from 58.5 in USA/Canada to 53.5 in Eastern Europe/Turkey. In the placebo group, adverse events were 1.6-1.7 times more common in Western Europe/Israel, USA/Canada, and Australia/South Africa than in Eastern Europe/Turkey. On the ADAS-Cog, Australia/South Africa and Western Europe/Israel showed the most worsening among patients receiving placebo (1.56 and 1.40 points, respectively), whereas South America/Mexico showed an improvement (-0.71 points). All regions worsened on the ADCS-ADL23, from -3.21 points in Western Europe/Israel to -0.59 points in Eastern Europe/Turkey. Conclusions: Regional heterogeneity - in terms of study conduct, patient characteristics, and outcomes - exists, and should be accounted for, when planning and conducting multinational AD clinical trials. Trial registration: ClinicalTrials.gov, NCT01955161. Registered on 27 September 2013. ClinicalTrials.gov, NCT02006641. Registered on 5 December 2013. ClinicalTrials.gov, NCT02006654. Registered on 5 December 2013.

OBJECTIVE: Several potentially modifiable risk factors for cognitive decline and dementia have been identified, including low educational attainment, smoking, diabetes, physical inactivity, hypertension, midlife obesity, depression, and perceived social isolation. Managing these risk factors in late midlife and older age may help reduce the risk of dementia; however, it is unclear whether these factors also relate to cognitive performance in older individuals without dementia. METHOD: Data from 14 201 non-demented individuals aged >50 years who enrolled in the online PROTECT study were used to examine the relationship between cognitive function and known modifiable risk factors for dementia. Multivariate regression analyses were conducted on 4 cognitive outcomes assessing verbal and spatial working memory, visual episodic memory, and verbal reasoning. RESULTS: Increasing age was associated with reduced performance across all tasks. Higher educational achievement, the presence of a close confiding relationship, and moderate alcohol intake were associated with benefits across all 4 cognitive tasks, and exercise was associated with better performance on verbal reasoning and verbal working memory tasks. A diagnosis of depression was negatively associated with performance on visual episodic memory and working memory tasks, whereas being underweight negatively affected performance on all tasks apart from verbal working memory. A history of stroke was negatively associated with verbal reasoning and working memory performance. CONCLUSION: Known modifiable risk factors for dementia are associated with cognitive performance in non-demented individuals in late midlife and older age. This provides further support for public health interventions that seek to manage these risk factors across the lifespan.

BACKGROUND: PD psychosis is often associated with cognitive impairment, including dementia, and involves dopaminergic, serotonergic, and cholinergic mechanisms. OBJECTIVE: to evaluate the differential effect of the antipsychotic pimavanserin, a selective serotonin 2A receptor inverse agonist, in PD psychosis patients with versus without cognitive impairment and in those receiving versus not receiving cognitive-enhancing medications. METHODS: Data from the pivotal randomized clinical trial of pimavanserin for PD psychosis were stratified by (1) screening MMSE score as cognitively impaired (21-24) versus unimpaired (≥25) and (2) concomitant use versus nonuse of cognitive-enhancing medications. The primary outcome measure was change in the PD-adapted Scale for the Assessment of Positive Symptoms. RESULTS: Mean (pimavanserin vs. placebo) change from baseline was larger in the cognitively impaired (n = 50; -6.62 vs. -0.91; P = 0.002) versus the cognitively unimpaired (n = 135; -5.50 vs. -3.23; p = 0.046) group. The comparable change was -6.04 versus -2.18 (P = 0.012) and -5.66 versus -3.15 (P = 0.041) in patients treated (n = 69) and not treated (n = 116) with concomitant cognitive-enhancing medication. Pimavanserin was similarly tolerated across all cognitive groups with no additional safety concerns identified. Overall adverse event rates were comparable across the concomitant cognitive-enhancing medication groups; however, rates of serious adverse events and discontinuations attributed to adverse events were increased in patients taking cholinesterase inhibitors. CONCLUSIONS: the antipsychotic effect of pimavanserin is robust in PD patients with cognitive impairment and may be enhanced by concomitant cognitive-enhancing medication use. Future prospective studies are needed to confirm these preliminary findings. © 2018 the Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Psychosis is common across dementia types with a prevalence of 20% to 70%. Currently, no pharmacologic treatment is approved for dementia-related psychosis. Atypical antipsychotics are frequently used to treat these disorders, despite significant safety concerns. Pimavanserin, a selective 5-HT2A inverse agonist/antagonist, was approved in the U.S. for treating hallucinations and delusions associated with Parkinson's disease psychosis (PDP). Patients in the pimavanserin group experienced a significant (p=0.001) improvement in Scale for the Assessment of Positive Symptoms - Parkinson's disease (SAPS-PD) scores vs. placebo. In a subgroup analysis of patients with cognitive impairment (MMSE score ≥21 but ≤24), the observed improvement on the SAPS-PD with pimavanserin (N=50) was also significant (p=0.002) and larger than in the overall study population without an adverse effect on cognition. In a Phase 2 study with pimavanserin in Alzheimer's disease psychosis, pimavanserin significantly (p=0.045) improved psychosis at Week 6 vs. placebo on the NPI-NH Psychosis Score (PS). In a prespecified subgroup of patients with a baseline NPI-NH PS ≥12, a substantively larger treatment effect (p=0.011) was observed vs. participants with NPI-NH PS

Mitochondrial dysfunction activates the mitochondrial retrograde signaling pathway, resulting in large scale changes in gene expression. Mitochondrial retrograde signaling in neurons is poorly understood and whether retrograde signaling contributes to cellular dysfunction or is protective is unknown. We show that inhibition of Ras-ERK-ETS signaling partially reverses the retrograde transcriptional response to alleviate neuronal mitochondrial dysfunction. We have developed a novel genetic screen to identify genes that modify mitochondrial dysfunction in Drosophila. Knock-down of one of the genes identified in this screen, the Ras-ERK-ETS pathway transcription factor Aop, alleviates the damaging effects of mitochondrial dysfunction in the nervous system. Inhibition of Ras-ERK-ETS signaling also restores function in Drosophila models of human diseases associated with mitochondrial dysfunction. Importantly, Ras-ERK-ETS pathway inhibition partially reverses the mitochondrial retrograde transcriptional response. Therefore, mitochondrial retrograde signaling likely contributes to neuronal dysfunction through mis-regulation of gene expression.

The conventional approach to finding structurally similar search models for use in molecular replacement (MR) is to use the sequence of the target to search against those of a set of known structures. Sequence similarity often correlates with structure similarity. Given sufficient similarity, a known structure correctly positioned in the target cell by the MR process can provide an approximation to the unknown phases of the target. An alternative approach to identifying homologous structures suitable for MR is to exploit the measured data directly, comparing the lattice parameters or the experimentally derived structure-factor amplitudes with those of known structures. Here, SIMBAD, a new sequence-independent MR pipeline which implements these approaches, is presented. SIMBAD can identify cases of contaminant crystallization and other mishaps such as mistaken identity (swapped crystallization trays), as well as solving unsequenced targets and providing a brute-force approach where sequence-dependent search-model identification may be nontrivial, for example because of conformational diversity among identifiable homologues. The program implements a three-step pipeline to efficiently identify a suitable search model in a database of known structures. The first step performs a lattice-parameter search against the entire Protein Data Bank (PDB), rapidly determining whether or not a homologue exists in the same crystal form. The second step is designed to screen the target data for the presence of a crystallized contaminant, a not uncommon occurrence in macromolecular crystallography. Solving structures with MR in such cases can remain problematic for many years, since the search models, which are assumed to be similar to the structure of interest, are not necessarily related to the structures that have actually crystallized. To cater for this eventuality, SIMBAD rapidly screens the data against a database of known contaminant structures. Where the first two steps fail to yield a solution, a final step in SIMBAD can be invoked to perform a brute-force search of a nonredundant PDB database provided by the MoRDa MR software. Through early-access usage of SIMBAD, this approach has solved novel cases that have otherwise proved difficult to solve.

See Attems and Jellinger (doi:10.1093/brain/awx360) for a scientific commentary on this article. Cognitive changes occurring throughout the pathogenesis of neurodegenerative diseases are directly linked to synaptic loss. We used in-depth proteomics to compare 32 post-mortem human brains in the prefrontal cortex of prospectively followed patients with Alzheimer's disease, Parkinson's disease with dementia, dementia with Lewy bodies and older adults without dementia. In total, we identified 10 325 proteins, 851 of which were synaptic proteins. Levels of 25 synaptic proteins were significantly altered in the various dementia groups. Significant loss of SNAP47, GAP43, SYBU (syntabulin), LRFN2, SV2C, SYT2 (synaptotagmin 2), GRIA3 and GRIA4 were further validated on a larger cohort comprised of 92 brain samples using ELISA or western blot. Cognitive impairment before death and rate of cognitive decline significantly correlated with loss of SNAP47, SYBU, LRFN2, SV2C and GRIA3 proteins. Besides differentiating Parkinson's disease dementia, dementia with Lewy bodies, and Alzheimer's disease from controls with high sensitivity and specificity, synaptic proteins also reliably discriminated Parkinson's disease dementia from Alzheimer's disease patients. Our results suggest that these particular synaptic proteins have an important predictive and discriminative molecular fingerprint in neurodegenerative diseases and could be a potential target for early disease intervention.

Antipsychotics have long been the mainstay of treatment for agitation and psychosis in Alzheimer's disease. Despite their current use successive studies have shown that they only confer a modest benefit which must be balanced against their well-established serious side effects (extrapyramidal symptoms, stroke, accelerated cognitive decline and mortality). Areas covered: This review outlines the current guidance on antipsychotic usage and the evidence of their continued usage against a backdrop of emerging pharmacological treatments and an increasing emphasis on the importance of non-pharmacological interventions. Expert commentary: the current justification for antipsychotic use in the context of the changing landscape of prescribing and provide a view on the most promising alternative candidates to this class of drug are appraised.

Purpose: Buprenorphine transdermal system is increasingly prescribed in people with advanced dementia, but no clinical trial has investigated the safety and factors associated with discontinuation due to adverse events in this population. Patients and methods: One hundred sixty-two people with advanced dementia and significant depression from 47 nursing homes were included and randomized to active analgesic treatment (acetaminophen/buprenorphine) or identical placebo for 13 weeks. In this secondary analysis, the main outcomes were time to and reasons for discontinuation of buprenorphine due to adverse events. Change in daytime activity as measured by actigraphy was a secondary outcome. Results: of the 44 patients who received active buprenorphine 5 µg/hour, 52.3% (n=23) discontinued treatment due to adverse events compared to 13.3% (6 of 45) in the placebo group (p,0.001). Psychiatric and neurological adverse events were the most frequently reported causes of discontinuation (69.6%, n=16). Concomitant use of antidepressants significantly increased the risk of discontinuation (HR 23.2, 95% CI: 2.95–182, p=0.003). Adjusted for age, sex, cognitive function, pain and depression at baseline, active buprenorphine was associated with 24.0 times increased risk of discontinuation (Cox model, 95% CI: 2.45–235, p=0.006). Daytime activity dropped significantly during the second day of active treatment (−21.4%, p=0.005) and decreased by 12.9% during the first week (p=0.053). Conclusion: Active buprenorphine had significantly higher risk of discontinuation compared with placebo in people with advanced dementia and depression, mainly due to psychiatric and neurological adverse events. Daytime activity dropped significantly during the first week of treatment. Concomitant use of antidepressants further reduced the tolerability of buprenorphine.

Background: the first consensus criteria for dementia with Lewy bodies (DLB) published in 1996 were revised in 2005, partly because the original clinical criteria had suboptimal sensitivity. Few studies have assessed the accuracy of the 2005 criteria applied prospectively in newly diagnosed patients who have been followed longitudinally. Objective: to explore the correlation between clinical and pathological diagnoses in patients with DLB and Parkinson's disease with dementia (PDD). Methods: from a prospective referral cohort study with enriched recruitment of patients with DLB and PDD, we included the first 56 patients coming to autopsy. Patients had mild dementia at inclusion and were followed annually until death with standardized clinical assessments. Pathological assessment was performed blind to clinical information according to standardized protocols and consensus criteria for DLB. Results: 20 patients received a pathological diagnosis of Lewy body disease; the corresponding clinical diagnoses were probable DLB (n = 11), PDD (n = 5), probable (n = 2) or possible (n = 2) Alzheimer's disease (AD). of 14 patients with a clinical diagnosis of probable DLB, 11 had DLB/PDD and 3 had AD at pathology. One patient with clinically possible DLB fulfilled criteria for pathological AD. Sensitivity, specificity, positive predictive value, and negative predictive values for probable DLB were 73%, 93%, 79%, and 90%. Conclusion: Our findings suggest that the international clinical consensus criteria forDLBperform reasonably well. However, false positive and false negative diagnoses still occur, indicating that the criteria need to be improved, that biomarkers may be needed, and that neuropathological feedback is vital to improve accuracy.

Dementia is a frequent problem encountered in advanced stages of Parkinson disease (PD). In recent years, research has focused on the pre-dementia stages of cognitive impairment in PD, including mild cognitive impairment (MCI). Several longitudinal studies have shown that MCI is a harbinger of dementia in PD, although the course is variable, and stabilization of cognition - or even reversal to normal cognition - is not uncommon. In addition to limbic and cortical spread of Lewy pathology, several other mechanisms are likely to contribute to cognitive decline in PD, and a variety of biomarker studies, some using novel structural and functional imaging techniques, have documented in vivo brain changes associated with cognitive impairment. The evidence consistently suggests that low cerebrospinal fluid levels of amyloid-β42, a marker of comorbid Alzheimer disease (AD), predict future cognitive decline and dementia in PD. Emerging genetic evidence indicates that in addition to the APOE*ε4 allele (an established risk factor for AD), GBA mutations and SCNA mutations and triplications are associated with cognitive decline in PD, whereas the findings are mixed for MAPT polymorphisms. Cognitive enhancing medications have some effect in PD dementia, but no convincing evidence that progression from MCI to dementia can be delayed or prevented is available, although cognitive training has shown promising results.

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

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.

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

With an ageing global population, the number of people with dementia, and its main cause Alzheimer's disease (AD), is growing. current licensed treatments available for ad are only alleviate the symptoms of the disease, and are effective only in some people with ad for a limited time. there are currently no therapies that target the disease process. Areas covered: This review summarizes the available treatments for AD and the emerging therapies in the clinical trials pipeline. There are ongoing trials at various stages of development, targeting different mechanisms and pathways implicated in the disease. This review focuses on amyloid and tau targeting drug candidates. Expert commentary: Despite research efforts targeted at understanding AD, the underlying mechanisms and optimal treatment targets have not been fully elucidated. There is a significant need for further research targeting the disease at an earlier stage and progress in biomarker and imaging technology are improving the outlook. It is critical to continue research into identifying the underlying pathology and disease process in Alzheimer's disease to enable development of effective targeted treatments.

The number of people with dementia, including Alzheimer's disease, is growing as a result of an ageing global population. Treatments available for AD only alleviate the symptoms of the disease, and are effective in some people with AD for a limited time. There is no disease-modifying treatment available, and despite research efforts, the underlying mechanisms of AD and optimal treatment targets have not been fully elucidated. Amyloid and tau are key pathological markers of AD with ongoing trials targeting both. However, there are also many trials at various stages of development that primarily target other markers and processes implicated in the disease, which are now being investigated. Areas covered: This review summarizes current treatment approaches for AD and explores both repositioned and novel therapies that target non amyloid and non tau mechanisms that are in the clinical trials pipeline. This includes treatments for cognitive and neuropsychiatric symptoms and potentially disease modifying therapies. The studies included in this review have been obtained from searches of PubMed and clinical trials databases. Expert commentary: There is a renewed energy in identifying better treatments for behavioural symptoms of AD using both novel drugs and repositioning existing drugs. Lack of success in clinical trials of drugs targeting amyloid and tau have led to a surge in targeting alternative mechanisms. Progress in the development of biomarkers will provide further tools for clinical trials of potential therapeutics for both symptomatic treatment and disease modification in AD.

INTRODUCTION: Knowledge regarding the longitudinal course, impact, or treatment implications of pain in people with dementia living in care homes is very limited. METHODS: We investigated the people with dementia living in 67 care homes in London and Buckinghamshire, United Kingdom. Pain, dementia severity, neuropsychiatric symptoms, depression, agitation, and quality-of-life were measured using appropriate instruments at baseline (N = 967) and after 9 months (n = 629). RESULTS: Baseline prevalence of pain was 35.3% (95% CI 32.3-38.3). Pain severity was significantly correlated with dementia severity, neuropsychiatric symptoms, depression, agitation, and quality of life at both time points. Regular treatment with analgesics significantly reduced pain severity. Pain was significantly associated with more antipsychotic prescriptions. Pain was significantly associated (OR 1.48; 95% CI 1.18-1.85) with all-cause mortality during follow-up. CONCLUSIONS: Pain is an important determinant of neuropsychiatric symptoms, mortality, quality-of-life, and antipsychotic prescriptions. Improved identification, monitoring, and treatment of pain are urgent priorities to improve the health and quality-of-life for people with dementia.

BACKGROUND: Very few interventional studies have directly examined the impact of treatment approaches on health-related quality of life (HRQL) in people with dementia. This is of particular importance in therapies to address behavioural symptoms, where HRQL is often severely affected. METHODS: Analysis within the WHELD cluster randomised factorial study in 16 UK care homes examining the impact of person-centred care in combination with antipsychotic review, social interaction and exercise interventions. This study analysed impact on HRQL through the DEMQOL-Proxy. RESULTS: Data on HRQL were available for 187 participants. People receiving antipsychotic review showed a significant worsening in two DEMQOL-Proxy domains (negative emotion: p = 0.02; appearance: p = 0.04). A best-case scenario analysis showed significant worsening for total DEMQOL-Proxy score. Social interaction intervention resulted in a significant benefit to HRQL (p = 0.04). There was no deterioration in HRQL in groups receiving both antipsychotic review and social interaction (p = 0.62). CONCLUSIONS: This demonstrates an important detrimental impact of discontinuation of antipsychotics in dementia on HRQL, highlighting the need for careful review of best practice guidelines regarding antipsychotic use and emphasising the importance of providing evidence-based non-pharmacological interventions in conjunction with antipsychotic review. Copyright © 2016 John Wiley & Sons, Ltd.

OBJECTIVE: to examine the impact of selective serotonin reuptake inhibitors (SSRIs) and depression on neurogenesis and cognition in dementia with Lewy bodies (DLB) and Parkinson disease dementia (PDD). METHODS: Late-stage progenitor cells were quantified in the subgranular zone (SGZ) of the hippocampal dentate gyrus of DLB/PDD patients (n = 41) and controls without dementia (n = 15) and compared between treatment groups (unmedicated, SSRIs, acetyl cholinesterase inhibitors [AChEIs], combined SSRIs and AChEIs). RESULTS: DLB/PDD patients had more doublecortin-positive cells in the SGZ compared to controls. The doublecortin-positive cell count was higher in the SGZ of patients treated with SSRIs and correlated to higher cognitive scores. CONCLUSION: SSRI treatment was associated with increased hippocampal neurogenesis and preservation of cognition in DLB/PDD patients.

Background: of the three transforming growth factor (TGF)-β isoforms known, TGFβ1 deficits have been widely reported in Alzheimer's disease (AD) and studied as a potential therapeutic target. In contrast, the status of TGFβ2, which has been shown to mediate amyloid-β (Aβ)-mediated neuronal death, are unclear both in AD and in Lewy body dementias (LBD) with differential neuritic plaque and neurofibrillary tangle burden. Objective: to measure neocortical TGFβ2 levels and their correlations with neuropathological and clinical markers of disease severity in a well-characterized cohort of AD as well as two clinical subtypes of LBD, dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), known to manifest relatively high and low Aβ plaque burden, respectively. Methods: Postmortem samples from temporal cortex (BA21) were measured for TGFβ2 using a Luminex-based platform, and correlated with scores for neuritic plaques, neurofibrillary tangles, α-synuclein pathology, dementia severity (as measured by annual decline of Mini-Mental State Examination scores) as well as soluble and total fractions of brain Aβ42. Results: TGFβ2 was significantly increased in AD and DLB, but not in PDD. TGFβ2 also correlated with scores for neurofibrillary tangles, Lewy bodies (within the LBD group), dementia severity, and soluble Aβ42 concentration, but not with neuritic plaque scores, total Aβ42, or monomeric α-synuclein immunoreactivity. Conclusions: TGFβ2 is increased in the temporal cortex of AD and DLB, and its correlations with neuropathological and clinical markers of disease severity as well as with soluble Aβ42 load suggest a potential pathogenic role in mediating the neurotoxicity of non-fibrillar Aβ. Our study also indicates the potential utility of targeting TGFβ2 in pharmacotherapeutic approaches to AD and DLB.

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

The translocase of the outer membrane (TOM) is a vital mitochondrial transport system facilitating the importation of nuclear encoded proteins into the organelle. While mitochondrial dysfunction, including perturbation of oxidative phosphorylation (OXPHOS) complex, is evident in Alzheimer's disease (AD), it remains unclear whether the observed OXPHOS deficits may be associated with TOM alterations. Objectives: to correlate TOM subunits with OXPHOS complex proteins in AD. Methods: Postmortem neocortex (BA40) fromADand age-matched controls were processed to obtain mitochondrial enriched homogenates for the measurement of Tom20, Tom22, Tom40, and Tom70 as well as components of OXPHOS complex I-V by immunoblotting.Results: Tom20 and Tom70 immunoreactivities were significantly reduced in AD, as were components of OXPHOS complex I and III. Both Tom20 and Tom70 positively correlated with complex III and V, while Tom20 also correlated with complex IV. Conclusion: Reductions in certain TOMsubunits and their correlations with specific OXPHOS complex proteins suggest that an impaired mitochondrial transportation system may contribute to previously observed oxidative phosphorylation deficits in AD. Follow-up studies are needed to corroborate the present correlative study.

Neuropsychiatric symptoms (NPSs) are hallmarks of Alzheimer's disease (AD), causing substantial distress for both people with dementia and their caregivers, and contributing to early institutionalization. They are among the earliest signs and symptoms of neurocognitive disorders and incipient cognitive decline, yet are under-recognized and often challenging to treat. With this in mind, the Alzheimer's Association convened a Research Roundtable in May 2016, bringing together experts from academia, industry, and regulatory agencies to discuss the latest understanding of NPSs and review the development of therapeutics and biomarkers of NPSs in AD. This review will explore the neurobiology of NPSs in AD and specific symptoms common in AD such as psychosis, agitation, apathy, depression, and sleep disturbances. In addition, clinical trial designs for NPSs in AD and regulatory considerations will be discussed.

This article reviews current treatment strategies and recent advances for the Lewy body dementias (LBDs). Current available symptom treatment strategies are based on monoaminergic, cholinergic and glutaminergic neurotransmitter systems. Relatively robust evidence exists for cholinesterase inhibitors for cognitive impairment in LBD and in Parkinson’s disease for antidepressants, clozapine and recently pimavanserin for psychosis. interpidine (RVT 101) and nelotanserin are currently under investigation. Non-pharmacological interventions, such as cognitive stimulation, physical exercises and neuromodulation strategies, may be useful in Parkinson’s disease but have not yet been tested in dementias. Disease-modifying approaches are aimed at preventing, slowing or ameliorating the production, aggregation and deposition of pathological proteins, including immunotherapy targeting α-synuclein and an ongoing trial using ambroxol which increases glucocerebrosidase activity to lower the levels of the protein alpha-synuclein. Other disease-modifying clinical trials are using agents to augment insulin signalling, stem cell therapy, reducing amyloid pathology and gene therapy.

BACKGROUND: Health and social care provision for an ageing population is a global priority. Provision for those with dementia and hip fracture has specific and growing importance. Older people who break their hip are recognised as exceptionally vulnerable to experiencing confusion (including but not exclusively, dementia and/or delirium and/or cognitive impairment(s)) before, during or after acute admissions. Older people experiencing hip fracture and confusion risk serious complications, linked to delayed recovery and higher mortality post-operatively. Specific care pathways acknowledging the differences in patient presentation and care needs are proposed to improve clinical and process outcomes. METHODS: This protocol describes a multi-centre, feasibility, cluster-randomised, controlled trial (CRCT) to be undertaken across ten National Health Service hospital trusts in the UK. The trial will explore the feasibility of undertaking a CRCT comparing the multicomponent PERFECTED enhanced recovery intervention (PERFECT-ER), which acknowledges the differences in care needs of confused older patients experiencing hip fracture, with standard care. The trial will also have an integrated process evaluation to explore how PERFECT-ER is implemented and interacts with the local context. The study will recruit 400 hip fracture patients identified as experiencing confusion and will also recruit "suitable informants" (individuals in regular contact with participants who will complete proxy measures). We will also recruit NHS professionals for the process evaluation. This mixed methods design will produce data to inform a definitive evaluation of the intervention via a large-scale pragmatic randomised controlled trial (RCT). DISCUSSION: the trial will provide a preliminary estimate of potential efficacy of PERFECT-ER versus standard care; assess service delivery variation, inform primary and secondary outcome selection, generate estimates of recruitment and retention rates, data collection difficulties, and completeness of outcome data and provide an indication of potential economic benefits. The process evaluation will enhance knowledge of implementation delivery and receipt. TRIAL REGISTRATION: ISRCTN, 99336264. Registered on 5 September 2016.

Lewy body dementia is the second most common neurodegenerative dementia and is pathologically characterized by α-synuclein positive cytoplasmic inclusions, with varying amounts of amyloid-β (Aβ) and hyperphosphorylated tau (tau) aggregates in addition to synaptic loss. A dysfunctional ubiquitin proteasome system (UPS), the major proteolytic pathway responsible for the clearance of short lived proteins, may be a mediating factor of disease progression and of the development of α-synuclein aggregates. In the present study, protein expression of a key component of the UPS, the RPT6 subunit of the 19S regulatory complex was determined. Furthermore, the main proteolytic-like (chymotrypsin- and PGPH-) activities have also been analyzed. The middle frontal (Brodmann, BA9), inferior parietal (BA40), and anterior cingulate (BA24) gyrus' cortex were selected as regions of interest from Parkinson's disease dementia (PDD, n = 31), dementia with Lewy bodies (DLB, n = 44), Alzheimer's disease (AD, n = 16), and control (n = 24) brains. Clinical and pathological data available included the MMSE score. DLB, PDD, and AD were characterized by significant reductions of RPT6 (one-way ANOVA, p 

Background Parkinson's Disease (PD) psychosis refers to the spectrum of illusions, formed hallucinations and delusions that occur in PD. Visual hallucinations and illusions are thought to be caused by specific cognitive and higher visual function deficits and patients who develop such symptoms early in the disease course have greater rates of cognitive decline and progression to dementia. To date, no studies have investigated whether such deficits are found prior to the onset of PD psychosis. Method Here we compare baseline cognitive, biomarker (structural imaging and cerebrospinal fluid) and other PD psychosis risk factor data in patients who go on to develop illusions or hallucinations within 3-4 years of follow-up in the Parkinson's Progression Markers Initiative cohort of newly diagnosed PD. Results of n=423 patients with PD, n=115 (27%) reported predominantly illusions with the median time of onset at 19.5 months follow-up. At study entry these patients had reduced CSF amyloid Aß 1-42, lower olfaction scores, higher depression scores and increased REM sleep behaviour disorder symptoms compared to patients without early onset PD psychosis but no differences in cognitive, higher visual or structural imaging measures. A subset of patients with early onset formed hallucinations (n=21) had reduced higher visual function at baseline, cortical thinning in parietal, occipital and frontal cortex and reduced hippocampal volume. Conclusions the findings suggest early onset illusions and formed hallucinations are linked to amyloid pathology in PD and point to a difference in the underlying pathophysiological mechanism of illusions and formed hallucinations, with implications for their respective links to future cognitive decline.

Recent findings of morphological and functional changes in Parkinson's disease brains have shown altered synapse formation, but their role in cognitive decline is still an area under exploration. Here we measured the concentration of three key synaptic proteins, Rab3A, SNAP25 and neurogranin by enzyme-linked immunosorbent assay, in cerebrospinal fluid from a total of 139 participants (87 controls and 52 Parkinson's disease patients out of which 30 were drug-naïve) and explored their associations with motor and cognitive symptoms. Associations with motor disease stage (assessed by Hoehn and Yahr scale) and cognitive performance (assessed by the Montreal Cognitive Assessment scores) were explored. An overall increase in the concentration of SNAP25 was found in Parkinson's disease patients (p = 0.032). Increased neurogranin levels were found in the drug naïve patients subgroup (p = 0.023). Significant associations were observed between increased concentration of neurogranin and cognitive impairment in total Parkinson's disease group (p = 0.017), as well as in the drug naïve (p = 0.021) and with motor disease stage (p = 0.041). There were no significant disease-driven changes observed in the concentration of Rab3a. Concentrations SNAP25 and neurogranin were increased in cerebrospinal fluid of Parkinson's disease patients in a disease specific manner and related to cognitive and motor symptom severity. Future longitudinal studies should explore whether cerebrospinal fluid synaptic proteins can predict cognitive decline in Parkinson's disease.

Objectives: to examine the cost of care for people with dementia in institutional care settings, to understand the major cost drivers and to highlight opportunities for service development. Methods: Data on 277 residents with dementia in 16 UK residential or nursing homes were collected. We estimated care and support costs and fitted models to the data. Sensitivity analyses were also conducted. Results: Care home residents cost £792 weekly: 95% of the costs accounted for by direct fees. Hospital contacts contributed the largest proportion of the additional costs. Having an established diagnosis of dementia (b = 0.070; p < 0.05) was associated with higher costs. No association was found between cost and needs (b = −0.002; p = 0.818). Conclusion: the absence of an association between cost and needs emphasizes the importance of a more needs-based costing system which could result in clinical and economic advantages. Copyright © 2016 John Wiley & Sons, Ltd.

Dementia with Lewy bodies is the second most common form of neurodegenerative dementia, yet scarce evidence is available about its prognosis and natural history, which are crucial to inform clinical practice and research. Patients with dementia with Lewy bodies might have a less favourable prognosis, with accelerated cognitive decline, shorter lifespan, and increased admission to residential care than patients with Alzheimer's disease. Health-care costs and, importantly, caregiver burden, are also reported to be higher in dementia with Lewy bodies than in Alzheimer's disease. It is probable that causative factors for this less favourable prognosis are the increased prevalence and early emergence of neuropsychiatric symptoms in patients with dementia with Lewy bodies, and the challenge of accurate diagnosis. Evidence concerning quality of life and hospital admission rates is limited, despite their clinical and economic relevance.

In 2007, the clinical and research profile of illusions, hallucinations, delusions and related symptoms in Parkinson disease (PD) was raised with the publication of a consensus definition of PD psychosis. Symptoms that were previously deemed benign and clinically insignificant were incorporated into a continuum of severity, leading to the rapid expansion of literature focusing on clinical aspects, mechanisms and treatment. Here, we review this literature and the evolving view of PD psychosis. Key topics include the prospective risk of dementia in individuals with PD psychosis, and the causal and modifying effects of PD medication. We discuss recent developments, including recognition of an increase in the prevalence of psychosis with disease duration, addition of new visual symptoms to the psychosis continuum, and identification of frontal executive, visual perceptual and memory dysfunction at different disease stages. In addition, we highlight novel risk factors - for example, autonomic dysfunction - that have emerged from prospective studies, structural MRI evidence of frontal, parietal, occipital and hippocampal involvement, and approval of pimavanserin for the treatment of PD psychosis. The accumulating evidence raises novel questions and directions for future research to explore the clinical management and biomarker potential of PD psychosis.

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

Background: Vascular dementia is the second most common cause of dementia affecting over seven million people worldwide, yet there are no licensed treatments. There is an urgent need for a clinical trial in this patient group. Subcortical ischaemic vascular dementia is the most common variant of vascular dementia. This randomised trial will investigate whether use of calcium channel blockade with amlodipine, a commonly used agent, can provide the first evidence-based pharmacological treatment for subcortical ischaemic vascular dementia. Methods/Design: This is a randomised controlled trial of calcium channel blockade with Amlodipine for the treatment oF subcortical ischaEmic vasCular demenTia (AFFECT) to test the hypothesis that treatment with amlodipine can improve outcomes for these patients in a phase IIb, multi-centre, double-blind, placebo-controlled randomised trial. The primary outcome is the change from baseline to 12 months in the Vascular Dementia Assessment Scale cognitive subscale (VADAS-cog). Secondary outcomes include cognitive function, executive function, clinical global impression of change, change in blood pressure, quantitative evaluation of lesion accrual based on magnetic resonance imaging (MRI), health-related quality of life, activities of daily living, non-cognitive dementia symptoms, care-giver burden and care-giver health-related quality of life, cost-effectiveness and institutionalisation. A total of 588 patients will be randomised in a 1:1 ratio to either amlodipine or placebo, recruited from sites across the UK and enrolled in the trial for 104 weeks. Discussion: There are no treatments licensed for vascular dementia. The most common subtype is subcortical ischaemic vascular dementia (SIVD). This study is designed to investigate whether amlodipine can produce benefits compared to placebo in established SIVD. It is estimated that the numbers of people with VaD and SIVD will increase globally in the future and the results of this study should inform important treatment decisions. Trial registration: Current Controlled Trials ISRCTN31208535. Registered on 7 March 2014.

Background: the association between mortality risk and use of antidepressants in people with dementia is unknown. Objective: to describe the use of antidepressants in people with different dementia diagnoses and to explore mortality risk associated with use of antidepressants 3 years before a dementia diagnosis. Methods: Study population included 20 050 memory clinic patients from the Swedish Dementia Registry (SveDem) diagnosed with incident dementia. Data on antidepressants dispensed at the time of dementia diagnosis and during 3-year period before dementia diagnosis were obtained from the Swedish Prescribed Drug Register. Cox regression models were used. Results: During a median follow-up of 2 years from dementia diagnosis, 25.8% of dementia patients died. A quarter (25.0%) of patients were on antidepressants at the time of dementia diagnosis, while 21.6% used antidepressants at some point during a 3-year period before a dementia diagnosis. Use of antidepressant treatment for 3 consecutive years before a dementia diagnosis was associated with a lower mortality risk for all dementia disorders and in Alzheimer's disease. Conclusion: Antidepressant treatment is common among patients with dementia. Use of antidepressants during prodromal stages may reduce mortality in dementia and specifically in Alzheimer's disease.

Objectives: to assess the long-term mortality risk associated with antipsychotic drug (AP) use in nursing homes. Design: a longitudinal study with 5 assessments over a 75-month follow-up period. Setting: a representative sample of nursing home patients in 4 Norwegian counties. Participants: at baseline, 1163 patients were included. At the last follow-up, 98 patients were still alive. Measurements: Prevalent drug use at each assessment was registered. Level of dementia, neuropsychiatric symptoms, level of functioning, medical health, and use of restraints were recorded at each assessment. A Cox regression model with time-dependent psychotropic drug use as the main predictor was estimated and adjusted for confounders. Results: in unadjusted Cox regression, a lower mortality risk was associated with the use of other psychotropic drugs, but not APs, compared with nonusers. In the adjusted analysis, neither use of APs nor other psychiatric drugs was associated with increased mortality risk. Higher age, male gender, not being married, medical disease burden, lower level of functioning, more severe degree of dementia, and a higher number of drugs were all associated with increased mortality risk. Conclusion: in this long-term study of nursing home patients, AP drug use was not associated with increased risk of mortality. This is in line with results from earlier studies of clinical samples, but contrasts with results from randomized controlled trials and registry-based studies. The findings should be interpreted with caution. Taking into account the modest benefit and high risk of adverse effects of AP drug use, nonpharmacological treatment remains the first-line treatment approach.

Objectives Apathy is common, impactful, and difficult to manage in people with dementia. We evaluated the efficacy of nonpharmacological interventions, exercise, and social interaction, in combination with antipsychotic review, to reduce apathy in people with dementia living in nursing homes in a cluster randomized controlled trial (RCT). Methods Well-being and health for people with dementia (WHELD) program included a 2 × 2 × 2 factorial cluster RCT involving people with dementia living in 16 nursing homes in the United Kingdom. All homes received training in person-centered care, and were randomized to receive antipsychotic review, social interaction, and exercise, either alone or in combinations. Apathy was one of the secondary outcomes of the WHELD trial, and it was measured by the Neuropsychiatric Inventory–nursing home version at baseline and 9 months (n = 273). We used multilevel mixed effects linear regression models to assess the impact of the interventions on apathy. Results Prevalence of apathy was 44.0% (n = 120; 95% confidence interval [CI] 38.1%–49.9%) at baseline. Severity of apathy had significant positive correlations with dementia severity, neuropsychiatric symptoms, depressive symptoms, agitation, and the needs of the people with dementia (P 

Objectives: We report the cognitive decline in persons diagnosed with mild dementia with Lewy bodies (DLB) and mild Alzheimer's disease (AD) during 5 years of annual follow-ups. Methods: Patients were recruited into the study from geriatric, psychiatric and neurology clinics in Western Norway during 2005-2013. They were diagnosed according to clinical consensus criteria, based on standardised clinical rating scales. Autopsy-based diagnoses were available for 20 cases. Cognitive decline for up to 5 years was assessed using the Clinical Dementia Rating (CDR) scale and the Mini-Mental State Examination (MMSE). Survival analysis including Cox regression (time to reach severe dementia) and linear mixed-effects (lme) modelling were used to model the decline on MMSE. Results: at least one follow-up assessment was available for 67 patients with DLB and 107 patients with AD, with a median follow-up time of 4.3 years. The time to reach severe dementia was significantly shorter in DLB (median 1793 days) compared with AD (1947 days; p=0.033), and the difference remained significant in the multiple Cox regression analysis (HR=2.0, p

Alpha-synuclein (β-syn) aggregations are the key pathological hallmark of dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), but are also frequently present in Alzheimer's disease (AD). Much remains unknown about the role of β-syn in the synapse and the wider role of synaptic dysfunction in these dementias. Changes in concentrations of key 'SNAP (Soluble N-ethylmaleimide Sensitive Factor Attachment Protein) Receptor' (SNARE) proteins as a consequence of alterations in the aggregation state of β-syn may contribute to synaptic dysfunction in patients with DLB, PDD, and AD and result in impaired cognition.We have studied a large cohort (n = 130) of autopsy confirmed DLB, PDD, AD, and control brains. Using semi-quantitative western blotting, we have demonstrated significant changes across the diagnostic groups of DLB, PDD, and AD in the SNARE and vesicle proteins syntaxin, Munc18, VAMP2, and monomeric β-syn in the prefrontal cortex, with a significant reduction of Munc18 in AD patients (p < 0.001). This correlated to the final MMSE score before death (p = 0.016). We also identified a significant negative correlation between the duration of dementia and the levels of the binding partners VAMP2 (p = 0.0004) and monomeric β-syn (p = 0.0002). Our findings may indicate that an upregulation of SNARE complex related proteins occurs in the early stages of disease as an attempt at compensating for failing synapses, prior to widespread deposition of pathological β-syn.

Down's syndrome is the most common genetic cause of learning difficulties, and individuals with this condition represent the largest group of people with dementia under the age of 50 years. Genetic drivers result in a high frequency of Alzheimer's pathology in these individuals, evident from neuroimaging, biomarker, and neuropathological findings, and a high incidence of cognitive decline and dementia. However, cognitive assessment is challenging, and diagnostic methods have not been fully validated for use in these patients; hence, early diagnosis remains difficult. Evidence regarding the benefits of cholinesterase inhibitors and other therapeutic options to treat or delay progressive cognitive decline or dementia is very scarce. Despite close similarities with late-onset Alzheimer's disease, individuals with Down's syndrome respond differently to treatment, and a targeted approach to drug development is thus necessary. Genetic and preclinical studies offer opportunities for treatment development, and potential therapies have been identified using these approaches.

Background: Dementia is a common feature of Parkinson's disease (PD), but the neuropathological changes associated with the development of Parkinson's disease dementia (PDD) are only partially understood. Mitochondrial dysfunction is a hallmark of PD but has not been studied in PDD. Methods: Molecular and biochemical approaches were used to study mitochondrial activity and quantity in postmortem prefrontal cortex tissue. Tissues from pathologically confirmed PD and PDD patients and from age-matched controls were used to analyze the activity of mitochondrial enzyme complex nicotinamide adenine dinucleotide:ubiquinone oxidoreductase, or complex I (the first enzyme in the mitochondrial respiratory chain), mitochondrial DNA levels, and the expression of mitochondrial proteins. Results: Complex I activity was significantly decreased (27% reduction; analysis of variance with Tukey's post hoc test; P

BACKGROUND: up to 90 % of people living with dementia in care homes experience one or more behaviours that staff may describe as challenging to support (BSC). of these agitation is the most common and difficult to manage. The presence of agitation is associated with fewer visits from relatives, poorer quality of life and social isolation. It is recommended that agitation is treated through psychosocial interventions. Dementia Care Mapping™ (DCM™) is an established, widely used observational tool and practice development cycle, for ensuring a systematic approach to providing person-centred care. There is a body of practice-based literature and experience to suggests that DCM™ is potentially effective but limited robust evidence for its effectiveness, and no examination of its cost-effectiveness, as a UK health care intervention. Therefore, a definitive randomised controlled trial (RCT) of DCM™ in the UK is urgently needed. METHODS/DESIGN: a pragmatic, multi-centre, cluster-randomised controlled trial of Dementia Care Mapping (DCM™) plus Usual Care (UC) versus UC alone, where UC is the normal care delivered within the care home following a minimum level of dementia awareness training. The trial will take place in residential, nursing and dementia-specialist care homes across West Yorkshire, Oxfordshire and London, with residents with dementia. A random sample of 50 care homes will be selected within which a minimum of 750 residents will be registered. Care homes will be randomised in an allocation ratio of 3:2 to receive either intervention or control. Outcome measures will be obtained at 6 and 16 months following randomisation. The primary outcome is agitation as measured by the Cohen-Mansfield Agitation Inventory, at 16 months post randomisation. Key secondary outcomes are other BSC and quality of life. There will be an integral cost-effectiveness analysis and a process evaluation. DISCUSSION: the protocol was refined following a pilot of trial procedures. Changes include replacement of a questionnaire, whose wording caused some residents distress, to an adapted version specifically designed for use in care homes, a change to the randomisation stratification factors, adaption in how the staff measures are collected to encourage greater compliance, and additional reminders to intervention homes of when mapping cycles are due, via text message. TRIAL REGISTRATION: Current Controlled Trials ISRCTN82288852. Registered on 16 January 2014. Full protocol version and date: v7.1: 18 December 2015.

Objectives: This paper reports on the acceptability and effectiveness of the FITS (Focussed Intervention Training and Support) into Practice Programme. This intervention was scaled up from an earlier cluster randomised-controlled trial that had proven successful in significantly decreasing antipsychotic prescribing in care homes.Method: an in depth 10-day education course in person-centred care was delivered over a three-month period, followed by six supervision sessions. Participants were care-home staff designated as Dementia Care Coaches (DCCs) responsible for implementing interventions in 1 or 2 care homes. The course and supervision was provided by educators called Dementia Practice Development Coaches (DPDCs).Effectiveness data included monitoring antipsychotic prescriptions, goal attainment, knowledge, attitudes and implementation questionnaires. Qualitative data included case studies and reflective journals to elucidate issues of implementation.Results: of the 100 DCCs recruited, 66 DCCs completed the programme. Pre-post questionnaires demonstrated increased knowledge and confidence and improved attitudes to dementia. Twenty per cent of residents were prescribed antipsychotics at baseline which reduced to 14% (31% reduction) with additional dose reductions being reported alongside improved personalised goal attainment. Crucial for FITS into Practice to succeed was the allocation and protection of time for the DCC to attend training and supervision and to carry out implementation tasks in addition to their existing job role. Evaluation data showed that this was a substantial barrier to implementation in a small number of homes.Discussion and conclusions: the FITS into practice programme was well evaluated and resulted in reduction in inappropriate anti-psychotic prescribing. Revisions to the intervention are suggested to maximise successful implementation.

Objective to contribute to an optimised training programme for care staff that supports the implementation of evidence-based psychosocial interventions in long-term care. Methods Qualitative study that involved focus group discussions with 119 care home staff within 16 care homes in the UK. Part of wider clinical trial aimed at developing and evaluating an effective and practical psychosocial intervention and implementation approach for people with dementia in long-term care. Inductive thematic analysis was used to identify themes and interpret the data. Results the findings highlighted that successful training and support interventions must acknowledge and respond to 'whole home' issues. Three overarching themes emerged as influential: the importance of contextual factors such as staff morale, interpersonal relationships within the home, and experience and perceived value of the proposed intervention. Conclusions Priority must be given to obtain the commitment of all staff, management and relatives to the training programme and ensure that expectations regarding interaction with residents, participation in activities and the reduction of medication are shared across the care home.

OBJECTIVE: This study evaluated the impact of antipsychotic review, social interaction, and exercise, in conjunction with person-centered care, on antipsychotic use, agitation, and depression in people with dementia living in nursing homes. METHOD: a cluster-randomized factorial controlled trial with two replications was conducted in people with dementia in 16 U.K. nursing homes. All homes received training in person-centered care. Eight homes were randomly assigned to antipsychotic review, to a social interaction intervention, and to an exercise intervention for 9 months, with most homes assigned to more than one intervention. The primary outcome measures were antipsychotic use, agitation, and depression. Secondary outcome measures were overall neuropsychiatric symptoms and mortality. RESULTS: Antipsychotic review significantly reduced antipsychotic use by 50% (odds ratio 0.17, 95% confidence interval [CI] 0.05 to 0.60). Antipsychotic review plus the social interaction intervention significantly reduced mortality (odds ratio 0.26, 95% CI 0.13 to 0.51) compared with the group receiving neither. The group receiving antipsychotic review but not the social intervention showed significantly worse outcome in neuropsychiatric symptoms compared with the group receiving neither (score difference +7.37, 95% CI 1.53 to 13.22). This detrimental impact was mitigated by concurrent delivery of the social intervention (-0.44, CI -4.39 to 3.52). The exercise intervention significantly improved neuropsychiatric symptoms (-3.59, 95% CI -7.08 to -0.09) but not depression (-1.21, CI -4.35 to 1.93). None of the interventions had a significant impact specifically on agitation. CONCLUSIONS: While reductions in antipsychotic use can be achieved by using a "real world" intervention, this may not be of benefit to people with dementia in the current climate of more judicious prescribing unless nonpharmacological interventions such as social interaction or exercise are provided in parallel.

Collapsin response mediator protein-2 (CRMP2) regulates axonal growth cone extension, and increased CRMP2 phosphorylation may lead to axonal degeneration. Axonal and synaptic pathology is an important feature of Lewy body dementias (LBD), but the state of CRMP2 phosphorylation (pCRMP2) as well as its correlations with markers of neurodegeneration have not been studied in these dementias. Hence, we measured CRMP2 phosphorylation at Thr509, Thr514 and Ser522, as well as markers of β-amyloid (Aβ), tau-phosphorylation, α-synuclein and synaptic function in the postmortem neocortex of a longitudinally assessed cohort of LBD patients characterized by low (Parkinson's disease dementia, PDD) and high (dementia with Lewy bodies, DLB) burden of Alzheimer type pathology. We found specific increases of pCRMP2 at Thr514 in DLB, but not PDD. The increased CRMP2 phosphorylation correlated with fibrillogenic Aβ as well as with losses of markers for axon regeneration (β-III-tubulin) and synaptic integrity (synaptophysin) in LBD. In contrast, pCRMP2 alterations did not correlate with tau-phosphorylation or α-synuclein, and also appear unrelated to immunoreactivities of putative upstream kinases glycogen synthase kinase 3β and cyclin-dependent kinase 5, as well as to protein phosphatase 2A. In conclusion, increased pCRMP2 may underlie the axonal pathology of DLB, and may be a novel therapeutic target. However, antecedent signaling events as well as the nature of pCRMP2 association with Aβ and other neuropathologic markers require further study.

Background: Postsynaptic cholinergic deficits, including reduced cortical muscarinic M1 receptor coupling to G-proteins, are neurochemical findings postulated to underlie the limited efficacy of presynaptically-targeted cholinergic replacement therapies in Alzheimer's disease (AD). While the loss of M1-G-protein coupling has been associated with β-amyloid (Aβ) burden in AD, the status of M1 coupling to G-proteins in Parkinson's disease-related or mixed dementias is unclear. Objective: to test the hypothesis that M1 receptor uncoupling is correlated with Aβ burden, we aimed to study muscarinic M1 neurochemical parameters in neurodegenerative dementias characterized by low and high Aβ loads. Methods: M1 receptors, M1 coupling to G-proteins as well as Aβ were measured in postmortem frontal cortex of a cohort of longitudinally assessed patients with Parkinson's Disease Dementia (PDD, low Aβ load) and AD with significant subcortical cerebrovascular disease (AD CVD, high Aβ load). Results: We found unchanged levels of M1 receptors in both dementia groups, while M1 coupling was reduced only in AD CVD (p

Individuals with Alzheimer's disease (AD) are in susceptible patient groups in which pain is an important clinical issue that is often underdiagnosed. However, it is unclear whether decreased pain complaints in patients with AD result from elevated pain tolerance or an impaired ability to communicate sensations. Here, we explored if AD-related pathology is present in key regions of the pain pathway and assessed whether nociceptive thresholds to acute noxious stimulation are altered in the double-mutant APPswe × PS1.M146V (TASTPM) transgenic mouse model of AD. TASTPM mice exhibited an age-dependant cognitive deficit at the age of 6 months, but not at 4 months, a deficit that was accompanied by amyloid plaques in the cortex, hippocampus, and thalamus. In the spinal cord, β-amyloid (APP/Aβ) immunoreactivity was observed in dorsal and ventral horn neurons, and the expression of vesicular glutamate transporter 2 (VGLUT2) was significantly reduced, while the expression of the inhibitory peptides enkephalins was increased in TASTPM dorsal horn, consistent with an increased inhibitory tone. TASTPM mice displayed reduced sensitivity to acute noxious heat, which was reversed by naloxone, an opioid antagonist. This study suggests that increased inhibition and decreased excitation in the spinal cord may be responsible for the reduced thermal sensitivity associated with AD-related pathology.

Introduction Our objective was to compare the levels of three synaptic proteins involved in different steps of the synaptic transmission: Rab3A, SNAP25, and neurogranin, in three common forms of dementia: Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and Parkinson's disease dementia. Methods a total of 129 postmortem human brain samples were analyzed in brain regional specific manner exploring their associations with morphologic changes and cognitive decline. Results We have observed robust changes reflecting synaptic dysfunction in all studied dementia groups. There were significant associations between the rate of cognitive decline and decreased levels of Rab3 in DLB in the inferior parietal lobe and SNAP25 in AD in the prefrontal cortex. of particular note, synaptic proteins significantly discriminated between dementia cases and controls with over 90% sensitivity and specificity. Discussion Our findings suggest that the proposition that synaptic markers can predict cognitive decline in AD, should be extended to Lewy body diseases.

Background: Antipsychotic (AP) drugs are commonly used to manage the behavioural symptoms of dementia. Nevertheless, international (i.e. the European Medicines Agency in Europe) and national (i.e. the Medicines and Healthcare products Regulatory Agency in the UK and the Italian Drug Agency) regulatory agencies issued safety warnings against AP use in dementia in 2004 and 2009. Objective: the aim of this study is to investigate the short- and long-term impact of safety warnings on the use of APs in UK and Italian persons with dementia using two nationwide databases: the Health Improvement Network (THIN) from the UK and the Health Search Database-Cegedim-Strategic Data-Longitudinal Patient Database (HSD-CSD-LPD) from Italy. Methods: We calculated the overall quarterly prevalence of AP use by class and by individual drug in persons with dementia aged ≥65 years and used generalized linear models to explore the effect of the safety warnings. Results: We identified 58,497 and 10,857 individuals aged ≥65 years with dementia from the THIN and HSD-CSD-LPD databases, respectively, over the period 2000–2012. After the 2004 warnings, the use of atypical APs decreased, whereas the use of conventional APs increased, in Italy and the UK until 2009. However, the trend for APs individually showed that the use of risperidone/olanzapine decreased, whereas the use of quetiapine increased in both countries. After the 2009 warnings (until 2012), the use of atypical and conventional APs decreased in the UK (from 11 to 9 and 5 to 3 %, respectively), but such use increased in Italy (from 11 to 18 and 9 to 14 %, respectively). Conclusion: the 2004 warnings led to a reduction in the use of olanzapine and risperidone and increased the use of quetiapine/conventional APs in both countries. From 2009, the use of APs decreased in persons with dementia in the UK but not in Italy. Possible reasons for the difference in AP use between the two countries include a more proactive approach towards reducing the use of APs in the UK than in Italy.

Aim: the unfolded protein response (UPR) is a pro-survival defence mechanism induced during periods of endoplasmic reticulum stress, and it has recently emerged as an attractive therapeutic target across a number of neurodegenerative conditions, but has not yet been studied in synuclein disorders. Methods: the level of a key mediator of the UPR pathway, glucose-regulated protein 78 (GRP78), also known as binding immunoglobulin protein (BiP), was measured in post mortem brain tissue of patients with dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) in comparison with Alzheimer's disease (AD) and age-matched controls using Western blot. The UPR activation was further confirmed by immunohistochemical detection of GRP78/BiP and phosphorylated protein kinase RNA-like endoplasmic reticulum (ER) kinase (p-PERK). Results: GRP78/BiP was increased to a greater extent in DLB and PDD patients compared with AD and control subjects in cingulate gyrus and parietal cortex. However, there were no changes in the prefrontal and temporal cortices. There was a significant positive correlation between GRP78/BiP level and α-synuclein pathology in the cingulate gyrus, while AD-type pathology showed an inverse correlation relationship in the parietal cortex. Conclusion: Overall, these results give emphasis to the role of UPR in Lewy body dementias, and suggest that Lewy body degeneration, in combination with AD-type pathologies, is associated with increased UPR activation to a greater extent than AD alone, possibly as a consequence of the increasing load of ER proteins. This work also highlights a novel opportunity to explore the UPR as a therapeutic target in synuclein diseases.

Vascular dementia (VaD) is a major contributor to the dementia syndrome and is described as having problems with reasoning, planning, judgment, and memory caused by impaired blood flow to the brain and damage to the blood vessels resulting from events such as stroke. There are a variety of etiologies that contribute to the development of vascular cognitive impairment and VaD, and these are often associated with other dementia-related pathologies such as Alzheimer disease. The diagnosis of VaD is difficult due to the number and types of lesions and their locations in the brain. Factors that increase the risk of vascular diseases such as stroke, high blood pressure, high cholesterol, and smoking also raise the risk of VaD. Therefore, controlling these risk factors can help lower the chances of developing VaD. This update describes the subtypes of VaD, with details of their complex presentation, associated pathological lesions, and issues with diagnosis, prevention, and treatment.

Background: to produce a practice guideline that includes a set of detailed consensus principles regarding the prescription of antipsychotics (APs) amongst people with dementia living in care homes. Methods: We used a modified Delphi consensus procedure with three rounds, where we actively specified and optimized statements throughout the process, utilizing input from four focus groups, carried out in UK, Norway, and the Netherlands. This was done to identify relevant themes and a set of statement that experts agreed upon using the Research and Development/University of California at Los Angeles (RAND/UCLA) methodology. Results: a total of 72 scientific and clinical experts and 14 consumer experts reached consensus upon 150 statements covering five themes: (1) General prescription stipulations, (2) assessments prior to prescription, (3) care and treatment plan, (4) discontinuation, and (5) long-term treatment. Conclusions: in this practice guideline, novel information was provided about detailed indication and thresholds of symptoms, risk factors, circumstances at which APs should be stopped or tapered, specific criteria for justifying long-term treatment, involvement of the multidisciplinary team, and family caregiver in the process of prescription. The practice guideline is based on formal consensus of clinicians and consumer experts and provides clinicians relevant practical information that is lacking in current guidelines.

Amyloid-β peptides and hyper-phosphorylated tau are the main pathological hallmarks of Alzheimer’s disease (AD). Given the recent failure of several large-scale clinical trials and the lack of disease-modifying pharmacological treatments, there is an urgent need to develop alternative therapies. A clinical grade human CTX0E03 neural stem cell line has recently passed phase I trials in people with stroke. However, this cell line has not been investigated in other neurodegenerative disorders. This study investigates the survival of CTX0E03 cells under conditions based on the underlying AD pathology. Cell viability assays showed a concentration dependence of this cell line to the toxic effects of Aβ1-42, but not Aβ1-40, and okadaic acid, a phosphatase 2A inhibitor. Notably, CTX0E03 cell line displayed toxicity at concentrations significantly higher than both rat neural stem cells and those previously reported for primary cultures. These results suggest CTX0E03 cells could be developed for clinical trials in AD patients.

Background: a common complication after stroke is development of cognitive impairment and dementia. However, effective strategies for reducing the risk of developing these problems remain undefined. Potential strategies include intensive lowering of blood pressure (BP) and/or lipids. This paper summarises the baseline characteristics, statistical analysis plan and feasibility of a randomised control trial of blood pressure and lipid lowering in patients post-stroke with the primary objective of reducing cognitive impairment and dementia. Methods: the Prevention of Decline in Cognition After Stroke Trial (PODCAST) was a multi-centre prospective randomised open-label blinded-endpoint controlled partial-factorial internal pilot trial running in secondary and primary care. Participants without dementia were enrolled 3-7 months post ischaemic stroke or spontaneous intracerebral haemorrhage, and randomised to intensive versus guideline BP lowering (target systolic BP

BACKGROUND: Nursing home patients have complex mental and physical health problems, disabilities and social needs, combined with widespread prescription of psychotropic drugs. Preservation of their quality of life is an important goal. This can only be achieved within nursing homes that offer competent clinical conditions of treatment and care. COmmunication, Systematic assessment and treatment of pain, Medication review, Occupational therapy, Safety (COSMOS) is an effectiveness-implementation hybrid trial that combines and implements organization of activities evidence-based interventions to improve staff competence and thereby the patients' quality of life, mental health and safety. The aim of this paper is to describe the development, content and implementation process of the COSMOS trial. METHODS/DESIGN: COSMOS includes a 2-month pilot study with 128 participants distributed among nine Norwegian nursing homes, and a 4-month multicenter, cluster randomized effectiveness-implementation clinical hybrid trial with follow-up at month 9, including 571 patients from 67 nursing home units (one unit defined as one cluster). Clusters are randomized to COSMOS intervention or current best practice (control group). The intervention group will receive a 2-day education program including written guidelines, repeated theoretical and practical training (credited education of caregivers, physicians and nursing home managers), case discussions and role play. The 1-day midway evaluation, information and interviews of nursing staff and a telephone hotline all support the implementation process. Outcome measures include quality of life in late-stage dementia, neuropsychiatric symptoms, activities of daily living, pain, depression, sleep, medication, cost-utility analysis, hospital admission and mortality. DISCUSSION: Despite complex medical and psychosocial challenges, nursing home patients are often treated by staff possessing low level skills, lacking education and in facilities with a high staff turnover. Implementation of a research-based multicomponent intervention may improve staff's knowledge and competence and consequently the quality of life of nursing home patients in general and people with dementia in particular. TRIAL REGISTRATION: ClinicalTrials.gov NCT02238652.

Objective Depression is a common symptom in dementia with Lewy bodies (DLB), Parkinson disease dementia (PDD), and Alzheimer disease (AD), yet its molecular basis remains unclear and current antidepressants do not appear to be effective. Cerebral zinc has been implicated in depression and synaptic dysfunction. We investigated the relationship between synaptic zinc regulation (for which zinc transporter 3 [ZnT3] is responsible) and depression in a large clinicopathologic study. Methods We examined brains from people with PDD (N = 29), DLB (N = 27), and AD (N = 15) and comparison subjects without depression or dementia (N = 24). Individuals were categorized according to the presence and severity of depression (on a scale of 0-3) based on standardized assessments during life (principally Neuropsychiatric Inventory). Western blotting was used to determine ZnT3 levels in Brodmann area 9 (BA9), and regression analysis was used to determine the relationship between ZnT3 and depression. Results Reductions in ZnT3 in BA9 were significantly associated with elevated depression scores in the study cohort (β = -0.351, df = 93, t = -3.318 p = 0.0004). This association remained when only individuals with DLB, PDD, and no dementia or depression were examined (β = -0.347, df = 78, t = -3.271, p = 0.002) or only individuals with AD and no dementia or depression were examined (β = -0.433, df = 37, t = -2.924, p = 0.006). Conclusion Although decreased zinc levels have been implicated in the genesis of depression in animal models and in major depressive disorder in humans, this study provides the first evidence of a role for zinc in depression in people with dementia and highlights zinc metabolism as a therapeutic target.

Drug repositioning offers an innovative approach to drug discovery with great potential in the field of Alzheimer's Disease and dementia therapeutics. Investigation of licensed compounds enables processing through the drug discovery pipeline in a rapid and cost-effective manner. A growing body of evidence supports the translation of priority compounds to be taken forward to clinical trials, based on established and proposed mechanisms of action. A number of drugs have already entered clinical trial following repositioning, and novel technologies have been created to enable high-throughput screening. This review discusses the novel approaches that build on transcriptional signature profiling to support repositioning in AD, and the novel candidate drugs that are emerging from this exciting new technique.

OBJECTIVES: to establish the mortality risk and adverse events associated with the use of atypical antipsychotic medications in people with Parkinson disease psychosis (PDP) in a clinically defined trial cohort. DESIGN: Post hoc analysis of data from a multicenter, open-label extension study of pimavanserin comparing people taking and not taking current antipsychotics. SETTING: Primary and secondary care medical centers in the United States, Canada, Europe, and India. PARTICIPANTS: a total of 459 people with PDP enrolled in the extension study. Participants were between ages 30 and 80 years, and had an established diagnosis of idiopathic Parkinson disease and moderate to severe psychosis. INTERVENTIONS: Participants were categorized into 2 groups: those receiving concomitant antipsychotic medications ("concurrent APD") and those who did not take antipsychotic medications at any time during the study ("no APD"). Participants were receiving 40 mg pimavanserin daily in addition to concurrent antipsychotics and Parkinson disease medications. MAIN OUTCOME MEASURES: Safety assessments at 2 weeks; 1, 3, 6, 9, and 12 months; and every 6 months thereafter, including evaluation of adverse events (AEs), vital signs, weight, physical examinations, 12-lead electrocardiograms, clinical laboratory tests (serum chemistry, hematology, and urinalysis), and the Unified Parkinson's Disease Rating Scale Parts II and III (UPDRS-II+III, activities of daily living and motor impairment, respectively). Differences between participants taking and not taking current antipsychotics were evaluated using incidence rate ratios (IRRs) with 95% confidence intervals (CIs). RESULTS: There was significant increase in the mortality rate for participants taking concurrent antipsychotics compared with the group not taking antipsychotic medications (IRR 4.20, 95% CI 2.13-7.96). Participants who received a concurrent antipsychotic were also significantly more likely to experience overall a serious AE (IRR 2.95, 95% CI 2.02-4.24), any antipsychotic-related event (IRR 1.66, 95% CI 1.18-2.29), cognition-related events (IRR 2.70, 95% CI 1.19-5.58), infections (IRR 1.97, 95% CI 1.17-3.16), and edema (IRR 2.61, 95% CI 1.09-5.59). The risk of falls, stroke, sedation, orthostatic hypotension, and thromboembolic events was also increased in these individuals but this was not significant. CONCLUSIONS: This study highlights a significant risk of mortality, and severe AEs in patients with Parkinson disease receiving atypical antipsychotics. This is similar to or greater than the risks seen in people with Alzheimer disease, although with a less clear-cut risk of stroke and a longer delay to increased mortality.

Objective: to determine whether depressive symptoms are associated with medial temporal lobe atrophy in older people with and without Alzheimer disease (AD). Method: a total of 368 memory clinic patients with AD, mild cognitive impairment, and subjective cognitive impairment (SCI) were included. Depressive symptoms were defined as a score of 8 or higher on Cornell Scale for Depression in Dementia or use of antidepressant medications. Magnetic resonance imaging and computer tomography scans were rated for medial temporal lobe atrophy (MTA), using the Scheltens scale. For a subsample (n = 57 patients), hippocampal volume was manually traced. Results: Based on visual assessment, AD patients with depressive symptoms had less atrophy of the right medial temporal lobe (odds ratio [OR] for having MTA: 0.39; 95% confidence interval [CI] 0.16-0.99) and decreased scores on Scheltens scale for the left medial temporal lobe (OR: 0.43, 95% CI 0.19-0.96) in comparison to AD patients without depressive symptoms. In the subgroup where manual tracing was used to measure hippocampal volume, people with SCI experiencing depressive symptoms had smaller right (mean difference: 0.28 cm3; P =. 005) and left (mean difference 0.32 cm3; P =. 002) hippocampal volumes compared to people with SCI who did not have depressive symptoms. Conclusion: Hippocampal atrophy was more pronounced among patients having SCI with depressive symptoms, while themedial temporal lobe was less atrophic in patients having AD with depressive symptoms than those without depressive symptoms. These findings suggest that different mechanisms underlie depression in older people with and without AD and may explain some of the inconsistent observations in previous studies.

Background: the management of disruptive neuropsychiatric symptom (NPS) such as agitation and aggression (A/A) is a major priority in caring for people with Alzheimer's disease (AD). Few effective pharmacological or non-pharmacological options are available. Results of randomized clinical trials (RCTs) of drugs for A/A have been disappointing. This may result from the absence of biological efficacy for medications tested in treating A/A. It may also be related to methodological issues such as the choice of outcomes. The aim of this review was to highlight key methodological issues pertaining to RCTs of current and emerging medications for the treatment of A/A in AD. Methods: We searched PubMed/Medline, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for RCTs comparing medications with either placebo or other drugs in the treatment of A/A in AD, between January 2008 and December 2013. Results: We identified a total of 18 RCTs; of these, 11 were completed and 7 ongoing. of the ongoing RCTs, only one is in Phase III. Seven of 10 completed RCTs with reported results did not report greater benefit from drug than placebo. Each of the completed RCTs used a different definition of clinically significant A/A. There was considerable heterogeneity in study design. The primary endpoints were largely proxy-based but a variety of scales were used. The definition of caregiver and scales used to assess caregiver outcomes were similarly heterogeneous. Placebo response was notable in all trials. Conclusions: This review highlights a great heterogeneity in RCTs design of drugs for A/A in AD and some key methodological issues such as definition of A/A, choice of outcome measures and caregiver participation that could be addressed by an expert consensus to optimize future trials design.

OBJECTIVE: in both dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), attentional dysfunction is a core clinical feature together with disrupted episodic memory. This study evaluated the cognitive effects of memantine in DLB and PDD using automated tests of attention and episodic memory. METHODS: a randomised double-blind, placebo-controlled, 24-week three centre trial of memantine (20 mg/day) was conducted in which tests of attention (simple and choice reaction time) and word recognition (immediate and delayed) from the CDR System were administered prior to dosing and again at 12 and 24 weeks. Although other results from this study have been published, the data from the CDR System tests were not included and are presented here for the first time. RESULTS: Data were available for 51 patients (21 DLB and 30 PDD). In both populations, memantine produced statistically significant medium to large effect sized improvements to choice reaction time, immediate and delayed word recognition. CONCLUSIONS: These are the first substantial improvements on cognitive tests of attention and episodic recognition memory identified with memantine in either DLB or PDD.

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.

Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are characterized by the presence of α-synuclein-containing Lewy bodies and Lewy neurites. However, both dementias also show variable degrees of Alzheimer's disease (AD) pathology (senile plaques and neurofibrillary tangles), particularly in areas of the cortex associated with higher cognitive functions. This study investigates the contribution of the individual and combined pathologies in determining the rate of cognitive decline. Cortical α-synuclein, phosphorylated tau (phosphotau) and Aβ plaque pathology in 34 PDD and 55 DLB patients was assessed semi-quantitatively in four regions of the neocortex. The decline in cognition, assessed by Mini Mental State Examination, correlated positively with the cortical α-synuclein load. Patients also had varying degrees of senile Aβ plaque and phosphotau pathology. Regression analyses pointed to a combined pathology (Aβ plaque plus phosphotau plus α-synuclein-positive features), particularly in the prefrontal cortex (BA9) and temporal lobe neocortex with the superior and middle temporal gyrus (BA21, 22), being a major determining factor in the development of dementia. Thus, cognitive decline in Lewy body dementias is not a consequence of α-synuclein-induced neurodegeneration alone but senile plaque and phosphorylated tau pathology also contribute to the overall deficits.

BACKGROUND: Reports of altered endogenous neurogenesis in people with Alzheimer's disease (AD) and transgenic AD models have suggested that endogenous neurogenesis may be an important treatment target, but there is considerable discrepancy among studies. We examined endogenous neurogenesis and glia changes across the range of pathologic severity of AD in people with and without dementia to address this key question. METHODS: Endogenous neurogenesis and glia in the subventricular zone and dentate gyrus neurogenic niches were evaluated using single and double immunohistochemistry and a validated antibody selection for stage-specific and type-specific markers in autopsy tissue from a representative cohort of 28 participants in the Medical Research Council Cognitive Function and Ageing Study. Immunopositive cells were measured blinded to diagnosis using bright-field and fluorescent microscopy. RESULTS: the number of newly generated neurons significantly declined only in the dentate gyrus of patients with severe tau pathology. No other changes in other neurogenic markers were observed in either of the neurogenic niches. Alterations in astrocytes and microglia were also observed in the dentate gyrus across the different stages of tau pathology. No change in any of the markers was observed in individuals who died with dementia compared with individuals who did not die with dementia. CONCLUSIONS: Alterations in endogenous neurogenesis appeared to be confined to a reduction in the generation of new neurons in the dentate gyrus of patients with AD and severe neurofibrillary tangle pathology and were accompanied by changes in the glia load. These data suggest that intervention enhancing endogenous neurogenesis may be a potential therapeutic target in AD.

Health-care stakeholders increasingly recognize that the scientific and economic challenges associated with Alzheimer's disease (AD) are simply too great for individual stakeholder groups to address solely from within their own silos. In the necessary spirit of collaboration, we present in this perspective a set of multicountry multistakeholder recommendations to improve the organization of existing AD and dementia care and the development of new treatments. In brief, the five recommendations are (1) health-care systems must make choices regarding the patient populations to be diagnosed and treated, (2) health-care systems should use an evidence-based standard of care, (3) increased collaboration between public and private institutions is needed to enhance research, (4) reimbursement end points need to be agreed on and validated, and (5) innovative business models should be used to spur the introduction of new medicines.

The loss of zinc transporter 3 (ZnT3) has been implicated in age-related cognitive decline in mice, and the protein has been associated with plaques. We investigated the levels of ZnT3 and postsynaptic density protein 95 (PSD95), a marker of the postsynaptic terminal, in people with Parkinson's disease dementia (PDD, n= 31), dementia with Lewy bodies (DLB, n= 44), Alzheimer's disease (AD, n= 16), and controls (n= 24), using semiquantitative western blotting and immunohistochemistry in 3 cortical regions. Standardized cognitive assessments during life and semiquantitative scoring of amyloid β (Aβ), tau, and α-synuclein at postmortem were used to investigate the relationship between ZnT3 and PSD95, cognition and pathology. Associations were observed between ZnT3 and PSD95 levels in prefrontal cortex and cognitive impairment (p= 0.001 and p= 0.002, respectively) and between ZnT3 levels in the parietal cortex and cognitive impairment (p= 0.036). Associations were also seen between ZnT3 levels in cingulate cortex and severity of Aβ (p= 0.003) and tau (p= 0.011) pathologies. DLB and PDD were characterized by significant reductions of PSD95 (p < 0.05) and ZnT3 (p < 0.001) in prefrontal cortex compared with controls and AD. PSD95 levels in the parietal cortex were found to be decreased in AD cases compared with controls (p= 0.02) and PDD (p= 0.005). This study has identified Zn2+ modulation as a possible novel target for the treatment of cognitive impairment in DLB and PDD and the potential for synaptic proteins to be used as a biomarker for the differentiation of DLB and PDD from AD.

There are around 35 million people worldwide with dementia, more than half of whom have Alzheimer's disease (AD). Presently there are only four licensed pharmacological treatments available for treating the neuropsychological symptoms of AD. These include cholinesterase inhibitors, licensed for the treatment of people with mild to moderate AD, and an N-methyl-D-aspartate antagonist (memantine) licensed for the treatment of people with moderate to severe AD. These treatment options have modest symptomatic benefits for at least 6 months and possibly for 2 years or longer. Increasing evidence from randomized controlled trials has shown the potential value of cognitive training and cognitive rehabilitation in people with AD. There is a good evidence base to support the use of cognitive stimulation as a nonpharmacological treatment approach for people with AD, of which the most promising is cognitive stimulation therapy (CST). CST has shown benefits for cognition and well-being in people with dementia across a number of randomized controlled trials. There are important key issues related to the use of CST for people with AD, such as long-term benefits, implementation of individualized CST, adjunctive benefits with pharmacological treatments, and optimizing overall implementation of CST. Some of these key issues are already being addressed by ongoing clinical trials. Nevertheless, the strength of the current evidence from randomized controlled trials gives strong support to clinical implementation of CST in practice. Ongoing clinical trials will help to refine and optimize the use of CST in clinical practice.

Context: Depression is common in dementia, especially in the early stages, with important clinical implications, but the etiology is unknown and most likely heterogeneous. Antidepressant use in the elderly without dementia has previously been shown to be associated with high risks of adverse events and with structural brain alterations. Objective: to investigate cortical changes associated with depression and antidepressant use in patients with mild Alzheimer's disease (AD) and Lewy body dementia (LBD). Methods: 74 subjects with mild AD and LBD from geriatric and psychiatry outpatient clinics in Western Norway were included. The Montgomery-Asberg Depression Rating Scale (MADRS) was used to assess depression. Automatic preprocessing using Freesurfer included steps for white and grey matter surface reconstruction. The resulting cortical thickness was analyzed using linear modeling. Results: Clusters of depression-associated thinning were found in prefrontal and temporal areas. Treatment-associated thinning was observed in the parahippocampal region and was significant even after correction for age, sex, AD/LBD diagnosis, and MADRS scores. Conclusion: Depression in mild AD and LBD is associated with cortical thinning in prefrontal and temporal areas. The findings suggest that depressive symptoms in mild dementia could develop due to neurodegeneration in the same neural circuits that are critical for depression across different brain disorders. Antidepressant use in patients with mild AD and LBD is associated with parahippocampal thinning. Taken together with low efficacy of antidepressants in cognitively impaired patients and high risks of adverse events, our results suggest a need to re-evaluate the treatment approaches for depression and the role of antidepressants in patients with dementia. (Am J Geriatr Psychiatry 2014; 22:4-13). © 2014 American Association for Geriatric Psychiatry.

Background: a large and increasing number of older people in the UK are living in care homes. Dementia is a frequent reason underlying admission and determining care needs, but prevalence data are becoming increasingly outdated and reliant on brief screening instruments. Objective: to describe the prevalence and severity of dementia, depression, behavioural problems and relevant medication use in a representative sample of residential and nursing care home residents. Design/setting: a survey conducted in 15 randomly selected South East London care homes. Consensus clinical dementia diagnoses were made from multi-source information, and the Clinical Dementia Rating (CDR) Scale applied. Depression was ascertained using the Cornell Depression in Dementia Scale and psychological/behavioural problems using the Neuropsychiatric Inventory (NPI). Participants: three hundred and one residents with a mean (SD) age of 83.5 (9.8) and 65.8% female were included. Results: dementia (CDR 1-3) prevalence was 75.1% overall, 55.8% in residential homes, 91.0% in residential elderly mentally infirm care and 77.0% in nursing homes. Depression prevalences were 26.5, 22.0 and 29.6%, respectively, and mean (95% CI) NPI severity scores 3.99 (3.47-4.50), 6.34 (5.29-7.39) and 6.10 (5.50-6.70) with 87.3% of the sample exhibiting at least one NPI symptom. Antidepressants were prescribed in 25.6, 25.0 and 41.3%, respectively, and antipsychotics in 7.0, 34.1 and 19.1%. Conclusion: dementia is substantially more common in care homes than recorded diagnoses would suggest, but studies using brief screening instruments may overestimate prevalence. High prevalences of depressive and/or behavioural symptoms and psychotropic use suggest significant unmet need. © the Author 2014. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved.

Dementia with Lewy bodies and Parkinson's disease dementia are different clinical phenotypes of Lewy body dementias differentiated by the temporal relationship between parkinsonism and dementia onset. At present, it is unclear whether the glutamatergic system is affected in these disorders. In this study, we measured α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor GluA subunits in the postmortem neocortex of a cohort of prospectively studied Lewy body dementia cases, as well as age-matched controls by immunoblotting. We found losses of GluA2/3/4 immunoreactivities in Lewy body dementias which correlated with higher pre-death Hoehn and Yahr scores and with longer Parkinson's disease duration before dementia onset, but not with dementia severity, cortical Lewy body burden, or amyloid plaque and neurofibrillary tangle burden. Our study suggests that GluA2/3/4 losses may be a neurochemical marker of motor disability in Lewy body dementias. © 2013 Springer-Verlag Wien.

Damage to sub-cortical white matter is a key substrate of vascular dementia (VaD) leading to deficits in executive function and cognitive processing speed. Dynamin1 is a 100. kDa protein, accounting for 0.4% of the total brain protein, and has a central role in many intracellular processes such as synaptic vesicle trafficking and recycling. In this study, we examined the status of Dynamin1 in the white matter from frontal cortex area. In order to measure the levels of Dynamin1, we isolated cortical white matter from a total of 34 post-mortem brains derived from controls (N= 11), mixed Alzheimer's disease (AD) and VaD (N= 8), VaD (N= 7), and stroke no dementia (SND, N= 8) subjects. A commercial ELISA kit was then used to determine the level of Dynamin1. In comparison to controls, Dynamin1 was elevated in patients SND (+400%) and reduced in patients with mixed VaD (-50%). Furthermore, levels of Dynamin1 were significantly associated with preserved cognition as indicated by the MMSE and CAMCOG and upregulation of vesicular glutamate transporter 1. This work indicates that Dynamin1 is associated with both preserved cognition and regenerative responses in older people with cerebrovascular disease and may represent a novel treatment target. © 2014.

Dementia with Lewy Bodies (DLB) and Parkinson's Disease Dementia (PDD) together, represent the second most common cause of dementia, after Alzheimer's disease (AD). The synaptic dysfunctions underlying the cognitive decline and psychiatric symptoms observed throughout the development of PDD and DLB are still under investigation. In this study we examined the expression level of Dynamin1 and phospho-CaMKII, key proteins of endocytosis and synaptic plasticity respectively, as potential markers of molecular processes specifically deregulated with DLB and/or PDD. In order to measure the levels of these proteins, we isolated grey matter from post-mortem prefrontal cortex area (BA9), anterior cingulated gyrus (BA24) and parietal cortex (BA40) from DLB and PDD patients in comparison to age-matched controls and a group of AD cases. Clinical and pathological data available included the MMSE score, neuropsychiatric history, and semi-quantitative scores for AD pathology (plaques - tangles) and for α-synuclein (Lewy bodies). Changes in the expression of the synaptic markers, and correlates with neuropathological features and cognitive decline were predominantly found in the prefrontal cortex. On one hand, levels of Dynamin1 were significantly reduced, and correlated with a higher rate of cognitive decline observed in cases from three dementia groups. On the other hand, the fraction of phospho-CaMKII was decreased, and correlated with a high score of plaques and tangles in BA9. Interestingly, the correlation between the rate of cognitive decline and the level of Dynamin1 remained when the analysis was restricted to the PDD and DLB cases, highlighting an association of Dynamin1 with cognitive decline in people with Lewy Body dementia.

Background Depression is common in nursing home (NH) patients with dementia, and often clustered with anxiety and other mood symptoms. An association between pain and depressive symptoms has been reported, but the impact of pain management on depression and other mood symptoms has not been investigated. Objective Secondary analyses of a cluster randomized clinical trial examine the response of dementia-related mood symptoms to a Stepwise Protocol of Treating Pain. Method Three-hundred fifty-two patients with moderate and severe dementia and significant behavioural disturbances, related to 60 clusters (i.e. clusters defined as single independent NH units) in 18 NHs of Western Norway, were included. All patients in the intervention group received individual daily pain treatment with paracetamol, extended release morphine, buprenorphine transdermal patch or pregabaline for 8 weeks, with additional follow-up assessment 4 weeks after completion of the intervention. Clusters randomized to control received usual treatment. A mood cluster consisting of depression, anxiety, sleep disorders, apathy and appetite items from the Neuropsychiatric Inventory-Nursing Home (NPI-NH) was the primary outcome. Results Analysed by Mann-Whitney U-tests, Stepwise Protocol of Treating Pain conferred significant benefit in treatment of the NPI-NH mood cluster (F = 13.4, df = 1;299, p < 0.001) and depression (F = 2.0, df = 1;301, p = 0.025). Further analyses highlighted improvements in apathy (F = 5.3, df = 1;300, p = 0.017), night-time behaviours (F = 3.1, df = 1;301, p = 0.050), and appetite items (F = 11.6, df = 1;301, p = 0.005), but not irritability (p = 0.092) and anxiety (p = 0.125). Conclusion Mood symptoms including depression significantly improved with pain treatment, emphasizing the importance of more rigorous treatment of pain in agitated people with dementia. Findings have potentially immediate clinical relevance. © 2013 the Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons Ltd.

The socio-economic impact of Alzheimer′s disease (AD) and other dementias is enormous, and the potential economic challenges ahead are clear given the projected future numbers of individuals with these conditions. Because of the high prevalence and cost of dementia, it is very important to assess any intervention from a cost-effectiveness viewpoint. The diagnostic criteria for preclinical AD suggested by the National Institute on Aging and Alzheimer's Association workgroups in combination with the goal of effective disease-modifying treatment (DMT) are, however, a challenge for clinical practice and for the design of clinical trials. Key issues for future cost-effectiveness studies include the following: (i) the consequences for patients if diagnosis is shifted from AD-dementia to predementia states, (ii) bridging the gap between clinical trial populations and patients treated in clinical practice, (iii) translation of clinical trial end-points into measures that are meaningful to patients and policymakers/payers and (iv) how to measure long-term effects. To improve cost-effectiveness studies, long-term population-based data on disease progression, costs and outcomes in clinical practice are needed not only in dementia but also in predementia states. Reliable surrogate end-points in clinical trials that are sensitive to detect effects even in predementia states are also essential as well as robust and validated modelling methods from predementia states that also take into account comorbidities and age. Finally, the ethical consequences of early diagnosis should be considered. © 2014 the Association for the Publication of the Journal of Internal Medicine.

BACKGROUND: Pain is frequent and distressing in people with dementia, but no randomized controlled trials have evaluated the effect of analgesic treatment on pain intensity as a key outcome. METHODS: Three hundred fifty-two people with dementia and significant agitation from 60 nursing home units were included in this study. These units, representing 18 nursing homes in western Norway, were randomized to a stepwise protocol of treating pain (SPTP) or usual care. The SPTP group received acetaminophen, morphine, buprenorphine transdermal patch and pregabalin for 8 weeks, with a 4-week washout period. Medications were governed by the SPTP and each participant's existing prescriptions. We obtained pain intensity scores from 327 patients (intervention n = 164, control n = 163) at five time points assessed by the primary outcome measure, Mobilization-Observation-Behaviour-Intensity-Dementia-2 (MOBID-2) Pain Scale. The secondary outcome was activities of daily living (ADL). We used a linear intercept mixed model in a two-way repeated measures configuration to assess change over time and between groups. RESULTS: the SPTP conferred significant benefit in MOBID-2 scores compared with the control group [average treatment effect (ATE) -1.388; p < 0.001] at week 8, and MOBID-2 scores worsened during the washout period (ATE = -0.701; p = 0.022). Examining different analgesic treatments, benefit was conferred to patients receiving acetaminophen compared with the controls at week 2 (ATE = -0.663; p = 0.010), continuing to increase until week 8 (ATE = -1.297; p < 0.001). Although there were no overall improvements in ADL, an increase was seen in the group receiving acetaminophen (ATE = +1.0; p = 0.022). CONCLUSION: Pain medication significantly improved pain in the intervention group, with indications that acetaminophen also improved ADL function.

BACKGROUND: People with dementia living in care homes often have complex mental health problems, disabilities and social needs. Providing more comprehensive training for staff working in care home environments is a high national priority. It is important that this training is evidence based and delivers improvement for people with dementia residing in these environments. Well-being and Health for People with Dementia (WHELD) combines the most effective elements of existing approaches to develop a comprehensive but practical staff training intervention. This optimised intervention is based on a factorial study and qualitative evaluation, to combine: training on person-centred care, promoting person-centred activities and interactions, and providing care home staff and general practitioners with updated knowledge regarding the optimal use of psychotropic medications for persons with dementia in care homes. DESIGN: the trial will be a randomised controlled two-arm cluster single blind trial that will take place for nine months across 80 care homes in the United Kingdom. DISCUSSION: the overarching goal of this trial is to determine whether this optimised WHELD intervention is more effective in improving the quality of life and mental health than the usual care provided to people with dementia living in nursing homes. This study will be the largest and best powered randomised controlled trial (RCT) evaluating the benefits of an augmented person-centred care training intervention in care homes worldwide. TRIAL REGISTRATION: Current controlled trials ISRCTN62237498 Date registered: 5 September 2013.

INTRODUCTION: Alzheimer's disease (AD), Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB) together account for the vast majority of individuals with dementia. Approximately 35 million people worldwide are affected with this condition, and despite decades of research, effective therapies that slow or reverse disease progression have not yet been developed. The recent failure of several large-scale clinical trials is beginning to challenge the magnitude of focus on amyloid-related therapies for AD, and newer drug targets that have shown promise in the laboratory are being investigated in clinical trials. AREAS COVERED: This review summarises the current understanding of the underlying biology of AD, PDD and DLB and outlines the most recent drug candidates in advanced clinical trials. EXPERT OPINION: the lack of success in drug discovery for disease-modifying therapies for AD, PDD and DLB can be attributed to limitations in the design of clinical trials and the narrow focus of molecular targets for treatment. New avenues for drug discovery including repositioning and novel target identification may now provide opportunities for success, provided a critical mass of clinical trials is achieved through increased investment.

Objective: to study mortality in subjects with mild dementia in Norway with a special focus on patients with Lewy body dementia (LBD) compared to Alzheimer's disease (AD). Methods: all referrals of mild dementia patients to dementia clinics in western Norway from March 2005 to March 2007 were included and followed until December 2012. Diagnoses were based on a comprehensive standardized assessment program. Results: of 209 patients, 137 (66%) had AD and 53 (25%) had LBD. Dementia was associated with increased mortality (standardized mortality ratio = 1.8, AD 1.5, LBD 2.6). The median survival time was 6.2 years (95% CI 5.4-6.9). Predictors of mortality were age at diagnosis (HR 1.1 per year) and LBD diagnosis (HR 2.4). Conclusion: Dementia patients had an increased mortality, particularly those with LBD. © 2014 S. Karger AG, Basel.

The potential role of rural land use in mitigating flood risk and protecting water supplies continues to be of great interest to regulators and planners. The ability of hydrologists to quantify the impact of rural land use change on the water cycle is however limited and we are not able to provide consistently reliable evidence to support planning and policy decisions. This shortcoming stems mainly from lack of data, but also from lack of modelling methods and tools. Numerous research projects over the last few years have been attempting to address the underlying challenges. This paper describes these challenges, significant areas of progress and modelling innovations, and proposes priorities for further research. The paper is organised into five inter-related subtopics: (1) evidence-based modelling; (2) upscaling to maximise the use of process knowledge and physicsbased models; (3) representing hydrological connectivity in models; (4) uncertainty analysis; and (5) integrated catchment modelling for ecosystem service management. It is concluded that there is room for further advances in hydrological data analysis, sensitivity and uncertainty analysis methods and modelling frameworks, but progress will also depend on continuing and strengthened commitment to long-term monitoring and inter-disciplinarity in defining and delivering land use impacts research.

Parkinson's disease (PD) affects 10 million people worldwide. Half will develop psychosis, the majority experiencing hallucinations rather than delusions. Emergence of psychosis increases the likelihood of institutionalization and mortality. Where pharmacological treatment is warranted, options are limited. Most currently licensed atypical antipsychotics are ineffective or worsen motor symptoms in people with PD. This review of provides an overview of the current landscape of treatments and the opportunities in emerging research. Clozapine is the only licensed antipsychotic with proven efficacy, although the associated side effects limit its use. With recent advances in understanding the role of serotonin, rational drug design approaches have delivered a novel pharmacological treatment with recently proven efficacy in clinical trials of people with PD and psychosis. Pimavanserin represents an important addition to treatment.

Objective There is great interest in conducting clinical trials of disease-modifying therapies in the prodromal (early, pre-dementia), asymptomatic stages of Alzheimer's disease. Diagnostic biomarker tests offer a means of identifying prodromal patients, but it is unclear how potential participants feel about their use. Deciding whether to take part in a clinical trial is a complex process in which eligible participants must balance risks and discomforts against uncertain benefits. We sought to explore the views of potential participants through qualitative research methods. Methods Focus groups with people with early memory problems, current and former family carers explored attitudes towards participating in clinical trials in the prodromal stages of the disease, using an example of anti-amyloid antibody-therapy (immunotherapy), which are currently in development. Results Despite the complexities involved, almost all participants had a clear idea about whether they, personally, would like to take part. Many were highly motivated to obtain an unambiguous diagnosis, regardless of their desire to participate in a clinical trial. Participants expressed minimal concern regarding the risk of adverse events associated with immunotherapy, whereas certain tests and trial procedures provoked greater anxiety. People with memory problems were found to assess the study demands in relation to their own priorities and circumstances. Conclusions the priorities of patients might be different to clinicians and those who design and regulate clinical trials. Patient views can be used to inform the ethical debate around the disclosure of biomarker status, the design of clinical trials and the content of trial information. Copyright © 2013 John Wiley & Sons, Ltd.

BACKGROUND: Parkinson's disease psychosis, which includes hallucinations and delusions, is frequent and debilitating in people with Parkinson's disease. We aimed to assess safety and efficacy of pimavanserin, a selective serotonin 5-HT2A inverse agonist, in this population. METHODS: in our 6 week, randomised, double-blind, placebo-controlled study, we enrolled adults (aged ≥40 years) with Parkinson's disease psychosis. Antipsychotic treatments were not permitted during the study, but controlled antiparkinsonian medication or deep brain stimulation was allowed. Eligible participants entered a 2 week non-pharmacological lead-in phase to limit the placebo response, after which they were randomly allocated (1:1) to receive pimavanserin 40 mg per day or matched placebo. The primary outcome was antipsychotic benefit as assessed by central, independent raters with the Parkinson's disease-adapted scale for assessment of positive symptoms (SAPS-PD) in all patients who received at least one dose of study drug and had a SAPS assessment at baseline and at least one follow-up. We assessed safety and tolerability in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01174004. FINDINGS: Between Aug 11, 2010, and Aug 29, 2012, we randomly allocated 199 patients to treatment groups. For 90 recipients of placebo and 95 recipients of pimavanserin included in the primary analysis, pimavanserin was associated with a -5·79 decrease in SAPS-PD scores compared with -2·73 for placebo (difference -3·06, 95% CI -4·91 to -1·20; p=0·001; Cohen's d 0·50). Ten patients in the pimavanserin group discontinued because of an adverse event (four due to psychotic disorder or hallucination within 10 days of start of the study drug) compared with two in the placebo group. Overall, pimavanserin was well tolerated with no significant safety concerns or worsening of motor function. INTERPRETATION: Pimavanserin may benefit patients with Parkinson's disease psychosis for whom few other treatment options exist. The trial design used in this study to manage placebo response could have applicability to other studies in neuropsychiatric disease. FUNDING: ACADIA Pharmaceuticals.

It is known that Alzheimer's disease (AD) presents at an early age in people with Down syndrome (DS). The trisomy 21 in DS provides an opportunity to study the effect of duplicated genes in AD. APP and BACE2 are 2 genes located in chromosome 21 and related to AD. We looked into our cohort of 67 DS cases with dementia for the effect of BACE2 variants in age of onset of dementia. of the 83 single-nucleotide polymorphisms (SNPs), 6 were associated with age of onset and another 8 SNPs were borderline associated. Our finding also replicated a previous study showing association of rs2252576 with AD. © 2014 the Authors.

Objective: to investigate short- and long-term mortality risk associated with the use of antipsychotics in dementia outpatients, assessing the risk over specific time frames and quantifying the risk by the individual antipsychotics. Methods: This populationbased study used data from the Norwegian Prescription Database. The study sample included 26,940 dementia outpatients aged 65 years or older prescribed antidementia drugs and psychotropics from Norwegian pharmacies between 2004 and 2010. Results: Cox survival analyses, adjusted for age, gender, mean daily defined dose, and severe medical conditions, showed that antipsychotic use compared with other psychotropics involved approximately twice the mortality risk in outpatients with dementia. Furthermore, these results are consistent for all investigated time points after first dispensing the drugs (hazard ratio [HR]30days = 2.1 [95% confidence interval {CI}: 1.6e2.9] to HR730e2,400days = 1.7 [95% CI: 1.6e1.9]). Haloperidol was associated with higher mortality risk (HR30days = 1.7 [95% CI: 1.0e3.0] to HR730e2,400days = 1.4 [95% CI: 1.0e1.9]) than risperidone. Conclusion: This first study to observe antipsychotic use and mortality in dementia outpatients over more than 6 years clearly shows that antipsychotics involve increased short- and long-term mortality risk. Physicians may justly consider antipsychotics to be the best option for some dementia patients among available nonpharmacologic and pharmacologic treatments. However, although causal conclusions are precluded due to limited adjustments in the analyses, the findings support the current treatment recommendations that antipsychotics should be avoided or used with great caution. © 2014 American Association for Geriatric Psychiatry.

To develop an evidence base to help predict the impacts of land management change on flood generation, four experimental sites were established on improved grassland used for sheep grazing at the Pontbren catchment in upland Wales, UK. At each site, three plots were established where surface runoff was measured, supplemented by measurements of soil infiltration rates and soil and vegetation physical properties. Following baseline monitoring, treatments were applied to two of the plots: exclusion of sheep (ungrazed) and exclusion of sheep and planting with native broadleaf tree species (tree planted), with the third plot acting as a control (grazed pasture). Due to a particularly dry summer that occurred pre-treatment, the soil hydrological responses were initially impacted by the effects of the climate on soil structure. Nevertheless, treatments did have a clear influence on soil hydrological response. On average, post-treatment runoff volumes were reduced by 48% and 78% in ungrazed and tree-planted plots relative to the control, although all results varied greatly over the sites. Five years following treatment application, near-surface soil bulk density was reduced and median soil infiltration rates were 67 times greater in plots planted with trees compared to grazed pasture. The results illustrate the potential use of upland land management for ameliorating local-scale flood generation but emphasise the need for long-term monitoring to more clearly separate the effects of land management from those of climatic variability. © 2013 John Wiley & Sons, Ltd.

Objectives: Behavioral disturbances and pain are common in nursing home (NH) patients with dementia. An association between pain and increased agitation has been suggested, and recently a significant reduction of agitation has been demonstrated by pain treatment in patients with moderate to severe dementia. We now examined which specific agitated behaviors respond to individualized pain treatment. Design: Cluster randomized clinical trial. Setting: 60 clusters (i.e. clusters defined as single independent NH units) in 18 NHs within five municipalities of Western Norway. Participants: 352 patients with moderate to severe dementia and clinically significant behavioral disturbances. Intervention: the control group received usual treatment and care. According to a predefined scheme for 8 weeks, all patients in the intervention group received individual daily pain treatment with acetaminophen, extended release morphine, buprenorphine transdermal patch, and/or pregabaline. Measurements: Cohen-Mansfield Agitation Inventory subscales and items. Results: Analyses demonstrated that Factor 3 (Verbally agitated behaviors) showed the largest significant difference (DF = 1204.0, t = -4.308, p

Objective: to investigate the effect on survival of treatment with memantine in patients with dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD). Methods: 75 patients with DLB and PDD were included in a prospective double-blinded randomised placebo-controlled trial (RCT) of memantine, of whom long-term follow-up was available for 42. Treatment response was recorded 24 weeks from baseline and measured by Clinical Global Impression of Change (CGIC). The participants were grouped as responders (CGIC 1-3) or non-responders (CGIC 4-7). The 24-week RCT was followed by open-label treatment and survival was recorded at 36 months. Results: After 36-month follow-up, patients in the memantine group had a longer length of survival compared with patients in the placebo group (log rank x2=4.02, p=0.045). Within the active treatment group, survival analysis 36 months from baseline showed that the memantine responders, based on CGIC, had higher rates of survival compared with the non-responders (log rank x2=6.595, p=0.010). Similar results were not seen in the placebo group. Conclusions: Early treatment with memantine and a positive clinical response to memantine predicted longer survival in patients with DLB and PDD. This suggests a possible disease-modifying effect and also has implications for health economic analysis. However, owing to the small study sample, our results should merely be considered as generating a hypothesis which needs to be evaluated in larger studies. Trial registration number: ISRCTN89624516.

Objectives: Little is known regarding the 'falsenegative' or 'false-positive' striatal dopamine transporter binding on SPECT for the diagnosis of dementia with Lewy bodies (DLB). We explored the clinical course in patients fulfilling the criteria for clinical DLB with a normal ( 123I)FP-CIT SPECT (ie, SPECT scan negative, clinical features positive (S-CF+)) and patients not fulfilling DLB criteria with an abnormal scan (S+CF-). Design: Longitudinal case study over 2-5 years. Setting: Consecutive referrals of patients with mild dementia to dementia clinics in western Norway. Participants: 50 patients (27 men and 23 women; mean age at baseline of 74 (range 52-88)) with (123I) FP-CIT SPECT images underwent cluster analysis: 20/50 patients allocated to a 'DLB' and 8 to a 'non-DLB' cluster were included. Outcome measures: Scores on standardised clinical rating scales for hallucinations, parkinsonism, fluctuations, rapid eye movement (REM) sleep behaviour disorder and visually rated (123I)FP-CIT SPECT. Results: During the follow-up period, in the S+CF- group (n=7), frequency and severity of DLB symptoms tended to increase, particularly parkinsonism (7/7) and cognitive fluctuations (7/7), while severity of visual hallucinations and REM sleep behaviour disorder remained stable. The S-CF+ (n=3) fulfilled the operationalised criteria for probable DLB both at baseline and at the end of the follow-up. Conclusions: the findings suggest that systematic visual analyses of (123I)FP-CIT SPECT can detect people with DLB prior to the development of the full clinical syndrome. In addition, the study indicates that some patients fulfilling clinical criteria for probable DLB have a normal scan, and further studies are required to characterise these patients better.

Objective: to examine the role of butyrylcholinesterase (BuChE) in cholinergic signaling and neurologic conditions, such as Alzheimer's disease (AD). The rationale for inhibiting cholinesterases in the management of AD, including clinical evidence supporting use of the dual acetylcholinesterase (AChE) and BuChE inhibitor rivastigmine, is discussed. Data Sources: PubMed searches were performed using butyrylcholinesterase as a keyword. English-language articles referenced in PubMed as of September 2011 were included. Study Selection and Data Synthesis: English-language articles related to BuChE considered to be of clinical relevance to physicians were included. English-language articles specifically related to AChE were not included, as the role of AChE in cholinergic signaling and the underlying pathology of AD is well documented. Reference lists of included publications were used to supplement the search. Results: AChE and BuChE play a role in cholinergic signaling; BuChE can hydrolyze acetylcholine and compensate for AChE when levels are depleted. In the AD brain, AChE levels decrease, while BuChE levels are reportedly increased or unchanged, with changes becoming more pronounced during the disease course. Furthermore, BuChE genotype may influence AD risk and rate of disease progression. Strategies that increase acetylcholine levels (eg, cholinesterase inhibitors) demonstrate symptomatic efficacy in AD. Rivastigmine has proven cognitive efficacy in clinical trials, and data suggest that its action is mediated, in part, by inhibition of BuChE. Retrospective analyses of clinical trials provide evidence that BuChE genotype may also influence treatment response. Conclusions: AChE-selective inhibitors and a dual AChE and BuChE inhibitor demonstrate symptomatic efficacy in AD. Mounting preclinical and clinical evidence for a role of BuChE in maintaining normal cholinergic function and the pathology of AD provides a rationale for further studies investigating use of rivastigmine in AD and the influence of BuChE genotype on observed efficacy. © 2013 Physicians Postgraduate Press, Inc.

Background/Aims: Post-operative cognitive decline is frequent in older individuals following major surgery; however, biomarkers of this decline are less clearly defined. Methods: Sixty-eight participants over the age of 60 provided blood samples at baseline and 24 h post-surgery. Cognitive decline was measured at baseline and 52 weeks post-surgery using the Cambridge Assessment for Mental Disorder in the Elderly, section B (CAMCOG) score. Plasma levels of neuron-specific enolase (NSE) and S100B were measured by ELISA. Results: Baseline NSE and the change in NSE levels between baseline and 24 h were correlated with the change in CAMCOG score between baseline and 52 weeks. Conclusion: NSE concentrations may be a useful predictor of individuals at risk of more severe long-term cognitive decline. Copyright © 2012 S. Karger AG, Basel.

The single nucleotide polymorphism (SNP) a > G rs2306604 in the gene encoding mitochondrial transcription factor a (TFAM) has been associated with Alzheimer's disease, with the a allele being recognised as a risk factor, but has not been studied in other types of dementia. We hypothesised that TFAM SNP rs2306604 might also be associated with Lewy body dementias. To test this hypothesis rs2306604 genotype was determined in 141 controls and 135 patients with dementia with Lewy bodies (DLB) or Parkinson's disease dementia (PDD). rs2306604 genotype frequencies were significantly different to controls in PDD (p = 0.042), but not in DLB (p = 0.529). The a allele was also associated with PDD (p = 0.024, OR = 2.092), but not DLB (p = 0.429, OR = 1.308). Moreover, the a allele was strongly associated with PDD in males (p = 0.001, OR = 5.570), but not in females (p = 0.832, OR = 1.100). Mitochondrial DNA copy number in the prefrontal cortex was also significantly reduced in PDD patients, but this reduction was not associated with rs2306604 genotype. These data show that the TFAM SNP rs2306604 a allele may be a risk factor for PDD, particularly in males, but not for DLB. Therefore, the genetic factors that predispose individuals to develop dementia may differ in PDD and DLB. © 2013 Elsevier Ireland Ltd.

&lt;b&gt;&lt;i&gt;Background/Aims:&lt;/i&gt;&lt;/b&gt; Cognitive impairment is a well-established correlate of psychotic symptoms in Alzheimer’s disease (AD-P). We review whether this relationship has confounded previous genetic association studies of 5HTTLPR and AD-P. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; We reviewed all studies on 5HTTLPR and conducted a semi-quantitative analysis. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; Three out of 4 studies with low MMSE reported a significant association, while 1 out of 4 with high MMSE reported a significant association. &lt;b&gt;&lt;i&gt;Conclusions:&lt;/i&gt;&lt;/b&gt; Variation in cognitive impairment in past studies has contributed to the inconsistency in findings. The findings presented here bring a greater clarity to our understanding of the role of 5HTTLPR in AD-P.

Background: Depression is a common and costly comorbidity in dementia. There are very few data on the cost-effectiveness of antidepressants for depression in dementia and their effects on carer outcomes. Aims: to evaluate the cost-effectiveness of sertraline and mirtazapine compared with placebo for depression in dementia. Method: a pragmatic, multicentre, randomised placebo-controlled trial with a parallel cost-effectiveness analysis (trial registration: ISRCTN88882979 and EudraCT 2006-000105-38). The primary cost-effectiveness analysis compared differences in treatment costs for patients receiving sertraline, mirtazapine or placebo with differences in effectiveness measured by the primary outcome, total Cornell Scale for Depression in Dementia (CSDD) score, over two time periods: 0-13 weeks and 0-39 weeks. The secondary evaluation was a cost-utility analysis using quality-adjusted life years (QALYs) computed from the Euro-Qual (EQ-5D) and societal weights over those same periods. Results: There were 339 participants randomised and 326 with costs data (111 placebo, 107 sertraline, 108 mirtazapine). For the primary outcome, decrease in depression, mirtazapine and sertraline were not cost-effective compared with placebo. However, examining secondary outcomes, the time spent by unpaid carers caring for participants in the mirtazapine group was almost half that for patients receiving placebo (6.74 v. 12.27 hours per week) or sertraline (6.74 v. 12.32 hours per week). Informal care costs over 39 weeks were £1510 and £1522 less for the mirtazapine group compared with placebo and sertraline respectively. Conclusions: in terms of reducing depression, mirtazapine and sertraline were not cost-effective for treating depression in dementia. However, mirtazapine does appear likely to have been costeffective if costing includes the impact on unpaid carers and with quality of life included in the outcome. Unpaid (family) carer costs were lower with mirtazapine than sertraline or placebo. This may have been mediated via the putative ability of mirtazapine to ameliorate sleep disturbances and anxiety. Given the priority and the potential value of supporting family carers of people with dementia, further research is warranted to investigate the potential of mirtazapine to help with behavioural and psychological symptoms in dementia and in supporting carers. © the British Journal of Psychiatry 2013.

It is known that individuals with Down syndrome develop Alzheimer's disease with an early age at onset, although associated genetic risk factors have not been widely studied. We tested whether genes that increase the risk of late-onset Alzheimer's disease influence the age at onset in Down syndrome using genome-wide association data for age at onset of dementia in a small sample of individuals (N= 67) with Down syndrome. We tested for association with loci previously associated with Alzheimer's disease risk and, despite the small size of the study, we detected associations with age at onset of Alzheimer's disease in Down syndrome with PICALM (β= 3.31, p= 0.011) and the APOE loci (β= 3.58, p= 0.014). As dementia in people with Down syndrome is relatively understudied, we make all of these data publicly available to encourage further analyses of the problem of Alzheimer's disease in Down syndrome. © 2013 Elsevier Inc.

The relationships between genome wide association study-identified and replicated genetic variants associated with Alzheimer's disease (AD) risk and disease progression or therapeutic responses in AD patients are almost unexplored. Seven hundred and one AD patients with at least 3 different cognitive evaluations and genotypic information for APOE and 6 genome wide association study-significant single-nucleotide polymorphisms were selected for this study. Mean differences in Global Deterioration Score and Mini Mental State Examination (MMSE) were evaluated using nonparametric tests, general linear model and mixed models for repeated measurements. Each chart was also reviewed for evidence of treatment with any cholinesterase inhibitor, memantine, or both. Relationships between therapeutic protocols, genetic markers, and progression were explored using stratified analysis looking for specific effects on progression in each therapeutic category separately. Neither calculation rendered a Bonferroni-corrected statistically significant difference in any genetic marker. Mixed model results suggested differences in the average point in MMSE test for patients carrying PICALM GA or AA genotype compared with GG carriers at the end of the follow-up (MMSE mean difference = -0.57; 95% confidence interval, -1.145 to 0.009; p = 0.047). This observation remained unaltered after covariate adjustments although it did not achieve predefined multiple testing significance threshold. The PICALM single-nucleotide polymorphism also displayed a significant effect protecting against rapid progression during pharmacogenetic assays although its observed effect displayed heterogeneity among AD therapeutic protocols (p = 0.039). None of the studied genetic markers were convincingly linked to AD progression or drug response. However, by using different statistical approaches, the PICALM rs3851179 marker displayed consistent but weak effects on disease progression phenotypes. © 2013 Elsevier Inc.

Background: People living in care homes often have complex mental and physical health problems, disabilities and social needs which are compounded by the use of psychiatric and other drugs. In the UK dementia care is a national priority with a vast impact on services. WHELD combines the most effective elements of existing approaches to develop a comprehensive but practical intervention. This will be achieved by training care staff to provide care that is focused on an understanding of the individual and their needs; and by using additional components such as exercise, activities and social interaction to improve mental health and quality of life (QoL) and reduce the use of sedative drugs. Design: Work Package 3 (WP3) is the pilot randomised trial and qualitative evaluation to help develop a future definitive randomised controlled clinical trial. The study design is a cluster randomised 2x2x2 factorial design with two replications in 16 care homes. Each care home is randomized to receive one of the eight possible permutations of the four key interventions, with each possible combination delivered in two of the 16 homes. Each cluster includes a minimum of 12 participants (depending upon size of the care home, the number of people with dementia and the number consenting). Discussion: the overarching goal of the programme is to provide an effective, simple and practical intervention which improves the mental health of, and reduces sedative drug use in, people with dementia in care homes and which can be implemented nationally in all UK care homes as an NHS intervention. Trial Registration: Current controlled trials ISRCTN40313497. © 2013 Whitaker et al.; licensee BioMed Central Ltd.

Neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) are widespread and disabling. This has been known since Dr. Alois Alzheimer's first case, Frau Auguste D. presented with emotional distress and delusions of infidelity/excessive jealousy, followed by cognitive symptoms. Being cognizant of this, in 2010 the Alzheimer's Association convened a research roundtable on the topic of NPS in AD. A major outcome of the roundtable was the founding of a Professional Interest Area (PIA) within the International Society to Advance Alzheimer's Research and Treatment (ISTAART). The NPS-PIA has prepared a series of documents that are intended to summarize the literature and provide more detailed specific recommendations for NPS research. This overview paper is the first of these living documents that will be updated periodically as the science advances. The overview is followed by syndrome-specific synthetic reviews and recommendations prepared by NPS-PIA workgroups on depression, apathy, sleep, agitation, and psychosis. © 2013 the Alzheimer¢s Association. All rights reserved.

Background: Stroke is a common cause of cognitive impairment and dementia. However, effective strategies for reducing the risk of post-stroke dementia remain undefined. Potential strategies include intensive lowering of blood pressure and/or lipids.Methods/Design: Design: multi-centre prospective randomised open-label blinded-endpoint controlled partial-factorial phase IV trial in secondary and primary care.Participants: 100 participants from 30 UK Stroke Research Network sites who are post- ischemic stroke or intracerebral haemorrhage by three to seven months.Interventions - all patients (1:1): intensive versus guideline blood pressure lowering (target systolic < 125 mmHg versus < 140 mmHg).Interventions - ischemic stroke (1:1): intensive versus guideline lipid lowering (target low density lipoprotein-cholesterol (LDL-c) < 1.4 mmol/l versus < 3 mmol/l).Hypotheses: does 'intensive' blood pressure lowering therapy and/or 'intensive' lipid control reduce cognitive decline and dementia in people with ischemic stroke; and does 'intensive' blood pressure lowering therapy reduce cognitive decline and dementia in patients with hemorrhagic stroke.Primary outcome: Addenbrooke's Cognitive Examination-Revised.Secondary outcomes: feasibility of recruitment and retention of participants, tolerability and safety of the interventions, achieving and maintaining the blood pressure and lipid targets, maintaining differences in systolic blood pressure (> 10 mmHg) and low density lipoprotein-cholesterol (> 1 mmol/l) between the treatment groups, and performing clinic and telephone follow-up of cognition measures.Randomisation: using stratification, minimization and simple randomization.Blinding: participants receive open-label management. Cognition is assessed both unblinded (in clinic) and blinded (by telephone) to treatment. Adjudication of events (dementia, vascular, serious adverse events) is blinded to management.Discussion: the PODCAST trial is ongoing with 78 patients recruited to date from 22 sites. Outcomes of cognitive impairment and dementia are accruing.Trial registration: ISRCTN85562386. © 2013 Blackburn et al.; licensee BioMed Central Ltd.

Behavioral and psychological symptoms of dementia (BPSD) frequently arise in people with Alzheimer's disease (AD) and other dementias. They cause significant distress and confer risk to the person and others, in addition to presenting a complex clinical challenge for treatment (Ballard et al. 2009b). There is good evidence for the value of first-line management strategies such as psychological interventions and treatment of concurrent medical conditions, particularly pain, which are known to be effective (Ballard et al. 2009b). However, there are limited pharmacological treatment options for severe aggression, which causes significant risk, and for other severe BPSD which do not respond to first-line approaches. The only pharmacological intervention with an adequate evidence base is the prescription of atypical antipsychotics, where 18 placebo-controlled trials have evaluated the effect of treatment over 6–12 weeks. The literature indicates modest but significant benefits in the treatment of aggression and psychosis with risperidone and aripiprazole (Cohen's d standardized effect size of 0.2), uncertain benefits with olanzapine, and no benefits with quetiapine (Ballard and Howard, 2006; Schneider et al. 2006a; Ballard et al. 2009b; Corbett et al. 2012). Unfortunately, the benefits of longer term prescribing are more limited (Schneider et al. 2006b; Ballard et al. 2008) and there have been increasing concerns regarding the potential for serious adverse outcomes, including accelerated cognitive decline, stroke, and death (Schneider et al. 2006b; Ballard et al. 2009a). There is therefore an urgent imperative to identify more effective pharmacological treatments for severe BPSD which have a better safety profile, particularly for long-term treatment and prophylaxis. Despite this urgency, there has been very little effort toward developing or evaluating potential novel therapies for the treatment of key symptoms such as aggression, psychosis, restlessness, and apathy.

Alzheimer's disease (AD) affects the majority of the 35 million people with dementia worldwide. Four pharmacological treatment options are available for this patient group, of which memantine is licensed for treatment of people with moderate to severe stages of the condition. Memantine acts through its function as an NMDA-glutamate receptor blocker and has an established safety profile. The evidence supporting its efficacy in people with AD includes a number of large randomized clinical trials showing benefit to cognition, function, and overall clinical outcome. Additional favorable health economics analyses have confirmed the clinical and cost-effectiveness of this drug. More recently an extended-release formulation has been developed. This review outlines the key evidence base supporting memantine as a treatment for moderate to severe AD, in addition to discussing the conditions under which it may provide additional value in combination with other drugs. The review also discusses the use of memantine to address behavioral and psychological symptoms of dementia (BPSD) arising in people with AD and the limited evidence around its use in AD in people with Down's syndrome. Finally the review considers the potential value of the extended release formulation in AD. © the author(s), publisher and licensee Libertas Academica Ltd.

Objective: Depression is common in dementia, causing considerable distress and other negative impacts. Treating it is a clinical priority, but the evidence base is sparse and equivocal. This trial aimed to determine clinical effectiveness of sertraline and mirtazapine in reducing depression 13 weeks post randomisation compared with placebo. Design: Multicentre, parallel-group, double-blind placebo-controlled randomised controlled trial of the clinical effectiveness of sertraline and mirtazapine with 13- and 39-week follow-up. Setting: Nine English old-age psychiatry services. Participants: a pragmatic trial. Eligibility: probable or possible Alzheimer's disease (AD), depression (4+ weeks) and Cornell Scale for Depression in Dementia (CSDD) score of 8+. Exclusions: Clinically too critical (e.g. suicide risk); contraindication to medication; taking antidepressants; in another trial; and having no carer. Interventions: (1) Sertraline; (2) mirtazapine; and (3) placebo, all with normal care. Target doses: 150 mg of sertraline or 45 mg of mirtazapine daily. Main outcome measures: Outcome: CSDD score. Randomisation: Allocated 1: 1: 1 through Trials Unit, independently of trial team. Stratified block randomisation by centre, with randomly varying block sizes; computer-generated randomisation. Blinding: Double blind: medication and placebo identical for each antidepressant. Referring clinicians, research workers, participants and pharmacies were blind. Statisticians blind until analyses completed. Results: Numbers randomised: 326 participants randomised (111 placebo, 107 sertraline and 108 mirtazapine). Outcome: Differences in CSDD at 13 weeks from an adjusted linear-mixed model: mean difference (95% CI) placebo-sertraline 1.17 (-0.23 to 2.78; p = 0.102); placebo-mirtazapine 0.01 (-1.37 to 1.38; p = 0.991); and mirtazapine-sertraline 1.16 (-0.27 to 2.60; p = 0.112). Harms: Placebo group had fewer adverse reactions (29/111, 26%) than sertraline (46/107, 43%) or mirtazapine (44/108, 41%; p = 0.017); 39-week mortality equal, five deaths in each group. Conclusions: This is a trial with negative findings but important clinical implications. The data suggest that the antidepressants tested, given with normal care, are not clinically effective (compared with placebo) for clinically significant depression in AD. This implies a need to change current practice of antidepressants being the first-line treatment of depression in AD. From the data generated we formulated the following recommendations for future work. (1) the secondary analyses presented here suggest that there would be value in carrying out a placebo-controlled trial of the clinical effectiveness and costeffectiveness of mirtazapine in the management of Behavioural and Psychological Symptoms of Dementia. (2) a conclusion from this study is that it remains both ethical and essential for trials of new medication for depression in dementia to have a placebo arm. (3) Further research is required to evaluate the impact that treatments for depression in people with dementia can have on their carers not only in terms of any impacts on their quality of life, but also the time they spend care-giving. (4) There is a need for research into alternative biological and psychological therapies for depression in dementia. These could include evaluations of new classes of antidepressants (such as venlafaxine) or antidementia medication (e.g. cholinesterase inhibitors). (5) Research is needed to investigate the natural history of depression in dementia in the community when patients are not referred to secondary care services. (6) Further work is needed to investigate the cost modelling results in this rich data set, investigating carer burden and possible moderators to the treatment effects. (7) There is scope for reanalysis of the primary outcome in terms of carer and participant CSDD results. © Queen's Printer and Controller of HMSO 2013.

The nature of causal links between land management in rural river catchments and the flood hydrograph is investigated. A catchment can be represented as a mosaic of tiles with different land use, land management, and soils. Over the mosaic, the causal links vary with the physical properties of the land and channel drainage network, and with the management practices and space-time variations in rainfall and evaporation. The river Hodder catchment in northwest England is represented using a custom-designed semi-distributed rainfall-runoff model. An adjoint, reverse algorithmic differentiation, version of the model is then used to find the sensitivity of the peak flow rate at the catchment outlet to the model parameters controlling runoff generation. Using this novel approach, the links between changes in land management and the impact on the peak flow rate are investigated by decomposing the impact in space to give maps that show the sources of impact, tile by tile. The method works quite well for the Hodder catchment, especially for rainfall events in the autumn and winter. Its strengths and weaknesses are discussed. © 2012 Royal Meteorological Society.

Background: DYRK1A is a kinase targeting several proteins associated with the pathology of dementias, including α-synuclein and amyloid precursor protein. It is not clear if DYRK1A genetics are associated with neurodegenerative conditions. Objective: to determine if DYRK1A also has a genetic association with α-synuclein dementias such as dementia with Lewy bodies and Parkinson's disease dementia. Methods: DNA samples from prospectively followed cohorts of control and dementia individuals were genotyped for the DYRK1A rs8126696 polymorphism. Results: the rs8126696 polymorphism altered the risk of developing an α-synuclein-associated dementia. Conclusion: DYRK1A could prove to be an important therapeutic target as it interacts with several proteins associated with the development of pathology in dementia. Copyright © 2012 S. Karger AG, Basel.

Many elderly people experience pain and regularly take analgesic medication. Pain is also frequent in people with dementia, particularly those with severe disease. As no robust clinical guidelines are available for the treatment of pain in the context of dementia, the risk of inadequate treatment in individuals with this condition is high. Furthermore, our understanding of the aetiology of pain and the potential role of dementia-associated neuropathology in pain is limited. These issues are important in the clinical management of individuals with dementia, as untreated pain is a major contributor to reduced quality of life and disability, and can lead to increased behavioural and psychological symptoms. Assessment scales to identify pain in people with dementia have been highlighted in recent studies, but there is little evidence for consistency between these tools. Numerous studies have evaluated various approaches for the treatment of pain, including stepped-care protocols and/or administration of paracetamol and opioid medications. In this Review, we summarize the best-available evidence regarding the aetiology, assessment and treatment of pain in people with dementia. Further validation of assessment tools and large-scale trials of treatment approaches in people with dementia are needed to improve clinical guidance for the treatment of pain in these individuals © 2012 Macmillan Publishers Limited. All rights reserved.

Despite the frequency and importance of dementia associated with Parkinson's disease (PDD) and dementia with Lewy bodies (DLB), there is relatively little evidence on which to base treatment. Evidence from meta-analysis suggests that rivastigmine can improve cognition and functioning in PDD and also reduce risk of falling. There is also evidence supporting its use in DLB. Recent evidence suggests that memantine may also be effective, particularly for PDD, although evidence is more conflicting. Memantine may also improve parkinsonism and dyskinesias. Few clinical trials of cognition in PD without dementia exist, but there is preliminary evidence for atomoxetine, memantine, and piribedil. There is a lack of systematic evidence for the treatment of visual hallucinations and depression in PDD and DLB. In addition, there is a need for studies of whether potentially disease-modifying agents can prevent or delay the progression to dementia in PD. © Springer Science+Business Media, LLC 2012.

Dementia is one of the most common and important aspects of Parkinson's disease and has consequences for patients and caregivers, and has health-related costs. Mild cognitive impairment is also common and frequently progresses to dementia. The underlying mechanisms of dementia associated with Parkinson's disease are only partly known and no mechanism-based treatments are available. Both dysmetabolism of α-synuclein and amyloid-protein and cholinergic deficits contribute to cognitive impairment in Parkinson's disease, and preliminary findings show that imaging and neurophysiological and peripheral biomarkers could be useful in diagnosis and prognosis. Rivastigmine is the only licensed treatment for dementia in Parkinson's disease, but emerging evidence suggests that memantine might also be useful. Whether these or other treatments can delay the progression from mild cognitive impairment to dementia in Parkinson's disease is a key research question. © 2012 Elsevier Ltd.

Depression occurs in around 35% of patients with Parkinson disease (PD) and is often persistent. Symptoms of depression can be evident in individuals at the time of diagnosis and might develop in the premotor stage of the disease. The underlying mechanisms of depression in PD are not known in detail, but changes in brain structure, signaling by neurotransmitters, and levels of inflammatory and neurotrophic factors are all suggested to contribute to its development. Psychosocial factors and pain could also have roles in depression. Changes in dopaminergic, noradrenergic and serotonergic systems in patients with PD might help to explain the incidence of depression in these individuals. Antidepressants that have dual serotonergic and noradrenergic effects are the drugs of choice for treating depression in PD. However, antiparkinsonian drugs might have beneficial effects not only on the motor symptoms of disease, but also on a patient's mood. Deep brain stimulation can worsen depression in some patients, but a preliminary study has suggested that transcranial magnetic stimulation could improve symptoms of depression. This Review describes the frequency and course of depression in patients with PD. The mechanisms that underlie depression in this disease are also discussed, and the management strategies for these patients are highlighted. © 2011 Macmillan Publishers Limited. All rights reserved.

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

Open ditch drainage has historically been a common land management practice in upland blanket peats, particularly in the UK. However, peatland drainage is now generally considered to have adverse effects on the upland environment, including increased peak flows. As a result, drain blocking has become a common management strategy in the UK over recent years, although there is only anecdotal evidence to suggest that this might decrease peak flows. The change in the hydrological regime associated with the drainage of blanket peat and the subsequent blocking of drains is poorly understood, therefore a new physics-based model has been developed that allows the exploration of the associated hydrological processes. A series of simulations is used to explore the response of intact, drained and blocked drain sites at field scales. While drainage is generally found to increase peak flows, the effect of drain blocking appears to be dependent on local conditions, sometimes decreasing and sometimes increasing peak flows. Based on insights from these simulations we identify steep smooth drains as those that would experience the greatest reduction in field-scale peak flows if blocked and recommend that future targeted field studies should be focused on examining surface runoff characteristics. © 2012 Author(s). CC Attribution 3.0 License.

Background: Agitation in Alzheimer's disease (AD) is common and associated with poor patient life-quality and carer distress. The best evidence-based pharmacological treatments are antipsychotics which have limited benefits with increased morbidity and mortality. There are no memantine trials in clinically significant agitation but post-hoc analyses in other populations found reduced agitation. We tested the primary hypothesis, memantine is superior to placebo for clinically significant agitation, in patients with moderate-to-severe AD. Methods and Findings: We recruited 153 participants with AD and clinically significant agitation from care-homes or hospitals for a double-blind randomised-controlled trial and 149 people started the trial of memantine versus placebo. The primary outcome was 6 weeks mixed model autoregressive analysis of Cohen-Mansfield Agitation Inventory (CMAI). Secondary outcomes were: 12 weeks CMAI; 6 and 12 weeks Neuropsychiatric symptoms (NPI), Clinical Global Impression Change (CGI-C), Standardised Mini Mental State Examination, Severe Impairment Battery. Using a mixed effects model we found no significant differences in the primary outcome, 6 weeks CMAI, between memantine and placebo (memantine lower -3.0; -8.3 to 2.2, p = 0.26); or 12 weeks CMAI; or CGI-C or adverse events at 6 or 12 weeks. NPI mean difference favoured memantine at weeks 6 (-6.9; -12.2 to -1.6; p = 0.012) and 12 (-9.6; -15.0 to -4.3 p = 0.0005). Memantine was significantly better than placebo for cognition. The main study limitation is that it still remains to be determined whether memantine has a role in milder agitation in AD. Conclusions: Memantine did not improve significant agitation in people with in moderate-to-severe AD. Future studies are urgently needed to test other pharmacological candidates in this group and memantine for neuropsychiatric symptoms. Trial Registration: ClinicalTrials.gov NCT00371059. Trial Registration: International Standard Randomised Controlled Trial 24953404. © 2012 Fox et al.

Psychosocial interventions can improve behaviour and mood in people with dementia, but it is unclear how to maximise their effectiveness or acceptability in residential settings. Aims to understand what underlies the successful implementation of psychosocial interventions in care homes. Method Systematic review and meta-synthesis of qualitative research. Results the synthesis of 39 qualitative papers revealed that beneficial psychosocial interventions met the needs of people with dementia to connect with others, make a meaningful contribution and reminisce. Successful implementation rested on the active engagement of staff and family and the continuing provision of tailored interventions and support. This necessitated staff time, and raised issues around priorities and risk, but ultimately helped redefine staff attitudes towards residents and the caregiving role. Conclusions the findings from the meta-synthesis can help to inform the development and evaluation of psychosocial interventions in care homes and support their widespread implementation in clinical settings.

Aims: Recent work has highlighted a significant increase of neural stem/progenitor cells after stroke in humans. In this study, we examined neurogenesis in small vessel disease, a key concurrent pathology in Alzheimer's disease. Methods: We assayed autopsy tissue from 13 vascular dementia patients with small vessel disease and 12 age-matched subjects without cerebrovascular pathology, undertaking immunohistochemistry in the affected brain area and the subventricular zone with a well-characterized battery of antibodies to detect neural stem cells/progenitors and immature neurones, as well as choline acetyltransferase immunoreactivity. Results: We showed significant increases ranging from 33% to 92% (P

In hydrological modeling, two areas of application present particular challenges, first the modeling of ungauged catchments, and second the modeling of catchment nonstationarity; for example due to effects of land use change. The ungauged catchment problem requires that prior knowledge of the catchment is combined with evidence of behavior; for example from a regionalization exercise and/or spot flow measurements. Simulation of the effects of land use change requires that prior knowledge of the catchment is combined with information on the effects of that change on model parameters, generally in the absence of direct observations with which to condition the parameters. In both cases, ideally, all available sources of information about the behavior should be considered, and integrated in a way that maximizes the value of the information for model identification and uncertainty estimation. Using a formal Bayesian procedure, we combine three different sources of knowledge into a catchment scale conceptual model: (1) small-scale physical properties; (2) regionalized signatures of flow; and (3) available flow measurements. Applying the methodology to a distributed model for the Hodder catchment, UK, the physics-based information source contributed most to improving model performance, followed by peak flow times, and lastly the regionalized signatures. The flood frequency curve was evaluated under scenarios of land use change, and those changes that were significant relative to model uncertainty were identified. © 2012. American Geophysical Union. All Rights Reserved.

Neurogenesis occurs in the subventricular zone and the sub-granular layer of the hippocampus and is thought to take place in 5 stages, including proliferation, differentiation, migration, targeting, and integration phases, respectively. In Alzheimer's disease (AD) both increased and decreased neurogenesis has been reported and cholinergic activity is assumed to be involved in neurogenesis. The aim of this study was to systematically assess different phases of neurogenesis and their relation to AD and cholinergic pathology.We investigated post-mortem brain tissue from 20 AD patients and 21 non-demented controls that was neuropathologically characterized according to standardized criteria. Hippocampal sections were stained with antibodies against neurogenic markers Musashi-1, nestin, PSA-NCAM, doublecortin, and β-III-tubulin as well as ChAT (choline-acetyltransferase). Using image analysis immunoreactivity was assessed in the subventricular zone, the sub-granular layer, and the granule cell layer by determining the integrated optical density.In the sub-granular layer and the granule cell layer Musashi-1 and ChAT immunoreactivities were significantly lower in AD and decreased with increasing Braak stages. Conversely, immunorreactivities of both nestin and PSA-NCAM were significantly higher in AD and increased with increasing Braak stages while no changes were seen for doublecortin and β-III-tubulin, except for significantly higher doublecortin levels in the granule cell layer of AD cases. of note, Musashi-1 immunoreactivity significantly correlated with ChAT immuonoreactivity across different Braak stages. In the subventricular zone only nestin immunoreactivity was significantly higher in AD and significantly increased with increasing Braak stages, while no significant differences were seen for all other markers.Our finding of a reduction of ChAT and Musashi-1 levels in AD is compatible with the assumption that cholinergic pathology per se has a detrimental influence on neurogenesis. We conclude that neurogenic abnormalities in AD differ between phases and areas of neurogenesis and stages of AD; while hippocampal stem cells (Musashi-1) decrease, proliferation (nestin) increases and differentiation/migration phase as well as axonal/dendritic targeting (doublecortin and β-III-tubulin) remains virtually unchanged. This suggests an attenuation of stem cells together with compensatory increased proliferation that, however, does not result in an increased number of migratory neuroblasts and differentiated neurons in AD. © 2012 Elsevier Inc.

Background/Aims: to compare neuropsychiatric symptoms in patients with Alzheimer's disease (AD) and dementia with Lewy bodies(DLB). Methods: Neuropsychiatric symptoms and caregiver distress were assessed using the Neuropsychiatric Inventory (NPI) in mild DLB (n = 57) and AD (n = 126), and compared across the two groups using non-parametric tests. Results: the DLB patients had a higher NPI totalscore (median 24 vs. 11.5, p < 0.005), more numerous symptoms (median 5 vs. 4, p = 0.001) and more clinically significant symptoms (3 vs. 1, p = 0.001). They also had higher item hallucinations (6 vs. 2, p < 0.005) and apathy (7 vs. 5, p = 0.002) subscores. Caregivers scored higher on the NPI total caregiver distress scale (12.5 vs. 6, p = 0.003). Conclusions: in mild dementia, DLB patients have more neuropsychiatric symptoms and more associated caregiver distress compared with AD. Copyright © 2012 S. Karger AG, Basel.

INTRODUCTION: Alzheimer's disease and other dementias represent a significant and increasing clinical challenge. Dementia is also associated with a substantial economic cost and burden to health service provision. Existing treatments slow the progression of symptoms of the disease, but their efficacy does not extend to all patients and is not sustained beyond an average of 6 months. It is, therefore, critical to address the current lack of effective treatments to target the underlying pathology and disease process in Alzheimer's disease. AREAS COVERED: This review aims to highlight the main areas of new therapeutic development and discuss some of the main therapies currently being evaluated in clinical trials. Despite a number of promising rationales for therapeutic treatments in Alzheimer's disease, very few of these avenues have been developed beyond preclinical studies. The predominant focus of the current article is on treatments currently in Phase II and Phase III clinical trials, but some other promising areas of development are also discussed. There are currently only three therapeutics being investigated in Phase III clinical trials. This emphasizes the substantial caution and underinvestment in treatment development in this area. EXPERT OPINION: There is a distinct lack of novel approaches in the pipeline, and whether there is a new disease-modifying therapy for Alzheimer's disease in the next 5 years almost entirely depends on the success of currently ongoing immunotherapy studies. Importantly, there is potential benefit in exploring existing licensed treatments alongside novel drug development to increase the focus on novel targets within this time frame.

A dysfunctional ubiquitin proteasome system may be a mediating factor of disease progression in Lewy body dementia (LBD). The effects of proteasome inhibition using lactacystin and epoxomicin in primary neuronal culture were studied to assess the validity of this model to reflect the cortical pathology of LBD. Treatment of primary cortical neurons with 5 μM lactacystin for 24 h led to a 38 % reduction in the levels of β-III-tubulin (p < 0.05), a 48 % reduction in the levels of synaptophysin (p < 0.05) and a 74 % reduction in the levels of drebrin (p < 0.01), when compared to controls. Results for epoxomicin were similar. The loss of neuronal protein occurred prior to any loss of mitochondrial activity or cell death. The results are reflective of the loss of synapses and the synaptic changes observed in LBD, which may be an early event in the neurodegeneration of LBD. The similarities with the pathological changes in LBD highlight the possibility that this model can potentially provide a platform to test novel treatments. © 2012 Springer-Verlag.

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.

People with Down syndrome (DS) develop Alzheimer's disease (AD) with an early age of onset. A tetranucleotide repeat, attt5-8, in intron 7 of the amyloid precursor protein has been associated with the age of onset of AD in DS in a preliminary study. The authors examine the impact of this polymorphism in a larger cohort of individuals with DS. Adults with DS were genotyped for attt5-8 and APOE. The results were analysed with respect to the age of onset of dementia. The presence of three copies of the six-repeat allele resulted in onset of dementia seven years earlier than in the presence of other genotypes. Further study is essential to elucidate the mechanism by which this polymorphism functions, with an exciting opportunity to identify novel treatment targets relevant for people with DS and AD. Copyright © 2011 Emma L. Jones et al.

Objective Alterations in plasma and in lumbar cerebrospinal fluid amyloid-B peptide (Aβ) levels have been reported in Alzheimer's disease. Studies have also suggested similar changes in depressed patients. No information is available on the impact of psychotropic drugs on this in patients with depression. We therefore quantified Aβ in ventricular cerebrospinal fluid (CSF) in a population of patients with treatment-resistant depression, with and without antipsychotic medication. Method a cross-sectional study of 32 patients undergoing subcaudate tractotomy for major (unipolar) depressive disorder. Ventricular CSF concentrations of Aβ peptide 1-40 and 1-42, also p-tau and total tau were determined by Western blotting or enzyme-linked immunosorbent assay. Results Patients taking antipsychotic medication in the 2 weeks prior to surgery demonstrated significantly higher levels of Aβ 1-40 (mean ± SD: 727.3 ± 382.3 vs. 440.9 ± 337.2 pg/ml; p = 0.032, Student's t-test) but unaltered Aβ 1-42 (mean 72.1 ± 67.5 vs. 60.0 ± 56.7 pg/ml; p = 0.587) compared to a matched sample not treated with antipsychotic drugs. The same group demonstrated elevated total tau (mean 945.0 ± 422.2 vs. 534.3 ± 388.3 pg/ml; p = 0.010) but not p-tau (mean 98.6 ± 71.5 vs. 88.1 ± 70.5 pg/ml; p = 0.694). No similar effect was found with lithium, antidepressants, carbamazepine or benzodiazepines. Conclusions This preliminary study suggests antipsychotic drugs, widely used in patients with severe depression across all age ranges, may be associated with alteration of Aβ 1-40 and total tau, indices strongly linked with progressive organic brain disease. Further confirmatory work is needed. Copyright © 2011 John Wiley & Sons, Ltd.

Background: the clinical distinction between Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) is sometimes difficult, particularly in mild cases. Although CSF markers such as amyloid β42 (Aβ42) and P-tau can distinguish between AD and normal controls, their ability to distinguish between AD and DLB is not adequate. Objective This study aims to investigate whether CSF markers, in particular levels of Aβ38, can differentiate between mild AD and DLB. Methods 85 individuals were included after standardised diagnostic procedures: 30 diagnosed as probable AD, 23 probable DLB, 20 probable Parkinson's disease dementia and 12 non-demented control subjects. CSF levels of Aβ38, Aβ40 and Aβ42 were determined using commercially available ultra-sensitive multi-array kit assay (MSD) for human Aβ peptides. Total tau (T-tau) and phosphorylated tau (P-tau) were analysed using ELISA (Innotest). In addition, combinations (Aβ42/Aβ38, Aβ42/Aβ40, Aβ42/P-tau and Aβ42/Aβ38/P-tau) were assessed. Results: Significant between group differences were found for all CSF measures, and all except Aβ40, Aβ42 and Aβ42/P-tau differed between AD and DLB. The Aβ42/Aβ38 ratio was the measure that best discriminated between AD and DLB (AUC 0.765; p

We measured cerebrospinal fluid (CSF) levels of the soluble isoforms of amyloid precursor protein (APP; sAPPα sAPPβ) and other CSF biomarkers in 107 patients with Alzheimer's disease (AD), dementia with Lewy body dementia (DLB), Parkinson's disease dementia (PDD), and normal controls (NC) using commercial kits. DLB and PDD were combined in a Lewy body dementia group (LBD). No differences were observed in sAPPα and sAPPβ levels between the groups. Significant correlations were observed between sAPPα and sAPPβ and between sAPPβ and Mini-Mental State Examination scores in the total group analysis as well as when LBD and AD groups were analyzed separately. sAPPα and sAPPβ levels correlated with Aβ38, Aβ40, Aβ42, and Tau in the LBD group. In AD, sAPPα correlated with p-Tau and sAPPβ with Aα40. The differential association between sAPPα and sAPPβ with Aβ and Tau species between LBD and AD groups suggests a possible relationship with the underlying pathologies in LBD and AD. © 2011 Ezra Mulugeta et al.

Background Depression is common in dementia, with important clinical implications. Few studies of depression in dementia with Lewy bodies are available, and the results are inconsistent. Objective to examine the frequency of depression and its characteristics and correlates, in people with mild dementia. Methods all referrals for patients with a first time diagnosis of dementia to geriatric and older psychiatry outpatient clinics in the counties of Rogaland and Hordaland in Western Norway from March 2005 to March 2007 were screened for the study. Participants and their caregivers underwent a comprehensive and standardised diagnostic and assessment procedure. The depression subitem of the neuropsychiatric inventory (NPId) and Montgomery and Ãsberg depression rating scale (MADRS) were used to estimate depression. Cut-off scores for any depression were 0/1 (NPId) and 6/7 (MADRS), and for clinically significant depression 3/4 and 14/15, respectively. Results Two hundered and twenty-three subjects with dementia participated, of whom 59 and 50% showed symptoms of depression assessed by NPI or MADRS, respectively, and 25 and 16% had clinically significant depression as measured by NPI and MADRS, respectively. Depression was more frequent in dementia with Lewy bodies (DLB) than in Alzheimer's disease (AD; p < 0.05). APOE genotype was available in 153 patients, and in AD, but not in DLB, a general linear model showed that the presence of APOE∈4 allele was significantly associated with depression (F = 4.14; p = 0.045). Conclusion Depression is common even in mild dementia, and more common and severe in DLB compared to AD. Future studies should explore the longitudinal course of depression in DLB, and the neural underpinnings of depression in DLB. Copyright © 2010 John Wiley & Sons, Ltd.

Objective: to explore the course of depression in people with mild dementia and identify predictors for depression at 1-year follow-up. Methods: Patients with mild dementia (n = 199) were assessed using Montgomery and sberg Depression Rating Scale (MADRS) and the depression item from Neuropsychiatric Inventory (NPI) at baseline and after 1 year. A score above 6 on MADRS indicates at least mild depression. Linear and logistic regression analyses were performed to identify predictors of change in depression scores. Results: Among subjects with depression at baseline, 68.1% remained depressed at follow-up, whereas 31.9% had remitted, based on MADRS. Among patients without depression at baseline, 77.1% remained non-depressed at follow-up, whereas 22.9% had incident depression. The proportion with persistent depression was higher in the combined dementia with Lewy bodies (DLB)/Parkinson's disease with dementia (PDD) group (45.5%) compared to AD (28%) (p < 0.05). Greater decline on the Mini Mental State Examination (p < 0.001) and higher baseline MADRS score (p < 0.001) were significant predictors of increased MADRS score. Conclusion: Two thirds of patients with depression at baseline were still depressed at follow-up, more so in DLB with PDD compared to AD. Cognitive decline was associated with worsening of depressive symptoms. Copyright © 2011 S. Karger AG, Basel.

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.

Background/Aims: to explore the presenting and early symptoms of dementia with Lewy bodies (DLB). Method: Patients with mild dementia fulfilling diagnostic criteria for DLB (n = 61) and Alzheimer's disease (AD) (n = 109) were recruited from outpatient dementia clinics in western Norway. At diagnosis, caregivers were asked which symptom had been the presenting symptom of dementia. Results: Caregivers reported that memory impairment was the most common presenting symptom in DLB (57%), followed by visual hallucinations (44%), depression (34%), problem solving difficulties (33%), gait problems (28%), and tremor/stiffness (25%). In contrast, 99% of AD carers reported impaired memory as a presenting symptom, whereas visual hallucinations were a presenting symptom in 3% of the AD cases. Conclusion: DLB should be suspected in predementia cases with visual hallucinations. Copyright © 2011 S. Karger AG, Basel.

Objective: This 30-week extension trial was a continuation of the first double-blind randomized controlled trial (RCT) to study memantine in dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). The objective was to evaluate the presence of recurrence of symptoms upon drug withdrawal. Furthermore, the aim was to explore washout dynamics in order to inform clinical practice. Methods: Patients were enrolled from psychiatric, memory and neurological outpatient clinics in Norway, Sweden and the UK. The trial comprised a 4-week washout period and a 26-week open-label treatment period. Outcome measures were presence of recurrence of symptom upon drug withdrawal, Clinical Global Impression of Change (CGIC) and modified motor Unified Parkinson's Disease Rating Scale (UPDRS). Results: recurrence of symptoms occurred more frequently (p=0.04) in patients receiving memantine (58%) than in patients receiving placebo (25%). There was a significant global deterioration (p=0.0003) during washout within the memantine group as measured by CGIC. The patients seemed to recover during the open-label treatment, however these findings were non-significant. Conclusions: the findings inform clinical practice that any possible memantine-associated benefits might be rapidly lost after drug withdrawal. The magnitude of deterioration suggests a symptomatic rather than a disease-modifying effect of the drug. Open-label results should merely be considered inspiration for future trials. Copyright © 2010 John Wiley & Sons, Ltd.

Objective: to determine whether a systematic approach to the treatment of pain can reduce agitation in people with moderate to severe dementia living in nursing homes. Design: Cluster randomised controlled trial. Setting: 60 clusters (single independent nursing home units) in 18 nursing homes within five municipalities of western Norway. Participants: 352 residents with moderate to severe dementia and clinically significant behavioural disturbances randomised to a stepwise protocol for the treatment of pain for eight weeks with additional follow-up four weeks after the end of treatment (33 clusters; n=175) or to usual treatment (control, 27 clusters; n=177). Intervention: Participants in the intervention group received individual daily treatment of pain for eight weeks according to the stepwise protocol, with paracetamol (acetaminophen), morphine, buprenorphine transdermal patch, or pregabaline. The control group received usual treatment and care. Main outcome measures: Primary outcome measure was agitation (scores on Cohen-Mansfield agitation inventory). Secondary outcome measures were aggression (scores on neuropsychiatric inventory-nursing home version), pain (scores on mobilisation-observation-behaviour-intensity-dementia- 2), activities of daily living, and cognition (mini-mental state examination). Results: Agitation was significantly reduced in the intervention group compared with control group after eight weeks (repeated measures analysis of covariance adjusting for baseline score, P

Background/Aims: Genetic risk factors have not been clearly established for vascular dementias (VaD) related to stroke and cerebrovascular disease. Methods: Samples were genotyped for APOE, MTHFR and ICAM. Aβ levels and choline acetyltransferase (ChAT) activities were assayed in controls and individuals with VaD. Results: Associations were found between the APOE-ε4 allele and mixed dementia, infarct/stroke dementia and subcortical ischemic vascular dementia (SIVD), and higher Aβ1-42 levels and decreased ChAT activity. MTHFR was more associated with SIVD, mixed dementia, and lower ChAT activity. Conclusions: the study demonstrates important differences in the genetic associations of VaD and begins to clarify the genetic basis of key pathological substrates. Copyright © 2011 S. Karger AG, Basel.

Open ditch drainage is a commonly implemented land management practice in upland blanket peatlands, particularly in the UK, where policy decisions between the 1940s and 1970s led to widespread drainage of the uplands. The change in the hydrological regime associated with the drainage of blanket peat is poorly understood, yet has perceived importance for flooding, low flows and water quality. We propose a new simplified physics-based model that allows the associated hydrological processes and flow responses to be explored. The model couples four one-dimensional models to represent a three-dimensional hillslope, allowing for the exploration of flow and water table response throughout the model domain for a range of drainage configurations and peat properties. The model is tested against a data set collected from Oughtershaw Beck, UK, with results showing good model performance for wet periods although less conformity with borehole observations during rewetting periods. A wider exploration of model behaviour indicates that the model is consistent with the hydrological response reported in the literature for a number of drained blanket peat sites, and therefore has potential to provide guidance to decision makers concerning the effects of management practices. Through a global sensitivity analysis, we conclude that further field investigations to assist in the surface and drain roughness parameterisation would help reduce the uncertainty in the model predictions. © 2011 Elsevier B.V.

Objective the aim of the study was to conduct a meta-analysis of epidemiological and case control studies to determine whether arterial hypertension is specifically associated with an increased risk of vascular dementia (VaD). Design Longitudinal and cross-sectional prospective studies using operationalised criteria to define VaD and hypertension, with a normal control comparison group were systematically reviewed. Cochrane Library, Embase, Medline, and PsycInfo data sources were searched along with reference lists of included articles and reviews. Original, prevalence or incidence studies were included if operationalised criteria for hypertension and VaD as well as number of cases with and without hypertension in VaD and non-demented groups were provided. Intervention studies and post-stroke and CADASIL studies were excluded. Results Eleven studies recruiting either volunteers or clinical patients, or which were population-based, examined a total of 768 people with VaD and 9857 control cases. A meta-analysis of the six longitudinal studies showed that hypertension was significantly associated with increased risk of incident VaD (odds ratio, OR: 1.59, CI: 1.29-1.95, p < 0.0001). A similar association between hypertension and the risk of prevalent VaD was found in the five cross-sectional studies (OR: 4.84, CI: 3.52-6.67, p < 0.00001). Conclusions Hypertension significantly increases the risk of vascular dementia. The current meta-analysis highlights the potential importance of rigorous treatment of hypertension as a key measure to help prevent the development of VaD. Copyright © 2010 John Wiley & Sons, Ltd.

Parkinson's disease (PD) and Dementia with Lewy bodies (DLB) are neurodegenerative diseases that are characterized by intra-neuronal inclusions of Lewy bodies in distinct brain regions. These inclusions consist mainly of aggregated α-synuclein (α-syn) protein. The present study used immunoprecipitation combined with nanoflow liquid chromatography (LC) coupled to high resolution electrospray ionization Fourier transform ion cyclotron resonance tandem mass spectrometry (ESI-FTICR-MS/MS) to determine known and novel isoforms of α-syn in brain tissue homogenates. N-terminally acetylated full-length α-syn (Ac-α-syn 1-140) and two N-terminally acetylated C-terminally truncated forms of α-syn (Ac-α-syn 1-139 and Ac-α-syn 1-103) were found. The different forms of α-syn were further studied by Western blotting in brain tissue homogenates from the temporal cortex Brodmann area 36 (BA36) and the dorsolateral prefrontal cortex BA9 derived from controls, patients with DLB and PD with dementia (PDD). Quantification of α-syn in each brain tissue fraction was performed using a novel enzyme-linked immunosorbent assay (ELISA). © 2011 the Author(s).

Since groundbreaking studies demonstrated the presence of progenitor cells in the adult human brain, there have been intense interests in their potential therapeutic application, but to date only limited data has been obtained in man. An immunohistological study was performed in order to examine neurogenesis in both the subventricular and peri-infarct zones of vascular dementia patients compared to age-matched controls.The results were striking, showing a significant increase of progenitor cells in both the subventricular zone and in peri-infarct area in patients with vascular dementia compared to controls, which was sustained even in patients with infarcts occurring more than three months prior to autopsy. Moreover, the peri-infarct response appeared to be unified with that of the subventricular zone via a stream of cells, with some of them differentiating into immature neurons. We conclude that neurogenesis is stimulated in vascular dementia patients and, specifically, in patients with visible infarcts. Progenitors may migrate from the neurogenic niche to areas of infarction and differentiate into neurons, even three months after cerebrovascular damage, thus implicating the feasibility of enhancing neurogenesis as a novel treatment approach. © 2010 Elsevier Inc.

Stroke is a major risk factor for the development of dementia in the elderly. It is unclear which genes influence risk of delayed dementia after stroke. We tested a single nucleotide polymorphism (SNP) in endothelial nitric oxide synthase (NOS3) gene at codon 298 (single-nucleotide polymorphism rs1799983; p.Asp298Glu) in a cohort of 355 older (>75 years) stroke survivors, who had detailed cognitive assessments from 3 months poststroke, i.e. baseline when the patients were free of dementia and subsequently at annual intervals. of these, 253 participants were genotyped for polymorphisms in NOS3 and apolipoprotein E (APOE). Our analysis showed that homozygosity for NOS3 TT rather than the GT or GG genotype was a significant factor in the development of dementia. The presence of TT genotype increased risk of incident dementia compared with GG genotype; hazard ratio, 3.14 (95% confidence interval, 1.64-5.99; p = 0.001). We hypothesize that this may be mediated by reduction of nitric oxide production and cerebral perfusion. Our findings, if replicated widely, have implications for treatments to ameliorate cognitive decline in stroke survivors. © 2011 Elsevier Inc.

Dementia with Lewy bodies (DLB) is associated with alpha synuclein pathology and slowly progressive dementia. Progenitor abnormalities have previously been reported in the subventricular zone (SVZ) adjacent to the lateral ventricle. To evaluate changes in neural stem cells and progenitors in the hippocampal neurogenic niche, immunohistochemistry (IHC) using the neural stem cell markers Musashi 1, nestin, proliferating cell nuclear antigen (PCNA), doublecortin, and glial fibrillary acidic protein (GFAP) were examined in age-matched control and DLB groups. Staining was quantified in the hippocampal SVZ, subgranular layer (SGL) and ependymal cell layer (EPL). There was a significant loss in DLB of Musashi 1 (P < 0.01) in all areas, an increase in PCNA in hippocampal SVZ (P = 0.01) and SGL (P = 0.05), and an increase in doublecortin in the hippocampal SVZ (P = 0.04) and EPL (P = 0.02). This is the first report of the changes in neurogenic markers in the hippocampal SVZ and EPL in DLB and may offer the potential for understanding disease pathology and in the devising of treatment. © 2010 Wiley-Liss, Inc.

OBJECTIVE: to review the key nonpharmacological treatment approaches to the cognitive and functional symptoms of Alzheimer disease (AD). METHODS: We searched and critically analyzed the most recent relevant literature pertaining to the nonpharmacological treatment of AD. RESULTS: There is evidence from a modest number of well-conducted randomized controlled trials (RCTs) that various nonpharmacological approaches, including cognitive training, cognitive rehabilitation, and cognitive stimulation therapy (CST), confer modest but significant benefits in the treatment of cognitive symptoms in people with AD, and that there may be additive benefits in combination with cholinesterase inhibitor therapy. Cognitive rehabilitation also appears to result in functional benefits in AD. The modest number of RCTs focusing on cognitive training in AD is consistent with the results of larger cognitive training trials in healthy older people. however, there is no convincing evidence of any benefits associated with brain training games. CONCLUSION: an emerging evidence base indicates that different approaches to cognitive training and cognitive stimulation in people with AD confer modest but significant benefits. The best evidence base is for CST, although this approach is labour-intensive, and requires further evaluation of cost-effectiveness. There is currently no evidence that brain training games provide any significant benefit to people with AD.

Background Advancing age is associated with high prevalence of both dementia and pain. Dementia is frequently accompanied by distressing behavioral and psychological symptoms, including agitation and aggression, particularly in nursing home patients. The etiology of agitation is multifactorial. It has been suggested that un-diagnosed and untreated pain may contribute to agitation in people with dementia. If this is correct, individual pain treatment could be of benefit in ameliorating agitation and other behavioral changes in people with dementia. Objective the objective of this paper is to conduct a systematic review of studies of whether pain medication can improve agitation in people with dementia. Methods a systematic search of the PubMed and Cochrane databases for the period 1992-2010 was performed, using dementia, agitation, aggression, depression, behavioral disturbances, behavioral and psychological symptoms (BPSD), pain, pain assessment, pain treatment, pain management, and analgesics as search terms. Inclusion criteria were: prospective studies including patients with dementia, interventions focusing on pain reduction, inclusion of a control condition, and outcome measures including agitation or other related behavioral disturbances. Results Only three controlled trials were identified; all were cross-over trials, and two included small sample sizes (

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. © 2011 Elsevier Ltd.

Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB) account for 10-15% of late onset dementias. Key treatment targets include cognitive and functional impairments, neuropsychiatric symptoms including intense and persistent visual hallucinations, and parkinsonism. Six-month, placebo-controlled randomized controlled trials (RCTs) of the cholinesterase inhibitor rivastigmine have indicated modest but significant benefits in cognition, function, global outcome and neuropsychiatric symptoms in both PDD and DLB. The evidence base for other cholinesterase inhibitors from RCTs is inconclusive. More recent RCTs with memantine in PDD/DLB patients indicate a benefit with regard to global outcome, with some suggestion of a specific benefit with respect to sleep disturbance. Given the risk of severe antipsychotic sensitivity reactions, antipsychotics should be avoided. A significant proportion of PDD/DLB patients are responsive to levodopa, but care needs to be taken with anti-parkinsonian treatments because of their potential propensity to exacerbate neuropsychiatric symptoms, particularly hallucinations.

Background: Alzheimer's disease (AD) pathology is found in a considerable portion of patients with Parkinson's disease (PD), particularly those with early dementia (PDD). Altered cerebrospinal fluid (CSF) levels of amyloid-β (Aβ) and tau proteins have been found in PDD, with intermediate changes for Aβ42 in non-demented PD. The authors investigated whether AD-related CSF protein levels are altered and relate to neuropsychological performance in early, untreated PD. Methods: CSF concentrations of Aβ42, Aβ40 and Aβ38 were measured by electrochemiluminiscene and levels of total tau (T-tau) and phosphorylated tau (P-tau) by ELISA in 109 newly diagnosed, unmedicated, non-demented, community-based PD patients who had undergone comprehensive neuropsychological testing, and were compared with those of 36 age-matched normal controls and 20 subjects with mild AD. Results: PD patients displayed significant reductions in Ab42 (19%; p=0.009), Aβ40 (15.5%; p=0.008) and Ab38 (23%; p=0.004) but not T-tau (p=0.816) or P-tau (p=0.531) compared with controls. CSF Aβ42 reductions in PD were less marked than in AD (53%; p=0.002). Sequential regression analyses demonstrated significant associations between CSF levels of Aβ42 (β=0.205; p=0.019), Ab40 (β=0.378; p

Objectives: to explore how the core and suggestive symptoms of dementia with Lewy bodies (DLB) cluster in persons with newly diagnosed mild dementia, and whether they are associated with a particular pattern of cognitive impairment. Method: Persons with mild dementia (n = 139) were recruited from dementia clinics in western Norway. Symptoms were rated using standardized instruments. A 2-step cluster analysis was applied to classify persons into groups according to scores on scales for hallucinations, parkinsonism, fluctuations and REM sleep behaviour disorder (RBD). Result: Four distinct clusters were revealed: a 'Lewy body dementia' (LBD) cluster with high scores for hallucinations, parkinsonism and fluctuation, and a 'non-LBD' cluster with low scores on all DLB symptom scales. In addition, 2 clusters with high scores on either RBD or cognitive fluctuation scales emerged. Persons in the LBD cluster had lower scores for visuospatial cognitive abilities as compared to the non-LBD group (p = 0.002). Conclusion: Applying cluster analysis, we identified distinct subgroups in mild dementia based on symptoms such as hallucinations, parkinsonism and cognitive fluctuations. Our findings provide empirical support for diagnosing DLB. Visual hallucinations and motor parkinsonism might be the most distinguishing symptoms for DLB in mild dementia. Copyright © 2010 S. Karger AG, Basel.

Mixed vascular dementia/Alzheimer's disease (AD) is a common condition, particularly in individuals over the age of 80. There are a number of potential explanations for this, including the likelihood that cerebrovacular disease triggers the development of AD pathology. In addition to the patients who separately meet operationalized diagnostic criteria for AD and VaD, a much larger number of patients have either AD with some VaD changes or VaD with modest Alzheimer type pathology. In these circumstances there is clearly an additive effect of the pathological substrates and a better classification is needed to reflect the overlap of pathologies and their contribution to the clinical dementia syndrome in a particular individual it is also important that there are many different types of cerebrovascular and Alzheimer pathologies, including infarcts, small vessel disease, amyloid, tau pathology and cerebral amyloid angiopathy, leading to a complex potential typography of "mixed dementia". There has been very little study of the biochemical characteristics of mixed VaD/AD, and further work will be important to identify the characteristic profile of biochemical alterations in different types of mixed VaD/AD to inform biomarker and treatment studies. There is evidence from several clinical trials that cholinesterase inhibitors may confer clinically significant benefit in patients with mixed VaD/AD, but further intervention studies also remain a priority.

OBJECTIVE: the aim of this study is to investigate the association of psychosocial factors and patient factors with stress in care staff in nursing homes. METHODS: in this cross-sectional survey, 197 care staff from 13 dementia wards from four nursing homes in the Stavanger region, Norway, participated. Stress in care staff was measured by Perceived Stress Scale, Hopkins Symptom Check List, and subjective health complaints. Agitation in patients was measured with the Cohen-Mansfield Agitation Inventory. Work-related psychosocial factors were measured by General Nordic Questionnaire for Psychosocial and Social Factors at Work (QPSNordic). Data were analyzed using multivariate regression analyses. RESULTS: Psychosocial factors (QPS Nordic) were significantly associated with all the three outcome measures of stress in care staff, whereas agitation was associated with subjective health complaints only. QPS Nordic subscales significantly associated with stress in care staff were those associated with leadership. CONCLUSIONS: Psychosocial factors were more important predictors of carer stress than patient-related factors such as dementia severity and agitation. The findings provide key background information in the planning of interventions to improve conditions for care staff and ultimately for nursing home residents.

Background: Physical exercise has several beneficial effects, including reduced risk for Alzheimer's disease. Although several studies of potential risk factors for vascular dementia (VaD) exist, including physical activity, the studies have usually included few participants and there are no meta-analyses addressing this key topic. Methods: the MEDLINE database was searched using the key words 'physical exercise' 'activity' or 'walking' in combination with 'dementia' and 'vascular dementia'. Potentially relevant studies were assessed and summarised by two of the authors, and longitudinal studies with operationalised definition of physical activity providing risk for VaD in both groups were included in the meta-analysis using pooled estimates from a random effects model. Results: a total of 24 longitudinal studies, including 1378 patients with VaD, were included in the review. The majority of individual studies did not report significant associations. Five studies fulfilled criteria for meta-analysis, including 10,108 non-demented control subjects and 374 individuals with VaD. The meta-analysis demonstrated a significant association between physical exercise and a reduced risk of developing VaD: OR 0.62 (95% CI 0.42-0.92). Conclusions: We conclude that there is evidence supporting the hypothesis that physical activity is likely to prevent the development of VaD, and should be highlighted as part of secondary prevention programmes in people at risk for cerebrovascular disease. © 2010 Taylor & Francis.

Alzheimer's disease (AD) is a complex progressive brain degenerative disorder that has effects on multiple cerebral systems. In addition to cognitive and functional decline, diverse behavioral changes manifest with increasing severity over time, presenting significant management challenges for caregivers and health care professionals. Almost all patients with AD are affected by neuropsychiatric symptoms at some point during their illness; in some cases, symptoms occur prior to diagnosis of the dementia syndrome. Further, behavioral factors have been identified, which may have their origins in particular neurobiological processes, and respond to particular management strategies. Improved clarification of causes, triggers, and presentation of neuropsychiatric symptoms will guide both research and clinical decision-making. Measurement of neuropsychiatric symptoms in AD is most commonly by means of the Neuropsychiatric Inventory; its utility and future development are discussed, as are the limitations and difficulties encountered when quantifying behavioral responses in clinical trials. Evidence from clinical trials of both non-pharmacological and pharmacological treatments, and from neurobiological studies, provides a range of management options that can be tailored to individual needs. We suggest that non-pharmacological interventions (including psychosocial/psychological counseling, interpersonal management and environmental management) should be attempted first, followed by the least harmful medication for the shortest time possible. Pharmacological treatment options, such as antipsychotics, antidepressants, anticonvulsants, cholinesterase inhibitors and memantine, need careful consideration of the benefits and limitations of each drug class. © 2010 International Psychogeriatric Association.

Neuropsychiatric symptoms are frequent and troublesome in people with dementia and present a major treatment challenge for clinicians. Most good practice guidelines suggest non-pharmacological treatments as the first-line therapy and there is emerging evidence, including randomized controlled trials, that a variety of psychological and training interventions, including social interaction and person-centred care training, are effective. There is evidence from meta-analyses that some atypical antipsychotic drugs, specifically risperidone and aripiprazole, confer benefit in the treatment of aggression in people with Alzheimer's disease over a period of up to 12 weeks. However, these benefits have to be considered in the context of significant adverse events, including extrapyramidal symptoms, accelerated cognitive decline, stroke and death. In addition, the limited evidence available does not indicate ongoing treatment benefits over longer periods of therapy. The evidence is limited for other pharmacological treatment approaches, but the best evidence is probably for carbamazepine, memantine and citalopram. There is very limited evidence for any therapies in non-Alzheimer dementias. In conclusion, it is important in most situations to limit the use of antipsychotic medication to short-term treatment (up to 12 weeks) of severe neuropsychiatric symptoms to limit harm. Non-pharmacological therapies offer a viable and effective alternative in many situations. Adequately powered randomized controlled trials for the treatment of clinically significant agitation are urgently needed to explore alternative pharmacological therapies.

Alpha-synuclein aggregation is a neuropathological hallmark of many neurodegenerative diseases including Parkinson's disease (PD), Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB), collectively termed the α-synucleinopathies. Substantial advances in clinical criteria and neuroimaging technology over the last 20. years have allowed great strides in the detection and differential diagnosis of these disorders. Nevertheless, it is clear that whilst the array of different imaging modalities in clinical use allow for a robust diagnosis of α-synucleinopathy in comparison to healthy subjects, there is no clear diagnostic imaging marker that affords a reliable differential diagnosis between the different forms of Lewy body disease (LBD) or that could facilitate tracking of disease progression. This has led to a call for a biomarker based on the pathological hallmarks of these diseases, namely α-synuclein-positive Lewy bodies (LBs). This potentially may be advantageous in terms of early disease detection, but may also be leveraged into a potential marker of disease progression. We here aim to firstly review the current status of neuroimaging biomarkers in PD and related synucleinopathies. Secondly, we outline the rationale behind α-synuclein imaging as a potential novel biomarker as well as the potential benefits and limitations of this approach. Thirdly, we attempt to illustrate the likely technical hurdles to be overcome to permit successful in vivo imaging of α-synuclein pathology in the diseased brain. Our overriding aim is to provide a framework for discussion of how to address this major unmet clinical need. © 2010 Elsevier B.V.

BACKGROUND: Understanding the underlying mechanisms and risk factors leading to agitation is crucial to reduce the severity of agitation and increase quality of life. International comparative studies offer special advantages in elucidating environmental risk factors by providing a wider diversity of environmental exposures such as nursing home structures, health care systems and genetic diversity. METHODS: Baseline data for three different intervention studies in Austria (n = 38), England (n = 302) and Norway (n = 163) were combined posthoc. Patients were grouped according to their dementia severity using the global deterioration scale (GDS), functional assessment staging (FAST) and clinical dementia rating (CDR) scales. For the measurement of agitation, the Cohen-Mansfield Agitation Inventory (CMAI) was used. Data analysis was performed using one-way ANOVA, multivariate and linear regression analysis. RESULTS: CMAI scores were available for 503 subjects with dementia. There were significant differences between the nursing home residents in the three countries regarding age, gender and dementia severity (all p values < 0.001). In the multivariate analyses, the level of agitation differed with higher mean scores in the Austrian (mean (SD) score 51.9(21.8)) compared to UK (43.3(16.1)) and Norwegian (41.6(13.2)) nursing homes (p = 0.002). Similarly, the use of psychotropic drugs differed significantly, with a higher proportion of neuroleptics in UK (48%, p < 0.001) and Austrian (52.6%; p = 0.001) compared to Norwegian (19%) nursing homes. CONCLUSION: We found differences in agitation and antipsychotic drug use which are likely related to structural and cultural differences in nursing homes in three European countries. These findings suggest that structural changes can improve quality of care and quality of life for nursing home residents.

Brain training, or the goal of improved cognitive function through the regular use of computerized tests, is a multimillion-pound industry, yet in our view scientific evidence to support its efficacy is lacking. Modest effects have been reported in some studies of older individuals and preschool children, and video-game players outperform non-players on some tests of visual attention. However, the widely held belief that commercially available computerized brain-training programs improve general cognitive function in the wider population in our opinion lacks empirical support. The central question is not whether performance on cognitive tests can be improved by training, but rather, whether those benefits transfer to other untrained tasks or lead to any general improvement in the level of cognitive functioning. Here we report the results of a six-week online study in which 11,430 participants trained several times each week on cognitive tasks designed to improve reasoning, memory, planning, visuospatial skills and attention. Although improvements were observed in every one of the cognitive tasks that were trained, no evidence was found for transfer effects to untrained tasks, even when those tasks were cognitively closely related. © 2010 Macmillan Publishers Limited. All rights reserved.

Objective to determine whether attentional impairments are reliable neuropsychological markers of sub syndrome delirium. Method a prospective cohort study with repeated assessment beginning pre-operatively and continuing through the first post-operative week. Computerized assessments of attention and the Mini-Mental State Examination were administered with one hundred patients admitted for elective orthopedic surgery, 70 years and over and free of dementia. Acute change of cognitive status was used to identify cases of sub syndrome delirium. Results There were significant differences of post-surgical performance between the 'no delirium' and 'sub-syndrome delirium' groups of reaction time, global cognition, accuracy and greater variability of reaction time (p < 0.041). There were significant within subject main effects on reaction time (p = 0.001), variability of reaction time (p = 0.022) and MMSE (p = 0.000) across the cohort; but no significant interaction effect of 'diagnosis'. 'time' on the computerized measures of attention (p > 0.195). Conclusion the distinction between people with sub syndrome delirium and no delirium is difficult to quantify but computerized measures of attention might provide a sensitive indicator. Sub syndrome delirium is an observable marker of a clinical abnormality that should be exploited to improve care management for vulnerable patients. © 2010 John Wiley & Sons, Ltd.

Objective Two common and characteristic sleep disturbances have been described in dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD); excessive daytime sleepiness and REM sleep behaviour disorder (RBD). This study is an analysis of a secondary outcome measure of a larger study already reported, aimed to determine whether memantine has an effect on the sleep disturbances in DLB and PDD patients. Methods Patients with DLB or PDD were included in a placebo-controlled, randomised controlled study of memantine (20 mg per day) for 24 weeks. The Stavanger Sleep Questionnaire and the Epworth Sleepiness Scale were used to evaluate the effect on sleep disturbances. Results Forty two patients started treatment; 20 with memantine and 22 with placebo. The primary analysis was the comparison of change between the two groups during a 24-week period, using the modified ITT population (last observation carried forward). At 24 weeks, patients treated with memantine were less physically active during sleep while patients in the placebo group worsened. Mean difference between the groups (0.5 [0.05-0.90]) was significant (p = 0.006). No significant change was observed in severity of excessive daytime sleepiness. Conclusions Memantine decreases probable REM sleep behaviour disorder in patients with DLB and PDD. Both diagnostic groups contributed equally to the outcome. © 2010 John Wiley & Sons, Ltd.

INTRODUCTION: Agitation is common in dementia and is associated with use of restraints and use of psychotropic drugs. The aim of this study was to determine whether an education and supervision intervention could reduce agitation and the use of restraints and antipsychotic drugs in nursing homes. METHOD: Four Norwegian nursing homes were randomly allocated to receive either treatment as usual or an intervention consisting of a 2-day educational seminar and monthly group guidance for 6 months. One hundred forty-five residents with dementia (based on medical records and corroborated with a Functional Assessment Staging score >or= 4) completed baseline and 6-month intervention assessments and were included in the analyses. The co-primary outcome measures were the proportion of residents subject to interactional restraint and the severity of agitation using the Cohen-Mansfield Agitation Inventory (CMAI). Patients were assessed at baseline, immediately after completion of the intervention at 6 months, and 12 months after baseline. Comparison of change in the 2 groups was made using repeated-measures analysis of variance (CMAI) and Mann-Whitney test (restraints). The study was conducted from 2003 to 2004. RESULTS: the proportion of residents starting new restraint was lower in the intervention than in the control group at 6-month evaluation (P =. 02), but no statistically significant differences were found at 12-month assessment (P =. 57). The total CMAI score declined from baseline to 6 and 12 months' follow-up in the intervention homes compared to a small increase in the control homes (F2,176 = 3.46, P =. 034). There were no statistically significant differences in use of antipsychotic drugs. CONCLUSIONS: a brief 2-day staff education program followed by continued monthly guidance was able both to improve quality of care by reducing the frequency of interactional restraints and to reduce severity of agitation.

Background: Cognitive decline is common in Parkinson's disease (PD). Although some of the aetiological factors are known, it is not yet known whether drugs with anticholinergic activity (AA) contribute to this cognitive decline. Such knowledge would provide opportunities to prevent acceleration of cognitive decline in PD. Objective: to study whether the use of agents with anticholinergic properties is an independent risk factor for cognitive decline in patients with PD. Methods: a community-based cohort of patients with PD (n=235) were included and assessed at baseline. They were reassessed 4 and 8 years later. Cognition was assessed using the Mini-Mental State Examination (MMSE). A detailed assessment of the AA of all drugs prescribed was made, and AA was classified according to a standardised scale. Relationships between cognitive decline and AA load and duration of treatment were assessed using bivariate and multivariate statistical analyses. Results: More than 40% used drugs with AA at baseline. During the 8-year follow-up, the cognitive decline was higher in those who had been taking AA drugs (median decline on MMSE 6.5 points) compared with those who had not taken such drugs (median decline 1 point; p=0.025). In linear regression analyses adjusting for age, baseline cognition and depression, significant associations with decline on MMSE were found for total AA load (standardised β=0.229, p=0.04) as well as the duration of using AA drugs (standardised β 0.231, p=0.032). Conclusion: Our findings suggest that there is an association between anticholinergic drug use and cognitive decline in PD. This may provide an important opportunity for clinicians to avoid increasing progression of cognitive decline by avoiding drugs with AA. Increased awareness by clinicians is required about the classes of drugs that have anticholinergic properties.

Objectives: Vascular dementia (VaD) accounts for approximately 15%-20% of all dementias, but the relationship of progressive cognitive impairment to neurochemical changes is poorly understood. We have therefore investigated glutamatergic synaptic markers in VaD. Methods: We used homogenates prepared from gray matter from 2 neocortical regions (Brodmann area [BA] 9 and BA 20) and Western blotting to determine the concentrations of key components of the glutamatergic neurotransmitter system, vesicular glutamate transporter 1 (VGLUT1) and excitatory amino acid transporter EAAT2 (GLT-1), and the ubiquitous synaptic protein, synaptophysin, in 73 individuals-48 patients with cerebrovascular disease with and without dementia, 10 patients with AD, and 15 controls-in a case-control design. Results: VGLUT1 concentrations in BA 20 and BA 9 were correlated with CAMCOG total (Rs 0.525, p = 0.018, n = 20; Rs 0.560, p = 0.002, n = 27) and CAMCOG memory scores (Rs 0.616, p = 0.004, n = 20; Rs 0.675, p = 0.000, n = 27). VGLUT1 concentration in BA 9 differed between the different dementia groups and the stroke no dementia group (1-way analysis of variance F = 6.69, p = 0.001 and Bonferroni p < 0.01 in each case), with subjects with stroke who did not develop dementia exhibiting the highest mean value for VGLUT1. Conclusions: These data suggest that loss of glutamatergic synapses is a feature of VaD and Alzheimer disease but the preservation of synapses, in particular glutamatergic synapses, in the frontal cortex against the temporal cortex plays a role in sustaining cognition and protecting against dementia following a stroke. Copyright © 2010 by AAN Enterprises, Inc.

Background: Dementia with Lewy bodies (DLB) accounts for 15-20% of the millions of people worldwide with dementia. Accurate diagnosis is essential to avoid harm and optimize clinical management. There is therefore an urgent need to identify reliable biomarkers. Methods: Mass spectrometry was used to determine the specificity of antibody α-synuclein (211) for α-synuclein. Using gel electrophoresis we measured protein levels detected by α-synuclein specific antibodies in the cerebrospinal fluid (CSF) of DLB patients and compared them to age matched controls. Results: a 24 kDa band was detected using α-synuclein specific antibodies which was significantly reduced in the CSF of DLB patients compared to age matched controls (p < 0.05). Further analysis confirmed that even DLB patients with mild dementia showed significant reductions in this protein in comparison to controls. Conclusions: the current study emphasizes the necessity for further studies of CSF α-synuclein as a biomarker of DLB and extends our previous knowledge by establishing a potential relationship between α-synuclein and the severity of cognitive impairment. The identification of this 24 kDa protein is the next important step in these studies. © International Psychogeriatric Association 2009.

People with Down syndrome develop Alzheimer's disease with an early age of onset. Plasma amyloid beta (Aβ) levels were measured in individuals with Down syndrome who were over the age of 40. No associations between age and Aβ1-40 and Aβ1-42 concentrations were found and nor were Aβ1-40 and Aβ1-42 levels found to vary between those with Alzheimer's-type dementia and those without dementia. The APOE genotype was not found to have an impact upon Aβ1-40 or Aβ1-42 concentrations. These data suggest that other factors play important roles in determining the onset and progression of dementia in the Down syndrome population. © 2008 Elsevier Ireland Ltd. 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. Copyright © 2009 American Association for Geriatric Psychiatry.

Apolipoprotein E (APOE) epsilon4 and butyrylcholinesterase-K (BuChE-K) are associated with an increased risk for Alzheimer's disease. The primary objective was to evaluate frequencies of these alleles in dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). A secondary objective was to evaluate influences on rate of cognitive decline. This analysis used data from participants consenting to pharmacogenetic testing in placebo-controlled rivastigmine studies. Allele frequencies in DLB and PDD were compared using logistic regression. Within the PDD placebo sample, associations with cognitive decline were evaluated (the DLB sample was too small for these evaluations). Fifty-seven DLB and 323 PDD subjects provided APOE and BuChE data. Allelic frequencies were higher in DLB, relative to PDD subjects, for BuChE-K (P = 0.06), APOE epsilon4 (P < 0.001), or both alleles together (P < 0.001). More rapid cognitive decline was seen in PDD patients carrying both alleles, compared with other genotypes. Subjects with hyperhomocysteinemia were associated with more rapid decline in the presence of BuChE-K, with or without APOE epsilon4. These results suggest that genetic and biochemical risk factors for AD and PDD pathology may be important in dementia onset and progression in these Lewy body disorders.

Background/Aim: Alterations in cholinergic activity have not been systematically studied in types of cerebrovascular disease. We examined cholinergic function at postmortem, focussing on stroke and vascular dementia (VaD). Methods: Post-mortem brain tissue was studied from 61 patients with stroke or VaD (13 infarct dementia; 8 stroke/no dementia; 11 sub-cortical ischaemic VaD, SIVD; 29 VaD and concurrent Alzheimer's disease, AD), 12 patients with AD and 23 controls. Choline acetyltransferase (ChAT) was measured in Brodmann areas (BA) 9 and 20/21. Results: There were significant reductions in ChAT activity in patients with VaD and concurrent AD compared to age-matched controls (BA9: t = 2.7, p = 0.009; BA20/21: t = 4.67, p = 0.000). In patients with infarct dementia, there was a significant 27% increase in ChAT activity in BA9 (t = 2.1, p = 0.047), but not in BA20/21 (t = 1.67, p = 0.106), compared to the age-matched control group. There was no relationship between ChAT activity and cognition in the VaD patients. Conclusions: Loss of cholinergic function is only evident in VaD patients with concurrent AD. A novel increase in cholinergic activity was identified in patients with infarct dementia, which may create important new treatment opportunities. © 2009 S. Karger AG, Basel.

Cholinesterase inhibitors (ChEIs) are widely used for the symptomatic treatment of Alzheimer's disease (AD). In vitro and in animal studies, ChEIs have been shown to influence the processing of Abeta and the phosphorylation of tau, proteins that are the principal constituents of the plaques and neurofibrillary tangles, respectively, in AD brain. However, little is known about the effects of these drugs on Abeta and tau pathology in AD. Using avidin-biotin immunohistochemistry and computer-assisted image analysis, we compared Abeta and tau loads in the frontal and temporal cortices of 72 brains from matched cohorts of AD patients who had or had not received ChEIs. Patients treated with ChEIs had accumulated significantly more phospho-tau in their cerebral cortex than had untreated patients (P = 0.004). Abeta accumulation was reduced but not significantly. These data raise the possibility that increased tau phosphorylation may influence long-term clinical responsiveness to ChEIs.

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. © 2009 Jones et al; licensee BioMed Central Ltd.

Background/Aims: Orthostatic hypotension (OH) and QTc prolongation have potentially important prognostic and therapeutic consequences but have rarely been studied in patients with mild dementia. Methods: Patients with mild dementia were diagnosed according to consensus criteria after comprehensive standardized assessment. OH and QTc were assessed using standardized criteria. Results: OH was significantly more common in the dementia than in the control group, and systolic drop was higher in those with dementia with Lewy bodies. There were no significant differences in QTc values between dementia and control subjects. Conclusion: OH occurs even in patients with mild dementia, in particular in dementia with Lewy bodies. QTc was not prolonged in patients with mild dementia compared with normal controls. Copyright © 2009 S. Karger AG, Basel.

Background: Falls are a major cause of morbidity and mortality in dementia, but there have been no prospective studies of risk factors for falling specific to this patient population, and no successful falls intervention/prevention trials. This prospective study aimed to identify modifiable risk factors for falling in older people with mild to moderate dementia. Methods and Findings: 179 participants aged over 65 years were recruited from outpatient clinics in the UK (38 Alzheimer's disease (AD), 32 Vascular dementia (VAD), 30 Dementia with Lewy bodies (DLB), 40 Parkinson's disease with dementia (PDD), 39 healthy controls). A multifactorial assessment of baseline risk factors was performed and fall diaries were completed prospectively for 12 months. Dementia participants experienced nearly 8 times more incident falls (9118/1000 person-years) than controls (1023/1000 person-years; incidence density ratio: 7.58, 3.11-18.5). In dementia, significant univariate predictors of sustaining at least one fall included diagnosis of Lewy body disorder (proportional hazard ratio (HR) adjusted for age and sex: 3.33, 2.11-5.26), and history of falls in the preceding 12 months (HR: 2.52, 1.52-4.17). In multivariate analyses, significant potentially modifiable predictors were symptomatic orthostatic hypotension (HR: 2.13, 1.19-3.80), autonomic symptom score (HR per point 0-36: 1.055, 1.012-1.099), and Cornell depression score (HR per point 0-40: 1.053, 1.01-1.099). Higher levels of physical activity were protective (HR per point 0-9: 0.827, 0.716-0.956). Conclusions: the management of symptomatic orthostatic hypotension, autonomic symptoms and depression, and the encouragement of physical activity may provide the core elements for the most fruitful strategy to reduce falls in people with dementia. Randomised controlled trials to assess such a strategy are a priority. © 2009 Allan et al.

Vascular dementia accounts for approximately 15-20% of all dementias. In addition, a significant subset of people with Alzheimer's disease have concurrent cerebrovascular disease. Vascular dementia is caused by different cerebrovascular morphological abnormalities including large artery territory infarction (multi-infarct vascular dementia) and sub-cortical ischaemic vascular dementia. Despite this distinction, there is a lack of studies examining the neurochemistry of individual vascular dementia subtypes. Serotonin is believed to play an important role in cognition, and serotonin receptors may provide a novel target for future anti-dementia therapeutics. This study aimed to determine levels of two serotonin receptors in subtypes of vascular dementia and relate any changes to cognition. We have determined, using saturation radioligand binding, the binding parameters (affinity and maximal binding) of ((3)H)-WAY 100635 binding to 5-HT(1A) receptors and ((3)H)-ketanserin binding to 5-HT(2A) receptors in post-mortem tissue from the frontal and temporal cortices of patients with either multi-infarct vascular dementia, sub-cortical ischaemic vascular dementia, mixed Alzheimer's disease/vascular dementia or stroke no dementia (SND). 5-HT(1A) and 5-HT(2A) receptor binding was significantly increased in the temporal cortex of patients with either multi-infarct vascular dementia or SND, compared to age-matched controls. 5-HT(1A) receptor maximal binding in the temporal cortex was also positively correlated with cognition as determined by Mini-Mental State Examination (MMSE) and Cambridge Assessment of Mental Health for the Elderly scores (CAMCOG). These results reveal an important distinction between the neurochemistry of multi-infarct vascular dementia/SND and sub-cortical ischaemic vascular dementia, suggesting that pharmacological manipulation of serotonin offers the possibility to develop novel therapies for stroke and multi-infarct vascular dementia patients. The results also highlight the importance of the cortical 5-HT(1A) receptor in mediating cognition.

Agitation and aggression are frequently occurring and distressing behavioral and psychological symptoms of dementia (BPSD). These symptoms are disturbing for individuals with Alzheimer disease, commonly confer risk to the patient and others, and present a major management challenge for clinicians. The most widely prescribed pharmacological treatments for these symptoms - atypical antipsychotics - have a modest but significant beneficial effect in the short-term treatment (over 6-12 weeks) of aggression but limited benefits in longer term therapy. Benefits are less well established for other symptoms of agitation. In addition, concerns are growing over the potential for serious adverse outcomes with these treatments, including stroke and death. A detailed consideration of other pharmacological and nonpharmacological approaches to agitation and aggression in patients with Alzheimer disease is, therefore, imperative. This article reviews the increasing evidence in support of psychological interventions or alternative therapies (such as aromatherapy) as a first-line management strategy for agitation, as well as the potential pharmacological alternatives to atypical antipsychotics - preliminary evidence for memantine, carbamazepine, and citalopram is encouraging.

Background: Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are common forms of dementia that substantially affect quality of life. Currently, the only treatment licensed for PDD is rivastigmine, and there are no licensed treatments for DLB. We aimed to test the safety and efficacy of the N-methyl D-aspartate (NMDA) receptor antagonist memantine in patients with PDD or DLB. Methods: We did a parallel-group, 24-week, randomised controlled study of memantine (20 mg per day) versus placebo at four psychiatric and neurological outpatient clinics in Norway, Sweden, and the UK during 2005-08. Patients were included if they fulfilled the UK Parkinson's Disease Society Brain Bank clinical diagnostic criteria for Parkinson's disease (PD) and developed dementia according to the Diagnostic and Statistical Manual of Mental Disorders 4th edition (DSM IV) criteria at least 1 year after the onset of motor symptoms (PDD) or met the revised consensus operationalised criteria for DLB. Patients were assigned to a computer-generated randomisation list. All physicians who had contact with patients were masked to treatment allocation. The primary outcome measure was clinical global impression of change (CGIC), which ranged from 1 to 7 points, and a low score means a better outcome. Analysis was by intention to treat based on the last observation carried forward. This trial is registered, number ISRCTN89624516. Findings: 72 patients with PDD or DLB were randomly assigned and started treatment: 34 with memantine and 38 with placebo. 56 (78%) completed the study. All withdrawals were owing to adverse events, but the proportion of withdrawals was similar in both groups. At week 24 the patients in the memantine group had better CGIC scores than those taking placebo (mean difference 0·7, 95% CI 0·04-1·39; p=0·03). With the exception of improved speed on attentional tasks in the memantine group (a quick test of cognition [AQT] form: difference 12·4, 95% CI 6·0-30·9; p=0·004), there were no significant differences between the groups in secondary outcome measures. Interpretation: Patients with DLB or PDD might benefit from treatment with memantine, which was well tolerated. Large-scale studies are now required to confirm our preliminary findings. Funding: the Western Norway Regional Health Authority; H Lundbeck A/S. © 2009 Elsevier Ltd. All rights reserved.

Subjects with Parkinson disease (PD) frequently develop dementia with greater than one-third meeting neuropathologic diagnostic criteria for Alzheimer disease (AD). The objective is to identify clinical and neuropathologic differences between Parkinson disease with dementia (PDD) subjects, with and without coexistent AD pathology. Neuropathologic examination was available on subjects diagnosed by clinicopathologic criteria with PDD-AD (N=23) and PDD+AD (N=28). A small subset of subjects with PDD-AD and PDD+AD had received at least 1 standardized neuropsychologic assessment. PDD+AD subjects were significantly older at age of PD onset and death, progressed to onset of dementia in less time, and had a shorter duration of PD symptoms before the onset of dementia. Education, responsiveness of L-dopa and dopaminergic medications, presence of cognitive fluctuations and hallucinations, and mean Mini-Mental State Examination, Global Deterioration Scale, Functional Assessment Staging, and Unified Parkinson Disease Rating Scale scores did not differ significantly between the 2 groups. The PDD+AD group had significantly greater total plaques, neuritic plaques, total tangles, and Braak stages compared with PDD-AD. This study suggests that it is difficult to distinguish PDD+AD and PDD-AD on the basis of movement, clinical, and neuropsychologic assessment. PDD-AD and PDD+AD have similar degrees of dementia and approximately half of PDD subjects have enough AD pathology to attain a neuropathologic diagnosis of AD. PDD can develop in the absence of significant Alzheimer pathology. Copyright © 2009 by Lippincott Williams & Wilkins.

Background: Data from 12-week placebo-controlled trials have led to mounting concerns about increased mortality in patients with Alzheimer's disease (AD) who are prescribed antipsychotics; however, there are no mortality data from long-term placebo-controlled trials. We aimed to assess whether continued treatment with antipsychotics in people with AD is associated with an increased risk of mortality. Methods: Between October, 2001, and December, 2004, patients with AD who resided in care facilities in the UK were enrolled into a randomised, placebo-controlled, parallel, two-group treatment discontinuation trial. Participants were randomly assigned to continue with their antipsychotic treatment (thioridazine, chlorpromazine, haloperidol, trifluoperazine, or risperidone) for 12 months or to switch their medication to an oral placebo. The primary outcome was mortality at 12 months. An additional follow-up telephone assessment was done to establish whether each participant was still alive 24 months after the enrolment of the last participant (range 24-54 months). Causes of death were obtained from death certificates. Analysis was by intention to treat (ITT) and modified intention to treat (mITT). This trial is registered with the Cochrane Central Registry of Controlled Trials/National Research Register, number ISRCTN33368770. Findings: 165 patients were randomised (83 to continue antipsychotic treatment and 82 to placebo), of whom 128 (78%) started treatment (64 continued with their treatment and 64 received placebo). There was a reduction in survival in the patients who continued to receive antipsychotics compared with those who received placebo. Cumulative probability of survival during the 12 months was 70% (95% CI 58-80%) in the continue treatment group versus 77% (64-85%) in the placebo group for the mITT population. Kaplan-Meier estimates of mortality for the whole study period showed a significantly increased risk of mortality for patients who were allocated to continue antipsychotic treatment compared with those allocated to placebo (mITT log rank p=0·03; ITT p=0·02). The hazard ratio for the mITT group was 0·58 (95% CI 0·35 to 0·95) and 0·58 (0·36 to 0·92) for the ITT population. The more pronounced differences between groups during periods of follow up longer than 12 months were evident at specific timepoints (24-month survival 46% vs 71%; 36-month survival 30% vs 59%). Interpretation: There is an increased long-term risk of mortality in patients with AD who are prescribed antipsychotic medication; these results further highlight the need to seek less harmful alternatives for the long-term treatment of neuropsychiatric symptoms in these patients. Funding: UK Alzheimer's Research Trust. © 2009 Elsevier Ltd. All rights reserved.

Background: There have been increasing concerns regarding the safety and efficacy of neuroleptics in people with dementia, but there are very few long-term trials to inform clinical practice. The aim of this study was to determine the impact of long-term treatment with neuroleptic agents upon global cognitive decline and neuropsychiatric symptoms in patients with Alzheimer disease. Methods and Findings: Design: Randomised, blinded, placebo-controlled parallel two-group treatment discontinuation trial. Setting: Oxfordshire, Newcastle and Gateshead, London and Edinburgh, United Kingdom. Participants: Patients currently prescribed the neuroleptics thioridazine, chlorpromazine, haloperidol trifluoperazine or risperidone for behavioural or psychiatric disturbance in dementia for at least 3 mo. Interventions: Continue neuroleptic treatment for 12 mo or switch to an identical placebo. Outcome measures: Primary outcome was total Severe Impairment Battery (SIB) score. Neuropsychiatric symptoms were evaluated with the Neuropsychiatric Inventory (NPI). Results: 165 patients were randomised (83 to continue treatment and 82 to placebo, i.e. discontinue treatment), of whom 128 (78%) commenced treatment (64 continue/64 placebo). of those, 26 were lost to follow-up (13 per arm), resulting in 51 patients per arm analysed for the primary outcome. There was no significant difference between the continue treatment and placebo groups in the estimated mean change in SIB scores between baseline and 6 mo; estimated mean difference in deterioration (favouring placebo) -0.4 (95% confidence interval [CI] -6.4 to 5.5), adjusted for baseline value (p1/4 0.9). For neuropsychiatric symptoms, there was no significant difference between the continue treatment and placebo groups (n = 56 and 53, respectively) in the estimated mean change in NPI scores between baseline and 6 mo; estimated mean difference in deterioration (favouring continue treatment) -2.4 (95% CI -8.2 to 3.5), adjusted for baseline value (p = 0.4). Both results became more pronounced at 12 mo. There was some evidence to suggest that those patients with initial NPI ≥ 15 benefited on neuropsychiatric symptoms from continuing treatment. Conclusions: for most patients with AD, withdrawal of neuroleptics had no overall detrimental effect on functional and cognitive status. Neuroleptics may have some value in the maintenance treatment of more severe neuropsychiatric symptoms, but this benefit must be weighed against the side effects of therapy. © 2008 Ballard et al.

RATIONALE: Species of Salvia (sage) have a long-standing reputation in European medical herbalism, including for memory enhancement. In recent controlled trials, administration of sage extracts with established cholinergic properties improved cognitive function in young adults. OBJECTIVES: This randomised, placebo-controlled, double-blind, balanced, five-period crossover study investigated the acute effects on cognitive performance of a standardised extract of Salvia officinalis in older adults. MATERIALS AND METHODS: Twenty volunteers (>65 years of age, mean = 72.95) received four active doses of extract (167, 333, 666 and 1332 mg) and a placebo with a 7-day wash-out period between visits. Assessment involved completion of the Cognitive Drug Research computerised assessment battery. On study days, treatments were administered immediately following a baseline assessment with further assessment at 1, 2.5, 4 and 6 h post treatment. RESULTS: Compared with the placebo condition (which exhibited the characteristic performance decline over the day), the 333-mg dose was associated with significant enhancement of secondary memory performance at all testing times. The same measure benefited to a lesser extent from other doses. There also were significant improvements to accuracy of attention following the 333-mg dose. In vitro analysis confirmed cholinesterase inhibiting properties for the extract. CONCLUSIONS: the overall pattern of results is consistent with a dose-related benefit to processes involved in efficient stimulus processing and/or memory consolidation rather than retrieval or working memory efficiency. These findings extend those of the memory-enhancing effects of Salvia extracts in younger populations and warrant further investigation in larger series, in other populations and with different dosing regimes.

There is evidence to suggest an involvement of the K variant of the butyrylcholinesterase gene (BCHE) in dementia. We have examined the relationship between BCHE genotype and butyrylcholinesterase (BuChE) activity in autopsy brain tissue. We studied 164 autopsy cases, 144 with dementia and 20 controls, including 13 K homozygotes and 48 K heterozygotes, from three centres: Newcastle, Oxford and London. Mean BuChE activity in temporal cortex was 37% higher in K homozygotes than in wild-type homozygotes. Linear regression analysis, controlling for gender, diagnosis, age at death and study centre, showed that the number of BCHE-K alleles was associated with increasing BuChE activity (p = 0.009). © 2008 Elsevier Ireland Ltd. All rights reserved.

When focusing on the needs of individuals with dementia and their support network, there is a broad range of key objectives; these include: diagnosis; information; treatment of dementia; treatment of secondary behavioural and psychological symptoms of dementia (BPSD); organization of a tailored care and support package; supporting carers. This article focuses on several specific aspects of treatment, particularly issues pertaining to the management of BPSD, and some of the principles of individualized care. © 2007.

Background: Serotonin 1A receptors (5-HT1A) have not been studied in dementia with Lewy bodies (DLB) or Parkinson's disease dementia (PDD) patients with depression. Aim: to examine 5-HT1A in DLB and PDD postmortem in relation to depression. Methods: [3H]8-hydroxy-2- dipropylaminotetralin binding to 5-HT1A was determined in temporal cortex (Brodmann areas, BA20 and BA36) from 10 DLB patients, 17 PDD patients and 9 controls. Results: 5-HT1A density was significantly higher in BA36 in combined DLB/PDD patients with depression, but was unaltered in BA20. Conclusion: Higher BA36 5-HT1A density in PDD and DLB patients than in control is dependent on whether the patient had experienced depression during life, not DLB/PDD diagnosis. A 5-HT1A antagonist adjuvant may improve treatment of depression in dementia. Copyright © 2008 S. Karger AG.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder, accounting for 700000 people in the UK and 25 million people worldwide with dementia1. Already licensed treatments, cholinesterase inhibitors and an NMDA (N-methyl-d-aspartate) receptor antagonist, confer important symptomatic benefits2, but at present, there are no treatments that can delay or halt the disease progression. This review outlines one of the main mechanisms currently thought to underpin the development of AD, and the treatments that are being developed based upon it. © 2008 the Biochemical Society.

Background: the clinical diagnostic criteria for dementia with Lewy bodies (DLB) have a low sensitivity, and there are no generally accepted biomarkers to distinguish DLB from other dementias. Our aim was to identify biomarkers that may differentiate DLB from Alzheimer's disease (AD). Method: We performed a systematic literature search for studies of EEG, imaging techniques and genetic and CSF markers that provide sensitivity and specificity in the identification of DLB. Results: the best evidence was for scintigraphy of the striatal dopamine transporter system using FP-CIT SPECT. Several small scintigraphy studies of cardiovascular autonomic function using metaiodobenzylguanidine SPECT have reported promising results. Studies exploring innovative techniques based on CSF have reported interesting findings for the combination of amyloid β (aβ) isoforms as well as α-synuclein, and there are interesting results emerging from preliminary studies applying proteomic techniques. Data from studies using structural MRI, perfusion SPECT, genetics and EEG studies show differences between DLB and AD but only at a group level. Conclusion: Several potential biomarkers for the differential diagnosis of probable DLB and AD have shown good diagnostic accuracy in the research setting. Data from large multicentre studies and from studies with autopsy confirmation exist for scintigraphy of the dopamine transporter system. Future studies should explore its value in possible DLB and for clinical management and health economics. Copyright © 2008 S. Karger AG.

Objective: the aim was to evaluate the efficacy, safety and tolerability of rivastigmine capsules in patients diagnosed with probable vascular dementia (VaD). Methods: VantagE (Vascular Dementia trial studying Exelon) was a 24-week, multicentre, double-blind study. VaD patients aged 50-85 years were randomized to rivastigmine capsules (3-12 mg/day) or placebo. Efficacy assessments included global and cognitive performances, activities of daily living and neuropsychiatric symptoms. Adverse events were recorded. Additional exploratory analyses determined whether heterogeneity in pathologies and symptoms extended to differential treatment effects. Trial registration: NCT00099216. Results: 710 patients were randomized. Rivastigmine demonstrated superiority over placebo on three measures of cognitive performance (Vascular Dementia Assessment Scale, Alzheimer's Disease Assessment Scale cognitive subscale, Mini-Mental State Examination; all p≤ 0.05, intent-to-treat population [ITT]), but not other outcomes. Predominant adverse events were nausea and vomiting. Exploratory analyses indicated that older patients (≥ 75 years old), assumed more likely to also have Alzheimer's disease (AD) pathology, demonstrated significant cognitive responses to rivastigmine and a safety profile similar to that seen in AD patients. Younger patients, assumed less likely to have concomitant AD pathology, showed no efficacy response and were associated with slight elevations of blood pressure, cerebrovascular accidents and mortality. Rivastigmine-placebo differences in patients with, versus those without, medial temporal atrophy (also suggestive of concomitant AD) showed a numerical difference similar to that seen between the older versus younger patients, but did not attain statistical significance. Conclusion: Consistent with trials evaluating other cholinesterase inhibitors, rivastigmine did not provide consistent efficacy in probable VaD. The efficacy apparent on cognitive outcomes was derived from effects in older patients likely to have concomitant Alzheimer pathology. This is supportive of an existing argument that the putative cholinergic deficit in VaD reflects the presence of concomitant Alzheimer pathology. © 2008 Informa UK Ltd.

Background: Despite evidence of limited efficacy, psychotropic medications are widely used as a first line treatment for those with behavioural and psychological symptoms of dementia (BPSD). Clearly various factors must be influencing their continued use; these are explored here. Aims: to examine the process by which consultant old age psychiatrists prescribe for BPSD and explore the factors that influence their decisions. Method: a focus group generated initial questions for interviews with eight consultant old age psychiatrists, using a grounded theory methodology. Results: Differences in how assessment information was utilised resulted in inconsistencies in choice of medication between psychiatrists. Psychiatrists felt pressured to prescribe, largely due to resource issues and lack of viable alternative treatments. Conclusion: the ways in which psychiatrists prescribe for BPSD varies amongst clinicians. Guidelines do exist, but are difficult to implement in practice. Alternative non-pharmacological strategies are required, but as yet they are difficult to access and have a questionable evidence base. © the Author 2008. Published by Oxford University Press on behalf of the British Geriatrics Society.

Objective: to find the proportion of dementia with Lewy bodies (DLB) in a referral cohort of patients with a first-time diagnosis of mild dementia. Background: the proportion of DLB among the dementia sufferers is not known and the clinical consensus criteria have low sensitivity. We employed the revised DLB criteria to study the proportion with DLB in a community sample of patients with mild dementia. Methods: from March 2005 to March 2007, we included 196 patients from referrals to all geriatric medicine, old age psychiatry and neurology outpatient clinics in Rogaland and Hordaland counties in Western Norway. Standardized clinical instruments and diagnostic criteria were employed. Results: 65% had Alzheimer dementia, 20% DLB (16% probable DLB), 5.6% vascular dementia, 5.6% Parkinson disease with dementia, 2.0% frontotemporal dementia and 1.5% alcoholic dementia. There were no significant differences in the proportion with DLB according to age bands and dementia severity groups. The revised criteria for a clinical diagnosis of DLB increased the proportion of probable DLB by 25% compared to the previous criteria. Conclusion: DLB is common in patients with mild dementia, and is the second most common type of dementia. The introduction of new clinical criteria for DLB leads to an increase in the proportion diagnosed with probable DLB. Copyright © 2008 S. Karger AG.

Vascular dementia (VaD) accounts for about 20% of all dementias, and vascular risk is a key factor in more than 40% of people with Alzheimer's disease (AD). Little is known about inflammatory processes in the brains of these individuals. We have examined inflammatory mediators (interleukin (IL)-1beta, IL-1alpha, IL-6 and tumour necrosis factor alpha) and chemokines (macrophage inflammatory protein 1, monocyte chemo-attractant protein (MCP)-1 and granulocyte macrophage colony-stimulating factor) in brain homogenates from grey and white matter of the frontal cortex (Brodmann area 9) from patients with VaD (n = 11), those with concurrent VaD and AD (mixed dementia; n = 8) and from age-matched controls (n = 13) using ELISA assays. We found a dramatic reduction of MCP-1 levels in the grey matter in VaD and mixed dementia in comparison to controls (55 and 66%, respectively). IL-6 decreases were also observed in the grey matter of VaD and mixed dementia (72 and 71%, respectively), with a more modest decrease (30%) in the white matter of patients with VaD or mixed dementia. In the first study to examine the status of inflammatory mediators in a brain region severely affected by white-matter lesions, our findings highlight - in contrast to previous reports in AD - that patients at the later stage of VaD or mixed dementia have a significantly attenuated neuro-inflammatory response.

Objective: Long-standing evidence indicates that Alzheimer's disease patients with behavioral symptoms have a worse prognosis and a more rapid disease progression. The current retrospective analysis evaluated the efficacy and safety of memantine in a subpopulation of patients with Alzheimer's disease exhibiting behavioral symptoms of agitation/aggression or psychosis at baseline. Method: a pooled analysis was conducted in people with agitation/aggression or psychosis from 3 large 6-month, randomized studies in moderately severe to severe Alzheimer's disease. The effect of memantine and placebo on these specific symptoms was evaluated using the Neuropsychiatric Inventory (NPI) subitem cluster of agitation and psychosis. Outcomes on global, cognitive, and functional measures were also analyzed. Results: Sixty percent of the total patient group had baseline symptoms of agitation/aggression, delusions, or hallucinations on the NPI. At both 12 and 24/28 weeks, there was a significant treatment advantage for memantine over placebo for the proportion of patients showing improvement on the defined neuropsychiatric symptom cluster (55.6% vs. 44.4% at week 12, p =. 008; 58.0% vs. 44.8% at week 24/28, p =. 002) and specifically for the treatment of agitation/aggression (55.3% vs. 43.1% at week 12, p =. 011; 61.0% vs. 45.0% at week 24/28, p <. 001). Placebo-treated patients in this population demonstrated an accelerated disease progression for global (Clinician's Interview-Based Impression of Change Plus Caregiver Input), cognitive (Severe Impairment Battery), and functional (Alzheimer Disease Cooperative Study Activities of Daily Living Inventory 19-item scale) outcomes, but memantine conferred statistically significant benefit for all measures. Tolerability in this population remained good, and fewer memantine-treated patients than placebo-treated patients withdrew due to adverse events. Conclusions: This post hoc analysis provides important evidence from placebo-controlled trials that memantine may be a safe and effective treatment in Alzheimer's disease patients with agitation/aggression or psychosis, who are otherwise prone to rapid progression. Memantine treatment provided benefits in cognitive, functional, and global outcomes in these patients and for their agitation/aggression.

Background: the aim of this study was to explore the relationship between cerebrospinal fluid biomarkers and neuropsychiatric symptoms in people with Alzheimer's disease. Psychosis, agitation, apathy and depression were assessed using standardised measures in 32 patients with mild Alzheimer's disease. Methods: the levels of the 42-amino-acid form of β-amyloid (Aβ1-42), tau and p-tau (phosphorylated at threonine 181) were quantified using the conventional enzyme-linked immunosorbent assay method. Results: Our result shows that apathy is significantly correlated with tau and p-tau but not with Aβ1-42. There were no significant correlations between indices of psychosis/agitation,or depression and cerebrospinal fluid Aβ1-42, tau or p-tau concentrations. Conclusion: Our finding suggests that apathy is associated with the level of neurofibrillary tangles in people with mild Alzheimer's disease. In contrast, the overall levels of neurofibrillary tangles or amyloid plaques do not seem to be associated with depression or psychosis, indicating that other brain changes contribute to these symptoms. Copyright © 2008 S. Karger AG.

Neuropsychiatric symptoms are frequent in people with dementia, result in distress for the people experiencing them and their caregivers, and are a common precipitant of institutional care. The safe and effective treatment of these symptoms is a key clinical priority, but is a long way from being achieved. Psychological interventions are recommended as the first line treatment strategy in most good practice guidelines, and there is emerging evidence of efficacy for agitation and depression. Neuroleptics remain the mainstay of pharmacological treatment, although meta-analyses indicate that they are mainly of benefit for the short-term (up to 12 weeks) treatment of aggression in people with Alzheimer's disease, and there have been increasing concerns about serious adverse effects including mortality. The evidence is limited for other pharmacological approaches for the treatment of agitation, and psychosis in people with Alzheimer's disease is limited, but post-hoc analyses do indicate that memantine may be a promising therapy and aromatherapy may be a useful alternative. Autopsy studies indicate that the adrenergic system may be an important therapeutic target. Clinical experience suggests that antidepressants are effective in people with severe depression in the context of dementia, but the evidence base regarding the broader value of antidepressants is far from clear. There are very few trials specifically focusing upon the treatment of neuropsychiatric symptoms in common non-Alzheimer dementias, which is a major limitation and urgently needs to be addressed to provide an evidence base to enable the safe and effective treatment of these individuals. © 2008 Informa Healthcare USA, Inc.

A dual radioligand binding and electrophysiological study, focusing on a range of ligand-gated ion channels, was performed with a chemically-validated essential oil derived from Melissa officinalis (MO), which has shown clinical benefit in treating agitation. MO inhibited binding of [35S] t-butylbicyclophosphorothionate (TBPS) to the rat forebrain gamma-aminobutyric acid (GABA)A receptor channel (apparent IC50 0.040±0.001 mg mL-1), but had no effect on N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropianate (AMPA) or nicotinic acetylcholine receptors. Electrophysiological analyses with primary cultures of rat cortical neurons demonstrated that MO reversibly inhibited GABA-induced currents in a concentration-dependent manner (0.01-1 mg mL-1), whereas no inhibition of NMDA- or AMPA-induced currents was noted. Interestingly, MO elicited a significant dose-dependent reduction in both inhibitory and excitatory transmission, with a net depressant effect on neurotransmission (in contrast to the classical GABAA antagonist picrotoxinin which evoked profound epileptiform burst firing in these cells). The anti-agitation effects in patients and the depressant effects of MO in in-vitro we report in neural membranes are unlikely to reflect a sedative interaction with any of the ionotropic receptors examined here. © 2008 the Authors.

Both Melissa officinalis (Mo) and Lavandula angustifolia (La) essential oils have putative anti-agitation properties in humans, indicating common components with a depressant action in the central nervous system. A dual radioligand binding and electrophysiological study, focusing on a range of ligand-gated ion channels, was performed with a chemically validated essential oil derived from La, which has shown clinical benefit in treating agitation. La inhibited [35S] TBPS binding to the rat forebrain gamma aminobutyric acid (GABA)A receptor channel (apparent IC50 = 0.040 ± 0.001 mg mL-1), but had no effect on N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) or nicotinic acetylcholine receptors. A 50:50 mixture of Mo and La essential oils inhibited [3H] flunitrazepam binding, whereas the individual oils had no significant effect. Electrophysiological analyses with rat cortical primary cultures demonstrated that La reversibly inhibited GABA-induced currents in a concentration-dependent manner (0.01-1 mg mL-1), whereas no inhibition of NMDA- or AMPA-induced currents was noted. La elicited a significant dose-dependent reduction in both inhibitory and excitatory transmission, with a net depressant effect on neurotransmission (in contrast to the classic GABAA antagonist picrotoxin which evoked profound epileptiform burst firing in these cells). These properties are similar to those recently reported for Mo. The anti-agitation effects in patients and the depressant effects of La we report in neural membranes in-vitro are unlikely to reflect a sedative interaction with any of the ionotropic receptors examined here. These data suggest that components common to the two oils are worthy of focus to identify the actives underlying the neuronal depressant and anti-agitation activities reported. © 2008 the Authors.

Dementia with Lewy bodies (DLB) accounts for 15-20% of the millions of people worldwide with dementia. In the current work we investigate the association between proteasome dysfunction and the development of cortical Lewy body pathology. Analysis of post-mortem cortical tissue indicated levels of the alpha-subunit of the 20S proteasome were significantly reduced in DLB cortex, but not Alzheimer's, in comparison to control and this reduction correlated with both the severity and duration of dementia. Application of proteasome inhibitors to rodent cortical primary neurones in vitro and by direct injection onto rodent cholinergic forebrain neurons in vivo gave rise to dose dependent neuronal death and in rodent cortex -- marked cholinergic deficits accompanied by the accumulation of inclusions that stained positive for alpha-synuclein and ubiquitin. These findings suggest that proteasomal abnormalities are present within cortical Lewy body disease and the experimental inhibition of proteasomal function mirrors the neuropathological changes seen within the disorder.

Objective: to determine whether attentional impairments are reliable neuropsychological markers of delirium. Method: a prospective cohort of one hundred patients admitted for elective orthopaedic surgery, 70 years and over, and free of dementia were recruited from an Orthopaedic unit in a university teaching hospital. Computerized assessments of attention and the Mini Mental State Examination were administered pre and post operatively. The Confusion Assessment Method was used to evaluate signs and symptoms of delirium. Results: over the first post operative week after surgery people with delirium scored lower on the MMSE (F=23.53 (1, 53); p=0.000); and performed less accurately (F=20.02 (1, 55); p=0.000), slower (F=14.58 (1, 54); p=0.000) and with greater variability of reaction time (F=31.52 (1, 53); p=0.000) than people without delirium. The group with delirium's neuropsychological performance was marked by a quadratic trend of accuracy (F=10.5 (1, 8); p=0.018) across the first post operative week. Conversely the group without delirium demonstrate quadratic trends for reaction time (F=6.91 (1, 49); p=0.011); and linear trends for the variability of reaction time (F=7.06 (1, 49); p=0.011) over this period. Conclusions: to date the absence of any well validated neuropsychological markers of delirium has hindered progress of research of delirium. The data within this study suggest key indices of attention and in particular fluctuating cognition may offer excellent discriminative utility for this clinically important condition. Copyright © 2008 John Wiley & Sons, Ltd.

OBJECTIVE: to evaluate the synergistic effects of the apolipoprotein E (APOE) ε4 and butyrylcholinesterase K-variant (BCHE-K) alleles on progression to Alzheimer's disease (AD) in individuals with mild cognitive impairment (MCI). METHODS: This was a post-hoc exploratory analysis from a 3-4-year, randomized, placebo-controlled study of rivastigmine in participants with MCI (InDDEx study). Participants who consented to genetic testing were included in the current analyses. The incidence of progression to AD, cognitive decline and changes in MRI brain volumes were investigated in participants from the placebo arm of the InDDEx study. RESULTS: of the 1018 participants in the overall study, 464 were successfully genotyped for both APOE and butyrylcholinesterase. of these, 68 (14.7%) carried ≥1 APOE ε4 and ≥1 BCHE-K allele. The presence of APOE ε4 was associated with a significantly higher incidence of progression to AD whereas the presence of BCHE-K had no independent effect on progression. A synergistic effect of the combined presence of APOE ε4 and BCHE-K on the time to clinical diagnosis of AD and on MRI brain volumes was seen. Progression to AD and hippocampal volumetric loss was greatest in participants who carried both APOE ε4 and BCHE-K alleles and lowest in BCHE-K carriers without the APOE ε4 allele. CONCLUSION: in MCI, the risk of cognitive decline, hippocampal volumetric loss and progression to AD seems to be the greatest in individuals who carry at least one copy of both the BCHE-K and APOE ε4 alleles. © 2008 Lippincott Williams & Wilkins, Inc.

Background/Aims: Most people with Down syndrome (DS) develop Alzheimer's disease (AD). The extended tau haplotype has been linked to AD. In this study, we examined the haplotype's effect on the age of onset of AD in DS. Methods: People with DS were assessed for dementia. Genotyping was performed for the extended tau haplotype, APOE anda polymorphism in APP, attt5-8. Results: Haplotype frequencies vary between those developing AD before 45 and those developing dementia after this age (p = 0.03). H1/H2 individuals are more likely to develop dementia before 45 than H1/H1 individuals (OR = 3, 95% CI = 1.01-8.91). Conclusion: Even in a condition driven by excess amyloid pathology, factors affecting tau are also important and should be considered as potential treatment targets. Copyright © 2008 S. Karger AG.

Objectives: to determine whether orthostatic hypotension (OH) is more common in patients with dementia than in older people without cognitive impairment and to identify key differences in the profile of the orthostatic response and the pulse drive during orthostatic challenge between Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). Methods: the orthostatic response was evaluated in 235 patients with AD, 52 patients with DLB and 62 elderly controls. The blood pressure and pulse rate were measured in supine position, immediately after standing up and after 1, 3, 5 and 10 min of standing. OH was defined as a reduction of systolic blood pressure (SBP) of at least 20 mm Hg or a reduction of diastolic blood pressure (DBP) of at least 10 mm Hg. Results: OH occurred in 69% of the DLB patients and in 42% of the AD patients, but only in 13% of the controls (p

OBJECTIVE:: Aggressive behavior in dementia is a major clinical management problem. METHOD:: Postmortem brain tissue was obtained from 24 patients with Alzheimer disease (AD) and 25 comparison cases. [3H] Prazosin binding to α1-AdR was determined. RESULTS:: Aggressive behavior was significantly correlated with α1-adrenoceptor number in patients with AD (Rs=0.454, N=24). Furthermore, patients receiving ongoing neuroleptics had significantly higher Bmax for [ 3H] prazosin (21 ± 2, N=9) than those who were not (16 ± 1, N=15). CONCLUSIONS:: Upregulation of α1-AdR is associated with aggressive behavior and chronic treatment with neuroleptic medication. © 2007 American Association for Geriatric Psychiatry.

BACKGROUND: There are no studies of autonomic function comparing Alzheimer's disease (AD), vascular dementia (VAD), dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). AIMS: to assess cardiovascular autonomic function in 39 patients with AD, 30 with VAD, 30 with DLB, 40 with PDD and 38 elderly controls by Ewing's battery of autonomic function tests and power spectral analysis of heart rate variability. To determine the prevalence of orthostatic hypotension and autonomic neuropathies by Ewing's classification. RESULTS: There were significant differences in severity of cardiovascular autonomic dysfunction between the four types of dementia. PDD and DLB had considerable dysfunction. VAD showed limited evidence of autonomic dysfunction and in AD, apart from orthostatic hypotension, autonomic functions were relatively unimpaired. PDD showed consistent impairment of both parasympathetic and sympathetic function tests in comparison with controls (all p

Cholinesterase inhibitors (ChEIs) are effective symptomatic treatments in dementia with Lewy bodies (DLB), although effects on pathologic mechanisms are unknown. In the first human autopsy study examining the impact of ChEI treatment on brain pathology, we compared treated patients with DLB with matched untreated patients for cortical β-amyloid (Aβ) and tau pathologies. Treated patients with DLB had significantly less parenchymal Aβ deposition, which is relevant to disease management and treatment of dementia patients using ChEI. ©2007AAN Enterprises, Inc.

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.) Copyright © 2007 Massachusetts Medical Society.

Background: Wandering occurs in 15-60% of people with dementia. Psychosocial interventions rather than pharmacological methods are recommended, but evidence for their effectiveness is limited and there are ethical concerns associated with some non-pharmacological approaches, such as electronic tracking devices. Objective: to determine the clinical and cost effectiveness and acceptability of non-pharmacological interventions to reduce wandering in dementia. Design: a systematic review to evaluate effectiveness of the interventions and to assess acceptability and ethical issues associated with their use. The search and review strategy, data extraction and analysis followed recommended guidance. Papers of relevance to effectiveness, acceptability and ethical issues were sought. Results: (i) Clinical effectiveness. Eleven studies, including eight randomised controlled trials, of a variety of interventions, met the inclusion criteria. There was no robust evidence to recommend any intervention, although there was some weak evidence for exercise. No relevant studies to determine cost effectiveness met the inclusion criteria. (ii) Acceptability/ethical issues. None of the acceptability papers reported directly the views of people with dementia. Exercise and music therapy were the most acceptable interventions and raised no ethical concerns. Tracking and tagging devices were acceptable to carers but generated considerable ethical debate. Physical restraints were considered unacceptable. Conclusions: in order to reduce unsafe wandering high quality research is needed to determine the effectiveness of non-pharmacological interventions that are practically and ethically acceptable to users. It is important to establish the views of people with dementia on the acceptability of such interventions prior to evaluating their effectiveness through complex randomised controlled trials. Copyright © 2006 John Wiley & Sons, Ltd.

Increased endogenous neurogenesis has a significant regenerative role in many experimental models of cerebrovascular diseases, but there have been very few studies in humans. We therefore examined whether there was evidence of altered endogenous neurogenesis in an 84-year-old patient who suffered a cerebrovascular accident 1 week prior to death. Using antibodies that specifically label neural stem/neural progenitor cells, we examined the presence of immunopositive cells around and distant from the infarcted area, and compared this with a control, age-matched individual. Interestingly, a large number of neural stem cells, vascular endothelial growth factor-immunopositive cells and new blood vessels were observed only around the region of infarction, and none in the corresponding brain areas of the healthy control. In addition, an increased number of neural stem cells was observed in the neurogenic region of the lateral ventricle wall. Our results suggest increased endogenous neurogenesis associated with neovascularization and migration of newly-formed cells towards a region of cerebrovascular damage in the adult human brain and highlight possible mechanisms underlying this process. © 2007 Future Medicine Ltd.

Stroke is an important risk factor for dementia, but the exact mechanisms involved in cognitive decline remain unclear. In this study, we related baseline MRI brain measures with later cognitive decline. Seventy-nine stroke survivors aged 75+ years without dementia were recruited 3-month post-stroke. They underwent yearly neuropsychological assessments and had an MRI at baseline and 2 years. Medial temporal lobe atrophy (MTA) was scored and volume of white matter hyperintensities (WMH) was measured at baseline. The rate of ventricular enlargement was measured by comparing the baseline and repeat images. Linear regression indicated that memory loss was related to both baseline memory and MTA (p = 0.001; standardized regression coefficient β = -0.35) but not WMH volume. The only independent predictor of ventricular enlargement was MTA (p = 0.003; β = 0.47). However, no baseline MRI variable differed between those who did (18%) and did not (82%) develop dementia. The association of MTA but not WMH with subsequent cognitive decline and increasing brain atrophy suggests a greater role for Alzheimer type than vascular pathology in delayed cognitive impairment after stroke. © 2006 Elsevier Inc. All rights reserved.

Dementia with Lewy bodies (DLB) is a progressive dementia frequently accompanied by psychotic symptoms. Similar symptoms can occur in Alzheimer's disease (AD) to a lesser extent. The use of neuroleptic medication to treat psychosis in both diseases is of modest efficacy and can induce severe adverse reactions in DLB. Dopamine D2 receptors in the cerebral cortex are the putative target for the antipsychotic action of these drugs, but the status of these receptors in DLB is unknown. Autoradiography was used to examine the density D2 receptors in postmortem temporal cortex tissue from prospectively assessed patients with neuropathologically confirmed DLB and AD. D2 receptors were substantially (over 40%) and significantly (P < 0.001) reduced in temporal cortex in DLB, and in DLB with concomitant Alzheimer pathology, but was not significantly changed in AD. This reduction correlated with greater cognitive decline (P < 0.01), but was not significantly related to visual or auditory hallucinations or delusions. D2 receptor density was inversely correlated with cortical Lewy body pathology in the neocortex (P < 0.001). The specific loss of D2 receptors associated with Lewy body pathology, in conjunction with our previous finding of low D2 receptors in striatum in DLB, provides a possible explanation for neuroleptic intolerance. That the reduction of D2 receptors correlated with cognitive decline suggests that neuroleptics, as dopamine D2 receptor antagonists, may have a deleterious effect on cognition in DLB. © 2007 Wiley-Liss, Inc.

Background: Previously, key studies of the risk profile for post-surgical delirium have focused on general medical and non-elective patients, few have examined elective cohorts. Accurate prediction is imperative for clinical trials and prevention strategies. Aims/Hypothesis: Our hypothesis was that subtle pre-operative impairments of attention will be associated with risk of post-operative delirium. Method: a prospective study evaluating pre- and post-operative neuropsychological performance in older (≥70) consecutive elective admissions for orthopaedic surgery, and free of dementia (n = 100) was initiated in a general medical hospital. Results: Pre-operative attentional deficits were closely associated with delirium. Patients who developed post-surgical delirium had significantly slower mean reaction times (p ≤ 0.011) and greater variability of reaction time (p = 0.017). A 4- to 5-fold increased risk of delirium was observed for people one standard deviation above the sample means on these variables. Conclusions: the present study describes a measurement of attentional performance which could form the basis of a neuropsychological marker of delirium. Copyright © 2007 S. Karger AG.

Dementia with Lewy bodies (DLB) is characterized by progressive dementia with two of three core symptoms; Parkinsonism, visual hallucinations or disturbances of consciousness/fluctuating attention. Dementia in Parkinson's disease (PDD) has similar neuropsychiatric characteristics. Reduced nigrothalamic dopamine and altered thalamic D2 receptors may mediate some of the non-motor symptoms of DLB and PDD. The study aims were to ascertain whether thalamic D2 density was altered in Parkinson's disease (PD), PDD and DLB, and whether D2 density was related to core symptoms. Thalamic D2 receptor binding was measured by post-mortem autoradiography in 18 cases of DLB, 13 PDD, 6 PD and 14 normal elderly controls. Highest D2 density in control cases was in the intralaminar, midline, anterior and mediodorsal nuclei. In PD without dementia D2 binding was elevated above controls in all thalamic regions, significantly in reticular, laterodorsal, centromedian, ventral centromedian, parafascicular, paraventricular, ventroposterior, ventrolateral posterior, and ventrointermedius nuclei. Compared to controls, DLB cases with Parkinsonism (DLB+EPS) had significantly elevated D2 receptor density in laterodorsal and ventrointermedius nuclei; PDD cases had significantly raised density in the ventrointermedius, and DLB cases without Parkinsonism (DLB-EPS) did not show increased D2 density in any areas. In DLB and PDD cases with disturbances of consciousness, cases treated with neuroleptics had higher D 2 binding in all thalamic regions, significantly in the mediodorsal and ventrolateral posterior nuclei. D2 receptor binding did not vary with cognitive decline (MMSE) or visual hallucinations, but was significantly higher with increased extrapyramidal symptoms. © 2006 Collegium Internationale Neuropsychopharmacologicum.

Agitation is a common symptom in people with severe dementia and is often treated with neuroleptic drugs which demonstrate severe side effects and limited efficacy. An encouraging alternative treatment involves the use of aromatherapy using essential oils from melissa (Melissa officinalis L.) or lavender (Lavandula angustifolia Mill.), both of which have recently been shown to reduce agitation in dementia patients. The present study has determined the receptor binding properties of essential oils from M. officinalis and L. angustifolia from four different suppliers at a number of ligand-gated and G-protein coupled receptors implicated in agitation. In addition, gas chromatography-mass spectrometry (GC-MS) analysis has been conducted to compare the chemical composition of the different oils. While both lavender and melissa oils significantly inhibited binding of radioligands to the muscarinic M1, 5-HT 2A, histamine H3 receptors and GABAA receptor channel site, melissa oil also affected binding to 5-HT1A receptors and the agonist site of the GABAA receptor. Moreover, melissa oil generally demonstrated greater potency than lavender oil with effects significant at concentrations of 0.1 mg/ml. The melissa oils obtained from different sources exhibited similar receptor binding and GC-MS profiles as did the lavender oils. This work represents the initial laboratory-based phase of a wider study examining the effectiveness of aromatherapy in the treatment of agitation in severe dementia. The purpose was to select one oil demonstrating maximum bioactivity to be used in a forthcoming clinical trial and to determine its chemical composition. With consideration given to the pharmacological and GC-MS data obtained in this study, melissa oil from Fytosan was chosen for use in the clinical trial. © Essential Oil Resource Consultants. All rights reserved.

Objectives: to determine the effectiveness and cost-effectiveness of non-pharmacological interventions (excluding subjective barriers) in the prevention of wandering in people with dementia, in comparison with usual care, and to evaluate through the review and a qualitative study the acceptability to stakeholders of such interventions and identify ethical issues associated with their use. Data sources: Major electronic databases were searched up until 31 March 2005. Specialists in the field. Review methods: Selected studies were assessed and analysed. The results of two of the efficacy studies that used similar interventions, designs and outcome measures were pooled in a meta-analysis; results for other studies which reported standard deviations were presented in a forest plot. Owing to a lack of cost-effectiveness data, a modelling exercise could not be performed. Four focus groups were carried out with relevant stakeholders (n = 19) including people with dementia and formal and lay carers to explore ethical and acceptability issues in greater depth. Transcripts were coded independently by two reviewers to develop a coding frame. Analysis was via a thematic framework approach. Results: Ten studies met the inclusion criteria (multi-sensory environment, three; music therapy, one; exercise, one; special care units, two; aromatherapy, two; behavioural intervention, one). There was no robust evidence to recommend any non-pharmacological intervention to reduce wandering in dementia. There was some evidence, albeit of poor quality, for the effectiveness of exercise and multi-sensory environment. There were no relevant studies to determine the cost-effectiveness of the interventions. Findings from the narrative review and focus groups on acceptability and ethical issues were comparable. Exercise and distraction therapies were the most acceptable interventions and raised no ethical concerns. All other interventions were considered acceptable except for physical restraints, which were considered unacceptable. Considerable ethical concerns exist with the use of electronic tagging and tracking devices and physical barriers. Existing literature ignores the perspectives of people with dementia. The small number of participants with dementia expressed caution regarding the use of unfamiliar technology. Balancing risk and risk assessment was an important theme for all carers in the management of wandering. Conclusions: There is no robust evidence so far to recommend the use of any non-pharmacological intervention to reduce or prevent wandering in people with dementia. High-quality studies, preferably randomised controlled trials, are needed to determine the clinical and cost-effectiveness of non-pharmacological interventions that allow safe wandering and are considered practically and ethically acceptable by carers and people with dementia. Large-scale, long-term cohort studies are needed to evaluate the morbidity and mortality associated with wandering in dementia for people both in the community and in residential care. Such data would inform future long-term cost-effectiveness studies.

To determine the effectiveness and cost-effectiveness of non-pharmacological interventions (excluding subjective barriers) in the prevention of wandering in people with dementia, in comparison with usual care, and to evaluate through the review and a qualitative study the acceptability to stakeholders of such interventions and identify ethical issues associated with their use. Major electronic databases were searched up until 31 March 2005. Specialists in the field. Selected studies were assessed and analysed. The results of two of the efficacy studies that used similar interventions, designs and outcome measures were pooled in a meta-analysis; results for other studies which reported standard deviations were presented in a forest plot. Owing to a lack of cost-effectiveness data, a modelling exercise could not be performed. Four focus groups were carried out with relevant stakeholders (n = 19) including people with dementia and formal and lay carers to explore ethical and acceptability issues in greater depth. Transcripts were coded independently by two reviewers to develop a coding frame. Analysis was via a thematic framework approach. Ten studies met the inclusion criteria (multi-sensory environment, three; music therapy, one; exercise, one; special care units, two; aromatherapy, two; behavioural intervention, one). There was no robust evidence to recommend any non-pharmacological intervention to reduce wandering in dementia. There was some evidence, albeit of poor quality, for the effectiveness of exercise and multi-sensory environment. There were no relevant studies to determine the cost-effectiveness of the interventions. Findings from the narrative review and focus groups on acceptability and ethical issues were comparable. Exercise and distraction therapies were the most acceptable interventions and raised no ethical concerns. All other interventions were considered acceptable except for physical restraints, which were considered unacceptable. Considerable ethical concerns exist with the use of electronic tagging and tracking devices and physical barriers. Existing literature ignores the perspectives of people with dementia. The small number of participants with dementia expressed caution regarding the use of unfamiliar technology. Balancing risk and risk assessment was an important theme for all carers in the management of wandering. There is no robust evidence so far to recommend the use of any non-pharmacological intervention to reduce or prevent wandering in people with dementia. High-quality studies, preferably randomised controlled trials, are needed to determine the clinical and cost-effectiveness of non-pharmacological interventions that allow safe wandering and are considered practically and ethically acceptable by carers and people with dementia. Large-scale, long-term cohort studies are needed to evaluate the morbidity and mortality associated with wandering in dementia for people both in the community and in residential care. Such data would inform future long-term cost-effectiveness studies.

BACKGROUND: Exciting preliminary work indicates an increase in progenitor activity in the subgranular zone of the dentate gyrus of people with Alzheimer's disease (AD) compared to that of controls. We examine progenitor activity in the other main progenitor niche, the subventricular zone (SVZ), as well as potential associations with key pathological and neurochemical substrates. METHOD: Immunocytochemistry techniques utilizing nestin and Musashi1 antibodies were used to examine progenitor activity in the SVZ and to enable comparisons between seven patients with AD and seven controls, based upon the quantification of the percentage area covered, using the Image Pro Plus v.4.1 image analysis system. AD pathology was staged using the Consortium to Establish a Registry for Alzheimer's Disease and Braak criteria. Choline acetyl transferase (ChAT) was measured in the temporal cortex as an indication of the severity of cortical cholinergic deficits. Glial fibrillary acidic protein (GFAP) was used to label astrocytes. RESULTS: There was a significant ninefold decrease (Z = 2.2, P =. 046) of Musashi1 immunoreactivity in the SVZ of patients with AD in comparison with that of controls, but there was a significant increase in nestin immunoreactivity in the same region (Z = 2.2, P =. 028) without any significant change in GFAP immunoreactivity. Reduced ChAT enzymatic activity was the main association of Musashi immunoreactivity (R = -.90, P =. 03). DISCUSSION: the current results indicate a significant reduction of progenitor cells (as labeled by Musashi1) in the SVZ of patients with AD, but an increase in GFAP-negative astrocyte-like cells with progenitor characteristics. Cortical cholinergic loss was strongly associated with the reduction of progenitors, with potential implications of important treatment targets.

Cholinesterase inhibition in patients with Alzheimer's disease (AD) may affect heart rate, sometimes inducing bradycardia. Additional cardiac safety considerations apply in patients with dementia with Lewy bodies (DLB) and Parkinson's disease (PDD), in whom cardiovascular autonomic nervous system dysfunction is common. We conducted a review of the safety data available for rivastigmine in these two conditions. A modest reduction in the mean heart rate of 1.5-2 bpm was seen. No clinically meaningful treatment differences in bradycardia or ECG abnormalities were apparent. Compared with placebo, rivastigmine appeared to be associated with fewer vascular disorder adverse events (AEs) (p = 0.002) and fewer AEs of syncope (p = 0.018) in PDD patients (n = 541). A smaller randomised, placebo-controlled study of rivastigmine in DLB (n = 120) showed similar findings. Rivastigmine appears to have a favourable cardiac safety profile in PDD and DLB patients. © Blackwell Publishing Ltd, 2006.

The British Association for Psychopharmacology (BAP) coordinated a meeting of experts to review the evidence on the drug treatment for dementia. The level of evidence (types) was rated using a standard system: Types 1a and 1b (evidence from meta-analysis of randomised controlled trials or at least one controlled trial respectively); types 2a and 2b (one well-designed study or one other type of quasi experimental study respectively); type 3 (non-experimental descriptive studies); and type 4 (expert opinion). There is type 1a evidence for cholinesterase inhibitors (donepezil, rivastigmine and galantamine) for mild to moderate Alzheimer's disease; memantine for moderate to severe Alzheimer's disease; and for the use of bright light therapy and aromatherapy. There is type 1a evidence of no effect of anti inflammatory drugs or statins. There is conflicting evidence regarding oestrogens, with type 2a evidence of a protective effect of oestrogens but 1b evidence of a harmful effect. Type 1a evidence for any effect of B12 and folate will be forthcoming when current trials report. There is type 1b evidence for gingko biloba in producing a modest benefit of cognitive function; cholinesterase inhibitors for the treatment of people with Lewy body disease (particularly neuropsychiatric symptoms); cholinesterase inhibitors and memantine in treatment cognitive impairment associated with vascular dementia; and the effect of metal collating agents (although these should not be prescribed until more data on safety and efficacy are available). There is type 1b evidence to show that neither cholinesterase inhibitors nor vitamin E reduce the risk of developing Alzheimer's disease in people with mild cognitive impairment; and there is no evidence that there is any intervention that can prevent the onset of dementia. There is type 1b evidence for the beneficial effects of adding memantine to cholinesterase inhibitors, and type 2b evidence of positive switching outcomes from one cholinesterase inhibitor to another. There is type 2a evidence for a positive effect of reminiscence therapy, and type 2a evidence that cognitive training does not work. There is type 3 evidence to support the use of psychological interventions in dementia. There is type 2 evidence that a clinical diagnosis of dementia can be made accurately and that brain imaging increases that accuracy. Although the consensus statement dealt largely with medication, the role of dementia care in secondary services (geriatric medicine and old age psychiatry) and primary care, along with health economics, was discussed. There is ample evidence that there are effective treatments for people with dementia, and Alzheimer's disease in particular. Patients, their carers, and clinicians deserve to be optimistic in a field which often attracts therapeutic nihilism.

Dementia with Lewy bodies is the second most prevalent of the neurodegenerative dementias and the published literature on this type of dementia has increased 30-fold over the last 10 years. This article will sum up some important aspects of this development, focusing on clinically relevant new information within epidemiology, advances in neuroimaging, genetics, clinical management, and diagnostic criteria and guidelines. Emerging evidence suggests that the clinical management of these patients differs from the management of other dementia patients, especially concerning drug treatment. Thus, identifying patients with dementia with Lewy bodies has important clinical implications. © 2006 Future Medicine Ltd.

We investigated whether previously reported differences between Alzheimer's disease and dementia with Lewy bodies (DLB) in resting occipital activity lead to activation differences within functionally specialized visual cortical areas and deactivation differences in the default network. Patients with Alzheimer's disease (n = 10; 5 male), DLB (n = 9; 4 male) and controls (n = 13; 5 male) performed three functional MRI (fMRI) scanning experiments involving visual colour, face or motion stimuli. Reaction time or accuracy in DLB and Alzheimer's disease differed significantly from controls but not between patient groups, with the exception of accuracy in the face task (DLB < Alzheimer's disease; P = 0.038). The most significant fMRI activations in the pooled data set were in left V4α for the colour task (Talairach coordinate: -30, -52, -24; P = 0.002 corrected), the right fusiform face area (FFA) for the face task (34, -48, -22; P = 0.005 corrected) and right intra-parietal sulcus (30, -66, 42; P = 0.003 corrected) for the motion task, with additional activity in right V5 (48, -64, 0; P = 0.015 corrected). Each task was associated with decreases in activity within the default network with prominent deactivation foci bilaterally in the posterior cingulate gyrus (±8, -48, 26; left P < 0.001; right P < 0.001 corrected) and medial frontal cortex (±18, 42, 32; left P < 0.001; right P < 0.001 corrected). Comparing patterns of task-related activity across groups, DLB patients showed more activation than Alzheimer patients within the superior temporal sulcus (STS) for the motion task (right STS: 44, 0, -20; P = 0.004 corrected; left STS: -40, -4, -26; P = 0.07 corrected). This difference could not be attributed to task performance, cognitive score or age [analysis of covariance (ANCOVA)F (2, 18) = 8.44, P = 0.003]. Within regions of interest, group activation differences were found for the face task (Alzheimer's disease > DLB P = 0.05; Alzheimer's disease > controls P = 0.14) and the motion task (DLB < Alzheimer's disease P = 0.031 and DLB < control P = 0.048). However, these differences could be explained by behavioural performance, failing to reach significance in the ANCOVA analysis. In the default network, group deactivation differences between controls and both patient groups were found for the colour and motion task (colour: control < Alzheimer's disease P = 0.02; control < DLB P = 0.019; motion: control < Alzheimer's disease P = 0.118; control < DLB P = 0.118) but could be accounted for by behavioural performance. The results suggest that cognitive fMRI can be used to detect both performance-dependant and performance-independent differences between Alzheimer's disease and DLB, reflecting the distribution of functional pathology in the two conditions. © the Author (2006). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.

BACKGROUND: the objective of this comparative neuropathologic study was to determine the extent to which dementia with Lewy bodies (DLB) and Parkinson disease dementia (PDD) are distinct entities or part of a continuum with respect to the duration of parkinsonism. METHODS: We evaluated the relationship between cortical alpha-synuclein pathology, plaques (Consortium to Establish a Registry for Alzheimer's Disease [CERAD]), tangles (Braak staging), and cholinergic deficits (choline acetyltransferase in temporal cortex) in 57 prospectively assessed patients (29 DLB, 28 PDD), confirmed at autopsy. The PDD group was divided according to the median duration of parkinsonism prior to dementia. RESULTS: There was an association between longer duration of parkinsonism prior to dementia and less severe cortical alpha-synuclein pathology (chi(2) 10.4, df 2, p = 0.006) and lower CERAD plaque scores (chi(2) 26.6, df 9, p = 0.002), but not Braak staging. These findings were confirmed in a further correlation analysis, which also identified an unexpected correlation between more pronounced cortical cholinergic deficits and longer duration of parkinsonism prior to dementia (R = -0.37, p = 0.04). CONCLUSION: While there is a clear relationship between the duration of Parkinson disease prior to the onset of dementia and key neuropathologic and neurochemical characteristics, there is a gradation of these differences across the dementia with Lewy bodies/Parkinson disease dementia spectrum and the findings do not support an arbitrary cut-off between the two disorders.

Objective: to evaluate the effectiveness of a training and support intervention for nursing home staff in reducing the proportion of residents with dementia who are prescribed neuroleptics. Design: Cluster randomised controlled trial with blinded assessment of outcome. Setting: 12 specialist nursing homes for people with dementia in London, Newcastle, and Oxford. Participants: Residents of the 12 nursing homes; numbers varied during the study period. Intervention: Training and support intervention delivered to nursing home staff over 10 months, focusing on alternatives to drugs for the management of agitated behaviour in dementia. Main outcome measures: Proportion of residents in each home who were prescribed neuroleptics and mean levels of agitated and disruptive behaviour (Cohen-Mansfield agitation inventory) in each home at 12 months. Results: at 12 months the proportion of residents taking neuroleptics in the intervention homes (23.0%) was significantly lower than that in the control homes (42.1%): average reduction in neuroleptic use 19.1% (95% confidence interval 0.5% to 37.7%). No significant differences were found in the levels of agitated or disruptive behaviour between intervention and control homes. Conclusions: Promotion of person centred care and good practice in the management of patients with dementia with behavioural symptoms provides an effective alternative to neuroleptics.

Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB) are common clinical dementias characterized neuropathologically by the presence of cortical Lewy body pathology and with distinct clinical and neurobiological similarities. Importantly, genetic factors seem to play a key role in the pathogenesis of Parkinson's disease. In the current article, we examine the evidence for a genetic component to DLB and PDD by reviewing studies of familial PDD and DLB as well as familial coincidental PDD and DLB, and report the genes involved. There is a convincing genetic overlap between both syndromes, suggesting that they share a common etiological factor. Copyright © 2006 S. Karger AG.

Within the spectrum of Lewy body disease cognitive impairment occurs in PD with dementia (PDD) and dementia with Lewy bodies (DLB). Although neocortical cholinergic deficits are associated with cognitive impairments in PDD and DLB, no neurochemical study has been published describing the thalamic cholinergic activity whereas the thalamus plays a major role in modulating cortical activity. Choline acetyltransferase (ChAT) activity was analyzed in reticular (Re), mediodorsal (MD) and centromedian (CM) thalamic nuclei in series of nine controls, five DLB with parkinsonism (DLB + P), five DLB without parkinsonism (DLB - P), six PD without dementia and 14 PDD cases. Significant reductions in ChAT were apparent in PDD as follows: in Re and MD nuclei compared with controls; in MD and CM nuclei compared with DLB + P; and in MD compared with PD. Increased ChAT activity was found in CM nuclei in DLB + P compared with DLB - P. These findings show that significant thalamic presynaptic cholinergic deficits occur only in cases of combined cortical and subcortical neurodegeneration in which dementia developed after prolonged parkinsonism. © 2005 Elsevier Inc. All rights reserved.

Neuroleptic (antipsychotic) drugs are often used to treat psychiatric symptoms frequently seen in dementia, but their use is controversial. We present a new meta-analysis to assess the efficacy of these drugs for the treatment of psychiatric symptoms in Alzheimer's disease, and discuss the more limited evidence for their potential benefits in other dementias. We recommend that these treatments be limited to the short-term treatment of psychiatric symptoms associated with serious distress or risk.

Clinicopathological observations suggest there is considerable overlap between vascular dementia (VaD) and Alzheimer's disease (AD). We used immunochemical methods to compare quantities of amyloid-beta (Abeta) peptides in post mortem brain samples from VaD, AD subjects and nondemented ageing controls. Total Abeta peptides extracted from temporal and frontal cortices were quantified using a previously characterized sensitive homogenous time-resolved fluorescence (HTRF) assay. The HTRF assays and immunocapture mass spectrometric analyses revealed that the Abeta(42) species were by far the predominant form of extractable peptide compared with Abeta(40) peptide in VaD brains. The strong signal intensity for the peak representing Abeta(4-42) peptide confirmed that these N-terminally truncated species are relatively abundant. Absolute quantification by HTRF assay showed that the mean amount of total Abeta(42) recovered from VaD samples was approximately 50% of that in AD, and twice that in the age-matched controls. Linear correlation analysis further revealed an increased accumulation with age of both Abeta peptides in brains of VaD subjects and controls. Interestingly, VaD patients surviving beyond 80 years of age exhibited comparable Abeta(42) concentrations with those in AD in the temporal cortex. Our findings suggest that brain Abeta accumulates increasingly with age in VaD subjects more so than in elderly without cerebrovascular disease and support the notion that they acquire Alzheimer-like pathology in older age.

Disturbances of consciousness (DOC) are common in dementia with Lewy bodies (DLB). Following previous findings of preserved temporal cortical high-affinity nicotinic binding relating to DOC, we investigated this receptor in thalamus, an area of high nicotinic receptor concentration, implicated in consciousness. 5-[125I]-A-85380 binding, primarily reflecting the alpha4beta2 subtype, was compared in 16 DLB patients with DOC and 6 without DOC, matched for duration and severity of dementia. Binding was higher in patients with DOC compared to patients without DOC in all thalamic nuclei examined, reaching significance in the reticular and ventral anterior thalamic nuclei. Comparing DLB patients with and without DOC to previously reported controls revealed similar binding levels in patients with DOC and lower binding in patients without DOC, reaching significance in the ventral anterior, indicating preserved nicotinic receptor density in DLB patients with DOC. These findings, together with previous neocortical data, implicate nicotinic modulation of thalamo-cortical circuitry as a key component in the control of conscious awareness in DLB.

BACKGROUND: Aggression, agitation or psychosis occur in the majority of people with dementia at some point in the illness. There have been a number of trials of atypical antipsychotics to treat these symptoms over the last five years, and a systematic review is needed to evaluate the evidence in a balanced way. OBJECTIVES: to determine whether evidence supports the use of atypical antipsychotics for the treatment of aggression, agitation and psychosis in people with Alzheimer's disease. SEARCH STRATEGY: the trials were identified from a last updated search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 7 December 2004 using the terms olanzapine, quetiapine, risperidone, clozapine, amisulpride, sertindole, zotepine, aripiprazole, ziprasidone. This Register contains articles from all major healthcare databases and many ongoing trials databases and is updated regularly. SELECTION CRITERIA: Randomised, placebo-controlled trials, with concealed allocation, where dementia and psychosis and/or aggression were assessed. DATA COLLECTION AND ANALYSIS: 1. Two reviewers extracted data from included trials2. Data were pooled where possible, and analysed using appropriate statistical methods3. Analysis included patients treated with an atypical antipsychotic, compared with placebo MAIN RESULTS: Sixteen placebo controlled trials have been completed with atypical antipsychotics although only nine had sufficient data to contribute to a meta-analysis and only five have been published in full in peer reviewed journals. No trials of amisulpiride, sertindole or zotepine were identified which met the criteria for inclusion. The included trials led to the following results:1. There was a significant improvement in aggression with risperidone and olanzapine treatment compared to placebo.2. There was a significant improvement in psychosis amongst risperidone treated patients.3. Risperidone and olanzpaine treated patients had a significantly higher incidence of serious adverse cerebrovascular events (including stroke), extra-pyramidal side effects and other important adverse outcomes.4. There was a significant increase in drop-outs in risperidone (2 mg) and olanzapine (5-10 mg) treated patients.5. The data were insufficient to examine impact upon cognitive function. AUTHORS' CONCLUSIONS: Evidence suggests that risperidone and olanzapine are useful in reducing aggression and risperidone reduces psychosis, but both are associated with serious adverse cerebrovascular events and extra-pyramidal symptoms. Despite the modest efficacy, the significant increase in adverse events confirms that neither risperidone nor olanzapine should be used routinely to treat dementia patients with aggression or psychosis unless there is marked risk or severe distress. Although insufficient data were available from the considered trials, a meta-analysis of seventeen placebo controlled trials of atypical neuroleptics for the treatment of behavioural symptoms in people with dementia conducted by the Food and Drug Administration (using data not in the public domain) suggested a significant increase in mortality (OR 1.7).

Background/Aims: There is little published data regarding autonomic symptoms in dementia. This study aimed to examine the prevalence and severity of autonomic symptoms in patients with different subtypes of dementia in comparison with healthy controls, and their association with levels of physical activity, depression, quality of life and ability to carry out activities of daily living. Methods: Prevalence and severity of autonomic symptoms in Parkinson's disease dementia (PDD, n = 46), dementia with Lewy bodies (DLB, n = 32), vascular dementia (VAD, n = 38), Alzheimer's disease (AD, n = 40) and healthy controls (n = 42) were assessed using a structured symptom scale. The associations between autonomic symptoms and physical activity, Bristol Activities of Daily Living Score, Geriatric and Cornell Depression Scores and quality of life (Medical Outcomes Study 36-Item Short Form Health Survey, SF-36) were examined by multiple linear regressions. Results: Total autonomic symptom scores, urinary symptoms, constipation and postural dizziness were significantly higher in PDD, DLB and VAD patients than either controls or AD patients (all p < 0.05). Higher autonomic symptom scores were associated with poorer outcomes in all measures of physical activity, activities of daily living, depression and quality of life. Conclusion: the burden of autonomic symptoms is high in non-Alzheimer's dementias. The identification of such symptoms is of importance because of the detrimental effect of these symptoms upon physical activity, depression, activities of daily living and quality of life. Copyright © 2006 S. Karger AG.

Choline acetyltransferase in temporal cortex was evaluated as a marker of cholinergic function in autopsied dementia cases (9 vascular dementia [VaD] cases, 12 "mixed" VaD and Alzheimer disease [AD] cases, 10 AD cases, 12 control subjects). Patients with AD (t = 2.5, p = 0.02) and "mixed" VaD and AD (t = 3.8, p = 0.001) had greater cholinergic deficits than age-matched control subjects and patients with "pure" VaD. The absence of cholinergic deficits in "pure" VaD may be relevant to the pharmacologic treatment of these patients.

OBJECTIVES: to determine the relationship between mild vascular cognitive impairment (mVCI) and functional disability in older stroke survivors without dementia. DESIGN: Cohort study. SETTING: Stroke patients from representative hospital-based stroke registers. PARTICIPANTS: Three hundred thirty-nine stroke survivors without dementia, aged 75 and older. MEASUREMENTS: Neuropsychological assessments were completed 3 months poststroke. Activities of daily living (ADLs) were evaluated using the Bristol scale. Operationalized criteria, including cognitive impairment no dementia (CIND), were applied for mVCI. RESULTS: Significant impairments of ADLs were evident in mVCI (CIND vs no CIND; basic care: z = 3.2; P =. 001, intermediate care: z = 3.6; P <. 001, complex management: z = 4.5; P <. 001) but varied according to the profile of cognitive impairments. Patients with attentional or global impairments had more severe functional disability than patients with isolated memory deficits, with an intermediate level of dysfunction in patients with executive impairments. CONCLUSION: the findings emphasize the importance of identifying early cognitive impairments to optimize rehabilitation, care planning, and secondary prevention of dementia in stroke patients. © 2005 by the American Geriatrics Society.

Heart rate variability (HRV) is a sensitive method for the assessment of autonomic function and requires little cooperation from the subject, making it suitable for use in dementia. Preliminary studies have suggested that HRV may be impaired in Alzheimer's disease (AD). HRV has not been studied in vascular dementia (VAD). We investigate autonomic function in AD and VAD, using power spectral analysis of HRV. One hundred and fourteen participants were evaluated (14 AD, 20 VAD and 80 controls). The resting ECG was recorded for 5 min with participants in the supine position. Power spectral analysis used to obtain spectral bands in the very-low-frequency (

BACKGROUND AND PURPOSE: Impaired autonomic function is common in the acute poststroke phase but little is known about the longer term effects, particularly in older people. We sought to determine if autonomic function is impaired after stroke recovery in older patients. METHODS: a cross-sectional case-control study comparing autonomic function in 76 nondemented stroke patients with 70 community-living controls aged older than 75 years. RESULTS: Cases were assessed on average 9 months after stroke. From power spectral analysis of heart rate variability, stroke patients had lower total (P=0.032) and low-frequency (P=0.014) spectral densities and impaired baroreflex sensitivity (alpha low-frequency baroreflex sensitivity, P=0.006). From a series of cardiovascular autonomic reflex tests, heart rate variation during forced respiration, Valsalva ratio, and blood pressure overshoot during Valsalva maneuver were significantly lower in stroke patients (P=0.003,

The most successful approach for treating people with Alzheimer's disease to date has been by improving cholinergic transmission using cholinesterase inhibitors. Many of these drugs selectively inhibit acetylcholinesterase but some agents inhibit both acetylcholinesterase and butyrylcholinesterase. Recent evidence from studies examining butyrylcholinesterase in post mortem brain samples from dementia patients and examining the relationship between butyrylcholinesterase polymorphisms and the progression of cognitive impairment in dementia with Lewy bodies and Alzheimer's disease add to a body of work suggesting that butyrylcholinesterase is present in key brain areas and may influence the maturation of plaques in Alzheimer's disease. These accumulating data suggest that butyrylcholinesterase contributes to disease progression in people with dementia, which may be particularly important in individuals with more severe dementia as butyrylcholinesterase activity increases with disease development. It is a priority for future clinical trials to determine whether agents which inhibit butyrylcholinesterase and acetylcholinesterase have a greater clinical efficacy.

Objective: to examine the relationship of the anatomic distribution of amyloid deposition to focal and global cognitive dysfunction in different subtypes of dementia. Methods: We quantified AB40 and AB42 in the temporal lobe and entorhinal cortex and examined their relation[A-Z] [A-Z]. ship to cognitive functions in Alzheimer's disease (AD), vascular dementia (VaD) and dementia with Lewy bodies (DLB). Results: We found a correlation between memory impairment, but not global cognitive impairment, and amyloid load in these areas in AD and VaD but not in DLB. This relationship was stronger for AB42 and in the entorhinal cortex. Conclusion: the anatomic location of amyloid deposition is an important factor-specific factor in memory impairment in AD and VaD. Copyright © 2005 S. Karger AG.

The dementia with Lewy bodies (DLB) Consortium has revised criteria for the clinical and pathologic diagnosis of DLB incorporating new information about the core clinical features and suggesting improved methods to assess them. REM sleep behavior disorder, severe neuroleptic sensitivity, and reduced striatal dopamine transporter activity on functional neuroimaging are given greater diagnostic weighting as features suggestive of a DLB diagnosis. The 1-year rule distinguishing between DLB and Parkinson disease with dementia may be difficult to apply in clinical settings and in such cases the term most appropriate to each individual patient should be used. Generic terms such as Lewy body (LB) disease are often helpful. The authors propose a new scheme for the pathologic assessment of LBs and Lewy neurites (LN) using alpha-synuclein immunohistochemistry and semiquantitative grading of lesion density, with the pattern of regional involvement being more important than total LB count. The new criteria take into account both Lewy-related and Alzheimer disease (AD)-type pathology to allocate a probability that these are associated with the clinical DLB syndrome. Finally, the authors suggest patient management guidelines including the need for accurate diagnosis, a target symptom approach, and use of appropriate outcome measures. There is limited evidence about specific interventions but available data suggest only a partial response of motor symptoms to levodopa: severe sensitivity to typical and atypical antipsychotics in ∼50%, and improvements in attention, visual hallucinations, and sleep disorders with cholinesterase inhibitors. Copyright © 2005 by AAN Enterprises, Inc.

As clinicians we talk about "the best interests of our patients". How can a treatment which doubles the rate of cognitive decline, triples the rate of stroke, doubles mortality, substantially increases falls and fractures and reduces quality of life be beneficial, especially, as in real life, once neuroleptics are started they are rarely discontinued with cumulative adverse effects? As there is clearly no rational reason for prescribing, we need to consider other explanations. We would suggest the following: Therapeutic impotence: Doctors, especially specialists feel they need to do something, and prescribing a familiar drug is the easiest option. Ignorance: Doctors are either unaware of the substantial evidence of harm with neuroleptics or are swayed by slick marketing information, portraying atypical neuroleptics in an "over-safe" light that does not reflect the actual data. Placebo effect: If neuroleptics are prescribed, the majority of patients experience an improvement in BPSD symptoms. This reinforces the apparent value of this practice, as we like to take the credit for any improvements that occur. The reality is that the majority of people would have experienced a comparable improvement with monitoring. Bowing to pressure: Sometimes the pressure to respond can be great, and a prescription is an easy way to relieve the pressure. This is understandable, and reflects a similar phenomenon to that of general practioners prescribing antibiotics for sore throats. In neither situation does it represent good practice. Lack of skills to implement non-pharmacological alternatives: the main evidence for alternative treatment options are for therapies that by and large are not a core part of the physician or psychiatrist's skill-base, such as psychological interventions (Cohen-Mansfield and Werner, 1997). Doctors therefore feel uncomfortable pursuing these options. Why for example is so little time spent on the non-pharmacological interventions that everyone agrees should be the first line of treatment for BPSD in people with dementia? it is largely assumed that the "enlightened clinician has already appropriately assessed and diagnosed the patient and exhausted all the possible environmental and behavioral interventions before resorting to the prescription pad." Accumulating evidence clearly indicates that the need for psychotropic medication is substantially reduced by proactive services or interventions which can provide training and promote psychological, social and environmental and sensory interventions (e.g. Rovner et al. 1996; Ballard et al. 2002; Burns et al. 2002). The prescription but is an easy but not an acceptable alternative. Over-adherence to prescribing guidance: There are pharmacological alternatives to neuroleptics if a prescription is needed. Although the evidence for the more promising alternatives needs to be developed much further, drugs such as cholinesterase inhibitors may offer a much less harmful alternative. The reluctance of clinicians to use cholinesterase inhibitors in this way is puzzling, and presumably is because of the culture of "guidance-prescribing" that has evolved around these agents. If the treatment of BPSD is to move forward, we need to challenge the way we have always done things, examine the evidence and move forward with new and flexible multi-disciplinary approaches if we are truly to look after the "best interests of our patients".

Background and Purpose - the apolipoprotein E4 allele (APOE4) associates with increased dementia risk, and hypertension may associate with mild cognitive deficits. We examined whether nondemented stroke patients with (1) a prestroke history of hypertension and (2) APOE4 were more cognitively impaired at 3 months after stroke. Methods - a total of 257 participants were genotyped and outcomes from neuropsychological evaluations analyzed using regression. Results - Total Cambridge Assessment for Mental Disorders in the Elderly (CAMCOG) and speed of working memory significantly associated with hypertension. No outcomes significantly associated with APOE4. Conclusions - Subjects with prestroke hypertension had more impaired global cognition and slower access to information held in working memory. © 2005 American Heart Association, Inc.

Alterations in cholinergic functions have been reported to be associated with neuropsychiatric symptoms in dementia. Increased M1 muscarinic receptor binding in temporal cortex is associated with delusions in dementia with Lewy bodies (DLB) patients and increased M2/M4 receptor binding with psychosis in Alzheimer's disease. However, the relation between M2 and M4 muscarinic receptor and psychotic symptoms in DLB is unknown. The aim of this study was to measure M2 and M4 receptors in the anterior cingulate cortex in DLB and to correlate the neurochemical findings with neuropsychiatric symptoms. Muscarinic M2 and M4 receptor levels in the anterior cingulate cortex and adjacent cortex (Brodmann's area [BA] 32) were measured separately by using a radioligand binding protocol based on binding of [3H]AF-DX 384 in the presence and absence of dicyclomine, a potent M4 receptor antagonist. M2 receptor binding was significantly increased, while M4 receptor binding was unchanged in the cingulate cortex and BA32 of DLB patients compared with age-matched controls. Impaired consciousness was significantly associated with increased M4 binding and delusions were significantly associated with increased M2 binding. Increased M2 and M4 receptor binding in DLB was also associated with visual hallucinations. Upregulation of M2 and M4 muscarinic receptors in cingulate and adjacent cortex may thus contribute to the development of psychosis in DLB, with potential implications for treatments with drugs acting on these receptors. © 2005 Elsevier B.V. All rights reserved.

BACKGROUND: Severe sensitivity to neuroleptic agents is a major clinical problem in dementia with Lewy bodies (DLB), but has not been determined in Parkinson's disease (PD) and PD with dementia (PDD). METHOD: Severe neuroleptic sensitivity reactions (NSRs) were evaluated according to an operationalized definition blind to clinical and neuropathologic diagnoses in prospectively studied patients exposed to neuroleptics from 2 centers. The study was conducted from June 1995 to May 2003. RESULTS: Ninety-four patients were included (15 with DLB, 36 with PDD, 26 with PD, 17 with Alzheimer's disease, all diagnosed with various operational criteria). Severe NSR only occurred in patients with Lewy body disease: DLB (8 [53%]), PDD (14 [39%]), and PD (7 [27%]), but did not occur in Alzheimer's disease (p =. 006). Severe NSR was not associated with other clinical or demographic features. In DLB, severe NSR was not associated with neuropathologic indices (Consortium to Establish a Registry for Alzheimer's Disease staging, Braak staging, or cortical distribution of Lewy bodies). CONCLUSIONS: an operationalized evaluation of severe NSR blind to diagnosis confirmed the high prevalence in DLB and identified high frequencies in Parkinson's disease and PDD with important implications for clinical practice.

Background: Neuroleptics are only modestly effective in dementia and asociated with a range of adverse effects including cognitive decline. Effects of the drugs on molecular pathology in brain tissue from people with dementia have not been investigated. Objectives: to compare the severity of Alzheimer type pathology in matched groups of people with dementia with Lewy bodies (DLB), treated and not treated with neuroleptics. Methods: the relationship between neuroleptics and Alzheimer-type pathology was determined in 40 (17 neuroleptic treated, 23 neuroleptic free, matched for age, disease duration and psychosis) clinically prospectively studied, autopsy diagnosed DLB patients. Results: in regression analyses, taking neuroleptics was significantly associated with increased neurofibrillary tangles but not amyloid plaques in cortical areas examined. The patient characteristics and the frequencies of key psychiatric symptoms were similar in the patients taking and not taking neuroleptics. Conclusion: Although patients were not randomized and the results which are observed need to be interpreted cautiously, if substantiated, this is an important finding with major implications for the pharmacological management of DLB patients and highlights the need to determine the impact of neuroleptics upon tangle pathology in AD. Copyright © 2005 John Wiley & Sons, Ltd.

Twenty-two patients with Parkinson's disease drawn from a community-based study were followed prospectively until their deaths. Even though 18 patients had dementia, none fulfilled Braak and Braak or the National Institute on Aging and Ronald and Nancy Reagan Institute of the Alzheimer's Association, whereas all patients had limbic or neocortical Lewy body disease. The Lewy body score and Braak and Braak stage were significantly associated with the rate of cognitive decline, but only the Lewy body score was associated with the rate of cognitive decline in the univariate analyses. This study strongly suggests that Lewy body disease is the main substrate driving the progression of cognitive impairment in Parkinson's disease.

Members of the Sage family, such as Salvia officinalis and Salvia lavandulaefolia, have a long history of use as memory-enhancing agents coupled with cholinergic properties that may potentially be relevant to the amelioration of the cognitive deficits associated with Alzheimer's disease. The current study utilised a placebo-controlled, double-blind, balanced, crossover design in order to comprehensively assess any mood and cognition modulation by S. lavandulaefolia. Twenty-four participants received single doses of placebo, 25 microl and 50 microl of a standardised essential oil of S. lavandulaefolia in an order dictated by a Latin square. Doses were separated by a 7-day washout period. Cognitive performance was assessed prior to the day's treatment and at 1, 2.5, 4 and 6 h thereafter using the Cognitive Drug Research (CDR) computerised test battery. Subjective mood ratings were measured using Bond-Lader visual analogue scales. The primary outcome measures were scores on the five cognitive factors that can be derived by factor analysis of the task outcomes from the CDR battery. The results showed that administration of S. lavandulaefolia resulted in a consistent improvement for both the 25- and 50-microl dose on the 'Speed of Memory' factor. There was also an improvement on the 'Secondary Memory' factor for the 25-microl dose. Mood was consistently enhanced, with increases in self-rated 'alertness', 'calmness' and 'contentedness' following the 50-microl dose and elevated 'calmness' following 25 microl. These results represent further evidence that Salvia is capable of acute modulation of mood and cognition in healthy young adults. The data also suggest that previous reports of memory enhancement by Salvia may be due to more efficient retrieval of target material.

OBJECTIVES: to compare the prevalence, severity, and type of gait and balance disorders in Alzheimer's disease (AD), vascular dementia (VaD), Parkinson's disease with dementia (PDD), dementia with Lewy bodies (DLB), Parkinson's disease without dementia (PD), and age-matched controls. DESIGN: Cross-sectional. SETTING: Secondary care clinics in geriatric psychiatry, neurology, and geriatrics. PARTICIPANTS: Two hundred forty-five participants aged 65 and older (AD, n = 40; VaD, n = 39; PDD, n = 46; DLB, n = 32; PD, n = 46; and controls, n = 42). MEASUREMENTS: Prevalence and severity of gait and balance disorders were assessed using the Tinetti gait and balance scale. The types of gait disorders in each diagnostic group were classified using the Nutt et al. classification. RESULTS: Gait and balance disorders were more common with PDD (93%), VaD (79%), and DLB (75%) than with PD (43%) and AD (25%) and in controls (7%). The risk of gait and balance disorder was higher in the non-Alzheimer's dementia groups (VaD, PDD, and DLB) than in the AD group (odds ratio = 15 (95% confidence interval = 6-37). If a gait disorder was present in mild dementia (Cambridge Examination for Mental Disorders of the Elderly cognitive subsection score >65), this was diagnostic of non-Alzheimer's dementia, with sensitivity of 78% and specificity of 100%. Non-Alzheimer's dementia groups had worse Tinetti gait and balance scores than the AD group (all P <. 001). The types of gait disorders discriminated between non-Alzheimer's dementias. CONCLUSION: the findings support the idea that gait and balance assessment may augment the diagnostic evaluation of dementia. © 2005 by the American Geriatrics Society.

Epidemiological evidence has identified key strategies that may be used in the prevention of both Alzheimer's disease and vascular dementia. These strategies may be loosely divided into three areas: treatment of vascular risk factors, neuroprotection and increasing neuronal reserves. Evidence from randomised controlled trials already exists for treatment of hypertension but results for statins have been disappointing. Most of the intervention trials currently in progress focus on one or two risk factors and include cognition or dementia only as a secondary outcome. The potential of intervention strategies awaits confirmation by randomised controlled trials that target multiple risk factors in at-risk people with mild cognitive impairment, with incident dementia as the primary outcome.

Psychiatric and behavioral symptoms are common in all types of dementia and have important consequences for patients, caregivers, and society. This paper reviews recent studies of the etiology and management of these symptoms. Genetic and neurochemical studies indicate that cholinergic, serotonergic, and dopaminergic systems may influence the risk of psychiatric symptoms in patients with dementia, There is still no consensus regarding the management of such symptoms. Controlled studies of psychosocial interventions, usually performed in the nursing home setting, report encouraging results. Atypical antipsychotics may be effective in some cases but have a high risk of adverse events. There is emerging evidence that cholinesterase inhibitors may reduce and prevent such symptoms. More studies are needed to clarify the role of cholinergic land other psychotropic agents as well as nonpharmacologic interventions for psychiatric and behavioral symptoms in patients with dementia. Copyright © 2005 by Current Science Inc.

Objectives: to determine the respective efficacy of quetiapine and rivastigmine for agitation in people with dementia in institutional care and to evaluate these treatments with respect to change in cognitive performance. Design: Randomised double blind (clinician, patient, outcomes assessor) placebo controlled trial. Setting Care facilities in the north east of England. Participants: 93 patients with Alzheimer's disease, dementia, and clinically significant agitation. Intervention: Atypical antipsychotic (quetiapine), cholinesterase inhibitor (rivastigmine), or placebo (double dummy). Main outcome measures: Agitation (Cohen-Mansfield agitation inventory) and cognition (severe impairment battery) at baseline and at six weeks and 26 weeks. The primary outcome was agitation inventory at six weeks. Results: 31 patients were randomised to each group, and 80 (86%) started treatment (25 rivastigmine, 26 quetiapine, 29 placebo), of whom 71 (89%) tolerated the maximum protocol dose (22 rivastigmine, 23 quetiapine, 26 placebo). Compared with placebo, neither group showed significant differences in improvement on the agitation inventory either at six weeks or 26 weeks. Fifty six patients scored > 10 on the severe impairment battery at baseline, 46 (82%) of whom were included in the analysis at six week follow up (14 rivastigmine, 14 quetiapine, 18 placebo). For quetiapine the change in severe impairment battery score from baseline was estimated as an average of -14.6 points (95% confidence interval -25.3 to -4.0) lower (that is, worse) than in the placebo group at six weeks (P = 0.009) and -15.4 points ( -27.0 to -3.8) lower at 26 weeks (P = 0.01). The corresponding changes with rivastigmine were -3.5 points ( -13.1 to 6.2) lower at six weeks (P = 0.5) and -7.5 points (-21.0 to 6.0) lower at 26 weeks (P = 0.3). Conclusions: Neither quetiapine nor rivastigmine is effective in the treatment of agitation in people with dementia in institutional care. Compared with placebo, quetiapine is associated with significantly greater cognitive decline.

Objective: to determine whether individuals with Alzheimer's disease (AD) and the K variant allele of butyrylcholinesterase have a slower rate of cognitive decline than those without the K variant allele of butyrylcholinesterase. Method: the cognitive status of 339 community based subjects with AD was assessed with the Mini Mental State Examination at baseline and yearly over a three year follow up period. The rates of cognitive decline of subjects with and without the K variant allele were compared. Result: Presence of the K allele was associated with a slower average rate of cognitive decline in subjects with severe AD. Conclusions: This finding is consistent with the suggestion that the K variant of butyrylcholinesterase has an important role in disease progression in AD, and this may have implications for treatment.

Accumulating evidence suggests that butyrylcholinesterase (BuChE) plays an important role in the progression of cognitive deficits and Alzheimer-type pathology in dementia patients. We examined the relationship between the K variant of BuChE and the severity of deposits of amyloid (Abeta(1-42)) and phosphorylated tau in the temporal cortex (BA36) of 30 prospectively studied autopsy-diagnosed dementia (Alzheimer's disease and dementia with Lewy bodies) patients. There was 42% less phosphorylated tau in BA36 in cases with > or =1 K compared with those with wild-type BuChE alleles (t = 2.2, p = 0.039), but no difference in the extent of Abeta(1-42) deposition. BuChE may play this role in the phosphorylation of tau, relevant to therapeutic inhibition of the enzyme.

Objective: Subcortical ischemic vascular lesions, which are closely related to small vessel disease, are a common substrate of cognitive impairment and dementia. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic variant of small vessel disease resulting from mutations in NOTCH3. Mutation carriers almost invariably develop cognitive deficits and eventually dementia. The current study describes the profile of cognitive abnormalities in CADASIL subjects. Method: a cross-sectional study of 65 mutation carriers (mean age=47.3 years, SD=10.5) and 30 m