Longitudinal effects of metabolic syndrome on Alzheimer and vascular related brain pathology.

Background/aimsThis study examines the longitudinal effect of metabolic syndrome (MetS) on brain-aging indices among cognitively normal (CN) and amnestic mild cognitive impairment (aMCI) groups [single-domain aMCI (saMCI) and multiple-domain aMCI (maMCI)].MethodsThe study population included 739 participants (CN = 226, saMCI = 275, and maMCI = 238) from the Alzheimer's Disease Neuroimaging Initiative, a clinic-based, multi-center prospective cohort. Confirmatory factor analysis was employed to determine a MetS latent composite score using baseline data of vascular risk factors. We examined the changes of two Alzheimer's disease (AD) biomarkers, namely [(18)F]fluorodeoxyglucose (FDG)-positron emission tomography (PET) regions of interest and medial temporal lobe volume over 5 years. A cerebrovascular aging index, cerebral white matter (cWM) volume, was examined as a comparison.ResultsThe vascular risk was similar in all groups. Applying generalized estimating equation modeling, all brain-aging indices declined significantly over time. Higher MetS scores were associated with a faster decline of cWM in the CN and maMCI groups but with a slower decrement of regional glucose metabolism in FDG-PET in the saMCI and maMCI groups.ConclusionAt the very early stage of cognitive decline, the vascular burden such as MetS may be in parallel with or independent of AD pathology in contributing to cognitive impairment in terms of accelerating the disclosure of AD pathology

Adjunct extended-release valproate semisodium in late life schizophrenia

Objective Adjunctive anticonvulsant medications may benefit some individuals with schizophrenia, however data on adjunct anticonvulsants in older adults with schizophrenia is limited. This prospective, 12-week open label study evaluated adjunct extended-release valproate semisodium (divalproex) in 20 older adults with schizophrenia. Methods The study was conducted at an academic psychiatry clinic in the mid-western United States. Participants were self-referred from posted advertisements or referred by clinic practitioners. Extended-release valproate semisodium was added onto antipsychotic treatment. Individuals with active substance use disorders or active significant medical comorbidity were excluded. Primary outcome measures included the Positive and Negative Syndrome Scale (PANSS), Geriatric Depression Scale (GDS) and Global Assessment Scale (GAS). Tolerability was evaluated via patient self-reported side effects, change from baseline in body weight and change on abnormal movement scales. Results Patients (mean age 61 years, range 49.8–79.2 years) had significant reductions in psychosis scores as measured by the Positive and Negative Syndrome Scale (PANSS) p  < 0.01, as well as in global functioning as measured by the Global Assessment Scale (GAS) p  < 0.01 and depression as measured by the Geriatric Depression Scale (GDS) p  < 0.05. Mean dose of extended-release valproate semisodium was 587.50 mg/day SD ± 247.02. Extended-release valproate semisodium was well tolerated in this older adult population. The primary adverse effect was sedation, which appeared to be relatively dose and titration-speed dependent. Weight change was not significant. Conclusion While extended-release valproate semisodium appears efficacious and well tolerated in older adults with schizophrenia, data from larger, controlled trials is needed. Copyright © 2007 John Wiley & Sons, Ltd.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/58029/1/1854_ftp.pd

Psychotropic use and associated neuropsychiatric symptoms among patients with dementia in the USA

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/136003/1/gps4452_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/136003/2/gps4452.pd

What is the therapeutic value of antidepressants in dementia? A narrative review

Objectives: Antidepressants are commonly used in dementia. Depression is a frequent and important co-morbidity in dementia and antidepressants are often used to treat depression and more widely. However there are questions about their utility in depression in dementia and other behavioural and psychological symptoms of dementia (BPSD). The aim of this narrative review is to summarise the evidence on whether there is therapeutic value in prescribing antidepressants to people with dementia. Methods: A PubMed search was performed to identify RCTs that prescribed antidepressants to people with dementia, either in the treatment of BPSD (depression, anxiety, agitation/aggression, psychosis, apathy) or for secondary outcomes (quality of life, carer burden, activities of daily living, cognition, clinical severity, adverse events). Results: Thirty-six RCTs were identified (participant n=3,386). A consistent finding in well-designed blinded placebo controlled trials in dementia is the lack of positive effect of antidepressants on outcomes of interest including depression. One large well-designed study has reported a significant reduction in agitation in people with dementia, but at the expense of clinically significant adverse events. Otherwise change observed in open trials is also seen in the placebo group, suggesting any effect is not attributable to the prescription of antidepressants. Conclusions: It is striking how few data there are on indications other than depression. We should question the use of antidepressants in dementia. Definitive trials of clinical effectiveness of specific indications such as anxiety and agitation in dementia and discontinuation of antidepressants in dementia are needed

DOMINO-AD protocol: donepezil and memantine in moderate to severe Alzheimer's disease - a multicentre RCT.

BACKGROUND: Alzheimer's disease (AD) is the commonest cause of dementia. Cholinesterase inhibitors, such as donepezil, are the drug class with the best evidence of efficacy, licensed for mild to moderate AD, while the glutamate antagonist memantine has been widely prescribed, often in the later stages of AD. Memantine is licensed for moderate to severe dementia in AD but is not recommended by the England and Wales National Institute for Health and Clinical Excellence. However, there is little evidence to guide clinicians as to what to prescribe as AD advances; in particular, what to do as the condition progresses from moderate to severe. Options include continuing cholinesterase inhibitors irrespective of decline, adding memantine to cholinesterase inhibitors, or prescribing memantine instead of cholinesterase inhibitors. The aim of this trial is to establish the most effective drug option for people with AD who are progressing from moderate to severe dementia despite treatment with donepezil. METHOD: DOMINO-AD is a pragmatic, 15 centre, double-blind, randomized, placebo controlled trial. Patients with AD, currently living at home, receiving donepezil 10 mg daily, and with Standardized Mini-Mental State Examination (SMMSE) scores between 5 and 13 are being recruited. Each is randomized to one of four treatment options: continuation of donepezil with memantine placebo added; switch to memantine with donepezil placebo added; donepezil and memantine together; or donepezil placebo with memantine placebo. 800 participants are being recruited and treatment continues for one year. Primary outcome measures are cognition (SMMSE) and activities of daily living (Bristol Activities of Daily Living Scale). Secondary outcomes are non-cognitive dementia symptoms (Neuropsychiatric Inventory), health related quality of life (EQ-5D and DEMQOL-proxy), carer burden (General Health Questionnaire-12), cost effectiveness (using Client Service Receipt Inventory) and institutionalization. These outcomes are assessed at baseline, 6, 18, 30 and 52 weeks. All participants will be subsequently followed for 3 years by telephone interview to record institutionalization. DISCUSSION: There is considerable debate about the clinical and cost effectiveness of anti-dementia drugs. DOMINO-AD seeks to provide clear evidence on the best treatment strategies for those managing patients at a particularly important clinical transition point. TRIAL REGISTRATION: Current controlled trials ISRCTN49545035.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Efficacy of antidepressants for depression in Alzheimer's disease: systematic review and meta-analysis

Background: Depression is common in people with Alzheimer’s disease (AD) affecting overall outcomes and decreasing quality of life. Although depression in AD is primarily treated with antidepressants, there are few randomized controlled trials (RCTs) assessing efficacy and results have been conflicting. Objectives: To systematically review evidence on efficacy of antidepressant treatments for depression in AD. Methods: Systematic review and meta-analysis of double blind RCTs comparing antidepressants versus placebo for depression in AD. We searched MEDLINE, CINAHL, EMBASE, PsycINFO, the Cochrane Controlled Trials Register and on line national and international registers. Primary outcomes were treatment response and depressive symptoms. Secondary outcomes were cognition, acceptability, and tolerability. Risk of bias was also assessed. Results: Seven studies met inclusion criteria. Three compared sertraline with placebo; one compared both sertraline and mirtazapine to placebo; imipramine, fluoxetine, and clomipramine were evaluated in one study each. In terms of response to treatment (6 studies, 297 patients treated with antidepressants and 223 with placebo), no statistically significant difference between antidepressants and placebo was found (odds ratio (OR) 1.95, 95% CI 0.97–3.92). We found no significant drug-placebo difference for depressive symptoms (5 studies, 311 patients, SMD –0.13; 95% CI –0.49 to 0.24). Overall quality of the evidence was moderate because of methodological limitations in studies and the small number of trials. Conclusion: Despite the importance of depression in people with AD, few RCTs are available on efficacy of antidepressants, limiting clear conclusions of their potential role. There is a need for further high quality RCTs

Improving mental health and reducing antipsychotic use in people with dementia in care homes: the WHELD research programme including two RCTs

BackgroundThe 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.ObjectiveThe 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.DesignThis 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.SettingThis programme was carried out in care homes in the UK.ParticipantsParticipants of this programme were people with dementia living in care homes, and the health and care professionals providing treatment and care in these settings.ResultsWork 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

Comprehensive analysis of epigenetic clocks reveals associations between disproportionate biological ageing and hippocampal volume

The concept of age acceleration, the difference between biological age and chronological age, is of growing interest, particularly with respect to age-related disorders, such as Alzheimer’s Disease (AD). Whilst studies have reported associations with AD risk and related phenotypes, there remains a lack of consensus on these associations. Here we aimed to comprehensively investigate the relationship between five recognised measures of age acceleration, based on DNA methylation patterns (DNAm age), and cross-sectional and longitudinal cognition and AD-related neuroimaging phenotypes (volumetric MRI and Amyloid-β PET) in the Australian Imaging, Biomarkers and Lifestyle (AIBL) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Significant associations were observed between age acceleration using the Hannum epigenetic clock and cross-sectional hippocampal volume in AIBL and replicated in ADNI. In AIBL, several other findings were observed cross-sectionally, including a significant association between hippocampal volume and the Hannum and Phenoage epigenetic clocks. Further, significant associations were also observed between hippocampal volume and the Zhang and Phenoage epigenetic clocks within Amyloid-β positive individuals. However, these were not validated within the ADNI cohort. No associations between age acceleration and other Alzheimer’s disease-related phenotypes, including measures of cognition or brain Amyloid-β burden, were observed, and there was no association with longitudinal change in any phenotype. This study presents a link between age acceleration, as determined using DNA methylation, and hippocampal volume that was statistically significant across two highly characterised cohorts. The results presented in this study contribute to a growing literature that supports the role of epigenetic modifications in ageing and AD-related phenotypes