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

Agitation in cognitive disorders: International Psychogeriatric Association provisional consensus clinical and research definition

Background: Agitation is common across neuropsychiatric disorders and contributes to disability, institutionalization, and diminished quality of life for patients and their caregivers. There is no consensus definition of agitation and no widespread agreement on what elements should be included in the syndrome. The International Psychogeriatric Association formed an Agitation Definition Work Group (ADWG) to develop a provisional consensus definition of agitation in patients with cognitive disorders that can be applied in epidemiologic, non-interventional clinical, pharmacologic, non-pharmacologic interventional, and neurobiological studies. A consensus definition will facilitate communication and cross-study comparison and may have regulatory applications in drug development programs. Methods: The ADWG developed a transparent process using a combination of electronic, face-to-face, and survey-based strategies to develop a consensus based on agreement of a majority of participants. Nine-hundred twenty-eight respondents participated in the different phases of the process. Results: Agitation was defined broadly as: (1) occurring in patients with a cognitive impairment or dementia syndrome; (2) exhibiting behavior consistent with emotional distress; (3) manifesting excessive motor activity, verbal aggression, or physical aggression; and (4) evidencing behaviors that cause excess disability and are not solely attributable to another disorder (psychiatric, medical, or substance-related). A majority of the respondents rated all surveyed elements of the definition as strongly agree or somewhat agree (68-88 across elements). A majority of the respondents agreed that the definition is appropriate for clinical and research applications. Conclusions: A provisional consensus definition of agitation has been developed. This definition can be used to advance interventional and non-interventional research of agitation in patients with cognitive impairment. Copyright © International Psychogeriatric Association 2014

Cognitive and Neural Effects of Vision-Based Speed-of-Processing Training in Older Adults with Amnestic Mild Cognitive Impairment: A Pilot Study

Objectives: To examine the cognitive and neural effects of vision-based speed-of-processing (VSOP) training in older adults with amnestic mild cognitive impairment (aMCI) and contrast those effects with an active control (mental leisure activities (MLA)). Design: Randomized single-blind controlled pilot trial. Setting: Academic medical center. Participants: Individuals with aMCI (N = 21). Intervention: Six-week computerized VSOP training. Measurements: Multiple cognitive processing measures, instrumental activities of daily living (IADLs), and two resting state neural networks regulating cognitive processing: central executive network (CEN) and default mode network (DMN). Results: VSOP training led to significantly greater improvements in trained (processing speed and attention: F1,19 = 6.61, partial η2 = 0.26, P = .02) and untrained (working memory: F1,19 = 7.33, partial η2 = 0.28, P = .01; IADLs: F1,19 = 5.16, partial η2 = 0.21, P = .03) cognitive domains than MLA and protective maintenance in DMN (F1, 9 = 14.63, partial η2 = 0.62, P = .004). VSOP training, but not MLA, resulted in a significant improvement in CEN connectivity (Z = −2.37, P = .02). Conclusion: Target and transfer effects of VSOP training were identified, and links between VSOP training and two neural networks associated with aMCI were found. These findings highlight the potential of VSOP training to slow cognitive decline in individuals with aMCI. Further delineation of mechanisms underlying VSOP-induced plasticity is necessary to understand in which populations and under what conditions such training may be most effective

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