An abstract is not available for this content. As you have access to this content, full HTML content is provided on this page. A PDF of this content is also available in through the ‘Save PDF’ action button.

Objective: We aim to estimate the risk of perpetrating aggression in Alzheimer disease (AD) and mild cognitive impairment (MCI) by conducting a systematic review and meta-analysis of primary studies. Methods: A systematic search was conducted in six bibliographic databases according to a preregistered protocol. Studies that reported aggressive behaviors in individuals with AD and MCI compared with healthy individuals or those with other dementia etiologies were identified. Risks of aggressive behaviors were assessed using random effects models to calculate pooled odds ratios (ORs). Publication bias was examined. Results: In total, 17 studies involving 6,399 individuals with AD and 2,582 with MCI were identified. Compared with healthy individuals, significantly increased risks of aggressive behaviors were found in AD (OR, 4.9, 95% CI, 1.8-13.2) but not in MCI (OR, 1.8, 95% CI, 0.7-4.3). When comparing AD with MCI, the risk in AD was higher (OR, 2.6, 95% CI, 1.7-4.0). We found no differences in risk of aggressive behaviors between AD and other dementia subtypes or between amnestic and nonamnestic MCI. Conclusion: Individuals with AD are at higher risk of manifesting aggressive behaviors than healthy individuals or those with MCI. Our findings not only underscore the necessity of treatment of aggressive behaviors in AD but also highlight the importance of preventing the transition from MCI to AD.

Is it possible to prevent atrophy of key brain regions related to cognitive decline and Alzheimer’s disease (AD)? One approach is to modify nongenetic risk factors, for instance by lowering elevated plasma homocysteine using B vitamins. In an initial, randomized controlled study on elderly subjects with increased dementia risk (mild cognitive impairment according to 2004 Petersen criteria), we showed that high-dose B-vitamin treatment (folic acid 0.8 mg, vitamin B6 20 mg, vitamin B12 0.5 mg) slowed shrinkage of the whole brain volume over 2 y. Here, we go further by demonstrating that B-vitamin treatment reduces, by as much as seven fold, the cerebral atrophy in those gray matter (GM) regions specifically vulnerable to the AD process, including the medial temporal lobe. In the placebo group, higher homocysteine levels at baseline are associated with faster GM atrophy, but this deleterious effect is largely prevented by B-vitamin treatment. We additionally show that the beneficial effect of B vitamins is confined to participants with high homocysteine (above the median, 11 µmol/L) and that, in these participants, a causal Bayesian network analysis indicates the following chain of events: B vitamins lower homocysteine, which directly leads to a decrease in GM atrophy, thereby slowing cognitive decline. Our results show that B-vitamin supplementation can slow the atrophy of specific brain regions that are a key component of the AD process and that are associated with cognitive decline. Further B-vitamin supplementation trials focusing on elderly subjets with high homocysteine levels are warranted to see if progression to dementia can be prevented.

Background: Homocysteine is a risk factor for Alzheimer's disease. In the first report on the VITACOG trial, we showed that homocysteine-lowering treatment with B vitamins slows the rate of brain atrophy in mild cognitive impairment (MCI). Here we report the effect of B vitamins on cognitive and clinical decline (secondary outcomes) in the same study. Methods: This was a double-blind, single-centre study, which included participants with MCI, aged = 70y, randomly assigned to receive a daily dose of 0.8mg folic acid, 0.5mg vitamin B12 and 20mg vitamin B6 (133 participants) or placebo (133 participants) for 2y. Changes in cognitive or clinical function were analysed by generalized linear models or mixed-effects models. Results: The mean plasma total homocysteine was 30% lower in those treated with B vitamins relative to placebo. B vitamins stabilized executive function (CLOX) relative to placebo (P= 0.015). There was significant benefit of B-vitamin treatment among participants with baseline homocysteine above the median (11.3mmol/ L) in global cognition (Mini Mental State Examination, P< 0.001), episodic memory (Hopkins Verbal Learning Test-delayed recall, P= 0.001) and semantic memory (category fluency, P= 0.037). Clinical benefit occurred in the B-vitamin group for those in the upper quartile of homocysteine at baseline in global clinical dementia rating score (P= 0.02) and IQCODE score (P= 0.01). Conclusion: In this small intervention trial, B vitamins appear to slow cognitive and clinical decline in people withMCI, in particular in those with elevated homocysteine. Further trials are needed to see if this treatment will slow or prevent conversion from MCI to dementia. Copyright (C) 2011 John Wiley & Sons, Ltd.

Introduction Moderately raised plasma total homocysteine (tHcy) is found in Alzheimer’s disease (AD) and vascular dementia, and is associated with increased risk of dementia and cognitive decline (Dufouil et al., 2003; meta-analysis in Wald et al., 2011). Concentrations of tHcy are largely determined by the body's status of certain B vitamins (folate, B6 and B12), which are cofactors or substrates for enzymes involved in homocysteine metabolism (Refsum et al., 2004). Several clinical trials have investigated the effect of high doses of B vitamins to lower tHcy with inconsistent results on cognitive outcomes (meta-analyses in Dangour et al., 2010 and Wald et al., 2010). This discrepancy might be due to differences in the combination of B vitamins used, their dosage, the duration of treatment, the population size and the population cognitive/clinical status – as most of them included participants who were either healthy or who already had dementia. This study, the VITACOG trial, therefore focused on elderly participants showing cognitive impairment – but not dementia – who were followed for two years. We previously reported that B vitamin treatment reduced wholebrain atrophy by 30% (Smith et al., 2010). However, it remains unanswered whether this reduction of atrophy actually corresponds to regions vulnerable to the AD process and showing significant atrophy in the placebo group.

Background: An increased rate of brain atrophy is often observed in older subjects, in particular those who suffer from cognitive decline. Homocysteine is a risk factor for brain atrophy, cognitive impairment and dementia. Plasma concentrations of homocysteine can be lowered by dietary administration of B vitamins.Objective: To determine whether supplementation with B vitamins that lower levels of plasma total homocysteine can slow the rate of brain atrophy in subjects with mild cognitive impairment in a randomised controlled trial (VITACOG, ISRCTN 94410159).Methods and Findings: Single-center, randomized, double-blind controlled trial of high-dose folic acid, vitamins B-6 and B-12 in 271 individuals (of 646 screened) over 70 y old with mild cognitive impairment. A subset (187) volunteered to have cranial MRI scans at the start and finish of the study. Participants were randomly assigned to two groups of equal size, one treated with folic acid (0.8 mg/d), vitamin B-12 (0.5 mg/d) and vitamin B-6 (20 mg/d), the other with placebo; treatment was for 24 months. The main outcome measure was the change in the rate of atrophy of the whole brain assessed by serial volumetric MRI scans. Results: A total of 168 participants (85 in active treatment group; 83 receiving placebo) completed the MRI section of the trial. The mean rate of brain atrophy per year was 0.76% [95% CI, 0.63-0.90] in the active treatment group and 1.08% [0.94-1.22] in the placebo group (P = 0.001). The treatment response was related to baseline homocysteine levels: the rate of atrophy in participants with homocysteine >13 mu mol/L was 53% lower in the active treatment group (P = 0.001). A greater rate of atrophy was associated with a lower final cognitive test scores. There was no difference in serious adverse events according to treatment category.Conclusions and Significance: The accelerated rate of brain atrophy in elderly with mild cognitive impairment can be slowed by treatment with homocysteine-lowering B vitamins. Sixteen percent of those over 70 y old have mild cognitive impairment and half of these develop Alzheimer's disease. Since accelerated brain atrophy is a characteristic of subjects with mild cognitive impairment who convert to Alzheimer's disease, trials are needed to see if the same treatment will delay the development of Alzheimer's disease.

OBJECTIVE:Moderately elevated levels of plasma total homocysteine are associated with an increased risk of developing Alzheimer's disease. We have tested whether baseline concentrations of homocysteine relate to the subsequent rate of cognitive decline in patients with established Alzheimer's disease (AD). METHODS:In 97 patients with AD, 73 pathologically-confirmed, we analysed the decline of global cognitive test scores (CAMCOG) over time from the first assessment for at least three 6-monthly visits up to a maximum of 9.5 years (in total 689 assessments). Non-linear mixed-effects statistical models were used. RESULTS:Baseline homocysteine levels showed a concentration-response relationship with the subsequent rate of decline in CAMCOG scores: the higher the homocysteine, the faster the decline. The relationship was significant in patients aged < 75 years who had not suffered a prior stroke. For example, in patients aged 65 years with a baseline homocysteine of 14 micromol/L, the decline from a CAMCOG score of 88 to a score of 44 occurred 19.2 (95% CI 6.8, 31.6) months earlier than in patients with a baseline homocysteine of 10 micromol/L. CONCLUSIONS:Raised homocysteine concentrations within the normal range among the elderly strongly relate to the rate of global cognitive decline in patients with Alzheimer disease. Plasma homocysteine can readily be lowered by B-vitamin treatment and trials should be carried out to see if such treatments can slow the rate of cognitive decline in relatively young patients with Alzheimer disease.

To determine whether treatment with vitamins B12, B6 and folic acid has an effect on memory performance over a 2-year period in those with Mild Cognitive Impairment (MCI) and whether memory performance and treatment response is modulated by other factors including baseline plasma total homocysteine (tHcy) level. A total of 271 participants with MCI, aged ≥70 years were randomised to B vitamins (0.8 mg folic acid, 0.5 mg B12, 20 mg B6 and per day, n = 138) or placebo (n = 133) after screening for MCI using the TICS-m and animal fluency scores. Data on age, sex, education and ApoE ∊4 status and baseline measures of tHcy and structural MRI were collected. Neuropsychological tests in domains of episodic and semantic memory, executive function and selective attention were conducted. After 2 years on treatment, the neuropsychological tests and MRI scans were repeated. The cognitive measures were a secondary outcome of the trial as it was powered for significant differences in rate of brain atrophy. Generalized linear mixed effects and generalized estimating equations models were fitted to the longitudinal (6 time-points) scores on the HVLT. The models estimated the expected performance on the HVLT from 9 to 24 months. After controlling for age, sex, education and ApoE ∊4 status, significant differences were found between the treatment and placebo groups. These differences were dependent on the baseline tHcy levels, so that with higher tHcy level at baseline (>10 μmol/L), the rate of decline in HVLT scores was significantly greater in the placebo group. This vitamin B trial was successful in showing a significant effect of treatment in slowing cognitive decline in those with MCI and raised tHcy at baseline. This suggests that long-term treatment with B vitamins for older people with no contra-indications may be beneficial to maintaining memory performance.

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.

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 (1717) 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% Cl 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.

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

BACKGROUND:Challenges to wills on the basis of lack of testamentary capacity and/or undue influence are likely to increase over the next generation. Since contemporaneous assessment of testamentary capacity can be a powerful influence on the outcome of such challenges, there will be an associated increase in requests for expert assessment of testamentary capacity. There is a need to provide such potential experts with the knowledge and guidelines necessary to conduct assessments that will be helpful to the judicial system. METHODS:A subcommittee of the International Psychogeriatric Association (IPA) task force on "Testamentary Capacity and Undue Influence" was formed to establish guidelines for contemporaneous assessment of testamentary capacity. RESULTS:The task-specific criteria for testamentary capacity as outlined by Lord Chief Justice Cockburn in the well-known Banks v. Goodfellow case are described. Additional issues are identified for probing and documentation. This is designed to determine whether the testator can formulate a coherent, rational testamentary plan that connects his/her beliefs, values and relationships with the proposed disposition of assets. Rules of engagement by the expert assessor are defined as well as an approach to the clinical examination for testamentary capacity resulting in a clear and relevant report. CONCLUSION:Guidelines for experts who are asked to provide a contemporaneous opinion on testamentary capacity should help to inform disputes resulting from challenges to wills. A consistent clinical approach will help the courts to make their determinations.

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