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In a randomized trial, solanezumab, a humanized monoclonal antibody against soluble amyloid, did not slow cognitive decline over a period of 80 weeks in patients with mild Alzheimer’s disease and with PET or CSF biomarkers of amyloid-related disease.

Summary Background Immunisation of patients with Alzheimer's disease with full-length amyloid-β peptide (Aβ42 ) can clear amyloid plaques from the brain. Our aim was to assess the relation between Aβ42 immune response, degree of plaque removal, and long-term clinical outcomes. Methods In June, 2003, consent for long-term clinical follow-up, post-mortem neuropathological examination, or both, was sought from 80 patients (or their carers) who had entered a phase I randomised, placebo-controlled trial of immunisation with Aβ42 (AN1792, Elan Pharmaceuticals) in September, 2000. The follow-up study was completed in September, 2006. Plaques were assessed in terms of the percentage area of the cortex with Aβ immunostaining (Aβ load) and in terms of characteristic histological features reflecting plaque removal. Survival of all 80 individuals until severe dementia or death was assessed with a Cox proportional hazard model. Findings 20 participants—15 in the AN1792 group, five in the placebo group—died before follow-up started. A further 22 patients—19 in the AN1792 group, three in the placebo group—died during follow-up. Nine of the deceased patients, all in the AN1792 group, had given consent for post-mortem analysis; one of these who did not die with Alzheimer's disease was excluded. In the remaining eight participants who received immunisation and who were examined neuropathologically, mean Aβ load was lower than in an unimmunised control group that was matched for age at death (2·1% [SE 0·7] in treated participants vs 5·1% [0·9] in controls; mean difference 3·0%, 95% CI 0·6–5·4; p=0·02). Although there was considerable variation in Aβ load and degree of plaque removal among immunised participants, the degree of plaque removal varied significantly with mean antibody response attained during the treatment study period (Kruskal-Wallis p=0·02). Seven of the eight immunised patients who underwent post-mortem assessment, including those with virtually complete plaque removal, had severe end stage dementia before death. In the whole cohort, there was no evidence of improved survival (hazard ratio 0·93, 95% CI 0·43–3·11; p=0·86) or of an improvement in the time to severe dementia (1·18, 0·45–3·11; p=0·73) in the AN1792 group versus the placebo group. Interpretation Although immunisation with Aβ42 resulted in clearance of amyloid plaques in patients with Alzheimer's disease, this clearance did not prevent progressive neurodegeneration. Funding Alzheimer's Research Trust, Medical Research Council.

Prevalence of Alzheimer's disease in people with Down's syndrome is very high, and many such individuals who are older than 40 years have pathological changes characteristic of Alzheimer's disease. Evidence to support treatment with Alzheimer's drugs is inadequate, although memantine is beneficial in transgenic mice. We aimed to assess safety and efficacy of memantine on cognition and function in individuals with Down's syndrome. In our prospective randomised double-blind trial, we enrolled adults (>40 years) with karyotypic or clinically diagnosed Down's syndrome, with and without dementia, at four learning disability centres in the UK and Norway. We randomly allocated participants (1:1) to receive memantine or placebo for 52 weeks by use of a computer-generated sequence and a minimisation algorithm to ensure balanced allocation for five prognostic factors (sex, dementia, age group, total Down's syndrome attention, memory, and executive function scales [DAMES] score, and centre). The primary outcome was change in cognition and function, measured with DAMES scores and the adaptive behaviour scale (ABS) parts I and II. We analysed differences in DAMES and ABS scores between groups with analyses of covariance or quantile regression in all patients who completed the 52 week assessment and had available follow-up data. This study is registered, number ISRCTN47562898. We randomly allocated 88 patients to receive memantine (72 [82%] had DAMES data and 75 [85%] had ABS data at 52 weeks) and 85 to receive placebo (74 [87%] and 73 [86%]). Both groups declined in cognition and function but rates did not differ between groups for any outcomes. After adjustment for baseline score, there were non-significant differences between groups of −4·1 (95% CI −13·1 to 4·8) in DAMES scores, −8·5 (–20·1 to 3·1) in ABS I scores, and 2·0 (–7·2 to 11·3) in ABS II scores, all in favour of controls. 10 (11%) of 88 participants in the memantine group and six (7%) of 85 controls had serious adverse events (p=0·33). Five participants in the memantine group and four controls died from serious adverse events (p=0·77). There is a striking absence of evidence about pharmacological treatment of cognitive impairment and dementia in people older than 40 years with Down's syndrome. Despite promising indications, memantine is not an effective treatment. Therapies that are effective for Alzheimer's disease are not necessarily effective in this group of patients. Lundbeck.

Agitation is common in patients with Alzheimer's disease and is distressing to both patients and their caregivers. In this randomized trial of 272 patients with Alzheimer's disease who had agitated behavior that did not respond to a psychosocial treatment program, donepezil (5 mg for 4 weeks and 10 mg for 8 weeks) was not more effective than placebo in reducing agitation. In patients with Alzheimer's disease who had agitated behavior that did not respond to a psychosocial treatment program, donepezil was not more effective than placebo in reducing agitation. Alzheimer's disease causes a progressive decline in cognitive and functional ability and distress on the part of both patients and their caregivers. Agitation, a cluster of related symptoms that includes anxiety, irritability, and motor restlessness, leading to behaviors such as pacing, wandering, shouting, and aggression, 1 is seen in 24% of people with Alzheimer's disease who live in the community 2 and in 48% of those living in residential care facilities. 3 Behavioral and psychological symptoms in Alzheimer's disease are distressing to caregivers 4 , 5 and often precipitate the transition to residential care. 6 Atypical neuroleptic agents remain the mainstay of drug treatment despite only . . .

The efficacy of galantamine has been shown in patients with mild, moderate, and advanced moderate Alzheimer's disease (AD). Here we report its efficacy in patients with severe AD. Between December, 2003, and March, 2007, patients aged 84 (SD 6) years with severe AD (mini-mental state examination [MMSE] score 5–12 points), in a nursing home setting were randomly assigned to receive galantamine (n=207), titrated initially to 24 mg/day, or placebo (n=200). Co-primary efficacy measures for cognitive function and ability to undertake normal daily activities were the severe impairment battery (SIB) and the seven-item minimum data set-activities of daily living (MDS-ADL), respectively. Adverse events, vital signs, laboratory parameters, and electrocardiograms were monitored. This trial is registered with ClinicalTrials.gov, number NCT00216593. 168 of 207 (81%) patients in the galantamine group and 161 of 200 (81%) in the placebo group completed the study. Mean SIB scores increased (improved) by 1·9 (95% CI −0·1 to 3·9) points with galantamine and decreased (worsened) by 3·0 (−5·6 to −0·5) points with placebo (between-group least squares mean difference 4·36, 1·3 to 7·5; p=0·006). Mean MDS-ADL self-performance score worsened by 1·2 (0·6 to 1·8) points and 1·6 (0·8 to 2·3) points, respectively (between-group least squares mean difference −0·41, −1·3 to 0·5; p=0·383). Nominally significant between-group differences in favour of galantamine occurred for the SIB domains of memory (p=0·006), praxis (p=0·010), and visuospatial ability (p=0.002), and for the MDS-ADL subitem locomotion on unit (p=0·021). 183 of 207 patients (88%) who received galantamine and 177 of 200 (89%) who received placebo had adverse events, which were mostly mild to moderate. Eight patients (4%) in the galantamine group and 21 patients (11%) in the placebo group died. ECG abnormalities were similar between the two groups. Galantamine can be started and used safely in elderly patients with severe AD. Galantamine improved cognitive function but failed to significantly improve the co-primary parameter of overall activities of daily living. Janssen-Cilag EMEA.

Alzheimer's disease management involves symptomatic drug treatments passed by the National Institute for Clinical Excellence. Disease modification is now the goal. To review current and developmental drugs for Alzheimer's disease, their usage, and the clinical context of known facts and proposed specific models. A brief evidence-based review was made, using literature where available, or evidence from consensus groups where it was absent. There is good evidence to support the use of cholinesterase inhibitors, and perhaps vitamin E. Oestrogen and anti-inflammatory agents show possibility, but there is not enough evidence to support routine use. Symptomatic treatments exist for Alzheimer's disease. Observational studies and increasing knowledge of brain biology are leading towards further treatment options. Old age psychiatrists have valuable treatments they now have to learn to use.

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. 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. 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. 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.

Links between Alzheimer’s disease (AD) and vascular dementia (VaD) have been examined, and this paper investigates the role of executive control function (ECF) within the dementia syndrome. 307 AD patients, 168 VaD patients and 208 controls were compared on tests of cognitive function. Results indicated that controls outperformed both patient groups (p < 0.001) on all tests. AD patients performed more poorly than VaD patients on 11 of the 18 cognitive tests (p < 0.05). Factor analysis of patient data indicated the existence of 3 factors generated from the battery of tests, relating to episodic memory, ECF and face recognition. It was primarily on tests of ECF that the AD and VaD groups did not differ significantly. It is concluded that ECF is a feature of cognition shared by the two pathologies, giving rise to an obligation to reconsider the current understanding of the core cognitive feature of dementia.

Purpose The purpose of this paper is to assess the legacy of six pioneer child care researchers. Design/methodology/approach An assessment of the achievements of a generation of child care researchers. Findings The early researchers were not only highly innovative in terms of theory and methodologies but also left a set of studies that stimulated and informed subsequent studies. Originality/value A review of the work of six pioneering child care researchers.

Carbon-11-labelled Pittsburgh compound B ( 11C-PiB) PET is a marker of cortical fibrillar amyloid-β load in vivo. We used 11C-PiB PET to investigate whether bapineuzumab, a humanised anti-amyloid-β monoclonal antibody, would reduce cortical fibrillar amyloid-β load in patients with Alzheimer's disease. Patients with mild-to-moderate Alzheimer's disease were randomly assigned to receive intravenous bapineuzumab or placebo in a ratio of seven to three in three ascending dose groups (0·5, 1·0, or 2·0 mg/kg). Each dose group was enrolled after safety review of the previous group. Randomisation was by interactive voice response system; masking was achieved with numbered kit allocation. Patients, investigators, study site personnel, sponsor staff, and carers were masked to treatment. Patients received up to six infusions, 13 weeks apart, and had 11C-PiB PET scans at baseline and at weeks 20, 45, and 78. The primary outcome was the difference between the pooled bapineuzumab group and the pooled placebo group in mean change from screening to week 78 in 11C-PiB cortical to cerebellar retention ratio averaged across six cortical regions of interest. Analysis was by modified intention to treat. This study is registered with EudraCT, number 2004-004120-12; ISRCTN17517446. 28 patients were assigned to bapineuzumab (n=20) or placebo (n=8). 19 patients in the bapineuzumab group and seven in the placebo group were included in the modified intention-to-treat analysis. Estimated mean 11C-PiB retention ratio change from baseline to week 78 was −0·09 (95% CI −0·16 to −0·02; p=0·014) in the bapineuzumab group and 0·15 (95% CI 0·02 to 0·28; p=0·022) in the placebo group. Estimated mean difference in 11C-PiB retention ratio change from baseline to week 78 between the bapineuzumab group and the placebo group was −0·24 (95% CI −0·39 to −0·09; p=0·003). Differences between the bapineuzumab group and the placebo group in the individual regions of interest were similar to the overall mean difference. Adverse events were typically mild to moderate in severity and transient. Two patients in the 2·0 mg/kg bapineuzumab group had transient cerebral vasogenic oedema. Treatment with bapineuzumab for 78 weeks reduced cortical 11C-PiB retention compared with both baseline and placebo. 11C-PiB PET seems to be useful in assessing the effects of potential Alzheimer's disease treatments on cortical fibrillar amyloid-β load in vivo. Elan Pharmaceuticals and Wyeth Research.