11C-PiB PET assessment of change in fibrillar amyloid-beta load in patients with Alzheimer's disease treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending-dose study.

BACKGROUND: Carbon-11-labelled Pittsburgh compound B ((11)C-PiB) PET is a marker of cortical fibrillar amyloid-beta load in vivo. We used (11)C-PiB PET to investigate whether bapineuzumab, a humanised anti-amyloid-beta monoclonal antibody, would reduce cortical fibrillar amyloid-beta load in patients with Alzheimer's disease. METHODS: 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 (11)C-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 (11)C-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. FINDINGS: 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 (11)C-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 (11)C-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. INTERPRETATION: Treatment with bapineuzumab for 78 weeks reduced cortical (11)C-PiB retention compared with both baseline and placebo. (11)C-PiB PET seems to be useful in assessing the effects of potential Alzheimer's disease treatments on cortical fibrillar amyloid-beta load in vivo. FUNDING: Elan Pharmaceuticals and Wyeth Research.

Efficacy and safety of memantine in moderate-to-severe Alzheimer disease: the evidence to date.

Memantine, a moderate-affinity, uncompetitive N-methyl-D-aspartate receptor antagonist, is currently the only agent approved for moderately severe to severe Alzheimer disease (AD) in Europe and for moderate-to-severe Alzheimer disease in the United States. In clinical trials, memantine has consistently demonstrated a reduced rate of deterioration on global, cognitive, functional, and behavioral measures, across a range of outcome measures compared with usual care. Notably, improvements versus placebo were seen in individual activities of daily living and behavior, particularly agitation. Efficacy was demonstrated in patients with newly diagnosed Alzheimer disease, patients previously or currently receiving acetylcholinesterase inhibitors, and both institutionalized and community-dwelling Alzheimer disease patients. Memantine has a tolerability profile similar to placebo. This review presents the results of key clinical trials, and includes clinically relevant analyses, such as numbers-needed-to-treat and effect sizes. Increased dependency and institutionalization are significant cost drivers in Alzheimer disease. Memantine is able to reduce dependency, caregiver time required, and mean monthly caregiver and societal costs. Recent studies of the relationship between Alzheimer disease progression, caregiver burden, and healthcare costs emphasize the need for treatments such as memantine that can slow the rate of decline in Alzheimer disease.

The needs of the caregiver in the long-term treatment of Alzheimer disease.

The long-term well-being of caregivers should be included as part of the treatment of patients with Alzheimer disease (AD). Throughout the process of caring for patients with AD, caregivers frequently experience social, emotional, physical, and financial losses, which become more significant as the disease progresses. Minimizing these losses is a goal in the overall management of AD. Successful treatment of the patient has been shown to positively impact quality of life for the caregiver. Randomized, controlled studies of acetylcholinesterase inhibitors (AChEIs) have demonstrated the effectiveness of these agents in stabilizing cognitive function and delaying behavioral symptoms. Moreover, a decrease in the incidence of nursing home placement has been associated with this therapy. The growing burden of AD on families and society as a whole warrants the investigation of ways to minimize the impact of AD. AChEIs play an important role in this effort. Further studies are needed to more closely examine the impact of specific AChEIs on caregiver burden.

Realistic expectations: the management of severe Alzheimer disease.

Alzheimer disease (AD) is a progressive neurodegenerative disorder characterized by a loss of memory and cognition, a decline in ability to perform activities of daily living, changes in personality and behavior, and an increase in resource utilization and medical care. The natural course of AD can be viewed as a gradual loss of independence divided into several stages (mild, moderate, and severe) that ultimately leaves the patient under the supervision of a caregiver. Acetylcholinesterase inhibitors are the most widely accepted and proven approach to the treatment of mild to moderate AD. However, management of patients with severe AD poses challenges to physicians because there are only limited treatment options for these patients. This article provides overviews of the natural history, current therapy, and diagnostic scales of AD, focusing on management of patients with severe AD. In addition, a brief summary of the existing clinical trials conducted in severe AD is presented.