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To what extent is it possible to plan ahead for children coming into care? How can we ensure that there are enough foster homes available for new entrants and that the range of facilities is sufficiently wide to meet all of their different needs? There are several possible approaches. We can wait and see what comes through the door and try to respond as best we can. Or, we can construct a range of services and try to fit the children into them. These strategies might be enough to contain the problem but will almost certainly lead to frustration, dissatisfaction and instability. So what else can be done? The Dartington Social Research Unit in England has developed a methodology to achieve a better match between the foster care that is provided and the needs of the children. It is called Matching Needs and Services (MNS).

The International Society for CNS Clinical Trials and Methodology (ISCTM) held its 4th Annual Autumn Conference in Toronto, Ontario, October 6-7, 2008. The purpose of the present report is to provide an overview of one of the sessions at the conference which focused on the designs and methodologies to be applied in clinical trials of new treatments for Alzheimer's disease (AD) with purported “disease-modifying” effects. The session began with a discussion of how neuroimaging has been applied in multiple sclerosis clinical trials (another condition for which disease modification claims have been achieved). The next two lectures provided a pharmaceutical industry perspective on some of the specific challenges and possible solutions for designing trials to measure disease progression and/or modification. The final lecture provided an academic viewpoint and the closing discussion included additional academic and regulatory perspectives on trial designs, methodologies, and statistical issues relevant to the disease modification concept.

AbstractBackground:Cholinesterase inhibitors are broadly established as first-line symptomatic therapy for Alzheimer's disease (AD). Symptomatic effects are mediated by the inhibition of acetyl- and/or butyryl-cholinesterase (AChE and/or BuChE) – the enzymes that degrade acetylcholine (ACh) in the synapse. However, ACh is also found outsidethe synapse (‘extracellular ACh’) where, among other activities, it plays a role in controlling inflammation and might impact on pathological changes.Objective/scope:New data and clinical findings are reviewed and discussed to build a preliminary case for possible disease-modifying effects of cholinesterase inhibition.Findings:Trials seeking to demonstrate disease-modifying effects in subjects with mild cognitive impairment failed to reach their primary endpoints, but these failures might relate to aspects of trial methods and analyses. A re-analysis of one of these trials, using a more sensitive model controlling for factors that predict progression to AD, showed a significant delay in progression to AD with dual cholinesterase inhibition over 3 to 4 years. Taken with other evidence, it is plausible that cholinesterase inhibition might contribute to disease modification. The detection of putative disease-modifying effects may be most easily implemented in certain patient subpopulations, and genotyping studies suggest a particular role for BuChE.Conclusion:Long-term inhibition of BuChE might be especially important when exploring any disease-modifying effects of cholinesterase inhibitors. Elucidation of the mechanisms involved could provide insights leading to the development of new treatments that modify the development and progression of AD. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

SUMMARY: 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. [ABSTRACT FROM AUTHOR]

Initial treatment of Alzheimer's disease (AD) with a cholinesterase (ChE) inhibitor may fail to provide benefits due to lack/loss of efficacy or poor tolerability. Since the available ChE inhibitors differ in their pharmacological profiles, switching is an option which should be considered when initial treatment is unsuccessful. Preliminary evidence from open studies and case series suggest that patients who fail to draw benefit from an initial drug may still improve when a second ChE inhibitor is administered. Switching should only be considered when a patient does not respond to the first drug, when initial efficacy is lost or when the drug is poorly tolerated. A proper trial of the first agent should be given, with appropriate doses for a sufficient length of time before concluding a therapeutic failure. Switching can be undertaken without a wash out period if the issue is lack/loss of efficacy, but a wash out period of 1-2 weeks should be allowed if a patient is switched for poor tolerability. [ABSTRACT FROM AUTHOR]

Background: Accumulating data suggest infectious agents are involved in Alzheimer's disease (AD). The two primary aims of this trial were to assess safety and efficacy of an antiviral drug combination on AD progression., Objective: The trial evaluated whether Apovir, a combination of two antiviral agents, pleconaril (active on enteroviruses) and ribavirin (active on several viruses), could slow AD progression., Methods: Sixty-nine patients 60-85 years were treated with Apovir or placebo for 9 months and followed until 12 months after end of treatment. Cognitive tests, safety, biomarkers, drug plasma, and cerebrospinal fluid concentrations were assessed., Results: The tolerability of Apovir was compromised as demonstrated by the large drop-out rate and increased frequency and severity of adverse events. The primary endpoint, demonstrating a difference in change from baseline to 9 months between groups in ADAS-cog total score, was not met ( p  = 0.1809). However, there were observations indicating potential effects on both ADAS-cog and CDR-SB but these effects need to be verified. Also, there was a decrease in cerebrospinal fluid amyloid-β in Apovir at 9 months ( p  = 0.0330) but no change in placebo., Conclusion: This was the first randomized, placebo controlled clinical trial exploring antiviral treatment on AD progression. The trial is considered inconclusive due to the large drop-out rate. New trials are needed to verify if the indications of effect observed can be confirmed and which component(s) in Apovir contributed to such effects. Pleconaril alone may be studied to improve the tolerability and to verify if enterovirus is involved in the disease process., Competing Interests: Nina Lindblom and Jacob Westman are full time employees at Apodemus AB. Roger Bullock and Mikael Åström and Suzanne Hendrix are consultants at Apodemus. Lars-Olof Wahlund and Lars Lindquist have not been personally compensated for their work on the clinical trial., (© 2021 – The authors. Published by IOS Press.)