Memantine for DS

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Another interesting finding.

Memantine Misses for Dementia in Down's Syndrome

January 12, 2012 — Results from the largest randomized controlled trial of patients with cognitive impairment in Down's syndrome show no benefit from treatment; the results do not bode well for the translation of therapies that have been shown to be effective in Alzheimer's disease to this population, despite similar pathology.

"Memantine is not an effective treatment in this group of patients," senior investigator Clive Ballard, MD, from King's College London in the United Kingdom, said in a news release. "We believe that this robust finding will have implications for clinical practice and research strategy in the future."

Results from the trial, known as MEADOWS, are published online January 10 in the Lancet.

In an accompanying comment, Gill Livingston, MD, and Andre Strydom, MD, from University College London in the United Kingdom, call the trial an "important attempt" to improve outcomes in adults with Down's.

"The MEADOWS trial is linked to a revolution in the understanding of the neurobiology of Down's syndrome that has occurred in the past 20 years," they note. "Chromosome 21 was one of the first to be sequenced, and we now know how the syndrome affects many aspects of brain development, brain function, and aging."

Cognitive Impairment Likely

The prevalence of dementia in patients with Down's syndrome is very high. Many of these patients are older than 40 years and experience pathological changes characteristic of Alzheimer's disease.

Memantine is an N-methyl-d-aspartate glutamate receptor antagonist licensed for the treatment of moderate to severe Alzheimer's disease.

In the study, led by Marisa Hanney, PhD, also at King's College in London, 173 people with Down's syndrome were randomly assigned to receive either treatment with memantine or placebo at centers in the United Kingdom and Norway.

The primary outcome was change in cognition and function, measured with Down's syndrome attention, memory, and executive function scales and the adaptive behavior scale parts I and II.

At 52 weeks, investigators saw no significant differences between the groups in outcome measures assessing cognitive performance and function. After adjusting for baseline score, there were nonsignificant differences between groups in favor of control participants.

Outcomes with Memantine Treatment vs Control

Outcome

Change (95% Confidence Interval)

Total Down's syndrome attention, memory, and executive function scales

−4.1 (−13.1 to 4.8)

Adaptive behavior scale part I

−8.5 (−20.1 to 3.1)

Adaptive behavior scale part II

2.0 (−7.2 to 11.3)

In total, 11% of participants in the memantine group and 7% of control participants had serious adverse events (P > = .33). Five patients in the memantine group and 4 control participants died from these events (P > = .77).

Despite similarities in underlying pathological features, therapies that are effective for the treatment of Alzheimer's disease are not necessarily effective in people with Down's syndrome, report the authors.

Disappointing Results

One explanation might be key differences in amyloid structures between these groups of patients. People with Down's syndrome show lifelong overproduction of amyloid, which is akin to some rare familial forms of Alzheimer's disease, but it is not the same as late-onset sporadic disease, in which the abnormalities of amyloid processing are more subtle and are more likely to be related to amyloid clearance.

"People with Down's syndrome also show important changes in neurogenesis, neuronal differentiation, myelination, and synaptogenesis," the authors explain, "and studies suggest a key role of the γ-aminobutyric acid receptors in memory in this group of patients."

Despite the disappointing results, editorialists say memantine was a rational choice for this trial.

"Glutamate contributes to the pathogenesis of Alzheimer’s disease, in that high glutamate concentrations are thought to be neurotoxic and in particular to contribute to destruction of cholinergic neurones and therefore worsen memory," they point out. "Defective N-methyl-d-aspartate glutamate receptor signaling has been associated with impaired hippocampal function, and memantine with improved learning and memory, in mouse models of Down's syndrome."

Other trials of anti-dementia treatments have also reported negative results in Down's syndrome.

Next Steps

"So little is known about the best way to treat dementia in people with Down's syndrome," coauthor Anne Corbett, PhD, research manager at the Alzheimer's Society in the United Kingdom, said in a news release. "Further investment is urgently needed to develop treatments that are effective in this important group of people."

The authors recommend an adequately powered randomized, controlled trial of cholinesterase inhibitors to establish whether this class of drug has any role in the treatment of this group of patients or those with a formal diagnosis of dementia. Recent Cochrane Reviews of donepezil, rivastigmine, and galantamine concluded that there is too little evidence to make an informed judgment about the potential value of cholinesterase inhibitors for the treatment of dementia in people with Down's syndrome.

This study was funded by Lundbeck. Dr. Hanney received grants from Lundbeck and consulting fees from Roche. Dr. Ballard received consultant and speaking fees from Lundbeck, Janssen, Novartis, and Acadia. Editorialist Gill Livingston has received funding from Lundbeck for unrelated research in Alzheimer's disease. Andre Strydom is an investigator in a trial sponsored by Roche to improve cognition in adults with Down's syndrome.

Lancet. Published online January 10, 2010. Abstract