13 Jan 2012

In a disappointing turn for Down's syndrome (DS) research, a trial to evaluate potential cognitive benefits of the drug memantine—already used as a treatment in Alzheimer's disease—showed no effectiveness. The study, published online January 10 in the Lancet, reported that the drug neither improved cognition nor activities of daily living in people with DS, aged 40 and older. "There was a clear lack of benefit in these individuals," said senior author Clive Ballard, Kings College London, UK. "It's disappointing because it clearly shows that treatments that work in older people with Alzheimer's disease don't necessarily have the same benefits in older people with Down's syndrome," said Ballard.

Memantine is an N-methyl-D-aspartate (NMDA) receptor antagonist that is supposed to prevent excitotoxicity that occurs when excess glutamate is released at the synapse in diseases such as Alzheimer's. The drug has been used to treat AD in Germany for almost two decades, in other European countries since 2003, and was approved by the U.S. Food and Drug Administration (FDA) in 2003 for treatment of moderate to severe dementia (see ARF related news story). Memantine improved activities of daily living and cognitive function in people with advanced Alzheimer's (see ARF related news story).

Since Alzheimer's disease is common in older people with Down's syndrome—present in half of those who reach the age of 60—and people with DS are living much longer than they used to, the need for a treatment for AD in this population is increasing. Researchers have long thought that treatments for Alzheimer's would work in people with DS, since some neuropathological features, including accumulation of amyloid-β deposits (see recent ARF Webinar), are similar between the two groups. Cholinesterase inhibitors have already been approved for use in DS in the UK, though their effect is modest at best (see Mohan et al., 2009). Memantine seemed to be a good candidate because evidence suggests that NMDA receptor activity is perturbed in people with Down's syndrome (see Siddiqui et al., 2008), and in transgenic mouse models of DS, memantine rescued learning and memory deficits and improved spatial learning and memory (see AbstractCosta et al., 2008; Rueda et al., 2010; Lockrow et al., 2011). The Memantine for Dementia in Adults Older Than 40 Years With Down’s syndrome (MEADOWS) trial put that idea to the test in humans.

First author Marisa Hanney and colleagues enrolled 173 DS patients over the age of 40, many with clinically diagnosed dementia, from four research centers in the UK and Norway. Roughly half the number of participants (88) were randomly assigned to receive oral memantine treatment (10 mg daily) while 85 received a placebo for 52 weeks. Hanney assessed the volunteers using the Down's Syndrome Attention, Memory, and Executive Function Scales and parts I and II of the Adaptive Behaviour Scale (which covers independent functioning for activities of daily living and maladaptive behaviors) at baseline, 12, 16, and 52 weeks. Both groups declined equally on both tests, leading the authors to conclude that memantine is not helpful for patients with DS.

The results support the idea that "there's probably no shortcut to Down's syndrome [treatment] through Alzheimer's disease [therapies]," said William Mobley, University of California, San Diego. For the time being, researchers are most likely going to have to rely on animal models to better understand the biology of Down's syndrome before moving into clinical trials, he told ARF.

However, the door may still be open for further investigation into memantine for DS, said Lon Schneider, University of Southern California Keck School of Medicine. The current small, heterogenous sample (some of whom did not have dementia) gave the study only enough statistical power to pick up a moderate to large effect, he said. It failed to find one, but "that doesn't mean there can't be a small effect," said Schneider.

Even a small effect could be beneficial, said Daphne Lo, University of Colorado Hospital, Aurora. Researchers should keep realistic goals in mind for treating dementia, both in AD and DS, she contended. "We would all love to find a cure, but I think more research can be done to find pharmacological and non-pharmacological therapies that improve quality of life in these patients."

Lotta Granholm-Bentley, Medical University of South Carolina, agreed that the heterogeneity of the subject pool may have influenced the results. "The fact that they included individuals without Alzheimer's disease made me think this would not work," she said. Several studies have shown that memantine has no effect in mild stages of AD (see ARF related news story on Schneider et al., 2011). If the study had enrolled only those with dementia, the outcome might have been different, she said. "I definitely think that it warrants further study."

Ballard is not so sure, saying there was not even a hint from these data that a small effect was present. In fact, there seemed to be a non-significant benefit for those on placebo. A more severely demented population would probably not matter, either, he said, since he and the study authors found no interaction between treatment and dementia in subgroup analyses. "The results were so negative, the chances of another study being positive are pretty small," he said. He acknowledges, however, that you can "never say never" based on just one trial.

Results will soon be available from a small trial of memantine in DS, led by Alberto Costa, University of Colorado, Denver. That trial, which is now complete, tested the efficacy of the drug in 40 young adults (aged 18-30) with DS and measured behavioral changes that depend on the hippocampus. Though he is not yet ready to reveal his results, which he is submitting for publication soon, he hinted at a different result than in the MEADOWS trial.

Several other types of treatments are in the works for DS. A Phase 1 clinical trial will look at the safety and tolerability of compound RG1662 in people with DS (see recent ARF Webinar). Sponsored by F. Hoffmann-La Roche Ltd., Basel, Switzerland, RG1662 is an inverse agonist of the GABAA receptor, a major component of the inhibitory system, which evidence suggests is overactive in the DS brain. Based on earlier work demonstrating rescue of cognition and long-term potentiation in mouse models of DS (see ARF related news story), Balance Therapeutics is developing another GABAA receptor antagonist, pentylenetetrazole, to address cognitive impairment in DS, and will be entering clinical studies this year. A UK-based trial involving adults with DS will examine whether lithium reduces myo-inositol, supposed to be elevated in the disease and related to reduced cognitive ability (see Beacher et al., 2005). The field also awaits results of a trial of the green tea extract epigallocatechin gallate for DS (see ClinicalTrials.gov).

Ballard also suggested that drugs effective in animal models of APP overproduction, such as the γ-secretase modulator Tarenflurbil (see ARF related news story), may be relevant for DS, even though they have been dropped because they are not effective in patients with AD. Patients with DS produce excess APP for their whole lives, he said, so these drugs could be worth a second look in this population.

Few researchers feel the urgent need for a treatment as much as Costa, who is raising a teenager with DS. "You spend a lifetime trying to teach your child adaptive skills and get them to be a productive member of society, just for that to be taken away from you early on by something like Alzheimer's AD," he said.—Gwyneth Dickey Zakaib

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References

News Citations

1. Memantine Wins FDA Approval 21 Oct 2003
2. Memantine Relieves Symptoms in Moderate to Severe AD 9 Apr 2003
3. Research Brief: Meta-Analysis Finds Memantine Forgettable for Mild AD 22 Apr 2011
4. GABA and Plasticity—Can Antagonists Improve Cognition? 5 Mar 2007
5. Paper Alert—Phase 3 Tarenflurbil Data Published 17 Dec 2009

Webinar Citations

1. Volunteers Help Scientists Explore Down’s, Alzheimer’s Nexus 1 Jun 2011

Paper Citations

1. Mohan M, Carpenter PK, Bennett C. Donepezil for dementia in people with Down syndrome. Cochrane Database Syst Rev. 2009;(1):CD007178. PubMed.
3. Costa AC, Scott-McKean JJ, Stasko MR. Acute injections of the NMDA receptor antagonist memantine rescue performance deficits of the Ts65Dn mouse model of Down syndrome on a fear conditioning test. Neuropsychopharmacology. 2008 Jun;33(7):1624-32. PubMed.
4. Rueda N, Llorens-Martín M, Flórez J, Valdizán E, Banerjee P, Trejo JL, Martínez-Cué C. Memantine normalizes several phenotypic features in the Ts65Dn mouse model of Down syndrome. J Alzheimers Dis. 2010;21(1):277-90. PubMed.
5. Lockrow J, Boger H, Bimonte-Nelson H, Granholm AC. Effects of long-term memantine on memory and neuropathology in Ts65Dn mice, a model for Down syndrome. Behav Brain Res. 2011 Aug 10;221(2):610-22. PubMed.
6. Schneider LS, Dagerman KS, Higgins JP, McShane R. Lack of evidence for the efficacy of memantine in mild Alzheimer disease. Arch Neurol. 2011 Aug;68(8):991-8. PubMed.
7. Beacher F, Simmons A, Daly E, Prasher V, Adams C, Margallo-Lana ML, Morris R, Lovestone S, Murphy K, Murphy DG. Hippocampal myo-inositol and cognitive ability in adults with Down syndrome: an in vivo proton magnetic resonance spectroscopy study. Arch Gen Psychiatry. 2005 Dec;62(12):1360-5. PubMed.

External Citations

1. small trial
2. Phase 1 clinical trial
3. UK-based trial
4. ClinicalTrials.gov

Further Reading

News

1. GABA and Plasticity—Can Antagonists Improve Cognition? 5 Mar 2007
2. Research Brief: Imaging Shows AD Pathology in Down’s Syndrome Brains 27 Jun 2011
3. Paper Alert—Phase 3 Tarenflurbil Data Published 17 Dec 2009
4. Memantine Wins FDA Approval 21 Oct 2003
5. Memantine Relieves Symptoms in Moderate to Severe AD 9 Apr 2003
6. Research Brief: Meta-Analysis Finds Memantine Forgettable for Mild AD 22 Apr 2011
7. Trial of Memantine/Donepezil Paves the Way for Combination Therapy 22 Jan 2004
8. New Findings Offer Hope for Down Syndrome 27 Jun 2010