Efficacy and Safety of Memantine Hydrochloride in Enhancing the Cognitive Abilities of Young Adults With Down Syndrome

Overview

The purpose of this 16-week research study is to determine whether a drug called memantine hydrochloride (memantine) has the potential to help improve memory and other cognitive abilities of young adults with Down syndrome (DS). Memantine (Namenda®) is a drug approved by the Food and Drug Administration (FDA) for patients with moderate to severe Alzheimer-type dementia. About 40 persons of both genders with Down syndrome aged 18-32 years will take part in this study. This is a randomized and double blind study. This means that subjects will have a 50/50 chance of being assigned to receive either the memantine pills or placebo (inactive pills). Neither the study participants nor the research personnel will know who is receiving active medication or placebo. Based on memantine's mode of action, current knowledge on brain pathology in persons with Down syndrome, and some preclinical data on mouse models of Down syndrome, we hypothesize that memantine may improve test scores of young adults with Down Syndrome on memory tests targeted at the function of the brain structure called the hippocampus. This research project has three specific aims: 1) investigate whether memantine has the potential to improve test scores on hippocampus-dependent measures in young adults with Down syndrome; 2) investigate whether memantine has the potential to improve test scores by these subjects on other cognitive measures; 3) investigate whether memantine is well tolerated by these subjects.

Down syndrome, which is the result of the trisomy of Chromosome 21, is the most common genetically defined cause of intellectual disabilities. The estimated number of people with Down syndrome in the United States is approximately 300,000, and this figure is expected to continue increasing due to projected increases in the life expectancy of people with Down syndrome. Although this population trend reflects improvements in the general health care of individuals with Down syndrome, there has not been a parallel progress in the understanding of the pathogenesis and potential treatment of the psychological and neurological components of this genetic condition. These include various degrees of intellectual disability, increased incidence of seizure disorder in relation to the general population, motor dysfunction (including hypotonia), abnormal oculomotor and vestibular functions, substantial visual deficits, a neuropathology indistinguishable from Alzheimer disease, and increased incidence of major depression and dementia in adults. Over the last fifteen years, progress in the quantitative description of specific traits associated with Down syndrome, the availability of postnatal-viable aneuploid mouse models of Down syndrome, and our progressively more sophisticated knowledge of the human and mouse genomes have provided investigators in this field with a realistic opportunity to start bridging the gap between basic and clinical research. Whereas individuals with Down syndrome maintain relatively high levels of social intelligence and procedural learning, they often suffer from grossly impaired declarative or explicit memory. Not surprisingly, brain structures associated with declarative memory, namely the hippocampal and parahippocampal regions of the medial temporal lobe, are the most severely affected in persons with Down syndrome. The nature of these deficits suggests that therapies targeting hippocampal function would be particularly efficacious in ameliorating the cognitive deficits seen in persons with Down syndrome and, consequently, would enhance their quality of life. Glutamatergic neurons form the major excitatory system in the brain and play a pivotal role in many physiological functions. Apart from the physiological role of glutamate, excessive activation of its receptors can also evoke neuronal dysfunction and even damage/death. Cell death ascribed to an excessive activation of glutamate receptors has been termed 'excitotoxicity' and seems to occur in acute insults such as stroke and trauma, but it may be also associated with chronic neurodegenerative diseases such as Alzheimer disease. N-methyl-D-aspartate (NMDA) receptor (NMDAR) mediated glutamate excitotoxicity is thought to play a major role in Aβ-induced neuronal death. This idea is part of the foundation of the glutamatergic hypothesis (as opposed to the cholinergic hypothesis) for Alzheimer disease. Memantine is an NMDAR antagonist that has been reported to be effective therapeutically in Alzheimer disease. It has been available in Germany as well as in most of the European Union for more than two decades. Recently, it has been approved for moderate to severe dementia in the US. The chemical name for memantine hydrochloride is 1-amino-3,5-dimethyladamantane hydrochloride. Memantine is an uncompetitive, moderate affinity, antagonist of NMDARs. It has been proposed that therapeutic doses of this drug inhibit the pathological effect of NMDAR activation while leaving unaffected NMDAR-mediated physiological processes involved in learning and memory. Recent preclinical data from the laboratory of this trial's P.I. on the mouse model for DS (Ts65Dn) have suggested a dysregulation of NMDAR activity in these animals and demonstrated improvement on learning and memory measures by the use of acute doses of memantine. In all clinical trials so far, memantine was found safe and well tolerated. The tolerability of an NMDAR antagonist depends upon its affinity towards the receptors, unbinding kinetics, and voltage dependency. Memantine is thought to improve the fidelity of synaptic transmission. Such action is predicted to provide both neuroprotection and symptomatic restoration of synaptic plasticity by one and the same mechanism. Recent open-label studies suggest that memantine may be clinically useful and well tolerated in young individuals with other conditions that produce cognitive disabilities, such as autism and attention deficit hyperactivity disorder (ADHD). Because of the ubiquity of Alzheimer disease-type pathology in persons with Down syndrome, the preclinical findings consistent with dysregulation of NMDAR activity in mouse models of Down syndrome, the safety profile of memantine (which is superior to the AChE inhibitors that are already being tested in persons with Down syndrome), and the possibility that memantine may indeed delay the onset of Alzheimer disease-type pathology in young adults with Down syndrome, all the professionals involved with this project decided that a small-scale randomized controlled clinical trial was warranted at present. We would like to emphasize that the goal of this study is to evaluate the efficacy, tolerability and safety of memantine hydrochloride in enhancing the cognitive abilities of young adults with Down syndrome aged 18-32 years. Therefore, the present investigation is a non-overlapping and complementary clinical trial to the randomized, placebo-controlled clinical trial on the efficacy and tolerability of memantine in preventing age-related cognitive deterioration and dementia in people with Down syndrome age 40 and over (http://www.clinicaltrials.gov/ct2/show/record/NCT00240760?term=down+syndrome\&rank=15) currently being carried out by our colleagues in London.