A Sixteen-Week, Randomized, Double Blind, Placebo-Controlled Evaluation of the Efficacy, Tolerability and Safety of Memantine Hydrochloride on Enhancing the Cognitive Abilities of Young Adults With Down Syndrome

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.