Down syndrome (DS) is the most common genetic cause of mental retardation (MR), affects all races, and has been recognized for centuries. Through recent advances in medical care and changing attitudes towards the care of mentally retarded people, the average life span of individuals with DS has increased from about 9 years in 1929 to over 56 years at present. As individuals with DS live longer, improving the quality of life in these individuals is of paramount importance. In addition to their intellectual deficits, adults with DS exhibit deficits in related areas such as adaptive behavior, expressive and receptive language, memory and mood. Adaptive behavior refers to the individual's ability to complete independently both complex and basic daily living activities. This also includes the functional consequences of language and written communication skills, self-care abilities, and their interest or participation in social situations. These deficits adversely impact the quality of life of both the DS individual and/or their caretakers. At present, there is no approved treatment specifically indicated for the adaptive and cognitive impairments associated with DS. Numerous studies have documented that DS and Alzheimer's disease (AD) share similar neuropathologic and neurochemical brain changes, with the brain changes in DS occurring at an earlier age. For example, soluble amyloid b peptide, a precursor to amyloid plaque formation, the hallmark of AD, has been detected as early as 21 gestational weeks in the brains of fetuses with DS. By the fourth decade, virtually all DS subjects will demonstrate brain changes of AD. There is also a marked reduction in the activity of choline acetyltransferase (ChAT), the enzyme that synthesizes acetylcholine (ACh) in the basal forebrain, resulting in a loss of cholinergic input to cortical and limbic areas. The cholinergic deficit is the most consistently demonstrated neurotransmitter abnormality in AD and is believed to underlie many of the cognitive and adaptive impairments in this disorder. Studies have also shown a correlation between the severity of cholinergic deficit, neuropathological markers, such as senile plaques, and the severity of dementia. ACh is degraded in the synaptic cleft by the enzyme cholinesterase (ChE). ChE inhibitors (ChEI) reduce the degradation of ACh and increase the synaptic availability of ACh at the post-synaptic receptor sites. ChEIs are currently the only class of agents that have been consistently proven in well controlled multicenter trials to benefit the symptoms associated with AD. Donepezil hydrochloride (donepezil), an FDA approved second-generation cholinesterase inhibitor, is the most widely used medication for the pharmacotherapy of cognitive and functional deficits in AD. The primary goal of the proposed project is to test the efficacy and safety of donepezil for treating key symptoms of young adults with DS. Specifically, we will examine the efficacy of this agent on adaptive (functional), behavioral and cognitive abilities in DS. The proposed study is a single center, randomized, double-blind crossover study with a 6-week washout period in between the 2 arms of the study. Each arm of the study is 24 weeks.
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