This study was conducted to assess the neuropsychological effects of a cholinesterase inhibitor and a muscarinic cholinergic antagonist used to model Alzheimer's dementia. Eight (total) healthy male and female subjects ranging in age from 65 to 81 years were randomly assigned to one of three treatment groups in a placebo controlled, double blind three-way cross-over design. Subjects were confined for 34 hours during three inpatient stays separated by a 7 day wash-out period. An IM injection of either 0.5 mg of Scopolamine (Sc), 0.5 mg of Physostigmine (Ph) or 1 MI of sterile water/Placebo (PI) was administered during each study period. Repeated computerized testing with the Automated Neuropsychological Assessment Metrics (ANAM) battery was used to assess neuropsychological performance (NP) on measures of mood, arousal, reaction time, attention, learning, visual-spatial ability, problem solving, and continuous performance. Testing was conducted at 1 hour and 30 min predose, and 1, 2, 4, and 8 hours postdose. Consistent negative effects on NP were shown for all eight subjects in the Sc group, while the Ph group showed improvement in four subjects. Two subjects showed no difference with Ph and two subjects became ill from Ph and could not be assessed. Sc effects were most significant on neuropsychological measures of memory recall, running memory, mathematical processing, and unstable tracking, while Ph effects were most significant on measures of memory recall, mathematical processing and spatial processing. Statistical measures which were most discriminating were throughput and performance speed. Results indicate that repeated computerized neuropsychological measures are highly useful in obtaining statistically significant results with a very small population sample in clinical trials, as evidenced by differentiating Ph as a cognitive enhancer and Sc as a cognitive suppressor. Implications for the assessment of CNS enhancing compounds in the elderly are addressed.
