Yet, ironically, a significant, number of clinical trials have been conducted to assess the impact of a variety of pharmacological agents on cognition in normal aging, AAMI, AACD, and MCI. Many of the therapeutic approaches to AD have been utilized in such populations, less often to assess the benefits for this population than as the first step in assessing their safety and efficacy for use in AD patients. Pharmacological approaches in AACD, MCI, and normal aging Neuro transmitter deficiencies Cholinergic deficits. Numerous studies suggest that central Inhibitors,research,lifescience,medical cholinergic activity declines with age. While

profound cell loss from the cortex itself has generally not, been observed, loss of subcortical cholinergic neurons may be associated with normal aging.13 Neurons located in the subcortical basal forebrain region provide cholinergic Inhibitors,research,lifescience,medical innervation to the hippocampus and neocortex. Degeneration of these neurons likely contributes to cognitive impairment. An age-related decrease in the presynaptic activity of CAT has been reported in humans.180 CAT is considered a marker of cholinergic neurons; thus its decline

with age indicates a loss of cholinergic neurons with increasing age. Since postsynaptic muscarinic receptor binding also Inhibitors,research,lifescience,medical decreases with age,181 it appears that both presynaptic and postsynaptic cholinergic degeneration are involved Inhibitors,research,lifescience,medical in the process of normal aging. Camptothecin manufacturer Baxter et al182 demonstrated in rodents that most of the age-related changes

in cholinergic markers were already present at ages at which behavioral impairment, was not yet maximal. A postmortem study in humans, however, somewhat, challenges this finding: cholinergic deficits, measured as activity of the cholinergic enzymes CAT and AChE, were apparent in elderly individuals with severe dementia, but not in individuals with moderate, mild, questionable, or no dementia.183 However, administration of the cholinergic antagonist scopolamine in humans has been Inhibitors,research,lifescience,medical found to impair the encoding of information into long-term memory and to impact other cognitive processes.22,184,185 Since a cholinergic antagonist, is associated with new impairments in memory and cognition, cholinergic enhancers, especially AChEIs, may ameliorate such impairments.186-188 Cholinergic enhancers (for example, arecoline, a muscarinic agonist, and choline, a precursor of ACh) have been tested on effects on performance of memory tasks in healthy volunteers after administration of the cholinergic antagonist methscopo lamine. Both drugs reversed scopolamine-induced impairment of serial learning.189 Poor baseline performers proved to be more vulnerable to both the enhancing effect, of the cholinergic agonist, and precursor and the impairment after cholinergic antagonist than good performers.