The Nicotinic Cholinergic System and Cognitive Aging

The cholinergic system has been shown to be the primary neurotransmitter system responsible
for cognitive symptoms in dementia. While therapeutic benefits are clear in dementia, what
remains uncertain is the role that the cholinergic system in general and the nicotinic system
specifically plays in cognition in healthy non-demented older adults (referred to as normal
cognitive aging in this application). This is critical because the expansion of the healthy
aging population will nonetheless show declines in cognition that fall short of dementia but
still impact functional abilities and independence. Understanding the effects of age-related
functional changes on the nicotinic system will elucidate one neurochemical mechanism
underlying age-related changes in cognition and will provide information about how nicotinic
dysfunction affects cognition in healthy older adults. Prior research has shown that the
nicotinic system has a roll in attention and memory in healthy adults. More recently, with
the increased use of brain functional magnetic resonance imaging (fMRI) in combination with
psychopharmacological manipulations, data patterns have emerged that further define the role
of the nicotinic system in cognition, aging, and dementia.

The investigators propose that nicotinic system changes are responsible for age differences
in working memory task performance and brain activation. The investigators can observe the
functioning of the nicotinic system by examining brain activation patterns in response to
nicotinic blockade and stimulation. Increased dorsolateral prefrontal cortex (DLPFC)
activation has been shown for older adults compared to younger adults and is hypothesized to
be a compensation response for the aging process. The investigators propose that temporary
antagonism of the nicotinic system will also produce increased DLPFC activation. However, the
relationship between this increased activation and performance will be in different
directions for older and younger adults. In older adults, the increased activation will be
positively correlated with performance because it is a compensatory response. In younger
adults, the increased activation will be negatively correlated with performance because it is
a non-adaptive response to the temporary nicotinic antagonism. Nicotinic stimulation in older
adults will reveal decreased DLPFC activation that will be negatively correlated with
performance and this represents the "younger" pattern of the performance and activation
relationship. The younger adults will have a similar pattern of activation and performance as
the older adults after nicotinic stimulation because they are already performing optimally
and will not receive any further enhancement. These data will further the understanding of a
neurochemical mechanism involved in normal aging and how brain activation patterns relate to
receptor function.

Inclusion Criteria:

- Normal cognition, not demented, no mild cognitive impairment. IQ greater than 80.

Exclusion Criteria:

- Current use of barbiturates, rifampin, insulin, carbamezepine, oral hypoglycemics,
antidepressants, diabetes, or untreated thyroid disease.

- In addition, the following exclusions are specific for the challenge drugs: heavy
alcohol or coffee use, significant cardiovascular disease, ischemic heart disease,
asthma, chronic obstructive pulmonary disease, active peptic ulcer, hyperthyroidism,
pyloric stenosis, narrow angle glaucoma, epilepsy, or current Axis I psychiatric
disorders.

- Current use of centrally active drugs and drugs with cholinergic properties. A minimum
of 14 days will elapse between discontinuing centrally active or psychoactive agents
and this study.