The Nicotinic Cholinergic System and Cognitive Aging
Condition: Healthy Aging
Study type: Interventional
Phase: Phase 1

Summary: 
      Prior research has shown that a chemical system in the brain called the cholinergic system is
      primarily responsible for cognitive symptoms seen in people with dementia. While therapeutic
      benefits are clear in dementia, what remains uncertain is the role that the cholinergic
      system in general and a subset of receptors called the nicotinic system plays in cognition in
      healthy non-demented older adults (referred to as normal cognitive aging). This is critical
      because the ever growing healthy aging population will show declines in cognition that fall
      short of dementia but still impact functional abilities and independence. Maintaining good
      nicotinic system functioning throughout adulthood may lessen the cognitive symptoms of aging.
      At this time, it is not clear what the biological cause of age-related changes in cognition
      is. This study will examine the role of the nicotinic system in the healthy aging brain and
      examine its role in memory and thinking processes in older and younger adults.
    

Detailed description: 
      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.
    

Intervention name(s): Nicotine patch, oral mecamylamine, placebo
Intervention type(s): Drug
Intervention description(s): Each participant randomly receives one active drug or placebo on each of three study days.
Intervention MeSH terms: Mecamylamine; Nicotine
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Healthy older adults aged 65-75 and healthy younger adults aged 18-30 will be recruited. Each participant will take part in 3 nicotinic drug challenge days. The three drugs are counterbalanced across study days within each group and balanced by sex.
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Basic Science
Keywords: nicotinic system; cognitive aging; working memory; fMRI