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The Nicotinic Cholinergic System and Cognitive Aging

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ClinicalTrials.gov Identifier: NCT03408574
Recruitment Status : Recruiting
First Posted : January 24, 2018
Last Update Posted : June 26, 2018
Sponsor:
Collaborator:
Vanderbilt University Medical Center
Information provided by (Responsible Party):
Julie Dumas, University of Vermont

Brief 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.

Condition or disease Intervention/treatment Phase
Healthy Aging Drug: Nicotine patch, oral mecamylamine, placebo Phase 1

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 96 participants
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)
Masking Description: This is a double blind study. The PI and all study personnel are blinded. Only the pharmacist dispensing the medication and the biostatistician who created the counterbalancing order are unblended.
Primary Purpose: Basic Science
Official Title: The Nicotinic Cholinergic System and Cognitive Aging
Actual Study Start Date : October 1, 2016
Estimated Primary Completion Date : January 31, 2021
Estimated Study Completion Date : January 31, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Older Adults
Healthy adults aged 65-75 will participate in three study days where they are randomly assigned to receive either nicotine patch, oral mecamylamine, placebo and perform a working memory task during the fMRI. BOLD signal is the outcome measure.
Drug: Nicotine patch, oral mecamylamine, placebo
Each participant randomly receives one active drug or placebo on each of three study days.

Experimental: Younger Adults
Healthy adults aged 18-30 will participate in three study days where they are randomly assigned to receive either nicotine patch, oral mecamylamine, or placebo and perform a working memory task during the fMRI.BOLD signal is the outcome measure.
Drug: Nicotine patch, oral mecamylamine, placebo
Each participant randomly receives one active drug or placebo on each of three study days.




Primary Outcome Measures :
  1. Age effects of nicotinic blockade [ Time Frame: After the completion of the third study day. ]
    Examine the effects of nicotinic blockade compared to placebo on the relationship between working memory performance and brain activation using fMRI BOLD signal in older and younger adults.

  2. Age effects of nicotinic stimulation [ Time Frame: After the completion of the third study day. ]
    Examine the effects of nicotinic stimulation compared to placebo on the relationship between working memory performance and brain activation using fMRI BOLD signal in older and younger adults.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03408574


Contacts
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Contact: Research Assistant 8028478248 jenna.makarewicz@uvmhealth.org
Contact: Jenna A Makarewicz, B.S. 8028478248 jenna.makarewicz@uvmhealth.org

Locations
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United States, Vermont
University of Vermont Recruiting
Burlington, Vermont, United States, 05401
Contact: Sponsored Program Administration    803-656-3360      
Contact: Sonya Stern    8026563360    spa@uvm.edu   
Principal Investigator: Julie A Dumas, Ph.D.         
Sub-Investigator: Alexandra Potter, Ph.D.         
Sub-Investigator: Hugh Garavan, Ph.D.         
Sub-Investigator: Janice Bunn, Ph.D.         
Sub-Investigator: Joshua Nickerson, M.D.         
Sub-Investigator: Magdalena R. Naylor, M.D., Ph.D.         
Sub-Investigator: Rchard Watts, D.Phil.         
Sponsors and Collaborators
University of Vermont
Vanderbilt University Medical Center
Investigators
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Principal Investigator: Julie A Dumas, Ph.D. University of Vermont
  Study Documents (Full-Text)

Documents provided by Julie Dumas, University of Vermont:

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Responsible Party: Julie Dumas, Associate Professor, University of Vermont
ClinicalTrials.gov Identifier: NCT03408574     History of Changes
Other Study ID Numbers: CHRMS 16-284
First Posted: January 24, 2018    Key Record Dates
Last Update Posted: June 26, 2018
Last Verified: June 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: Deidentified data will be available to be shared with other researchers. The Principal Investigator will make fMRI and behavioral data available as requested by researchers after the study is completed and data sets have been cleaned for quality and locked.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Julie Dumas, University of Vermont:
nicotinic system
cognitive aging
working memory
fMRI

Additional relevant MeSH terms:
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Nicotine
Cholinergic Agents
Mecamylamine
Ganglionic Stimulants
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Nicotinic Agonists
Cholinergic Agonists
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Antihypertensive Agents
Ganglionic Blockers
Nicotinic Antagonists
Cholinergic Antagonists