Cholinergic Health After Menopause (CHAMP)

NCT04129060 | Completed Early Phase 1 FDA Drug

• 1 other identifier: STUDY00000581
• Study Type: interventional
• Target: 120
• Locations: 1 country
• Sites: 2

Brief Summary

Women are at increased risk for Alzheimer's disease (AD). Notably at menopause, some women experience a change in cognition. However, not all women experience negative effects of menopause on cognition. The cognitive changes that occur at menopause have not yet been connected to late life risk for pathological aging including AD. Thus, understanding the neurobiological factors related to individual differences in cognition at menopause is critical for understanding normal cognitive aging and for determining risk for pathological aging. The challenge in understanding the role of estrogen loss on the risk for AD is the long lag time between the hormonal changes at menopause and the clinical manifestations of AD. Thus, identifying how the hormone changes after menopause are related to AD risk will alter the risk calculus for postmenopausal women in the future. The novel study proposed here will examine an established AD-related neurotransmitter-based mechanism that may also underlie cognitive changes after menopause. The investigators propose that the change in the hormonal milieu at menopause interacts with the cholinergic system and other brain pathologies to influence a woman's risk for cognitive decline. Preclinical studies have shown that estrogen is necessary for normal cholinergic functioning and its withdrawal leads to cholinergic dysfunction and cognitive impairment. It is important to determine whether menopause-related cognitive changes correlate with both cholinergic functional integrity and established AD biomarkers that portend increased risk for late-life cognitive impairment or dementia. This study will examine brain functioning following cholinergic blockade to separate individuals into those who are able to compensate for the hormone change after menopause and those who are not. The investigators hypothesize women with poor compensation have increased sensitivity to cholinergic blockade by showing poor performance on a cognitive task, altered brain activation, and decreased basal forebrain cholinergic system (BFCS) volume. These cholinergic markers will be related to menopausal factors associated with poor cognition and biomarkers of AD. Specific Aim 1 is to examine cholinergic functional "integrity" by measuring working memory performance, functional brain activation, and BFCS structure in postmenopausal women. Specific Aim 2 will examine whether individual differences in menopause-relevant symptoms and known AD biomarkers are related to cognition and brain activation after anticholinergic challenge. The public health significance of this study is that it will identify individual difference factors that are associated with cognitive performance changes after menopause and their relationship to structural, functional, and biomarker evidence of risk for later life cognitive dysfunction. Knowledge of these factors will serve to advance personalized future risk-mitigation strategies for women including hormonal, medication, cognitive remediation, etc. that will be the subject of further research.

Conditions

Postmenopausal Symptoms; Aging; Alzheimer Disease

Outcome Measures

Primary Outcomes (3)

• Blood Oxygen Dependent (BOLD) functional magnetic resonance imaging (fMRI)

  BOLD fMRI signal will be measured while each participant performs the N-back test.

  Two hours post drug administration

• Working Memory Performance

  We will assess performance on the N-back test of working memory test.

  Two hours post drug administration

• Basal Forebrain Cholinergic System Volume

  We will measure basal forebrain cholinergic system volume from the T1 images acquired during the MRI scan.

  Two hours post drug administration

Study Arms (2)

Mecamylamine Challenge

EXPERIMENTAL

One of the two study days will be the oral mecamylamine.

Drug: Cholinergic antagonist

Placebo Challenge

EXPERIMENTAL

One of the two study days will be the oral placebo.

Drug: Cholinergic antagonist

Interventions

Cholinergic antagonist DRUG

The cholinergic antagonist drug mecamylamine will be administered as a a 20 mg oral pill and matching placebo

Mecamylamine Challenge; Placebo Challenge

Eligibility Criteria

• Age: 50 Years - 70 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Women aged 50-70 years
• Postmenopausal
• Nonsmokers
• Not taking hormone therapy, selective serotonin uptake inhibitors (SSRIs(, phytoestrogens, selective estrogen receptor modulators (SERMS), or antiestrogen medications and will be at least one year without such treatment
• Physically healthy
• No cardiovascular disease other than mild hypertension. Subjects will also not have current untreated or unremitted Axis I or II psychiatric or cognitive disorders (see screening below).
• Intelligence quotient (IQ) in the normal range \>80
• Normal neuropsychological test performance

You may not qualify if:

• Mild Cognitive Impairment (MCI) or dementia - Montreal Cognitive Assessment \<26, Mattis Dementia Rating Scale \<130, and Global Deterioration Scale \>2
• History of cancer treatment with cytotoxic and/or ongoing (current) maintenance targeted chemotherapy
• Blood pressure \> 160/100 (untreated)
• Untreated thyroid disease
• Significant cardiovascular disease
• Asthma or chronic obstructive pulmonary disease (COPD)
• Active peptic ulcer
• Hyperthyroidism
• Epilepsy
• Current untreated or unremitted Axis I psychiatric disorders
• Use of medications that are on our prohibited medications list

Sponsors & Collaborators

• University of Vermont: lead
• Vanderbilt University Medical Center: collaborator

Study Sites (2)

Vanderbilt University Medical Center

Nashville, Tennessee, 37212, United States

Location

University of Vermont

Burlington, Vermont, 05401, United States

Location

MeSH Terms

Conditions

Alzheimer Disease

Interventions

Cholinergic Antagonists

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Cholinergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Physiological Effects of Drugs

Study Officials

• Julie A Dumas, Ph.D.

  University of Vermont

  PRINCIPAL INVESTIGATOR

• Paul A Newhouse, M.D.

  Vanderbilt University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: Medication will be administered double blind. The investigators, nurses working on the project, and participants will not know which drug they receive on any study day.
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Model Details: This study is a randomized, placebo-controlled trial of the effects of nicotinic blockade on working memory performance and brain activation in healthy postmenopausal women.

Study Record Dates

• First Submitted: October 9, 2019
• First Posted: October 16, 2019
• Study Start: March 15, 2020
• Primary Completion: December 16, 2024
• Study Completion: December 16, 2024
• Last Updated: December 16, 2025

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, ANALYTIC CODE
• Time Frame: Data will be available at the end of the study
• Access Criteria: We will have the same requirements for data sharing as the NDA has run by the NIMH.

Locations

US (2)