Cholinergic Health After Menopause (CHAMP)

• Status: Recruiting
• Trial end date: 2024-05-31
• Target enrollment: 0
• Participant gender: Female

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.

• Phase: Early Phase 1
• Accepts Healthy Volunteers?: Accepts Healthy Volunteers

Details

• Lead Sponsor: University of Vermont
• Collaborator: Vanderbilt University Medical Center
• Treatments: Cholinergic Agents; Cholinergic Antagonists; Mecamylamine

Criteria

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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