Cholinergic Antagonist for Postmenopausal Cognitive Decline

(CHAMP Trial)

Recruiting in Palo Alto (17 mi)

+1 other location

Overseen by Paul A Newhouse, M.D.

Age: 18+

Sex: Female

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase < 1

Recruiting

Sponsor: University of Vermont

No Placebo Group

Approved in 2 Jurisdictions

Trial Summary

What is the purpose of this trial?

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.

Do I have to stop taking my current medications to join the trial?

Yes, you must stop taking certain medications. Participants cannot be on hormone therapy, SSRIs, phytoestrogens, SERMs, or antiestrogen medications for at least one year before joining the trial. Additionally, you cannot use medications that are on the prohibited medications list.

What data supports the idea that Cholinergic Antagonist for Postmenopausal Cognitive Decline is an effective drug?

The available research does not support the idea that Cholinergic Antagonists are effective for postmenopausal cognitive decline. Instead, the studies highlight potential negative effects of these drugs, especially in older adults. For example, one study found that anticholinergic drugs are linked to increased risks of memory problems, confusion, and even falls in older people. Another study suggests that stopping these drugs might improve memory and daily functioning. Overall, the research suggests caution in using these drugs for cognitive issues in older adults. ^{1 2 3 4 5}

What safety data exists for anticholinergic treatments for cognitive decline?

Existing safety data indicates that anticholinergic drugs, including cholinergic antagonists, are associated with adverse cognitive effects, particularly in older adults. These effects include cognitive decline, increased risk of dementia, and potential mobility impairment. High anticholinergic burden, which is the cumulative effect of these medications, is a significant risk factor for cognitive impairment. Deprescribing interventions to reduce anticholinergic burden may help mitigate these risks. ^{6 7 8 9 10}

Is the drug used in the trial 'Cholinergic Antagonist for Postmenopausal Cognitive Decline' a promising treatment?

The research suggests that cholinergic antagonists, which are drugs that block certain brain receptors, can affect memory and brain activity in postmenopausal women. However, the studies also highlight the importance of estrogen in improving cognitive performance when these drugs are used. This means that while the drug might have some effects, its promise as a treatment could depend on whether estrogen is also involved. ^{3 11 12 13 14}

Research Team

JUlie A Dumas, Ph.D.

Principal Investigator

University of Vermont

Paul A Newhouse, M.D.

Principal Investigator

Vanderbilt University

Eligibility Criteria

The CHAMP study is for women aged 50-70 who are postmenopausal, non-smokers, and in good physical health without serious psychiatric or cognitive disorders. Participants should not have cardiovascular disease (except mild hypertension), be off certain hormone therapies and medications for a year, and must have normal IQ and neuropsychological test results.

Inclusion Criteria

I am a woman aged between 50 and 70.

I have gone through menopause.

Your IQ is higher than 80, which means it is in the normal range.

Exclusion Criteria

Your blood pressure is higher than 160/100 without taking any medication for it.

I have asthma or COPD.

I have an overactive thyroid.

Treatment Details

Interventions

• Cholinergic antagonist (Cholinergic Antagonist)

Trial Overview This trial investigates how hormonal changes after menopause might affect the risk of Alzheimer's Disease by studying the brain's cholinergic system. It involves testing memory performance, brain activation, and brain structure following administration of a cholinergic antagonist to assess cognitive resilience.

Participant Groups

Group I: Placebo Challenge Experimental Treatment 1 Intervention

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

Group II: Mecamylamine Challenge Experimental Treatment 1 Intervention

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

Who Is Running the Clinical Trial?

University of Vermont

Lead Sponsor

Trials

283

Recruited

3,747,000+

Dr. Dragos Banu

University of Vermont

Chief Medical Officer

MD from Saba University School of Medicine

Dr. Richard Page

University of Vermont

Chief Executive Officer since 2018

MD from Duke University

Vanderbilt University Medical Center

Collaborator

Trials

922

Recruited

939,000+

Jeffrey R. Balser

Vanderbilt University Medical Center

Chief Executive Officer since 2009

MD and PhD from Vanderbilt University

Rick W. Wright

Vanderbilt University Medical Center

Chief Medical Officer since 2023

MD from University of Missouri-Columbia

Findings from Research

In a study of 329 elderly patients in a geriatric ward, 40.73% were found to be using at least one anticholinergic drug, with 13.98% experiencing a clinically significant anticholinergic burden, highlighting the prevalence of these medications despite their risks.

Higher anticholinergic burden scores were significantly linked to conditions such as dementia, increased risk of falls, and severe disability, indicating that careful monitoring of anticholinergic use in older adults is crucial to prevent negative health outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anticholinergic Burden of Geriatric Ward Inpatients. Wilczyński, K., Gorczyca, M., Gołębiowska, J., et al.[2021]

Discontinuing medications with anticholinergic properties may lead to improved cognitive performance in older adults, as suggested by two prospective cohort studies included in the review.

The overall impact of stopping anticholinergic medications on cognitive function is still not well understood, highlighting the need for more extensive research with larger sample sizes and better assessment methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of anticholinergic discontinuation on cognitive outcomes in older people: a systematic review. Salahudeen, MS., Duffull, SB., Nishtala, PS.[2021]

In a study of 2058 individuals aged 60-64 over four years, those using anticholinergic medications showed poorer performance on the Symbol Digit Modalities Test, indicating a negative impact on complex attention.

However, the study found no significant evidence that anticholinergic medication use was linked to greater cognitive decline over time, suggesting that while caution is warranted in prescribing these medications, they may not necessarily accelerate cognitive deterioration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of medications with anticholinergic properties and cognitive function in a young-old community sample. Low, LF., Anstey, KJ., Sachdev, P.[2009]

Anticholinergic medications, which block the neurotransmitter acetylcholine, are commonly prescribed to older adults, with one-third to one-half of their medications having this activity, potentially leading to cognitive and functional impairments.

The cumulative anticholinergic burden is a significant predictor of adverse health outcomes in older adults, suggesting that healthcare providers should aim to minimize this burden by avoiding or reducing the use of these medications when possible.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anticholinergics: theoretical and clinical overview. Nishtala, PS., Salahudeen, MS., Hilmer, SN.[2022]

Cholinomimetic drugs, particularly acetylcholinesterase (AChE) inhibitors, are effective in treating cognitive impairments in Alzheimer's disease, but their benefits may primarily stem from enhancing attention rather than directly improving cognitive function.

These drugs may also be useful for addressing non-cognitive behavioral changes associated with Alzheimer's, suggesting a broader therapeutic potential beyond just cognitive symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cholinergic therapies for Alzheimer's disease: progress and prospects. Palmer, AM.[2005]

In a study of 177 older adults, it was found that even one anticholinergic drug per day can lead to cognitive and mobility impairments, particularly in those aged 75 and older.

The research indicates that anticholinergic drugs negatively affect cognitive functions and mobility, suggesting that healthcare providers should minimize their use in older patients to prevent these adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Effects of Anticholinergic Drugs on Cognition and Mobility: Cutoff for Impairment in a Cross-Sectional Study in Young-Old and Old-Old Adults. Attoh-Mensah, E., Loggia, G., Schumann-Bard, P., et al.[2020]

Anticholinergic medications are linked to a moderate to strong risk of cognitive decline and dementia in older adults, based on multiple studies regardless of their design or methodology.

There is a dose-response relationship, meaning that higher use of anticholinergics increases the risk of dementia, suggesting that managing and reducing anticholinergic use could help lower this risk in older patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anticholinergic medications and risk of dementia in older adults: Where are we now? Chatterjee, S., Talwar, A., Aparasu, RR.[2022]

A systematic review of three trials involving 299 older adults found insufficient evidence to conclude that reducing anticholinergic medication improves cognitive outcomes, with results rated as very low certainty.

While some trials successfully reduced anticholinergic burden, there were no significant improvements in cognitive performance or other clinical outcomes, indicating a need for larger studies to explore the long-term effects of such interventions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anticholinergic deprescribing interventions for reducing risk of cognitive decline or dementia in older adults with and without prior cognitive impairment. Taylor-Rowan, M., Alharthi, AA., Noel-Storr, AH., et al.[2023]

A systematic review of 25 studies involving 968,428 older adults suggests that a higher anticholinergic burden is associated with an increased risk of cognitive decline or dementia, with an odds ratio of 2.63 for those with significant anticholinergic effects.

The Anticholinergic Cognitive Burden scale (ACB scale) was particularly highlighted, showing that as the severity of anticholinergic burden increases, so does the risk of cognitive decline, indicating a potential need for careful medication management in older adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anticholinergic burden (prognostic factor) for prediction of dementia or cognitive decline in older adults with no known cognitive syndrome. Taylor-Rowan, M., Edwards, S., Noel-Storr, AH., et al.[2022]

In a study of 19,114 healthy older adults, a high anticholinergic burden (ACB score of ≥ 3) was linked to a significantly increased risk of ischemic stroke (58% higher risk) and dementia (36% higher risk) after a median follow-up of 4.7 years.

The results suggest that minimizing exposure to anticholinergic medications in older adults is crucial, as these medications may have a vascular effect contributing to the increased risk of cognitive decline and stroke.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Cohort Study of Anticholinergic Medication Burden and Incident Dementia and Stroke in Older Adults. Lockery, JE., Broder, JC., Ryan, J., et al.[2022]

In a pilot study involving six healthy postmenopausal women, the anticholinergic drugs mecamylamine and scopolamine did not significantly impair working memory performance, suggesting that cholinergic modulation may not universally affect cognitive function in this population.

Functional MRI results indicated that brain activation patterns in the frontal lobe were greater during placebo conditions compared to drug conditions, highlighting the sensitivity of brain circuitry to cholinergic modulation and the potential for different effects from nicotinic versus muscarinic receptor blockade.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nicotinic versus muscarinic blockade alters verbal working memory-related brain activity in older women. Dumas, JA., Saykin, AJ., McDonald, BC., et al.[2021]

In a pilot study involving six healthy postmenopausal women, the use of anticholinergic drugs scopolamine and mecamylamine showed similar patterns of brain activation during memory tasks, indicating that cholinergic modulation may influence cognitive processes after menopause.

The study found increased activation in the hippocampus and frontal areas during memory encoding, suggesting that changes in the cholinergic system could contribute to cognitive changes experienced by postmenopausal women.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cholinergic modulation of hippocampal activity during episodic memory encoding in postmenopausal women: a pilot study. Dumas, JA., McDonald, BC., Saykin, AJ., et al.[2021]

In a study of 40 postmenopausal women aged 50-60, treatment with 1 mg of oral estradiol did not improve cognitive performance under anticholinergic blockade and actually worsened attention task performance compared to a placebo.

Women with higher self-reported cognitive complaints showed poorer performance on working memory tasks, suggesting that these complaints may indicate a decline in cholinergic function that affects cognitive abilities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Estradiol treatment in young postmenopausal women with self-reported cognitive complaints: Effects on cholinergic-mediated cognitive performance. Conley, AC., Albert, KM., McDonald, BC., et al.[2023]

In a study of 22 postmenopausal women, younger participants (ages 50-62) showed improved verbal memory when pretreated with estradiol before anticholinergic challenges, indicating a beneficial interaction between estradiol and the cholinergic system.

Conversely, older participants (ages 70-81) experienced impaired performance on memory tasks with estradiol treatment, suggesting that the cognitive benefits of estradiol may be more pronounced in younger postmenopausal women and highlighting a critical period for its use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Estradiol interacts with the cholinergic system to affect verbal memory in postmenopausal women: evidence for the critical period hypothesis. Dumas, J., Hancur-Bucci, C., Naylor, M., et al.[2021]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Anticholinergic Burden of Geriatric Ward Inpatients. [2021]

2. New Zealand pubmed.ncbi.nlm.nih.gov

Impact of anticholinergic discontinuation on cognitive outcomes in older people: a systematic review. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Use of medications with anticholinergic properties and cognitive function in a young-old community sample. [2009]

4. England pubmed.ncbi.nlm.nih.gov

Anticholinergics: theoretical and clinical overview. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Cholinergic therapies for Alzheimer's disease: progress and prospects. [2005]

6. New Zealand pubmed.ncbi.nlm.nih.gov

Adverse Effects of Anticholinergic Drugs on Cognition and Mobility: Cutoff for Impairment in a Cross-Sectional Study in Young-Old and Old-Old Adults. [2020]

7. England pubmed.ncbi.nlm.nih.gov

Anticholinergic medications and risk of dementia in older adults: Where are we now? [2022]

8. England pubmed.ncbi.nlm.nih.gov

Anticholinergic deprescribing interventions for reducing risk of cognitive decline or dementia in older adults with and without prior cognitive impairment. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Anticholinergic burden (prognostic factor) for prediction of dementia or cognitive decline in older adults with no known cognitive syndrome. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

A Cohort Study of Anticholinergic Medication Burden and Incident Dementia and Stroke in Older Adults. [2022]

11. England pubmed.ncbi.nlm.nih.gov

Nicotinic versus muscarinic blockade alters verbal working memory-related brain activity in older women. [2021]

12. United States pubmed.ncbi.nlm.nih.gov

Cholinergic modulation of hippocampal activity during episodic memory encoding in postmenopausal women: a pilot study. [2021]

13. England pubmed.ncbi.nlm.nih.gov

Estradiol treatment in young postmenopausal women with self-reported cognitive complaints: Effects on cholinergic-mediated cognitive performance. [2023]

14. United States pubmed.ncbi.nlm.nih.gov

Estradiol interacts with the cholinergic system to affect verbal memory in postmenopausal women: evidence for the critical period hypothesis. [2021]