Cholinergic Antagonist for Postmenopausal Cognitive Decline

(CHAMP Trial)

Recruiting in Palo Alto (17 mi)

+1 other location

Overseen by JUlie A Dumas, Ph.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}

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.

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

Vanderbilt University Medical Center Nashville, TN

University of Vermont Burlington, VT

Who Is Running the Clinical Trial?

University of Vermont Lead Sponsor

Vanderbilt University Medical Center Collaborator

References

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

Anticholinergic Burden of Geriatric Ward Inpatients. [2021] Background and Objectives: Anticholinergic drug use in the pharmacotherapy of elderly persons is common despite the increased risk of side effects. We examined the prevalence of anticholinergic drug use and total anticholinergic drug burden among patients admitted to an acute care geriatric ward in Poland. Materials and Methods: Cross-sectional study of 329 subjects hospitalized at the geriatric ward. Patient condition was assessed with a comprehensive geriatric assessment. The Anticholinergic Cognitive Burden (ACB) scale was used to estimate the total anticholinergic load. Results: Mean patient age was 79.61 &#177; 6.82 years. 40.73% of them were burdened with at least one anticholinergic drug. The clinically significant anticholinergic burden was observed in 13.98% of subjects. Patients with dementia, risk of falls, and severe disability had significantly higher total ACB scores compared to other groups. The receiver operating characteristics (ROC) curve revealed that the total ACB score &#8805; 1 was significantly associated with dementia and the risk of falls. Total ACB score &#8805; 2 was significantly associated with severe disability. Conclusions: Patients admitted to an acute care geriatric ward had an anticholinergic cognitive burden score comparable to other patient populations. We found associations at both low and elevated levels of anticholinergic burden with dementia and risk of falls. At elevated anticholinergic burden levels, we found associations with severe disability. Despite recommendations against the use of anticholinergics in older adults these medications are still commonly prescribed. Further study is necessary to define the characteristics of anticholinergic medication most closely associated with negative outcomes in elderly populations.

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

Impact of anticholinergic discontinuation on cognitive outcomes in older people: a systematic review. [2021] Medicines with anticholinergic properties increase the risks of functional and cognitive decline, morbidity and mortality, institutionalization and length of hospital stay in older people. It is postulated that minimizing anticholinergic burden should result in improved short-term memory, confusion and delirium, and may improve the quality of life and daily functioning of older people.

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

Use of medications with anticholinergic properties and cognitive function in a young-old community sample. [2009] To examine whether anticholinergic medications have effects on the level of cognitive function or cognitive decline in persons in their early to mid 60s.

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

Anticholinergics: theoretical and clinical overview. [2022] Anticholinergics are a class of medicines that block the neurotransmitter, acetylcholine, in the brain and peripheral tissues. Medicines with anticholinergic activity are widely prescribed for and used by older people for various medical conditions. One-third to one-half of the medicines commonly prescribed for older people have anticholinergic activity. Several studies have reported anticholinergic burden to be a predictor of cognitive and functional impairments in older people.

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

Cholinergic therapies for Alzheimer's disease: progress and prospects. [2005] Cholinomimetic drugs are now available to treat the cognitive impairments associated with Alzheimer's disease (AD), although evidence indicates that the effects of acetylcholinesterase (AChE) inhibitors on measures of cognitive function may be secondary to an action on attentional mechanisms. There is also convincing evidence suggesting that cholinomimetic drugs (e.g., AChE inhibitors and agents acting on cholinergic receptors) will have utility in the treatment of other, non-cognitive changes in behavior that are often associated with AD. This review describes some of the approaches to cholinergic therapy and considers the symptoms that are best suited to these treatment modalities.

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] Drugs with anticholinergic properties are commonly prescribed in older adults despite growing evidence of their adverse outcomes. Several issues regarding these detrimental effects remain unresolved, such as the putative existence of a threshold above which anticholinergic drug consumption impairs cognitive or mobility performance.

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

Anticholinergic medications and risk of dementia in older adults: Where are we now? [2022] Anticholinergic medications are effective for a wide variety of indications, but are associated with significant central adverse effects, especially cognitive decline and dementia in older adults.

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] Anticholinergics are medications that block the action of acetylcholine in the central or peripheral nervous system. Medications with anticholinergic properties are commonly prescribed to older adults. The cumulative anticholinergic effect of all the medications a person takes is referred to as the anticholinergic burden. A high anticholinergic burden may cause cognitive impairment in people who are otherwise cognitively healthy, or cause further cognitive decline in people with pre-existing cognitive problems. Reducing anticholinergic burden through deprescribing interventions may help to prevent onset of cognitive impairment or slow the rate of cognitive decline.

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] Medications with anticholinergic properties are commonly prescribed to older adults. The cumulative anticholinergic effect of all the medications a person takes is referred to as the 'anticholinergic burden' because of its potential to cause adverse effects. It is possible that high anticholinergic burden may be a risk factor for development of cognitive decline or dementia. There are various scales available to measure anticholinergic burden but agreement between them is often poor.

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

A Cohort Study of Anticholinergic Medication Burden and Incident Dementia and Stroke in Older Adults. [2022] Anticholinergic medications may increase risk of dementia and stroke, but prospective studies in healthy older people are lacking.

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

Nicotinic versus muscarinic blockade alters verbal working memory-related brain activity in older women. [2021] An important aspect of furthering our understanding of the central nervous system function after menopause is to examine the cerebral circuitry that appears to be influenced by cholinergic antagonist drugs in the presence and absence of estrogen. This pilot study investigated the effects of two anticholinergic drugs on brain activation and working memory performance in postmenopausal women not taking estrogen. This approach simulates the effects of age- or disease-related neuroreceptor or neuronal loss by temporarily blocking pre- and postsynaptic muscarinic and nicotinic cholinergic receptors.

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

Cholinergic modulation of hippocampal activity during episodic memory encoding in postmenopausal women: a pilot study. [2021] The cholinergic system has been shown to modulate estrogen effects on cognitive performance in postmenopausal women. In an effort to further understand cholinergic contributions to cognition after menopause, this pilot study investigated the effects of two receptor-specific anticholinergic drugs on brain activation and episodic memory encoding in postmenopausal women not taking estrogen.

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] Older women are at increased risk of developing Alzheimer's disease compared to men. One proposed reason is that following menopause there is a decline in estrogens. Estrogens are important for cholinergic functioning and attenuate the impact of cholinergic antagonists on cognitive performance in postmenopausal women. Self-reported or subjective cognitive complaints in middle or older age may represent a harbinger of cognitive decline and those who endorse cognitive complaints appear more likely to develop future cognitive impairment. However, the response of individuals with cognitive complaints after menopause to estrogen and the relationship to cholinergic functioning has not been investigated. This study investigated the effect of estrogen treatment using 17β-estradiol on cognitive performance following anticholinergic blockade in postmenopausal women and the relationship of this interaction with the level of self-reported (subjective) postmenopausal cognitive complaints.

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] Estradiol has been shown to interact with the cholinergic system to affect cognition in postmenopausal women. This study further investigated the interaction of estradiol and cholinergic system functioning on verbal memory and attention in two groups of healthy younger (ages 50-62) and older (ages 70-81) postmenopausal women. Twenty-two postmenopausal women were randomly and blindly placed on 1 mg of 17-beta estradiol orally for 1 month then 2 mg for 2 months or matching placebo pills after which they participated in three anticholinergic challenge sessions when verbal memory and attention were assessed. Subjects were administered either the antimuscarinic drug scopolamine (SCOP), the antinicotinic drug mecamylamine (MECA), or placebo. After the first challenge phase, they were crossed over to the other hormone treatment for another 3 months and repeated the challenges. Results showed that estradiol pretreatment significantly attenuated the anticholinergic drug-induced impairments on a test of episodic memory (the Buschke Selective Reminding Task) for the younger group only, while estradiol treatment impaired performance of the older group. The results suggest that younger subjects may experience more cholinergic benefit from estradiol treatment than older subjects, supporting the concept of a critical period for postmenopausal estrogen use.