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College of Medicine

Clinical Neuroscience Research Unit

Professional Study Summaries

Acute: Acute vs. Chronic Estrogen Modulation Effects on Cholinergic Function in Normal Post-Menopausal Women

Menopausal Memory Concerns

The primary goal of this research is to examine in detail the acute effects of estrogen on cognitive functions that are affected by the cholinergic systems of the brain in postmenopausal women. These systems have critical relevance for the development of age-related cognitive and behavioral changes as well as the symptoms of dementing disorders such as Alzheimer's disease. Changes in estrogen levels after surgical and natural menopause are associated with negative changes in cognitive and behavioral functioning which are preventable by estrogen administration. Administration of estrogen after menopause is associated with a lower risk on Alzheimer's disease.

Specifically, this study examines the effects of estrogen on the cholinergic system of the human brain that is thought to be critical for attention, learning, memory, and psychomotor performance. This study utilizes a well-established method for probing the integrity of central cholinergic mechanisms utilizing cholinergic (muscarininc and nicotinic) antagonists. Preliminary data suggest that short-term administration of estrogen partially protects women from the negative cognitive effects of cholinergic antagonists. This effect could be mediated by trophic effects of estrogen on central cholinergic neurons. Estrogen has a substantial effect on the expression and activity of trophic factors such as Nerve Growth Factor (NGF) and its receptors, thereby directly producing neuroprotective and trophic effects, particularly in the cholinergic neurons of the basal forebrain. Estrogen also appears to have signal transduction modulating properties. This study examines the acute vs. chronic effects of estrogen on anti-cholinergic induced cognitive changes. This study will provide knowledge regarding the magnitude and type of effects of estrogen on cholinergic system integrity and will contribute to an understanding of the potential impact of estrogen in late life for maintenance of cognitive functioning during normal aging and the prevention and/pr treatment of age-related cognitive disorders such as mild cognitive impairment and Alzheimer's disease.

Cognitive Complaints: The Relationship Between the Effects of Estrogen on Sensitivity to Cholinergic Blockade, Cognitive Symptomatology, and Brain Morphology in Younger Post-Menopausal Women

The primary goal of this research is to combine clinical, cognitive, and neuroimaging methodologies to continue our investigations of how estrogen influences cognitive functions of the cholinergic systems of the human brain. We have moved beyond our original investigations to begin to develop an understanding of the biological, clinical, and cognitive relationships between positive or negative effects of estrogen on cholinergic-related cognitive functioning in older women. There is evidence that the postmenopausal estrogen treatment may slow or prevent cognitive decline, enhance cognitive functioning, and may lower the risk of developing Alzheimer's disease (AD) if administered in the early postmenopausal period. However, large prospective studies such as the Women's Health Initiative (WHI) have suggested that under certain circumstances, hormone therapy may actually increase the risk for cognitive dysfunction. In our previous research, we have consistently shown that benefits of estrogen treatment on cognitive functioning may be mediated through interactions with CNS cholinergic systems by specifically enhancing cholinergic-sensitive cognitive operations including attention, psychomotor speed, and episodic memory. The current study proceeds to the next logical steps to more fully understand the nature of the estrogen-cholinergic interactions and utilize new approaches (e.g. neuroimaging) to develop a better grasp of the relationships between individual biological and cognitive characteristics and the responsiveness of the CNS cholinergic system to estradiol stimulation.

Specifically, this study will examine the relationship between the effects of estrogen on cholinergic system-related cognitive performance and individual characteristics of postmenopausal women that may bear a relationship on whether estrogen has cognitively enhancing effects. This study involves our model of short-term estrogen treatment and cholinergic antagonist challenge in normal postmenopausal women successfully utilized in our previous studies. We are examining the influence of subjective and objective baseline cognitive symptomatology, structural brain imaging, and genetic markers on the relationship between the ability of estrogen to enhance cholinergic-related cognitive function. This research will have important implications for understanding the effects of hormonal loss on brain function and the potential benefits versus risks of postmenopausal hormone therapy on cognition and behavior.

The Effects of Estradiol Administration on Emotional Responses and Brain Activation to Emotional Stimuli in Older Women: a Pilot Study

The primary aim of this study, funded by the University of Vermont College of Medicine, is to examine the relationships between functional brain activity measured with fMRI, estrogen and subjective emotional responses in post-menopausal women. This study utilizes functional magnetic resonance imaging (fMRI) to examine the activity of brain structures involved in the production of emotional responses in women to whom we have administered fixed doses of E2. In addition we will examine the associations between brain activation, E2 level and subjective responses, something that has not been done before. This will help us establish the relationship between activation or deactivation of emotion-associated brain structures, and the emotional cognition associated with negative emotional stimuli. This study will contribute to an understanding of how exogenous estrogen affects emotional processing in post-menopausal women.

The Effects of Physostigmine on Cognition in Postmenopausal Women

This study will address the hypothesis that age effects on brain activation seen on tests of attention, working memory, and episodic memory result from age and/or menopause-related changes in the cholinergic system. We will examine the effects of three months of estradiol treatment on brain activity during physostigmine and scopolamine challenges in postmenopausal women. We will examine ability of estradiol to modulate brain activity during cognitive tasks that is modulated by the cholinergic system.

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