The primary goal of this competing continuation (renewal) proposal is to combine clinical, cognitive and neuroimaging methodologies to continue our investigations of how estrogen and related compounds influence the cognitive functions of the cholinergic systems of the human brain. We will move 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 the first five year period of this grant, 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. This proposal 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 E2 stimulation. Specifically, the first study (1) 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 will involve our model of short-term estrogen treatment and cholinergic antagonist challenge in normal postmenopausal women successfully utilized in the prior grant period. We will examine 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. In the second study (2), we will examine the relationship between age and potential benefit to cholinergic-related cognitive performance. We will explicitly examine this version of the """"""""critical period hypothesis"""""""" by utilizing our established estrogen- cholinergic challenge model and examining for age-related differences in brain activity with fMRI that are associated with cognitive differences in estrogen-cholinergic responsivity. This continued work will have important implications for understanding of the effects of hormonal loss on brain function and the potential benefits versus risks of postmenopausal hormone therapy on cognition and behavior.

Public Health Relevance

We have established evidence that estradiol administration in normal postmenopausal women specifically enhances cognitive operations that are influenced by central cholinergic systems including attention, psychomotor speed, and episodic memory. This proposal attempts to more fully understand how estrogen-cholinergic interactions in the brain affect attention and memory and develop an understanding of the relationships between individual, chronological, biological, and cognitive characteristics of older women and the responsiveness of the CNS cholinergic system using new technologies (e.g. neuroimaging). The over arching goal is to develop information to allow the development of models to potentially predict which women may benefit from the cognitive effects of estradiol after menopause.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Wagster, Molly V
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University of Vermont & St Agric College
Schools of Medicine
United States
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Albert, Kimberly; Hiscox, Jessica; Boyd, Brian et al. (2017) Estrogen enhances hippocampal gray-matter volume in young and older postmenopausal women: a prospective dose-response study. Neurobiol Aging 56:1-6
Albert, Kimberly; Gau, Violet; Taylor, Warren D et al. (2017) Attention bias in older women with remitted depression is associated with enhanced amygdala activity and functional connectivity. J Affect Disord 210:49-56
Vega, Jennifer N; Zurkovsky, Lilia; Albert, Kimberly et al. (2016) Altered Brain Connectivity in Early Postmenopausal Women with Subjective Cognitive Impairment. Front Neurosci 10:433
Albert, Kimberly; Pruessner, Jens; Newhouse, Paul (2015) Estradiol levels modulate brain activity and negative responses to psychosocial stress across the menstrual cycle. Psychoneuroendocrinology 59:14-24
Newhouse, Paul; Albert, Kimberly (2015) Estrogen, Stress, and Depression: A Neurocognitive Model. JAMA Psychiatry 72:727-9
Dumas, Julie A; Newhouse, Paul A (2015) Impaired working memory in geriatric depression: an FMRI study. Am J Geriatr Psychiatry 23:433-6
Newhouse, Paul; Dumas, Julie (2015) Estrogen-cholinergic interactions: Implications for cognitive aging. Horm Behav 74:173-85
Jucaite, Aurelija; Öhd, John; Potter, Alexandra S et al. (2014) A randomized, double-blind, placebo-controlled crossover study of ?4? 2* nicotinic acetylcholine receptor agonist AZD1446 (TC-6683) in adults with attention-deficit/hyperactivity disorder. Psychopharmacology (Berl) 231:1251-65
Vega, Jennifer N; Newhouse, Paul A (2014) Mild cognitive impairment: diagnosis, longitudinal course, and emerging treatments. Curr Psychiatry Rep 16:490
Dumas, Julie A; Kutz, Amanda M; McDonald, Brenna C et al. (2013) Increased working memory-related brain activity in middle-aged women with cognitive complaints. Neurobiol Aging 34:1145-7

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