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.
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.
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|Jucaite, Aurelija; Ohd, 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|
|Zurkovsky, Lilia; Taylor, Warren D; Newhouse, Paul A (2013) Cognition as a therapeutic target in late-life depression: potential for nicotinic therapeutics. Biochem Pharmacol 86:1133-44|
|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|
|Dumas, Julie A; Kutz, Amanda M; Naylor, Magdalena R et al. (2012) Estradiol treatment altered anticholinergic-related brain activation during working memory in postmenopausal women. Neuroimage 60:1394-403|
|Newhouse, Paul A; Potter, Alexandra S; Dumas, Julie A et al. (2011) Functional brain imaging of nicotinic effects on higher cognitive processes. Biochem Pharmacol 82:943-51|
|Dumas, Julie A; Newhouse, Paul A (2011) The cholinergic hypothesis of cognitive aging revisited again: cholinergic functional compensation. Pharmacol Biochem Behav 99:254-61|
|Brigidi, Bartholomew D; Achenbach, Thomas M; Dumenci, Levent et al. (2010) Broad spectrum assessment of psychopathology and adaptive functioning with the Older Adult Behavior Checklist: a validation and diagnostic discrimination study. Int J Geriatr Psychiatry 25:1177-85|
|Dumas, Julie A; McDonald, Brenna C; Saykin, Andrew J et al. (2010) Cholinergic modulation of hippocampal activity during episodic memory encoding in postmenopausal women: a pilot study. Menopause 17:852-9|
|Dumas, Julie A; Kutz, Amanda M; Naylor, Magdalena R et al. (2010) Increased memory load-related frontal activation after estradiol treatment in postmenopausal women. Horm Behav 58:929-35|
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