Jeri S. Janowsky - US grants

DESCRIPTION: (adapted from investigator's abstract) In studies leading to this application the investigators studied the modulatory role of sex hormones on the behavior of young subjects, older subjects whose sex hormones had declined, and older subjects with hormone supplementation. The investigators identified age, sex differences and hormonal effects on cognition. Mental rotation was found to be mediated by the parietal lobe and working memory by the pre-frontal lobe. Mental rotation was modulated by estrogen in women but not men, and working memory was modulated by testosterone in men, but not women. The goals of the next four years are to examine whether the cognitive effects of hormone replacement attenuate with chronic supplementation in older women, as compared to the short-term supplementation previously tested. The modulating effect of progesterone on estrogen replacement will be investigated. In the proposed series of three studies investigators will examine: 1) the effect of steroidal hormone replacement in young and older women on cognitive function in the areas of verbal skills, visual-spatial processing, and memory; 2) sex differences in cognitive function relative to hormone replacement; 3) the neural specificity of hormonal modulation effects on mental rotation and working memory tasks via functional magnetic resonance imaging (fMRI) in young and older men and women. The understanding of the cognitive effects in the proposed studies will be extended by examining directly the brain basis of sex hormones on cognition.

age difference; gender difference; sex hormones; cognition; progesterone; vision; hormone regulation /control mechanism; human old age (65+); estrogens; visual perception; behavioral /social science research tag; human subject; clinical research;

Little is known about frontal lobe mediated attention in the oldest greater than 85 years of age). Yet this is the age range with the highest rate of progression to dementia. In addition, memory decline in this age range is common. Whether cognitive change, particularly memory decline, in this age range signals impending dementia or "benign" age-associated cognitive change is a diagnostic challenge. We suggest that other higher cortical functions, such as attention, may better distinguish those who will remain cognitively healthy from those in the early stages of dementia in the oldest old. Therefore, this pilot study will examine attention in cognitively healthy oldest old in comparison to a sample of oldest old in the "preclinical" stages of dementia using functional magnetic resonance imaging (fMRI). This pilot study will also help establish fMRI as a useful technology for the study of the neural basis of cognitive change in the elderly.

The aim of this research study is to obtain information about the effects of sex hormones on a person's ability to think and reason.

DESCRIPTION (provided by applicant): The goal of this research program has been to use a cognitive neuroscience framework to delineate the cognitive processes and neural systems that are modulated by sex steroids in aging. We continue this approach in this renewal (Years 8-11) by examining the effects of aging and sex steroids on the modulation of emotional memory. The role of the amygdala in arousal, and its importance in the affective modulation of memory, have been well delineated at the pharmacological, physiological and behavioral levels in both animals and humans. Studies also show that the amygdala and hippocampus have sex steroid receptors, and that sex steroids modulate their anatomy, physiology and function. However, neither the effects of aging, nor the effects of sex steroids on the amygdala's modulation of memory have been examined. Thus, we propose to expand our studies to examine the effects of sex steroids on the modulation of emotion and emotional memory in aging. We will examine age-related changes in emotion and emotional memory by comparing arousal, ratings of valence, and emotional memory for words, faces, pictures, stories, and fear conditioning in healthy older and younger people (Aim 1/Study 1). We examine sex steroid effects on these same measures in older women by examining the effects on performance of estrogen, estrogen + progesterone, estrogen + testosterone replacement versus no replacement (Aim 2/Study 2). Finally, we will examine sex steroid effects on these measures in older men by examining the effects of testosterone administered in a double blind placebo controlled manner (Aim 3/Study 3). We hypothesize that the memory impairment in aging for emotional stimuli will not be due to a primary lack of arousal or inability to recognize emotion, but rather the transfer of that information for use by the memory encoding and storage system. We also hypothesize that sex steroids will modify emotional memory in the elderly. This work will expand our understanding of factors that modify cognition, and in particular memory in aging, as well as the potential neural basis of these changes. This work is particularly important because those over 65 years of age are the fastest growing segment of the population, and are also those most likely to have cognitive decline and age-related degenerative diseases that preclude productivity and independence.

DESCRIPTION (provided by applicant): The last several years have seen an explosion of studies showing relationships between cognitive performance and sex steroid supplementation in men and women. These studies are most notable for their implications for cognitive aging and because they raise the possibility of protection against age-related neurologic diseases or age-related cognitive decline. The mechanism(s) that underlie the cognitive effects of sex steroids in humans are unknown. The overall goal of this research program is to initiate studies of the metabolic pathways that underlie the cognitive effects of sex steroids in human aging. Therefore, we will examine which androgen pathway underlies cognitive effects of androgen supplementation in men (Aim 1) by comparing cognitive performance before and after manipulation of sex steroids. We will administer a gonadotropin releasing hormone agonist, and simultaneously replaced with testosterone (T), T+ an aromatase inhibitor (preventing T's conversion to estradiol (E2)), or a placebo in a double blind manner in both younger and older men. We will examine whether T has cognitive effects in older women and the pathway of these effects by testing cognition in older women before and after T, T+aromatase inhibitor, E2 alone, or no replacement (Aim 2). This research program utilizes a cognitive neuroscience framework such that the critical brain systems for each cognitive domain (working memory, perception, verbal and nonverbal memory, motor sequence learning) have been delineated in previous studies. The tasks are those that particularly decline in aging, and have shown sex differences and/or sex steroid effects in previous studies. Findings that cognitive effects are due to aromatization to E2 in men versus action at T receptors, and findings that T affects cognition in women would give significant direction to the creation of tissue specific, sex steroid-related pharmacologic treatments for brain aging.

human therapy evaluation; memory; hormone therapy; emotions; sex hormones; aging; patient oriented research; clinical research; human subject;

human therapy evaluation; cognition; menopause; hormone therapy; estrogens; estradiol; patient oriented research; clinical research; human subject; female; women's health;

[unreadable] DESCRIPTION (provided by applicant): The goals of this pre- and post-doctoral training program are to create scientists with a broad understanding of the neuroscience of aging, including an understanding of the clinical manifestations and basic neuroscience of so-called "normal aging," as well as age-related neuropathologies. This will be accomplished by providing instruction in molecular, cellular, systems, and behavioral approaches to research on the age-related changes of the nervous system, as well as experience with the clinical manifestations of aging and age-related nurodegenerative diseases. The training will be accomplished through course work, seminars, and specialized laboratory and clinical research rotations. Faculty will come from across the OHSU campus, and will train pre-doctoral students through the Neuroscience and Behavioral Neuroscience programs. Most faculty have research collaborations across the following areas of aging research: Aging and Dementia, Cardiovascular Risk and Stroke, Cognition, Aging and Movement Disorders, Sensory Function in Aging, and Neuroendocrinology. The expectation is that this training program will permit the trainees to go on as neuroscientists of aging but with an understanding of how their basic science work is applicable to clinical cures for aging and age-related disorders. Similarly we expect that the clinical research trainees will be able to inform basic scientists on the directions whereby mechanistic work will prove fruitful for clinical application. We request funding for 8 pre-doctoral and 8 post-doctoral trainees over the course of this training grant, to be supported for 2-3 years of training. Pre-doctoral students will enter the program in their second year of graduate school when they have committed to a mentor's lab, and to research on the neuroscience of aging. There are currently no other mechanisms to fund trainees who seek to concentrate on the neuroscience of aging. [unreadable] [unreadable]