Julie A. Dumas, Ph.D. - US grants

DESCRIPTION (provided by applicant): The combination of the increasing size of the older adult population and the recent controversy over the administration of estrogen and progesterone to alleviate symptoms of menopause makes it imperative that we learn about the effects of gonadal steroids on cognition. The proposed research is based on a neurobiological model of the interaction of estrogen and the acetylcholine system and the effects of this interaction on normal cognition. Data indicate that estrogen attenuates the impairments on cognitive tests during anticholinergic drug challenge. Thus far, the role of progesterone in this model has not been elucidated. In order to understand the interaction of estrogen and progesterone with the cholinergic system, Study 1 will examine the performance of postmenopausal women who have taken these hormones for three months and then perform cognitive tests during anticholinergic drug challenges. Further, in an effort to learn about the brain circuitry affected by the hormones and anticholinergic drugs, Study 2 will involve drug challenge sessions conducted during functional magnetic resonance imaging. Thus, this research will provide knowledge about the interaction of gonadal steroids and the cholinergic system, the neuroanatomy of such interactions, and their influence on cognition in postmenopausal women.

DESCRIPTION (provided by applicant): This application is for an NIH K01 Mentored Research Scientist Development Award where I will gain the xpertise necessary to establish myself as an independent investigator exploring the neurobiology underlying cognitive aging. I will receive training in a specific approach to investigating the neurobiological underpinnings of cognitive aging with the combined use of psychopharmacological manipulations of cognition and functional magnetic resonance imaging (fMRI) from two established experts in these fields, Paul Newhouse, M.D. and Andrew Saykin, Psy.D. Under the mentorship of Drs. Newhouse and Saykin, I will participate in on-site residencies, tutorials, courses, and hands-on research projects. This training will provide me with unique expertise as I combine my prior training in cognitive psychology with the ability to utilize the cutting edge combination of psychopharmacological manipulations and fMRI to study the neurobiology of cognitive aging. As an integral part of my training I will conduct two pharmacological fMRI studies that will extend my findings showing the importance of cholinergic integrity in observing effects of estrogen on cognition. Study 1 will test the hypothesis that neural compensation that is observed when older women activate more frontal relative to occipital cortex is modulated by cholinergic integrity and estrogen treatment. Study 2 will test the hypothesis that aging of the cholinergic system is principally responsible for age-associated neural compensation seen in attention, working memory, and episodic memory tasks. Study 2 will also use estrogen to modulate cholinergic-related cognitive processes. These studies will be the first to combine the powerful manipulations of cholinergic pharmacological challenge, sex hormone treatment, and fMRI to examine the neurotransmitter-hormone interaction effect on cognition. The results of these studies will provide evidence for the importance of cholinergic integrity and estrogen treatment on brain and cognitive functioning in older women. Understanding the neurobiology underlying the estrogen effect on cognition is important for the future development of treatment strategies for age-related cognitive dysfunction. RELEVANCE (See instructions): These studies will emphasize the importance of knowledge of the neurobiology underlying cognitive aging for the furure design of clinical interventions. The results will also be important for an understanding why prior trials of estrogen effects on cognition have failed because cholinergic systems in older women were impaired such that no positive effects of estrogen were seen.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Some studies have suggested that there are large gender differences in how women and men process and respond to emotional information. More recently there has been a great deal of research concerning the sexual dimorphism of an area of the brain called the amygdala. The amygdala is involved in the recall of emotional and arousing memory. These studies have concluded that emotional memory is processed in different hemispheres of the amygdala by men and women. In women amygdala activation occurs in the left hemisphere when encoding emotion memory and in the right hemisphere of the amygdala with in men. In addition, several studies have suggested that there may be a neurobiological underpinning to transgender identity that suggests that transgender individuals have biological organization more similar to their gender identity than to their biological sex. Prior research conducted on brain lateralization in transsexuals has reported that transsexuals have cerebral brain lateralization in congruence with their gender identity rather than biological sex. Understanding why there are gender differences in how the brain processes and remembers emotional information is important because there are a number of psychiatric disorders that have large gender differences and also involve the impaired processing of emotional information. Two examples of disorders that involve emotional dysregulation and affect one sex more than the other are depression and post traumatic stress disorder (PTSD). Depression occurs in 20 percent of women compared to 10 percent of men. The exact reason for this sex difference is unknown, however it is suggested that it is due to sex related differences in brain structures and functioning, as well as cognitive functions and styles. It has also been suggested that elevated physiological activity in the amygdala appears to be implicated in emotional behavior. Other research has found that depression is linked to enhanced activity of the left amygdala predominantly found in women. It has been reported that the trans community have higher than the average rates of depression and that their risk of suicide is also higher. This higher incidence of depression is largely influenced by societal norms and beliefs which are in part influenced by the notion that there is no biological cause underlying transgender identity. Therefore, the link between the amygdala processing of emotional information and gender is of utmost importance for the trans community due their higher than average risk of depression. It is important to further investigate the neurobiology of the amygdala and its relationship to depression, as well as understanding its functioning in everyone, including transgender individuals. Learning more about the neurobiology of gender differences in emotional memory and related brain activation will be important for the future development of treatments for these clinical disorders. This proposal will describe a study to examine emotional memory and related brain activation in transgender subjects both on and off hormones in order to learn more about the relationship between biological sex, hormones and the sexually dimorphic pattern of brain activation observed for remembering emotional information. This is a brain imaging study examining the patterns of brain activation during emotional memory tests in transgender individuals. Two groups of transgender individuals will be studied, 12 male to female transgender and 12 female to male transgender. Within each group 6 participants will be taking hormone treatment and 6 will not. Each participant will participate in one study day in which we will use fMRI to assess their amygdale activation during emotional memory encoding. The knowledge gained from this study will provide important information about the neurobiological underlying of gender differences in emotional memory, as well as in transgender individuals, while furthering knowledge about gender influenced psychiatric disorders.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Studies have suggested that nicotine causes a decrease in mood and concentration when administered to non-smokers. However other studies have shown that nicotine can facilitate cognitive functioning and improve memory in patients suffering from psychiatric disorders, such as Schizophrenia. Thus, nicotine seems to have an effect on emotional processing, however the specific mechanisms and underlying functional brain anatomy are not known. Nicotine acts on similar chemical pathways in the brain as the naturally occurring chemical acetylcholine. Acetylcholine, a component of the cholinergic system, is associated with learning and memory. We will examine whether manipulating nicotine has an affect on memory tasks, specifically targeting the emotional memory processing in normal healthy volunteers. This study involves functional brain imaging using an MRI scanner of 16 healthy, non-smoking, young adults. Subjects will complete two study days where they will either receive a nicotine patch or a placebo patch. We will then examine brain areas activated during the encoding of emotional information using functional magnetic resonance imaging (fMRI). The nicotine patch is used to stimulate targeted brain systems. The memory tasks are emotionally-valenced;meaning that subjects will be shown words and images that are either neutral or negatively charged. By observing the brain areas activated during the memory task given in the MRI scan and examining how a subject later recognizes the words and images they studied, we will be able to assess the brain circuitry affected by this nicotinic stimulation. These results will help us understand the neurobiology of emotional memory and thus facilitate the search for treatment for disorders affecting our emotional processing.

DESCRIPTION (provided by applicant): The hormonal change at menopause is arguably the most important biochemical event in a woman's life related to normal as well as pathological cognitive aging. At menopause some women experience declines in memory, attention, problem solving, and motor skills from premenopausal levels. However, not all women experience negative effects of menopause on cognition. Thus, understanding the neurobiological factors related to individual differences in cognition at menopause is critical for determining risk factor for pathological aging. We propose that the change in the hormonal milieu at menopause interacts with dopaminergic functioning in the frontal cortex of the brain to influence a woman's risk for cognitive decline after menopause. The Study proposed in this R21 Exploratory/Developmental Research Grant will examine how different genotypes that code for the enzyme catechol-O-methyltransferase (COMT) affect cognition in women after menopause. COMT is an enzyme responsible for dopamine metabolism in the frontal cortex and a common single nucleotide polymorphism (Val158Met) results in different levels of dopamine metabolism that affect cognition. Met/Met compared to Val/Val homozygotes have decreased dopamine metabolism, increased cognitive performance, and decreased frontal cortex activation as measured by functional magnetic resonance imaging (fMRI). Collectively this data pattern is interpreted as more efficient cognitive processing. Estrogen has the ability to directly modulate dopaminergic functioning by interacting with two estrogen response elements on the COMT promotor to decrease COMT transcription and thereby increase dopaminergic functioning and affect dopaminergically driven cognition. Thus, the estradiol change at menopause is likely to have effects on cognitive processes that are regulated by normal dopaminergic functioning and modulated by COMT genotype. This study will recruit healthy postmenopausal women who will perform a working memory task during fMRI, provide a blood sample for genetic and hormone analyses, and perform neuropsychological tests to assess individual differences in cognition after menopause. This study will advance understanding of the genetic mechanisms potentially involved in successful and pathological cognitive aging. This innovative study will impact what is known about the effects of menopause on cognition by 1) allowing for a refinement of theories of cognitive aging by incorporating genetic mechanisms, 2) providing a genetic-based neurotransmitter target for drug discovery to modulate cognition after menopause in addition to the hormone-based strategies, and 3) enabling the prediction of individual vulnerability for pathological aging.

? DESCRIPTION (provided by applicant): The cholinergic system has been shown to be the primary neurotransmitter system responsible for cognitive symptoms in dementia. While therapeutic benefits are clear in dementia, what remains uncertain is the role that the cholinergic system in general and the nicotinic system specifically plays in cognition in healthy non-demented older adults (referred to as cognitive aging in this application). This is critical becaus the expansion of the healthy aging population will nonetheless show declines in cognition that fall short of dementia but still impact functional abilities, independence, and financial decision making. Understanding the effects of age-related functional changes on the nicotinic system will elucidate one neurochemical mechanism underlying age-related changes in cognition and will provide information about how nicotinic dysfunction affects cognition in healthy older adults. Prior research has shown that the nicotinic system has a roll in attention and memory in healthy adults. More recently, with the increased use of brain functional magnetic resonance imaging (fMRI) in combination with psychopharmacological manipulations, data patterns have emerged that further define the role of the nicotinic system in cognition, aging, and dementia. We propose that nicotinic system changes are responsible for age differences in working memory task performance and brain activation. We can observe the functioning of the nicotinic system by examining brain activation patterns in response to nicotinic blockade and stimulation. Increased medial frontal gyrus (MFG) activation has been shown in older adults compared to younger adults. We propose that temporary antagonism of the nicotinic system will model this older pattern of impaired performance and increased MFG activation. We hypothesize that older adults will have greater performance impairments and increased MFG activation compared to younger adults after nicotinic blockade. We also propose that nicotinic stimulation will result in younger patterns of better performance and decreased MFG activation. We hypothesize that nicotinic stimulation will improve performance and this improvement will be greater for older adults compared to younger adults. We will also observe decreased MFG activation that will be greater for older adults compared to younger adults. These data will further the understanding of one neurochemical mechanism involved in normal aging and how brain activation patterns relate to receptor function. As the search continues for safe and effective cognitive enhancers, it will be important to understand the role of the nicotinic system in cognitive aging and whether nicotinic mechanisms have the potential to benefit cognition in healthy adults.

Despite advances in the understanding of age-related changes in cognition, there is still a need to unravel the biological mechanisms underlying normal cognitive aging, which has important financial and public health implications for society. Cognitive aging is not dementia and does not result in the loss of neurons, but rather changes in neurotransmission that affect brain functioning. Therefore, there is potential for remediation. Observational studies suggest that following a diet that is high in the monounsaturated fatty acid (FA), oleic acid (OA), and low in the saturated FA, palmitic acid (PA), lowers the rate of cognitive decline with aging, but these studies do not primarily assess mechanism. The study proposed in this application will determine whether and how dietary PA and OA alter brain functioning. Data from this laboratory showed that a high dietary PA/OA ratio, in a reversible fashion, enhanced systemic inflammatory tone, affected activation of brain regions that regulate cognition, and decreased physical activity in younger adults. In addition, the literature suggests that dietary PA will reduce sleep efficiency as well as brain expression of brain-derived neurotrophic factor (BDNF). The objective of this proposal is to test the hypothesis that lowering the dietary PA/OA ratio will decrease inflammatory signaling and will lead to better memory performance and increased hippocampal activation during an episodic memory task. To evaluate this hypothesis, a randomized, double-masked, cross-over trial in healthy, older adults, aged 65-75 years is proposed. Each subject will receive, in random order either a high PA diet (HPA) or a low PA, high OA diet (HOA), each for a duration of three weeks and each preceded by a one week, low-fat control diet. Specific Aim 1 is to determine if dietary PA and OA differentially and reversibly affect brain functioning in older adults. Hypothesis 1a is that the HOA diet compared to the HPA diet will result in improved episodic memory performance in older adults. Hypothesis 1b is that the HOA diet compared to the HPA diet will result in increased hippocampal activation during episodic memory encoding in older adults during fMRI. Specific Aim 2 is to determine if pro-inflammatory cytokines and blood concentrations of BDNF are related to dietary FA-induced changes in brain functioning in older adults. Hypothesis 2 is that decreased inflammation after the HOA diet, compared to the HPA diet, will be associated with improved episodic memory performance, hippocampal brain activation, and increased blood concentration of BDNF. In addition, we will conduct exploratory studies to determine if the following factors modify this relationship: physical activity, sleep efficiency, emotional stress, and both percent body fat and plasma leptin concentration at baseline. The results of this study will impact the understanding of how short-term changes in the dietary PA/OA ratio reversibly influence brain functioning in older adults, providing a novel basis for linking diet to dynamic variations in inflammatory activity and cognitive functioning that occur with normal aging.

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. We 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. We 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.