Kirk I. Erickson, Ph.D. - US grants

DESCRIPTION (provided by applicant): This application proposes to add a neuroimaging arm to an NIH funded 12-month diet and physical activity intervention. Obesity is currently at epidemic proportions in the United States, affecting over 1/3rd of American adults. Impaired cognitive and brain function - manifested as mood disorders, impulsivity, and an increased risk for neurological pathology - are often unrecognized consequences of obesity. These consequences are especially unsettling in view of the increased prevalence of obesity during childhood and adolescence, when the education, intellectual growth, and the preparation for future career seeking are at its peak. Hence, it is a public health imperative to rigorously investigate the effects of obesity on neurocognitive functions and to explore the potential for weight loss to restore cognitive and brain function. The parent study has three groups: diet only (DIET), diet + moderate physical activity (MOD-PA), diet + high physical activity (HIGH-PA) and will be collecting a myriad of outcome measures including aortic pulse wave velocity, inflammatory markers, glucose and insulin, abdominal adiposity and body composition using dual-energy X-ray absorptiometry, cardiorespiratory fitness using a graded exercise test, accelerometry measured physical activity, and energy intake. In addition to the subjects collected in the parent study we will collect a group of no-contact control (CON) participants for both reliability and comparison purposes. Therefore, by adding brain imaging to this intervention, our proposal reflects a cost effective and innovative approach to investigate links between physical activity, weight loss, brain integrity, metabolic outcomes, and cognitive processing and offers an opportunity to collect data on brain health with minimal additional costs. Testing these links could transform the way that brain-body associations are considered when assessing the risk for brain dysfunction or treating obesity related behavioral problems. Our main aims include: Aim 1. To examine whether a 12-month physical activity and weight loss intervention on overweight and obese adults increases cortical volume and improves microstructural white matter integrity, Aim 2: Examine how increased physical activity and weight loss can change the functional dynamics of the brain as assessed by both task-related neural responses, cerebral blood flow, and resting state brain connectivity, Aim 3. Link the changes in brain integrity, function, and connectivity with intervention-induced changes in physiological measures of metabolic and inflammatory molecular pathways. Our project represents the first attempt to associate weight loss in a long-term intervention to changes in brain networks. It is highly innovative, cost-effective, and will add significantly to the scientifc literature. By leveraging an existing NIH funded program and by focusing on neuroimaging outcomes with a skilled and productive team of experts in both weight loss interventions and cutting-edge neuroimaging techniques, we will be able to address unanswered questions that have important theoretical and translational implications for obesity and brain health.

? DESCRIPTION (provided by applicant): Nearly 61% of women with breast cancer experience a decline in cognitive function with adjuvant therapy. We found declines in attention and working memory with aromatase inhibitor (AI) therapy in women with breast cancer and poorer executive function compared to healthy controls. Multiple biological mechanisms likely underlie this cognitive decline including estrogen (E2) reduction and cytokine dysregulation. AI therapy provides near complete E2 withdrawal and we found that lower E2 levels were related to poorer psychomotor efficiency, attention and executive function with breast cancer therapy. Increases in pro- inflammatory cytokines occur with cancer and persist up to 5 years post-treatment. We found that higher IL-6 levels are related to poorer executive function and reduced gray matter volume. The effect of AIs on cognitive function may also be mediated by symptoms experienced by women with breast cancer including fatigue, sleep problems, depression and anxiety. A promising method for improving cognitive and brain function in older adults is moderate intensity aerobic exercise. Our neuroimaging studies have shown that only modest amounts of aerobic exercise increase hippocampal volume and modify intrinsic connectivity and task-related functional dynamics in the prefrontal cortex and hippocampus. We also found that exercise reduces pro- inflammatory cytokines that are directly linked to hippocampal size and memory formation. Exercise also reduces depression and anxiety and the severity of fatigue and sleep problems in women with breast cancer. We propose a clinical trial in which post-menopausal women with early stage breast cancer are randomized to receive a 6-month, moderate-intensity aerobic exercise intervention or usual care. We will examine whether a well-controlled and monitored site-based exercise intervention, initiated before AI therapy, improves cognitive function and explore whether neuroimaging metrics of brain health, pro-inflammatory biomarkers (IL-6, CRP, TNF-?), and symptoms (fatigue, sleep problems, depression, anxiety) mediate the effects of exercise on cognitive function. Furthermore, we will explore whether the magnitude of the improvements in cognitive function are modified by E2. The specific aims include: 1) Compared to usual care, examine whether the 6-month exercise intervention improves cognitive function over the first six months of AI therapy in postmenopausal women with early stage breast cancer. 2) Compared to usual care, examine the direct effects of exercise on neuroimaging metrics of brain health including regional gray matter volume, white matter architecture and functional dynamics of the brain and pro-inflammatory biomarkers (IL-6 and CRP as primary outcomes; TNF-? as secondary) and explore the direct effects of exercise on symptoms (fatigue, sleep problems, depression, anxiety). 3) Compared to usual care, explore whether the effects of exercise on cognitive function are mediated by neuroimaging metrics of cognitive function, pro-inflammatory cytokines and symptoms and moderated by E2.

Abstract Despite the ubiquity of normal age-related cognitive decline there is an absence of effective approaches for improving neurocognitive health. Fortunately, moderate intensity physical activity (PA) is a promising method for improving brain and cognitive health in late life, but its effectiveness remains a matter of continued skepticism and debate because of the absence of a Phase III clinical trial. Here we propose a Phase III multi- site randomized clinical trial called IGNITE (Investigating Gains in Neurocognition in an Intervention Trial of Exercise) to more definitively address whether exercise influences cognitive and brain health in cognitively normal older adults. We are proposing a 12-month, multi-site, randomized dose-response exercise trial (i.e., brisk walking) in 639 cognitively normal adults between 65-80 years of age. Participants will be randomized to a (a) moderate intensity aerobic exercise condition at the public health recommended dose of 150 minutes/week (N=213), (b) a moderate intensity exercise condition at 225 minutes/week (N=213), or (c) to a stretching-and-toning control condition for 150 minutes per week (N=213). Participants will meet 3 days/week for site-based exercise and do home-based activity on two more days of the week for 12 months. A comprehensive state-of-the-science battery of cognitive, MRI, amyloid imaging, physiological biomarkers, cardiorespiratory fitness, physical function, and quality of life measures will be assessed at baseline and after completion of the intervention. We have assembled a highly creative, productive, and interdisciplinary team with a long history of collaboration and experience conducting exercise interventions in older adults to test the following aims: Aim 1: Using a comprehensive neuropsychological battery and the NIH Toolbox, we will test whether a 12-month moderate intensity exercise intervention improves cognitive performance in older adults and (b) test whether the improvements occur in a dose-dependent manner. Aim 2: We will test whether a 12- month PA intervention augments MRI markers of brain health and whether these changes happen in a dose- dependent manner. Aim 3: We will test the hypothesis that cardiometabolic, inflammatory, and neurotrophic changes mediate improvements in brain and cognition. Aim 4: We will examine subgroups (i.e., individual differences) that attenuate or magnify the effect of the intervention on cognitive, brain, and physiological systems to better understand the factors that predict `responders' versus `non-responders' to the intervention. We will explore three categories of variables: (1) demographic (e.g., age) (2) genetic (e.g., APOE), and (3) baseline A? burden. Exploratory Aims: We will explore (a) whether baseline brain health metrics predict adherence and compliance to 12-months of PA, and (b) the utility of multi-modal brain imaging analytical approaches to more comprehensively understand the effects of PA on the aging brain. The results from this trial could transform scientific-based policy and health care recommendations for approaches to improve cognitive function in cognitively normal older adults.

Neurocognitive changes with breast cancer and its treatment are significant symptoms in the majority of women with this disease. Unfortunately, very little is known about the mechanisms that underlie these neurocognitive changes, which in turn limits the development of effective treatments and prevention strategies. Evidence supports that DNA methylation impacts cognitive function (CF) and brain health (BH), exercise impacts DNA methylation, and exercise impacts CF and BH. Although investigating DNA methylation patterns has potential to uncover novel biological underpinnings to help us understand neurocognitive changes within the context of breast cancer and its treatment, no DNA methylation study has evaluated the interrelationships among CF, BH and exercise within the context of breast cancer and its treatment. The purpose of the proposed study is to examine the dynamic DNA methylome to identify genes and biological pathways that are involved with CF and BH within the context of breast cancer and its treatment. This project capitalizes on data and samples generated through an ongoing project that involves women newly diagnosed with early stage breast cancer who will receive aromatase inhibitor (AI) therapy and randomizes them to an exercise intervention or usual care. Because breast cancer and AI therapy impact CF and BH in a negative manner and exercise impacts CF and BH in a positive manner; this project offers an exemplar, unique opportunity to identify biological mechanisms involved in CF and BH within the context of breast cancer and its treatment. Phenotype data for CF will focus on cognitive domains that deteriorate with AI therapy including attention, working memory, and executive function, and brain health will be measured using neuroimaging including regional gray matter volume, white matter architecture, and functional dynamics of the brain. Cognitive function may be mediated by commonly occurring symptoms therefore this study will include evaluating fatigue, sleep problems, depression, and anxiety for their potential to mediate or moderate the impact of DNA methylation on CF and BH. Whole genome DNA methylation data will be generated for all women at two time points: at enrollment when all women will be pre AI therapy and not yet randomized and post 6 months intervention for those randomized to the exercise intervention and usual care. This allows us to address mechanisms for CF and BH within the context of breast cancer prior to therapy, within the context of AI therapy, and within the context of an exercise intervention. An additional aim of this project will replicate significant findings using data and DNA samples from a project that recruits older healthy individuals, randomizes them to an identical exercise intervention, similarly measures CF and BH phenotypes, and collects biological samples at the same time points. Findings from this project have the potential to inform evidence based, mechanistically driven therapeutic interventions to mitigate the negative consequences of cancer and its treatment.

ABSTRACT Project 3 (Kirk Erickson, PL) Exercise effects on neural circuits for CVD risk The mechanisms by which physical activity (PA) may reduce CVD risk remain unclear. Multiple lines of evidence, however, show that PA ? particularly aerobic exercise ? exerts beneficial effects on brain health and brain plasticity. Critically, the brain areas reliably affected by exercise are visceral control areas under study in Projects (Ps) 1 and 2. These areas regulate aspects of peripheral autonomic, neuroendocrine, and immune physiology that are involved in conferring CVD risk and favorably affected by exercise. Accordingly, we propose to integrate historically separate lines of work on (1) exercise and CVD risk, (2) exercise and brain plasticity, and (3) exercise and stress, affect, and physiological control. To this end, we propose a 12-month intervention in which 150 midlife and inactive adults will be randomized to (1) 150 min/wk of moderate exercise (e.g., brisk walking; N=75) or (2) a light stretching control group with similar health instruction and social interaction as the treatment group (N=75). We will collect neuroimaging measures integral to Ps 1-2: behaviorally-evoked neural activity, cerebral perfusion and functional connectivity, white matter integrity, and gray matter morphology at 3 waves (baseline, 6-months, 12-months). Moreover, we use ambulatory CV monitoring and ecological momentary assessment (EMA) methods for the first time to test whether exercise impacts daily life stress physiology and affect, and whether these effects are partly explained by changes to visceral control areas. Our design allows us to test several hypotheses by the following Aims: Aim 1: To determine the neurobiology of exercise and biological CVD risk factors: (1A) Body-to-Brain hypothesis: Exercise-induced changes in peripheral markers of CVD risk (e.g., insulin resistance, cardiorespiratory fitness, peripheral vascular function) will precede and partly explain (statistically mediate) some of the exercise-induced changes in functional and structural features of areas defining visceral control circuits. (1B) Brain-to-Body hypothesis: Exercise-induced changes in functional and structural features of areas defining visceral control circuits precede and partly explain (statistically mediate) consequent changes in autonomic and neuroendocrine mediators of CVD risk that are under neural regulation, including baroreflex sensitivity, heart rate variability, and glucocorticoid control. Aim 2: To determine the neurobiology of exercise and stress- and affect-related CVD risk factors: (2A) Stress-related parameters of CVD risk: Exercise will induce changes in visceral control areas engaged by an fMRI stress battery, and these changes will partly explain exercise-induced reductions in cardiovascular stress reactivity in daily life (synergy with P's 1 & 2). (2B) Affect-related parameters of CVD risk: Exercise will induce changes in visceral control areas engaged by an fMRI emotion processing and regulation paradigm in synergy with P1, and these changes will partly explain exercise-induced improvements in affect measured in daily life by EMA and by conventional self-report instruments in synergy with P2. The public health significance of this Project is that it is designed to more precisely define and refine neurobiological targets to reduce CVD risk.

Abstract African Americans are almost two times more likely than whites (i.e., Caucasians) to experience Alzheimer's disease or other dementias. For those over the age of 65, the prevalence of cognitive impairment is 8.8% in whites and 23.9% in African Americans. Even in the age range of 55-64, African Americans are 4 times more likely to experience cognitive impairment than their age-matched white counterparts. Increased risk of dementia among African Americans may be attributed to lower levels and quality of education, lower socioeconomic status (SES), and higher prevalence of vascular diseases, Type II diabetes, hypertension, and obesity, all of which are recognized as risk factors for dementia. A critical public health question emerges from these statistics that we intend to address in this proposal: Is there an effective method for reducing or eliminating the race disparities in cognitive and brain health? Fortunately, physical activity (PA) interventions may be effective at improving neurocognitive function and reducing risk for dementia. Despite these promising results, prior PA interventions have had few African Americans making it difficult to stratify results by race to determine whether African Americans respond to PA in a similar manner and magnitude as whites. In addition, the terms `physical activity' and `exercise' are often considered unpleasant, painful, and fatiguing, which can negatively influence interest, enrollment, and long-term adherence. Methods that increase PA without using the term PA (e.g., dancing) could be effective at improving health outcomes while simultaneously having a wider impact on translation and long- term adherence. Here we propose an innovative and culturally sensitive method of increasing PA in older (60- 80 yrs) African Americans. We propose a randomized intervention where 180 older African Americans are assigned to either a moderate intensity African Dance group 3 days per week (N=90) or to an African Education group 3 days per week (N=90) for 6-months. Both before and at the completion of the intervention, we will collect a comprehensive neuropsychological battery and MRI metrics of brain health and function to identify biological pathways by which PA influences neurocognitive health in an African American population. This proposal has the potential to utilize community-based activities to improve health of older African Americans. In addition, it could establish a platform (i.e., dance) to implement future interventions targeting minority populations to reduce health disparities. We have three primary aims: Aim 1. Examine whether a 6- month African Dance intervention improves cognitive performance compared to an educational control group. Aim 2. Examine whether African Dance influences brain morphology, task-evoked neural responses, cerebral blood flow, and resting state connectivity. Aim 3. Explore potential physiological and socioemotional mechanisms of the dance intervention. We will collect measures of physical and psychosocial health such as waist circumference, blood pressure, blood glucose and lipid levels, mood, anxiety, depression, and loneliness and examine whether intervention-related changes to these measures mediate improvements in cognitive performance.

Abstract Despite the ubiquity of normal age-related cognitive decline there is an absence of effective approaches for improving neurocognitive health. Fortunately, moderate intensity physical activity (PA) is a promising method for improving brain and cognitive health in late life, but its effectiveness remains a matter of continued skepticism and debate because of the absence of a Phase III clinical trial. Here we propose a Phase III multi- site randomized clinical trial called IGNITE (Investigating Gains in Neurocognition in an Intervention Trial of Exercise) to more definitively address whether exercise influences cognitive and brain health in cognitively normal older adults. We are proposing a 12-month, multi-site, randomized dose-response exercise trial (i.e., brisk walking) in 639 cognitively normal adults between 65-80 years of age. Participants will be randomized to a (a) moderate intensity aerobic exercise condition at the public health recommended dose of 150 minutes/week (N=213), (b) a moderate intensity exercise condition at 225 minutes/week (N=213), or (c) to a stretching-and-toning control condition for 150 minutes per week (N=213). Participants will meet 3 days/week for site-based exercise and do home-based activity on two more days of the week for 12 months. A comprehensive state-of-the-science battery of cognitive, MRI, amyloid imaging, physiological biomarkers, cardiorespiratory fitness, physical function, and quality of life measures will be assessed at baseline and after completion of the intervention. We have assembled a highly creative, productive, and interdisciplinary team with a long history of collaboration and experience conducting exercise interventions in older adults to test the following aims: Aim 1: Using a comprehensive neuropsychological battery and the NIH Toolbox, we will test whether a 12-month moderate intensity exercise intervention improves cognitive performance in older adults and (b) test whether the improvements occur in a dose-dependent manner. Aim 2: We will test whether a 12- month PA intervention augments MRI markers of brain health and whether these changes happen in a dose- dependent manner. Aim 3: We will test the hypothesis that cardiometabolic, inflammatory, and neurotrophic changes mediate improvements in brain and cognition. Aim 4: We will examine subgroups (i.e., individual differences) that attenuate or magnify the effect of the intervention on cognitive, brain, and physiological systems to better understand the factors that predict `responders' versus `non-responders' to the intervention. We will explore three categories of variables: (1) demographic (e.g., age) (2) genetic (e.g., APOE), and (3) baseline A? burden. Exploratory Aims: We will explore (a) whether baseline brain health metrics predict adherence and compliance to 12-months of PA, and (b) the utility of multi-modal brain imaging analytical approaches to more comprehensively understand the effects of PA on the aging brain. The results from this trial could transform scientific-based policy and health care recommendations for approaches to improve cognitive function in cognitively normal older adults.

Abstract Exercise is one of the most promising methods for positively influencing neurocognitive function in late adulthood. Yet, despite this recognition, several major knowledge gaps preclude the ability to broadly prescribe exercise to prevent or treat cognitive impairment. This R35 proposal includes a series of innovative and potentially groundbreaking studies that will contribute to major advancements in the field of exercise and brain health. The studies that we describe in this proposal would be led by several highly promising junior scientists with the support of an experienced and dedicated mentorship team. The conceptual and scientific framework for the hypotheses described in this proposal orbit around three major challenges facing the field of exercise and cognitive aging: (1) We have a poor understanding of the mechanisms by which exercise influences cognitive function in late adulthood, (2) We have a poor understanding of the factors that moderate, or explain individual variation in, the response to exercise, and (3) We do not understand the factors that predict long- term adoption of exercise behavior and how to reduce barriers and enhance incentives for individuals who find it challenging to continue to exercise. Despite the clear benefits of an active lifestyle, most people fail to meet public health recommendations for exercise. The more we know about the factors that predict and enhance long-term adoption of exercise, the more we will know about whether exercise influences incidence of Alzheimer?s Disease and best practices for prescribing and maintaining exercise for the prevention and treatment of cognitive impairment. We propose to conduct secondary analysis of banked data from two rigorous and well-controlled supervised exercise randomized clinical trials (RCTs) and to conduct a 3-year follow-up of >570 participants from both of these RCTs of exercise to assess cognitive, cardiorespiratory fitness, and physical activity levels. In particular, we propose to examine whether exercise-induced changes in cardiometabolic and sleep measures mediate exercise-derived benefits to cognitive and brain outcomes. We will also target moderators of exercise including APOE genotype and racial disparities to better characterize which individual difference variables influence the magnitude of effects of exercise on brain health. Finally, we propose a discovery aim that would leverage our rich measurement of participants at the genetic, physiological, brain, cognitive, and socioemotional levels to perform predictive modeling to forecast long-term adoption of exercise (or barriers prohibiting long-term adoption). In short, this research proposal describes a broad and ambitious line of work that will produce groundbreaking and innovative studies to address significant gaps in our understanding of exercise and brain health in late adulthood. The aims target several major AD/ADRD milestones identified by NIH and will position junior scientists in leadership roles to advance the field forward in significant and pioneering ways.