Mind Body & Health
COGNITIVE FUNCTIONING AFTER BREAST CANCER TREATMENT
PI: Patricia Ganz, MD; Julienne Bower, PhD, Co-I
Cognitive complaints have been anecdotally reported among women receiving adjuvant chemotherapy for breast cancer, and recently this has been subjected to more rigorous study. Cerebral functioning can be assessed by self-report, standardized neuropsychological testing, and through examination of brain metabolism (all of which have been studied in our laboratory). The literature suggests a relationship between chemotherapy exposure and poorer performance on neurocognitive testing; however, patients with cognitive complaints do not necessarily test poorly and their complaints are often associated with symptoms of depression and anxiety. Preliminary work in our laboratory suggests that hormonal changes associated with menopause and adjuvant endocrine therapy for breast cancer also influence the effects of chemotherapy on cognitive functioning. Little is known about the potential mechanisms by which adjuvant endocrine therapy influences cerebral functioning after breast cancer treatment, and in this study we will address this question by studying women who have recently completed their primary breast cancer treatments (surgery, radiation, chemotherapy) and who are about to initiate adjuvant endocrine therapy (with tamoxifen or aromatase inhibitors). We will examine the potential mechanisms by which endocrine therapy affects cerebral functioning, by consideration of a comprehensive framework that includes the role of constitutional symptoms (fatigue, depression, anxiety), and immune alterations, in addition to specific cancer treatments (chemotherapy, hormonal treatments), and endogenous endocrine exposures (estrogen, cortisol). In this longitudinal, observational cohort study, we propose the following specific aims: 1)To evaluate the effects of adjuvant endocrine therapy on cognitive functioning through standardized questionnaires and neuropsychological assessments in 260 breast cancer patients at the end of primary treatment (baseline) when endocrine treatment is initiated, and one year later (follow-up). 2)To examine the association between cognitive functioning and measures of cerebral metabolism by obtaining positron emission tomography (PET) brain imaging, at rest and with a memory challenge, in close temporal proximity to the baseline assessment of cognitive functioning in a subset of 60 women, with a follow-up assessment one year later. 3)To explore the biopsychosocial mechanisms by which adjuvant endocrine therapy influences cerebral functioning by examining changes in cognitive functioning and brain metabolism, and their relationship to immune and endocrine function, mood and symptoms between the baseline and follow-up assessment one year later. Lay summary: Breast cancer is the most common cancer in women. After treatments for breast cancer, some women complain of difficulty in concentrating and thinking. This study will examine the effects of breast cancer treatments on cognitive, psychological, immune and endocrine function to try to understand the biological mechanisms of these complaints so that they may be better prevented or treated in the future.
BIOBEHAVIORAL INFLUENCES AND THE OVARIAN TUMOR MICROENVIRONMENT
PI: Susan Lutgendorf, PhD, Iowa PI / George Slavich, PhD, UCLA PI
Ovarian cancer is the second most common gynecologic cancer. Because of low rates of survival for the majority of ovarian cancer patients, identification of factors contributing to tumor progression is of paramount importance. Epidemiologic studies have suggested an association between biobehavioral factors such as life stress, depression, and social support and cancer progression. This study examines a novel pathway that may underlie these links in ovarian cancer, specifically, the relationship of biobehavioral factors with resident macrophages within the tumor microenvironment. It is now acknowledged that the tumor microenvironment is critical in supporting or inhibiting tumor progression. We have previously reported associations of depression and low social support with a poorer cellular immune response in ovarian cancer patients in the tumor microenvironment. We have also demonstrated direct links between biobehavioral factors and cytokines supporting angiogenesis, the formation of new blood vessels that enhance tumor growth and progression. Macrophages are major components of the tumor microenvironment where they are predominantly converted from an anti-tumor phenotype to a pro-tumor phenotype and play a key role in supporting inflammation and tumor progression. However, little is known regarding whether biobehavioral factors influence tumor associated macrophages (TAM) and interactions between TAM and tumor cells in a way that favors tumor growth. Based on compelling preliminary data, we propose that biobehavioral influences on both TAM and tumor cells in the tumor microenvironment have significant effects on production of factors supporting tumor growth and progression. We focus on TAM because of their key role in the tumor microenvironment, and because of indications of macrophage sensitivity to stress factors in the cardiovascular literature and in our preliminary data. Thus, the overarching goal of this proposal is to examine pathways by which biobehavioral factors contribute to a permissive local environment for interactions between resident cells (TAM) and tumor cells that favor tumor growth in ovarian cancer. The proposed project will prospectively examine the relationship of biobehavioral factors (life stress, depression, and social support) and TAM products (inflammatory cytokines and tumor growth factors) in the tumor microenvironment in 206 ovarian cancer patients. Association of biobehavioral factors with upregulation of gene transcripts related to inflammation and proliferation in tumor cells will also be examined. Based on preliminary data we will examine the role of adrenergic signaling as a mediator in these relationships. To determine the clinical significance of these biological alterations, the investigation will assess progression-free and overall survival during the 24 months following diagnosis. Findings will have implications for innovative behavioral and pharmacological intervention strategies for ovarian cancer patients. PUBLIC HEALTH RELEVANCE: There has been very little research examining systemic effects on the tumor microenvironment. This research examines a novel pathway by which biobehavioral factors may contribute to a permissive milieu for tumor growth and disease progression in the tumor microenvironment among ovarian cancer patients. A clearer understanding of biobehavioral risk factors and pathways by which they operate is critical for identifying targets for psychosocial and pharmacological intervention for ovarian cancer patients who may be at risk.
EMOTION REGULATION AND DEPRESSION IN BREAST CANCER SURVIVORSHIP
PI: Annette L. Stanton, PhD
Both in individuals living with cancer and in the general population, the experience of clinical depression exacts a profound psychological, physical, and economic toll. Little research has examined the unfolding risk for depressive symptoms and episodes after a breast cancer diagnosis with careful assessments repeated over time. Moreover, theory and research in depression and in emotion science have not been integrated and tested in sophisticated biopsychosocial models to advance understanding of risk and protective factors/processes for depression in cancer patients. Accordingly, this study has three specific aims. Aim 1 is to investigate how personal vulnerabilities, cancer-related (e.g., treatments/side effects) and noncancer-related stressors, and emotion regulation processes shape trajectories of depression in women following diagnosis of breast cancer. Personal vulnerabilities include general depressive diatheses (history of depression, neuroticism, harsh early environment) and emotion dysregulation diatheses (low emotional awareness and acceptance, high emotional suppression, no intimate confiding relationship). Aim 2 is to examine a diathesis- stress model, in which interactions of personal vulnerabilities, genetic factors (a functional polymorphism of the serotonin transporter gene), and stressors shape depressive response. Aim 3 is to examine a proximal model of how emotion regulation processes (approach and avoidance) mediate the effects of personal vulnerabilities on depressive symptoms and episodes. We will accomplish these aims in longitudinal research beginning within three months of diagnosis (Time 1) of 450 women (study completers) with new diagnoses of initial or recurrent invasive breast cancer and subsequent assessments every six weeks through six months (Time 2-5) and at 9 months (Time 6) and 12 months (Time 7). DNA extraction, validated questionnaires and interviews, and measures of expressive behavior will be administered. Primary dependent variables are depressive symptoms and depressive disorder. Effects of age, ethnicity, and mental health treatment receipt will be explored. Findings will influence public health by informing the next generation of targeted preventive and therapeutic interventions for depression in cancer patients, thereby reducing the disorder's health and economic burden. PUBLIC HEALTH RELEVANCE: Cancer patients are more likely than the general population to evidence depressive symptoms and clinical depression, but little is known about the factors that put individuals at risk for clinical depression when they have cancer. This project will provide information about who is at risk and factors contributing to high risk for depression, when they can be identified, and ingredients of interventions that are likely to be effective in reducing depression in women diagnosed with breast cancer. This research will help to target limited mental health resources to make the largest impact in preventing and treating depression in the face of cancer.
DAILY EXPERIENCE IN ADOLESCENCE AND BIOMARKERS OF EARLY RISK FOR ADULT HEALTH
PI: Andrew Fuligni, PhD / Michael R. Irwin, MD, Co-I
Despite calls for the identification of early risk factors for the development of chronic health conditions, there has been little longitudinal research on biomarkers of health that has been conducted in persons younger than 25 years of age. In addition, there is only a minimal understanding of how biological indices of early risk for adult health develop among adolescents with Latin American and Asian backgrounds, the two fastest rising ethnic groups in theUnited States, who are at differential risk for adverse health outcomes as compared to European Americans. An understanding of these processes is necessary for the development of ethnically and culturally relevant prevention efforts. We propose a 3-wave longitudinal study of adolescents and their caregivers from Mexican, Chinese and European backgrounds in order to assess the impact of daily experience on biological indicators of early risk for adult health. Our focus on daily experience stems from the need to identify the mechanisms by which global social factors identified in demographic surveys, such as lower education and income, play themselves out in individuals' daily lives. Daily experiences such as social conflict, excessive demands, emotional distress, threat, and sleep behaviors have been shown to be linked to both global risk factors and multiple biological indices of health risk among adults. The project will include both intensive behavioral assessments and detailed biological markers of health risk from both adolescents and their parents in order to address the following specific aims: (1) describe the development during adolescence of biological indices of early risk for adult health; (2) assess the role of daily experience in the development of early health risk; (3) examine the existence of ethnic disparities in early health risk; and (4) explore the role of potential protective factors in the development of early health risk. Approximately 540 pairs of adolescents and primary caregivers (180 from each ethnic group) will be assessed when the adolescents are approximately 15-16, 17-18, and 19-20 years of age. Each year, both adolescents and caregivers will participate in interviews that include measures of global social factors such as socioeconomic background and potential protective factors such as social connectedness. Participants will report daily experiences using a nightly diary checklist for 9 consecutive days. Salivary cortisol will be obtained at 4 time points each day for 4 of these days in order to analyze HPA activity, and participants will wear wrist actigraphs for the same 4 days to measure objective sleep behaviors. Blood pressure, BMI, and waist/hip ratio will be assessed, and dried blood spots will be obtained for the assessment of c-reactive-protein (CRP), cholesterol, and high density lipoproteins (HDL). Finally, peripheral blood samples will be provided by a subsample of 120 families for the assessment of plasma interleukin-6 (IL-6), a pro-inflammatory cytokine, and for gene expression analyses of molecular signaling pathways driving inflammatory biology. PUBLIC HEALTH RELEVANCE: There is only a minimal understanding of how biological indices of early risk for adult health develop among adolescents with Latin American and Asian backgrounds, the two fastest rising ethnic groups in theUnited States, who are at differential risk for adverse health outcomes as compared to European American. More in-depth examinations of the daily lives of adolescents from these populations could identify both the sources of these disparities as well as unique risk and protective factors. An understanding of these processes is necessary for the development of ethnically and culturally relevant prevention efforts.
INFLAMMATION-INDUCED DEPRESSED MOOD: THE ROLE OF SOCIAL NEUROCOGNITIVE MECHANISMS
PI: Naomi Eisenberger, PhD
This application is submitted to the NIMH DATR Mood/Sleep Research Program A2-AID. Depressive disorders occur at a high rate in patients with inflammatory disorders, with a point prevalence of 15-29%, which is two to three times greater than that observed in the general population. Substantial evidence has shown that inflammation and increases in proinflammatory cytokine activity play a critical role in the onset and perpetuation of depression and depressive symptoms (e.g. insomnia, fatigue) in those who are co-morbid for inflammatory disorders (Miller et al., 2009). Consistent with this, experimental work has shown that an inflammatory challenge can increase depressed mood in an otherwise healthy sample (Reichenberg et al., 2001). Based on these findings, there has been a growing interest in whether inflammatory processes can contribute to depression in a causal manner and how these effects might occur. Given the observation that inflammatory processes trigger social withdrawal (Dantzer, 2001; Hart, 1988), coupled with evidence that feelings of 'social disconnection' play a critical role in the onset and perpetuation of (non-inflammatory forms of) depression (Heinrich & Gullone, 2006), it is surprising that the social psychological consequences of inflammation and their contribution to depression have not been more fully explored. Here, we suggest that inflammation may increase feelings of social disconnection and that these social psychological changes may be an important contributor to inflammation-associated depression. Indeed, preliminary data demonstrated that an experimentally-induced inflammatory challenge (endotoxin) led to increases in self-reported feelings of social disconnection (e.g., "I feel disconnected from others") in addition to increases in depressed mood (Eisenberger et al., 2009b). Aside from these findings, however, there are no studies that have explored the effect of inflammatory processes on social experience in humans. The over- arching objective of this proposal is to explore the experiential and neural correlates of inflammatory- induced changes in social experience (e.g., feelings of social disconnection), which may provide a critical missing link in understanding the relationship between inflammation and depression. Participants (n=100) will be randomly assigned to receive either endotoxin or placebo and will then be monitored for the next six hours. Blood draws to assess cytokine levels as well as self-reported feelings of social disconnection and depressed mood will be collected hourly. In addition, at the time of peak cytokine response, participants will complete a neuroimaging session to examine the effect of inflammatory challenge on neural sensitivity to social rejection and social acceptance. It is hypothesized that endotoxin will increase feelings of social disconnection over time, and that the underlying neural sensitivities that give rise to these feelings (e.g., increased neural sensitivity to social rejection; decreased neural sensitivity to social acceptance) will contribute to inflammatory-induced depressed mood. PUBLIC HEALTH RELEVANCE: Although substantial evidence has demonstrated links between inflammation and depression, the mechanisms underlying this relationship are poorly understood. Based on the observation that inflammation triggers social withdrawal, coupled with evidence that feelings of social disconnection play a critical role in depression, the proposed research will examine the social psychological consequences of inflammation and their relation to depressive symptoms for the first time. In addition, the proposed research will examine the neural correlates that underlie these social psychological changes to better understand the central mechanisms that contribute to inflammatory-induced depressive symptoms.
PRO-INFLAMMATORY CYTOKINES & NEUROBEHAVIORAL SYMPTOMS IN BREAST CANCER PATIENTS
PI: Sunita Patel, PhD / Elizabeth Breen, PhD, Co-I
Pro-inflammatory cytokines and neurobehavioral symptoms in women with breast cancer. Abstract Survivors of breast cancer report debilitating behavioral symptoms, such as fatigue and neurocognitive dysfunction, which are evident in some individuals even at pre-treatment baseline. There is sufficient evidence from varied lines of research to propose that cancer-related neurobehavioral symptoms may be driven, at least in part, by activation of the pro-inflammatory cytokine network. Concentrations of specific pro-inflammatory cytokines (IL-6, TNF) and soluble receptors in serum obtained prior to treatment in breast cancer patients are significantly higher than levels found in healthy individuals and have prognostic value; however, these pre- treatment elevations have not yet been evaluated with respect to their association with either acute or chronic behavioral symptoms. Among survivors of breast cancer, elevated levels of circulating sIL-6R and IL-1ra have emerged as prominent biomarkers of persistent fatigue in cross-sectional studies of women several years post chemotherapy. No similar work has identified biomarkers of neurocognitive dysfunction in this patient population, and it is not known if the cytokine links with fatigue, or other behavioral symptoms, exist closer to the diagnosis period or evolve over time as "late effects". In this study, we will address this knowledge gap as we will evaluate this association prior to cancer treatment, and again following treatment completion. We will compare these associations in a minimum of 137 breast cancer patients relative to two comparison groups at pre-treatment, and longitudinally evaluate only the breast cancer group after treatment. Findings are expected to increase our knowledge about the possible biomarkers associated with neurobehavioral symptoms in breast cancer patients, for the purpose of better identifying and treating those at risk for such effects. PUBLIC HEALTH RELEVANCE: Findings are expected to increase knowledge about the possible biomarkers associated with neurobehavioral symptoms in breast cancer patients, for the purpose of better identifying and treating those at risk for such effects.
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