Kathi L. Heffner - US grants

[unreadable] DESCRIPTION (provided by applicant): For older adults, holding negative beliefs about one's own aging can be detrimental to health and longevity. Our long term goal is to elucidate the psychophysiological mechanisms by which aging beliefs lead to health outcomes. We propose that negative aging self-perceptions will lead to older adults' repeated and heightened physiological responding to stereotypically age-related hassles. Such heightened stress responses will in turn contribute to the dysregulation of physiological systems, setting the stage for illness and disease. On the contrary, more positive aging perceptions may weaken the impact of negative aging stereotypes, improving individuals' coping with age-stereotype relevant stress, and thus, benefiting health. This R03 application is a reframing of an initial R21 proposal: Reviewers' feedback suggested seeking a funding mechanism better suited for research constituting, not the exploration of a new area, but rather, extending systematically the understanding of the role of aging beliefs and stereotypes in health outcomes. The specific aim of the proposed research is to examine how older adults' current beliefs about their own aging and exposure to aging stereotypes impact markers of autonomic (cardiovascular), endocrine (cortisol) and immune (IL-6) reactivity. Older adults will be exposed to negative, stereotype confirming or positive, stereotype disconfirming information about aging and memory, or age-irrelevant information, prior to performing a challenging memory task. Cardiovascular, cortisol and IL-6 measures will be assessed prior to, during, and following the memory challenge. We hypothesize that among adults 50 and older, positive beliefs about their own aging will buffer the effects of negative aging stereotype exposure on physiological responses to the memory challenge. This pilot work incorporates social psychological theory with psychophysiological models that implicate multiple physiological systems in mind-body pathways linking stress to health. Identifying autonomic, endocrine and immune correlates of individual and social representations of aging will extend previous findings in the study of aging beliefs and health. This pilot research will lay the foundation for programmatic research aimed at delineating mechanisms linking aging beliefs and stereotypes to health in order to develop cost-effective interventions designed to reduce the burden of these factors on older adults' health. This project is a first step toward understanding the physiological pathways that link negative aging beliefs and stereotypes to older adults' negative health outcomes. It seeks to identify the physiological consequences of exposure to negative aging stereotypes, whether personal negative beliefs about aging increase the physiological impact of these stereotypes, and, importantly, whether positive aging beliefs can reduce the impact of negative aging stereotypes. Understanding how aging beliefs and stereotypes interact to impact physiological well-being can contribute to the development of interventions aimed at reducing older adults' health care costs. [unreadable] [unreadable] [unreadable] [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Posttraumatic Stress Disorder (PTSD), which occurs in at least 15-20% of individuals exposed to a traumatic event, is a chronic condition associated with the development of a multitude of negative physical and mental health consequences and the co-occurrence of Major Depressive Disorder (MDD). Sleep disturbances, and especially nightmares and insomnia, are quite common in patients with PTSD, but the standard treatments for PTSD do not directly focus on sleep problems. Perhaps as a result, sleep disturbances are one of the most common residual symptoms following both PTSD treatments and depression treatments. Importantly, insomnia, depression and PTSD are each characterized by similar biological dysregulation, including alterations in important aspects of sleep (rapid eye movement sleep and slow wave sleep) as well as processes linked to health and disease (stress system responses and inflammatory processes). Directly treating sleep in the context of PTSD and MDD is feasible and can lead to robust improvements in sleep, though whether improving sleep can enhance PTSD and MDD outcomes remains to be established. This study will enroll and randomize 150 participants with PTSD, MDD and insomnia. Following baseline assessments (T1) participants will be randomized to receive cognitive-behavioral therapy for insomnia (CBTi), a well-supported and highly effective insomnia treatment, or to a monitor only control condition. Following this first intervention period all participants will receive cognitive processing therapy a trauma-focused therapy with known effects on PTSD and depression. The study will test whether and how CBTi may (1) achieve improvements in PTSD and MDD symptom severity and (2) lead to enhanced response to subsequent treatment with cognitive processing therapy. Intervening with CBTi prior to a PTSD-specific treatment and measuring biomarkers longitudinally, will allow for the testing of specific effects of sleep improvement on PTSD, depressive symptoms, objective aspects sleep and stress and inflammatory markers, thereby advancing basic understanding of biobehavioral mechanisms in PTSD and depression. Importantly, the proposed approach utilizes a treatment sequence that may appeal to trauma survivors with post-traumatic event symptoms who may be resistant to or unprepared to fully engage in standard PTSD treatments. Confirmation of the study hypotheses could support immediate translation of the findings to clinical practice. PUBLIC HEALTH RELEVANCE: Post-traumatic stress disorder (PTSD) and co-occurring depression are associated with considerable distress, health disparities, and increased health care utilization. To the extent that addressing sleep disturbance with a targeted intervention prior to a PTSD-specific intervention produces improvements in PTSD and depression symptoms and/or remission rates compared to PTSD treatment alone, this will provide an important complement to existing PTSD treatments. Further, since the health disparities observed in PTSD and depression are believed to be partially mediated by endocrine and inflammatory dysregulation, if these pathways are altered by improving sleep, this may ultimately have long term health benefits in PTSD populations.

DESCRIPTION (provided by applicant): Osteoarthritis (OA), also known as degenerative joint disease, represents the most common form of joint disorder in the United States and is a large contributor to functional impairment and reduced independence in older adults. For older adults with OA, and with other chronic pain conditions more generally, sleep disturbance is a significant complaint, reducing quality of life and increasing functional disability. Although pain can contribute to disrupted sleep, sleep disturbance can likewise augment pain perception. Our long-term objective is to identify psycho-neurobiological mechanisms contributing to bi-directional associations between chronic pain and sleep disturbance. Recent psychoneuroimmunological models of pain and of sleep, and our own preliminary work, strongly suggest that stress-associated inflammatory processes provoked by pain may serve a critical role in bi-directional associations between persistent pains and sleep disturbance. Further, deep, non rapid eye movement sleep, known as slow wave sleep (SWS), may play a specific role in links between poor sleep, inflammation and pain. We propose that sleep disturbance, especially SWS, exacerbate inflammatory responses to acute pain, diminish pain thresholds, and, thus, contribute to an enduring cycle of chronic pain and disability. To generate proof of concept for this model, we propose a study aimed at examining the effects of manipulating sleep on inflammatory and pain processes in older adults with knee OA pain and insomnia. The specific aim of this R21 application is to examine whether sleep improvement, via a cognitive behavioral intervention for insomnia, and SWS improvement in particular, is associated with inflammatory cytokine levels and pain thresholds in response to acute laboratory pain, and clinical OA pain. The proposed study tests a novel and innovative hypothesis that chronic sleep disturbance serves as a pain augmenter in individuals with chronic OA pain through its impact on enhancement of stress-related inflammatory responses. By comparing inflammatory responses to acute pain before and after treatment for insomnia, the proposed study will test the notion that reversal of poor sleep, especially SWS, can attenuate inflammatory responses in individuals with chronic pain. The growing population of adults 50 years of age and older, the high prevalence of OA among older adults, the economic burden of OA and chronic pain, and the pernicious impact of pain conditions on older adults' well-being require that new approaches to managing chronic pain are developed. Support for the hypothesized pathway will extend the separate sleep and pain literatures and support a shift toward more explicit elaboration of neuroinflammatory connections between sleep and pain. This elaboration has strong potential to contribute to pain treatment development and clinical pain practices by highlighting sleep and associated inflammatory processes as primary therapeutic targets, especially in older adults with OA.

Exposure to chronic stressors ? that is, demanding life situations that persist for long periods of time ?accelerates the aging of the immune system. Termed immunosenescence, this immune aging is marked by increasingly altered T cell numbers and activity and elevated markers of inflammation. Our long-term objective is to identify appropriate therapeutic targets for older adults to reduce the psycho-immunological burden of chronic stress. Recent models of stress adaptation and neurobiological regulation suggest that similar neural structures and networks support cognition, the autonomic nervous system (ANS) and emotion regulation, each of which are important for physiological and emotional adaptation to stressors. For older adults, a combination of aging- and chronic stress-related neurological changes may compromise the regulation of these domains, thereby reducing stress adaptation capacity and increasing susceptibility to accelerated immunosenescence. Our current objective is to examine the role of cognitive function in adaptive capacity and stress-related immune alterations that signal immunosenescence. Our central hypothesis is that cognitive decline will accelerate immunosenescence in older adults exposed to chronic stressors, insofar as such decline reflects an overall reduction in adaptive capacity ? that is, the capacity to respond flexibly and adaptively to environmental challenges. We propose to test this hypothesis in older caregivers of a family member with Alzheimer?s Disease (AD) or AD-related dementia (ADRD), a population at high risk for stress-associated immune aging. We aim to directly probe the role of cognitive contributions to adaptive capacity and immunosenescence by using a cognitive training program shown previously to improve so-called fluid cognitive abilities, particular processing speed and attention, in healthy older adults. Importantly, this training also led to better emotional well-being in older adults. A longitudinal design will afford repeated assessments of fluid cognitive abilities, ANS responses and emotion regulation, general emotional well-being and immune markers (inflammatory cytokines and T-cell markers), and analyses of mediational effects. Specifically, AD/ADRD family caregivers will be randomly assigned to engage in home-based, computerized cognitive training, or to a no-training control group. We will then examine the ensuing cognitive, psychophysiological, emotional and immunological changes that occur over a 12-month period. Our aims are to: (1) identify effects of cognitive training on caregivers? cognitive, autonomic and emotion markers of adaptive capacity (2) identify effects of cognitive training on caregivers? inflammatory cytokine levels and markers of T cell senescence, and (3) determine cognitive, autonomic, and emotion-related mediators of cognitive training effects on immune outcomes. The work proposed here is expected to identify mechanisms involved in older adults? poor emotional well-being and immunosenescence arising from caregiving stress. This identification will afford insight into new intervention targets, like cognitive training, to promote AD caregivers? health and well-being.

? DESCRIPTION (provided by applicant): Influenza infection results in 41,000 deaths every year in the US and is the seventh leading cause of death. Strikingly, older adults, and especially those at risk for chronic medical disorders, account for approximately 90% of these deaths. Studies comparing influenza vaccine responses of older adults with those of young adults show that immune responses are significantly decreased in older adults. It is estimated that influenza vaccine efficacy is approximately 30-50% in older adults, compared to 70-90% in young-middle aged adults. Compounding this age-related decline in response to vaccination are findings that depression and chronic stress further impair older adults' immune responses to influenza vaccination. Caregiving for a family member with dementia is a robust stressor, and is associated with poor responses to influenza vaccination in older adults, as well as increased levels of proinflammatory biomarkers, which mediate many of the chronic diseases of aging. In this proposal, we consider the immunological consequences of the significant psychological distress experienced by older adult caregivers of family members with dementia. A wide variety of psychosocial interventions can lessen the psychological burden of family or spousal dementia caregiving; Mindfulness Based Stress Reduction (MBSR) in particular has psychological benefit for caregivers, yet its biological effects for these burdened caregivers remain unknown. Here we propose a randomized controlled trial (RCT) of MBSR for older adult caregivers of family dementia patients. Notably, no RCT to-date has done all of what we propose to do: focus on older adult family dementia caregivers who experience significant psychological distress; have as the primary outcome measure adaptive humoral and cellular immune response to influenza vaccine; include surveillance for influenza-like disease during flu season; include evaluation of proinflammatory biomarkers associated with morbidity and mortality in older adults; consider changes in mindfulness and stress as mediators of MBSR's effects on immune function; and include a long-term follow-up of MBSR practice activities. Our aims are to: Aim 1. Identify the effects of MBSR training and practice on adaptive immune responses to influenza vaccination as well as outcomes following influenza infection in stressed older adult family dementia caregivers. Aim 2. Identify the effects of MBSR training and practice on circulating levels of the proinflammatory biomarkers IL-6, tumor necrosis factor (TNF)-?, IL-17 and the acute phase reactant C-reactive protein (CRP), which are elevated in older adults and associated with many chronic diseases of aging. Exploratory Aim 3. Examine relationships among improved adaptive immunity, inflammation and flu outcomes following naturally-acquired influenza infection using a full mediation model. Overall, this research will illuminate whether MBSR can slow the age-related changes in immunity known as immunosenescence, which is accelerated by chronic stress.

Abstract The Management and Administrative Core will provide overall scientific leadership for the Rochester Roybal Center for Social Ties & Aging Research (STAR Center). It will provide overall administration and coordination of all STAR Center activities, and will orchestrate communication among STAR Center stakeholders (including STAR Center faculty, the Advisory Committee, the Roybal Coordinating Center, NIA program staff, and UR institutional leadership). The primary goal of the Management and Administrative Core is to provide a solid, highly connected infrastructure that affords optimal social connectedness intervention development across the NIH Stage Model, with a particular focus on family caregivers of a family member with Alzheimer?s? disease or related dementia (ADRD). With vision- and value-driven leadership, outstanding scientific and community expertise, Stage- model guided research planning, and seamless coordination of pilot study resources, the Core will serve as the vehicle through which the STAR Center can achieve its mission to impact social connectedness in innovative ways that ensure social vitality and healthy aging in those who provide care for a family member with ADRD. The Core will be responsible for: (1) setting policies and procedures for the STAR Center that support its strategic vision and mission to support social vitality and healthy aging in later life; (2) managing a quarterly- convened Advisory Committee that oversees and monitors Center activities, and conducts strategic planning sessions that inform Center decision-making and assists the Directors in setting policies and scientific direction; (3) establishing a monthly-convened Steering Committee to implement and monitor the Pilot Award Program, determining scientific priorities and resource allocation, as well as approval submissions to NIA; (4) establishing the Pilot Core and administering its centralized resources to support pilot studies, including the Scientific Outreach, Recruitment & Study Coordination, and Data Analyses sub-cores; (5) organizing and coordinating key Center committees, and coordinating travel to the annual NIA Roybal Center meeting; (6) transparent financial management; (7) ensuring regulatory compliance and annual reporting to NIA; (8) promoting internal and external research partnerships that result in new multidisciplinary collaborations that accelerate social connectedness intervention research through Stages 0-IV; (9) maintaining open lines of communication between Center members, other stakeholders, and Center leadership; (10) verse conduct of programmatic evaluation that results in effective decision-making and leads to continued improvement and high impact outcomes.

Abstract Our recently completed R01 suggested that processing speed and attention (PS/A) oriented cognitive training (VSOP) produced robust effect on PS/A and working memory, but not in cognitive control or episodic memory, and long-term effects were overall modest. In the proposed R01 renewal, we propose to identify additional attributes to further enhance transferred and long-term effects of PS/A training in older adults with amnestic mild cognitive impairment (MCI) by addressing adaptation capacity that underpins adaptive learning and neuroplasticity. The goal of the stage II double-blinded randomized trial is to test whether adding resonance frequency breathing (RFB) training to VSOP will strengthen multiple contributors to adaptation capacity, particularly the central and peripheral pathways of autonomic nervous system (ANS) flexibility, which will strengthen VSOP training effect on cognitive and brain function and slow the progress of dementia in MCI. Our central hypothesis is that strengthening adaptation capacity, via improving autonomic nervous system (ANS) flexibility, will enhance neuroplasticity and slow progress of dementia in MCI, since adaptation capacity is critical for neuroplasticity of VSOP, but compromised in neurodegenerative process. Older adults with MCI (n = 114) will be randomly assigned to an 8-week combined intervention (RFB+VSOP), VSOP with guided imagery relaxation (IR) control, and a waitlist IR control, with periodical booster training sessions at follow-ups. Mechanistic and distal outcomes include ANS flexibility and multiple markers of dementia progress. Data will be collected across a 14-month period. The two primary aims are to examine long-term effects of the combined intervention on ANS flexibility (Aim 1), as well as the cognitive, behavioral, and functional capacity (Aim 2). The exploratory aim will be to determine the preliminary long-term effect of the combined intervention on neurodegeneration. We consider this a reasonable renewal plan from our completed R01, aiming to identify additional attributes to further enhance transferred and long-term effects of cognitive training in MCI. This will be among the first RCTs to examine a novel, combined intervention targeting adaptation capacity in MCI, with an ultimate goal for slowing neurodegeneration. The proposed work is aligned with NINR strategic plan to advance nursing science, eps. symptoms management (in this case, improving cognitive and functional symptoms in MCI) using a non-pharmacological intervention approach and understanding relevant mechanisms.