Patricia A. Boyle, Ph.D. - US grants

Alzheimer's disease (AD) is associated with significant cognitive and neuropsychiatric disturbance and is a leading cause of disability in the elderly. Much of the disability associated with AD is a result of impairments in activities of daily living (ADLs). ADL impairments compromise the ability to live independently, result in a markedly diminished quality of life for AD patients and their caregivers, and contribute to increased health care utilization. Despite the awareness of the disability associated with ADL impairment in AD, the determinants of functional impairment in AD remain unclear. The proposed study will examine the role of specific cognitive and neuropsychiatric factors in determining performance of ADL's in patients with AD as compared to healthy elderly controls. Participants will include 40 patients with AD and 40 healthy elderly controls. Relationships between specific aspects of cognition, neuropsychiatric symptoms, and ADLs will be examined using multiple regression analyses. The results of the current project are expected to contribute to the knowledge of the factors associated with disability in AD. These data will be used as pilot data for a planned R01 involving a longitudinal investigation of the relationship between cognition, neuropsychiatric status, and functional impairment in patients with AD. These data will be also be used in future research studies of the effectiveness of specific behavioral interventions for treating neuropsychiatric disturbance in patients with AD.

behavior therapy; human therapy evaluation; behavior disorders; psychological adaptation; behavioral medicine; Alzheimer's disease; caregivers; mental health education; psychological stressor; medical complication; home health care; behavior modification; psychotherapy; behavioral /social science research tag; human subject; clinical research;

DESCRIPTION (provided by applicant): This is an application for a Mentored, Patient-Oriented Research Career Development Award (K23) entitled, "Effects of Vascular Disease in Mild Cognitive Impairment." The aim of this study is to examine the effects of vascular factors in Mild Cognitive Impairment (MCI). Although MCI is associated with an increased risk of dementia, MCI is a heterogeneous condition with multiple etiologies, presentations, and outcomes. Vascular disease may be an under-recognized determinant of MCI and may account for some of the heterogeneity among individuals with MCI. Vascular risk factors and related white matter hyperintensities (WMH) confer an increased risk of MCI, and the term 'vascular MCI' has been proposed to refer to patients with cognitive impairment of presumed vascular origin. However, few studies have investigated the role of vascular disease in MCI and the cognitive profiles and long-term outcomes of vascular-related MCI remain unknown. The proposed study was designed to investigate longitudinal relationships between midlife vascular risk, later-life WMH, and cognition among individuals with MCI. Primary aims are: 1) to determine the extent to which midlife vascular risk predicts later-life WMH, and 2) to determine the extent to which WMH predict cognitive declines over 2 years among individuals with MCI. Participants will include 120 individuals from the Framingham Heart Study (FHS), a population based study of risk factors for heart disease, stroke, and dementia. The FHS has been in existence since 1948 and provides a well-characterized population in which to examine the role of vascular factors in MCI. Vascular causes of cognitive impairment likely are more preventable and treatable than are other causes of cognitive impairment in aging, and an improved understanding of the role of vascular disease in MCI may inform interventions to reduce age-related cognitive impairment and dementia. The candidate, Patricia Boyle, Ph.D., completed a NIA-sponsored Postdoctoral Individual National Research Service Award and is an Assistant Professor in the Department of Neurology at the Boston University School of Medicine. The integrated research and training program described in this application extends her prior work and involves new training in: 1) the neurobiology of aging, 2) vascular and genetic risk assessment, and 3) quantitative neuroimaging techniques. Training will involve intensive instruction with mentors, didactic coursework and seminars, and collaborations with senior FHS investigators. The knowledge and skills gained via the proposed multidisciplinary training will facilitate Dr. Boyle's rapid development into an independent investigator in patient-oriented, aging research. Findings from the proposed study will provide the foundation for a program of research investigating the predictors of age-related cognitive decline and will be used as pilot data in future grant applications to be submitted prior to the completion of this award.

? DESCRIPTION (provided by applicant): Prevention of cognitive decline in old age ranks among the most important public health challenges. Identification of healthy cognitive aging has long been considered an essential step. However, despite decades of research, the profile of healthy cognitive aging remains unknown because pathologic processes that impair cognition often are present but not accounted for in studies of healthy cognitive aging. Most of the available studies have examined cognitive change in persons without dementia. However, many persons without cognitive impairment who come to autopsy have extensive neuropathologic evidence of common diseases known to cause cognitive impairment in old age (i.e., AD, CVD, and LBD). Moreover, recent data suggest that additional neuropathologies also are common in persons without dementia (e.g., TDP-43, hippocampal sclerosis, white matter disease). Further, most older persons exhibit a precipitous decline in cognition in the years just prior to death (i.e, terminal decline). Terminal decline represents a separate pathologic process that has not been accounted for in studies of healty cognitive aging. We propose a novel conceptualization of healthy cognitive aging as the cognitive change not accounted for by pathologic processes known to impair cognition in old age (i.e., neuropathologies and terminal cognitive decline). The overall goal of the proposed continuation is to identify the profile of healthy cognitive aging and distinguish it from pathologic and terminal cognitive decline. Our research capitalizes on data from two ongoing studies of aging, the Religious Orders Study and the Memory and Aging Project, that collect the unique longitudinal cognitive and detailed post-mortem data required to identify healthy cognitive aging. We will first quantify the cognitive change due to neuropathologic and terminal cognitive decline (i.e., pathologic cognitive aging). Then, we will identify healthy cognitive aging (i.e., the residual cognitive change). Toward this end, the proposed study will employ a multimodal approach to quantify several new pathologic indices (i.e., neuropathologic indices of TDP- 43, hippocampal sclerosis, white matter disease, and multiple indices of brain integrity derived from neuroimaging) and use innovative analyses to examine their contribution to cognitive trajectories, above and beyond AD, CVD, and LBD. The proposed study offers a rare opportunity to identify the profile of healthy cognitive aging and distinguish it from neuropathologic and terminal cognitive decline. We are not aware of other studies that quantify essentially all of the pathologic processes known to impair cognition in old age as will be done here and in which similar analyses could be performed. The proposed study offers an innovative approach to address a fundamental and longstanding challenge in cognitive aging research. Knowledge of the trajectory of healthy cognitive aging is essential for the early identification of persons who will benefit most from effective intervention and, ultimately, for th prevention of cognitive decline in old age.

DESCRIPTION (provided by applicant): The overall goal of the proposed epidemiologic study is to examine the causes and consequences of impaired decision-making in old age. Decision-making refers to the ability to generate and process multiple competing alternatives and choose a favorable behavior. Virtually all behaviors result from some decision-making process, and efficient decision-making is thought to be critical for maintaining independence, health and well-being in modern society. Emerging data suggest that older persons, even some without dementia, exhibit impaired decision-making, and impaired decision-making may be a sign of preclinical Alzheimer's disease (AD). However, surprisingly few studies have rigorously examined decision-making in older persons and longitudinal data are sorely lacking. The proposed study will quantify the rate of change in financial, healthcare, and socioemotional decision-making in a large cohort of community-based older persons without dementia and test the hypothesis that impaired decision-making is associated with adverse health outcomes (i.e., decreased well-being, disability, nursinghome placement, dementia, and death). Further, we will examine the role of affective and contextual factors in decision-making and test the hypothesis that select affective and contextual factors can sustain decision-making even in the face of cognitive decline. Finally, in an effort to understand the neurobiologic basis of impaired decision-making, we will test the hypothesis that AD pathology contributes to impaired decision-making in older persons without dementia who come to autopsy. The proposed study will capitalize on the unique infrastructure provided by the Rush Memory and Aging Project (R01AG17917), a large ongoing epidemiologic clinical-pathologic study of aging and AD, and will quantify decision-making and new pathologic indices in more than 800 community-based participants without dementia;all have agreed to detailed annual clinical evaluations including cognitive assessments and brain donation. By linking the newly collected data on decision-making and AD pathology in brain regions that subserve decision-making with the available data from the Memory and Aging Project, we will have an unprecedented opportunity to examine the causes and consequences of impaired decision-making in old age. Knowledge of the causes and consequences of impaired decision-making is essential for the development of effective interventions to promote independence, health, and well-being in old age. PUBLIC HEALTH RELEVANCE: The proposed study has the potential to generate new knowledge with important public health implications. Older persons are faced with a host of decisions that are critical for maintaining independence, health and well-being in modern society, and finding that a sizeable number of older persons without dementia exhibit impaired decision-making would suggest an immediate need for interventions and public policy efforts to promote efficient decision-making in aging. Further, knowledge of the causes and consequences of impaired decision-making is essential for the development of such interventions and, to the extent that AD pathology underlies impaired decision-making, may suggest that a much larger group of persons including those without overt dementia ultimately may benefit from effective treatment and prevention strategies developed for AD.

? DESCRIPTION (provided by applicant): Many of life's most complex and influential decisions are made in old age, paradoxically just as neuropathology accumulates and cognitive function declines. Despite increased recognition that poor decision making in old age poses a critical public health and economic challenge, decision making has received surprisingly little scientific focus in aging research. In the first funding period, we assessed decision making in >800 older persons without dementia from the Memory and Aging Project, an ongoing longitudinal clinical-pathologic study of aging. We reported that decision making requires diverse resources (i.e., cognitive, affective, and contextual), and that many older persons without dementia exhibit poor decision making in domains critical for independence and well being (e.g., financial, healthcare). Poor decision making also is associated with a substantially increased risk of Alzheimer's disease (AD) and mild cognitive impairment, suggesting that it may be an early manifestation of preclinical dementia. The overall goal of the proposed continuation (R01AG33678) is to examine the causes and consequences of age-related changes in decision making over time. We will quantify changes in decision making over many years in a large cohort of older persons without dementia and document the association of change in decision making with critical health and psychological outcomes. Next, based on compelling preliminary data showing that the neuropathologies of AD and cerebrovascular disease (CVD) are associated with decision making, we will test the hypothesis that common neuropathologies contribute to age-related changes in decision making. Further, based on research demonstrating the important role of aminergic systems as modulators of decision making, we will test the hypothesis that aminergic systems help preserve decision making in the face of neuropathology. Finally, we will examine how contextual and other behavioral factors interact with neurobiologic indices to influence decision making. The proposed study offers a unique opportunity to integrate up to 12 years of annual decision making and clinical data with neurobiologic indices of the most common neuropathologies known to impair function in old age (i.e., AD, CVD, Lewy body pathology) and aminergic systems (i.e., dopamine, norepinephrine) in order to identify the neurobiologic basis and consequences of age-related changes in decision making. We are not aware of other studies in which similar analyses could be performed. This study is uniquely poised to inform on the consequences and causes of age-related changes in decision making and will facilitate new therapeutic approaches to promote independence, health and well-being in old age.

ABSTRACT ? RESEARCH EDUCATION COMPONENT The overall goal of the Research Education Component (REC) is to increase the number of high quality investigators engaged in transformative interdisciplinary aging research. Recent advances, particularly the application of high throughput biochemical and molecular techniques and novel approaches to integrate multilevel and multiethnic data, offer an unprecedented opportunity for scientific progress but also pose unique challenges for investigators engaged in aging research. Optimization of emerging methodologies in high impact research requires talented scientists capable of sharing knowledge and methodologies across disciplines. Truly interdisciplinary research can be difficult to accomplish, however. Barriers include limited shared knowledge among investigators from diverse disciplines and changing dynamics in the field; junior investigators increasingly hold expertise in emerging methodologies but often lack a full appreciation of their potential to address critical gaps in knowledge, and senior investigators with a deep understanding of these gaps are often unfamiliar with emerging methodologies. New integrative and multidirectional learning opportunities (i.e., learning flows from investigators of all levels across disciplines and institutions) are needed to facilitate efficient knowledge transfer and productive partnership among diverse investigators. The REC will capitalize on a highly multidisciplinary faculty and implement an integrative and multidirectional approach to facilitate truly interdisciplinary aging research with a focus on emerging methodologies and high priority areas such as health disparities. Toward this end, the REC will provide cross-disciplinary training in key disciplines relevant to aging and link this to new training in emerging methodologies and health disparities research using the highly unique clinical, biologic and biospecimen data generated at Rush. The REC will work with all other Rush ADCC Cores to implement and oversee a variety of educational activities, including 1) a monthly Neuroepidemiology of Aging Seminar; 2) intensive mini-internship training in emerging methodologies and health disparities, 3) participation in the Rush Alzheimer?s Disease Center annual Aging Research Forum, 4) use of a novel platform, Synergy Landscapes, to facilitate interdisciplinary collaborations, and 5) individualized mentoring. Through careful integration with the other Rush ADCC Cores, the REC will develop skilled interdisciplinary investigators capable of leveraging contemporary approaches in high impact aging and Alzheimer?s disease research.

ABSTRACT Sound decision making is important for maintaining independence and well-being across the lifespan but is critical in old age, when some of life?s most complex and impactful decisions are made. Recent work from our group and others has shown that decision making requires cognitive, contextual and psychosocial resources and that many older persons?even those without cognitive impairment?are vulnerable to poor decision making in key domains such as finance and health and frequently become victims of fraud. Poor decision making in aging predicts several adverse health outcomes including Alzheimer?s disease, incident mild cognitive impairment and mortality and poses a major public health and economic challenge. Importantly, however, most of the research on decision making to date has involved White participants. Relatively little is known about decision making among African Americans, despite well documented racial differences in the cognitive, contextual (e.g., socioeconomic status) and psychosocial (e.g., psychological distress) resources that influence decision making. Building on our conceptual model of decision making in aging and compelling preliminary data that suggest racial differences, we hypothesize that racial differences in decision making contribute to disparities in health outcomes and that contextual and psychosocial factors account for these differences. The goal of the proposed study, submitted in response to PAR-16-448, is to elucidate the determinants and adverse health consequences of racial differences in decision making. This study will leverage the unique resources of an ongoing study of African Americans, the Minority Aging Research Study, to collect new longitudinal data on multiple aspects of decision making (i.e., financial and health decision making, temporal discounting, scam susceptibility, fraud victimization) and related contextual and psychosocial factors in 600 older African Americans without dementia. These newly collected data will be linked with identical longitudinal decision making data already available from an ongoing study of more than 1,100 Whites from the Memory and Aging Project to support analyses of: 1) racial differences in decision making among African Americans and Whites matched on demographics and cognition, 2) the contextual and psychosocial factors that drive them, and 3) the degree to which racial differences in decision making contribute to disparities in health. Thus, this study is uniquely poised to efficiently identify the determinants and public health impact of racial differences in decision making and will facilitate new therapeutic approaches to promote independence, health and well-being among diverse older persons.

ABSTRACT ? RESEARCH EDUCATION COMPONENT The overall goal of the Research Education Component (REC) is to develop high quality investigators engaged in transformative interdisciplinary research on the etiology, pathogenesis, diagnosis, treatment, and prevention of Alzheimer?s dementia and related dementias (AD/ADRD). Recent advances, particularly the application of high throughput biochemical and molecular techniques and novel approaches to integrate multilevel and multiethnic data, offer an unprecedented opportunity for scientific progress but also pose unique challenges for investigators engaged in aging research. Optimization of emerging methodologies in high impact research requires talented scientists capable of sharing knowledge and methodologies across disciplines. Truly interdisciplinary research can be difficult to accomplish, however. Barriers include limited shared knowledge among investigators from diverse disciplines and changing dynamics in the field; junior investigators increasingly hold expertise in emerging methodologies but may lack a full appreciation of their potential to address critical gaps in knowledge, and senior investigators with a deep understanding of these gaps may be unfamiliar with emerging methodologies. New integrative and multidirectional learning opportunities (i.e., learning flows from investigators of all levels across disciplines and institutions) are needed to facilitate efficient knowledge transfer and productive partnership among diverse investigators. The REC will capitalize on a highly multidisciplinary faculty and implement an integrative and multidirectional approach to facilitate truly interdisciplinary aging research with a focus on emerging methodologies and high priority areas such as health disparities. Toward this end, the REC will provide cross-disciplinary training in key disciplines relevant to aging and link this to new training in emerging methodologies and health disparities research using the highly unique clinical, biologic and biospecimen data generated at Rush. The REC will work with all other Rush ADRC Cores to implement and oversee a variety of educational activities, including 1) a monthly Neuroepidemiology of Aging Seminar; 2) intensive mini-internship training in emerging methodologies and health disparities, 3) individualized mentoring, and 4) participation in the RADC annual Aging Research Forum. Via careful integration with the other Rush ADRC Cores, the REC will develop highly skilled interdisciplinary investigators capable of leveraging contemporary approaches in high impact and innovative AD/ADRD research.