Martin Sliwinski - US grants

Changes in intellectual functioning in the aged is a serious public health concern that has far reaching social and economic consequences. Recent research has demonstrated that cognitive changes observed in aging are caused by mental slowing. Therefore, understanding the causes of cognitive slowing in the aged is necessary for understanding changes in intellectual ability that occur with advanced age. Important long-term objectives are to elucidate the nature and mechanisms of age-related cognitive slowing; improve our ability to identify brain correlates of cognitive slowing in the aged; provide needed information for identifying risk factors predictive of pathologic cognitive slowing; and distinguish between normal age-related cognitive slowing and that caused by dementing disorders, such as Alzheimer's Disease. Specific aims are to (1) determine whether certain kinds of mental operation are more susceptible to the effects of aging than others; (2) determine whether certain types of cognitive processing are exempt from the effects of aging; (3) determine whether all aged individuals show equivalent amounts of cognitive slowing; (4) determine to what extent cognitive slowing in the aged is due to increased processing variability, by formal (mathematical) modeling of the response characteristics of individuals; (5) test the major competing models of cognitive aging, the Generalized Slowing (task-independent) and interactive (task-specific) models; and (6) provide a conceptual and analytic framework that can be used by future studies to clarify whether significant age differences reflect change in a specific cognitive function or are simply due to a global decline in information processing speed. Experimental methods that permit the measurement of the rate of executing basic mental operations will be used in a sequence of four inter-related studies. Competing models of cognitive aging and theory-based predictions will be tested using regression techniques. Data from individual subjects will be modeled and analyzed using the ex-Gaussian distribution function to distinguish the effect of aging on mental slowing from its effect on performance (intra-subject) variability in aged individuals. The findings from this investigation will advance experimental research techniques so that they can be used in clinical settings to characterize and identify changes in cognition that are indicative of age-associated pathologic conditions, such as Alzheimer's Disease. The results will provide information needed for pharmacologic testing and treatment, and to correlate with physiologic, biochemical and pathologic changes in aging.

The overall goals of the Statistical Core are to: (1) To insure quality of data and its accessibility to project investigators; (2) To insure proper analysis of data for hypothesis testing and hypothesis generation; and (3) to insure that the data collected in each project and core are optimally utilized for both project specific and cross-project analyses. Specific aims of the Statistical Core are: (1) To insure a high quality of data for each of the projects and Cores; (2) To assist investigators in the analyses of the data on both a collaborative and consultive basis; (3) To facilitate the exchange of data and ideas among projects and cores; (4) To assist investigators in framing testable hypothesis and in generating hypothesis involving data from multiple projects; (5) To assist project investigators in conducting hypothesis testing using both cross-sectional and longitudinal data whenever possible; (6) To develop 'robust' cognitive test norms that are optimal for diagnosing AD (and other dementia) and identifying memory impairment in preclinical individuals; and (7) To develop methods to distinguish neuropsychological, neurologic, and neuropathologic deficits exhibited in early AD from changes which occur normal aging.

stimulus /response

[unreadable] DESCRIPTION (provided by applicant): A large body of empirical research has established a link between excessive stress and a number of adverse health outcomes. Since the discovery of corticosteroid receptors in the rat hippocampus there has also been considerable interest in how stress affects memory, and more generally, cognition. Although a large number of studies have examined how physiological components of the stress response relate to cognition, there is surprisingly little research on how the experience of naturally occurring stress relates to cognitive impairment. Some recent evidence suggests that stress could impact not only declarative memory, but also working memory and executive function, and that these effects may be amplified in older compared to younger adults. Our overall goal is to examine the relationship between naturally occurring stress, cortisol, and specific aspects of working memory function. We propose two studies to accomplish goal. The first study is a cross-sectional multivariate experiment focused on between-person relationships between stress and cognition and the second is longitudinal measurement-burst design that will examine the temporal dynamics of the within-person relationship between stress and cognition across a wide range of time intervals (days to months). Our research has the following Specific Aims: (1): To examine whether that stress affects cognition by depleting attentional resources; (2): To examine which aspect of the stress response predicts cognitive performance by using multiple approaches to measuring stress (i.e., life events, daily stress, subjective severity) and its psychological and physiological effects; (3): To examine the hypothesis that aging amplifies the effect of stress on cognition; and (4) To examine whether stress and cognition are coupled within individuals. This will involve testing hypotheses that the above aim at both the between- person level and the within-person level of analysis, by examining the within-person coupling of stress and cognition over a broad sampling of time intervals, ranging from days to months to years. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Decades of research have linked stress to adverse physical and emotional health outcomes in aging adults. More recently, studies have identified stress-related variables as important predictors of cognitive aging. However, there is considerable variability in the negative effects of stress, both within and across individuals. Characteristics of different stressors contribute to this variation, but individuals exposed to the same or similar stressors still exhibit substantial differences in their responses. Understanding the mechanisms that can account for this variability represents a critical challenge for explaining how stress affects cognitive health as well as many other aging-related physical and emotional health outcomes. A person's tendencies to recurrently think about and mentally 'relive' problematic situations and events can amplify and extend emotional and physiological responses, even after cessation of the eliciting stressor. We hypothesize that such unconstructive repetitive thought (URT), which encompasses concepts such as worry and rumination, operates as a final psychological pathway by which stressors exert their harmful effects on cognitive health. We propose to test this hypothesis by conducting a longitudinal investigation of URT as a potential mediator of the effects of stress (current and cumulative) on cognitive function. Because early indicators of cognitive aging manifest long before old age, the proposed sample will consist of 320 racially diverse individuals in early adulthood and midlife (ages 25-65). Our design will be a 'measurement-burst', consisting of 8 biannual 'bursts' of 14 daily assessments of cognition, stress, URT, affect and physiological markers. This design will allow modeling of lead-lag relationships among these variables across time-scales that range from days to years. This study will address four aims: Aims 1 and 2 examine the role of URT in accounting for the effects of current stress on short-term (daily) and mid-term (biannual) in traindividual cognitive variability and change. Aims 3 and 4 examine URT as a mediator of the cumulative effects of stress on long-term (across years) cognitive change. This significance of this study lies in: 1) improved understanding of how stress in early adulthood and midlife affects risk for cognitive aging; 2) identifying a mechanism (URT) that links the experience of stress to cognitive aging; 3) resolving inconsistencies regarding the time course relating stress, HPA axis function and cognition; and 4) determining the temporal ordering of stress and cognitive change. Areas of conceptual and methodological innovation include: (1) a novel theoretical framework that can explain both acute and chronic stress effects on cognition, with important implications for a broad range of mental and physical health outcomes; (2) use of a measurement burst design to evaluate mediational hypotheses by examining lead-lag relationships across different time scales ranging from days to years; and (3) use of an analytic approach to examine both in train individual and in train individual facets of cognitive change. PUBLIC HEALTH RELEVANCE: The impact of the proposed research derives from improving our understanding of how environmental, psychological and physiological stress-related influences accumulate to affect cognitive health. By identifying a targetable mechanism for interventions, the knowledge from this research will directly inform prevention strategies to promote cognitive health in aging adults.

Project Summary Accurate and sensitive measurement of cognitive change is required to advance understanding of normative cognitive aging and neurocognitive impairments, such as Alzheimer's disease 2. Unfortunately, methodological barriers that constrain temporal precision and introduce confounds in impede progress in the study of cognitive change. Mobile assessment approaches afford novel opportunities to overcome these barriers by mitigating geographic, space and personnel constraints imposed by in-person cognitive testing. We believe that using mobile technology to assess cognition ?anytime, anyplace? holds great potential to transform biomedical research by improving detection and accurate monitoring of cognitive change. We will develop cognitive tests and software for use in ecological momentary assessment (EMA) measurement burst studies, an intensive longitudinal design which involves bursts of frequent, repeated assessments in naturalistic environments. We will also use mobile assessments to enhance traditional longitudinal designs by incorporating novel designs features (e.g., double- baseline assessments), and by increasing the frequency of longitudinal assessments. In response to RFA-AG-18-012, we propose to develop infrastructure for the Mobile Monitoring of Cognitive Change (M2C2) that will provide the research community with open, flexible, and usable tools to enable scientific progress that depends on the sensitive and accurate measurement of cognitive change. We will build this infrastructure by accomplishing the following aims. First, we will establish rapid iterative piloting and test development procedures that accelerate our capacity to prototype, deploy, evaluate, and optimize candidate mobile cognitive tests to meet psychometric, accessibility, and engagement benchmarks (Aim 1: Iterative Design & Piloting). Second, evaluate reliability, construct validity, and longitudinal validity of mobile cognitive testing procedures (Aim 2: Reliability & Validity) in a racially diverse probability sample. Third, we replicate psychometric results in an independent, nationally representative probability based sample, and create nationally representative norms (Aim 3: Replication). And fourth, we will test our pipeline and procedures for incorporating new measures into the mobile assessment infrastructure by evaluating novel measures for inclusion that are nominated by investigators outside of our immediate research team (Aim 4: Extension).

Project Summary Loss of independence, cognitive decline, and difficulties in everyday function are areas of great concern for older adults and their families. From a public health perspective, successful efforts that enable older adults to age within their homes, as compared to nursing homes, will save an estimated $80 billion dollars per year. Cognitive training is one low cost, noninvasive training intervention that has repeatedly demonstrated reliable transfer effects to maintained cognition, everyday function, health, and most recently, a 29% reduction in incident dementia. Importantly, many of these everyday function effects are maintained across five to ten years including: maintained driving mobility, 50% reduction in at-fault vehicle crashes, and maintained Instrumental Activities of Daily Living (IADL). Although clearly an important and effective intervention, the moderators and mechanisms underlying this program are unknown. Our overall objective in this planning grant is to lay the conceptual and methodological foundation to explore cognitive, psychosocial, lifestyle behaviors, biomarker, and neural mechanisms of two forms of conceptually driven cognitive training. Additionally, we will examine how cognitive and psychosocial factors within daily life account for the transfer of cognitive training to everyday function. We will use a factorial design to randomize adults ages 45-90 to 10, 20, 30, or 40 hours of two forms of cognitive training, a combined training, or an active control condition. This study will allow us to test the feasibility of our enrollment, assessment and training protocols for a future multisite clinical trial. This exploratory study is the first of its kind and will be used to provide important data relevant to a future larger randomized controlled trial examining mediators of cognitive training in a representative sample of adults. This information will assist in the future development of more effective home- and community-based interventions that maintain everyday function.