Guy G. Potter, Ph.D. - US grants

This proposal responds to research topic 12 (Cognition in Context), with secondary relevance to topic 19 (Genetics, Behavior and Aging). The aging of the U.S. population has stimulated public health interest in identifying factors that can preserve the cognitive functioning of older adults. Complex work may be one activity that has a salutary effect on late-life cognitive function, but factors like intelligence, educational level, and early environmental exposures are potential confounds to this association. Twin studies allow for control of many of these confounding factors. The goal of this project is to determine whether occupational complexity is associated with better late-life cognitive functioning in a sample of elderly twins, using data collected by the Duke Twins Study of Memory in Aging on members of the National Research Council-National Academy of Sciences (NAS-NRC) Registry of World War II veteran twins. Specific Aim 1 of this project is to classify each twin's primary lifetime occupation using the Dictionary of Occupational Titles (DOT), from which a measure of complexity can be derived. This allows additional Specific Aims (SA) to be tested using co-twin control analyses: (SA 2) estimate the association between occupational complexity and cognitive status, (SA 3) estimate the association between occupational complexity and change in cognitive status over time, and (SA 4) estimate the extent to which intelligence moderates the relationship between occupational complexity and cognitive status. The study sample, which comprises approximately 1000 monozygotic and 1000 dizygotic twin pairs, has been administered a cognitive status examination every 3-4 years since 1990 as part of a screening and assessment protocol for dementia. Approximately 300 of these pairs also have scores on standard armed services intelligence tests. Logistic regression dependent on twin pair will be used to estimate association between a factor-based measure of occupational complexity from the DOT and either baseline (SA 2) or change scores (SA 3) from the cognitive status measure. Analyses for SA 4 will be similar, using the intelligence test score as a covariate. If occupational complexity is found to enhance late-life cognitive functioning, this modifiable factor could inform cognitive interventions and influence decisions about occupational activities and retirement. Follow-up twin studies can explore whether complex work is a protective factor for dementia.

DESCRIPTION (provided by applicant): The challenges of dissociating the cognitive effects of depression from those of aging have limited the translation of cognitive neuroscience to patient-oriented research in geriatric depression. This has created a critical need for behavioral paradigms that can quantify how key features of cognitive performance interact with depression and age, and for experimental studies that can identify their neural and clinical correlates. This K23 Mentored Patient-Oriented Career Development Award will allow the candidate to become a leader in research that integrates cognitive neuroscience with clinical research on the nature and outcomes of cognitive dysfunction in depression. The career development plan builds upon the candidate's background as a clinical neuropsychologist and will enable him to design and execute cognitive neuroscience research that is clinically informed, as well as clinical research that is based on sound neuroscience. The training plan includes academic study of the theories and methodologies of cognitive neuroscience, in conjunction with intensive hands-on experience developing cognitive tasks and collecting and processing functional neuroimaging data. The candidate's training will allow him complete the aims of the proposed research study, which are to: 1) examine the effects of depression on the efficiency of attentional control in young and old adults during visual search, 2) examine the mediating effects of anhedonia on the efficiency of attentional control in depression, and 3) examine influences of age, anhedonia, and depression on the neural mechanisms of attentional control using functional magnetic resonance imaging. Future study proposals will extend these findings by integrating assessments of specific symptom profiles and clinical outcomes in depression with experimental analysis of their cognitive and neural correlates. The candidate's program of research has the potential to identify clinical phenotypes of depression that are associated with cognitive deficits across the adult lifespan, and to provide preliminary validation of visual search as a clinical measure of attention in depression. Both of these outcomes are important to translating cognitive neuroscience tasks to patient-oriented research in treatment discovery and development. PUBLIC HEALTH RELEVANCE: The relevance of this project to public health is that differentiating the cognitive deficits of depression and anhedonia from those of aging has the potential to advance understanding of the pathophysiology of depression. This advancement will improve clinical diagnosis, and ultimately contribute to more efficacious approaches to prevent, manage, and cure depression.

Among older adults, major depressive disorder with cognitive impairment (CI) is associated with increased disability, higher healthcare utilization, and increased risk of dementia. From a clinical standpoint, gaining knowledge about proximate (i.e., within 5 years) predictors of adverse cognitive outcomes among currently depressed older adults is crucial to timely and targeted intervention for at-risk individuals. From a scientific standpoint, identifying phenotypes and genotypes associated with cognitive diagnostic outcomes?both positive and negative?will advance research on mechanisms, prevention, and treatment. The NIMH- supported Neurocognitive Outcomes of Depression in the Elderly (NCODE) Study at Duke University and Neurobiology of Late-life Depression (NBOLD) Study at the University of Connecticut (UConn) are among the few prospective studies that include both longitudinal cognitive diagnostic outcomes and a formal clinical diagnosis of major depression in late life (LLD). In addition, these studies share common features related to clinical and cognitive assessment, neuroimaging, and genetic analysis. Consistent with PAR-14-165, the objective of the proposed clinical collaboration is to complete a two-site prospective study of cognitive diagnostic outcomes of LLD that will capitalize on the power of the combined data to: 1) identify clinical and biological phenotypes that predict cognitive diagnostic outcomes, and 2) understand the neural and genetic mechanisms associated with them. We seek support to extend current 2-year study enrollments to a 5-year clinical follow-up period in order to increase sample sizes to identify clinical, neuroimaging and genetic predictors of three key diagnoses our data find in 90% of cognitive diagnostic outcomes over a 5-year period: 1) normal cognition (CN), 2) persistent cognitive impairment without dementia (PCI), and 3) Alzheimer?s disease (AD). Our central hypothesis is that the 5-year likelihood of each cognitive diagnostic outcome is associated with distinct clinical, cognitive, and neural phenotypes during acute LLD, which in turn have distinct genotypic correlates. Specifically, CN individuals will have earlier first onset of depression relative to AD, report greater negative life stress compared to AD and PCI, and have greater white matter integrity; additionally, CN will be associated with the AA genotype of COMTval158met, which may confer both neuroprotection and higher sensitivity to stress. PCI will be associated with earlier age of depression onset relative to AD, greater frailty, and lesser white matter integrity than NC. AD will be associated with later age of depression onset, appetite/weight loss, lower anxiety, smaller hippocampal volume, and memory impairment. We propose to test all of these putative associations in our Specific Aims. The proposed research will identify and integrate biological and behavioral markers associated with proximate cognitive diagnostic outcomes in LLD (NIMH Strategic Objective 1), and has the potential to yield tools that better define and identify risk and protective factors for adverse outcomes of depression through the course of later life (NIMH Strategic Objective 2).