Natalie Denburg - US grants

DESCRIPTION (provided by applicant): This revised Mentored Research Scientist Development (K01) application is a request for funding to support the training and research necessary for Natalie Denburg, Ph.D. to become an independent investigator in aging, cognition, and structural imaging. The applicant is seeking additional training and education in neuroimaging, in particular, and the University of Iowa is a superb place to carry out such training. Dr. Denburg's long-term research objective is to have an independent program of research aimed at the study of aging cognition from the perspectives of both psychological processes and neural substrates. The study aims at investigating the hypothesis that some seemingly normal older persons (i.e., without overt neurological or psychiatric disease) have deficits in reasoning and decision-making, due to dysfunction in a neural system which includes the ventromedial prefrontal cortices (VMPC). This hypothesis addresses the question of why so many older adults fall prey to fraud, and is relevant to the comprehensive study of aging. Pilot data from the laboratory where the PI has been trained have suggested that a sizeable number of normal older adults are impaired on a laboratory task (the Gambling Task; GT) sensitive to reasoning and decision-making defects in patients with acquired damage to the VMPC. To test this hypothesis, 120 adults aged 26-85, all free of neurological and psychiatric disease, will be studied. Three specific objectives will be pursued aimed at behavioral, psychophysiological, and neuroanatomical levels: (1) A significant proportion of older adults will be impaired on the GT. Evaluation of the participants' medical histories (e.g., evidence of cardiovascular disease), neuropsychological profiles (e.g., executive dysfunction), and real-world decisionmaking abilities (e.g., miscomprehension of deceptive advertising claims), will allow for an examination of the extent to which these factors can account for, or correlate with, the GT defect. Older adults with decisionmaking defects on the GT will manifest (2) defective psychophysiological responses, particularly in anticipation of dsky decisions, and (3) disproportionate structural changes in VMPC. Alternative hypothesized neural substrates for decision-making (e.g., medial temporal lobe) will also be examined. The findings may inform intervention, in addition to influencing legal and social policy regarding advertising.

? DESCRIPTION (provided by applicant): Older adults face many complex demands in their economic and financial decision-making-e.g., critical decisions regarding estate planning, independent living, out-of-pocket medical expenses, and sudden changes in financial roles following the death of a spouse. Moreover, these decisions are frequently made under highly stressful conditions. However, little is known about the influence of stress on decision-making among older adults, and there is a critical need to improve our understanding of this issue. Here, our objective is to characterize the neurobehavioral phenotypes of healthy older persons who are at differing levels of risk for poor decision-making under stress. Our proposal is framed around two specific aims: (1) To investigate the influence of stress on complex decision-making behavior (temporal discounting and decision-making under uncertainty), and the neurobiological correlates of such behavior; and (2) To explore individual difference variables (personality, interoceptive awareness, life stress, executive cognitive functions, prefrontal cortex morphometry, age, and sex) that may influence how stress affects decision-making in older persons. BOLD fMRI and decision-making tasks (decomposable into basic cognitive and economic constructs consisting of validated utility parameters) will be used to investigate decision-making under stress (induced with an fMRI compatible stressor that entails uncontrollability, unpredictability, and social evaluation). We will carry out the aforementioned aims in a population of 200 healthy older persons (ages 60-84 years) comprised of an age- and sex-stratified sample consisting of equal numbers of men and women in each five-year age band, which will allow for an unprecedented examination of how the findings may be age- and sex-related. Our findings will facilitate the detection of older persons at risk for suboptimal decision-making under stress, as well as inform interventions to prevent or treat poor decision-making-e.g., our data will provide foundational knowledge for the development of educational tools to make older persons aware of biases and errors that commonly arise during decision-making under stress, while knowledge of the brain circuits involved could inform targeted pharmacological interventions. The findings could also inform public policy to protect vulnerable elders dealing with life stressors, e.g., from fraudulent advertising, telemarketing schemes, and similar ploys.

Abstract Treatments that can slow Alzheimer's disease (AD) progression can reduce care burden significantly. Sleep interventions may be among treatments with such disease-modifying potential. Evidence from animal models suggests there is a bi-directional relationship between sleep and AD pathophysiology such that sleep disruptions can facilitate amyloid beta (A?) accumulation and its aggregation into plaques and downstream formation of tau-tangles, and conversely, that AD pathophysiology can be reversed with sleep agents. Many key findings from animal models translate to human models of the disease, such as diurnal variation in A? (higher in wakefulness, lower in sleep), reduced clearance of A? to cerebrospinal fluid (CSF) in sleep deprivation and disruption, and weakening of the A? circadian rhythm with both normative aging and those with A? plaques. Epidemiologic studies supplement these smaller sample findings to indicate sleep and circadian disruptions can predict incident MCI/AD over 4-6 years. However, other evidence suggests these predictions are consistent with poor aging in general and may not be specific to AD. Experimental studies with efficacious sleep aids can address these questions. Melatonin improves sleep, has a good safety record for long-term use among older adults, and improves cognitive outcomes over a 9-month period in non-randomized studies among MCI patients. However, whether melatonin affects biomarkers in the A?-cascade is unknown. The proposed pragmatic trial will test efficacy of 5mg of melatonin on both memory and AD-biomarker outcomes in the spectrum of preclinical to prodromal AD using stratified randomization of MCI+ and MCI- to active and placebo arms using a short-term longitudinal framework. The participants will be observed with actigraphy to objectively track both sleep and circadian rhythm in daily life for a two month period in the sleep-as-usual phase#1, ending with CSF sampling of AD biomarkers and brief cognitive testing. Following stratified randomization, participants will be followed for another two-month period with actigraphic monitoring in the sleep-intervention-phase#2, also ending with CSF sampling of AD biomarkers and brief cognitive testing. Phase#3 long-term follow-up will extend the melatonin treatment to 9 months without actigraphic monitoring, ending with CSF sampling of AD biomarkers and cognitive testing. Dense, repeated, objective sampling of both sleep and circadian function in the real-world and the coupling of those objective assessments with AD biomarker sampling both prior to and after two-months of melatonin treatment will permit a methodologically rigorous evaluation of whether melatonin has disease-modifying treatment potential. Project's specific aims are organized around the central prediction that improvements in episodic memory will lag those seen in biomarkers, and that biomarker improvements will mediate the effects of improved sleep on episodic memory. Findings will address whether previously reported associations of sleep / circadian function with AD outcomes speak to the potential of these interventions to slow disease progression.