Social and Behavioral Sciences Commons^™

Rapamycin Rescues Vascular, Metabolic And Learning Deficits In Apolipoprotein E4 Transgenic Mice With Pre-Symptomatic Alzheimer’S Disease, Ai-Ling Lin, Jordan B. Jahrling, Wei Zhang, Nicholas Derosa, Vikas Bakshi, Peter Romero, Veronica Galvan, Arlan Richardson

Sanders-Brown Center on Aging Faculty Publications

Apolipoprotein E ɛ4 allele is a common susceptibility gene for late-onset Alzheimer's disease. Brain vascular and metabolic deficits can occur in cognitively normal apolipoprotein E ɛ4 carriers decades before the onset of Alzheimer's disease. The goal of this study was to determine whether early intervention using rapamycin could restore neurovascular and neurometabolic functions, and thus impede pathological progression of Alzheimer's disease-like symptoms in pre-symptomatic Apolipoprotein E ɛ4 transgenic mice. Using in vivo, multimodal neuroimaging, we found that apolipoprotein E ɛ4 mice treated with rapamycin had restored cerebral blood flow, blood–brain barrier integrity and glucose metabolism, compared …

Inter-Organizational Network Effects On The Implementation Of Public Health Services, Glen P. Mays

Health Management and Policy Presentations

Background: The Affordable Care Act created new incentives for hospitals, insurers, public health agencies, and others to contribute to disease prevention and health promotion activities, potentially changing inter-organizational relationships and expanding implementation of strategies that improve population health. This study uses data from the 1998-2014 National Longitudinal Survey of Public Health Systems to examine: (1) the extent and nature of change in inter-organizational contributions to public health activities; (2) whether network changes attenuate or exacerbate disparities in public health implementation across communities; and (3) how network changes affect preventable mortality and resource use.

Methods: We follow a longitudinal cohort of …

Mice Deficient In Endothelial Α5 Integrin Are Profoundly Resistant To Experimental Ischemic Stroke, Jill Roberts, Leon De Hoog, Gregory J. Bix

Sanders-Brown Center on Aging Faculty Publications

Stroke is a disease in dire need of better therapies. We have previously shown that a fragment of the extracellular matrix proteoglycan, perlecan, has beneficial effects following cerebral ischemia via the α5β1 integrin receptor. We now report that endothelial cell selective α5 integrin deficient mice (α5 KO) are profoundly resistant to ischemic infarct after transient middle cerebral artery occlusion. Specifically, α5 KOs had little to no infarct 2–3 days post-stroke, whereas controls had an increase in mean infarct volume over the same time period as expected. Functional outcome is also improved in the α5 KOs compared with controls. Importantly, no …

Early Shifts Of Brain Metabolism By Caloric Restriction Preserve White Matter Integrity And Long-Term Memory In Aging Mice, Janet Guo, Vikas Bakshi, Ai-Ling Lin

Sanders-Brown Center on Aging Faculty Publications

Preservation of brain integrity with age is highly associated with lifespan determination. Caloric restriction (CR) has been shown to increase longevity and healthspan in various species; however, its effects on preserving living brain functions in aging remain largely unexplored. In the study, we used multimodal, non-invasive neuroimaging (PET/MRI/MRS) to determine in vivo brain glucose metabolism, energy metabolites, and white matter structural integrity in young and old mice fed with either control or 40% CR diet. In addition, we determined the animals’ memory and learning ability with behavioral assessments. Blood glucose, blood ketone bodies, and body weight were also measured. We …

Estimating Health & Economic Gains From Public Health Delivery System Transformation, Glen P. Mays

Health Management and Policy Presentations

Objectives: The Affordable Care Act created new resources and incentives for hospitals, insurers, public health agencies, and others to contribute to disease prevention and health promotion activities, potentially changing the structure of public health delivery systems and expanding the implementation of strategies that improve population health. This study uses data from the 1998-2014 National Longitudinal Survey of Public Health Systems to examine: (1) the extent and nature of change in inter-organizational contributions to public health activities, which we use as indicators of public health system change; and (2) the effects of these changes on preventable mortality and resource use. Methods: …

Residual Impact Of Previous Injury On Musculoskeletal Characteristics In Special Forces Operators, Jeffrey J. Parr, Nicholas C. Clark, John P. Abt, Julie Y. Kresta, Karen A. Keenan, Shawn F Kane, Scott M. Lephart

Physical Therapy Faculty Publications

Background: Musculoskeletal injuries are a significant burden to United States Army Special Operations Forces. The advanced tactical skill level and physical training required of Army Special Operators highlights the need to optimize musculoskeletal characteristics to reduce the likelihood of suffering a recurrent injury.

Purpose: To identify the residual impact of previous injury on musculoskeletal characteristics.

Study Design: Cross-sectional study; Level of evidence, 3.

Methods: Isokinetic strength of the knee, shoulder, and back and flexibility of the shoulder and hamstrings were assessed as part of a comprehensive human performance protocol, and self-reported musculoskeletal injury history was obtained. Subjects were stratified based …

Kentucky’S Public Health Strategic Plan: Strengthening Foundational Services & Improving Population Health, Glen P. Mays

Health Management and Policy Presentations

This session examines recent progress toward the 2012 Institute of Medicine recommendation to identify the components and costs of a "minimum package" of public health services and foundational capabilities to be available across the U.S. Research about the health and economic benefits of Foundational Public Health Services has begun to shape Kentucky's strategic plan for transforming the public health system.

Analytic Approaches For Causal Inference With Complex Multi-Component Interventions, Glen P. Mays, Arnold J. Stromberg, Jing Li, Mark V. Williams

Health Management and Policy Presentations

Estimating the causal effects of complex, multi-component health interventions is a task with many challenges in measurement and methodology. This presentation profiles the methods being used as part of the PCORI-funded Project Achieve, a national study to estimate the comparative effectiveness of heterogeneous care transition programs designed to help hospitalized patients and their caregivers navigate care delivery systems effectively and return back to the community with optimal health and wellbeing.

Trends In Health Care Delivery Systems: Implications For Cancer Prevention And Control, Glen P. Mays

Health Management and Policy Presentations

The Affordable Care Act and larger economic forces are leading both health care providers and public health agencies to renegotiate their roles and responsibilities within the U.S. health system. This session reviews major changes occurring in both health care and public health delivery systems, with a focus on the implications for cancer prevention and control. The information infrastructure created by cancer registries and other health information systems are increasingly important for enabling greater coordination, alignment and accountability within the nation's changing delivery systems.

The National Health Security Preparedness Index: Proposed Updates For 2015-16, Glen P. Mays

Health Management and Policy Presentations

The U.S. Centers for Disease Control and Prevention (CDC) initiated development of the National Health Security Preparedness Index in 2012 to create a platform for measuring the nation’s progress in preparing for, responding to, and recovering from disasters and other large-scale emergencies that pose risks to health and well-being in the United States. As a measurement tool, the Index is designed to summarize levels of preparedness achieved within individual states and for the nation as a whole. This session summarizes proposed updates to the Index for 2015-16 that are designed to improve the validity and reliability of Index measures and …

Time-Dependent Effects Of Cx3cr1 In A Mouse Model Of Mild Traumatic Brain Injury, Heidi Y. Febinger, Hannah E. Thomasy, Maria N. Pavlova, Kristyn M. Ringgold, Paulien R. Barf, Amrita M. George, Jenna N. Grillo, Adam D. Bachstetter, Jenny A. Garcia, Astrid E. Cardona, Mark R. Opp, Carmelina Gemma

Sanders-Brown Center on Aging Faculty Publications

BACKGROUND: Neuroinflammation is an important secondary mechanism that is a key mediator of the long-term consequences of neuronal injury that occur in traumatic brain injury (TBI). Microglia are highly plastic cells with dual roles in neuronal injury and recovery. Recent studies suggest that the chemokine fractalkine (CX3CL1, FKN) mediates neural/microglial interactions via its sole receptor CX3CR1. CX3CL1/CX3CR1 signaling modulates microglia activation, and depending upon the type and time of injury, either protects or exacerbates neurological diseases.

METHODS: In this study, mice deficient in CX3CR1 were subjected to mild controlled cortical impact injury (CCI), a model of TBI. We evaluated …

Albumin Administration In Acute Ischemic Stroke: Safety Analysis Of The Alias Part 2 Multicenter Trial, Michael D. Hill, Renee H. Martin, Yuko Y. Palesch, Claudias S. Moy, Diego Tamariz, Karla J. Ryckborst, Elizabeth B. Jones, David Weisman, L. Creed Pettigrew, Myron D. Ginsberg

Sanders-Brown Center on Aging Faculty Publications

BACKGROUND: Albumin treatment of ischemic stroke was associated with cardiopulmonary adverse events in previous studies and a low incidence of intracranial hemorrhage. We sought to describe the neurological and cardiopulmonary adverse events in the ALIAS Part 2 Multicenter Trial.

METHODS: Ischemic stroke patients, aged 18-83 and a baseline NIHSS ≥ 6, were randomized to treatment with ALB or saline control within 5 hours of stroke onset. Neurological adverse events included symptomatic intracranial hemorrhage, hemicraniectomy, neurological deterioration and neurological death. Cardiopulmonary adverse events included pulmonary edema/congestive heart failure, acute coronary syndromes, atrial fibrillation, pneumonia and pulmonary thromboembolism.

RESULTS: …

Using Research And Roi To Drive Partnerships In Public Health Delivery Systems, Glen P. Mays

Health Management and Policy Presentations

Stimulating public-private partnerships (PPP) for health and economic development initiatives requires research that can answer key questions: (1) what are the health and economic returns likely to be realized; (2) over what time frames and with what certainty; (3) what investments are required to achieve results; and (4) what are the implementation strategies most likely to succeed. This presentation reviews ongoing research on the PPPs used to deliver public health services in the U.S., and explores the lessons this research offers PPPs in low and middle income countries. We examine how scientific evidence on public health delivery systems and their …

Estimating Patient-Centered And Community-Centered Treatment Effects: Examples From Medical Care And Public Health, Glen P. Mays

Health Management and Policy Presentations

Health services researchers face growing clinical and policy imperatives for estimating how the effectiveness of medical and public health interventions vary across patients, population groups, and community settings. Recent advances in local instrumental variables estimation techniques allow for the estimation of person-specific and community-specific treatment effects in the presence of unobserved heterogeneity. This presentation explores examples from both medicine and public health following the local IV methods developed by Basu et al. (2013).

Foundational Public Health Services And Health System Reform, Glen P. Mays

Health Management and Policy Presentations

The Institute of Medicine's 2012 report on public health financing recommended a national initiative to identify the components and costs of a "minimum package" of public health programs and infrastructure that should be available in every U.S. community. In response, efforts are now underway to reach consensus on a set of "Foundational Public Health Services" for the nation, and to identify resource requirements for implementing these services. This presentation reviews existing research on the current availability of Foundational Public Health Services across the U.S. and the health and economic effects attributable to these services. We also review progress on ongoing …

Fundamentals Of Economic Evaluation For Public Health, Glen P. Mays, Cezar Mamaril

Health Management and Policy Presentations

This workshop provides an overview of the design and implementation of economic evaluation studies of public health programs and policies. Strategies for integrating economic evaluation principles, measurement strategies, analytic approaches, and results into the routine operations of public health agencies are examined.

Medicaid Crowd-Out Of Other Public Health Spending: Modeling Economic & Health Effects, Glen P. Mays

Health Management and Policy Presentations

MOTIVATION: Thirty states are expanding Medicaid eligibility under the Affordable Care Act (ACA) as of 2015, and while federal funds cover most costs for newly eligible recipients, states must share the additional costs of covering previously-eligible state residents who enroll in Medicaid. States, together with their local government counterparts, also provide the vast majority (87%) of public sector funds for public health programs designed to promote health and prevent disease and injury on a population-wide basis. Fiscal constraints and generous federal matching funds create strong budgetary incentives for states to channel their health-related spending to Medicaid rather than to other …

Altered Lysosomal Proteins In Neural-Derived Plasma Exosomes In Preclinical Alzheimer Disease, Edward J. Goetzl, Adam Boxer, Janice B. Schwartz, Erin L. Abner, Ronald C. Petersen, Bruce L. Miller, Dimitrios Kapogiannis

Sanders-Brown Center on Aging Faculty Publications

OBJECTIVE: Diverse autolysosomal proteins were quantified in neurally derived blood exosomes from patients with Alzheimer disease (AD) and controls to investigate disordered neuronal autophagy.

METHODS: Blood exosomes obtained once from patients with AD (n = 26) or frontotemporal dementia (n = 16), other patients with AD (n = 20) both when cognitively normal and 1 to 10 years later when diagnosed, and case controls were enriched for neural sources by anti-human L1CAM antibody immunoabsorption. Extracted exosomal proteins were quantified by ELISAs and normalized with the CD81 exosomal marker.

RESULTS: Mean exosomal levels of cathepsin D, lysosome-associated membrane …

Low Neural Exosomal Levels Of Cellular Survival Factors In Alzheimer's Disease, Edward J. Goetzl, Adam Boxer, Janice B. Schwartz, Erin Abner, Ronald C. Petersen, Bruce L. Miller, Olga D. Carlson, Maja Mustapic, Dimitrios Kapogiannis

Sanders-Brown Center on Aging Faculty Publications

Transcription factors that mediate neuronal defenses against diverse stresses were quantified in plasma neural-derived exosomes of Alzheimer's disease or frontotemporal dementia patients and matched controls. Exosomal levels of low-density lipoprotein receptor-related protein 6, heat-shock factor-1, and repressor element 1-silencing transcription factor all were significantly lower in Alzheimer's disease patients than controls (P < 0.0001). In frontotemporal dementia, the only significant difference was higher levels of repressor element 1-silencing transcription factor than in controls. Exosomal transcription factors were diminished 2-10 years before clinical diagnosis of Alzheimer's disease. Low exosomal levels of survival proteins may explain decreased neuronal resistance to Alzheimer's disease neurotoxic proteins.

Using Network Analysis To Understand Public Health Delivery Systems & Community Health Initiatives, Glen P. Mays

Health Management and Policy Presentations

The increasingly connected world of health care delivery relies on an expanding frontier of multi-stakeholder structures and processes, from interdisciplinary patient-centered care teams, to virtual accountable care organizations (ACOs), to complex community-level interventions. This session highlights recent advances in applying social network analysis (SNA) methods to study the implementation and impact of these types of innovations. This methods workshop examines the benefits and limits of novel SNA applications based on the expanding availability of large, linkable electronic clinical and administrative data sources with dependent data structures. This paper profiles examples of using SNA principles and methods to study the implementation …

Learning From Network Analysis: Care Transitions, Market Competition, & Community Interventions, Glen P. Mays

Health Management and Policy Presentations

The increasingly connected world of health care delivery relies on an expanding frontier of multi-stakeholder structures and processes, from interdisciplinary patient-centered care teams, to virtual accountable care organizations (ACOs), to complex community-level interventions. This methods workshop highlights recent advances in applying social network analysis (SNA) methods to study the implementation and impact of these types of innovations. This session will examine the benefits and limits of novel SNA applications based on the expanding availability of large, linkable electronic clinical and administrative data sources with dependent data structures.

Learning From Delivery System Behavior, Dynamics & Interactions To Advance A Culture Of Health, Glen P. Mays

Health Management and Policy Presentations

A new "Systems for Action" national research program flows directly from the Robert Wood Johnson Foundation's Culture of Health action framework. This program will build evidence on how best to align the delivery and financing systems for medical care, public health, and community services & supports so as to promote wellbeing and resiliency, realize efficiencies in resource use, and reduce inequities in health.

Changes In Public Health System Capital And Long-Run Health And Economic Outcomes: 1998 To 2014, Glen P. Mays, Cezar B. Mamaril

Health Management and Policy Presentations

Research Objective: The Affordable Care Act created new resources and incentives for hospitals, insurers, public health agencies, and others to contribute to disease prevention and health promotion activities, potentially changing the structure of public health delivery systems and expanding the implementation of strategies that improve population health. This study uses data from the 1998-2014 National Longitudinal Survey of Public Health Systems to examine: (1) the extent and nature of change in inter-organizational contributions to public health activities, which we use as indicators of public health “system capital”; and (2) the effects of these changes on preventable mortality and resource use. …

Apoε2 And Education In Cognitively Normal Older Subjects With High Levels Of Ad Pathology At Autopsy: Findings From The Nun Study, Diego Iacono, Peter Zandi, Myron Gross, William R. Markesbery, Olga Pletnikova, Gay Rudow, Juan C. Troncoso

Sanders-Brown Center on Aging Faculty Publications

Asymptomatic Alzheimer's disease (ASYMAD) subjects are individuals characterized by preserved cognition before death despite substantial AD pathology at autopsy. ASYMAD subjects show comparable levels of AD pathology, i.e. β-amyloid neuritic plaques (Aβ-NP) and tau-neurofibrillary tangles (NFT), to those observed in mild cognitive impairment (MCI) and some definite AD cases. Previous clinicopathologic studies on ASYMAD subjects have shown specific phenomena of hypertrophy in the cell bodies, nuclei, and nucleoli of hippocampal pyramidal neurons and other cerebral areas. Since it is well established that the allele APOε4 is a major genetic risk factor for AD, we examined whether specific alleles of APOE …

The National Health Security Preparedness Index: National Advisory Committee Meeting, Glen P. Mays, Michael Childress, Anna Goodman Hoover, Chris Bollinger

Health Management and Policy Presentations

This meeting of the National Advisory Committee for the National Health Security Preparedness Index program discussed strategies for improving the theoretical framework, measures, and analytic methodologies used in assessing and comparing preparedness levels across U.S. states and the nation as a whole.

Calcium Channel Blockers, Progression To Dementia, And Effects On Amyloid Beta Peptide Production, Mark A. Lovell, Erin Abner, Richard Kryscio, Liou Xu, Shuling X. Fister, Bert C. Lynn

Sanders-Brown Center on Aging Faculty Publications

Previous epidemiologic studies suggest that antihypertensive drugs may be protective against cognitive decline. To determine if subjects enrolled in the University of Kentucky longitudinal aging study who used antihypertensive drugs showed diminished progression to dementia, we used a 3-parameter logistic regression model to compare the rate of progression to dementia for subjects who used any of the five common categories of antihypertensive drugs to those with similar demographic characteristics but who did not use antihypertensives. Regression modeling showed that subjects who used calcium channel blockers (CCBs) but not the other classes of antihypertensives showed a significant decrease in the rate …

Cost Estimation In Public Health Services & Systems Research, Glen P. Mays

Health Management and Policy Presentations

Considerable uncertainty persists about the resources required to implement public health programs and policies, and about the factors that drive variation in resource needs and utilization across community and institutional settings. This paper reviews several alternative approaches to cost estimation that we have used in the field of public health services & systems research (PHSSR). This review was prepared for an expert panel meeting convened as part of a study commissioned by the U.S. Assistant Secretary for Planning and Evaluation (ASPE) to estimate the costs associated with public health emergency preparedness capabilities.

Closed Head Injury In An Age-Related Alzheimer Mouse Model Leads To An Altered Neuroinflammatory Response And Persistent Cognitive Impairment, Scott J. Webster, Linda J. Van Eldik, D. Martin Watterson, Adam D. Bachstetter

Sanders-Brown Center on Aging Faculty Publications

Epidemiological studies have associated increased risk of Alzheimer's disease (AD)-related clinical symptoms with a medical history of head injury. Currently, little is known about pathophysiology mechanisms linked to this association. Persistent neuroinflammation is one outcome observed in patients after a single head injury. Neuroinflammation is also present early in relevant brain regions during AD pathology progression. In addition, previous mechanistic studies in animal models link neuroinflammation as a contributor to neuropathology and cognitive impairment in traumatic brain injury (TBI) or AD-related models. Therefore, we explored the potential interplay of neuroinflammatory responses in TBI and AD by analysis of the temporal …

Attenuation Of Traumatic Brain Injury-Induced Cognitive Impairment In Mice By Targeting Increased Cytokine Levels With A Small Molecule Experimental Therapeutic, Adam D. Bachstetter, Scott J. Webster, Danielle S. Goulding, Jonathan E. Morton, D. Martin Watterson, Linda J. Van Eldik

Sanders-Brown Center on Aging Faculty Publications

BACKGROUND: Evidence from clinical studies and preclinical animal models suggests that proinflammatory cytokine overproduction is a potential driving force for pathology progression in traumatic brain injury (TBI). This raises the possibility that selective targeting of the overactive cytokine response, a component of the neuroinflammation that contributes to neuronal dysfunction, may be a useful therapeutic approach. MW151 is a CNS-penetrant, small molecule experimental therapeutic that selectively restores injury- or disease-induced overproduction of proinflammatory cytokines towards homeostasis. We previously reported that MW151 administered post-injury (p.i.) is efficacious in a closed head injury (CHI) model of diffuse TBI in mice. Here we test …

Geographic Variation In The Delivery Of Public Health Services: Understanding Causes And Consequences, Glen P. Mays

Health Management and Policy Presentations

The implementation and reach of evidence-based prevention and public health programs varies widely across the U.S., as does the availability of cross-cutting infrastructure and foundational capabilities required to support these interventions. This talk profiles ongoing research to uncover the causes and consequences of variation in public health delivery. This research points to policy and administrative strategies that can reduce inequities and inefficiencies in public health protections.