IMPH Research in Aging

Cardiac Function As a Mechanism for Maladaptive Brain Aging 
Cost-Effectiveness of Nutrition Intervention in
Long Term Care 
Cost-Effectiveness of Weight Loss Prevention in Nursing Homes: A Controlled Trial 
Effectiveness of the Influenza Vaccine in the Aging Population 
The MIND-USA Study 

Opiod Analgesics and the Risk of Serious Infections in Seniors 
Opiod Selection and the Risk of Serious Infections in Older Adults 
Prevention of Weight Loss in Long Term Care Veterans 
Preventing Cognitive Decline in Older Adults with Dementia in Assisted-Living Facilities 
The Pat Summitt Foundation of the East Tennessee Foundation 
Vascular Factors Underlying Abnormal Cognitive Aging

Cardiac Function As a Mechanism for Maladaptive Brain Aging

As the population continues to age, the incidence of dementia is dramatically increasing, resulting in an urgent need to identify risk factors for abnormal brain aging and dementia. Alterations in cardiac function influence systemic blood flow, which impacts cerebral blood flow homeostasis as demonstrated by animal models. Such changes in cerebral blood flow homeostasis may pose a risk for accelerating age-related brain injury. Our preliminary research suggests that cardiac function is related to markers of maladaptive brain aging. It is not yet clear if cardiac function accelerates neuroimaging or cognitive markers of cerebrovascular or Alzheimer's disease among aging individuals with mild cognitive impairment (MCI). Individuals with MCI are at increased risk for cognitive progression and susceptible to more rapid abnormal brain aging when concomitant vascular disease is present. Our proposed study will examine relations between cardiac function and maladaptive brain aging and provide important information for developing novel strategies to delay the progression from MCI to dementia. Using a prospective observational matched design, we will cross-sectionally and longitudinally relate cardiac function to neuroimaging and cognitive markers of early Alzheimer's disease and cerebrovascular changes among aging adults with MCI and age-, sex-, and race-matched cognitively normal adults. Clinical or subclinical cardiac dysfunction may be due to complex systemic mechanisms that are preventable or treatable, such as enhanced inflammatory markers and insulin resistance, or genetic factors, such as apolipoprotein E. Therefore, we will consider systemic and genetic factors as potential mediating mechanisms in relations between cardiac function and brain aging. The proposed study leverages an existing Alzheimer's Association funded study directed by the principal investigator, the participant registry of our NIA-funded Boston University Alzheimer's Disease Center, a recent American Recovery & Reinvestment Act supplement grant focused on African American recruitment and retention, and the unique resources afforded by our local Clinical and Translational Science Institute housing the General Clinical Research Unit. Read more.

Funding Source: NIH/NIA 
PI: Angela L. Jefferson

Cost-Effectiveness of Nutrition Intervention in Long Term Care

This funded translational study utilizes the federal regulation to train non-nursing staff for nutritional care delivery.  Specifically, this study uses a controlled, intervention design to determine the cost-effectiveness of a between-meal snack intervention relative to a usual care control group in a group of 200 residents in 4 community nursing homes. Non-nursing staff trained as “feeding assistants” will offer residents in the intervention group a choice between supplements and other snack foods and fluids twice daily, five days per week, for 24 weeks while also providing a standardized prompting protocol to enhance intake and independence in eating.  The impact of the training program on residents’ nutritional status is monitored by research staff during this time period. Read more.

Funding Source: NIH/NIA
PI: Sandra F. Simmons, PhD

Cost-Effectiveness of Weight Loss Prevention in Nursing Homes: A Controlled Trial

This funded study uses a controlled, intervention design to determine the cost-effectiveness of oral liquid nutritional supplements with an alternative nutrition intervention that offers residents a choice between supplements and other foods and fluids (i.e., snacks) between meals in a group of 200 residents in four community nursing homes.  Each intervention is being implemented for 24 weeks while research staff monitor nutritional intake, body weight and other health outcomes. Read more.

Funding Source: Agency for Healthcare Research and Quality
PI:Sandra F. Simmons, PhD

Effectiveness of the Influenza Vaccine in the Aging Population

This study application is a secondary analysis of an existing database in response to the Program Announcement, PA-09-265: Secondary Analyses of Existing Data Sets and Stored BioSpecimens to Address Clinical Aging Research Questions (R01) to determine influenza vaccine effectiveness in older adults. Recent work has shown that more is needed to be known about influenza vaccine effectiveness in older adults and the methodology used to determine that vaccine effectiveness. This database is an accumulation of three studies that prospectively tested older adults for influenza. This data will be used to determine if the current methodology of test-negative controls will actually control for the bias of frailty, will determine vaccine effectiveness in the very old, and will explore if vaccne manufacturing process impacts effectiveness. Read more.

Funding Source: NIH/NIA
PI: H. Keipp Talbot

The MIND-USA Study

The long-term objective of the proposed MIND-USA (Modifying the Impact of ICU-Induced Neurological Dysfunction-USA) Study is to define the role of antipsychotics in the management of delirium in vulnerable critically ill patients. We and others have shown that delirium is an independent predictor of more death, longer stay, higher cost, and long-term cognitive impairment often commensurate with moderate dementia. The rapidly expanding aging ICU population is especially vulnerable to develop delirium, with 7 of 10 medical and surgical ICU patients developing this organ dysfunction. Antipsychotics are the first-line pharmacological agents recommended to treat delirium, and over the past 30 years they gained widespread use in hospitalized patients globally prior to adequate testing of efficacy and safety for this indication. Haloperidol, the most commonly chosen antipsychotic, is used by over 80% of ICU doctors for delirium, while atypical antipsychotics are prescribed by 40%. Antipsychotics safety concerns include lethal cardiac arrhythmias, extrapyramidal symptoms, and the highly publicized increased mortality associated with their use in non-ICU geriatric populations. The overarching hypothesis is that administration of typical and atypical antipsychotics-haloperidol and ziprasidone, in this case-to critically ill patients with delirium will improve short- and long-term clinical outcomes. Aim 1 will determine whether haloperidol or ziprasidone will increase days alive without acute brain dysfunction (referred to as delirium/coma-free days or DCFDs) over a 14-day period compared with placebo and compared to one another. Aim 2 will determine whether haloperidol or ziprasidone will improve 30-day, 90-day, and 1-year survival compared with placebo and compared to one another. Aim 3 will determine whether haloperidol or ziprasidone will reduce ICU length of stay compared with placebo and compared to one another. Aim 4 will determine whether haloperidol or ziprasidone will reduce the incidence, severity, and/or duration of long-term neuropsychological dysfunction and improve quality of life at 90-day and 1-year follow-up compared with placebo and compared to one another. To address these Aims, we will conduct this multi-center, double blind, randomized, placebo-controlled investigation in 876 critically ill, delirious medical/surgical ICU patients who are (a) on mechanical ventilation or non-invasive positive pressure ventilation or (b) in shock on vasopressors. In each group (haloperidol, ziprasidone, and placebo), 292 patients will be enrolled and treated until delirium has resolved for 48 hours or to 14 days (whichever occurs first) and followed for 1 year. We will monitor many safety parameters such as cardiac dysrhythmias and extrapyramidal symptoms. This study will have adequate power to detect the effect of antipsychotics in 4 important subgroups including age >65 years, severity of illness (APACHE II > 25), severe sepsis at enrollment, and medical vs. surgical ICU patients, and a hypothesis generating analysis of patients with pre- existing cognitive impairment. Read more.

Funding Source: NIH/NIA
PI: E. Wesley Ely

Opiod Analgesics and the Risk of Serious Infections in Seniors

Opioid analgesics are one of the most commonly prescribed medication classes in the United States. Although these medications have been available for medical use for decades, their safety and effectiveness remain unclear. Available data from clinical trials are limited to highly selected patients and short term efficacy outcomes. Of great concern, information on the safety profile of these medications is even more scant. Several lines of in vivo experimental evidence indicate that opioid analgesics have significant immunosuppressive properties and could render opioid users susceptible to serious, potentially life-threatening infections. The immunosuppressive effects of opioid analgesics could be particularly troublesome for the elderly, who are commonly affected by persistent pain and are already at increased risk for infections. Given concerns about the safety of alternate analgesics (e.g. NSAIDs and COX-2 inhibitors), and the increasing widespread use of opioids, the determination and quantification of this potential risk is of great public health interest. Furthermore, there are a number of opioid analgesics currently available, but not all are expected to have the same immunosuppressive properties. Identifying those opioids with the lowest propensity to facilitate serious infections will be crucial to inform the selection of analgesics for the elderly. We propose to conduct a retrospective study of elderly persons enrolled in TennCare (Tennessee Medicaid) with the following specific aims: 1) To test the hypothesis that use of opioid analgesics increases the risk of serious infections; and, 2) To test the hypothesis that there is variation of the risk of serious infections for individual opioids. Th proposed studies will use a self-controlled case-series design, in which cases serve as their own controls, cancelling out the effects of fixed measured and unmeasured confounders, allowing control of relevant time-varying covariates; and, thus, allowing an unbiased estimation of the relative risk. Read more.

Funding Source: NIH/NIA 
PI: Carlos G. Grijalva

Opiod Selection and the Risk of Serious Infections in Older Adults

There is substantial evidence that opioid analgesic use impairs immune system responses and there has been a long-standing concern that these effects increase the risk of serious, potentially life-threatening infections. In vivo studies in animal models and human subjects have demonstrated that opioids affect surrogate markers of immune functions that are crucial for prevention of serious infections, such as white cell migration and phagocytosis. Although studies have demonstrated significant dose-dependent suppression of immunological functions in animal models and humans as well as a dose-dependent increase in the risk of serious infections in animal models, the clinical relevance of these findings in humans remains unclear. These concerns are particularly relevant for older adults, who are commonly affected by pain and are at increased risk for infections. A number of opioid analgesics are currently available, but not all have the same immunosuppressive properties. Studies in animal models suggest that, taking the chemical structure of morphine as reference, opioids with hydroxyl groups at both C3 and C6 (e.g. morphine), have the strongest immunosuppressive effects, whereas modification at C3 alone (e.g. codeine) reduces immunosuppression, and substitution of a carbonyl group at C6 (e.g. hydromorphone) eliminates the immunosuppressive effects. Identifying those opioids that are the least likely to increase the risk of serious infections will be crucial to inform the selection of analgesics for vulnerable older adults. Furthermore, the immunosuppressive effects of opioids are dose-dependent and for several opioids, in vivo data suggest that concurrent use of opioids and other commonly used medications that inhibit opioid metabolism could markedly increase the serum concentration of opioids. We propose to conduct a series of studies of older adults with the following specific aims: 1) Test the hypothesis that the risk of serious infections in new users of codeine (which is metabolized to morphine) is greater than in new users of other opioids with comparable analgesic properties; 2) Test the hypothesis that the risk of serious infections in new users of morphine is greater than in new users of other opioids with comparable analgesic properties; and, 3) Test the hypothesis that concurrent use of oxycodone or methadone and strong inhibitors of their metabolism increases the risk of serious infections relative to such use without metabolic inhibitors. The proposed studies will use a retrospective cohort study design and data from Tennessee Medicaid, to compare the incidence of serious infections associated with the use of selected opioids while controlling for the effect of relevant baseline and time-varying covariates. Our research team has the combination of experience and expertise needed to successfully complete the proposed projects. The proposed studies are designed to have a high impact on the field of pain therapeutics, advance our understanding of the effects of opioid analgesics on the risk of serious infections and inform the clinical care of older adults. Read more.

Funding Source: NIH/NIA 
PI: Carlos G. Grijalva

Prevention of Weight Loss in Long Term Care Veterans

This translational research study involves a staff training and management intervention in two VA facilities to improve daily nutritional care practices both during and between meals as provided by routine nursing home staff. Read more.

Funding Source: VA HSR&D Merit Award
PI: Sandra F. Simmons, PhD

Preventing Cognitive Decline in Older Adults with Dementia in Assisted-Living Facilities

The purpose of this study is to evaluate two structured cognitive stimulation – activity programs in a local assisted-living facility on residents’ cognitive and psychosocial status.  Research staff will administer a battery of neuropsychological assessments in conjunction with other behavioral measures to determine the impact of each program on resident functioning and quality of life. Read more.

Funding Source: West End Home Foundation
PI: Sandra F. Simmons, PhD

The Pat Summitt Foundation of the East Tennessee Foundation

This foundation grant was used to develop a guide for consumers in selecting a dementia care facility titled, "How to Evaluate the Quality of Residential Care for Persons with Dementia" (see attached web-friendly pdf version).  An overview of dementia care in both long-term care and residential care is provided as well as consumer tips and guidelines for what questions to ask and what to look for when visiting a facility.  The goal of this guide is to empower the consumer with the same knowledge and expertise that the authors of this guide have obtained based on years of both clinical and research experience in evaluating dementia care quality. Read more.

PI: Sandra Simmons, PhD, John Schnelle, PhD, and Anna Rahman, PhD

Vascular Factors Underlying Abnormal Cognitive Aging

As the population ages, cognitive decline and Alzheimer's disease (AD) are becoming increasingly important public health issues. Mild cognitive impairment (MCI) is considered a precursor to AD, and early identification of MCI and effective management of risk factors associated with conversion from MCI to dementia is an important step in managing the public health crisis of AD. Unfortunately, MCI is an unstable diagnostic construct, and key predictors of conversion and reversion are poorly understood. Multiple vascular factors and prevalent cardiovascular disease are known risks for the development of AD, so a plausible predictor of diagnostic fluctuations in MCI is the presence of concomitant micro vascular disease in the brain. This proposal will leverage the existing and robust dataset from the Alzheimer's Disease Neuroimaging Initiative to examine neuroimaging markers of micro vascular and microstructural tissue changes in the white matter with cognitive trajectory among cognitively normal older adults and individuals with MCI. We will (1) assess how stable versus progressive cerebral micro vascular disease and micro structural changes in white matter affect maladaptive cognitive aging over time and (2) assess the mediating effect of baseline systemic vascular disease (using a vascular health index) in the longitudinal relation between micro vascular and micro structural white matter changes and diagnostic conversion and cognitive trajectory. Insights regarding complex relations between systemic vascular disease and micro vascular or microstructural changes in the brain have important public health implications because they will contribute to early identification of a vulnerable population at high risk for cognitive progression. Furthermore, because vascular risk factors can be modified over the life course to reduce the burden of cerebrovascular disease in older adults, this vulnerable population would benefit most from novel strategies to delay or prevent progression, which is particularly valuable in light of the aging of the population and increasing prevalence of AD. Read more.

Funding Source: NIH/NHLBI
PI: Angela Jefferson