2008 Center on Aging Pilot Grant Program Recipients
Michael K. Gardner, Ph.D.
Professor and Associate Chair, Department of Educational Psychology
Motor skills training of PINS in the elderly with and without MCI
Abstract
The proposed project will explore efficacy of a procedurally-based motor skills training program for teaching older individuals 4 four-digit personal identification numbers (PINS). The rationale for this approach is that procedural memory is supported by different neural systems than delarative memory, and that these systems may be less impacted by the negative effects of aging in general, and certain disease states (e.g., mild cognitive impairment [MCI]) in particular (Squire, 1986, 1987).
The performance of three groups of older (60 years of age or older) adults will be compared: (1) 30 normal, healthy individuals using motor-skills training; (2) 30 individuals diagnosed with MCI using motor-skills training; and (3) 30 normal, healthy individuals in a control condition, in which they are not given explicit memory instructions. It is expected this group will rely on declarative memory strategies such as rehearsal.
Our predictions are: (1) normal individuals given motor-skill training will show increased recall compared to normal individuals in the control condition; and (2) MCI individuals given motor-skill training will show increased recall performance compared to normal individuals in the control condition.
We discuss (briefly) how such procedurally-based training programs could be expanded to other daily living tasks (e.g., programming a microwave oven) in effort to improved the quality of life in older persons who are experiencing memory deficits.
Joanne Lafleur, PharmD, MSPH
Research Assistant Professor, Department of Pharmacotherapy
Gathering evidence for clinical decision support in male osteoporosis in veterans
Abstract
While generally associated with women, men are also at risk for developing osteoporosis; one in four men over age 50 will have a fragility fracture in their remaining lifetime. There are numerous clinical risk factors recognized by research clinical communities that are associated with the risk of osteoporosis-related fracture. Many of these risk factors are routinely recorded in the process of patient care. With the increasing use of electronic medical records (EMRs) there exists a potential to automatically calculate fracture risk using data routinely collected in EMRs to alert health care providers when patients are at high risk of fracture. The hypothesis of this pilot study is that data routinely collected in the Veterans Health Administration (VHA) EMR in the local Veteran Integrated Service Network (VISN) can be used as measures of fracture risk and are therefore predictive of osteoporotic fractures in male veterans. Thus, this study will assess whether data corresponding to fracture risk factors is captured adequately by the VISN database and will estimate the risk for fracture in male Veterans associated with these measured clinical risk factors. This pilot research will also inform the design and implementation of a national level project to validate the predictive power of EMR data for detecting fracture risk in men in the overall VHA system. The ultimate aim of this research is to provide the evidence for the development of an electronic osteoporosis fracture risk tool that would facilitate the identification of at-risk patients for fracture prevention interventions.
Raminder Nirula, MD, MPH
Assistant Professor, Department of Surgery
StO2 monitoring of geriatric trauma patients to stratify outcome
Abstract
Morbidity and mortality are greater for elderly trauma victims compared to similarly injured younger patients. Early, aggressive resuscitation of these patients is associated with an improved outcome; however, many of these patients have a blunted sympathetic response to injury and shock. This leads to delayed recognition and resuscitation of the subclinical shock state which is associated with greater morbidity and mortality.
One approach to this problem is to admit all injured elderly patients to the ICU and place invasive hemodynamic monitors to assess their degree of shock and perfusion. This would lead to significant resource utilization and place many patients at unnecessary risk for complications related to invasive monitoring. Ideally, a rapid, noninvasive measurement of tissue perfusion to identify patients in subclinical shock would permit its early recognition and target resuscitative efforts to those most likely to benefit.
Tissue oxygenation measurement using near infrared spectroscopy (StO2) is a technology that has recently been demonstrated to correlate with shock and the need for emergent interventions. A recent study demonstrated its ability to stratify patients with severe shock from mild to moderate shock; however, this study did not specifically address its utility in identifying patients with subclinical shock - specifically, the elderly.
The proposed study will determine if StO2 measurements during the first 24 hours post injury correlate with mortality, complications, hospital length of stay and discharge disposition. In doing so, this study will provide pilot data to support a multicenter clinical trial of StO2 targeted resuscitation in the elderly trauma patient.
Yong Wang, Ph.D.
Assistant Professor, Department of Surgery, Division of Otolaryngology
Synaptic mechanisms of auditory temporal acuity during aging
Abstract
The fundamental function of the central auditory system is to extract the timing information embedded in the acoustic signal for survival. In humans, temporal processing is also the key for speech recognition because speech is comprised of sounds with spectro-temporal varying cues. As we age, not only our ability to detect sound (hearing sensitivity), but also our ability to extract timing from sound (acuity) deteriorates. It has long been assumed that temporal processing is secondary to hearing loss. However, certain lines of evidence have indicated that there may be age-related reduction in temporal processing that is independent of hearing threshold; i.e., one can hear "just fine" but may have difficulty understanding conversation. So a key unanswered question is: "Are there physiological changes in the central auditory neurons during aging that could account for this observed loss of temporal processing acuity?" In order to tease apart the hearing loss-related acuity change from the age-related acuity change, we intend to study cellular mechanisms that may underlie the loss of temporal acuity in older animals without the presence of hearing loss. This way, we can exclude the hearing loss variable and directly study the effect of aging on central auditory neurons. In this proposal, we will use CBA mice to study neurons in the inferior colliculus (IC), an auditory brainstem nucleus that is principally involved in extracting interaural timing difference in mammals. Our central hypothesis is that there are cellular physiological changes in IC neurons in normal hearing, older CBA mice (12-14 months) compared to normal hearing, young mice (1-2 months). The specific hypotheses we will be testing are: 1) the excitatory synaptic input to IC principal neurons is "sluggish" in older animals; i.e., AMPA receptor-mediated synaptic current has long latency and longer decay time constant, and 2) GABAergic inhibitory synaptic input to IC neurons is weakened such that discrete excitatory inputs show temporal summation and become less discrete. This study will complement our knowledge regarding to changes in IC that are associated with hearing impairment, and provide a foundation to better understand age-related hearing loss (presbycusis).
Zachary Zimmer, Ph.D.
Senior Scholar, IPIA
Professor, Department of Sociology
Disability trajectories amond older adults in China and Taiwan
Abstract
Past research has suggested there is no one disability pathway experienced by all older adults. Individuals can experience a variety of transitions into and out of states of disability. Thus, various pathways or trajectories are possible. For instance, some may remain fully functional until they die, others may experience several onsets followed by recovery from disability, and still others may deteriorate steadily. Tracking these trajectories is challenging. First, it requires multi-wave panel data. Second, summarizing multi-wave data to identify typical trajectories is methodologically demanding. Previous strategies, based on subjective classification and latent growth curve modeling, are not ideal. This project will adopt an improved and innovative methodological approach that identifies disability patterns based on group-level analysis. Disability will be measured by items that track ADLs and functional limitations. The approach will categorize individuals with similar disability trajectories and then predict membership in these categories based on a set of determinants that fall within five domains: demographic, socioeconomic, network, behavioral and chronic conditions. The analyses will be based on longitudinal surveys conducted in China and Taiwan. These data are among the best available for such work. Moreover, focusing on these settings will allow for policy statements useful for targeting limited resources within societies undergoing rapid population aging. The methodological advances resulting from the project will have broad implications and have the potential to change the way in which disability trajectories are analyzed and conceptualized. A separate aim is to use the results and experience as a springboard for an NIH submission.
2007 Center on Aging Pilot Grant Program Recipients
Maurine Hobbs, Ph.D.
Assistant Professor, School of Medicine, Department of Internal Medicine, Division of Infectious Diseases
MnSOD genotypes and Aging-related mtDNA mutations
Abstract
We previously hypothesized that a common polymorphism (A16V) in MnSOD - shown to impair mitochondrial import [7] - would lead to the accumulation of ROS and increase mtDNA damage; this would impact longevity in a normal population as well as the phenotypic expression of a mitochondrial disease (Charcot-Marie-Tooth type 2A (CMT2A)). The A16V genotype did seem to correlate with increased severity
of disease in CMT2A families, but did not impact MnSOD mRNA levels, mtDNA damage, or longevity in the normal population. However, a 5’ UTR MnSOD polymorphism (G/G genotype) correlated with reduced MnSOD mRNA levels and higher average mtDNA damage (A3243G assay). Additionally, the CEPH longitudinal data allowed us to demonstrate for the first time that individuals with the highest levels of
A3243G mtDNA damage had significantly reduced survival among normal individuals.
However, several observations in our study need clarification: 1) severity of phenotype in some CMT2A families correlated with both MnSOD genotype and maternal inheritance (suggesting a possible role of mtDNA genotype in these families), and 2) although MnSOD 5’-UTR G/G genotypes correlated with decreased expression and higher A3243G damage, paradoxically, they seem to have a slightly increased survival. Since only 10% of the CEPH grandparents had this genotype, this may be too few to give an
accurate assessment of its effects on survival. We hypothesize that 1) mtDNA genotypes modify the effects of MnSOD genotypes; and 2) increased survival of those with lower MnSOD expression may reflect small sample size, or individuals with lower oxidative stress due to mtDNA genotype, lower inflammation, or leaner body mass. The identification of a relationship between MnSOD genotype, mtDNA haplotypes, mtDNA damage, and alterations in longevity or expression of disease has implications both for biologic mechanisms of aging and mitochondrial disease as well as for therapeutics.
Mary T. Lucero, Ph.D.
Professor,
School of Medicine, Department of Physiology
Dysregulation of Fluid Balance and Aging-Related Loss of Regenerative Olfactory Function
Abstract
Humans lose their sense of smell as they age. Dehydration of the body occurs with aging, and may contribute to aging-related loss of olfactory sensory neurons (OSNs) and failure in OSN regeneration. Fluid balance in cells occurs through complex systems of ionic pumps, transporters, and channels that maintain osmotic gradients. Water passively follows ionic gradients via transport through water-specific channels (aquaporins) or non-specifically through other open channels. In the CF mouse, knock-out of the Cystic Fibrosis Transmembrane Conductance Regulator channel disrupts fluid balance in the olfactory epithelium (OE) and causes postnatal loss of OSNs. Normally, transmembrane potassium flow through glial cells is tightly coupled to aquaporin function. In the absence of aquaporins, extracellular potassium increases causing edema and excitotoxicity. In addition, the loss of intracellular potassium causes activation of the apoptotic cascade and cell death. The neuropeptide PACAP is neuroprotective in the OE and cultured olfactory neurons. PACAP reduces both potassium efflux and pro-apoptotic caspases in primary olfactory cultures. We propose to examine whether PACAP can suppress the molecular cascade that causes the dysregulation of OE fluid balance which leads to loss of OSNs and aging- associated anosmia. We will test if PACAP knock-outs exhibit premature OE aging by looking for alterations in cell proliferation, cell type profiles and morphology, and aquaporin expression. A model for OE dehydration, the CF mouse will be examined for potential changes in PACAP and aquaporin expression in vivo. In vitro assays will examine whether PACAP is protective to OE explants grown under hypertonic conditions. Collectively, these studies will identify dehydration-induced changes in OE physiology which lead to age-related anosmia.
Robin Marcus, Ph.D.
Assistant Professor,
College of Health, Division of Physical Therapy
Mechanisms of Improved Glucose Utilization in Elders With Type 2 Diabetes
Abstract
The incidence of T2DM is growing at an astronomical rate, and especially hard hit are the elderly in whom the combined prevalence of T2DM and impaired glucose tolerance is nearly 45%. The elderly also suffer from age-related loss of skeletal muscle mass, strength and function, collectively termed sarcopenia. Because lean skeletal muscle is quantitatively the most important tissue involved in maintaining glucose homeostasis under insulin-stimulated conditions, and is a major site of insulin resistance, loss of lean tissue is thought to play an important role in the development of T2DM, especially in the elderly. The focus of this project is on changes in lean muscle mass and its impact on glucose utilization in an insulin resistant elderly cohort. While our overall goal is to capitalize on resistance exercise (a type of exercise that is more easily tolerated than aerobic exercise) to improve glucose utilization in elders with T2DM, we hypothesize that the exercise itself, rather than the muscle size improvement is responsible for the increase in glucose utilization. Two specific aims are proposed: 1)To determine whether increased quadriceps muscle mass will improve LMGU as measured with positron emission tomography (PET), and 2) to determine whether changes in insulin signaling occur 24 hours and 1 week following the final resistance exercise bout of a 12-week
RENEW protocol. We are proposing a repeated measures design with subjects serving as their own controls to minimize between subjects variability. We will simultaneously measure mass changes, glucose utilization, and insulin signaling in the quadriceps muscles of insulin resistant elders, something not previously done. Three sources [leg muscle glucose utilization by PET, insulin signaling by mRNA from biopsy samples, mass changes from magnetic resonance imaging (MRI)] from the tissue - the quadriceps - specifically targeted in the resistance exercise program are essential to identify the mechanisms of glucose uptake and will be employed. Outcomes will be measured serially at three times to allow us to answer the important question of whether the acute effects of exercise itself, rather than increased muscle mass is the important factor in improving glucose utilization in the elderly. The answer to this question has practical consequences in terms of the type of exercise that is prescribed for the elderly, where both sarcopenia and glucose intolerance are often important health issues.
Monica Vetter, Ph.D.
Professor, School of Medicine, Department of Neurobiology & Anatomy
Role of Microglia in Glaucoma Onset and Progression
Abstract
A significant health problem for our aging population is the prevalence of progressive degenerative diseases of the central nervous system. Glaucoma is a neurodegenerative disease of the retina that is the leading cause of blindness in the US, and is characterized by a progressive loss of vision due to the decline of retinal ganglion cells (RGCs). This is often due to elevated intraocular pressure (IOP), although many cases of normal tension glaucoma exist. The most consistent risk factor for developing glaucoma is aging – the risk of developing glaucoma increases 6-fold for people over 60 years old. Glaucoma shares many hallmark features with other age-related neurodegenerative diseases including progressive loss of neuronal viability, loss of axonal integrity and function, and involvement of non-neuronal populations including microglia. We have investigated retinal changes in a mouse model of glaucoma and have found significant activation of
microglia that precedes other detectable changes in retinal glia or neurons. We hypothesize that microglia are directly involved in the recognition and progressive degradation of declining optic axons. We propose to: 1) determine the earliest age at which adult microglial activation, proliferation and phagocytosis start, 2) characterize the topographical distribution of microglia in relation to declining RGCs, 3) determine whether high-dose irradiation can deplete dysregulated, overactivated microglia from the retina and prevent RGC injury. This treatment has previously been shown to abrogate glaucoma-like pathology through unknown mechanisms. Together these experiments may shed light on the mechanisms underlying neurodegenerative diseases associated with aging.
Jason Watson, Ph.D.
Assistant Professor,
College of Social and Behavioral Sciences, Department of Psychology
Localizing Impairment In Executive Function In Early Alzheimer’s Disease With Neuroimaging
Abstract
Although memory loss is well-established in early Alzheimer’s disease (AD), there is increasing evidence that executive function (EF) is also impaired. EF is defined as the ability to stay on task and to avoid distraction. EF is supported by a complex network of interconnected brain regions including a prominent role for prefrontal cortex in goal-directed, controlled cognition. Although change in EF may not be clinically evident, it can be documented with carefully designed and innovative experimental procedures. For
example, functional magnetic resonance imaging (fMRI) could be used to localize the neural correlates of EF. However, few fMRI studies have addressed the integrity of the EF network in early AD with most of the research emphasis concentrated on the neuroimaging of memory. Hence, the primary goal of the current study is to use fMRI to determine the neural mechanisms underlying the breakdown in EF in early AD. To
achieve this goal, twenty-five healthy older adults and 25 age-matched early AD patients will receive wholebrain fMRI, white matter diffusion tensor imaging (DTI), and neuropsychological testing. Compared to controls, early AD patients will have (1) reduced neural activity in prefrontal cortex as measured by fMRI due to increased presence of frontal plaques, (2) impaired white matter functional connectivity with prefrontal cortex as measured by DTI, and (3) poorer performance on neuropsychological tests of frontal-executive function. To summarize, the current study represents an application of fMRI to the identification and localization of subtle but clinically important deficits in executive function in early AD.
2006 Center on Aging Pilot Grant Program Recipients
Maurine Hobbs, Ph.D.
Assistant Professor of Internal Medicine; Division of Infectious Diseases
Abstract
Reactive oxygen species (ROS) generated by the mitochondria have been implicated as a common feature linking age-related diseases and the aging of organisms. One of the enzymes involved in the scavenging of damaging ROS is mitochondrial manganese superoxide dismutase (MnSOD). MnSOD converts superoxide (O2.-) to hydrogen peroxide (H2O2), which is then converted to H2O and O2 by catalase. While increased levels of MnSOD have been associated with increased longevity in drosophila [1,2], a 50% reduction in activity in heterozygous MnSOD (+/-) mice produced no detectable reduction in lifespan [3]. MnSOD (-/-) mice however die within 8 days of birth with dilated cardiomyopathy due to increased superoxide damage to mitochondrial DNA (mtDNA) and enzymes [4].
In humans, the A16V common (49%) polymorphism in MnSOD disrupts the mitochondrial targeting signal (MTS). This polymorphism impairs the transport of the protein across the inner mitochondrial membrane, resulting in 80% lower activity in Val-MnSOD cells [5]. We hypothesize that this reduced activity leads not only to the accumulation of damaging ROS, but also impairs mtDNA replication, maintenance and repair, with accumulation of mtDNA deletions. The resulting accumulation of mtDNA deletions may impact longevity as well as the phenotypic expression of mitochondrial disease. We propose therefore to study the incidence of MnSOD polymorphisms in aged individuals from a well-defined healthy population (CEPH families) and from a population with a variably expressive mitochondrial disorder due to defects in a mitochondrial fusion protein. As part of our proposal we will develop assays to quantitatively measure mitochondrial DNA deletion. We will apply these assays to both healthy, aged individuals and to disease individuals that differ in severity, regardless of MnSOD genotype. The identification of a relationship between MnSOD genotype, mtDNA defects, and alterations in expression of longevity or disease has implications both for biologic mechanisms of aging and mitochondrial disease as well as for therapeutics.
Petr Trvdik, Ph.D. and Scott Rogers, Ph.D.
Research Associate; Department of Human Genetics and Professor; Department of Neurobiology and Anatomy
Abstract
Alzheimer’s disease (AD) is the most common neurogenerative disease affecting the elderly, often associated with a marked decline in the cholinergic system in various brain regions. We will use the mouse model to investigate the protective role of the cholinergic system during brain aging. Our initial focus will be on the cholinergic nicotinic receptor alpha 7 (Chrna7), the role of which in AD is poorly understood. We will take advantage of two lines of mice, in which we have altered the endogenous Chrna7 gene: The control line, which co-expresses the green fluorescent protein (GFP); and a mutant line, which in addition to GFP also harbors two amino acid changes that genetically mimic the effect of nicotine by desensitization of the alpha7 receptor channel. Both lines will be crossed to the transgenic mouse model of AD and the development of plaques of amyloid-beta protein in disease-relevant regions will be measured. The outcome will elucidate the relevance of Chrna7 in the early onset and progress of the plaque formation. Next, we will generate targeting vectors allowing us to introduce the Cre recombinase in the Chrna7 and Chrna4 loci. This work will provide foundation for future research that will use the Cre/lox technology to identify cell lineages expressing these two receptors, addressing the question as to whether the decline in the cholinergic system is due to a decrease in gene expression or an increase in specific cell death. The proposed project has a high relevance for assessing the role of smoking in Alzheimer’s disease.
