2004 Pilot Studies Awarded:

1. Executive Function, Postural Control and Cholinergic Functions in WMD
   Project Leader: Stephanie Studenski, MD, MPH
   
   Falls are common in older adults and causes are known to be diverse. Age-related changes in visual, somatosensory and vestibular systems are well documented. White matter lesions or disease (WMD) are commonly observed on brain imaging studies with a prevalence of 34-38% or more in non-demented community-dwelling elderly. WMD has been associated with cognitive, gait and balance impairments. Surprisingly, a recent study found that these well-known aging factors, even when combined with scores of WMD severity, only had minor predictive value on gait and balance in the elderly. There may well be additional common underlying factors associated with aging and risk of falling. Preliminary evidence indicates that difficulty with dual-task behaviors during motor functions, like talking during walking, may increase risk for falls, especially in patients with cognitive (executive) impairment, such as seen in Parkinson's disease (PD).
   Subjects with WMD have been shown to have executive cognitive deficits. Neurochemical studies have shown cholinergic deficits in WMD. Using acetylcholinesterase (AChE) PET imaging, our preliminary data suggests that cortical cholinergic denervation in patients with PD (even in the absence of dementia) is associated with executive disturbances and that executive functions improve after cholinergic therapy in Alzheimer's disease. Therefore, cholinergic denervation may be a neurobiological model of executive dysfunction across patient populations. We have VA funding for a study to assess WMD in otherwise normal elderly and to relate WMD to postural control and dopaminergic brain activity using PET imaging. This study has a 6-month prospective falls assessment. We now propose to expand the VA study by performing brain AChE PET imaging and detailed cognitive (executive) testing in the subjects identified with WMD. The overarching goal of this project is to examine the degree to which cerebral cholinergic deficits are associated with executive cognitive deficits and relate to measures of postural control and gait during (executive cognitive-motor) dual-task behaviors in subjects with WMD. In the course of examining the 'cholinergic' hypothesis of executive dysfunction and postural control, striatal dopamine transporter information (as obtained in the VA study) will be used for a validation analysis.



2. Does Skill Acquisition Exercise Improve Balance and Mobility in Persons with Peripheral Neuropathy or White Matter Disease?
   Project Leader: Jessie VanSwearingen, PhD, PT
   
   While balance exercise appears to improve physical performance and may reduce falls, less is known about the specific effects of balance exercise when underlying impairments differ. Therapeutic exercises for balance are heterogeneous, but do not consistently focus on problem solving as a method of skill enhancement, an approach that has been found to be important for motor learning in animal models. This two-year pilot study will assess the feasibility and preliminary effects of a skill-acquisition-based exercise intervention in three groups of 10 subjects each; 1) those with a dominant central cause of imbalance (MRI confirmed significant leukoariosis (white matter disease WMD), 2) those with a dominant peripheral cause of imbalance (peripheral neuropathy (PN), and 3) those with neither condition (healthy controls, HC). All subjects will participate in a 12 week program of progressive skill building and problem solving balance exercise.
   Our primary aims are to:
   1. Evaluate the feasibility of, and barriers to, delivering a group-based exercise regimen of skill-enhancement strategies to older adults with and without WMD and PN. We will refine our intervention based on these findings
   
   
   2. Develop initial estimates of treatment effect in the three subject groups on clinical indicators of gait, balance and balance confidence
   
   
   3. Develop initial estimates of treatment effect in the three subject groups on laboratory indicators of gait in two conditions
   1. Usual gait
   
   
   2. Response to a sudden request to turn. Findings from this study will be used to develop independently funded studies of skill exercise in older adults.
   
   



3. Beliefs and preferences aout participation in clinical research among older adults
   Project Leader: Elizabeth Schlenk, MD
   
   Not enough is known about the factors that enhance retention of older adults with mobility and balance disorders in clinical protocols or the impact of measurement strategies on the ability to complete clinical protocols. Therefore, to provide more specific targeted consultation to Pepper Center investigators, we will embark on a two-phase study. The specific aims of this developmental study are to (a) examine from the perspective of older adults, the expectations, benefits, and barriers to participation in clinical research, with attention to studies of mobility and balance, and (b) examine the preferences and capabilities of older adults for using physical activity assessment strategies in clinical studies in particular. Using a qualitative design in Phase 1, we will interview 40 older adults in the Pepper Center Registry about their expectations, benefits, and barriers of participation in clinical research. The interview data will be audiotaped, transcribed, and coded. In Phase 2, we will enroll 18 older adults in the Pepper Center Registry to evaluate six measures of walking over a 12-week period (paper diary, PDA diary, Web diary, accelerometer, pedometer, and telephone). Using a Latin Square design, each subject will utilize each of the six strategies for one week in random order with a one-week wash out between strategies. Subjects will be asked to record three times during the day the number of times they walked 10 or more continuous minutes during that portion of the day (using paper diary, PDA diary, Web diary, and telephone) or to wear the accelerometer and pedometer from time of arising to time of retiring. Subjects will complete a telephone survey after using each strategy and a mailed survey at Week 12 about ease of use and preference for use of the strategies. Descriptive statistics will be used to analyze the data. The results from the developmental study will be used to advise Pepper Center investigators about retention strategies for older adults with balance disorders who participate in clinical research and preferences and capabilities of older adults using physical activity measurement strategies.




4. Influence of PENS Back Pain Reduction on Attention and Balance
   Project Leader: Debra Weiner, MD
   
   
   Low back pain and balance difficulties are common symptoms in older adults. In younger individuals, mechanical low back pain without neurological deficits is known to impair postural stability. In healthy older adults, compromised attentional control processes are known to negatively impact balance.
   The aims of this pilot study are to determine:
   1. Whether pain affects attention and sensory integration required for postural control in community dwelling older adults with chronic low back pain (CLBP)
   2. Whether pain reduction following treatment is associated with improved attention, sensory integration, postural control and clinical balance in these individuals.
   The pilot is a sub-study of an R01, “Functional Impact of PENS for 65+ Chronic Low Back Pain,” designed to test the effectiveness of a neuroanatomical form of electroacupuncture, percutaneous electrical nerve stimulation (PENS) for the treatment of CLBP in community dwelling older adults. For the sub-study, 24 subjects, 12 each from the PENS and control-PENS arms of the parent study, will be assessed at two time points; before and after the six week treatment phase. The non-pharmacologic nature of the intervention will help to minimize the effects of pain medications on assessment of balance. The assessments for the sub-study will include clinical balance examinations (gait speed, Short Physical Performance Battery, falls history and assessment of fear of falling) and postural control laboratory tests of a dual-task paradigm previously designed to determine the influence of attention on standing postural control in older adults. The dual tasks include postural tasks of varying difficulty and concurrent information processing tasks. Subjects will stand on the platform under the different postural conditions while concurrently performing the information processing tasks. Measures will include magnitude and velocity of center of pressure excursion as assessments of postural sway, and reaction times. If we demonstrate improved postural control with reduced pain, future studies will be designed that incorporate attention training in dual balance tasks in CLBP patients, and determine the relative effects of different CLBP treatments on attention and balance.

2005 Pilot Studies Awarded:

1. Neurotoxin-Induced DA Neurodegeneration: Assessment of Mobility and ERK5 Signaling with Aging
   Project Leader: Jane Cavanaugh, PhD
   
   Dopaminergic function in the CNS is critical for movement. Age related decline in dopamine neurons is modified by neurotrophic factors which may attenuate decline and by environmental toxins. The purpose of this study is to examine the effects of age on DA response to low levels of MPTP toxin and to assess the effect of age on the ERK5 neurotrophic response to toxin. Using 2 month and 24 month old mice, these studies will test the following hypothesis; MPTP-induced motor deficits and DA neuronal death increase with age. This is due, in part, to a decreased expression and activity of ERK 5. Chronic intraperitoneal MPTP injection will be compared to a control chronic vehicle injection. Measures include behavioral tests of motor skills, western blot analysis, immunocytochemistry, image analysis, DA neuron cultures, neuronal cultures and quantitation of cell death.
   
   
2. Fear of Falling: Integrating Psychological and Gait Constructs
   Project Leader: Rakie Cham, PhD
   
   
   The Long term goal is the development of multidisciplinary interventions centered on the integrative management of fear of falling (FOF). The proposed project is focused on the relationship between FOF, its psychological correlates and associated gait/mobility impairments. We will study the effects of FOF on responses to induced fear in subjects with mild mobility impairments. Two groups of older subjects, with and without self-reported FOF, with mild mobility impairments will be recruited. Anxiety and fear symptoms will be compared between the 2 groups. Then, fear will be induced experimentally in a gait laboratory using slippery floors warnings and adaptive fear and gait responses will be evaluated and contrasted between subjects with and without FOF. Additionally, gait performance will be correlated with anxiety and fear-related psychological symptoms. Finally, we will investigate whether repeated exposure to the feared stimulus can reduce maladaptive gait responses to fear.
   
   
   
   The specific aims are to:
   1. Investigate anxiety and fear-related symptoms in subjects with and without FOF
   2. Investigate the impact of induced fear on gait maladaptations (increased variability, stiffness, and attentional demands of walking and reduced gait speed), resulting slipping risk (biomechanical frictional requirements of gait), and fear responses (self-report, heart rate / HR, galvanic skin conductance / GSC and facial expressions of fear / FEF) in subjects with and without FOF
   3. Investigate adaptations in gait and fear responses associated with repeated exposure to induced fear.
   
   
   
3. Modeling Sensory Integration and Attention in Balance of Elderly Subjects
   Project Leader: Patrick Loughlin, MS, PhD
   
   Sensory re-weighting appears to influence postural responses as a form of adaptation to environmental conditions and are manifest as a characteristic form of delayed response. Various forms of divided attention also delay responses. The purpose of this study is to investigate and model interactions between attention and dynamic regulation of sensory integration in elderly and young adults during posturally challenging conditions.
   There are two hypotheses:
   1. Performing an attention –requiring task concurrent with a balance challenge increases the time delay of the postural control system. This effect will be greater in older subjects
   2. The increase in time delay will be greater for an auditory memory task versus and auditory choice reaction time task. This effect will be greater in older subjects.
   Eight healthy young and 8 healthy older ( >60) subjects will undergo clinical examination and then perform standing balance tasks on a posture platform rotating randomly or on a sway – referenced platform while performing a sequence of information processing task conditions (none), auditory choice reaction and auditory memory tasks. Body and platform motion measurements during random platform motion will be used to compute response estimates for which model-based curve fits will be made. Analysis of variance will be used to estimate effects of age and information processing condition. For the sway referenced platform trials, a variety of time varying responses will be estimated, including body sway velocity and A-P hip velocity. Analysis of variance will be used to estimate effects of age and attention condition.

1. National Estimates of Disability after Prolonged Mechanical Ventilation in the Elderly
   Project Leader: Amber Barnato, MD, MPH, MSc
   
   
   Every year, approximately 750,000 older Americans undergo prolonged (>96 hours) mechanical ventilation (MV) in an intensive care unit (ICU) for respiratory failure due to a variety of causes. Although most survive to hospital discharge, there is mounting evidence of ongoing mortality and morbidity post-discharge. Morbidity includes myopathy and muscle wasting, neurocognitive defects, depression and post-traumatic stress disorder, impaired functional status, a wide range of somatic symptoms, failure to return to usual activities, and poor quality of life. The magnitude of this problem is unknown.
   The specific aims are to:
   
   1. To estimate changes in mobility, activities of daily living (ADL), and instrumental activities of daily living (IADL) among survivors of prolonged mechanical ventilation in comparison to changes among those who are hospitalized without mechanical ventilation and to changes among those who are not hospitalized
   
   
   2. To identify demographic, clinical, and treatment-related factors (e.g., use of post-acute care services) that affect the magnitude and direction of changes in physical function
   
   
   3. To estimate the national burden of limitations in physical function after prolonged mechanical ventilation.
   
   
   
2. Effects of Exercise and Weight Loss on Skeletal Muscle Size, Strength and Quality in Older Adults
   Project Leader: Bret Goodpaster, PhD
   
   The loss of muscle mass with aging, sarcopenia, is associated with the loss of muscle strength and a decline in lower extremity function. However, like the rest of the U.S. population, our older adults are also becoming more overweight and obese. Therefore the question of whether older adults should intentionally lose weight and risk the potentially accompanying loss of lean mass is important to consider. Virtually nothing in the literature has addressed whether there may be optimal strategies for older adults to lose weight. This project will examine the ability of exercise, both aerobic, e.g. walking, and resistance training to preserve skeletal muscle mass, strength and muscle quality during intentional diet-induced weight loss in older adults.
   The specific ams are to:
   1. We will determine the effects of calorie restriction-induced weight loss (dieting) on skeletal muscle mass, strength, quality, and lower extremity performance in older adults
   2. We will determine the ability of exercise to attenuate the loss of muscle mass and quality as well as lower extremity performance that may occur with diet-induced weight loss in older adults
   3. We will determine the differential effects of aerobic exercise (e.g. walking) and resistance exercise (e.g. light weight training) on muscle mass, strength, quality and lower extremity performance in older adults undergoing intentional weight loss.



3. Determining and validating minimally meaningful changes in gait speed
   Project Leader: Subashan Perera, PhD
   
   Background: The predictive value of physical performance measures in the elderly in identifying those at risk of future adverse outcomes is well-documented. Emerging literature indicates that changes over time of these measures are also independently informative. If these measures are to be used in clinical practice, magnitudes corresponding to a minimally clinically important within-individual change (MCID) in different subpopulations need to be determined. Our preliminary work has shown that a within-individual change of about 0.05 meters/second in gait speed and 20 meters in 6-minute walk distance (6MWD) may be considered minimally clinically important, while a change of about 0.10 meters/second in gait speed, one point in Short Physical Performance Battery (SPPB) and 50 meters in 6MWD may be considered substantial. Population: Community dwelling older adults from the Health, Aging and Body Composition (HABC) Study (N=3075). Methods: First, distribution- and anchor-based methods of effect size, standard error of measurement and means comparison across anchors will be used to determine MCIDs for gait speed, SPPB, HABC Modified Performance Battery, and 400-meter walk time (400MWT). Change in performance measures between years 1 and 4, will be used as main variables with self-reported difficulty/ease in walking a 1/4 mile and climbing 10 steps as anchors. Analyses will be stratified by baseline status to obtain context-specific estimates. Next, once the criteria for meaningful change are determined, year 6 outcomes between those with and without change will be compared. Specific Aims: To (1) evaluate effect of specific anchors and time period on MCIDs by comparing estimates of MCID to prior estimates obtained using other smaller studies, (2) evaluate the effect of baseline performance on the estimates of MCID, and (3) assess the predictive validity of MCID criteria using outcome status at year 6, accounting for baseline performance. Future Use of Data: The results will be useful in monitoring of older adults in clinical settings, evaluating the benefit of interventions to improve physical performance, and performing rigorous sample size and power estimates in planning of studies with these measures as primary outcomes.



4. Physical Performance and Vitamin B12 Levels in Caucasian and African-American Older Adults
   Project Leader: Elsa Strotmeyer, PhD, MPH
   
   Vitamin B12 deficiency is associated with poor lower extremity function and is an established cause of clinical peripheral neuropathy. However, little is known about how marginal vitamin B12 status, that is very common in older adults, affects physical performance or peripheral nerve function. Vitamin B12 status may be associated with performance through its relationship to peripheral nerve function. Our pilot data for the Health, Aging and Body Composition (Health ABC) Study indicates a strong relationship between poor results on each of the sensory and motor nerve tests and worse lower extremity function.
   The specific aims are:
   1. To determine if low vitamin B12 status is associated with poor sensory and motor peripheral nerve function
   2. To determine if low vitamin B12 status is associated with worse physical performance
   3. To determine if poor peripheral sensory and motor nerve function explains the relationship between low vitamin B12 status and worse physical performance.

2006 Pilot Studies Awarded:

1. Sleep disturbances of Aging: Relationships with Balance and Falls
   Project Leader: Stephanie Studenski, MD
   
   Falls and balance disorders are endemic among older adults. Sleep disturbances of aging, especially self-reports of difficulty starting or maintaining sleep and/or of daytime sleepiness, and objective measures of altered time in deeper sleep stages, increased arousal rates and sleep disordered breathing (SDB) are also very common among older adults. These sleep disturbances of aging have the potential to be frequent but unrecognized contributors to balance disorders and falls, either through direct effects on attention and reaction time, via indirect effects on progression of cerebrovascular disease or hypoxic damage to the brain over time, or other mechanisms. The Pittsburgh Pepper Center has a unique opportunity to begin to build capacity to examine the effect of sleep disturbances of aging on balance and falls. The mission of the Pepper Center is to promote research on balance and aging. This pilot study provides the opportunity to build new bridges to another important research area (sleep disturbances of aging), to create a multidisciplinary team with appropriate expertise and to begin to use data to determine if potentially important relationships exist. Several major studies with extensive relevant information are Pepper Participating Studies. The proposed work for this pilot study will incorporate information on a common set of participants who provided data to the Sleep Heart Health Study (Newman PI), the Cardiovascular Health Study (Newman PI) and the CHS GaitMat Pittsburgh Ancillary Study (Brach PI). This pilot study will create a multidisciplinary research work group with combined and increasingly shared expertise in sleep, balance, gait and secondary data analysis.
   The PRIMARY AIMS of this pilot study are:
   
   
   1. To create working databases for studies of sleep disturbances of aging and balance/falls.
   
   
   2. To perform initial bivariate estimates using the databases in order to establish the potential for further research in this area.
   
   
   
2. A Loading-induced increse in capillarity preserves skeletal muscle regenerative capacity in aged rodents
   Project Leader: Fabrisia Ambrosio, MD
   
   Background: Aged skeletal muscle is characterized by muscle weakness, increased susceptibility to injury, and a decreased regenerative capacity. These factors may contribute to the decreased balance, increased likelihood for falls, and decreased overall function in the elderly. The ability of muscle for hypertrophy or regeneration after injury is dependent on satellite cell activation and proliferation. Through this pilot study, we intend to take preliminary steps towards understanding the underlying mechanism by which exercise results in the maintenance and/or enhancement of muscle mass and regenerative capacity in aging skeletal muscle. Population: A total of 20 young and 20 aging mice will be divided into four groups (n=10 each): 1) young baseline, 2) aged baseline, 3) young overloaded and 4) aged overloaded. Specific Aims: 1. To investigate the role of capillarization on the loading-induced increase in satellite cell count in young and aged mice, 2. to investigate the association of a loading-induced increase in muscle capillarization and improvements in the regenerative capacity of aged skeletal muscle and 3. to investigate the possible mediation by capillarization for satellite cell count and regenerative capacity. Method: Bilateral extensor digitorum (EDL) muscles of the young and aged overloaded groups will undergo a compensatory hypertrophy by excision of the EDL synergist, and will be overloaded for a total of 8 weeks. EDL muscles in the young and aged groups will be harvested at 3 and 10 months, respectively, and analyzed for capillarity, satellite cell count, and regenerative capacity. The relationship between satellite cell count and capillarization following overload will be examined using regression analysis with the age of muscle as a moderating variable. In addition, the whole muscle weight and muscle fiber diameter from baseline and overloaded animals will be compared using regression or ANOVA/ANCOVA methods, considering the age of the muscle as a possible moderator. Future Use of Data: Achieving a mechanistic understanding of the beneficial effects of loading on muscle will provide the framework for future studies in the development of targeted rehabilitation strategies to improve skeletal muscle quality in elderly individuals. Specifically, we will investigate clinically applicable methods to stimulate angiogenesis for the maintenance of muscle mass, enhancement of muscle healing and improvement of functional mobility in the elderly population.
   
   
3. Structural Brain Imaging and Attention-Balance Interference
   Project Leader: Joseph Furman, MD
   
   This pilot study builds on existing research from Dr. Furman’s NIA-funded R01 studies of balance and attention and Dr Aizenstien’s NIH-funded studies of brain imaging. The pilot study also uses resources from the Pepper Center to advance the research efforts in the area of the effects of aging on mobility and balance. The population will consist of 20 subjects enrolled in Dr. Furman’s R01 who will be recruited to participate in this add-on study. They will include healthy community-dwelling older persons: 10 men and 10 women equally divided between two age groups: 65-74 years and 75-85 years. As part of the parent R01, subjects will have undergone extensive cognitive, balance and attention-balance interference testing. This add-on pilot study involves MRI scanning to assess white matter tracts and gray matter losses. This study will provide important preliminary data for several planned new and competing continuation R01’s by Pepper Investigators interested in studying the relationship between structural brain changes and balance. Specifically, Dr. Furman and Dr Nebes have currently funded R01 grants that will use these data for their continuation proposals. Dr. Sparto will use these data for his R01 application. Additionally, this pilot study will provide data for Dr. Aizenstein’s, Dr. Rosano’s, and Ms. Davis’ studies of imaging the aging brain.
   The goal of this pilot project is to explore the hypothesis that intersubject variability regarding the interference between balance and cognition can be explained in part by changes in brain structure. We plan to acquire structural brain imaging on a small group of older individuals who will have been well-characterized with respect to upright balance and gait, vestibular function, sensory interaction, cognition, and attention-balance interference. These data will provide important preliminary data for several planned new and competing continuation R01’s by Pepper Investigators interested in studying the relationship between structural brain changes and balance. This is an exploratory pilot study in which we aim to evaluate the relationship between several brain imaging markers, e.g., gray and white matter volume, white matter hyperintensities, and diffusion tensor imaging measures, with other factors associated with changes in balance and mobility in older persons. This is a pilot study that is combining the resources of two Pepper-affiliated laboratories and the technology core of the Pepper Center. This proposal builds on existing externally peer- reviewed research programs to develop new directions in our studies of balance and mobility in older Americans.
   
   
4. Age-related changes in strength, mobility and balance after critical illness
   Project Leader: Eric Milbrandt, MD, MPH
   
   Each year, over 5 million Americans are discharged alive from intensive care following an episode of critical illness, perhaps the most extreme example of an acute medical insult. It is becoming increasingly evident that patient-reported quality of life after critical illness is poor, especially in the physical function domain. There is a surprising paucity of objective documentation of post-critical illness physical function deficits, their risk factors, and the underlying biologic processes that lead to their development. It is essential that we seek a better understanding of these elements to direct future efforts to prevent or mitigate critical illness-associated functional decline and to inform policy making decisions about payment for rehabilitation services. Eligible patients for this pilot study are those enrolled over the first two years of the parent study, an observational cohort study of 380 mechanically ventilated adult ( 18 years) ICU patients who require >24h of mechanical ventilation. Ages are expected to range from 18 to 95+ years, with >50% of subjects aged ≥65 yrs. We will augment the existing ICU cohort study with additional measures of baseline and within-hospital nutrition, strength, muscle mass, and other potential explanatory variables, including serial plasma samples for analysis of the cytokine response to critical illness. As our primary outcome, we will evaluate survivor strength, mobility, and balance at hospital discharge and at 1, 3 and 6 months after hospital discharge as determined dynamometer-assessed grip/quad strength, the Short Physical Performance Battery (SPPB), and the Survey of Activities and Fear of Falling in the Elderly (SAFFE). We will use the data generated by these investigations as key preliminary work for future R01 and other NIH-based grant proposals aimed at developing and testing screening tools to identify high-risk individuals early in the course of their illness and assessing potential early intervention strategies.