UNIVERSITY OF PITTSBURGH
Claude D. Pepper Older Americans Independence Center

Jennifer Brach, PhD, PT, FAPTA
Principal Investigator		   412-383-6533   jbrach@pitt.edu
Steven Handler, MD, PhD, CMD
Co-Director		   412-647-1452   steven.handler@va.gov
Bari Guzikowski
Program Manager		   412-692-2477   bmg96@pitt.edu
     
CENTER DESCRIPTION

Gait and balance disorders in older persons are common, disabling and complex. In order to prevent and treat these disorders, a concentrated, multidisciplinary effort to understand causes and consequences, and to develop innovative treatments, is needed. The team of investigators at Pittsburgh offers complementary expertise, outstanding research productivity, and ongoing studies to address this need through a Claude D. Pepper Older Americans Independence Center. This program includes investigators from medicine, bioengineering, rehabilitation, epidemiology/public health, biostatistics, psychology, pharmacology, biology, imaging, informatics, and health services research. Our long range goals are: to address the critical need to improve mobility, balance, and falls risk, both through improved understanding of their causes and through development of preventive and therapeutic interventions.

Our specific aims for the current cycle are to:

  1. Promote multidisciplinary research to elucidate the causes, consequences and management of age-related changes in mobility and balance.
  2. Further extend our work into two high potential areas: a) translational investigations to examine interactions between multiple systems at the level of molecules, signaling systems, cells and their organelles, and tissues, as they impact mobility and balance in living organisms, and b) impact on individual older adults of novel interventions to enhance mobility and balance.
  3. Train young investigators from multiple disciplines to become national leaders in age-related mobility and balance problems in a vibrant, collaborative environment and build a translational sciences workforce through collaborative basic and clinical sciences team mentoring.
  4. Serve as a champion and invaluable resource for investigators, research programs, institutions, OAICs and the public in the area of mobility and balance in older adults.

The Program has 7 Cores:

  • Leadership/Administration Core
  • Pilot Exploratory Studies Core
  • Research Career Development Core
  • Clinical Populations Outcomes Core
  • Integrative Systems Core
  • Data Management, Analysis and Informatics Core
  • Biology of Mobility and Aging Core

Training support is provided directly to Pepper Scholars and also to trainees in related programs.

Research strategies to achieve OAIC goals:

  1. Use Resource Cores to share expertise among projects and investigators.
  2. Use pilot and developmental funds to extend existing studies and develop new studies.
  3. Promote and reward collaborative multidisciplinary teams of investigators with complementary expertise by prioritizing them for funds and support.
  4. Encourage new partnerships with highly productive investigators and programs by offering to partner with our expertise and resources.
  5. Reward development of new methods and techniques.
  6. Facilitate the use of a common set of core measures of mobility, balance and falls in human studies so results can be merged or compared.
  7. Leverage resources by collaborating with other Centers at Pitt, other OAICs, and Centers around the US.
  8. Sponsor seminar series to promote general awareness of expertise and resources, review progress in ongoing projects and facilitate new collaborations.
  9. Support the new OAIC career development program with salary-funded Pepper Scholars in addition to resource support for Novice, Transition to Independence, and Visiting Scholars, with a focus on multidisciplinary teamwork, thematic knowledge, and specific skills.
  10. Promote national discussion through programs at national meetings and other dissemination methods.
  11. Provide administrative infrastructure, intellectual leadership, and oversight.

CORES
Leadership and Administrative Core (LAC)
Leader 1:    Jennifer Brach, PhD, PT, FAPTA   jbrach@pitt.edu
Leader 2:    Steven Handler, MD, PhD, CMD   steven.handler@va.gov
The Leadership Administrative Core (LAC) is responsible for the organizational, communication and regulatory functions of the Pittsburgh Pepper OAIC. The LAC receives valuable input and direction from 5 advisory groups including 1) the External Advisory Board (EAB) (national experts), 2) the Institutional Advisory Board (multidisciplinary group of experts on aging from the University and the UPMC health system), 3) the Community Advisory Board (representatives from local health care agencies, IRB, media, and local leaders), 4) the REC Advisory and the PESC Advisory groups (both internal and external experts). These boards provide advice and insight to the Executive Committee composed of leaders and co-leaders of OAIC cores.

The specific aims of the LAC are to:
  1. Foster communication and multidisciplinary collaboration among OAIC investigators, cores and projects.
  2. Promote awareness and involvement in our work by relevant investigators and research programs in and outside the University of Pittsburgh.
  3. Represent the OAIC to the University through the Institutional and Community Advisory Boards.
  4. Represent the OAIC to other OAICs and the larger academic, NIH, clinical and lay communities.
  5. Through the EAB, maintain independent oversight of OAIC processes, resources and progress.
  6. Establish new independent REC and PESC oversight committees as requested by NIA.
  7. Provide research oversight and safety monitoring for all OAIC human studies and help establish a Data and Safety Monitoring Board as necessary.
  8. Sponsor a Research Seminar series, an Annual Retreat, Workgroups, a publication/communication committee, formal grant reviews, and new partnership initiatives.
  9. Increase basic and translational research partnerships.
  10. Provide administrative support and manage financial records for the OAIC as a whole.
  11. Collaborate outside the Institution on OAIC related themes.



Research Education Component (REC)
Leader 1:    Elsa Strotmeyer, PhD, MPH   strotmeyere@edc.pitt.edu

The goal of the Research Education Component Core (REC) of the Pittsburgh OAIC is to provide a comprehensive, individualized career development program to prepare future investigators for mobility, balance, and aging research. Our ultimate goal is to develop highly qualified investigators to conduct high quality and high impact research in the field of mobility, balance, and aging and who will become leaders in this field nationally and internationally. We continue to improve our programs with input from our trainees, mentors, Executive Committee, and External Advisory Committee.

Our specific aims of the REC are to:

1. Promote careers in mobility, balance, and aging research among junior investigators at 3 levels:

  • Novices: research mentees at the pre-and post-doctoral level
    Goal: submission and funding of their first research award (F series, Foundation, etc.)
  • Pepper Scholars: junior faculty with initial expertise who receive OAIC salary support
    Goal: submission and funding of a career or R-type award
  • Transition to Independence Investigators: junior faculty with independent career awards
    Goal: submission and funding of an R-type award

2. Foster Trainee success with a comprehensive training program that:

  • Prepares trainees to engage in translational teams across basic, clinical, and health services science
  • Educates in aspects of basic and clinical research via the Clinical and Translational Science Institute (CTSI) and our complimentary sessions that focus on aging, mobility, and balance
  • Creates and monitors individualized teams of experienced mentors
  • Offers multidisciplinary research experiences involving OAIC Cores and investigators, as well as retreats, and a peer-led seminar series that includes sessions for manuscript and grant review, career development, and leadership with CTSI
  • Sponsors a 2-semester intensive grant writing course resulting in a polished grant proposal
  • Uses stipends to protect Scholar time for research and training and provides targeted financial support for initial pilot projects and other opportunities
  • Provides individualized advice, feedback, career guidance, and support to trainees and mentors.

3. Manage all aspects of the training program, including promotion, recruitment, selection, scheduling, monitoring, and evaluation of trainees and the program. The REC helps every Scholar complete a Customized Career Development Plan (CCDP) that is used to plan activities and monitor progress.

4. Collaborate with other cores and units within and outside the institution for OAIC related themes.

5. Enrich Scholar training through participation in the OAIC Coordinating Center’s Visiting Scholar Program.



Pilot and Exploratory Studies Core (PESC)
Leader 1:    Daniel E. Forman, MD   formand@pitt.edu
Leader 2:    Aditi Gurkar, PhD   agurkar1@pitt.edu

The goal of the Pilot/Exploratory Studies Core (PESC) of the Pittsburgh OAIC is to promote and fund innovative multidisciplinary pilot research in the topic areas of mobility, balance and aging and their interfaces. The expected outcomes for funded pilot studies are their successful completion in a timely manner, that the findings be presented at a national scientific meeting and submitted for publication in the peer review literature. Moreover, the findings from these pilot studies are expected to support the development of mentored career development awards and independent federally funded grant applications.


The specific aims of the PESC are to:

  1. Promote innovative multidisciplinary research on mobility, balance and aging.
  2. Act as a bridge to foster interactions between the basic geroscience, clinical and community-based research communities.
  3. Encourage supplements to leverage ongoing basic, translational, clinical and community-based studies.
  4. Promote innovative techniques and methods for research on mobility, balance and aging.
  5. Partner with other University of Pittsburgh groups (e.g. Clinical and Translational Science Institute and Aging Institute) that also offer pilot study awards, in addition to the Division of Geriatrics, to increase overall funding for individual pilot projects.
  6. Promote, evaluate, and select for funding Pilot projects ($40,000 per year), small REC Pilots (up to $10,000), and Developmental projects ($70,000 over two years).
  7. Conduct post-award processes (e.g., monitor adherence to ethics, safety, privacy, tracking of subsequent productivity and other related matters) for pilot and developmental projects.



Biology of Mobility and Aging Core (BMAC)
Leader 1:    Toren Finkel, MD, PhD   FINKELT@pitt.edu
Leader 2:    Stacey Rizzo, PhD   RIZZOS@pitt.edu

Problems with mobility and balance with aging are due to changes in multiple systems that develop due to age-related alterations in basic biological processes. Insights accumulated over the last two decades in the basic biology of aging are poised to be rapidly translated into new interventions to promote a longer healthspan, which depends in large part on maintaining mobility and balance. However, significant barriers must be overcome before the approaches and technologies of basic science can be efficiently translated into clinical practice. While the OAIC partnered over the last 10 years with individual basic scientists who study aging, there was not yet a critical mass of activity to justify a distinct Pepper Core. With a major new investment creating an Aging Institute dedicated to using biological sciences to advance aging basic discovery and translation, the OAIC now proposes a Biology of Mobility and Aging Core (BMAC). The goal of this new core is to promote both basic-to-human and human-to-basic translation. The BMAC will provide an engine of discovery and innovation to guide and enhance our clinical and translational efforts. Specific emphasis includes using basic science approaches to uncover novel biomarkers and compounds that might aid in the treatment of age-related alterations in mobility and balance. Moreover, the BMAC will assist in the development and characterization of innovative pre-clinical animal models that can be used to mechanistically explore the fundamental basis of age-related changes in mobility, gait and balance.

The specific aims of the BMAC are to: 

  1. Provide expertise in biomarker development as potential intermediate markers of the aging processes in human studies of aging. This will include the development of novel model systems to accelerate biomarker development.
  2. Provide access and guidance to the design and analysis of high throughput screening (HTS) systems and ‘omic’ technologies for identifying potential molecular targets relevant for mobility, balance and aging.
  3. Provide access to and interpretation of various preclinical model systems. This includes cellular (e.g. muscle stem cells), rodent, zebrafish, and drosophila organisms and establish a preclinical phenotyping platform that faithfully reflects age-related mobility impairment in humans to enable translational studies.
  4. Support the research training mission of the Pepper Center by enhancing the capacity for Team Science and promoting basic-translational-clinical interactions.



Clinical and Population Outcomes Core (CPOC)
Leader 1:    Steven Albert, PhD, MSPH   smalbert@pitt.edu
Leader 2:    Andrea Rosso, PhD, MPH   alr143@pitt.edu

The Clinical and Population Outcomes Core (CPOC) is dedicated to promoting multidisciplinary research on mobility, balance, and aging through 1) access to human subjects for studies and advice on screening, recruitment, and consent, 2) access to existing data sets from Pitt aging studies for secondary analysis, and 3) resources and space for clinical assessment of mobility and balance. To meet these aims, we provide registries of interested community-dwelling older participants and a Long-Term Care (LTC) Registry of residents from participating institutions, a searchable database on existing Pitt Aging data sets from longitudinal and clinical trial studies, a library of tests and scales with instructions, scoring and advice on implementation, and information on use of our Senior Mobility in Aging Research and Training (SMART) Center space for clinical studies. We successfully launched the Platinum LTC Registry (seniors residing in assisted living and skilled nursing facilities who have consented to research contact).  To date, over 40 facilities signed agreements to participate as recruitment sites, and over 400 residents consented to be contacted.  Our Community Registry, with over 2500 older participants, was a key recruitment source for 60 research studies.  The CPOC SMART Center provided clinical research space for multiple pilot and external projects.  Our Community Advisory Board (CAB) continued to foster community collaboration, stakeholder involvement and feedback on OAIC activities.


Our specific aims of the CPOC are to:

  1. Engage older adults from the community and LTC settings in research by expanding large registries of consented and well-characterized older adults accessible to investigators.
  2. Provide training to investigators on appropriate contact, screening, and consent strategies for research with older populations.
  3. Recruit and maintain a diverse community advisory board of older adults and leaders in aging services to review proposed research and advise the OAIC.
  4. Provide access to ongoing and completed Pitt cohort studies, specimens, clinical trials, and existing databases.
  5. Provide expertise in clinical assessment methodology by providing a standardized set of forms and instructions to promote a common dataset of core assessments for mobility, balance, and falls.
  6. Use noninvasive, portable technology to examine mobility, balance, and physical activity in clinics and in the field through our novel mobile laboratory.
  7. Provide access to space and equipment for OAIC-related studies through our SMART Center.
  8. Promote dissemination of our findings within and outside the Pittsburgh community.



Data Management, Analysis and Informatics Core (DMAIC)
Leader 1:    Subashan Perera, PhD   pereras@dom.pitt.edu
Leader 2:    Charity Moore Patterson, PhD, MSPH   CGP22@pitt.edu

The overarching goal of the Data Management, Analysis and Informatics Core (DMAIC) is to ensure data and analytic integrity, transparency and reproducibility by continuing to serve as a central source of methodological expertise and a service provider to the researchers of the Pittsburgh Older Americans Independence Center (OAIC).  Methodological expertise is most beneficial when provided by a team such as DMAIC familiar with the balance and mobility in aging theme, specialized measures and methods of the OAIC.


Our specific aims of the DMAIC are to:

  1. Meet data management requirements of Pittsburgh OAIC PESC, REC, developmental and external projects. 
  2. Support quantitative and facilitate qualitative analysis needs of Pittsburgh OAIC projects.
  3. Provide informatics expertise to Pittsburgh OAIC projects.
  4. Support the training mission of the Pittsburgh OAIC with Pepper Scholars and other trainees.
  5. Develop new techniques, as wells as novel application of existing methods to address OAIC-related unmet needs and methodological challenges. 
  6. Collaborate with other cores and units within and outside the institution on OAIC theme-related activities.


Integrative Systems Core (ISC)
Leader 1:    Caterina Rosano, MD, MPH   car2350@pitt.edu
Leader 2:    Mark Redfern, PhD   mredfern@pitt.edu

Problems of mobility and balance in the aged require multidisciplinary study because they are complex and multifactorial. Advances require integrating expertise and technical resources from biomechanics, physiology, neural control of movement and biology. Thus, the goal of the Integrative Systems Core (ISC) is to provide integrative, multidisciplinary knowledge, skills and techniques that foster an understanding of the biomechanical, structural, functional, physiological and biological influences on age-related mobility and balance. 

Our specific aims of the ISC are to:

  1. Provide cutting-edge resources and expertise to concurrently study both whole-body as well as multiple systems and physiologic mechanisms affecting mobility and balance during aging, both during study planning as well as during implementation and analysis.
  2. Develop and test novel techniques and approaches to address gaps and needs for multi-system evaluation of mobility and balance.
  3. Support the training mission of the OAIC by educating and supporting the work of Pepper trainees through workgroups, seminars, “field trips” and active involvement in trainee research projects.
  4. Collaborate with other cores and Centers in and outside Pitt on OAIC-related activities.
  5. Continuously monitor, evaluate and communicate about Core activities both within and among Core laboratory leaders, as well as with other Pepper Cores, Pepper leadership and NIA.
CAREER DEVELOPMENT
REC Scholar, Research & Grants Funded During Pepper Supported Time Years /
Publications
 
Aimee N. Pickering, MD, MS
Assistant Professor / University of Pittsburgh School of Medicine
implementation strategy for deprescribing inappropriate medications in older adults with diabetes
 2023-2025 /
11 (total)
6 (1st/Sr)
 
Brendan McNeish, MD
Assistant Professor / University of Pittsburgh, Physical Medicine and Rehabilitation
aging related structural brain assessment using neuro-imaging
 2023-2025 /
16 (total)
9 (1st/Sr)
 
Nami Safai Haeri, MD
Assistant Professor / University of Pittsburgh School of Medicine
A Novel Method to Examine Muscle Health in Frail Elderly
 2022-2024 /
10 (total)
7 (1st/Sr)
 
Megan M. Marron, PhD
Assistant Professor / University of Pittsburgh School of Public Health
Using –omics to better understand the underlying biology of decline in muscle, liver, and physical functioning with aging
 2022-2024 /
31 (total)
14 (1st/Sr)
 
Marcelo Rocha, MD PhD
Assistant Professor / University of Pittsburgh School of Medicine
Dimethyl-Arginine and Large Vessel Occlusion Stroke in Older Adults
 2022-2024 /
32 (total)
7 (1st/Sr)
 
Past Scholars
Mary Kotlarczyk, PhD, University of Pittsburgh School of Medicine (2017-2020)
Emily Rocha PhD, University of Pittsburgh School of Medicine (2019-2021)
Lena Makaroun MD, MS, University of Pittsburgh/VA Pittsburgh Center for Health (2019-2021)
Samaneh Farsijani, PhD, MSc, University of Pittsburgh School of Medicine (2020-2021)

PILOT/EXPLORATORY PROJECTS (8 Pilot Projects Listed)
1. Project Title: The relationship between dietary protein intake, gut microbiome and mobility in older adults
  Leader: Samaneh Farsijani, PhD; Co-Is: Drs. Anne Newman and Subashan Perera
 

This study builds on the NIA-funded Study of Skeletal Muscle and Mobility in Older Adults (SOMMA), with an add-on study focused on the role of nutrition and the microbiome in influencing muscle health and mobility. 

Significance: The imbalanced composition of gut microbiome(dysbiosis), in aging is associated with gait speed and frailty. Protein intake is an important anabolic stimulus for muscle protein synthesis and may influence the gut microbiome, which can in turn affect muscle function and walking ability. Despite emerging evidence supporting the roles of amount, source and pattern of protein intake in promoting muscle health and mobility, associations with age-related dysbiosis are unclear. This study will determine the relationships between dietary proteins and gut microbiome and help inform development of age-specific dietary recommendations to maintain muscle health and mobility by promoting a healthy gut microbiome. 

Hypothesis: Higher amount and even within-day distribution of protein intake, as well as higher quantity of plant-based proteins are independently associated with increased diversity of the gut microbiome.

Approach: Two 24-h food recalls, a food frequency questionnaire, and fecal samples (for 16S rRNA analysis) will be collected from 200 SOMMA participants (age ? 70-y) residing in Pittsburgh at baseline, for 80% power with ?=0.05 for detection of R2=0.065 between protein intake measures and microbial diversity. 

Innovation: This is the first study to address associations between dietary protein parameters and gut microbiome composition in older adults and will provide preliminary data to test associations with gait speed and mobility in SOMMA. 

Core Collaborations/grants: ISC (Forman and SOMMA), DMAIC (analysis), REC (Scholar). 

Future: Findings will support Dr. Farsijani’s K01 application. 
 
2. Project Title: Increasing gait automaticity in older adults by exploiting locomotor adaptation
  Leader: Gelsy Torres-Oviedo, PhD; Co-Is: Andrea Weinstein, PhD, Andrea Rosso, MPH, PhD , Douglas Weber, PhD
 

This study integrates the insights of 4 dynamic investigators with complementary expertise in a pilot study of mechanisms and clinical effects of locomotor adaptability training. 

Significance: Age-related deficits in locomotor adaptation are common and linked to disability and falls. Older adults are slower at adjusting movements when interacting with a new environment and have difficulty switching motor patterns when transitioning across walking conditions. While locomotor training using split-belt walking (SBW), in which legs move at different speeds, has known efficacy, neither the underlying mechanisms nor clinical relevance of improvements are known. 

Hypothesis: SBW-related improvements in locomotor adaptation will translate to increased community mobility activity in older populations by reducing the high cognitive load associated with walking. 

Approach: Locomotor adaptation will is studied with a novel SBW protocol. Initial walking automaticity is assessed with wireless functional near-infrared spectroscopy (fNIRS) during dual-task treadmill walking. Mobility performance is evaluated with instrumented walking surfaces and portable sensors recording body motion and muscle activity. Community mobility is assessed with integrated analysis of accelerometry and global positioning system (GPS)-based measures of walking in-home and in the community. We focus on two measures of adaptability: 1) rate at which individuals adapt to SBW and 2) capacity to switch between context-specific walking patterns. We also determine if improving locomotor adaptability changes the neural and cognitive characteristics post-training. We plan for 30 participants for sufficient power. 

Innovation. SBW targets locomotor adaptability. We characterize the relation between locomotor adaptability and GPS-based measures of community mobility, and functional gait assessment predicting fall risk. 

Future: This will provide needed data for an NIH grant. 

Core Collaborations: ISC (Torres-Oviedo and Redfern labs), DMAIC (analysis). 
 
3. Project Title: The muscle-brain axis: Exploring the effect of skeletal muscle activity on the connectome and transcriptome of aging animals
  Leader: Amrita Sahu, PhD
  Aims: The overarching goal of these studies is to test the central hypothesis that skeletal muscle contractile activity promotes a more youthful cognitive connectome (Aim 1) and spatially defined transcriptomic profile (Aim 2), ultimately contributing to enhanced cognitive capacity. Background: Physical activity attenuates age-related declines in neurostructual, neurofunctional, and neuromolecular profile of the brain. However, the mechanisms that underlie this beneficial effect of physical activity on aging brains are poorly understood. Individual approaches of cognitive testing, brain architecture analyses, and neuromolecular probing are often used to understand the aging process within the brain. In order to gain a comprehensive mechanistic understanding of aging brain and its response to physical activity, an integrated approach combining behavioral testing (cognition), connectomics (neuroimaging), and spatial –omics (neuromolecular) analyses are warranted. Methods: All animal experiments will be performed with prior approval from the Institutional Animal Care and Use Committee of the University of Pittsburgh. Young and aged male C57BL/6 mice will be used in the studies (Young: 3-6 months, Aged: 21-24 months,). For inducing physical activity in animals, mice will be subjected to a neuromuscular electrical stimulation (NMES) protocol to elicit repetitive skeletal muscle contractions. Mice will receive five stimulation sessions over a period of two weeks, with each session consisting of 20 repetitions. Two days after the last session, animals will be subjected to behavioral testing (spatial memory, short-term memory, and motor activity) or neuroimaging (connectomics). After neuroimaging, the brains will be probed for spatial transcriptomic. Future use of data: We anticipate that using this integrated approach we will be able to identify mechanisms that underlie the benefit of skeletal muscle contractile activity on brain health. Findings from this study will lay the groundwork for developing targeted rehabilitation protocols designed to enhance cognitive functioning in an older population. Preliminary results from this study will also be leveraged to apply for larger funding to determine the effect of NMES on cognitive connectome based on sex. Core Collaborations: BMAC, ISC
 
4. Project Title: Interplay between Balance, Gait and Sleep in Older Adults with Glaucoma
  Leader: Rakié Cham, PhD, Shachi Tyagi, MD, MS
  Background. Falls are a major health risk for adults with glaucoma. While glaucoma-related changes in vision certainly contribute to falls, other well established risk factors for falls occurring at a greater rate in glaucoma than in older adults need to be considered. Poor sleep, an example of such risk factors, is well documented in glaucoma. In older adults without glaucoma, poor sleep negatively impacts falls risk and postural control, and causes other adverse health outcomes. Yet, we do not know if poor sleep function and disruption in sleep architecture associated with glaucoma, i.e. beyond aging-related symptoms, contribute to the increased prevalence of falls and reduced postural control in this clinical population. The overarching goal of the proposed project is to understand the interplay between sleep and postural control in glaucoma. Specific Aims. Three specific aims will be pursued. In Aim 1, participants with undergo detailed sleep assessments. In Aim 2, the relationship between sleep metrics and postural control function during standing and walking will be examined. In Aim 3, dual-task paradigms will also be used during balance/gait testing to examine attentional influences on postural control. Methods. Adults with advanced glaucoma and controls will participate in the proposed experiments. Our well-established balance/gait assessment protocols including dual-task experiments will be conducted to assess postural control function in various sensory challenging conditions. These protocols probe the ability to integrate multisensory information relevant for mobility through dynamic computerized posturography and gait analyses. In addition, rigorous assessments of sleep will be performed, including validated self-reported measures of sleep function and in-home EEG-based sleep testing. This state-of-the-art sleep assessment technology will provide detailed information related to sleep architecture by recording objective measures of various sleep stages duration. Appropriately constructed mixed linear statistical models will be used to test the hypotheses associated within each aim. The potential mediating effects of sleep on postural control impairments in glaucoma will be of primary interest. Future use of data. The findings can be used to identify specific sleep domains as potentially modifiable risk factors to improve balance/gait and reduce falls-related adverse health outcomes in glaucoma. The data collected in the proposed project may be used to plan larger-scale intervention studies. Core Collaborations: DMAIC, ISC
 
5. Project Title: The muscle-brain axis: Exploring the effect of skeletal muscle activity on the connectome and transcriptome of aging animals
  Leader: Sahu, A
  Aims: The overarching goal of these studies is to test the central hypothesis that skeletal muscle contractile activity promotes a more youthful cognitive connectome (Aim 1) and spatially defined transcriptomic profile (Aim 2), ultimately contributing to enhanced cognitive capacity. Background: Physical activity attenuates age-related declines in neurostructual, neurofunctional, and neuromolecular profile of the brain. However, the mechanisms that underlie this beneficial effect of physical activity on aging brains are poorly understood. Individual approaches of cognitive testing, brain architecture analyses, and neuromolecular probing are often used to understand the aging process within the brain. In order to gain a comprehensive mechanistic understanding of aging brain and its response to physical activity, an integrated approach combining behavioral testing (cognition), connectomics (neuroimaging), and spatial –omics (neuromolecular) analyses are warranted. Methods: All animal experiments will be performed with prior approval from the Institutional Animal Care and Use Committee of the University of Pittsburgh. Young and aged male C57BL/6 mice will be used in the studies (Young: 3-6 months, Aged: 21-24 months,). For inducing physical activity in animals, mice will be subjected to a neuromuscular electrical stimulation (NMES) protocol to elicit repetitive skeletal muscle contractions. Mice will receive five stimulation sessions over a period of two weeks, with each session consisting of 20 repetitions. Two days after the last session, animals will be subjected to behavioral testing (spatial memory, short-term memory, and motor activity) or neuroimaging (connectomics). After neuroimaging, the brains will be probed for spatial transcriptomic. Future use of data: We anticipate that using this integrated approach we will be able to identify mechanisms that underlie the benefit of skeletal muscle contractile activity on brain health. Findings from this study will lay the groundwork for developing targeted rehabilitation protocols designed to enhance cognitive functioning in an older population. Preliminary results from this study will also be leveraged to apply for larger funding to determine the effect of NMES on cognitive connectome based on sex.
 
6. Project Title: Interplay between Gait and Bladder in Older Women with Urgency Urinary Incontinence and Nocturia
  Leader: Shachi Tyagi, MD, MS; Becky Clarkson, PhD
  Background. Falls, a critical geriatric syndrome, affects over 1 in 4 older adults (65 years and older). This risk of falls increases several fold in individuals with urgency urinary incontinence (UUI) particularly during toiletingrelated activities during the day and at night, but the cause of this increased risk is not well established. Previous studies suggest a prioritization of cortical bladder control over gait and stability during the state of urgency and strong desire to void (SDV) but do not establish direct causality. Sleep disruption has a similar effect due to impaired daytime attention. Divided attention theory states that a person’s information processing capacity is finite, and each task being performed takes away a proportion of it. Thus, if the tasks being performed require more processing capacity than is available then the performance of one or more tasks will be affected due to the mechanism of prioritization of one task over the other. Given the high prevalence of both bladder urgency and poor sleep in older women with UUI and nocturia, according to divided attention theory, executive control of gait reduces leading to high risk of falls. The effect of poor sleep and UUI on gait is not well studied. We propose to assess in older women with UUI and nocturia the effect of SDV on gait parameters at baseline, and when challenged by attentionally demanding dual task. We also propose to study the effect of bladder and sleep treatments on these parameters. The exploratory goal of this project is to examine overnight gait characteristics at home in women with nocturia. Specific Aims. Three specific aims will be pursued. Aim 1, To quantify the effect of bladder fullness (post void (PV) vs. SDV) on dual task gait parameters in older women with UUI and nocturia. In Aim 2, we will quantify the effect of treating UUI with or without behavioral sleep intervention on dual task gait parameters in this population. In our exploratory Aim 3, overnight gait characteristics at home in women with nocturia will be examined. Methods. Women over 60 years of age with UUI and nocturia already participating in our sleep and nocturia study will undergo the additional gait assessment. We will use a dual task walking paradigm to examine the impact of divided attention on gait speed, timing, and quality in two physiological bladder conditions (empty bladder: post void (PV), and full bladder with strong desire to void (SDV)) before and after 8-week treatment with mirabegron an FDA-approved, first-line treatment for UUI with or without 4-week behavioral sleep intervention (brief behavioral treatment for insomnia: BBTI). These protocols measure the effect of additional UUI and sleep information on gait parameters as a proxy for stability and mobility within the home environment. Appropriately constructed mixed linear statistical models will be used to test the hypotheses associated within each aim. The effects of bladder fullness on the change in gait parameters during dual tasking (dual task cost) will be of primary interest. Future use of data. The findings can be used to identify specific gait measures impacted so that specific interventions can be designed for screening and treatment to prevent and reduce falls-related adverse health outcomes in individuals with UUI and nocturia. The data collected in the proposed project may be used to plan larger-scale intervention studies.
 
7. Project Title: Identifying genetic variants associated with human rapid agers
  Leader: Satoshi Okawa, PhD
  Specific Aims: The aims of the current proposal are to (1) perform genome-wide association study (GWAS) on rapid ager (RA) and healthy ager (HA) populations from UK BioBank. (2) Perform whole genome sequencing (WGS) of RAs and HAs from the Solve-it cohort and validate candidate single nucleotide variants (SNVs) from (1). (3) Develop Healthy Aging Genetic (HAG) index based on SNVs. (4) Carry out causal inference between the SNVs and differentially abundant metabolites and SASP. Background: Aging comprises of diverse phenotypes influenced by multiple factors including genetics, epigenetics, environmental influences, diet, exercise and the microbiome. Currently, it remains unclear to what degree genetics influence the varying rates of aging among individuals, the extent of their impact, and their causal relationship with RA-related metabolites and SASP. Uncovering such genetic influencers of biological age could serve as powerful predictors of an individual's health span and susceptibility to age-related diseases, potentially shifting the paradigm of current precision medicine. This study aims to bridge this gap between biological aging and genetics using WGS data. Methods: RA and HA populations will be derived from UK BioBank based on participants’ walking speeds. Subsequently GWAS will be conducted on these populations to identify candidate SNVs associated with rapid aging. These SNVs will be validated in the geographically independent Solve-it cohort through WGS of its participants to ensure the generalizability of our findings. Using machine learning approaches on the candidate SNVs, we will develop the HAG index to predict genetically healthy/rapid agers. Finally, statistical causal inference will be applied between the SNVs and our metabolomics and senescence associate secretome data from the same cohort to elucidate the potential mechanisms by which these SNVs influence biological aging through metabolic pathways. Future Uses: The hit SNVs and HAG index will be applied to other cohorts to assess their broad applicability, especially in predicting falls, mobility issues, frailty, critical care patient outcomes, risks of aging-related degenerative diseases, and overall healthy aging. In particular, this pilot study will generate crucial data for future grant applications to fund our long-term goal of comprehensively characterizing RAs by producing more WGS and epigenetic data. This will facilitate the development of accurate predictive tools for clinical use, helping to prevent falls and frailty and to elucidate the molecular mechanisms of rapid aging, from genetics through to metabolic pathways.
 
8. Project Title: Defining age-related changes in brain collateral arterioles with a novel vessel mapping algorithm and high-resolution magnetic resonance angiography
  Leader: Marcelo Rocha, MD, PhD; Minjie Wu, PhD; Howard Aizenstein, MD, PhD
  Background: The brain collateral circulation includes small anastomotic arterioles which interconnect mid to distal cortical arterial beds and plays key roles in normal function and compensatory blood flow during cerebral ischemia. However, the relationship between collateral arteriole and aging, cognitive or gait decline is undefined in humans. Advanced neuroimaging methods are currently lacking to directly visualize collateral arteriole anatomy at baseline. Studying collateral arteriole availability has the potential to improve our understanding of cerebrovascular mechanisms promoting healthy aging or cognitive impairment. The overarching hypothesis is that collateral arteriole availability is preserved in healthy aging and decreased in vascular cognitive and gait decline. In this multi-disciplinary collaborative project, we will apply a small vessel segmentation algorithm to measure anatomical features of cerebral collaterals on high-resolution magnetic resonance angiography (MRA) and examine collateral association with cognitive function or physical activity. Specific Aims: 1. Characterize brain collateral arteriole diameter and density in cortical regions of older adults. 2. Examine the association of regional cerebral collateral arteriole availability with age, cognitive function, and physical activity. Methods: In aim 1, we will use the validated automated 3D vessel segmentation algorithm, VesslMapper, to retrospectively quantify anatomical availability of collateral arterioles in cortical arterial border zone regions on available brain MRA images from the Normal Aging Study dataset (N=48). In aim 2, we will use regression modeling to examine the association of regional collateral arteriole anatomic features with chronological subject age, cognitive function and physical activity. Future Studies: Dr. Rocha is preparing for a research career to help develop treatment options for enhancing cerebrovascular reserve to delay the onset of vascular cognitive and gait dysfunction. Data collected from this pilot award will provide the necessary preliminary data for securing independent funding from NIH that focuses on novel mechanisms and biomarkers of cerebrovascular health in older adults.
 
DEVELOPMENT PROJECTS (2 Development Projects Listed)
1. Project Title: Automated Neighborhood Walkability Audits by Machine Learning
  Leader: Andrea Rosso, PhD, MPH, Ervin Sejdik, PhD
  Core(s): Clinical and Population Outcomes Core (CPOC)
Data Management, Analysis and Informatics Core (DMAIC)
 

Significance: In-person environmental audits provide important information on physical barriers to mobility7 but can be time-consuming. Google Street View now provides access to free, online street-level images. We recently used Google Street View’s historical images to add environmental data retrospectively to the Health ABC cohort (R21 AG054666-01, PI: Rosso). Use of these images for environmental audits has been demonstrated to be valid and reliable for street-level characteristics.14-19 Because Google Street View images are in the public domain and will not be linked to individual data, this research is not considered human subjects research. 

Innovation: No automated methods for environmental features relevant to mobility and falls in older adults currently exist for use in research studies. 

Aims: 1) Identify the environmental components most relevant to falls using existing published literature, and 2) Based on findings in Aim 1, develop computer methods to assess these features in an efficient, reliable, and automated way. 

Approach: We will develop computer-based, automated methods for auditing Google Street View images for environmental features most relevant to mobility and falls in older adults. We first determine the most relevant environmental features through a systematic literature review. We then use machine learning methods to develop automated auditing processes. Since Google Street View images provide visuals of house exteriors, nature, landscaping, and vehicles on the street20, we can use deep learning to identify environmental features by looking for key urban design qualities; walkability: imageability, enclosure, human scale, transparency and complexity.21 Prior studies used several methods to detect and estimate pedestrian volume, visual enclosure, automotive vehicles, and curbsides. Since overlapping images are taken from different perspectives and have different levels of color and illumination, deformable part models (DPM) can be used22-27. Each "deformable part" represents an object model by taking on the appearance properties of the object. The deformations are then linked. Histogram of Oriented Gradient (HOG) is also used to capture the image's region's gradient's intensity and direction23,25,26. Algorithms such as the Aggregated Channel Features (ACF) algorithm can increase computational efficiency by large-scale estimating of HOG and then discarding parts in small-scale images23. Artificial Neural Networks (ANN) can be used to analyze color and texture in Google Street View images27. Feature extraction and segmentation can be performed to isolate regions such as the sky, objects that obstruct the view, and other environmental features of interest22. Extracted features from HOG-ACF or ANN can be used for classification using Support Vector Machine, Decision Trees, Adaboost, or other supervised classification algorithms,23,26,27. Convolutional Neural Networks (CNN) may be able to recognize a wide variety of environmental objects that may affect walkability due to CNN's ability in object classification20. However, CNN is a supervised machine learning method that requires a training set of labeled images. Another method is to use a combination of Region Proposal Networks (RPN) and Fast Region-CNN (RCNN)25. RPN is also a convolutional network that can propose areas or regions in the image, while detection of these regions is done by Fast RCNN. The results of the machine learning audits will be validated against human audits. 

Core Collaborations: CPOC, DMAIC 

Future Uses: These methods would be made available through the CPOC for wide general research use to expand efficient research assessments into community risk factors for any study focused on mobility and falls.
 
2. Project Title: A Novel Method to Examine Muscle Health in Community-Dwelling Elderly
  Leader: Safai Haeri, N
  Core(s):
  Background: The assessment of muscle mass in elderly is challenging. This information is important as we try to characterize sarcopenia (loss of muscle) in older adults to improve muscle mass, strength, and function. Although we can measure lean mass by dual X-ray absorptiometry (DXA), DXA is a controversial measure for characterizing sarcopenia and is not well-correlated with strength or function. The deuterated creatine (D3-creatine) dilution method is a novel assessment of total body muscle mass based on the knowledge that nearly all creatine is stored in skeletal muscle, creatine is converted to creatinine at a steady rate, and creatinine is excreted in urine. Muscle mass measured by this method is associated with gait speed, physical function, serious falls and mobility limitation in ambulatory community-dwelling older men. However, the usefulness of this measure has not been established in frail older adults, who have the largest loss of muscle mass and would have the greatest benefits from assessments. Longitudinal measures are also sparse. Rate of muscle loss or gain would be a key determinant for future therapeutic modalities to preserve muscle function and strength in older adults. Aims: Aim 1: Obtain preliminary data on the impact of two different classes of osteoporosis medications on longitudinal changes in skeletal muscle function, muscle strength and lean mass in older adults. Hypothesis 1.1: Older adults on denosumab (a RANKL inhibitor) will exhibit greater preservation or improvement in lean mass (D3-creatine; primary outcome, whole-body DXA, muscle ultrasound), grip strength and muscle function (Short Physical Performance Battery) over 12 months compared to zoledronic acid (an osteoclast inhibitor). Aim 2: Explore associations between measures of bone mass and skeletal muscle health. Hypothesis 2.1: Measures of bone and muscle health will be associated both cross-sectionally and longitudinally. From previous studies in patients with osteoporosis who took denosumab or zoledronic acid and had their lean mass measured by whole-body DXA, patients who took denosumab, unlike zoledronic acid, preserved their lean mass. Nevertheless, this effect has not been assessed by the D3-creatine method which is a much better surrogate for lean mass compared with the whole-body DXA. This pilot study addresses an important knowledge gap regarding muscle mass assessment in older adults and fits well with the mission of the Pepper OAIC that focuses on mobility, gait, falls and function. Most importantly, for many other Pepper investigators interested in muscle health, this study will lay the groundwork to establish a feasible and novel muscle mass measurement for participants under treatment for osteoporosis. The data will be directly used for sample size and power computations involving Pepper studies that propose to use the measure. Therefore, other investigators who want to use this measurement technique will have it established within the Pepper center. Methods: We propose to perform the D3-creatine test in 20-30 community-dwelling older adults. We have measures of DXA lean mass, grip strength, gait speed and function. In an IRB-approved study, we will perform the D3-creatine method in addition to our standard assessments. Participants will ingest 30 mg D3-creatine, and a fasting spot urine sample will be collected 3-6 days later. D3-creatinine, unlabeled creatinine, and creatine will be measured by liquid chromatography and tandem mass spectroscopy. Total body skeletal muscle mass will be calculated using established algorithms based on the ratio of labeled to unlabeled urinary creatinine. We will repeat the D3-creatine, DXA and function measures, 6 months later to estimate rate of muscle loss. Future Use of Data: These data will demonstrate that this assessment is feasible in older adults, and can be added to 2 other R01-funded ongoing osteoporosis trials. This study will provide preliminary data for a career development award for Dr. Nami Safai Haeri, MD. Finally, if successful, this method will establish a new assessment for many other Pepper investigators with a focus on muscle health.
 
RESEARCH (0 Projects Listed)
PUBLICATIONS
2024
  1. Low-dose aspirin and incident atrial fibrillation in healthy older individuals: a post-hoc analysis of the ASPREE trial.
    Ball J, Neumann JT, Tonkin AM, Kirchhof P, Freedman B, Brodtmann A, Reid C, Nelson MR, Beilin LJ, Fitzgerald S, Stub D, Woods RL, McNeil JJ
    Eur Heart J Cardiovasc Pharmacother, 2024 Jan 5, 10(1): 81-82
    https://doi.org/10.1093/ehjcvp/pvad082 | PMID: 37951294 | PMCID: PMC10766903
    Citations: 1 | AltScore: 5.2
  2. Skeletal Muscle Health, Physical Performance, and Lower Urinary Tract Symptoms in Older Adults: The Study of Muscle, Mobility, and Aging.
    Bauer SR, Parker-Autry C, Lu K, Cummings SR, Hepple RT, Scherzer R, Covinsky K, Cawthon PM
    J Gerontol A Biol Sci Med Sci, 2024 Jun 1, 79(6):
    https://doi.org/10.1093/gerona/glad218 | PMID: 37694941 | PMCID: PMC11083634
    Citations: 0 | AltScore: NA
  3. Associations between regional adipose tissue distribution and skeletal muscle bioenergetics in older men and women.
    Brennan AM, Coen PM, Mau T, Hetherington-Rauth M, Toledo FGS, Kershaw EE, Cawthon PM, Kramer PA, Ramos SV, Newman AB, Cummings SR, Forman DE, Yeo RX, Distefano G, Miljkovic I, Justice JN, Molina AJA, Jurczak MJ, Sparks LM, Kritchevsky SB, Goodpaster BH
    Obesity (Silver Spring), 2024 Jun, 32(6): 1125-1135
    https://doi.org/10.1002/oby.24008 | PMID: 38803308 | PMCID: PMC11139412
    Citations: 0 | AltScore: 1.75
  4. Dissemination and implementation of evidence-based programs for people with chronic disease: the impact of the COVID-19 pandemic.
    Coyle P, Tripken J, Perera S, Juarez GA, Spencer-Brown L, Cameron K, Brach JS
    Front Public Health, 2023, 11: 1276387
    https://doi.org/10.3389/fpubh.2023.1276387 | PMID: 38274541 | PMCID: PMC10808618
    Citations: 0 | AltScore: NA
  5. Energetics and clinical factors for the time required to walk 400 m: The Study of Muscle, Mobility and Aging (SOMMA).
    Cummings SR, Lui LY, Glynn NW, Mau T, Cawthon PM, Kritchevsky SB, Coen PM, Goodpaster B, Marcinek DJ, Hepple RT, Patel S, Newman AB
    J Am Geriatr Soc, 2024 Jan 19, 72(4): 1035-1047
    https://doi.org/10.1111/jgs.18763 | PMID: 38243364
    Citations: 1 | AltScore: 2.6
  6. TAVR in Older Adults: Moving Toward a Comprehensive Geriatric Assessment and Away From Chronological Age: JACC Family Series.
    Damluji AA, Bernacki G, Afilalo J, Lyubarova R, Orkaby AR, Kwak MJ, Hummel S, Kirkpatrick JN, Maurer MS, Wenger N, Rich MW, Kim DH, Wang RY, Forman DE, Krishnaswami A
    JACC Adv, 2024 Apr, 3(4):
    pii: 100877. https://doi.org/10.1016/j.jacadv.2024.100877 | PMID: 38694996 | PMCID: PMC11062620
    Citations: 0 | AltScore: 21.45
  7. Childhood adverse life events and skeletal muscle mitochondrial function.
    Duchowny KA, Marcinek DJ, Mau T, Diaz-Ramierz LG, Lui LY, Toledo FGS, Cawthon PM, Hepple RT, Kramer PA, Newman AB, Kritchevsky SB, Cummings SR, Coen PM, Molina AJA
    Sci Adv, 2024 Mar 8, 10(10): eadj6411
    https://doi.org/10.1126/sciadv.adj6411 | PMID: 38446898 | PMCID: PMC10917337
    Citations: 0 | AltScore: 212.342
  8. Age Is Associated With Dampened Circadian Patterns of Rest and Activity: The Study of Muscle, Mobility, and Aging (SOMMA).
    Erickson ML, Blackwell TL, Mau T, Cawthon PM, Glynn NW, Qiao YS, Cummings SR, Coen PM, Lane NE, Kritchevsky SB, Newman AB, Farsijani S, Esser KA
    J Gerontol A Biol Sci Med Sci, 2024 Apr 1, 79(4):
    https://doi.org/10.1093/gerona/glae049 | PMID: 38416053 | PMCID: PMC10972577
    Citations: 0 | AltScore: 10.95
  9. Associations Between Walking Speed and Gut Microbiome Composition in Older Men From the MrOS Study.
    Farsijani S, Cauley JA, Cawthon PM, Langsetmo L, Orwoll ES, Kado DM, Kiel DP, Newman AB
    J Gerontol A Biol Sci Med Sci, 2024 Apr 1, 79(4):
    https://doi.org/10.1093/gerona/glae030 | PMID: 38271209 | PMCID: PMC10924448
    Citations: 0 | AltScore: 1.75
  10. Usual-paced 400 m long distance corridor walk estimates cardiorespiratory fitness among older adults: The Study of Muscle, Mobility and Aging.
    Garcia RE, Cawthon PM, Nicklas BJ, Goodpaster BH, Coen PM, Forman DE, Cummings SR, Newman AB, Glynn NW
    J Am Geriatr Soc, 2024 Mar, 72(3): 858-865
    https://doi.org/10.1111/jgs.18713 | PMID: 38149438 | PMCID: PMC10947881
    Citations: 0 | AltScore: 4.85
  11. A molecular index for biological age identified from the metabolome and senescence-associated secretome in humans.
    Hamsanathan S, Anthonymuthu T, Prosser D, Lokshin A, Greenspan SL, Resnick NM, Perera S, Okawa S, Narasimhan G, Gurkar AU
    Aging Cell, 2024 Mar 7, 23(4): e14104
    https://doi.org/10.1111/acel.14104 | PMID: 38454639 | PMCID: PMC11019119
    Citations: 1 | AltScore: 271.46
  12. Associations of Skeletal Muscle Mass, Muscle Fat Infiltration, Mitochondrial Energetics, and Cardiorespiratory Fitness With Liver Fat Among Older Adults.
    Igudesman D, Mucinski J, Harrison S, Cawthon PM, Linge J, Goodpaster BH, Cummings SR, Hepple RT, Jurczak MJ, Kritchevsky SB, Marcinek D, Coen PM, Corbin KD
    J Gerontol A Biol Sci Med Sci, 2024 Apr 1, 79(4):
    https://doi.org/10.1093/gerona/glae047 | PMID: 38366047 | PMCID: PMC10949442
    Citations: 0 | AltScore: 2
  13. Skeletal Muscle Energetics Explain the Sex Disparity in Mobility Impairment in the Study of Muscle, Mobility and Aging.
    Kramer PA, Coen PM, Cawthon PM, Distefano G, Cummings SR, Goodpaster BH, Hepple RT, Kritchevsky SB, Shankland EG, Marcinek DJ, Toledo FGS, Duchowny KA, Ramos SV, Harrison S, Newman AB, Molina AJA
    J Gerontol A Biol Sci Med Sci, 2024 Apr 1, 79(4):
    https://doi.org/10.1093/gerona/glad283 | PMID: 38150179 | PMCID: PMC10960628
    Citations: 1 | AltScore: 10.2
  14. The Association of Skeletal Muscle Energetics With Recurrent Falls in Older Adults Within the Study of Muscle, Mobility and Aging.
    Kramer PA, Zamora E, Barnes HN, Strotmeyer ES, Glynn NW, Lane NE, Coen PM, Cawthon PM, Goodpaster BH, Newman AB, Kritchevsky SB, Cummings SR
    J Gerontol A Biol Sci Med Sci, 2024 Apr 1, 79(4):
    https://doi.org/10.1093/gerona/glae018 | PMID: 38206375 | PMCID: PMC10924446
    Citations: 1 | AltScore: 0.25
  15. Novel attentional gait index reveals a cognitive ability-related decline in gait automaticity during dual-task walking.
    Liu S, Rosso AL, Baillargeon EM, Weinstein AM, Rosano C, Torres-Oviedo G
    Front Aging Neurosci, 2023, 15: 1283376
    https://doi.org/10.3389/fnagi.2023.1283376 | PMID: 38274986 | PMCID: PMC10808635
    Citations: 0 | AltScore: 2.1
  16. Associations between performance-based and patient-reported physical functioning and real-world mobile sensor metrics in older cancer survivors: A pilot study.
    Low CA, Bartel C, Fedor J, Durica KC, Marchetti G, Rosso AL, Campbell G
    J Geriatr Oncol, 2024 Mar, 15(2): 101708
    https://doi.org/10.1016/j.jgo.2024.101708 | PMID: 38277879 | PMCID: PMC10923123
    Citations: 0 | AltScore: 3.2
  17. Muscle Mitochondrial Bioenergetic Capacities Are Associated With Multimorbidity Burden in Older Adults: The Study of Muscle, Mobility and Aging.
    Mau T, Blackwell TL, Cawthon PM, Molina AJA, Coen PM, Distefano G, Kramer PA, Ramos SV, Forman DE, Goodpaster BH, Toledo FGS, Duchowny KA, Sparks LM, Newman AB, Kritchevsky SB, Cummings SR
    J Gerontol A Biol Sci Med Sci, 2024 Jul 1, 79(7):
    https://doi.org/10.1093/gerona/glae101 | PMID: 38605684 | PMCID: PMC11167490
    Citations: 0 | AltScore: 3.5
  18. Neighborhood Walkability Is Associated With Global Positioning System-Derived Community Mobility of Older Adults.
    Moored KD, Crane BM, Carlson MC, Dunlap PM, Brach JS, Rosso AL
    J Gerontol A Biol Sci Med Sci, 2024 Jul 1, 79(7):
    https://doi.org/10.1093/gerona/glae132 | PMID: 38777885 | PMCID: PMC11170293
    Citations: 0 | AltScore: NA
  19. Vigor to Frailty As a Continuum-A New Approach in the Study of Muscle, Mobility, and Aging Cohort.
    Newman AB, Blackwell TL, Mau T, Cawthon PM, Coen PM, Cummings SR, Toledo FGS, Goodpaster BH, Glynn NW, Hepple RT, Kritchevsky SB
    J Gerontol A Biol Sci Med Sci, 2024 Jan 1, 79(1):
    https://doi.org/10.1093/gerona/glad244 | PMID: 37847228 | PMCID: PMC10733210
    Citations: 0 | AltScore: 15.7
  20. Care cascades following low-value cervical cancer screening in dually enrolled Veterans.
    Pickering AN, Zhao X, Sileanu FE, Lovelace EZ, Rose L, Schwartz AL, Hale JA, Schleiden LJ, Gellad WF, Fine MJ, Thorpe CT, Radomski TR
    J Am Geriatr Soc, 2024 May 9
    https://doi.org/10.1111/jgs.18956 | PMID: 38721922
    Citations: 0 | AltScore: 3.35
  21. Prefrontal cortex activation while walking did not change but gait speed improved after a randomized physical therapy intervention.
    Rosso AL, Baillargeon EM, Perera S, VanSwearingen J, Rosano C, Huppert TJ, Brach JS
    Aging Clin Exp Res, 2024 Feb 17, 36(1): 43
    https://doi.org/10.1007/s40520-023-02666-7 | PMID: 38367207 | PMCID: PMC10874329
    Citations: 1 | AltScore: NA
  22. Association between performance fatigability and GPS-measured community mobility.
    Schumacher BT, Moored KD, Qiao YS, Brach JS, Rosso AL, Glynn NW
    J Am Geriatr Soc, 2024 May 30
    https://doi.org/10.1111/jgs.19009 | PMID: 38814723
    Citations: 0 | AltScore: 0.25
  23. Fear of falling in community-dwelling older adults: What their gait acceleration pattern reveals.
    Suri A, Hubbard ZL, VanSwearingen J, Torres-Oviedo G, Brach JS, Redfern MS, Sejdic E, Rosso AL
    Comput Methods Programs Biomed, 2024 Feb, 244: 108001
    https://doi.org/10.1016/j.cmpb.2023.108001 | PMID: 38199138
    Citations: 0 | AltScore: 0.25
  24. Association of Gait Quality With Daily-Life Mobility: An Actigraphy and Global Positioning System Based Analysis in Older Adults.
    Suri A, VanSwearingen J, Baillargeon EM, Crane BM, Moored KD, Carlson MC, Dunlap PM, Donahue PT, Redfern MS, Brach JS, Sejdic E, Rosso AL
    IEEE Trans Biomed Eng, 2024 Jan, 71(1): 130-138
    https://doi.org/10.1109/TBME.2023.3293752 | PMID: 37428666 | PMCID: PMC10792545
    Citations: 0 | AltScore: 2.35
  25. Shared plasma metabolomic profiles of cognitive and mobility decline predict future dementia.
    Tian Q, Yao S, Marron MM, Greig EE, Shore S, Ferrucci L, Shah R, Murthy VL, Newman AB
    Geroscience, 2024 Jun 3
    https://doi.org/10.1007/s11357-024-01228-7 | PMID: 38829458
    Citations: 0 | AltScore: NA
  26. Expression of mitochondrial oxidative stress response genes in muscle is associated with mitochondrial respiration, physical performance, and muscle mass in the Study of Muscle, Mobility, and Aging.
    Tranah GJ, Barnes HN, Cawthon PM, Coen PM, Esser KA, Hepple RT, Huo Z, Kramer PA, Toledo FGS, Zhang X, Wu K, Wolff CA, Evans DS, Cummings SR
    Aging Cell, 2024 Jun, 23(6): e14114
    https://doi.org/10.1111/acel.14114 | PMID: 38831629 | PMCID: PMC11166362
    Citations: 0 | AltScore: 9.05
  27. Cardiopulmonary Exercise Testing in a Prospective Multicenter Cohort of Older Adults.
    Wolf C, Blackwell TL, Johnson E, Glynn NW, Nicklas B, Kritchevsky SB, Carnero EA, Cawthon PM, Cummings SR, Toledo FGS, Newman AB, Forman DE, Goodpaster BH
    Med Sci Sports Exerc, 2024 Apr 11
    https://doi.org/10.1249/MSS.0000000000003444 | PMID: 38598351
    Citations: 0 | AltScore: 1.25
  28. Implications of metabolism on multi-systems healthy aging across the lifespan.
    Yao S, Colangelo LA, Perry AS, Marron MM, Yaffe K, Sedaghat S, Lima JAC, Tian Q, Clish CB, Newman AB, Shah RV, Murthy VL
    Aging Cell, 2024 Jan 29, 23(4): e14090
    https://doi.org/10.1111/acel.14090 | PMID: 38287525 | PMCID: PMC11019145
    Citations: 1 | AltScore: 4.1
  29. Percutaneous biopsies of skeletal muscle and adipose tissue in individuals older than 70: methods and outcomes in the Study of Muscle, Mobility and Aging (SOMMA).
    Zamora Z, Lui LY, Sparks LM, Justice J, Lyles M, Gentle L, Gregory H, Yeo RX, Kershaw EE, Stefanovic-Racic M, Newman AB, Kritchevsky S, Toledo FGS
    Geroscience, 2024 Feb 5, 46(3): 3419-3428
    https://doi.org/10.1007/s11357-024-01087-2 | PMID: 38315316 | PMCID: PMC11009187
    Citations: 0 | AltScore: 3.35
 
2023
  1. Non-esterified fatty acids and risk of peripheral artery disease in older adults: The cardiovascular health study.
    Ahiawodzi P, Solaru KW, Chaves PHM, Ix JH, Kizer JR, Tracy RP, Newman A, Siscovick D, Djousse L, Mukamal KJ
    Atherosclerosis, 2023 Apr, 370: 25-32
    https://doi.org/10.1016/j.atherosclerosis.2023.01.020 | PMID: 36754661 | PMCID: PMC10079601
    Citations: 1 | AltScore: 17.08
  2. Influence of Recent Standing, Moving, or Sitting on Daytime Ambulatory Blood Pressure.
    Barone Gibbs B, Muldoon MF, Conroy MB, Paley JL, Shimbo D, Perera S
    J Am Heart Assoc, 2023 Sep 5, 12(17): e029999
    https://doi.org/10.1161/JAHA.123.029999 | PMID: 37589152 | PMCID: PMC10547321
    Citations: 1 | AltScore: 15.85
  3. The BACPAC Research Program Data Harmonization: Rationale for Data Elements and Standards.
    Batorsky A, Bowden AE, Darwin J, Fields AJ, Greco CM, Harris RE, Hue TF, Kakyomya J, Mehling W, O'Neill C, Patterson CG, Piva SR, Sollmann N, Toups V, Wasan AD, Wasserman R, Williams DA, Vo NV, Psioda MA, McCumber M
    Pain Med, 2023 Jan 31, 24(Suppl 1): S95-S104
    pii: pnad008. https://doi.org/10.1093/pm/pnad008 | PMID: 36721327
    Citations: 2 | AltScore: 1.35
  4. Treatment effect modifiers for individuals with acute low back pain: secondary analysis of the TARGET trial.
    Beneciuk JM, George SZ, Patterson CG, Smith CN, Brennan GP, Wegener ST, Roseen EJ, Saper RB, Delitto A
    Pain, 2023 Jan 1, 164(1): 171-179
    https://doi.org/10.1097/j.pain.0000000000002679 | PMID: 35543647 | PMCID: PMC9703897
    Citations: 0 | AltScore: 4.95
  5. Social networks, social support, and life expectancy in older adults: the Cardiovascular Health Study.
    Bhatia R, Hirsch C, Arnold AM, Newman AB, Mukamal KJ
    Arch Gerontol Geriatr, 2023 Aug, 111: 104981
    https://doi.org/10.1016/j.archger.2023.104981 | PMID: 36965200 | PMCID: PMC11026051
    Citations: 2 | AltScore: 10.08
  6. Exercise interventions, postural control, and prefrontal cortex activation in older adults.
    Bohlke K, Perera S, Baillargeon EM, Redfern MS, Sparto PJ, Sejdic E, Rosso AL
    Brain Cogn, 2023 Oct, 171: 106063
    https://doi.org/10.1016/j.bandc.2023.106063 | PMID: 37523831 | PMCID: PMC10529535
    Citations: 1 | AltScore: NA
  7. Accelerometry applications and methods to assess standing balance in older adults and mobility-limited patient populations: a narrative review.
    Bohlke K, Redfern MS, Rosso AL, Sejdic E
    Aging Clin Exp Res, 2023 Oct, 35(10): 1991-2007
    https://doi.org/10.1007/s40520-023-02503-x | PMID: 37526887 | PMCID: PMC10881067
    Citations: 0 | AltScore: 0.5
  8. Preferences on Delivery of Cancer Rehabilitation Services for Cancer-Related Disability Among Older Individuals Surviving Breast Cancer: A Qualitative Study.
    Brick R, Lyons KD, Bender C, Eilers R, Ferguson R, Pergolotti M, Toto P, Skidmore E, Leland NE
    Rehabil Oncol, 2023 Jul, 41(3): 139-148
    https://doi.org/10.1097/01.reo.0000000000000341 | PMID: 37841364 | PMCID: PMC10574708
    Citations: 0 | AltScore: 5.2
  9. Associations of body size with all-cause and cause-specific mortality in healthy older adults.
    Carr PR, Webb KL, Neumann JT, Thao LTP, Beilin LJ, Ernst ME, Fitzgibbon B, Gasevic D, Nelson MR, Newman AB, Orchard SG, Owen A, Reid CM, Stocks NP, Tonkin AM, Woods RL, McNeil JJ
    Sci Rep, 2023 Mar 7, 13(1): 3799
    https://doi.org/10.1038/s41598-023-29586-w | PMID: 36882434 | PMCID: PMC9992380
    Citations: 2 | AltScore: 5.25
  10. Evaluation of Associations of Growth Differentiation Factor-11, Growth Differentiation Factor-8 and their Binding Proteins Follistatin and Follistatin-like protein-3 with Measures of Skeletal Muscle Mass, Muscle Strength and Physical Function in Older Adults.
    Cawthon PM, Patel S, Newman AB, Bhasin S, Peng L, Tracy R, Kizer JR, Lee SJ, Ferrucci L, Ganz P, LeBrasseur NK, Cummings S
    J Gerontol A Biol Sci Med Sci, 2023 Feb 8, 78(11): 2051-2059
    pii: glad045. https://doi.org/10.1093/gerona/glad045 | PMID: 36752218 | PMCID: PMC10613016
    Citations: 2 | AltScore: 1
  11. Mitohormesis.
    Cheng YW, Liu J, Finkel T
    Cell Metab, 2023 Nov 7, 35(11): 1872-1886
    https://doi.org/10.1016/j.cmet.2023.10.011 | PMID: 37939657 | PMCID: PMC10632604
    Citations: 4 | AltScore: 46.13
  12. The Study of Muscle, Mobility and Aging (SOMMA). A Unique Cohort Study about the Cellular Biology of Aging and Age-related Loss of Mobility.
    Cummings SR, Newman AB, Coen PM, Hepple RT, Collins R, Kennedy K, Danielson M, Peters K, Blackwell T, Johnson E, Mau T, Shankland EG, Lui LY, Patel S, Young D, Glynn NW, Strotmeyer ES, Esser KA, Marcinek DJ, Goodpaster BH, Kritchevsky S, Cawthon PM
    J Gerontol A Biol Sci Med Sci, 2023 Feb 9, 78(11): 2083-2093
    pii: glad052. https://doi.org/10.1093/gerona/glad052 | PMID: 36754371 | PMCID: PMC10613002
    Citations: 33 | AltScore: 11.9
  13. Sarcopenia and Cardiovascular Diseases.
    Damluji AA, Alfaraidhy M, AlHajri N, Rohant NN, Kumar M, Al Malouf C, Bahrainy S, Ji Kwak M, Batchelor WB, Forman DE, Rich MW, Kirkpatrick J, Krishnaswami A, Alexander KP, Gerstenblith G, Cawthon P, deFilippi CR, Goyal P
    Circulation, 2023 May 16, 147(20): 1534-1553
    https://doi.org/10.1161/CIRCULATIONAHA.123.064071 | PMID: 37186680 | PMCID: PMC10180053
    Citations: 47 | AltScore: 730.410000000003
  14. The Association between Frailty and Dementia-Free and Physical Disability-Free Survival in Community-Dwelling Older Adults.
    Ekram ARMS, Ryan J, Espinoza SE, Newman AB, Murray AM, Orchard SG, Fitzgerald SM, McNeil JJ, Ernst ME, Woods RL
    Gerontology, 2023, 69(5): 549-560
    https://doi.org/10.1159/000528984 | PMID: 36617406 | PMCID: PMC10238577
    Citations: 2 | AltScore: 0.5
  15. The association between frailty and incident cardiovascular disease events in community-dwelling healthy older adults.
    Ekram ARMS, Tonkin AM, Ryan J, Beilin L, Ernst ME, Espinoza SE, McNeil JJ, Nelson MR, Reid CM, Newman AB, Woods RL
    Am Heart J Plus, 2023 Apr, 28:
    pii: 100289. https://doi.org/10.1016/j.ahjo.2023.100289 | PMID: 37168270 | PMCID: PMC10168683
    Citations: 3 | AltScore: 2
  16. Relation Between Dietary Protein Intake and Gut Microbiome Composition in Community-Dwelling Older Men: Findings from the Osteoporotic Fractures in Men Study (MrOS).
    Farsijani S, Cauley JA, Peddada SD, Langsetmo L, Shikany JM, Orwoll ES, Ensrud KE, Cawthon PM, Newman AB
    J Nutr, 2023 Jan 14, 152(12): 2877-2887
    https://doi.org/10.1093/jn/nxac231 | PMID: 36205552 | PMCID: PMC9839986
    Citations: 7 | AltScore: 27.004
  17. Comprehensive assessment of chrononutrition behaviors among nationally representative adults: Insights from National Health and Nutrition Examination Survey (NHANES) data.
    Farsijani S, Mao Z, Cauley JA, Newman AB
    Clin Nutr, 2023 Oct, 42(10): 1910-1921
    https://doi.org/10.1016/j.clnu.2023.08.007 | PMID: 37625320 | PMCID: PMC10528735
    Citations: 2 | AltScore: 111.572
  18. Impact of Geroscience on Therapeutic Strategies for Older Adults With Cardiovascular Disease: JACC Scientific Statement.
    Forman DE, Kuchel GA, Newman JC, Kirkland JL, Volpi E, Taffet GE, Barzilai N, Pandey A, Kitzman DW, Libby P, Ferrucci L
    J Am Coll Cardiol, 2023 Aug 15, 82(7): 631-647
    https://doi.org/10.1016/j.jacc.2023.05.038 | PMID: 37389519 | PMCID: PMC10414756
    Citations: 5 | AltScore: 24.6
  19. Sex- and race-specific associations of bone mineral density with incident heart failure and its subtypes in older adults.
    Gao H, Patel S, Fohtung RB, Cawthon PM, Newman AB, Cauley JA, Carbone L, Chaves PHM, Stein PK, Civitelli R, Kizer JR
    J Am Geriatr Soc, 2023 Mar, 71(3): 742-755
    https://doi.org/10.1111/jgs.18121 | PMID: 36334030 | PMCID: PMC10023291
    Citations: 2 | AltScore: 1.6
  20. Measuring and Understanding the Health Impact of Greater Fatigability in Older Adults: A Call to Action and Opportunities.
    Glynn NW, Qiao YS
    Fatigue, 2023, 11(2-4): 188-201
    https://doi.org/10.1080/21641846.2023.2252612 | PMID: 38074079 | PMCID: PMC10707490
    Citations: 1 | AltScore: NA
  21. Systematic Review and Meta-analysis of Interventions to Reduce Adverse Drug Reactions in Older Adults: An Update.
    Gray SL, Perera S, Soverns T, Hanlon JT
    Drugs Aging, 2023 Nov, 40(11): 965-979
    https://doi.org/10.1007/s40266-023-01064-y | PMID: 37702981 | PMCID: PMC10600043
    Citations: 1 | AltScore: 2
  22. The association of vitamin D with bone microarchitecture, muscle strength, and mobility performance in older women in long-term care.
    Haeri NS, Perera S, Greenspan SL
    Bone, 2023 Nov, 176: 116867
    https://doi.org/10.1016/j.bone.2023.116867 | PMID: 37544395 | PMCID: PMC10528338
    Citations: 0 | AltScore: 0.75
  23. Preoperative Rehabilitation Is Feasible in the Weeks Prior to Surgery and Significantly Improves Functional Performance.
    Hall DE, Youk A, Allsup K, Kennedy K, Byard TD, Dhupar R, Chu D, Rahman AM, Wilson M, Cahalin LP, Afilalo J, Forman DE
    J Frailty Aging, 2023, 12(4): 267-276
    https://doi.org/10.14283/jfa.2022.42 | PMID: 38008976 | PMCID: PMC10683858
    Citations: 3 | AltScore: 16.95
  24. The Association Between Severity of Radiographic Knee OA and Recurrent Falls in Middle and Older Aged Adults: The Osteoarthritis Initiative.
    Harris R, Strotmeyer ES, Sharma L, Kwoh CK, Brach JS, Boudreau R, Cauley JA
    J Gerontol A Biol Sci Med Sci, 2023 Jan 26, 78(1): 97-103
    https://doi.org/10.1093/gerona/glac050 | PMID: 35184161 | PMCID: PMC9879744
    Citations: 7 | AltScore: 10.2
  25. Associations of Change in Body Size With All-Cause and Cause-Specific Mortality Among Healthy Older Adults.
    Hussain SM, Newman AB, Beilin LJ, Tonkin AM, Woods RL, Neumann JT, Nelson M, Carr PR, Reid CM, Owen A, Ball J, Cicuttini FM, Tran C, Wang Y, Ernst ME, McNeil JJ
    JAMA Netw Open, 2023 Apr 3, 6(4): e237482
    https://doi.org/10.1001/jamanetworkopen.2023.7482 | PMID: 37036703 | PMCID: PMC10087052
    Citations: 8 | AltScore: 1105.47
  26. Pragmatic evaluation of events and benefits of lipid lowering in older adults (PREVENTABLE): Trial design and rationale.
    Joseph J, Pajewski NM, Dolor RJ, Sellers MA, Perdue LH, Peeples SR, Henrie AM, Woolard N, Jones WS, Benziger CP, Orkaby AR, Mixon AS, VanWormer JJ, Shapiro MD, Kistler CE, Polonsky TS, Chatterjee R, Chamberlain AM, Forman DE, Knowlton KU, Gill TM, Newby LK, Hammill BG, Cicek MS, Williams NA, Decker JE, Ou J, Rubinstein J, Choudhary G, Gazmuri RJ, Schmader KE, Roumie CL, Vaughan CP, Effron MB, Cooper-DeHoff RM, Supiano MA, Shah RC, Whittle JC, Hernandez AF, Ambrosius WT, Williamson JD, Alexander KP, PREVENTABLE Trial Research Group
    J Am Geriatr Soc, 2023 Jun, 71(6): 1701-1713
    https://doi.org/10.1111/jgs.18312 | PMID: 37082807 | PMCID: PMC10258159
    Citations: 10 | AltScore: 1.25
  27. The Association of Intensive Blood Pressure Treatment and Non-Fatal Cardiovascular or Serious Adverse Events in Older Adults with Mortality: Mediation Analysis in SPRINT.
    Krishnaswami A, Rich MW, Kwak MJ, Goyal P, Forman DE, Damluji AA, Solomon M, Rana JS, Kado DM, Odden MC
    Eur J Prev Cardiol, 2023 Apr 25, 30(10): 996-1004
    pii: zwad132. https://doi.org/10.1093/eurjpc/zwad132 | PMID: 37185634 | PMCID: PMC10390235
    Citations: 2 | AltScore: 2.35
  28. Life's Essential 8: Optimizing Health in Older Adults.
    Kumar M, Orkaby A, Tighe C, Villareal DT, Billingsley H, Nanna MG, Kwak MJ, Rohant N, Patel S, Goyal P, Hummel S, Al-Malouf C, Kolimas A, Krishnaswami A, Rich MW, Kirkpatrick J, Damluji AA, Kuchel GA, Forman DE, Alexander KP
    JACC Adv, 2023 Sep, 2(7):
    pii: 100560. https://doi.org/10.1016/j.jacadv.2023.100560 | PMID: 37664644 | PMCID: PMC10470487
    Citations: 1 | AltScore: 121.95
  29. E3 ubiquitin ligase ZBTB25 suppresses beta coronavirus infection through ubiquitination of the main viral protease MPro.
    Lear TB, Boudreau ?N, Lockwood KC, Chu E, Camarco DP, Cao Q, Nguyen M, Evankovich JW, Finkel T, Liu Y, Chen BB
    J Biol Chem, 2023 Oct 27, 299(12): 105388
    https://doi.org/10.1016/j.jbc.2023.105388 | PMID: 37890782 | PMCID: PMC10679490
    Citations: 0 | AltScore: 0.25
  30. Program Factors Affecting Weight Loss and Mobility in Older Adults: Evidence From the Mobility and Vitality Lifestyle Program (MOVE UP).
    Liu X, Kieffer LA, King J, Boak B, Zgibor JC, Smith KJ, Burke LE, Jakicic JM, Semler LN, Danielson ME, Newman AB, Venditti EM, Albert SM
    Health Promot Pract, 2023 Mar 28, 25(3): 492-503
    https://doi.org/10.1177/15248399231162377 | PMID: 36975377
    Citations: 0 | AltScore: 1
  31. Frailty predicts referral for elder abuse evaluation in a nationwide healthcare system-Results from a case-control study.
    Makaroun LK, Rosland AM, Mor MK, Zhang H, Lovelace E, Rosen T, Dichter ME, Thorpe CT
    J Am Geriatr Soc, 2023 Jan 25, 71(6): 1724-1734
    https://doi.org/10.1111/jgs.18245 | PMID: 36695515 | PMCID: PMC10258119
    Citations: 1 | AltScore: 16.45
  32. The association between chrononutrition behaviors and muscle health among older adults: The study of muscle, mobility and aging.
    Mao Z, Cawthon PM, Kritchevsky SB, Toledo FGS, Esser KA, Erickson ML, Newman AB, Farsijani S
    Aging Cell, 2023 Dec 7, 23(6): e14059
    https://doi.org/10.1111/acel.14059 | PMID: 38059319 | PMCID: PMC11166361
    Citations: 3 | AltScore: 81.25
  33. Lower muscle mitochondrial energetics is associated with greater phenotypic frailty in older women and men: the Study of Muscle, Mobility and Aging.
    Mau T, Barnes HN, Blackwell TL, Kramer PA, Bauer SR, Marcinek DJ, Ramos SV, Forman DE, Toledo FGS, Hepple RT, Kritchevsky SB, Cummings SR, Newman AB, Coen PM, Cawthon PM
    Geroscience, 2023 Nov 21, 46(2): 2409-2424
    https://doi.org/10.1007/s11357-023-01002-1 | PMID: 37987886 | PMCID: PMC10828481
    Citations: 3 | AltScore: 14.25
  34. Dual Roles of Cardiorespiratory Fitness and Fatigability in the Life-Space Mobility of Older Adults: The Study of Muscle, Mobility and Aging (SOMMA).
    Moored KD, Qiao YS, Rosso AL, Toledo FGS, Cawthon PM, Cummings SR, Goodpaster BH, Kritchevsky SB, Glynn NW
    J Gerontol A Biol Sci Med Sci, 2023 Aug 2, 78(8): 1392-1401
    https://doi.org/10.1093/gerona/glad037 | PMID: 36715332 | PMCID: PMC10395561
    Citations: 2 | AltScore: 2.6
  35. The Epidemiology and Societal Impact of Aging-Related Functional Limitations: A Looming Public Health Crisis.
    Newman AB
    J Gerontol A Biol Sci Med Sci, 2023 Jun 16, 78(Suppl 1): 4-7
    https://doi.org/10.1093/gerona/glad021 | PMID: 37325965 | PMCID: PMC10272977
    Citations: 2 | AltScore: 3.25
  36. Evaluation of Associations of Growth Differentiation Factor-11, Growth Differentiation Factor-8 and their Binding Proteins Follistatin and Follistatin-like protein-3 with Dementia and Cognition.
    Newman AB, Patel S, Kizer J, Lee SJ, Bhasin S, Cawthon P, LeBrasseur N, Tracy RP, Ganz P, Cummings S
    J Gerontol A Biol Sci Med Sci, 2023 Jan 20, 78(11): 2039-2047
    pii: glad019. https://doi.org/10.1093/gerona/glad019 | PMID: 36660892 | PMCID: PMC10613013
    Citations: 2 | AltScore: 1
  37. The Health, Aging, and Body Composition (Health ABC) Study-Ground-Breaking Science for 25 Years and Counting.
    Newman AB, Visser M, Kritchevsky SB, Simonsick E, Cawthon PM, Harris TB
    J Gerontol A Biol Sci Med Sci, 2023 Oct 28, 78(11): 2024-2034
    https://doi.org/10.1093/gerona/glad167 | PMID: 37431156 | PMCID: PMC10613019
    Citations: 1 | AltScore: 13.45
  38. SARS-CoV-2 control on a large urban college campus without mass testing.
    O'Donnell C, Brownlee K, Martin E, Suyama J, Albert S, Anderson S, Bhatte S, Bonner K, Burton C, Corn M, Eng H, Flage B, Frerotte J, Balasubramani GK, Haggerty C, Haight J, Harrison LH, Hartman A, Hitter T, King WC, Ledger K, Marsh JW, McDonald MC, Miga B, Moses K, Newman A, Ringler M, Roberts M, Sax T, Shekhar A, Sterne M, Tenney T, Vanek M, Wells A, Wenzel S, Williams J
    J Am Coll Health, 2023 Jan 3 1-9
    https://doi.org/10.1080/07448481.2022.2153600 | PMID: 36595575
    Citations: 2 | AltScore: 1
  39. A two-cohort study on the association between the gut microbiota and bone density, microarchitecture, and strength.
    Okoro PC, Orwoll ES, Huttenhower C, Morgan X, Kuntz TM, McIver LJ, Dufour AB, Bouxsein ML, Langsetmo L, Farsijani S, Kado DM, Pacifici R, Sahni S, Kiel DP
    Front Endocrinol (Lausanne), 2023, 14: 1237727
    https://doi.org/10.3389/fendo.2023.1237727 | PMID: 37810879 | PMCID: PMC10551180
    Citations: 1 | AltScore: 240.092
  40. Combinatorial interventions in aging.
    Parkhitko AA, Filine E, Tatar M
    Nat Aging, 2023 Oct, 3(10): 1187-1200
    https://doi.org/10.1038/s43587-023-00489-9 | PMID: 37783817
    Citations: 2 | AltScore: 22.4
  41. The Emergency Medical Services Sleep Health Study: A cluster-randomized trial.
    Patterson PD, Martin SE, Brassil BN, Hsiao WH, Weaver MD, Okerman TS, Seitz SN, Patterson CG, Robinson K
    Sleep Health, 2023 Feb, 9(1): 64-76
    https://doi.org/10.1016/j.sleh.2022.09.013 | PMID: 36372657
    Citations: 3 | AltScore: 1.25
  42. Are short duration naps better than long duration naps for mitigating sleep inertia? Brief report of a randomized crossover trial of simulated night shift work.
    Patterson PD, Okerman TS, Roach DGL, Hilditch CJ, Weaver MD, Patterson CG, Sheffield MA, Di Salvatore JS, Bernstein H, Georges G, Andreozzi A, Willson CM, Jain D, Martin SE, Weiss LS
    Prehosp Emerg Care, 2023 Jun 22, 27(6): 807-814
    https://doi.org/10.1080/10903127.2023.2227696 | PMID: 37347968
    Citations: 2 | AltScore: 2.95
  43. Effect of short versus long duration naps on blood pressure during simulated night shift work: A randomized crossover trial.
    Patterson PD, Okerman TS, Roach DGL, Weaver MD, Patterson CG, Martin SE, Okwiya N, Nong L, Eyiba C, Huff JR, Ruzicka A, Ruggieri J, McIlvaine Q, Weiss LS
    Prehosp Emerg Care, 2023 Jun 22, 27(6): 815-824
    https://doi.org/10.1080/10903127.2023.2227891 | PMID: 37347964
    Citations: 2 | AltScore: 6.55
  44. Longitudinal association between handgrip strength, gait speed and risk of serious falls in a community-dwelling older population.
    Pham T, McNeil JJ, Barker AL, Orchard SG, Newman AB, Robb C, Ernst ME, Espinoza S, Woods RL, Nelson MR, Beilin L, Hussain SM
    PLoS One, 2023, 18(5): e0285530
    https://doi.org/10.1371/journal.pone.0285530 | PMID: 37155689 | PMCID: PMC10166501
    Citations: 4 | AltScore: 14.45
  45. A blood-based marker of mitochondrial DNA damage in Parkinson's disease.
    Qi R, Sammler E, Gonzalez-Hunt CP, Barraza I, Pena N, Rouanet JP, Naaldijk Y, Goodson S, Fuzzati M, Blandini F, Erickson KI, Weinstein AM, Lutz MW, Kwok JB, Halliday GM, Dzamko N, Padmanabhan S, Alcalay RN, Waters C, Hogarth P, Simuni T, Smith D, Marras C, Tonelli F, Alessi DR, West AB, Shiva S, Hilfiker S, Sanders LH
    Sci Transl Med, 2023 Aug 30, 15(711): eabo1557
    https://doi.org/10.1126/scitranslmed.abo1557 | PMID: 37647388 | PMCID: PMC11135133
    Citations: 5 | AltScore: 2230.296
  46. Validation of the Pittsburgh Performance Fatigability Index in the Study of Muscle, Mobility and Aging.
    Qiao YS, Harezlak J, Cawthon PM, Cummings SR, Forman DE, Goodpaster BH, Hawkins M, Moored KD, Nicklas BJ, Toledo FGS, Toto PE, Santanasto AJ, Strotmeyer ES, Newman AB, Glynn NW
    J Gerontol A Biol Sci Med Sci, 2023 Dec 1, 78(12): 2387-2395
    https://doi.org/10.1093/gerona/glad197 | PMID: 37566383 | PMCID: PMC10692427
    Citations: 2 | AltScore: NA
  47. Associations between skeletal muscle energetics and accelerometry-based performance fatigability: Study of Muscle, Mobility and Aging.
    Qiao YS, Santanasto AJ, Coen PM, Cawthon PM, Cummings SR, Forman DE, Goodpaster BH, Harezlak J, Hawkins M, Kritchevsky SB, Nicklas BJ, Toledo FGS, Toto PE, Newman AB, Glynn NW
    Aging Cell, 2023 Oct 16, 23(6): e14015
    https://doi.org/10.1111/acel.14015 | PMID: 37843879 | PMCID: PMC11166367
    Citations: 1 | AltScore: 7.65
  48. MetfOrmin BenefIts Lower Extremities with Intermittent Claudication (MOBILE IC): randomized clinical trial protocol.
    Reitz KM, Althouse AD, Forman DE, Zuckerbraun BS, Vodovotz Y, Zamora R, Raffai RL, Hall DE, Tzeng E
    BMC Cardiovasc Disord, 2023 Jan 21, 23(1): 38
    https://doi.org/10.1186/s12872-023-03047-8 | PMID: 36681798 | PMCID: PMC9862509
    Citations: 2 | AltScore: NA
  49. Weekly minutes of moderate to vigorous physical activity is associated with movement quality in overweight and obese older adults, independent of age.
    Rekant J, Chambers A, Suri A, Hergenroeder A, Sejdic E, Brach J
    Aging Clin Exp Res, 2023 Dec, 35(12): 2941-2950
    https://doi.org/10.1007/s40520-023-02584-8 | PMID: 37861959 | PMCID: PMC10735209
    Citations: 0 | AltScore: NA
  50. Racial and Ethnic Disparities in Health Care Use and Access Associated With Loss of Medicaid Supplemental Insurance Eligibility Above the Federal Poverty Level.
    Roberts ET, Kwon Y, Hames AG, McWilliams JM, Ayanian JZ, Tipirneni R
    JAMA Intern Med, 2023 Apr 10, 183(6): 534-543
    https://doi.org/10.1001/jamainternmed.2023.0512 | PMID: 37036727 | PMCID: PMC10087092
    Citations: 4 | AltScore: 317.7
  51. The effect of depressive symptoms on disability-free survival in healthy older adults: A prospective cohort study.
    Roebuck G, Lotfaliany M, Agustini B, Forbes M, Mohebbi M, McNeil J, Woods RL, Reid CM, Nelson MR, Shah RC, Ryan J, Newman AB, Owen A, Freak-Poli R, Stocks N, Berk M, ASPREE Investigator Group
    Acta Psychiatr Scand, 2023 Jan, 147(1): 92-104
    https://doi.org/10.1111/acps.13513 | PMID: 36281968 | PMCID: PMC10026010
    Citations: 4 | AltScore: 4.1
  52. Increase in skeletal muscular adiposity and cognitive decline in a biracial cohort of older men and women.
    Rosano C, Newman A, Santanasto A, Zhu X, Goodpaster B, Miljkovic I
    J Am Geriatr Soc, 2023 Sep, 71(9): 2759-2768
    https://doi.org/10.1111/jgs.18419 | PMID: 37282843 | PMCID: PMC10524226
    Citations: 4 | AltScore: 376.068
  53. Racial and Ethnic Disparities in the Incidence of High-Impact Chronic Pain Among Primary Care Patients with Acute Low Back Pain: A Cohort Study.
    Roseen EJ, Smith CN, Essien UR, Cozier YC, Joyce C, Morone NE, Phillips RS, Gergen Barnett K, Patterson CG, Wegener ST, Brennan GP, Delitto A, Saper RB, Beneciuk JM, Stevans JM
    Pain Med, 2023 Jun 1, 24(6): 633-643
    https://doi.org/10.1093/pm/pnac193 | PMID: 36534910 | PMCID: PMC10233486
    Citations: 9 | AltScore: 24.45
  54. Association of Vascular Health Measures and Physical Function: A Prospective Analysis in the Framingham Heart Study.
    Sahni S, Dufour AB, Wang N, Kiel DP, Hannan MT, Jacques PF, Benjamin EJ, Vasan RS, Murabito JM, Newman AB, Fielding RA, Mitchell GF, Hamburg NM
    J Gerontol A Biol Sci Med Sci, 2023 May 15, 78(7): 1189-1197
    pii: glad097. https://doi.org/10.1093/gerona/glad097 | PMID: 37183502 | PMCID: PMC10329234
    Citations: 0 | AltScore: 163.1
  55. The association between frailty and perceived physical and mental fatigability: The Long Life Family Study.
    Schumacher BT, Kehler DS, Kulminski AM, Qiao YS, Andersen SL, Gmelin T, Christensen K, Wojczynski MK, Theou O, Rockwood K, Newman AB, Glynn NW, LLFS Research Group
    J Am Geriatr Soc, 2023 Oct 10, 72(1): 219-225
    https://doi.org/10.1111/jgs.18624 | PMID: 37814920 | PMCID: PMC10843058
    Citations: 0 | AltScore: 5.35
  56. Hand Dexterity Is Associated with the Ability to Resolve Perceptual and Cognitive Interference in Older Adults: Pilot Study.
    Schwalbe M, Satz S, Miceli R, Hu H, Manelis A
    Geriatrics (Basel), 2023 Feb 27, 8(2):
    https://doi.org/10.3390/geriatrics8020031 | PMID: 36960986 | PMCID: PMC10037645
    Citations: 2 | AltScore: NA
  57. Discordant Biological and Chronological Age: Implications for Cognitive Decline and Frailty.
    Shaaban CE, Rosano C, Zhu X, Rutherford BR, Witonsky KR, Rosso AL, Yaffe K, Brown PJ
    J Gerontol A Biol Sci Med Sci, 2023 Oct 28, 78(11): 2152-2161
    https://doi.org/10.1093/gerona/glad174 | PMID: 37480573 | PMCID: PMC10613009
    Citations: 1 | AltScore: 4.75
  58. Structured Moderate Exercise and Biomarkers of Kidney Health in Sedentary Older Adults: The Lifestyle Interventions and Independence for Elders Randomized Clinical Trial.
    Sheshadri A, Lai M, Hsu FC, Bauer SR, Chen SH, Tse W, Jotwani V, Tranah GJ, Lai JC, Hallan S, Fielding RA, Liu C, Ix JH, Coca SG, Shlipak MG
    Kidney Med, 2023 Nov, 5(11): 100721
    https://doi.org/10.1016/j.xkme.2023.100721 | PMID: 37915963 | PMCID: PMC10616412
    Citations: 1 | AltScore: NA
  59. Temporal Sequence of Laryngeal Vestibule Closure and Reopening is Associated With Airway Protection.
    Shu K, Perera S, Mahoney AS, Mao S, Coyle JL, Sejdic E
    Laryngoscope, 2023 Mar, 133(3): 521-527
    https://doi.org/10.1002/lary.30222 | PMID: 35657100 | PMCID: PMC9718890
    Citations: 1 | AltScore: 0.25
  60. Prevalence and Predictors of Ambulatory Care Physicians' Documentation of Mobility Limitations in Older Adults.
    Shuman V, Brach JS, Bean JF, Freburger JK
    Arch Phys Med Rehabil, 2023 May, 104(5): 719-727
    https://doi.org/10.1016/j.apmr.2022.11.018 | PMID: 36731767 | PMCID: PMC10164109
    Citations: 1 | AltScore: 2
  61. The essential role of animal models in the advancement of our understanding of human behaviors: A Commentary on the Special issue on the 30th Anniversary of the International Behavioral Neuroscience Society (IBNS).
    Sukoff Rizzo SJ
    Neurosci Biobehav Rev, 2023 Jun, 149: 105182
    https://doi.org/10.1016/j.neubiorev.2023.105182 | PMID: 37076055
    Citations: 0 | AltScore: NA
  62. Speaking the Same Language: Team Science Approaches in Aging Research for Integrating Basic and Translational Science With Clinical Practice.
    Sukoff Rizzo SJ, Finkel T, Greenspan SL, Resnick NM, Brach JS
    Innov Aging, 2023, 7(4): igad035
    https://doi.org/10.1093/geroni/igad035 | PMID: 37213324 | PMCID: PMC10198772
    Citations: 0 | AltScore: 1.75
  63. Uneven surface and cognitive dual-task independently affect gait quality in older adults.
    Suri A, VanSwearingen J, Rosano C, Brach JS, Redfern MS, Sejdic E, Rosso AL
    Gait Posture, 2023 Sep, 106: 34-41
    https://doi.org/10.1016/j.gaitpost.2023.08.010 | PMID: 37647710 | PMCID: PMC10591986
    Citations: 0 | AltScore: NA
  64. Lysosomes in senescence and aging.
    Tan JX, Finkel T
    EMBO Rep, 2023 Oct 9, 24(11): e57265
    https://doi.org/10.15252/embr.202357265 | PMID: 37811693 | PMCID: PMC10626421
    Citations: 4 | AltScore: 22.45
  65. The relationship between visual function and physical performance in the Study of Muscle, Mobility and Aging (SOMMA).
    Thompson AC, Johnson E, Miller ME, Williamson JD, Newman AB, Cummings S, Cawthon P, Kritchevsky SB
    PLoS One, 2023, 18(9): e0292079
    https://doi.org/10.1371/journal.pone.0292079 | PMID: 37756354 | PMCID: PMC10529600
    Citations: 0 | AltScore: 8
  66. Dual cognitive and mobility impairments and future dementia - Setting a research agenda.
    Tian Q, Montero-Odasso M, Buchman AS, Mielke MM, Espinoza S, DeCarli CS, Newman AB, Kritchevsky SB, Rebok GW, Resnick SM, Thambisetty M, Verghese J, Ferrucci L
    Alzheimers Dement, 2023 Apr, 19(4): 1579-1586
    https://doi.org/10.1002/alz.12905 | PMID: 36637077 | PMCID: PMC10101877
    Citations: 9 | AltScore: 9.25
  67. Insomnia symptoms and postoperative healthcare utilization in veterans undergoing decompressive laminectomy for lumbar spinal stenosis.
    Tighe CA, Bachrach RL, Perera S, Weiner DK
    Sleep Adv, 2023, 4(1): zpad005
    https://doi.org/10.1093/sleepadvances/zpad005 | PMID: 37193289 | PMCID: PMC10108638
    Citations: 1 | AltScore: 1.5
  68. Impact of sleep on chronobiology of micturition among healthy older adults.
    Tyagi S, Resnick NM, Clarkson BD, Zhang G, Krafty RT, Perera S, Subramanya AR, Buysse DJ
    Am J Physiol Renal Physiol, 2023 Oct 1, 325(4): F407-F417
    https://doi.org/10.1152/ajprenal.00025.2023 | PMID: 37560770 | PMCID: PMC10639023
    Citations: 0 | AltScore: 47.75
  69. Vaccination Against Pneumonia May Provide Genotype-Specific Protection Against Alzheimer's Disease.
    Ukraintseva S, Duan M, Simanek AM, Holmes R, Bagley O, Rajendrakumar AL, Yashkin AP, Akushevich I, Tropsha A, Whitson H, Yashin A, Arbeev K
    J Alzheimers Dis, 2023, 96(2): 499-505
    https://doi.org/10.3233/JAD-230088 | PMID: 37807778 | PMCID: PMC10657669
    Citations: 3 | AltScore: 7
  70. Transient exposure to rotenone causes degeneration and progressive parkinsonian motor deficits, neuroinflammation, and synucleinopathy.
    Van Laar AD, Webb KR, Keeney MT, Van Laar VS, Zharikov A, Burton EA, Hastings TG, Glajch KE, Hirst WD, Greenamyre JT, Rocha EM
    NPJ Parkinsons Dis, 2023 Aug 11, 9(1): 121
    https://doi.org/10.1038/s41531-023-00561-6 | PMID: 37567894 | PMCID: PMC10421849
    Citations: 2 | AltScore: 39.5
  71. Veterans Health Administration research in aging: Opportunities for high impact across the academic career.
    Vaughan CP, Brown RT, Hastings SN, Makris UE, Forman DE
    J Am Geriatr Soc, 2023 Apr 24, 71(9): 3001-3004
    https://doi.org/10.1111/jgs.18393 | PMID: 37093614 | PMCID: PMC10693935
    Citations: 1 | AltScore: 7.2
  72. Toward the Identification of Distinct Phenotypes: Research Protocol for the Low Back Pain Biological, Biomechanical, and Behavioral (LB3P) Cohort Study and the BACPAC Mechanistic Research Center at the University of Pittsburgh.
    Vo NV, Piva SR, Patterson CG, McKernan GP, Zhou L, Bell KM, Anderst W, Greco CM, Schneider MJ, Delitto A, Dicianno BE, Darwin J, Sowa GA
    Pain Med, 2023 Jan 30, 24(Suppl 1): S36-S47
    pii: pnad009. https://doi.org/10.1093/pm/pnad009 | PMID: 36715642 | PMCID: PMC10403299
    Citations: 2 | AltScore: 2.35
  73. Disparities in the Prevalence of Osteoporosis and Osteopenia in Men and Women Living in Sub-Saharan Africa, the UK, and the USA.
    Ward KA, Pearse CM, Madanhire T, Wade AN, Fabian J, Micklesfield LK, Gregson CL
    Curr Osteoporos Rep, 2023 Aug, 21(4): 360-371
    https://doi.org/10.1007/s11914-023-00801-x | PMID: 37351757 | PMCID: PMC10393839
    Citations: 1 | AltScore: 0.5
  74. Role of Perceived Physical and Mental Fatigability Severity on Prospective, Recurrent, and Injurious Fall Risk in Older?Men.
    Welburn SC, Fanning EE, Cauley JA, Brown PJ, Strotmeyer ES, Boudreau RM, Bear TM, Moored KD, Cawthon PM, Stone KL, Glynn NW
    J Gerontol A Biol Sci Med Sci, 2023 Aug 27, 78(9): 1669-1676
    https://doi.org/10.1093/gerona/glad061 | PMID: 36801938 | PMCID: PMC10460552
    Citations: 1 | AltScore: NA
  75. Recent sarcopenia definitions-prevalence, agreement and mortality associations among men: Findings from population-based cohorts.
    Westbury LD, Beaudart C, Bruy?re O, Cauley JA, Cawthon P, Cruz-Jentoft AJ, Curtis EM, Ensrud K, Fielding RA, Johansson H, Kanis JA, Karlsson MK, Lane NE, Lengel? L, Lorentzon M, McCloskey E, Mellstr?m D, Newman AB, Ohlsson C, Orwoll E, Reginster JY, Ribom E, Rosengren BE, Schousboe JT, Shiroma EJ, Harvey NC, Dennison EM, Cooper C, International Musculoskeletal Ageing Network
    J Cachexia Sarcopenia Muscle, 2023 Jan 5, 14(1): 565-575
    https://doi.org/10.1002/jcsm.13160 | PMID: 36604970 | PMCID: PMC9891989
    Citations: 12 | AltScore: 9.7


EXTERNAL ADVISORY BOARD MEMBERS

Luigi Ferrucci, MD, PhD
National Institutes of Aging
Serving since 2004 (20 years)

Nicolaas Bohnen, MD, PhD
University of Michigan
Serving since 2004 (20 years)

Pamela Duncan
Wake Forest
Serving since 2004 (20 years)

Ken Covinsky MD, MPH
University of California San Francisco
Serving since 2021 (3 years)

Rozalyn Anderson, PhD
University of Wisconsin, Veterans Administration Hospital
Serving since 2021 (3 years)

RECOGNITION AND AWARDS (2023-2024)
Aarohee Fulay, PhD, MPH (2023)
  • RCCN Workshop Travel Award for Early Career Investigators on Healthy Aging Through Nutrition
Anna Bailes, PT, DPT (2023)
  • 2023, August - Selected for 3-minute thesis competition at American Society of Biomechanics annual meeting in Knoxville TN
Arjumand Ghazi, PhD (2023)
  • Reproductive Geroscience K07 Award
Brendan McNeish, MD (2023)
  • 2023 - President’s Initiative Abstract Award, AANEM Research Title: Chemotherapy-induced peripheral neuropathy is associated with reduced executive function in chemotherapy-treated cancer survivors
  • 2023 – 2025 - NIH Loan Repayment Plan Awardee, NIA
Caterina Rosano, MD, MPH (2024)
  • 2024, March – Provost Mentoring Award
Cristiane Carlesso, MS, PT (2023)
  • 2023 Best Rehabilitation Research Award in the Pre-doctoral Training Category on the 19th Annual Rehabilitation Institute Research Day at the University of Pittsburgh Research Title: Reliability of a Nover Computed Tomography Image Analysis Method to Evaluate Lumbar Paraspinal Muscles in Adults with Chronic Low Back Pain
Daniel Forman, MD (2023)
  • Director, American Association of Cardiovascular and Pulmonary Rehabilitation (AACVPR) Annual Meeting
Julie Faieta, PhD, MOT OTR/L (2023)
  • 2023 - Women in Neurodegenerative Disease Rehabilitation Science Award 2023 recipient, Neurodegenerative Networking Group, American Congress of Rehabilitation Medicine
  • 2024 - SHRS Innovation Challenge, 3rd place recipient The Safer Seat: Prototype Refinement, (Principal Investigator)
Lilcelia Williams, PhD, MBA, BSRT(T) (2023)
  • 2023 - (OSCAR) Scholar – Outreach and Engagement Core
  • 2023 - Knight ADRC Conference Junior Investigator Travel Award
  • 2023 - Optimizing Scientific Careers in Alzheimer’s Disease Research
  • 2023 - abstract has been accepted for presentation at The Gerontological Society of America (GSA) 2023 Annual Scientific Meeting
  • 2024 - Alzheimer’s Association Interdisciplinary Summer Research Institute – Psychosocial Fellow
Pamela Dunlap, DPT, PhD (2024)
  • 2024, February - Learning Health Systems Scholar ($20,000) - Awarded through the Learning Health Systems Rehabilitation Research Network (LeaRRn) (NICHD-NCMRR P2CHD101895)
  • 2024 – Selected attendee 2024 Training in Grantsmanship for Rehabilitation Researchers (TIGRR)
Regan Harrell, PT, DPT (2023)
  • 2023 - SHRS Doctoral Award ($7500)
  • 2023 - Promotion for Doctoral Studies II award from the Foundation of Physical Therapy ($15000)
Samaneh Farsijani, PhD, RD (2023)
  • RCCN Workshop Travel Award for Early Career Investigators on Healthy Aging Through Nutrition

MINORITY RESEARCH

General Brief Description of Minority Activities:

Our REC conducts career development sessions on topics of Diversity, Equity and Inclusion (DEI) through in-depth workshops that focus on recognizing bias/cultural differences and navigating diverse viewpoints in the workplace, research and clinical settings utilizing the Intercultural Development Continuum, a widely recognized, valid and effective cross-cultural assessment for building cultural competence.

Minority Trainee(s):
  • Diana Alvarez-Davidek MD, Novice REC Member
    Age-related mitochondrial decline in lung function
  • Gardenia Juarez, Pepper Novice Trainee
    Reducing Fear of Falling and Preventing Falls
  • Gelsy Torres-Oviedo, PhD, Pepper REC Transitioned to Independence Trainee
    Increasing gait automaticity in older adults by exploiting locomotor adaptation
  • Ikenna D. Ebuenyi, MBBS, PhD , Novice REC Member
    Rehabilitation in the Face of Progressive Decline: Practice and Perspectives
  • Lilcelia Williams, PhD, MBA, BSRT(T), Novice REC Member
    She will explore beliefs, values, and perspectives about Mild Cognitive Impairment and associated health care services in black and African American older adults.

Minority Grant(s):
1. Project Title: LRRK2 KINASE ACTIVITY AND MITOCHONDRIAL DNA DAMAGE IN PARKINSONS DISEASE
  Leader(s): SANDERS, LAURIE
    THE UNIVERSITY OF PITTSBURGH
    MICHAEL J FOX FOUNDATION / (2016-2018)
  LRRK2 is a protein regulated by kinases (protein regulators) and is also subject to autophosphorylation (auto-regulation). Several mutations of LRRK2 increase the kinase activity of the enzyme, thus LRRK2 inhibitors are potential preventative or disease-modifying drugs for Parkinon's disease (PD). There is considerable effort being put forward in the pharmaceutical industry towards designing and implementing pharmacological approaches to inhibit LRRK2 kinase activity. We have found that white blood cells from those with LRRK2-related PD have damage to their mitochondrial DNA (powerhouses of the cell; mtDNA). We will screen the ability of drugs that inhibit LRRK2 kinase activity to repair or fix mtDNA damage. We will also determine whether reversal of mtDNA damage is associated with altered LRRK2 activity.
 
2. Project Title: Nitrite Supplementation to Mitigate Fatigability and Increase Function in Long COVID Patients
  Leader(s): FORMAN, DANIEL E.
    VETERANS HEALTH ADMINISTRATION
    VA 1I21RX004409 / (2023-2025)
  Prevalence of long COVID is surging among Veterans, and Veterans afflicted with this disease typically incur progressive declines in function, diminished quality of life and increased disability. Skeletal muscle pathophysiology has been implicated as a significant determinant of long COVID pathophysiology and clinical declines. Dr. Forman is a cardiologist and geriatrician who is currently engaged in research studying benefits of nitrite supplementation with investigational new drug (IND) nitrite capsule supplements in older adults with sedentariness and/or heart failure. In that work, he is focusing primarily on the utility of nitrites to increase skeletal muscle mitochondrial respiration. Secondarily, he is exploring if mitochondrial respiration changes correlate to changes in physical function. In particular, he is studying if increased serum and skeletal muscle nitrite elevations correlate to improvements in cardiorespiratory fitness (i.e., peak oxygen utilization [VO2]), and to decreased fatigability (i.e., rating of perceived exertion [RPE] during steady-state submaximal [1.5 miles per hour] walking). In this SPiRE application, Dr. Forman proposes to redirect his expertise in nitrite therapeutics to Veterans with long COVID. Nitrites will be administered as nitrate-rich beetroot juice versus nitrate-poor placebo. When beetroot juice is ingested, nitrates are metabolized to nitrite. Compared to IND nitrite capsules, beetroot juice is relatively easier to administer, less expensive, and hemodynamically safer. Whereas serum nitrite levels have not been consistently high in studies of beetroot juice interventions as compared to nitrite capsules, this proposal aims to optimize nitrite levels using 210 ml per day of Beet-It nitrate beverage (James White Drinks Ltd., Ipswich, UK) to provide 16 mmol of nitrate/day for 14 days versus a 210 ml of nitrate- depleted placebo. All participants will also undergo physical therapy. Endpoints in this SPiRE study are oriented principally to physical function. Endpoints (measured pre- and post- the 2-week intervention) include fatigability as well as walking efficiency (VO2/kg) during steady-state walking. Furthermore, traditional functional indices of peak VO2, VO2 at anaerobic threshold, 6-minute walk distance, short physical performance battery, and pulmonary function tests will also be assessed. Nitrite levels (both serologically and in the skeletal muscle itself) will be measured to best ascertain the relationship of nitrite and putative clinical changes. In addition, analyses of skeletal muscle will clarify if nitrite-mediated changes in physical function correlate to changes in skeletal muscle respiration. Overall, this proposal aligns with the Veteran?s Affairs Office of Research and Development?s commitment to research that helps Veterans affected by COVID-19, and it also aligns with the Rehabilitation Research and Development?s mission to maximize Veterans? functional independence, quality of life and participation in their lives and community. Dr. Forman anticipates applying the data and momentum from this compelling SPiRE-based analysis to pursue a subsequent MERIT trial that reinforces the value of nitrite therapeutics more definitively for long COVID patients.
 
3. Project Title: TRAINING IN MOLECULAR EPIDEMIOLOGY: LINKING GENES TO PHYSICAL FUNCTION IN OLDER ADULTS
  Leader(s): SANTANASTO, ADAM J
    THE UNIVERSITY OF PITTSBURGH
    NIH K01AG057726 / (2018-2023)
  Age-related declines in physical function are common and lead to increased health care costs, institutionalization andmortality. As a traditional epidemiologist with unique expertise in skeletal muscle aging and physical function, I haveresearched lifestyle interventions (weight loss, aerobic and resistance training) to prevent age-related declines in physicalfunction. However, lifestyle changes are difficult to adopt, especially for those at the highest risk for functional decline. Toextend the benefits of these interventions, it is imperative to understand biological processes underlying changes in functionwith aging and following intervention. As such, the current proposal will provide the candidate with advanced training inmolecular epidemiology and biology of aging, yield novel insight on the genetic and biological basis of physical functionamong older adults and lay the foundation for future research. Specially, Aim 1 will identify genes and genetic variants forphysical function and changes in physical function with aging. Aim 2 will examine blood RNA expression for componentsof the transforming growth factor beta (TGF-?) pathway, which is implicated in muscle dysfunction and pathogenic fibrosis,with physical function and its change with aging. Aim 3 will test if serum levels of TGF-? and procollagen type 3 N-terminal propeptide (P3NP - a biomarker of pathogenic fibrosis) are related physical function among older adults. I willleverage robustly collected physical function measures, biological samples, and an ultra-high-density genome-widepolymorphism map from the NIA-funded Long Life Family Study (LLFS), a multi-center study of exceptional aging andlongevity in families and fromThe Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE)Consortium. The proposed research and training is very innovative. First, despite being implicated in several age-relatedconditions there have been no human studies that have examined the relationship between TGF-? or P3NP and physicalfunction. Further, LLFS has a large number of ?oldest old?, who are understudied and at the highest risk for functionaldecline. There has also been limited research on the genetics of physical function. The proposed career development awardwill provide the applicant with essential new mentorship, knowledge and skills in human genetics and molecularepidemiology including but not limited to blood RNA expression and protein biomarker development (Aim 2 and 3),genome wide association (GWA) and linkage analyses (Aim 1), meta-analysis(Aim 1) and bioinformatics (Aim 1)approaches to follow-up association and linkage analyses. Finally, this award will be critical for facilitating my transitionto an independent research career in aging and molecular epidemiology with a focus on physical function. As anepidemiologist with expertise in both traditional and molecular methods,I will be well-positioned to contribute to theadvancement of the evolving field of GeroScience.
 
4. Project Title: The relationship between protein intake, gut microbiome, inflammaging and loss of mobility in older adults
  Leader(s): FARSIJANI, SAMANEH
    UNIVERSITY OF PITTSBURGH AT PITTSBURGH
    NIH K01AG071855 / (2022-2026)
  This K01 application is for Dr. Samaneh Farsijani to establish a research career in Nutritional Epidemiology and acquire skills to integrate omics (gut microbiome) and non-omics (dietary intake) data towards her long-term goal in ?Precision Nutrition? to develop age-specific dietary recommendations, replacing the current one-size-fits-all approach, to promote healthy aging. The proposal is derived from the candidate?s extensive training in nutrition and interdisciplinary research background in biology and epidemiology. The proposed training goals are directed to advance candidate?s skills in 1) aging & nutritional epidemiology; 2) advanced biostatistics; 3) gut microbiome; and 4) career development. Acquired skills will be applied toward the proposed scientific goal to determine the relationships between protein intake, gut microbiome, inflammation, and mobility loss in older adults. Aging is associated with inefficient utilization of dietary proteins, due to anabolic resistance, which potentially leads to functional losses. Also, up to 50% of US older adults fail to meet the Recommended Dietary Allowance (RDA) for protein (0.8 g/kg body weight/d). Therefore, a higher protein intake, above the RDA (1.0-1.2 g/kg/d), has been suggested to compensate for changes in protein metabolism and to maintain muscle health in aging. However, this strategy has not been incorporated into dietary guidelines due to inconclusive evidence from small and short- term studies, which were unable to show the underlying mechanisms and causal relationships between protein intake and mobility function in older adults. Gut dysbiosis (i.e., changes in gut microbiome) and inflammaging (i.e., low-grade chronic inflammation in aging) have been linked to frailty in older adults. Since diet plays a key role in shaping the gut microbiome and inflammation, it may be speculated that the effects of protein intake on mobility function are mediated through alterations of dysbiosis and inflammaging. Our central hypotheses are: i) high protein intake reduces the risk of mobility limitation by ameliorating inflammaging; ii) different protein intake metrics are independently associated with gut microbiome and inflammaging; and iii) gut dysbiosis is associated with mobility impairment in older adults. This proposal will leverage data from Health, Aging & Body Composition (Health ABC), and Study of Muscle, Mobility & Aging (SOMMA) cohorts to address three Aims: Aim 1: To simulate a pragmatic clinical trial using the Health ABC cohort to determine i) the effect of protein intake on the risk of mobility limitation, and ii) its causal mediation by amelioration of inflammaging. Aim 2: a) To characterize the associations between different metrics of protein intake (i.e., quantity, source and within-day distribution pattern), gut microbiome composition, and fecal metabolites; and b) to determine the association between gut dysbiosis and inflammaging in SOMMA. Aim 3: To determine the cross-sectional associations between gut microbial composition and fecal metabolites with mobility (i.e., gait speed) in older adults from SOMMA. This project will broaden our insights into the influence of protein intake, as a modifiable factor, on gut microbiome, inflammaging, and muscle health in aging with the ultimate goal to drive age-specific dietary advice.
 
5. Project Title: A COMPUTATIONAL APPROACH FOR UNDERSTANDING LOCOMOTOR LEARNING POST-STROKE
  Leader(s): TORRES-OVIEDO, GELSY
    THE UNIVERSITY OF PITTSBURGH
    NIH K01NS092785 / (2016-2019)
  DESCRIPTION (provided by applicant): Step asymmetry post-stroke (i.e., limp) substantially affects the quality of life of stroke survivors because it impairs patients' mobility, thereby limiing their daily activities and increasing their dependency on others. Consequently, a primary interest for patients, clinicians, and researchers is to correct the step asymmetry in stroke survivors. Promising studies show that patients can re-learn to walk symmetrically if their step asymmetry is exaggerated with a split-belt treadmill that moves the legs at different speeds. While these results are encouraging, gait improvements are highly contextual and do not persist when walking over ground. To address this critical issue for gait rehabilitation, the PI is proposing a combination of computational and experimental approaches to identify key factors regulating the generalization of locomotor learning after stroke. The PI's central hypothesis is that inherent features from one's movement (e.g., kinematic errors and walking speed) regulate the generalization of locomotor learning. This hypothesis was formulated on the basis of the PI's preliminary data showing more generalization of treadmill learning to over ground walking when kinematic errors or walking speed during split-belt adaptation are similar to those naturally experienced. In the proposed computational approach, model inputs are errors that subjects experience during split-belt walking (for example, unexpected leg motions disturbing one's balance), model outputs are actions to correct these errors (for example, a larger step to prevent falling). The mathematical relationship between inputs and outputs is used to predict the effect of error size (Aim 1) and walking speed (Aim 2) on the generalization of learning in an individual basis. Once factors mediating the generalization of learning are identified, they can beharnessed to develop interventions that improve the gait of stroke survivors during real-life situations. PI qualifications: the PI is a prolific and creative bioengineer. Her first class trainng in physics, biomechanics, and neuroscience, in addition to her strong interest in rehabilitation make her the adequate individual for doing the proposed work. Her studies in human motor control are well recognized (>700 citations; h-index 11) in a relatively short, but highly productive academic career. Through this award she will receive mentorship from two extraordinary investigators with complementary expertise: Michael Boninger, MD, PhD. (clinical rehabilitation) and Reza Shadmehr, PhD (computational motor control). They will serve as primary co-mentors. In addition the PI will receive mentorship from an expert panel of collaborators including Dr. Subashan Perera (biostatistics), Dr. Steven Graham (neurology), Dr. Julie Fiez (neuropsychology) and Dr. Skidmore (post-stroke rehabilitation). Thus, this award will provide the mentorship and career development allowing the PI to become an independent researcher able to compete for R01-level funding to study gait deficits post-stroke through computational modeling.
 
6. Project Title: Human Factors of Aging Program
  Leader(s): REDFERN, MARK S
    UNIVERSITY OF PITTSBURGH AT PITTSBURGH
    NIH K07AG061256 / (2021-2025)
  Abstract: The candidate, Mark S Redfern, PhD, is a professor at the University of Pittsburgh with a primary appointment in the Department of Bioengineering, Swanson School of Engineering, and secondary appointments in Otolaryngology, School of Medicine, and Physical Therapy, School of Health and Rehabilitation Science. He is applying for a K07 to establish a new program in Human Factors of Aging to educate and support researchers, clinicians and students focused on improving the lives of older adults. A unique aspect of the curriculum is including design for cognitive decline and Alzheimer?s disease through a partnership with Pitt?s Alzheimer?s Disease Research Center (ADRC). Research often leads to ideas and findings that can have direct application to improve the lives of people of all ages. One limiting step in the translation of these new ideas is the incorporation of human factors in the design. Incorporating the human factors of aging is a critical component of any medical device design for an older population. There are physical (e.g. mobility, dexterity, anthropometry, strength, range of motion), sensory (e.g. vision, hearing, vestibular, proprioception) and cognitive considerations (e.g. memory, executive function, cognitive speed). Translation of ideas for older adults with cognitive decrements and Alzheimer?s disease is particularly difficult. The interactions of cognitive decrements with the physical and sensory changes associated with aging require special attention during design that to-date is not addressed. To address this need, Dr. Redfern, in collaboration with the ADRC, will establish a new and novel educational program with a curriculum to bring the necessary knowledge of Human Factors of Aging to the research community. This curriculum will address not only physical and sensory considerations, but also the unique requirements for adults with cognitive decline, and how they interact with other age-related issues. The long-term goal is to improve the development of new medical devices and interventions that are targeted to be used by/with older adults taking into consideration cognitive decline. The specific aims are to: 1) partner with the ADRC to educate clinicians, researchers, and engineers in the human factors of aging to improve the translation of their ideas into effective interventions 2) support investigators with collaborative advising and consultation on special issues in aging-related applications and availability of the Human Factors in Medical Device Laboratory for development and evaluation of medical devices/interventions targeting for older populations; and 3) develop a multidisciplinary community of investigators with interests and expertise in human factors of aging; including experts from the ADRC. Dr. Redfern?s background as a senior NIH/NIA researcher, longtime educator in Human Factors/Ergonomics, and positions in academic leadership make him the ideal person to create a sustainable and effective program. The proposed partnership with the ADRC will bring together a unique strength found nowhere else.
 
7. Project Title: GAIT VARIABILITY: EPIDEMIOLOGY, ASSESSMENT & MANAGEMENT
  Leader(s): BRACH, JENNIFER S
    THE UNIVERSITY OF PITTSBURGH
    NIH K23AG026766 / (2005-2011)
  DESCRIPTION (provided by applicant): Dr. Brach is a physical therapist and a board certified geriatric clinical specialist who aims to become a nationally-recognized leader in the field of mobility and aging research. Physical therapists are experts in the examination and treatment of musculoskeletal and neuromuscular problems that affect mobility. Therefore, physical therapists should play an important role in the multidisciplinary approach to treating mobility problems and should be key players in research aimed at improving mobility. As a physical therapist Dr. Brach has developed strong skills in the assessment and treatment of mobility problems, and her training in epidemiology has given her a strong foundation in research methods and basic statistical techniques. She now seeks additional focused training in longitudinal data analysis, advanced gait analysis (including time series analysis), and clinical trial methodology. As her primary mentor on the proposed Paul B. Beeson Career Development Award in Aging, Dr. Stephanie Studenski, herself a national leader in mobility and aging research, will supervise Dr. Brach's research training and career development towards becoming an independent investigator and leader in the field of aging. Her research program and career development will be overseen by a multi-disciplinary team including an Epidemiologist/Geriatrician, a Statistician, a Bioengineer, and a Physical Therapist. The rich resources of the University of Pittsburgh Claude D. Pepper OAIC will also be utilized for her support and development. In line with her goal of becoming a nationally recognized leader in the field of aging and mobility, Dr. Brach designed a series of three research projects that will allow her to examine in detail gait variability and adaptability, a component of mobility. In project 1, Dr. Brach will use an established dataset from the Cardiovascular Health Study to examine the contributors and consequences of gait variability in a biracial sample of over 500 older adults. Since many older adults with mobility problems are not identified when tested under low demand situations, in project 2 Dr. Brach will develop a measure of gait adaptability to test older persons walking under high demand conditions. The final project (project 3) will be a small RCT to examine exercise interventions to improve gait variability and adaptability in older persons.
 
8. Project Title: NOVEL BRAIN NEUROIMAGING MARKERS OF AGE-RELATED MOBILITY IMPAIRMENT
  Leader(s): ROSANO, CATERINA
    THE UNIVERSITY OF PITTSBURGH
    NIH K23AG028966 / (2006-2009)
  DESCRIPTION (provided by applicant): Gait slowing and balance problems often develop in older adults in the absence of a specific disease or acute clinical event, but rather as a consequence of age-related changes in the nervous, musculoskeletal or cardiorespiratory system. A multidisciplinary study of such unexplained age-related mobility impairment looks both at its peripheral and central contributors and it therefore requires a strong foundation in geriatric assessment, neuroimaging and neuroepidemiology. Dr. Rosano is a physician neuroepidemiologist who aims to prevent age-related mobility impairment by targeting structural and functional brain integrity. As a new Pepper scholar and junior faculty, her line of research provides evidence for an independent association between subclinical white matter (WM) abnormalities and focal gray matter (GM) atrophy with mobility. She now seeks external funding for a 3 year career award application to address the following three aims: 1) to identify the earliest structural WM and GM changes associated with unexplained age-related mobility impairment, 2) to examine the spatial and temporal relationship of WM and GM subclinical abnormalities in mobility-related areas and 3) to identify the possible causes and risk factors of such brain abnormalities. The application consists of two complementary projects. In Project 1, she will utilize existing paired brain MRIs collected 5 year apart in 2,109 participants of the Cardiovascular Health Study (CHS) to measure the association between changes in focal WM hyperintensities and GM atrophy with mobility. In Project 2, she will use advanced neuroimaging techniques to acquire 250 brain MRIs from the Health, Aging and Body Composition study participants (Health ABC) and she will measure WM, GM and cortical connections' abnormalities that are undetectable with conventional MRI. Dr. Rosano will exploit the CHS and Health ABC unique longitudinal cohorts data on mobility, health related factors, cardiovascular and inflammatory markers that span a follow-up time of over 10 years. Dr. Anne Newman, an internationally recognized leader in multidisciplinary aging research, and a team of experts in cerebrovascular epidemiology, mobility research, and geriatric neuroimaging will assist Dr. Rosano's work. This award will consolidate Dr. Rosano's knowledge of longitudinal data analysis, will advance her expertise of cutting-edge neuroimaging techniques, and will strengthen her ability to independently execute large longitudinal epidemiological studies.
 
9. Project Title: FUNCTIONAL RECOVERY IN POST-ACUTE CARE
  Leader(s): HARDY, SUSAN E
    THE UNIVERSITY OF PITTSBURGH
    NIH K23AG030977 / (2008-2013)
  Hospitalization is one of the most common precipitants of disability, and skilled nursing facilities (SNFs) arencreasingly the site where the most vulnerable older adults receive the post-acute medical and rehabilitativecare crucial for their functional recovery. Changes in the health care system have led to patients' beingdischarged from the hospital quicker and sicker, but the structure of SNF-based post-acute care (PAC) hasnot kept up with their increasing medical illness. Failure to regain pre-hospitalization function during thiscritical juncture results in morbidity, institutionalization, and even death, yet there is little evidence to guideSNF-based PAC. Clinical observations suggest that medical instability, delirium, and depressive symptomsare common but often unrecognized among PAC patients, interfere with rehabilitation and functionalrecovery, and are modifiable. Delirium and depression have well developed assessment tools, while medicalinstability can be identified with simple markers such as vital signs and symptoms at rest and with exercise.The overall goal of the proposed research is to improve the management of medically ill patients in PAC andultimately to improve functional recovery. The specific aims are 1) to identify SNF-based PAC patients withsubstantial yet modifiable risk of poor functional recovery using data from the Medicare Current BeneficiarySurvey, 2) to follow a prospective cohort of 180 new admissions to SNF-based PAC to determine the effectof medical instability, delirium, and depressive symptoms on function after one week and at SNF discharge,and 3) to pilot test an intervention to screen for these three factors on admission to SNF-based PAC.The proposed career development and research plans will build upon analytic and methodologic skillsgained through my doctoral training in Investigative Medicine. I wish to add competencies in 1) analysis ofadministrative data; 2) primary research design and implementation, and 3) intervention development for theSNF setting. Upon completion of the proposed work, I will have built a strong evidence base for and gainedextensive experience with the PAC population and the SNF setting. I will then be prepared to design, securefunding for, and implement a full-scale clinical trial of a refined intervention to address medical instability,delirium, and depressive symptoms, and ultimately to improve functional recovery in SNF-based PAC.Public health relevance: Failure to recover from functional decline after hospitalization can be catastrophicfor older adults and costly to the health care system. If older adults admitted to nursing homes for additionalpost-acute care are still medically unstable, confused, and depressed from their acute illness, they may havetrouble participating in rehabilitation and regaining their previous function. This research will determine theeffect of these factors on functional recovery among older adults in nursing homes for rehabilitation anddevelop a method for identifying these problems when patients are admitted to the nursing home.
 
10. Project Title: ROLE OF BRAIN IN BLADDER CONTROL AND CONTINENCE IN ELDERLY WOMEN
  Leader(s): TADIC, STASA DUSAN
    THE UNIVERSITY OF PITTSBURGH
    NIH K23AG031916 / (2008-2013)
  DESCRIPTION (provided by applicant): Urge urinary incontinence (Ul) is the most common form of geriatric Ul, with significant impact on patients' lives and on society as a whole. It is manifested by urgency to void and urine leakage, associated with involuntary bladder contraction (detrusor overactivity), implying failure of the brain to fulfill its role in controlling the bladder. Rapidly emerging neuroimaging data support this role, at least in healthy young volunteers. The candidate has been working with a team that has pioneered the study of brain control of bladder (functional brain imaging with simultaneous urodynamics). Together they have shown, in older women with urge Ul, a different response to bladder filling in 2 key brain regions involved in mapping and monitoring bladder afferent signals, combined with impaired response in frontal cortex (responsible for executive control of voiding) and recruitment of compensatory pathways to suppress urgency and prevent urine leakage. The present proposal is designed to provide the candidate with the additional skills needed to become an independent investigator capable of continuing to address the complex syndrome of geriatric Ul in an innovative, cross-disciplinary manner. Activities are structured in two major components: 1) academic, with further development of theoretical and practical expertise in neuroimaging, urodynamics and urinary incontinence, obtained by performing the relevant procedures and clinical consults under the direct supervision of designated mentors, and supported by coursework in neuroscience, statistics and imaging techniques; and 2) scientific, by carrying out a research plan based on hypotheses derived from previous observations. The proposed Research Plan is strongly oriented toward aging, as it aims: 1) to test existing preliminary observations in a larger sample of older urge incontinent subjects; and 2) to investigate the role of age-associated white matter hyperintensities (WMHI) in urge Ul, because of their known association with urge incontinence and detrusor overactivity and their negative effect on frontal cortex (executive) function. Relevance: geriatric urinary incontinence affects 15% of US elderly and thus represents an important public health issue for which therapeutic efficacy has advanced little in the past half century. The proposed training ill provide the candidate with academic development and a novel set of skills to use in investigating the potential causes of geriatric Ul and in developing new treatment strategies.
 
11. Project Title: THE AGING BRAIN AND THE COGNITION-MOBILITY INTERFACE IN CLINICALLY NORMAL OLDER ADULTS
  Leader(s): NADKARNI, NEELESH K
    THE UNIVERSITY OF PITTSBURGH
    NIH K23AG049945 / (2015-2020)
  DESCRIPTION (provided by applicant):This Mentored Patient-Oriented Research Career Development Award (K23) application is designed to enable the candidate, Neelesh Nadkarni, MD, PhD, FRCPC, to become an independent investigator through the study of the influence of three major brain pathologies (amyloidosis, neurodegeneration and small-vessel disease) on the cognition-mobility interface in older adults. Dr. Nadkarni is a licensed practicing geriatricia with residency and fellowship training acquired in the United States and Canada in internal medicine, geriatric medicine, geriatric and cognitive neurology, and hospital medicine. Dr. Nadkarni also completed a PhD in medical sciences and neurosciences following completion of his clinical training. This K23 award will train Dr. Nadkarni to develop research skills in the application of advanced neuroimaging to study brain amyloidosis and neurodegeneration and enhance his knowledge of small-vessel disease imaging. It will also train him to develop the cognition-mobility interface (COMBINE) through the refinement of a protocol of dual-tasks (gait- cognition tasks). The K23 research application will test the hypothesis that amyloidosis, neurodegeneration and small-vessel disease are related to the COMBINE, which can predict impending cognitive and/or mobility decline in clinically normal older adults (defined here as those without cognitive or mobility impairment). This application is based on the premise that in clinically normal older adults, progressive functional impairment stemming from cognitive or mobility decline is a continuum that commences with deficits in cognition and/or mobility. Concurrent performance of cognitive tasks while walking assesses the COMBINE, which can serve as 'stress tests' of the brain. Pathological age-related disease burden in brain regions important to cognitive or mobility processes, can manifest as deficits in the COMBINE in clinically normal older adults. This study will quantify amyloidosis by measuring Pittsburgh B ligand retention on Positron Emission Tomography (PET), small-vessel disease by determining volume of white matter hyperintensities on magnetic resonance imaging (MRI), and neurodegeneration by measuring fluoro-2-deoxy-glucose uptake on PET. The study will evaluate the relationships between the three pathologies affecting the COMBINE in 120 cognitively normal older adults, who will be recruited from an ongoing longitudinal study of brain amyloid deposition (RF1 AG025516; PI: Klunk). The findings from this research can provide new insights into mechanisms and clinical approaches for early detection of cognitive and mobility decline in older adults, ultimately leading to novel targets for interventions to prevent adverse outcomes of aging. This K23 training and research application involves a stellar multidisciplinary team of experts in dementia, PET and MRI neuroimaging, neuropsychology, locomotion measurement, statistics, cognitive and motor aging, postural control and geriatrics. This team of renowned leaders is committed to provide the candidate with mentorship and consultation on a regular basis through the entire duration of this award. The K23 related training and research activities will be conducted at the University of Pittsburgh which is ideallysuited to undertake this work. This K23 award will ultimately enable the geriatrician-candidate to become an independent investigator conducting patient-oriented research and a leader in brain aging and the cognition-mobility interface.
 
12. Project Title: Activity and Participation in Vestibulopathy
  Leader(s): KLATT, BROOKE
    UNIVERSITY OF PITTSBURGH AT PITTSBURGH
    NIH K23DC020215 / (2022-2027)
  Current vestibular rehabilitation intervenes upon vestibular impairments (balance, gaze stability, and dizziness). Activity and participation are reduced in people with vestibulopathy, but are not addressed in vestibular rehabilitation protocols. Approximately 40% of people with vestibulopathy do not fully recover and transition to a state of chronic disability, which often results from reductions in activity and participation, and. Evidence from rehabilitation science within other populations suggest that return to full activity and participation is related to functional mobility status, and also several behavioral, personal, and environmental factors. Similarly, we suspect that cognitive, mood, and personal (confidence, coping, and fear avoidance) factors that are modifiable, may impact activity and participation in people with vestibulopathy. It is also unknown whether improvements in activity and participation are related to remediation of impairments following vestibular rehabilitation. Activity and participation represent important domains to target to optimize outcomes and reduce chronic disability. This career development award will establish Dr. Brooke Klatt as a clinical scientist with expertise in 3 primary domains: (1) cohort design and analysis; (2) qualitative methodology, and (3) complex rehabilitation intervention development and behavioral clinical trial methodology. Dr. Klatt has assembled a multi-disciplinary team of experts in rehabilitation intervention development and implementation (Jennifer Brach, PhD, PT and Elizabeth Skidmore, PhD, OTR/L), activity and participation assessment and epidemiological methods (Andrea Rosso, PhD, MPH), behavioral impacts on vestibular recovery (Jeffrey Staab, MD), and clinical trial methodology (Megan Hamm, PhD and Charity Patterson, PhD, MSPH). Dr. Klatt will conduct a series of studies to develop an enhanced vestibular intervention that will augment current vestibular rehabilitation targeted to improve activity and participation. She will investigate whether impairments (balance, gait, gaze stability, dizziness, cognition, and mood) as well as personal factors (confidence, coping skills, and fear avoidance) are related to activity and participation in people with vestibulopathy (Aim 1), and she will determine if reductions in vestibular impairment is related to improvements in activity and participation (Aim 2). She will use stakeholder input from clinicians and patients to determine the delivery features that show the greatest promise for improving activity and participation in people with vestibulopathy (Aim 3). Dr. Klatt?s is plan to develop effective interventions to enhance current vestibular rehabilitation addresses the NCMRR research priorities to mitigate acquisition of secondary conditions by using a multimodal approach to promote vestibular plasticity and sensorimotor function. The proposed training will be the foundation for a future R01 application examining the efficacy of the enhanced vestibular intervention to improve activity and participation and the quality of life for individuals with vestibulopathy.
 
13. Project Title: MIDCAREER INVESTIGATOR AWARD IN TRANSLATIONAL PATIENT-ORIENTED RESEARCH IN AGING
  Leader(s): BRACH, JENNIFER S
    THE UNIVERSITY OF PITTSBURGH
    NIH K24AG057728 / (2017-2022)
  Midcareer Investigator Award in Translational Patient-Oriented Research in AgingThis application is for a K24 Midcareer Investigator Award in Patient-Oriented Research to promote mentoringand career development in dissemination and implementation research that improves mobility and preventsdisability in community-dwelling older adults. Dr. Jennifer Brach, PI of the proposed award, is a physicaltherapist, epidemiologist and scientist committed to mentoring health professional trainees and junior facultyand working to improve the mobility and quality of life of older adults. For over 15 years, she has conductedpatient-oriented research studies focused on increasing successful aging among vulnerable older adults andshe has built a strong multi-disciplinary network of research collaborators who are available to co-mentortrainees and junior faculty. Her long-term goal is to bridge the gap between clinical research, public health, andeveryday practice by transferring the findings from clinical trials to practice settings and communities, wherethe findings will improve mobility and prevent disability in older adults and to train health professionals andjunior faculty for a successful career in academic investigation. Dr. Brach seeks support from a NIA K24 careeraward to: 1) establish a research training and mentoring program that will prepare beginning scholars tobecome successful, independent patient-oriented researchers in disability prevention in aging, 2) obtainadditional training and participate in practical experiences in dissemination and implementation science thatwill enhance her translational research skills, and 3) extend her currently funded work to bridge the gapbetween clinical research and practice settings and the community. Dr. Brach has a substantial and growingtrack record of mentorship of trainees from a variety of disciplines; the requested K24 support would allow herto curtail teaching and administrative responsibilities so that she can focus the majority of her time on researchand mentoring.
 
14. Project Title: THE ROLE OF USP30 IN IDIOPATHIC PARKINSONS DISEASE
  Leader(s): ROCHA, EMILY MANGANO
    THE UNIVERSITY OF PITTSBURGH
    MICHAEL J FOX FOUNDATION MJFF-008849 / (2021-2023)
  Dopamine neurons are highly vulnerable to age-dependent increases in mitochondrial dysfunction, oxidative stress, and protein accumulation due to their high metabolic activity, low antioxidant capacity and post-mitotic nature. Failure to remove these damaged mitochondria will likely lead to a bioenergetic crisis that ultimately contributes to the onset and/or progression of Parkinson?s disease. The deubiquitinating enzyme, ubiquitin specific protease 30 (USP30) blocks mitochondrial degradation. In Parkinson?s disease, USP30 is increased in dopamine neurons, therefore, blocking USP30 may be neuroprotective by allowing damaged / dysfunctional mitochondria to be degraded. We hypothesize that using targeted genetic technology to block USP30 will allow damaged mitochondria to be removed, and the overall pool of healthy mitochondria to increase. This will enhance dopamine neuron bioenergetics, reduce oxidative stress and promote neuronal survival.
 
15. Project Title: BIOBEHAVIORAL STUDIES OF CARDIOVASCULAR DISEASE
  Leader(s): GIANAROS, PETER J
    THE UNIVERSITY OF PITTSBURGH
    NIH P01HL040962 / (1997-2023)
  ABSTRACTBiobehavioral Studies of Cardiovascular Disease (PO1-HL040962)This Program Project (P01) continuation application focuses on the human brain substrates of behavioral andsocio-environmental influences on cardiovascular disease (CVD) risk in midlife adults. Proposed are 3 Projectsthat are conceptually cross-linked and supported by 3 Core Units. Collaborative investigators representmultiple disciplines, including psychology, neuroscience, biophysics, medicine, psychoneuroimmunology,epidemiology, machine learning, bioinformatics, and statistics. Project 1 aims to elucidate functional andstructural brain phenotypes that predict the multiyear progression of preclinical vascular disease anddysfunction, with a focus on neural circuitries for visceral control that coordinate autonomic, neuroendocrine,hemodynamic, and immune physiology with stress- and emotion-related behavioral processes. Project 2 aimsto establish whether functional characteristics of these visceral control circuits moderate the influences ofstress-related environmental exposures on the progression of preclinical vascular disease and dysfunction,tracking individuals' behavior and cardiovascular physiology in daily life to test a novel neuro-diathesis modelof CVD risk. Project 2 also tests for the first time whether daily life physical activity associates with daily lifestress physiology through its effects neural circuits for visceral control. Project 3 aims extend those of the otherProjects by elucidating the neural and peripheral processes linking physical activity with physiological andpsychophysiological markers of CVD risk (including daily life affect and stress physiology) using anexperimental intervention methodology. These P01 aims are unique in cardiovascular behavioral medicine, andthey will be pursued in the context of multi-component data collection efforts that satisfy all project-specificaims. As a result, the P01 will create new opportunities for integrative and translational science on the humanneurobiology of CVD risk that cuts across multiple methods and levels of analysis. Helping to advance itsparent field, the P01 will generate and disseminate original and expansive public-domain resources and tools tothe broader scientific and clinical communities through comprehensive data and software sharing andeducational objectives. Enabling a precise focus on early CVD etiology, the study cohorts comprise nearly 900midlife adults without clinically apparent CVD, and study methods will include novel combinations ofneuroimaging, ecological momentary assessments of experienced environments, ambulatory hemodynamicmonitoring, autonomic, neuroendocrine, immune, and vascular assessments, laboratory clinical evaluations,hetero-method health behavior assessments, and arterial imaging. The 3 Core Units of this P01 provide forsynergy and inter-project coordination by administrative, data management and participant accrual services;measurement and instrumentation support; and direction in cutting-edge bio-statistical and data-intensive(machine learning) analyses. The present application thus represents a thematic continuation and next-generation extension of translational neurobiological research on CVD by this P01, which was initiated in 1988.
 
16. Project Title: TASK SPECIFIC TIMING AND COORDINATION EXERCISES TO IMPROVE MOBILITY IN OLDER ADULTS
  Leader(s): BRACH, JENNIFER S
    THE UNIVERSITY OF PITTSBURGH
    NIH R01AG045252 / (2015-2020)
  DESCRIPTION (provided by applicant): Walking difficulty is common and costly in older adults. While traditional exercise has been shown to promote physical and mental health and may prevent walking difficulty, such exercise has focused on strength and endurance, and has overlooked a critical component of walking ability; the timing and coordination of movement. Aging and disease alter timing and coordination as reflected by slowed neuromotor performance, increased gait variability and reduced smoothness of movement. Task specific timing and coordination exercise that includes practice of smooth coordinated aspects of gait over multiple walking conditions has the potential to improve walking ability greater than a standard program. Our preliminary data suggest that interventions on timing and coordination of gait impact mobility greater than the standard strength and endurance program. The next key step and the objective of this proposal is to combine the two interventions to determine if potential gains in mobility, activity and participation obtained from a standard plus timing and coordination program, are larger than the gains obtained from the standard program alone. Therefore, the primary aim of the proposed project is to evaluate the impact of adding timing and coordination training to standard strength and endurance training on mobility. Secondary aims include examining 1) additional outcomes representing the components of the intervention and measures of activity and participation, 2) the delayed and sustained effects of the intervention, and 3) the effects of the intervention within various other subgroups of interest. This randomized clinical trial in older adults who walk slowly (i.e. < 1.20 m/s) will compare a 372community-dwelling non-intervention attention control and a standard 12 week strength, endurance and flexibility program to a 12 week 'standard- plus' program of strength, endurance, flexibility plus task specific timing and coordination training. The primary outcome is gait speed at 12 weeks. We will also examine secondary and tertiary outcomes representing components of the intervention and measures of activity and participation and the delayed and sustained effects at 24 and 36 weeks. The findings from this efficacy trial will provide evidence for the added value of task specific timing and coordination training for promoting walking abilityin older adults and will form the basis for future effectiveness trials. Future work includes translation to nonprofessional exercise leaders with the long-term goal to incorporate neurological training into standard exercise programs for health promotion for older adults.
 
17. Project Title: INVESTIGATING GAINS IN NEUROCOGNITION IN AN INTERVENTION TRIAL OF EXERCISE SUPPLEMENT
  Leader(s): ERICKSON, KIRK I ; BURNS, JEFFREY MURRAY ; KRAMER, ARTHUR F. ; MCAULEY, EDWARD ;
    THE UNIVERSITY OF PITTSBURGH
    NIH R01AG053952 / (2016-2021)
  AbstractDespite the ubiquity of normal age-related cognitive decline there is an absence of effective approaches forimproving neurocognitive health. Fortunately, moderate intensity physical activity (PA) is a promising methodfor improving brain and cognitive health in late life, but its effectiveness remains a matter of continuedskepticism and debate because of the absence of a Phase III clinical trial. Here we propose a Phase III multi-site randomized clinical trial called IGNITE (Investigating Gains in Neurocognition in an Intervention Trial ofExercise) to more definitively address whether exercise influences cognitive and brain health in cognitivelynormal older adults. We are proposing a 12-month, multi-site, randomized dose-response exercise trial (i.e.,brisk walking) in 639 cognitively normal adults between 65-80 years of age. Participants will be randomized toa (a) moderate intensity aerobic exercise condition at the public health recommended dose of 150minutes/week (N=213), (b) a moderate intensity exercise condition at 225 minutes/week (N=213), or (c) to astretching-and-toning control condition for 150 minutes per week (N=213). Participants will meet 3 days/weekfor site-based exercise and do home-based activity on two more days of the week for 12 months. Acomprehensive state-of-the-science battery of cognitive, MRI, amyloid imaging, physiological biomarkers,cardiorespiratory fitness, physical function, and quality of life measures will be assessed at baseline and aftercompletion of the intervention. We have assembled a highly creative, productive, and interdisciplinary teamwith a long history of collaboration and experience conducting exercise interventions in older adults to test thefollowing aims: Aim 1: Using a comprehensive neuropsychological battery and the NIH Toolbox, we will testwhether a 12-month moderate intensity exercise intervention improves cognitive performance in older adultsand (b) test whether the improvements occur in a dose-dependent manner. Aim 2: We will test whether a 12-month PA intervention augments MRI markers of brain health and whether these changes happen in a dose-dependent manner. Aim 3: We will test the hypothesis that cardiometabolic, inflammatory, and neurotrophicchanges mediate improvements in brain and cognition. Aim 4: We will examine subgroups (i.e., individualdifferences) that attenuate or magnify the effect of the intervention on cognitive, brain, and physiologicalsystems to better understand the factors that predict `responders' versus `non-responders' to the intervention.We will explore three categories of variables: (1) demographic (e.g., age) (2) genetic (e.g., APOE), and (3)baseline A? burden. Exploratory Aims: We will explore (a) whether baseline brain health metrics predictadherence and compliance to 12-months of PA, and (b) the utility of multi-modal brain imaging analyticalapproaches to more comprehensively understand the effects of PA on the aging brain. The results from thistrial could transform scientific-based policy and health care recommendations for approaches to improvecognitive function in cognitively normal older adults.
 
18. Project Title: ROLE OF EXTRACELLULAR MATRIX IN AGE-RELATED DECLINES OF MUSCLE REGENERATION
  Leader(s): AMBROSIO, FABRISIA ; LEDUC, PHILIP R ;
    THE UNIVERSITY OF PITTSBURGH
    NIH R01AG061005 / (2019-2024)
  ABSTRACT Skeletal muscle trauma resulting from an injury or surgery often results in significant functional declinesin older adults. These declines are at least partially attributed to failed muscle healing. Muscle regeneration ispredominantly dictated by the action of muscle stem, or ?satellite?, cells (MuSCs), a reserve cell population thattypically demonstrates considerable dysfunction with increasing age. According to the stem cell ?niche?concept, stem cell responses are largely determined by biophysical and biochemical cues that emanate fromthe surrounding microenvironment. Indeed, expanding recognition of the influence of the microenvironment onstem cell behavior has led to a recent surge in the development of bioinspired and engineered extracellularmatrix (ECM) approaches for the treatment of skeletal muscle injuries. Still lacking, however, is an in-depthknowledge of whether and how pathogenic instructional characteristics of the native ECM disrupt MuSCfunction and skeletal muscle regeneration. While it is evident that MuSC activation, self-renewal, proliferationand differentiation are influenced by physical and dynamic niche interactions, a mechanistic understanding ofthe direct impact of age-related ECM alterations on skeletal muscle regenerative capacity is unknown. The over-arching goal of this project is to test our central hypothesis that age-related biophysicalalterations in the skeletal muscle ECM promotes a fibrogenic conversion in MuSCs, ultimately drivingimpaired skeletal muscle regeneration. Further, we hypothesize that these pathogenic biophysicalchanges may be reverted, at least partially, by mechanical stimulation. To achieve this goal, we willemploy an integrated approach that encompasses cutting-edge super-resolution imaging and 3-D tissueengineering methods to address two specific aims. Aim 1 studies will measure, manipulate, and mimic thebiophysical properties of young and aged skeletal muscle ECM in order to dissect the effect of age-relatedarchitectural and elastic ECM modifications on MuSC fate. Aim 2 studies will identify mechanisms by whichmechanical stimulation modulates biophysical properties of the aged ECM to promote MuSC myogenicity andmuscle regeneration. Successful achievement of these aims will further our understanding of 1) theinstructional capabilities of the native ECM on MuSC lineage specification, 2) how these instructionalcapabilities change over time, and 3) the molecular mechanisms controlling age-related declines in skeletalmuscle regenerative potential. Taken together, successful completion of these studies may provide afoundation for the identification of novel ECM targets in the treatment of skeletal muscle injuries for a geriatricpopulation. More broadly, an improved insight into how age-associated alterations in biomechanical,architectural and dynamic ECM properties direct MuSC function will expand our fundamental understanding ofaging and stem cell biology.
 
19. Project Title: Comprehensive functional genomic analysis of the multi-disease associated CDKN2A/B locus
  Leader(s): LI, GANG ; FINKEL, TOREN ;
    UNIVERSITY OF PITTSBURGH AT PITTSBURGH
    NIH R01AG065229 / (2021-2026)
  ABSTRACT The incidence of cardiovascular disease (CVD), Type 2 diabetes (T2D) and cancers all dramatically increase as a function of age. The underlying mechanisms of these diseases, which vary, are incompletely understood. Genome-wide association studies (GWAS) have identified many SNPs that are associated with these conditions. One of the strongest associations comes from the CDKN2A/B locus on chromosome 9p21.3 which has been associated with multiple age-related diseases, as well as overall human lifespan. Within this 200 kb locus, there are three encoded proteins, p16INK4a, p14ARF and p15INK4b, and one antisense non-coding RNA, the inhibitor of CDK4 (INK4) locus (AS/ANRIL). To date, it has not been firmly established which, if any, of these genes are the risk genes for the associated diseases. There are ~193 disease-associated, noncoding SNPs in linkage disequilibrium (LDs) across this 200 kb region, represented by 18 lead SNPs used for GWAS analysis. While the mechanisms underlying the contribution of these SNPs to specific diseases are not fully understood, a single genetic region associated with multiple different age-related diseases suggests that this locus may modulate these conditions by promoting aging itself, perhaps via induction of cellular senescence as a common mechanism. In this application, we propose to apply an experimental approach using high throughput techniques we have recently developed including Reel-seq and FREP/SDCP-MS, to systematically dissect this locus. We will first identify the disease-associated functional SNPs (fSNPs), as well as the regulatory elements across the 58 kb core region primarily associated with cardiovascular diseases using Reel-seq. Next, we will identify the regulatory proteins that specifically bind to all the fSNPs, as well as the regulatory elements, using FREP/SDCP- MS. A range of relevant cell types related to atherosclerosis will be used to generate the nuclear extract required for our screens. We will demonstrate the role of these regulatory proteins by confirming their direct effects on p16INK4a, p14ARF, p15INK4b and AS/ANRIL expression, and subsequently on cell cycle regulation and cellular senescence. A range of complementary techniques such as RNAi, CRISPR/cas9 gene editing, will be employed. Such analysis will provide the first in-depth understanding of this critical genomic region, as well as a unique strategy to uncover unifying biochemical pathways that simultaneously regulate atherosclerosis, as well as potentially multiple other age-related diseases.
 
20. Project Title: INVESTIGATION OF BRAIN MECHANISMS INVOLVED IN THE URINARY CONTINENCE MECHANISM ASSOCIATED WITH AGING
  Leader(s): RESNICK, NEIL M.
    THE UNIVERSITY OF PITTSBURGH
    NIH R01AG065288 / (2020-2025)
  PROJECT SUMMARY Prevalent, morbid, and costly ($66 billion/year in 2007), incontinence is a major problem, especially for older adults, in whom the most common type is urgency incontinence (UUI). Generally ascribed to bladder spasms, UUI's actual causes are unknown, and therapy remains inadequate. Recent data suggest that one cause is poor bladder control by the brain. In our recent R01 we used biofeedback (BFB) as a probe to explore this. The exciting findings suggest that one `phenotype' of UUI in older adults seems to be caused by a breakdown in brain control, which can be restored by successful behavioral therapy, while another is refractory. Our proposed new study will explore this further by attempting to differentiate the mechanisms associated with disease and aging. The goal is to identify which brain mechanisms should be suppressed because they are contributing to or causing UUI, which should be enhanced because they are helping to compensate for UUI, and which should be ignored because they are incidental to aging and not related to UUI. Current data suggest that bladder control comprises 3 cerebral circuits that maintain continence by suppressing the voiding reflex in the midbrain. In our UUI phenotype that responded to BFB, the mechanism involved enhancing deactivation of the first brain circuit (medial prefrontal cortex, mPFC) which resulted in less activation of the second circuit (which includes the midcingulate cortex). In the phenotype that was resistant to BFB, no brain changes were seen. Yet, although we have an emerging picture of the brain's role in UUI, we have only rudimentary understanding of what is `normal', i.e. how the brain normally controls the bladder. More relevant, we do not know whether this control mechanism is the same across the lifespan, or if it changes owing to the impact of aging. Thus, our overall aim is to characterize continence control in both young and old people, and examine how changes due to bladder control failure differ in each age group. Our specific aims are to characterize normal voiding in the continent old and young in order to better understand and verify the working model and to use the comparison to older adults with UUI to understand the mechanism of brain failure in these individuals. To address these aims, we will conduct a detailed clinical and neuroimaging study to study 80 asymptomatic women and 80 UUI women, each group divided equally into young (18-45) and old (65+ years). The study will enable us to evaluate the changes in brain structure and function and to identify brain mechanisms involved in continence control, changes due to aging (both benign and contributory to UUI), and changes due to disease. The study will provide the comprehensive data on brain mechanisms involved in the normal continence mechanism in order to better corroborate our working model, understand the aging process, and assess targets for therapy. It will thereby enable scientists to develop novel and more effective new therapies based on the revolution in neuroscience?and more hope for UUI sufferers.
 
21. Project Title: INNOVATIVE APPROACH TO GERIATRIC OSTEOPOROSIS
  Leader(s): GREENSPAN, SUSAN L
    THE UNIVERSITY OF PITTSBURGH
    NIH R01AG066825 / (2020-2025)
  Although close to 85% of residents in long-term care facilities (LTC) have osteoporosis and the risk of osteoporotic fractures is nearly 10 times that of community dwelling elderly, few are treated and studies are scarce. The large pivotal osteoporosis trials in postmenopausal women exclude those who are sedentary, frail or functionally impaired even though this is the group at highest fracture risk. Before a fracture reduction study can be justified in this cohort, an investigation demonstrating efficacy and predictability is a necessary first step. We have previously demonstrated that zoledronic acid (ZOL) can maintain bone mineral density (BMD) and is safe in frail elderly. However a dual action anabolic antiresorptive agent has a distinct advantage to build bone rapidly. The newly approved once monthly dual action romosozumab (ROMO), provides significant improvements in BMD and fracture reduction in 1 year. If ROMO were given prior to a potent antiresorptive medication such as ZOL, this combination (rapid boost over a year with ROMO and maintain integrity 2nd year with ZOL) could provide a novel treatment paradigm in this high risk population. The concern for ROMO is the potential increase risk of cardiovascular events demonstrated in one pivotal study. Before a large fracture reduction trial can be justified in this frail population, a study demonstrating BMD efficacy and safety is imperative. We will test the hypotheses that in frail institutionalized women, one year of ROMO prior to one year of ZOL will 1) be more efficacious compared to one year of calcium plus vitamin D prior to a year of ZOL as demonstrated by improvements in conventional bone density measurements, 2) improve novel measures of bone trabecular microstructure and bone turnover markers, and 3) provide characteristics associated with responders and non-responders. To address these hypotheses, we propose to conduct a 2-year, randomized, double-blind controlled trial to test the efficacy and safety of ROMO (year 1) and ZOL (year 2) compared to calcium+vitamin D (year 1) and ZOL( year 2), in 200 institutionalized frail women age 65+ in LTC. Safety will be carefully monitored. Serious adverse events (SAE's) will be obtained by a novel electronic alert system that provides real time notifications including ROMO associated cardiovascular SAE's. This study includes innovative features: 1) focus on the neglected LTC population of frail residents in whom we have a track record of successful enrollment, 2) inclusion of a newly approved potent dual action agent feasible in LTC, 3) assessments of bone structure, 4) point of care vertebral fracture images, 5) mobile lab allowing onsite participation, and 6) electronic alerts for real time adverse events. Despite the call by national consensus groups for the past 2 decades to address osteoporosis in frail elderly, trials and treatments are sparse. This study will challenge the current paradigm of avoiding anti-osteoporosis therapy and provide an innovative approach for geriatric osteoporosis, and help target robust responders.
 
22. Project Title: ROLE OF LIFESPAN INTERVENTION ON THE REGULATION AND PROGRESSION OF ALZHEIMER'S DISEASE
  Leader(s): RIZZO, STACEY J
    THE UNIVERSITY OF PITTSBURGH
    NIH R01AG067289 / (2020-2025)
  Project Summary/Abstract Our long-term goal is to identify therapeutic agents that can prevent the pathogenesis of Alzheimer?s disease (AD). The number of AD cases is rising dramatically worldwide, and there is an urgent need to develop new therapies that are more efficacious than the four currently approved drugs for AD which provide only modest symptomatic relief. Every clinical trial to date has failed to demonstrate disease-modifying efficacy for AD, which may in part be due to our limited understanding of the mechanisms that precede the pathogenesis of AD, and that are distinct from normal healthy aging. The overall aims of our proposal are to further understand the mechanisms underlying dysregulation of the autophagy-inflammation network that becomes progressively dysregulated with age, and accelerated by pathological conditions. Systemic inflammation is a biomarker of this dysregulation, as exemplified by its prevalence in many aging-related disorders including cardiovascular disease, diabetes, cancers, and neuroinflammation in neurodegenerative disorders such Alzheimer?s disease (AD). We hypothesize that mechanisms which drive systemic inflammation are common to both the biology of aging and AD and propose that interventions which target the shared feature of systemic inflammation, via regulation of the autophagy-inflammation network, may have potential as therapeutic agents for the prevention of conversion to disease pathogenesis in AD, as well as improve healthspan and longevity in aging populations. For this proposal we will use a combination of genetic and pharmacological tools to understand which brain specific cell types may be involved in the regulation of the autophagy-inflammation network via both mTOR dependent and mTOR-independent mechanisms that modulate inflammation. Findings from our studies will provide mechanistic insights at a cellular level and innovative therapeutic strategies for further research. Specifically, we will investigate the individual cell types that contribute to the neuroprotective effects of mTOR inhibition in progressive AD, and confirm and extend the data on the beneficial effects of lifespan and healthspan in sporadic AD with prophylactic treatment of rapamycin. Critically, since age and genetics are the leading risk factors for AD, we will evaluate interventions in preclinical model systems that incorporate both aging and genetic risk factors for AD. We will therefore test the role of direct manipulation of AMPK on modulation of lifespan and healthspan in normal aging and in AD susceptible models, and the beneficial role of MAG lipase inhibition in normal healthy aging and in the pathogenesis of AD in comparison to the effects of rapamycin in a mouse model of late onset AD.
 
23. Project Title: Preeclampsia and the Brain: Small vessel disease and cognitive function in early midlife
  Leader(s): CATOV, JANET M ; ROSANO, CATERINA ;
    MAGEE-WOMEN'S RES INST AND FOUNDATION
    NIH R01AG072646 / (2022-2026)
  Cerebral small vessel disease (cSVD) predisposes to vascular cognitive impairment and dementia, including Alzheimer?s Disease. Preeclampsia (PE), a pregnancy-specific disorder with acute hypertension and placental SVD, is emerging as a sex-specific risk factor for dementia later in life. How PE is implicated in the etiology of dementia is not known. Women with PE have SVD also in other vascular beds, including the brain, after pregnancy and worsening with older age, suggesting this process evolves over time. However, studies on SVD in midlife are sparse. Midlife is an ideal time to assess this risk as PE-differences in cognition are already detectable, and yet there is time to mitigate progression to dementia. Cerebral SVD (cSVD) in midlife may hold the key to understand how PE is implicated in cognitive impairment. Placental SVD, known as maternal vascular malperfusion (MVM) predicts worse short-term pregnancy outcomes. We find MVM and PE combined predict long-term worse maternal vascular health in cardiac, sublingual, and cerebral beds. In our pilot study (n=24) MVM and PE combined predicted lower cerebrovascular reactivity (CVR, an early stage of cSVD), especially in fronto-parietal areas; in turn, lower CVR in these regions was associated with, and appeared to explain, PE-related worse cognition. Importantly, these findings were independent of hypertension, suggesting PE has direct and lasting vascular effects . PE and MVM may be early indicators of a future cerebrovascular phenotype, manifesting in midlife as lower CVR, and may explain how PE affects cognition. We propose to study midlife women with and without prior PE to: 1) Characterize the neural basis of PE-related poorer cognitive performance, 2) Assess whether placental SVD (MVM) predicts cSVD and cognition, and 3) Explore whether sublingual SVD and circulating markers of SVD are markers of cSVD and cognition. We propose a neurocognitive study to capture early stages of cSVD and cognitive status in a racially diverse cohort of 450 women (1:1 PE and non PE) from our ongoing WINDOWS study, mean age=45, 15 years post- pregnancy, 30% black, with existing data on PE, MVM, and sublingual SVD 10 years after pregnancy. We will use our advanced multimodal neuroimaging protocols to quantify cSVD (including CVR, blood flow, connectivity), standardized validated protocols to measure cognition, and non-invasive markers of SVD (sublingual SVD, and circulating biomarker profiles) . Our project is uniquely positioned to identify a previously occult high-risk group that can be identified at delivery by placental pathology, and who may benefit from risk- stratification for dementia, to mitigate or delay disease progression.
 
24. Project Title: Sleep and Bladder Study
  Leader(s): TYAGI, SHACHI
    UNIVERSITY OF PITTSBURGH AT PITTSBURGH
    NIH R01AG076575 / (2022-2026)
  PROJECT SUMMARY Prevalent, morbid, and costly (=$83 billion/year), urgency urinary incontinence (UUI) is a major problem, especially for older women. With etiology usually ascribed to bladder spasms, the available therapies are bladder-targeted and provide only a modest benefit. Despite inadequate response and poor adherence, there has been little change in therapeutic approach to UUI in decades, and a novel holistic approach to complement or enhance current treatment will have a significant impact on care of those with the debilitating symptoms. UUI has strong bidirectional relationship with poor sleep, a prevalent complaint in older adults. Up to 50% of older adults report poor sleep, which increases the risk of UUI by up to 55% over 5 years. The brain plays a vital role in the continence mechanism and sleep is known to affect the pathways involved in executive continence control. Specifically, sleep loss is associated with hypoactivity in the medial prefrontal cortex (mPFC) ? a region we have identified to be involved in executive control of voiding, and potential therapeutic response to biofeedback-assisted pelvic floor muscle therapy. Hence, we hypothesize that poor sleep inhibits bladder control as it does with cognitive tasks; and addressing sleep will improve executive control of the bladder complementing concurrent bladder-targeted UUI therapy. Our overall goals are to: (a) assess the additional benefit of behavioral sleep intervention on UUI to the standard of care (?3- adrenoceptor agonist mirabegron) providing evidence for assessing and addressing sleep for treatment of UUI, and (b) better understand the brain?s role in the effect of sleep on UU providing rationale to investigate other ameliorative brain-based therapies targeting the identified brain pathways. Specific aims are to examine the effect of adjunctive Brief Behavioral Treatment of Insomnia (BBTI) with the first-line pharmacotherapy: mirabegron on (1) UUI; (2) nocturia; (3) mPFC activity to confirm therapeutic mechanisms by assessing the effect of sleep on currently understood mediators; and (4) durability of therapeutic response. We will randomize 100 women aged = 60 years to receive 8 weeks of either mirabegron alone or mirabegron+BBTI, assessing bladder symptoms, sleep, and functional and structural brain changes pre- and post-intervention. We will also explore the durability of therapeutic response at 6-months post-intervention. The study will provide the first-ever data on a comprehensive multicomponent brain-bladder therapy for incontinence targeting the known brain mechanisms involve in continence control. It will evaluate clinical response and durability of this novel pairing and provide an understanding of the underlying pathways involved in its therapeutic mechanism.
 
25. Project Title: Preserving Geriatric Muscle with an Osteoporosis Medication
  Leader(s): GREENSPAN, SUSAN L
    UNIVERSITY OF PITTSBURGH AT PITTSBURGH
    NIH R01AG081359 / (2023-2028)
  Approximately one third of older adults in senior communities fall each year, and falls are the leading cause of morbidity and mortality in this age group. Falls are associated with poor quality of life, disability, and death; the medical cost is over $30 billion annually. Despite these statistics, fall reduction strategies have had limited impact for frail seniors. The most devastating fall-related outcome is a hip or other fracture. Over 90% of hip and nonvertebral fractures occur from a fall, and approximately 85% of long-term care (LTC) residents have osteoporosis. Recently, investigators have reported cross-talk between muscle and bone through mechanical and biochemical pathways. Osteosarcopenia, a newly described geriatric syndrome, involves the coexistence of osteoporosis (low bone mass) and sarcopenia (low muscle mass/function). The coexistence of these conditions puts patients at even greater risk for fall/fracture-related serious adverse outcomes. Denosumab (DEMAB), a medication approved for osteoporosis, acts on molecular targets shared between muscle and bone. In the DEMAB pivotal trial and a meta-analysis in healthy adults, investigators reported a reduction in recalled falls in addition to a decrease in fractures. Therefore, DEMAB has the potential to reduce both falls and fractures in a vulnerable population at high risk for both events. Our goal is to demonstrate efficacy of the novel agent DEMAB to improve or preserve muscle health, strength, mobility and function in frail older adults. If successful, this would lay the groundwork for a larger multicenter trial to examine the dual-action for fall and fracture prevention. To bridge this knowledge gap we propose to conduct a 1-year, randomized, double-blind, active-controlled trial to test the efficacy of DEMAB (expected active muscle agent) versus zoledronic acid (ZOL, muscle control) in 248 underserved, LTC, frail institutionalized men and women (age=65) with osteoporosis. Muscle strength, power, quality, markers, function and bone measures will be collected in a mobile lab. At trial completion, all participants receive ZOL for osteoporosis therapy and to prevent potential bone loss following DEMAB discontinuation. Our objectives include Aim 1: Evaluate efficacy of DEMAB to preserve/improve muscle strength, power, mass and structure. Aim 2: Examine the mechanistic biochemical components of the muscle-bone connection. Aim 3: Explore if the DEMAB effect extends to distal functional outcomes. This study includes a number of innovative features: 1) focus on the neglected LTC population of frail older men and women in whom we have a track record of successful enrollment, 2) inclusion of an approved osteoporosis agent feasible in the LTC setting with a novel focus on muscle strength, power, structure, and function, 3) mobile lab allowing onsite participation, 4) assessment of muscle and bone parameters by portable techniques, and 5) electronic alerts for falls and SAEs. This study will challenge the current paradigm of avoiding anti-fracture/fall therapy in vulnerable fallers and establish the necessary conditions to justify a large trial to maintain muscle and bone health to reduce falls and fractures.
 
26. Project Title: INFLUENCE OF EXERCISE ON NEUROCOGNITIVE FUNCTION IN BREAST CANCER
  Leader(s): BENDER, CATHERINE M. ; ERICKSON, KIRK I ;
    THE UNIVERSITY OF PITTSBURGH
    NIH R01CA196762 / (2016-2021)
  DESCRIPTION (provided by applicant): Nearly 61% of women with breast cancer experience a decline in cognitive function with adjuvant therapy. We found declines in attention and working memory with aromatase inhibitor (AI) therapy in women with breast cancer and poorer executive function compared to healthy controls. Multiple biological mechanisms likely underlie this cognitive decline including estrogen (E2) reduction and cytokine dysregulation. AI therapy provides near complete E2 withdrawal and we found that lower E2 levels were related to poorer psychomotor efficiency, attention and executive function with breast cancer therapy. Increases in pro- inflammatory cytokines occur with cancer and persist up to 5 years post-treatment. We found that higher IL-6 levels are related to poorer executive function and reduced gray matter volume. The effect of AIs on cognitive function may also be mediated by symptoms experienced by women with breast cancer including fatigue, sleep problems, depression and anxiety. A promising method for improving cognitive and brain function in older adults is moderate intensity aerobic exercise. Our neuroimaging studies have shown that only modest amounts of aerobic exercise increase hippocampal volume and modify intrinsic connectivity and task-related functional dynamics in the prefrontal cortex and hippocampus. We also found that exercise reduces pro- inflammatory cytokines that are directly linked to hippocampal size and memory formation. Exercise also reduces depression and anxiety and the severity of fatigue and sleep problems in women with breast cancer. We propose a clinical trial in which post-menopausal women with early stage breast cancer are randomized to receive a 6-month, moderate-intensity aerobic exercise intervention or usual care. We will examine whether a well-controlled and monitored site-based exercise intervention, initiated before AI therapy, improves cognitive function and explore whether neuroimaging metrics of brain health, pro-inflammatory biomarkers (IL-6, CRP, TNF-a), and symptoms (fatigue, sleep problems, depression, anxiety) mediate the effects of exercise on cognitive function. Furthermore, we will explore whether the magnitude of the improvements in cognitive function are modified by E2. The specific aims include: 1) Compared to usual care, examine whether the 6-month exercise intervention improves cognitive function over the first six months of AI therapy in postmenopausal women with early stage breast cancer. 2) Compared to usual care, examine the direct effects of exercise on neuroimaging metrics of brain health including regional gray matter volume, white matter architecture and functional dynamics of the brain and pro-inflammatory biomarkers (IL-6 and CRP as primary outcomes; TNF-a as secondary) and explore the direct effects of exercise on symptoms (fatigue, sleep problems, depression, anxiety). 3) Compared to usual care, explore whether the effects of exercise on cognitive function are mediated by neuroimaging metrics of cognitive function, pro-inflammatory cytokines and symptoms and moderated by E2.
 
27. Project Title: IMAGING BIOMARKERS OF ACCELERATED BRAIN AGING IN TYPE-1 DIABETES
  Leader(s): ROSANO, CATERINA
    THE UNIVERSITY OF PITTSBURGH
    NIH R01DK089028 / (2010-2016)
  DESCRIPTION (provided by applicant): As adults with Type 1 Diabetes (T1D) live longer, they are increasingly more likely to develop brain abnormalities in addition to multiple micro- and macro-vascular complications. These brain features are strikingly similar to those observed in older adults and should not be considered benign. Similar to what is known for age-related brain changes, the potential mechanisms of brain abnormalities in T1D include vascular damage secondary to hyperglycemia and insulin dysfunction. We propose to quantify the nature, severity and risk factors re brain abnormalities in a large group of middle-aged adults with T1D. We will use cutting-edge imaging technology to measure neural activation, blood flow and micro-structural abnormalities that are not visible on conventional brain magnetization resonance imaging (MRI). Our preliminary results indicate that brain atrophy and lower cerebral blood flow in T1D are localized within fronto-parietal and subcortical regions. Therefore, we hypothesize that middle-aged adults with T1D have accelerated brain aging within the fronto-parietal and subcortical regions and connecting tracts and that cumulative exposure and severity of T1D-specific factors and complications can explain the burden of focal accelerated brain aging. We propose to obtain 190 brain magnetization resonance imaging (MRI) from participants of the ongoing longitudinal Epidemiology of Diabetes Complications (EDC) cohort study (mean age [SD]: 48 [7.6], 50% women, 95% white) who have been followed from 1989 to date. Brain MRI data will be a) compared with existing data of two groups of non diabetic adults of similar age (n=96) and of older age (N=167); b) related to diabetes-risk factors and complications that have been directly ascertained for 22 years in the EDC; c) examined in relationship with measures of processing speed. Results from this project will be the stepping stone for future studies in the EDC cohort to examine progression of brain damage and rate of cognitive decline. Results of this study also have the potential to clarify mechanisms underlying brain degeneration in Type 2 diabetes. This proposal is uniquely timed to capture important information during the funded data collection phase of the EDC cohort beginning in 2009. Our project has been strategically designed to complete the scope of work within four years. This project will use an existing recruitment infrastructure, a brain MRI center with scanners dedicated to research to collect new data, a team of research staff and investigators with track record of multidisciplinary previous collaborations in neuroepidemiology and imaging, and existing longitudinal data on diabetes complications collected over 22 years. PUBLIC HEALTH RELEVANCE: Brain changes are common in persons with Type 1 Diabetes (T1D) and they are strikingly similar to abnormalities observed in older adults. We propose to characterize the nature of accelerated brain aging in T1D (cerebral perfusion, neural activation and micro-structure level) and identify their determinants.
 
28. Project Title: INFLUENCE OF PHYSICAL ACTIVITY AND WEIGHT LOSS ON BRAIN PLASTICITY
  Leader(s): ERICKSON, KIRK I
    THE UNIVERSITY OF PITTSBURGH
    NIH R01DK095172 / (2012-2018)
  DESCRIPTION (provided by applicant): This application proposes to add a neuroimaging arm to an NIH funded 12-month diet and physical activity intervention. Obesity is currently at epidemic proportions in the United States, affecting over 1/3rd of American adults. Impaired cognitive and brain function - manifested as mood disorders, impulsivity, and an increased risk for neurological pathology - are often unrecognized consequences of obesity. These consequences are especially unsettling in view of the increased prevalence of obesity during childhood and adolescence, when the education, intellectual growth, and the preparation for future career seeking are at its peak. Hence, it is a public health imperative to rigorously investigate the effects of obesity on neurocognitive functions and to explore the potential for weight loss to restore cognitive and brain function. The parent study has three groups: diet only (DIET), diet + moderate physical activity (MOD-PA), diet + high physical activity (HIGH-PA) and will be collecting a myriad of outcome measures including aortic pulse wave velocity, inflammatory markers, glucose and insulin, abdominal adiposity and body composition using dual-energy X-ray absorptiometry, cardiorespiratory fitness using a graded exercise test, accelerometry measured physical activity, and energy intake. In addition to the subjects collected in the parent study we will collect a group of no-contact control (CON) participants for both reliability and comparison purposes. Therefore, by adding brain imaging to this intervention, our proposal reflects a cost effective and innovative approach to investigate links between physical activity, weight loss, brain integrity, metabolic outcomes, and cognitive processing and offers an opportunity to collect data on brain health with minimal additional costs. Testing these links could transform the way that brain-body associations are considered when assessing the risk for brain dysfunction or treating obesity related behavioral problems. Our main aims include: Aim 1. To examine whether a 12-month physical activity and weight loss intervention on overweight and obese adults increases cortical volume and improves microstructural white matter integrity, Aim 2: Examine how increased physical activity and weight loss can change the functional dynamics of the brain as assessed by both task-related neural responses, cerebral blood flow, and resting state brain connectivity, Aim 3. Link the changes in brain integrity, function, and connectivity with intervention-induced changes in physiological measures of metabolic and inflammatory molecular pathways. Our project represents the first attempt to associate weight loss in a long-term intervention to changes in brain networks. It is highly innovative, cost-effective, and will add significantly to the scientifc literature. By leveraging an existing NIH funded program and by focusing on neuroimaging outcomes with a skilled and productive team of experts in both weight loss interventions and cutting-edge neuroimaging techniques, we will be able to address unanswered questions that have important theoretical and translational implications for obesity and brain health.
 
29. Project Title: CHARACTERIZATION OF BRAIN NOISE USING MULTIMODAL MUTUAL INFORMATION
  Leader(s): HUPPERT, THEODORE JAMES
    THE UNIVERSITY OF PITTSBURGH
    NIH R01EB013210 / (2011-2015)
  DESCRIPTION (provided by applicant): The objective of this project is to utilize concurrent multimodal recordings using functional magnetic resonance imaging (fMRI), near-infrared optical (NIRS) and measures of systemic physiology in order to separate the contributions of each of these types of noise. The novelty of this project will be the use of mutual information shared between these concurrent measurements in order to identify the sources of noise in the brain-imaging signal. This will allow us to better understand the nature of this noise, to better design filters and analysis to remove it, and to improve the detection of small changes in activity in the brain. We hypothesize that i) mutual information between concurrent optical and fMRI signals will generate more realistic models of the noise structure in these modalities and ii) that a better quantitative understanding of this noise will lead to the identification of limitations in current analysis procedures and to the optimization of improved statistical techniques. Aim 1. Identify the contributions of instrumental and systemic sources of noise to the fMRI BOLD (blood oxygen level dependent) signal using concurrent multimodal optical and fMRI recordings. Aim 2. Characterize the role of baseline physiology in systematic biases during inter- and intra-subject test-retest experiments using median-nerve stimulation with concurrent NIRS and fMRI. Aim 3. Investigate the role of subject attention in mediating single-trial variability in the fMRI BOLD signal. Aim 4. Compare approaches for reducing physiological noise in fMRI and NIRS and determine the effect of realistic noise on the assumptions of the standard analysis model. PUBLIC HEALTH RELEVANCE: Although functional MRI can produce high quality images of brain activity, these images require the averaging of data over many trial repetitions because of the high level of noise typically associated with fMRI signals. Preliminary data has suggested that much of this noise originates inside the brain and may be associated with time-dependent factors such as subject attention or vigilance in the task. The goal of this work is to improve the ability to detect small and infrequent events in the brain by better understanding the nature of this noise through concurrent multimodal methods and by optimizing data analysis methods to improve detection of functional events.
 
30. Project Title: THE ASPIROMETER: A NONINVASIVE TOOL TO DETECT SWALLOWING SAFETY AND EFFICIENCY
  Leader(s): SEJDIC, ERVIN ; COYLE, JAMES ;
    THE UNIVERSITY OF PITTSBURGH
    NIH R01HD074819 / (2013-2023)
  ABSTRACTImpaired swallowing (oropharyngeal dysphagia or OPD) causes nearly 150,000 annual hospitalizations andover 220,000 additional hospital days, and prolongs hospital lengths of stay by 40%. OPD risk is typicallyidentified through subjective standard institutional screening (SIS) protocols and those identified throughscreening undergo gold standard imaging testing such as videofluoroscopy (VF). However, SIS methods over-or underestimate risk, and completely fail to identify patients with silent OPD who silently aspirate food intotheir lungs, raising their risk of pneumonia and other adverse events. Pre-emptive detection of silent or near-silent aspiration is essential. Our long-term goal is to develop an instrumental dysphagia screening approachbased on high-resolution cervical auscultation (HRCA) to accurately predict OPD-related adverse events, andinitiate more timely intervention measures to mitigate them. The overall objective here is to develop accurate,advanced data analysis approaches to translate HRCA signals to swallowing events observed in VF images.Our strong preliminary data has led us to our central hypothesis: HRCA coupled with advanced data analyticstools are powerful approaches to automate and improve existing dysphagia screening protocols. The rationaleis that a reliable, robust early-warning instrumental OPD screening approach will reduce adverse events inpatients with silent aspiration/dysphagia, shorten length of stay, reduce cost, and improve patient health.Guided by strong preliminary data, we will pursue the following three specific aims: (1) define HRCA signalsignatures that characterize the entire continuum swallowing safety from unimpaired to severely impaired; (2)translate HRCA swallow signal signatures and equate them to validated measures of swallowing impairment;and (3) prospectively assess the effectiveness of our HRCA system in predicting clinically significant OPD andaspiration in a randomized, controlled trial. Under the first aim, we will collect HRCA swallow signatures fromunimpaired people, and combine and analyze them along with our large database of swallows of people withOPD to characterize the entire range of swallowing function from unimpaired through severe OPD. Under thesecond aim, we will develop HRCA OPD severity cutoffs and match them to gold standard derived OPDimpairment cutoffs to establish HRCA?s ability as a diagnostic surrogate that differentiates clinically significantOPD and aspiration from benign swallowing impairments. Under the third aim, we will test HRCA in a clinicalsetting by deploying HRCA with consenting patients, and comparing the accuracy of independent HRCA,independent SIS, and HRCA+SIS to VF data from all participants. The approach is innovative, as it willcombine technology with clinical judgment to shift the OPD screening paradigm and fundamentally improveefforts to reduce morbidity and mortality caused by OPD. Our work is significant, because it will translate to anearly-warning HRCA screening tool that will elevate the current standard of patient care by ensuring thatpatients with OPD are correctly identified before adverse events can occur.
 
31. Project Title: INSTRUMENTAL SCREENING FOR DYSPHAGIA BY COMBINING HIGH-RESOLUTION CERVICAL AUSCULTATION WITH ADVANCED DATA ANALYSIS TOOLS TO IDENTIFY SILENT DYSPHAGIA AND SILENT ASPIRATION
  Leader(s): SEJDIC, ERVIN
    THE UNIVERSITY OF PITTSBURGH
    NIH R01HD092239 / (2017-2021)
  ABSTRACTDysphagia (disordered swallowing) causes nearly 150,000 annual hospitalizations and over 220,000 additionalhospital days, and prolongs hospital lengths of stay by 40%. Dysphagia risk is typically identified throughsubjective screening methods and those identified through screening undergo gold standard imaging testingsuch as videofluoroscopy (VF). However, screening methods over- or underestimate risk, and completely fail toidentify patients with silent dysphagia (e.g., silent aspiration) that can cause pneumonia and other adverseevents. Pre-emptive detection of silent or near-silent aspiration is essential. The long term goal is to developan instrumental dysphagia screening approach based on high-resolution cervical auscultation (HRCA) in orderto early predict dysphagia-related adverse events, and initiate intervention measures to mitigate them. Theoverall objective here is to develop accurate, advanced data analysis approaches to translate HRCA signals toswallowing events observed in VF images. Our strong preliminary data has led us to our central hypothesis:advanced data analytics tools are suitable approaches for the analysis of HRCA in order to automatedysphagia screening. The rationale is that a reliable, robust early-warning instrumental dysphagia screeningapproach will reduce adverse events in patients with silent aspiration/dysphagia, shorten length of stay andimprove overall clinical outcomes. Guided by strong preliminary data, we will pursue the following three specificaims: (1) develop machine learning algorithms to differentiate HRCA signals produced by swallowingphysiologic events from similar, non-swallow related signals produced during swallowing; (2) translate HRCAswallowing-signal signatures to actual swallow physiologic events to detect abnormal swallowing physiology;and (3) discriminate normal from abnormal airway protection and swallow physiology via machine-learninganalysis of HRCA signals with similar accuracy as VF. Under the first aim, a machine learning approach will beused to detect pharyngeal swallowing events and differentiate them from speech, cough and other non-swallow events, with 90% accuracy, when compared to a human expert?s interpretation of our VF data sets.Under the second aim, objective swallowing physiology observations from VF will be matched to swallowingevents observed with HRCA in order to show that abnormal swallow physiology and airway protection willproduce distinctive HRCA signal signatures that predict the same events identified with VF. Under the thirdaim, analytical algorithms will be used to detect signs of disordered airway protection in HRCA signalsignatures with 90% accuracy when compared to a human expert?s airway protection ratings from VF images.The approach is innovative, as it will produce analysis tools that will infer about dysphagia and aspirationbased on the analysis of HRCA with unprecedented accuracy, before patients are placed in harm?s way. Ourwork is significant, because it will translate to an early-warning HRCA screening tool that predicts dysphagia-related adverse events in asymptomatic patients reducing medical adverse events, and length of stay.
 
32. Project Title: THE ROLE OF CALCIUM ENTRY THROUGH THE MITOCHONDRIAL UNIPORTER IN REGULATING CARDIAC METABOLISM AND PHYSIOLOGY
  Leader(s): FINKEL, TOREN
    THE UNIVERSITY OF PITTSBURGH
    NIH R01HL142589 / (2019-2023)
  The entry of calcium into the mitochondria is fundamentally important in regulating bioenergeticcapacity and modulating cell death thresholds. For nearly fifty years, mitochondria were knownto have a selective calcium-selective pore in the inner mitochondrial membrane. Entry ofcalcium through this pore, often termed the calcium uniporter, was believed to be essential inboosting ATP production by augmenting the activity of multiple calcium-sensitive mitochondrialmatrix enzymes. This increase in mitochondrial calcium therefore allowed for a rapid butregulated increase in mitochondrial ATP under conditions of increased energetic demand. Whileunder these conditions, the entry of calcium appears beneficial, additional evidence suggestedthat excessive calcium entry triggers a mitochondrial cell death program characterized byopening of the mitochondrial permeability transition pore (mPTP). Such situations appear to beparticularly relevant to tissue injury occurring in the setting of ischemia-reperfusion injury. Whileconsiderable electrophysiological, biophysical and physiological data existed on themitochondrial inner membrane calcium pore, its molecular identity remained elusive for over fiftyyears. That situation has demonstrably changed in the last five years with the rapididentification of the components of the inner mitochondrial calcium uniporter complex (MCUC)now known to be composed of at least four proteins. These components include the pore-forming protein MCU, its apparent membrane scaffold EMRE and two calcium-sensitiveregulators MICU1 and MICU2. The molecular identity of the MCUC paved the way for thecreation of mouse models in which one or more component of the complex has been deleted.This, in turn, allows for a more detailed and precise analysis of the physiological role ofmitochondrial calcium in regulating both bioenergetics and cell death. Here, we propose toanalyze the role of the MCUC in basal and stress-induced cardiovascular physiology. Ourparticular emphasis will be on the role of the MCUC in ischemia/reperfusion injury, metabolismand aging. This analysis, we believe, will increase our fundamental understanding of bothmitochondrial biology and cardiac physiology and potentially pave the way for new treatmentstrategies targeting a diverse array of conditions ranging from reperfusion injury to the age-dependent decline in cardiac function.
 
33. Project Title: Mapping the cell specific DNA damage-induced molecular and bioelectrical responses in the 3D cardiac unit
  Leader(s): COHEN-KARNI, TZAHI ; GURKAR, ADITI U;
    CARNEGIE-MELLON UNIVERSITY
    NIH R01HL161106 / (2021-2026)
  PROJECT SUMMARY This project will test the hypothesis that DNA damage in cardiomyocytes activates p53 leading to mitochondrial alterations and secretion of paracrine factors that drive heart failure. The premise for this has been established from our preliminary data and from the work of others. First, DNA damage and activated DNA damage response (DDR) have been observed in cardiovascular disease (CVD) in humans. Second, studies also show evidence that multiple cell types in the cardiac unit, including cardiomyocytes (CM) and cardiac fibroblasts (CF) display markers of DNA damage and cellular senescence in several disease pathologies. Third, we have recently identified that nuclear DNA damage drives dilated cardiomyopathy. Specifically, cardiomyocyte-depletion of the DNA repair endonuclease, ERCC1-XPF in mice, upregulates the DNA damage response gene, p53, and leads to irregular mitochondrial cristae, accumulation of lipids and increased oxidative stress. Additionally, there is an increase in several cardiac failure and senescence associated markers. However, the exact molecular underpinnings and cell-specificity of these DNA damage-induced changes is poorly understood. One barrier to addressing this question in vivo has been lack of appropriate tools, where DNA damage can be introduced in only one cell type (e.g., CM) and its effect on CF and cardiac function can be investigated. Additionally, 2D cell culture and co-culture systems fall short, as they cannot reproduce tissue dynamics present in a cardiac unit. Herein, we have developed several tools enable the study of cell-cell communication of 3D multicellular system. Specific Aim 1 will map the molecular, functional, and architectural changes upon loss of ERCC1 in CM. In this aim, we will test the mechanistic role of p53 and reactive oxygen species on a number of cellular and mitochondrial parameters, as well as cardiomyocyte electrophysiology. Specific Aim 2 will test whether stochastic, spontaneous DNA damage in the CM or CF drives cardiac electromechanical dysfunction in a cell- autonomous or cell non-autonomous manner through a paracrine effect on neighboring cells. Here, we will analyze the pathological secretome upon genotoxic stress, as well as test the role of eliminating senescent cells on cardiac health. This work is technically innovative as it uses a number of unique tools including concomitant optical and bioelectrical measurements in 3D cardiac organoids. These contributions will be significant because DNA damage is unavoidable and intimately linked to cardiac health and disease. Our team is uniquely qualified to perform this work, with expertise in DNA damage/ repair, cellular senescence, nanofabrication, human iPSC- derived cardiac tissue engineering, and data science. This analysis, we believe, will increase our fundamental understanding of the connection between DNA damage and heart disease and potentially pave the way for new treatment strategies.
 
34. Project Title: POST-ACUTE CARE AND FUNCTIONAL RECOVERY AFTER HOSPITALIZATION
  Leader(s): HARDY, SUSAN E
    THE UNIVERSITY OF PITTSBURGH
    NIH R03AG032291 / (2008-2011)
  DESCRIPTION (provided by applicant): Functional decline and disability are common consequences of hospitalization in older adults. Over the last decade, increasing numbers of older adults received post-acute rehabilitative services at skilled nursing facilities (SNFs) and the dominant admission diagnoses have shifted from acute disabling conditions such as stroke and hip fracture to general medical conditions such as pneumonia and heart failure. While medical acuity seems to be increasing in SNFs, the organization and content of medical care remains underdeveloped, and medical care is not explicitly coordinated with rehabilitative care. Although recovery from hospitalization- associated disability is critical for maintaining health and function, relatively little is known about the determinants and outcomes of SNF-based post-acute care (PAC), especially for general medical conditions. The proposed project will lay a foundation for research to improve medical care and to increase coordination of medical and rehabilitative care in the SNF setting. To better understand who uses SNF care and what happens to them, this project will identify the characteristics that determine the use of post-acute care (PAC) among older adults, compare outcomes across post-acute settings, and identify factors associated with the functional outcomes of SNF-based PAC. This study will use the 1996-2003 Medicare Current Beneficiary Survey (MCBS), a nationally-representative in-person panel survey of Medicare beneficiaries linked with claims data. The specific aims are 1) to identify the demographic, medical, and health status factors that predict the use of PAC among hospitalized community-dwelling older persons and, among users, the type of PAC (SNF-based versus a home health agency (HHA) or rehabilitation hospital); 2) to compare outcomes of PAC in SNF versus HHA or rehabilitation hospital, after adjusting for primary diagnosis, comorbidity, prior functional status, and health care utilization; and 3) to determine the effect of intensity of PAC on outcomes among SNF patients, after adjustment for comorbidity, prior functional status, principal rehabilitation diagnosis, and health care utilization. The MCBS is uniquely suited to these aims because it contains information for community-dwelling and institutionalized participants about PAC use, discharge diagnoses, self-report health status and functional information from both before and after an episode of PAC use. Information about SNF-based PAC as it has evolved in recent years will establish a foundation for more clinically detailed prospective studies of PAC outcomes, specifically studies to develop an index of medical issues that influence functional recovery. This future index, like an APACHE score, could support prognostic and ultimately treatment guidelines for care of medically complex, recently disabled older adults. The preliminary information obtained from this nationally representative sample will allow us to define representative samples, estimate outcome rates and specify influential patient factors as we proceed. PUBLIC HEALTH RELEVANCE: Over the last decade, more and more older adults are discharged from the hospital too sick and weak to go home, and so spend time in the rehabilitation program at a skilled nursing facility. This study will determine who is using nursing facilities after hospitalization, the kinds of medical and functional problems they face, and will help determine the individual and health system factors that are associated with functional recovery. The long term goal of this research is to improve medical and rehabilitative care in the skilled nursing facility in order to provide older adults with the best opportunity for functional recovery and return to home.
 
35. Project Title: DEVELOPMENT OF A HYPERSPECTRAL FD-NIRS DEVICE FOR MUSCLE PHYSIOLOGY
  Leader(s): HUPPERT, THEODORE JAMES
    THE UNIVERSITY OF PITTSBURGH
    NIH R03EB020078 / (2016-2018)
  ABSTRACTNear-infrared spectroscopy (NIRS) is a non-invasive optical technique to measure chromophoreconcentrations in tissue including hemoglobin, myoglobin, water, lipid, and cytochrome C oxidase. Continuouswave (CW-) NIRS systems are widely used but are limited to the measurement of changes in chromophoreconcentrations and have low quantitative accuracy in reporting absolute concentrations due to the unknownpathlength factors related to the diffusion of light in tissue. Frequency-domain (FD-) NIRS is a variation of thismethod that uses amplitude modulated light and the measurement of the amplitude and phase of the lightpassing through tissue to provide more quantitative estimates of baseline optical properties. However, currentFD-NIRS systems are limited to only a few optical wavelengths due to the cost and complexity of thesemodulation circuits. In this project, we propose to develop a novel hyperspectral FD-NIRS system, which usesa broadband white light source and CCD spectrometer detection system. The unique innovation of this systemis the use of electro-optical modulators (EOMs), which will be used to directly modulate the light rather thanrelying on electrical modulation of laser diodes. Two devices will be used to enable heterodyne downshifting ofthese MHz signals for CCD detection. This approach will be a much simpler and more cost effective way toincrease the number and range of wavelengths used by the system in comparison to previous versions of CW-and FD-NIRS systems. This device will improve the way in which NIRS is collected across a wide range ofapplications. The aims of this study are:Aim 1. Construct a hyperspectral FD-NIRS device and characterize sensitivity and noise properties ofthe instrument.Aim 2. Investigate the sensitivity and specificity of CW- and FD-NIRS measurements in simulatedmuscle tissue using Monte Carlo techniques to look at the effect of realistic muscle structure on photonmigration.Aim 3. Characterize the sensitivity and specificity of the measurement of physiological compoundsusing the device in phantoms and compare with Monte Carlo simulation results.This proposed R03 study will develop this unique system and allow us to apply these advanced NIRStechniques in future studies of muscle physiology including injury risk assessment, the impact of aging anddiabetes, among various other work.
 
36. Project Title: IMPACT OF SLEEP ON CHRONOBIOLOGY OF MICTURITION
  Leader(s): TYAGI, SHACHI
    THE UNIVERSITY OF PITTSBURGH
    NIH R21AG050892 / (2016-2019)
  DESCRIPTION (provided by applicant): Prevalent, morbid, and costly ($1.5 billion/year in 2008), nocturia is a major problem, especially for older adults. It increases the risk of falls, fractures, depression, nursing home placement, and death. Yet management of nocturia remains inadequate because its etiology is not fully understood, especially that of its most prevalent attribute: nocturnal polyuria (NP), or increased urine production during sleep. Disruption of diurnal excretory pattern, with higher nighttime urine production is common in older adults. Recent evidence suggests the impact of sleep on nocturnal urine production, but pathophysiology is not fully understood. The goal of the proposed new study is to assess the role of endogenous circadian rhythm on the diurnal variation of urine production in older adults and the impact of sleep. Urine production follows a circadian pattern in which transition from wake to sleep is followed by a pronounced decrease in excretion of water, electrolytes and other osmotically active substances. Studies in young population have established that physiological urine production follows a circadian rhythm, which is regulated by diurnal variation in secretion of hormones controlling water and salt excretion such as arginine vasopressin (AVP), renin-angiotensin-aldosterone system (RAAS), and atrial natriuretic peptide (ANP). Sleep deprivation blunts nocturnal surge of these hormones and consequently alter water and salt excretion thereby increase nocturnal urine volume (NUV) leading to NP. NP is common in older adults even in the absence of lower urinary tract symptoms, peripheral edema or fluid overload. The underlying pathophysiology of disrupted circadian pattern of urine production in older adults, and the contribution of sleep, is not known. The knowledge about circadian variations in hormonal regulation in older adults is scarce and contradictory. Therefore, aims of the present proposal are to better characterize, in the elderly: 1) the circadian rhythms of hormones regulating salt and water excretion; and 2) the impact of sleep on these rhythms. Our overall hypothesis is that sleep suppresses nocturnal urinary output via increased secretion of AVP, activated renin and ANP, and that these hormones have weak endogenous circadian rhythmicity. Thus sleep disruption associated with older age may disinhibit the physiologic dip in nocturnal in urine output, hence lead to NP. To accomplish our goals we will recruit healthy older adults = 60 years, without insomnia or lower urinary tract symptoms (n=20) who will undergo two 24-hour studies at Clinical and Translational Research Center 6 weeks apart: 1) a constant routine protocol that removes the masking influence of sleep, posture, and other confounders, and 2) a normal sleep-wake (nychthemeral) protocol. During each 24-hour study we will collect plasma (every 2 hours 8am-7pm, and every 30 minutes 7pm-7am) to assess diurnal variation in secretion of hormones regulating salt and water excretion. Circadian rhythms will be assessed with phase and amplitude of plasma melatonin rhythms. The study will enable us to assess the diurnal variation in secretion of the renal regulatory hormones in healthy older adults and the impact of sleep. Regardless of the results, knowledge from this study will contribute substantially to current understanding of disrupted diurnal excretory pattern in older adults and potentially modifiable underlying factors. Such knowledge may also allow differentiation of different phenotypes of NP and facilitate development of more targeted therapy.
 
37. Project Title: IMPACT OF BEHAVIORAL TREATMENT OF INSOMNIA ON NIGHTTIME URINE PRODUCTION
  Leader(s): TYAGI, SHACHI
    THE UNIVERSITY OF PITTSBURGH
    NIH R21AG060292 / (2018-2020)
  PROJECT SUMMARYPrevalent, morbid, and costly ($61 billion/year in 2012), nocturia is a major problem, especially for older adults.It increases the risk of falls, fractures, depression, nursing home placement, and death. Yet management ofnocturia remains inadequate. Most behavior and pharmacotherapies for nocturia focus on bladder-relatedetiologies, and it?s most prevalent attribute nocturnal polyuria (NP), or increased urine production during sleepremains poorly understood and inadequately treated with little advancement over the last 50 years. Disruptionof diurnal excretory pattern, with higher nighttime urine production is common in older adults. While studies inyoung adults show that sleep plays a critical role in regulating nighttime urine production, among older adultsthe role of poor sleep in NP is under-investigated.Urine production follows a circadian pattern in which transition from wake to sleep is followed by a pronounceddecrease in excretion of water, electrolytes and other osmotically active substances. Studies in youngpopulation have established that physiological urine production follows a circadian rhythm, which is regulatedby diurnal variation in secretion of hormones controlling water and salt excretion such as arginine vasopressin,renin-angiotensin-aldosterone system, and atrial natriuretic peptide. Sleep deprivation blunts nocturnal surge ofthese hormones and consequently alter water and salt excretion thereby increase nighttime urine volumeleading to NP.Recent evidence suggests that poor sleep quality, frequent sleep interruptions especially in the first part of thenight and shorter duration of first uninterrupted sleep period are associated with NP but its pathophysiology isnot fully understood. Additionally, among older adults with poor sleep, we have shown that a behavioralintervention directed solely towards sleep (BBTI- brief behavioral treatment of insomnia an efficaciousmultimodal behavioral treatment for insomnia) not only improves sleep, but also nocturia. Hence, we postulatethat sleep interruptions in the first part of the sleep impacts the hormonal regulation of nighttime urineproduction causing NP. In addition, we postulate that interventions to prolong the first uninterrupted sleepperiod will decrease NP and hence nocturia.The, aims of the present proposal are to: 1) examine the impact of BBTI on duration of the first ofuninterrupted sleep period and NP in elderly with nocturia; and 2) establish NP and duration of firstuninterrupted sleep as mechanisms by which BBTI impacts nocturia. Our hypothesis is that BBTI improvesnocturia not only by improving sleep, (and specifically, duration of the first uninterrupted sleep period), but alsoby decreasing NP.To accomplish our goals we will recruit 60 community dwelling adults (aged >65) with nocturia and NP. Sleepwill be assessed subjectively with the Insomnia Severity Index and objectively by 7-day sleep diary and wristactigraph. Concurrently we will collect 3-day bladder diary data to document their voiding pattern and volumeduring day and night. Participants will be randomized to receive the 4-week behavioral sleep intervention BBTIby a trained therapist or an information control intervention. The participants will repeat the study measurespost-intervention.The study results will provide important insights into shared pathological mechanisms underlying poor sleep,nocturia and nighttime urine production. We will use these findings to construct a larger R01 to explore in theelderly biological mechanisms of NP, circadian rhythms of hormones regulating salt and water excretion, andthe impact of sleep treatment on these rhythms.
 
38. Project Title: RETINAL IMAGING MARKERS OF COGNITION IN MIDDLE-AGED ADULTS WITH TYPE 1 DIABETES
  Leader(s): ROSANO, CATERINA
    THE UNIVERSITY OF PITTSBURGH
    NIH R21DK107926 / (2015-2017)
  DESCRIPTION (provided by applicant): This R21 proposal aims to develop a risk score for cognitive complications of Type 1 Diabetes (T1D) by using longitudinal imaging markers of the retinal vasculature and state-of-the art neurocognitive assessment. Cognitive impairment (CI) is a common and severely disabling complication of T1D. With increasing incidence and survival rates in T1D, there will soon be an increase in the number of patients who are at risk of developing CI. Therefore, an urgent public health priority in T1D is to develop a biomarker that can detect brain changes before clinically overt signs of CI develop, to identify the patients at greater risk of developing CI. Although brain imaging is the gold standard to quantify neurovascular imaging abnormalities underlying CI, it is not an ideal tool for population screening because of high costs and variable access. Similarly, extensive neurocognitive batteries are not routinely administered to T1D patients and require complex adjudication procedures to classify CI with reliability. The retinal circulation offers a unique perspective on the cerebral microcirculation in vivo and retinal vascular imaging (RVI) measures are promising biomarkers of CI and neurovascular abnormalities. RVI measures have been pointed out as potential tools to increase accuracy of diagnosis of dementia in the general population of older adults. However, these associations have not been well characterized in patients with T1D. Most evidence is from cross-sectional studies of mostly young patients, and consists of associations of variable strength between retinopathy, cognitive tests and neurovascular abnormalities. This proposal marks a critical first step in the overall path toward the development and validation of RVI measures as biomarkers of CI. We propose to develop a risk score of CI using existing longitudinal RVI measures (arteriolar and venular diameter, tortuosity, nicking), neuroimaging and state of the art cognitive assessment. The proposed study leverages two existing ongoing studies of patients with T1D: the Epidemiology of Diabetes Complication Study (R37 DK034818-28, PI: Orchard), which has been following these patients since 1986-88 with repeated RVI measures, extensive characterization of health- and diabetes-related measures and a vast biorepository of blood sample; the Neurovascular Imaging Study (R01 DK089028-03, PI: Rosano) which has obtained cutting-edge neuroimaging and cognitive assessment in 2011-12. A total of 209 participants have received a 1st cognitive assessment and has retrospective repeated RVI since 1986 to time of cognitive assessment. We propose to add a 2nd cognitive assessment in a subsample of these participants who are scheduled to return for their regular visit in 2016-17. We propose to relate repeated RVI measures with neurovascular imaging abnormalities, CI and cognitive decline. This R21 application responds PA-12-15 because it proposes secondary analyses of existing data, combined with additional new data collection; the results of this project will inform and support subsequent applications tofurther our understanding of the pathogenesis of cognitive complications in middle-aged patients with T1D and design future intervention strategies.
 
39. Project Title: A CEREBRAL FUNCTIONAL UNIT MODEL FOR MULTIMODAL IMAGING OF NEUROVASCULAR COUPLING
  Leader(s): HUPPERT, THEODORE JAMES
    THE UNIVERSITY OF PITTSBURGH
    NIH R21NS064457 / (2009-2012)
  DESCRIPTION (provided by applicant): The efficiency of the brain is a measure of the degree to which the neural, metabolic, and vascular systems work together collectively to perform cerebral function. The coordination of physiological events between these systems, which collectively comprise a functional unit of the brain, is believed to be an important marker of brain fitness. Concurrent multimodal hemodynamic and electrophysiological measurements offer the unique ability to quantify these neurovascular relationships and thereby investigate the properties of the cerebral functional unit. In this project, we propose to develop novel multimodal experimental and model-based analysis tools to characterize the properties of the cerebral functional unit. We hypothesize that multimodal characterization of the relationships between neural, metabolic, and vascular changes will provide more robust and intrinsic assessments of the brain in comparison to autonomous (single- modality) measurements alone. We will develop an analysis framework based on a bottom-up model of the cerebral functional unit that will allow us to better utilize the unique attributes of concurrent multimodal measurements. Our model will be applied to simultaneous non-invasive, near-infrared optical imaging (NIRS) and magnetoencephalography (MEG) measurements in order to develop, test, and refine our methods based on the application of our model to a set of somatosensory experiments. The specific aims of this project are: Aim 1. Integrate optical and MEG imaging systems to allow for concurrent neurovascular measurements. We will improve existing instrumentation, hardware, and analysis framework, which will allow for collection and coregistration of concurrent near-infrared optical (NIRS) and MEG signals. Aim 2. Quantify the relationships between neural and hemodynamic evoked signals. Using a combination of visual and somatosensory stimulation paradigms with parametric inputs, we will experimentally investigate the canonical relationships between neural and vascular evoked responses. Aim 3. Develop the cerebral functional unit model. We will develop and characterize an integrated multimodal model of the cerebral functional unit to incorporate information from concurrent neural and vascular measurements. PUBLIC HEALTH RELEVANCE: Within a healthy brain, the neural, metabolic, and vascular systems are highly coupled to balance the use of energy by neural and synaptic processes and the supply of substrates and removal of waste products by the vascular system. While it is generally accepted that such coupling is important to the health of the brain, analysis and interpretation methods to investigate these effects have not been adequately developed to allow detailed characterization of these relationships. In particular, the utility of multimodal neuroimaging experiments can be improved by developing new analysis methodologies that are specific to the unique characteristics of concurrent multimodal measurements. We propose to develop a state-space model of the neural, metabolic, and vascular units of the brain that will allow us to statistically combine concurrent measurements from differing neuroimaging techniques, specifically near-infrared spectroscopy (NIRS) and magnetoencephalography (MEG), into a unified estimate of brain function. This model will provide a new tool to investigate and characterize the underlying relationships between neural, metabolic, and vascular physiology and will offer a novel framework for fusion of experimental multimodal information.
 
40. Project Title: IMAGING AND MODELING THE BIOMECHANICS OF LARGE CEREBRAL BLOOD VESSELS USING HIGH-SPEED DYNAMIC MRI
  Leader(s): HUPPERT, THEODORE JAMES
    THE UNIVERSITY OF PITTSBURGH
    NIH R21NS102393 / (2017-2019)
  ABSTRACTThe objective of this proposed R21 work is to develop and demonstrate a novel high-speed (10Hz) multi-slicedynamic MRI acquisition and model-based analysis technique to quantify the biomechanical properties ofcerebral blood vessels. This novel approach measures T1-weighted inflow fluctuations (related to bloodflow/velocity) in large arterial and venous blood vessels. Fluid mechanics model-based analysis is thenapplied to examine the frequency-dependent dampening and phase between velocity waveforms measuredfrom proximal and distal ends of blood vessel segments allows the characterization of the biophysicalproperties of these segments including vascular resistance, inductance, and compliance. These high temporalsignals are combined with structural MRI angiography to provide a spatial map of the blood vessel propertiesand topology.We believe that these quantifiable biomechanical and mathematical parameters can be linked to cerebralvascular diseases, since these directly reflect properties such as the rigidity and flow resistance of the vessels.The development of these methods has significant clinical implications toward quantitative assessment ofcerebral vascular physiology in the context of vascular disorders such as hypertension, stenosis, and risk ofstroke. As a proof-of-concept of this approach, and to initially investigate the sensitivity of this method, thistechnique will be applied to characterize the cerebral vascular properties of two groups of patients with chronichypertension and isolated systolic hypertension in comparison to age-matched normotensive controls. Thespecific aims of this project are:Aim 1. Optimize methods for high-speed MR arterial compliance mapping.Aim 2. Demonstrate proof-of-concept for high-speed MR arterial compliance mapping in chronichypertensive (HT) and isolated systolic hypertension (ISH) patients and compared to age-matchednormotensive (NT) healthy controls.We hypothesize that:Hypothesis 1. Measurements of vascular resistance and compliance is sensitive to hypertrophic changes inHT and ISH patients and can be reliably measured using our proposed high-speed MR arterial compliancemapping approach.Hypothesis 2. HT and ISH patients will show increased resistance (stiffness) and decreased capacitance(compliance) compared to NT controls. These changes will be larger in the ISH group. The dynamic cerebralauto-regulation index (dCAI) will be impaired in both HT and ISH.
 
41. Project Title: Reducing slip-and-fall accidents in the workplace: Role of small-scale roughness of floor surfaces to improve friction
  Leader(s): BESCHORNER, KURT E ; JACOBS, TEVIS ;
    UNIVERSITY OF PITTSBURGH AT PITTSBURGH
    Centers for Disease Control and Prevention R21OH012126 / (2021-2023)
  Project Summary Fall-related injuries burden over 140,000 workers annually, causing significant human suffering and an economic cost of $10 billion in Workers' Compensation. Approximately half of occupational falls are caused by slipping. An under-explored pathway to preventing these slip-and-fall events is to design flooring for workplaces with high friction performance. High-friction flooring prevents the slip events that lead to a fall. Unfortunately, current methods to characterize floor-surface topography are unable to predict friction performance, limiting innovation in this area. In order to catalyze innovation in high-friction flooring, there is a need for improved scientific understanding of the flooring factors that contribute to friction. Our preliminary studies and existing literature suggest that small-scale topography (features at the 1-nm to 1-?m scale) is critical for predicting floor performance, but is not measurable using conventional characterization techniques. The purpose of this R21 project is to measure these small-scales of floor-surface topography, and to use them to develop a mechanics-based predictive model for friction. This research is innovative because it will employ novel experimental methods and analysis techniques that have never been applied to flooring surfaces, and because it will develop a mechanics-based model to predict the relationship between floor structure and friction performance, where prior research has relied solely on empirical correlations. The proposed research will be accomplished through two Aims: Aim 1: Quantify the dependence of shoe-floor friction performance on small-scale topography. This Aim will investigate the ability of small-scale topography to explain variations in shoe-floor friction performance that cannot be explained using current measurement techniques. Then we will test the first hypothesis: Hypothesis 1: Roughness parameters that consider the full range of scales will improve our ability to predict COF values compared with those using just stylus profilometry. Aim 2: Establish a predictive mechanics-based model for shoe-floor friction based on multiscale surface topography. In this Aim, we will develop and validate a multiscale finite element model that captures viscoelastic contributions to friction across all length scales. We will test the second hypothesis: Hypothesis 2: A mechanics-based model using multiscale topography will more accurately predict shoe-floor friction compared with conventional approaches, i.e., statistical models based on stylus profilometry. This research is expected to lead to foundational knowledge and a modeling tool for optimizing high-friction flooring in workplaces. Working with an industry trade group, the Tile Council of North America (TCNA), this research will achieve impact by guiding the evidence-based development of high-friction flooring for workplaces. Thus, the proposed research is expected to achieve impact in improving workplace safety.
 
42. Project Title: Physical Activity and Dementia: Mechanisms of Action
  Leader(s): ERICKSON, KIRK I
    UNIVERSITY OF PITTSBURGH AT PITTSBURGH
    NIH R35AG072307 / (2021-2026)
  Abstract Exercise is one of the most promising methods for positively influencing neurocognitive function in late adulthood. Yet, despite this recognition, several major knowledge gaps preclude the ability to broadly prescribe exercise to prevent or treat cognitive impairment. This R35 proposal includes a series of innovative and potentially groundbreaking studies that will contribute to major advancements in the field of exercise and brain health. The studies that we describe in this proposal would be led by several highly promising junior scientists with the support of an experienced and dedicated mentorship team. The conceptual and scientific framework for the hypotheses described in this proposal orbit around three major challenges facing the field of exercise and cognitive aging: (1) We have a poor understanding of the mechanisms by which exercise influences cognitive function in late adulthood, (2) We have a poor understanding of the factors that moderate, or explain individual variation in, the response to exercise, and (3) We do not understand the factors that predict long- term adoption of exercise behavior and how to reduce barriers and enhance incentives for individuals who find it challenging to continue to exercise. Despite the clear benefits of an active lifestyle, most people fail to meet public health recommendations for exercise. The more we know about the factors that predict and enhance long-term adoption of exercise, the more we will know about whether exercise influences incidence of Alzheimer?s Disease and best practices for prescribing and maintaining exercise for the prevention and treatment of cognitive impairment. We propose to conduct secondary analysis of banked data from two rigorous and well-controlled supervised exercise randomized clinical trials (RCTs) and to conduct a 3-year follow-up of >570 participants from both of these RCTs of exercise to assess cognitive, cardiorespiratory fitness, and physical activity levels. In particular, we propose to examine whether exercise-induced changes in cardiometabolic and sleep measures mediate exercise-derived benefits to cognitive and brain outcomes. We will also target moderators of exercise including APOE genotype and racial disparities to better characterize which individual difference variables influence the magnitude of effects of exercise on brain health. Finally, we propose a discovery aim that would leverage our rich measurement of participants at the genetic, physiological, brain, cognitive, and socioemotional levels to perform predictive modeling to forecast long-term adoption of exercise (or barriers prohibiting long-term adoption). In short, this research proposal describes a broad and ambitious line of work that will produce groundbreaking and innovative studies to address significant gaps in our understanding of exercise and brain health in late adulthood. The aims target several major AD/ADRD milestones identified by NIH and will position junior scientists in leadership roles to advance the field forward in significant and pioneering ways.
 
43. Project Title: POPULATION NEUROSCIENCE OF AGING AND ALZHEIMER'S DISEASE (PNA)
  Leader(s): ROSANO, CATERINA ; GANGULI, MARY ;
    THE UNIVERSITY OF PITTSBURGH
    NIH T32AG055381 / (2018-2023)
  Training Grant in Population Neuroscience of Aging & Alzheimer?s Disease (PNA) The objective of this new pre- and post-doctoral training program is to train highly talented individuals to pursuesuccessful independent research in the etiology of Alzheimer?s Disease and other age-related dementia (ADRD). Eligibleapplicants are PhD graduates or candidates in Epidemiology, Neuroscience, Information Science, Biostatistics,Biomedical informatics and MD/DO graduates with training in Neurology, Psychiatry, Geriatric medicine, and relateddisciplines. We request support for 3 pre-doctoral and 2 post-doctoral positions annually, with a period of training of up to3 years for post-docs and 4 years for pre-docs (up to 5 in some cases). The field of brain aging has profoundly changed because of the collision of two phenomena: worldwide increase ofour aging population, and rapid technological advancements in health measurements in general and in brain science inparticular. Our successes in extending lifespan, with marginal improvements in healthspan, have not only increased thenumber of adults reaching very old ages, but they have also increased the heterogeneity of age-related neurocognitivephenotypes. For these ?new? older adults, there is a very high burden of chronic conditions affecting the central nervoussystem either directly (e.g. stroke) or indirectly (heart conditions, diabetes). Cumulative exposure to chronic conditions,biological ageing, chronological aging and possibly to other life-long environmental factors, interact with each other invery complex ways and are all strong drivers of increased risks of developing dementia. While it is reasonable to expectbrain integrity to decline and dementia rates to increase over time, we cannot assume that chronological years and yearsspent with a disease would have linearly additive effects on brain integrity. Understanding these complex pathways is fundamentally important to conduct rigorous etiological research intocauses and determinants of brain degeneration and dementia. Unfortunately, training and research in the field to date havefocused on dementia as an individual condition, and have mostly considered ?older age? as an homogenous population,while relegating multiple chronic conditions and other health issues as ?collateral problems?, or as completely separateproblems. However, it is clear that to understand these complex issues and improve the brain health of the growingpopulation of elderly living with chronic diseases for a long time, it is necessary to have expertise in diseases of both thebrain/central nervous system and also other organ systems. We are also living through a time of great technologicaladvances in non-invasive and automated methods to measure brain abnormalities, the application of which is providingever more precise phenotypes but also very large and complex datasets. Such data require careful sampling designs andanalytical approaches infused with an understanding of the condition being studied to effectively produce new knowledgeto move research to treatment and prevention. We propose that the successful clinical neuroepidemiological investigatorsof the future must be able to link comorbidities, environmental exposures, lifestyles, genomics, e.g. host susceptibility,with knowledge of modern technology of neurosciences and measurement of brain disease and data science. Our proposed T32 in Population Neuroscience of Aging & Alzheimer?s Disease (PNA) merges this gap and aims tocross-train researchers in these inter-related fields. Co-directors Drs. Rosano (Epidemiology) and Ganguli (Psychiatry)have designed a new training formula that benefits from the extensive resources and faculty affiliated with the Schools ofPublic Health (Biostatistics), Medicine (Neurology, Biomedical Informatics), Arts and Science (Neuroscience,Psychology), and Information Science, as well as several University Centers and Institutes: the Alzheimer DiseaseResearch Center, the Center for the Neural Basis of Cognition, the Brain Institute, the Center for Aging, Population andHealth, the Claude Pepper, the Aging Institute. Our curriculum responds to the changing landscape of career pathways, by including: a) foundationalknowledge in data science; b) availability of multi-center and international databases; c) enhanced training incutting-edge multimodal methodologies to measure brain changes with age, including neuroimaging and post-mortemassessments; d) hands-on experiences with internet-based designs for recruitment and data collection. Training in theresponsible conduct of research and efforts to increase diversity are important objectives of the program.
 
44. Project Title: NEUROBIOLOGICAL DRIVERS OF MOBILITY RESILIENCE: THE DOPAMINERGIC SYSTEM
  Leader(s): ROSANO, CATERINA ; BOHNEN, NICOLAAS IDA ;
    THE UNIVERSITY OF PITTSBURGH
    NIH U01AG061393 / (2018-2023)
  ABSTRACT In older age, walking becomes slower and less automated, requiring more attention and prefrontal resources.Common causes of age-related walking impairments are cerebral small vessel disease (cSVD) and changes inperipheral systems. We have recently discovered that ~20% of older adults maintain fast gait speed even in thepresence of common locomotor risk factors, thus appearing resilient. Our work suggests that the nigrostriataldopamine (DA) system may be a source of this resilience. We hypothesize that higher nigrostriatal DAneurotransmission drives resilience to locomotor risk factors via higher connectivity with sensorimotornetworks, thus reducing prefrontal-mediated motor control and restoring automated control of walking. Resilience due to the nigrostriatal DA system is a novel and highly promising area of inquiry. Unlike vascularlesions and brain structural impairments, DA neurotransmission is potentially modifiable, thereby offering novelapproaches to reduce age-related walking impairments. Although of substantial potential value to wellbeing inaging, there is a critical gap in knowledge of age-related mobility with simultaneous measures of nigrostriatalDA system, cSVD and peripheral system impairments. Our aims are: AIM 1: Quantify the DA-related contribution to mobility resilience, cross-sectionally and longitudinally.We hypothesize that nigrostriatal DA neurotransmission predicts walking performance, during usual and dualtask conditions and reduces the negative effects of cSVD and peripheral system impairment on walkingperformance. AIM 2: Assess DA-related automated control of walking, cross-sectionally and longitudinally. Wehypothesize nigrostriatal DA neurotransmission acts synergistically with connectivity of sensorimotor networksto predict higher walking performance and lower prefrontal activation while walking. As a first translational step in testing the effects of DA on resilience, we propose to collect pilot data for amechanistic target-engagement study in slow-walking older adults with cSVD and pronounced age-associatedstriatal DA loss. Exploratory AIM 3: To assess the effects of 1 week of L-DOPA administration on connectivityand gait speed as a function of molecular markers of striatal DA release in non-resilient elderly withpronounced age-associated striatal DA losses. This research is innovative in that it goes beyond explaining impairments, to revealing resilience factors andtheir mechanisms as the basis for novel interventions. It has high impact because recent findings suggest thatpharmacological and behavioral interventions can improve DA signaling. Our team has unique expertise in theuse of novel technologies and represents decades as thought leaders in the study of aging, brain and mobility.
 
45. Project Title: Defining the impact of stromal aging on ovarian cancer initiation
  Leader(s): COFFMAN, LAN ; BUCKANOVICH, RONALD J; FINKEL, TOREN ;
    UNIVERSITY OF PITTSBURGH AT PITTSBURGH
    NIH U01AG077923 / (2021-2026)
  Age is a major risk factor for high grade serous ovarian cancer (HGSOC) with an average age at diagnosis of 63. Ovulation and aging induce inflammatory changes in the fallopian tube microenvironment, the origin of most HGSOC. Over time, cells become senescent and secrete regulatory factors known as the senescence associated secretory phenotype (SASP). SASP-induced changes in the local microenvironment have been implicated in cancer promotion. However, the role of the aging microenvironment in ovarian cancer initiation is unknown creating a major barrier to effective early detection and prevention strategies for this deadly disease. The goal of this proposal is to define the impact of aging on interactions between stromal cells and cancer initiating cells (CIC) that drive ovarian cancer formation. Mesenchymal stromal/stem cell (MSC) are multipotent stromal progenitor cells critical to tissue homeostasis across the lifespan. In cancer, MSCs undergo epigenomic reprogramming to become pro-tumorigenic cancer associated MSCs (CA-MSCs). The pro-tumorigenic CA-MSC phenotype is driven by the activation of the Wilms tumor 1 (WT1) transcription factor. WT1 induces the secretion of CA-MSC derived BMP4 which increases the pool of ovarian CICs. Preliminary data demonstrate that with increasing age, MSCs can express WT1 and adopt a cancer promoting phenotype even before cancer starts. We have termed these cells ?high risk? MSCs (hrMSCs). Preliminary data indicate that hrMSCs (i) recapitulate the CA-MSC phenotype and are enriched in the stroma of pre-malignant epithelial cells, (ii) secrete SASP-like proteins which both induce epithelial cell DNA damage and support the survival of DNA damaged epithelial cells and (iii) support established cancer cell growth. AMP-activated protein kinase (AMPK) may be critical to CA- MSC/hrMSC formation. In a clinical trial Metformin, which increases AMPK, reversed the CA-MSC phenotype in some patients correlating with improved survival. Preliminary data shows a more potent, novel AMPK activator, BC1618, alters the hrMSC secretome. We hypothesize that aging induces epigenetic changes which convert MSCs to hrMSCs and that hrMSCs create a pro-tumorigenic microenvironment that supports the growth of ovarian CICs. Our collaborative team with expertise in aging, stromal stem cells and CICs propose to: 1) Determine the impact of aging on the fallopian tube MSC phenotype and spatial relationship to CICs. We hypothesize that aged MSCs obtain a high risk phenotype through altered DNA methylation and support adjacent CIC formation. 2) Determine the impact of aged hrMSCs on CIC formation and ovarian cancer progression. We hypothesize that aged hrMSCs promote CIC formation and progression via WT1-mediated BMP4 and SASP secretion. 3) Target aging hrMSCs to limit ovarian cancer formation. We hypothesize that the AMPK activator, BC1618, through altering age-related MSC epigenetic changes, will decrease hrMSC formation and ovarian cancer initiation. This work will broaden our understanding of ovarian cancer initiation by defining the critical role of aging stroma in CIC formation and offer new avenues for early detection and prevention strategies.
 
46. Project Title: Generation, Characterization, and Validation of Marmoset Models of Alzheimer's Disease
  Leader(s): SILVA, AFONSO C ; CARTER, GREGORY W; RIZZO, STACEY J;
    UNIVERSITY OF PITTSBURGH AT PITTSBURGH
    NIH U19AG074866 / (2022-2024)
  PROJECT SUMMARY OVERALL Alzheimer?s disease (AD) is a devastating neurodegenerative disorder affecting nearly 6 million Americans and is expected to increase over the next several years. Our limited understanding of the mechanisms that trigger the emergence of AD has contributed to the lack of interventions that stop, prevent, or fully treat this disease. We propose to establish the marmoset as the first primate-specific model to reveal the earliest cellular and molecular events of AD processes and allow charting AD progression from its inception. To do so, we will draw from a self-sufficient and large colony of research marmosets with dedicated veterinary and husbandry teams, state-of-the-art in vivo neuroimaging and molecular assays, and a multidisciplinary team of experts in aging biology, AD genetics and genomics, animal model development and characterization, behavioral and cognitive phenotyping, and marmoset gene-editing technologies. Our proposal?s overarching goals are to develop marmoset models of early-onset AD (EOAD) and late-onset AD (LOAD) to enable the investigation of the underlying cellular and molecular root causes of the pathogenesis and progression of AD and support future translational studies. We believe that the simultaneous assessment of genetic, molecular, functional, behavioral, and pathological phenotypes in marmosets will provide translatable knowledge of the origins and progression of AD in human populations. Furthermore, we posit that the comprehensive study of gene-edited marmoset models of AD from neurodevelopment through aging will identify emerging phenotypes that precede frank neuropathology. Our proposal consists of 3 integrated Research Projects that aim to: (1) Conduct characterization and validation of PSEN1 mutations in marmosets as a model for the study of EOAD, and investigate early life molecular determinants of AD disease pathogenesis associated with genetic risk for EOAD; (2) Identify and enhance LOAD-related signatures in outbred and genetically-engineered marmosets; and (3) Conduct a comparative multimodal phenotypic characterization of marmoset models of AD. These projects will be supported by 5 Research Cores focused on project administration, bioinformatics, genetic engineering, multimodal disease characterization, and veterinary and colony management. These supporting cores will integrate marmoset and human genomic signatures and provide data dissemination and resources to the greater research community as part of our commitment to open science, generate novel gene-edited marmoset models of AD, develop optimized protocols for studying disease onset and trajectory in line with clinical protocols, evaluate therapeutic strategies, and provide specialized animal care and support, respectively, allowing complete characterization of the marmoset models. At the conclusion of this project, we will have genetically engineered three AD risk variants into marmoset models, established a disease characterization pipeline for comprehensive phenotyping, and shared these resources with the greater research community.
 
47. Project Title: Biospecimen-Core
  Leader(s): ROJAS, MAURICIO
    UNIVERSITY OF PITTSBURGH AT PITTSBURGH
    NIH U54AG075931 / (2021-2026)
  ABSTRACT Biospecimen Core: Lung and heart function and aging are major determinants of human health and lifespan, respectively. Combined, lung and heart diseases are the leading cause of morbidity and mortality world-wide (WHO?s Global Health Estimates 2020). The Biospecimen Core (BC) will generate high-quality, clinically annotated, and pathologically evaluated specimens from normal human lung and heart (and corresponding vessels and lymph nodes) to provide the fundamental basis for the creation of high-resolution, multi-modal, and multi-dimensional senescence maps. The BC investigators will use their expertise in collecting, processing, annotating, classifying, and distributing tissue samples and primary cells lines for lung and heart senescence mapping. The core will excel in providing already catalogued tissues with as little ischemia-induced artifacts as possible, and meet all legal and ethical standards including broad donor consent. The BC follows NIH/NCI Best Practices for Biorepositories, with standard operating procedures (SOPs) in place to ensure the highest biospecimen and clinical information quality to meet all legal and ethical standards. The biorepository efforts are approved through OSU, Pitt, and URMC IRB protocols that cover the procurement, processing, and distribution of human biospecimens. The BC will collect whole tissue from humans across the lifespan and will provide whole tissue, precision cut tissue slices (PCTS), and purified cells to the TriState SenNet TMC. Together with the Data Analysis Core (DAC), the BC will use established metadata collection protocols to collect metadata in a consistent and interoperable format.