Claude D. Pepper Older Americans Independence Center

  Principal Investigator    Jeremy Walston, M.D.  410-550-1003
  Program Administrator    Brian Buta, MHS  410-502-3412

Since its inception in 2003, the Johns Hopkins University (JHU) Older Americans Independence Center (OAIC) has pursued a rigorous and distinctive scientific approach considering physical frailty as a biologically-rooted state of decreased resiliency and reserve, which induces a syndromic phenotype and specific etiological mechanisms. As evidenced by peer-reviewed publications and associated NIH grant funding, this specific conceptualization of frailty has provided a highly productive framework for population-based, clinical, and biological discovery, for the development of potential prevention and treatment strategies, and for the training of junior investigators for academic careers in frailty and aging research. This center’s mission remains, in many respects, as it has been throughout the life of our OAIC: To make fundamental etiological discoveries related to frailty, move these towards frailty-focused interventions, develop evidence-based guidelines for the prevention and management of adverse outcomes in frail older individuals, identify new investigators dedicated to these ends, and provide supported investigators with the expertise, resources, and training necessary to lead the next generation of frailty-related scholarship and practice. Given the rapidly growing interest in frailty, its detection, its management, and the critical mass of frailty-related knowledge that this OAIC has generated, we have launched an Information Dissemination Core (IDC) to enable our OAIC to more comprehensively disseminate frailty-related findings so as to better impact clinical and public health practice. We pursue our mission through the following specific aims:

  1. To stimulate, lead and develop effective frailty-focused interdisciplinary research programs that promote the maintenance of independence. This has helped to create a vibrant and growing center with scientific vigor and a rich interdisciplinary milieu of experienced faculty and successful trainees focused on frailty research.
  2. To translate the new knowledge generated in this OAIC into targeted prevention and treatment strategies that help older adults maintain independence. An existing clinical translational resource core, an IDC, and the national OAIC network facilitate this effort.
  3. To provide the highest quality expertise, support, infrastructure and technology in biological, data analytic and clinical research methodologies to OAIC investigators.
  4. To support the development of new and innovative methodologies, research strategies and technologies essential to the study of frailty. Aims 3 and 4 are organized through Biostatistics, Biological Mechanisms, and Clinical Translational cores.
  5. To provide tailored training and mentorship to junior investigators interested in developing careers focused on frailty in older adults. We continue with a leadership team that has demonstrated expertise and commitment to training the next generation of investigators.
  6. To attract outstanding investigators and trainees to frailty research from across the Johns Hopkins University and beyond. We augment our successful local approach to this by providing highly visible educational and training activities on a local and national level, and through the IDC.

  Information Dissemination Core (IDC)
Leader 1:    Jeremy Walston, MD
Leader 2:    Tara Sullivan, PhD   

To improve the reach and use of the evidence-based knowledge on frailty that emanates from JHU OAIC-supported research and elsewhere, we have developed a state-of-the art Information Dissemination Core (IDC) with a highly experienced partner: Johns Hopkins Center for Communication Programs (CCP). CCP has long standing, high-profile expertise and experience in knowledge management (KM) and dissemination science, with clients including USAID, The Bill and Melinda Gates Foundation, and UNICEF. The development of this close partnership between knowledge management experts at CCP and the frailty related content experts who lead this OAIC provides a highly rigorous yet accessible approach to more efficiently and effectively disseminate frailty-related findings and recommendations to a broader audience using cutting edge approaches. We envision that this audience will include researchers, students, clinicians, professional societies and foundations, policymakers, and older adults seeking information on frailty. Indeed, our overarching goal is to have this IDC become a national and international ‘go-to’ resource for the latest information and resources related to frailty science from this OAIC and as well as other authoritative sources: We seek ultimately to accelerate incorporation of best practices for addressing frailty in health practice and promotion, so as to benefit older adults. 

Leadership and Administrative Core (LAC)
Leader 1:    Karen Bandeen-Roche, PhD
Leader 2:    Jeremy Walston, MD
The Leadership/Administrative Core (LAC) spearheads the vision for the Johns Hopkins Older Americans Independence Center (JHU OAIC), sets goals through which to implement it, and assures energy and quality in accomplishing goals. It leads in identifying the next generation of research on frailty that should be created, supports research planning and recruitment of investigators, and sets and monitors progress benchmarks. It is the OAIC base for recruiting and nurturing a critical mass of investigators dedicated to the creation of high impact, innovative research essential to the prevention and treatment of frailty in older adults. It administrates the OAIC and its Cores for soundness of operations and accomplishes required reporting. It promotes a stimulating intellectual environment around scholarship on frailty so as to attract outstanding researchers and knit them into an interdisciplinary community. It creates visibility for the accomplishments of the OAIC locally and globally: In the current cycle it leverages a new Information Dissemination Core (IDC) to amplify these efforts. The LAC is led by OAIC Co-Principal Investigators with broad interdisciplinary scientific expertise and institutional reach. They work closely with the other OAIC Cores Directors, and with a diverse Leadership Council and Internal Advisory Committee to develop and promote a frailty-focused agenda across the Johns Hopkins University. An experienced External Advisory Board reviews this OAIC annually, and provides crucial feedback and additional scientific vision. The LAC provides essential leadership in planning, integrating, sustaining, implementing and monitoring OAIC operations. Its goals are to envision and then support research leading to new strategies to enhance independence in older Americans and to create a new generation of research leaders in the field

Pilot and Exploratory Studies Core (PESC)
Leader 1:    Neal Fedarko, PhD
The major goal of Pilot and Exploratory Studies Core (PESC) is to cultivate and support innovative pilot and exploratory studies that are needed to develop crucial larger scale and confirmatory studies to advance the development of effective prevention and/or therapies for frailty, and hence facilitate independence in older adults. The PESC provides funding, access to biostatistical, biological, and clinical research core resources, and mentoring and oversight pilot and exploratory studies. Because of the importance of these studies to the development of new scientific priorities, additional resources are provided to this core to help maximize flexibility, efficiency, and rapid development of areas of focus for this OAIC. The PESC Core, in close collaboration with the OAIC Leadership Council, sets ideas the next stages of research most essential to advancing science on frailty, and then works to identify investigators whose expertise and career goals are applicable to furthering knowledge in these target areas. The leadership and resources of these cores are then focused on the development, conduct and eventual translation of high impact pilot studies. The proposed studies must be novel and either hypothesis-driven or focused on development of methods needed to validly address hypotheses: they ideally address potential mechanisms, etiologies, or screening approaches for frailty, or lay groundwork for evaluating potential therapies to prevent or treat the frailty and its consequences and hence maintain independence. It is expected that PESC-supported studies establish preliminary data that will lead to substantive, long term external funding that can bring the research initiated to completion. Given our roadmap goals of accelerating translation of frailty to increase healthspan in clinical and public health settings, elucidating the biological underpinnings and role of multisystem dysregulation in frailty and resilience, and improving ascertainment of frailty measurement in settings that challenge measurement, special focus was given to these areas for the PESC studies articulated in this application.

Research Education Component (REC)
Leader 1:    Gary Gerstenblith, MD
The purpose of the Research Education Core (REC) is to foster the career development of junior faculty from multiple disciplines into academic scientists in gerontology and geriatrics, focusing on the theme of exercise and activity rehabilitation and recovery research. The REC supports mentor-based research training and education to promote the career development of REC Scholars as well as other junior faculty, fellows, and students pursuing research careers in aging. The UM-OAIC has a successful history of mentored training that crosses traditional disciplinary boundaries to develop novel research for improving function and independence in older persons. This has enriched the cadre of scientists at UM and elsewhere conducting aging research in exercise and rehabilitation science.

Resource Core 1 (RC1): Biostatistics Core (RC1)
Leader 1:    Karen Bandeen-Roche, PhD
Leader 2:    Qian-Li Xue, PhD

The Johns Hopkins Older Americans Independence Center (OAIC) has empowered by many-fold the creation of significant research, training and practice paradigms for addressing frailty in older adults. The functions supplied by this Biostatistics Core have been central in this. They include: our key roles in the mentorship and training of junior colleagues in the statistics of frailty and aging; our development and dissemination of emerging resources and technologies for data management and analysis; our provision of database and statistical expertise and support to scholarship on frailty and aging, needed methodological innovation, and collaborative intellectual leadership for the creation and translation of research on frailty. Outcomes of this Core, in collaboration in this OAIC and beyond, include advancement of knowledge on the ascertainment, biological and etiological underpinnings, health consequences, and treatment of frailty, research surmounting significant methodological challenges to the study of frailty, and the creation of intellectual capital and infrastructure for further advances. These have laid crucial groundwork for intervening on frailty. For more than 15 years our Biostatistics Core has dedicated a critical mass of leadership from gerontologically informed biostatisticians toward the amelioration of frailty in older adults through our OAIC, and its leadership has dedicated the same to research on aging for nearly 30 years. Our leadership and our external advisory committee consider it crucial that this Core continue to contribute to the OAIC’s overarching aims through the intellectual innovation, collaboration and support it provides.  

Resource Core 2 (RC2): Biological Mechanisms Core (RC2)
Leader 1:    Peter Abadir, MD, PhD
Leader 2:    Dan Arking, PhD

Advances in in understanding of molecular and physiological processes that influence aging phenotypes, and in methodologies that help to measure these changes, have greatly improved our ability to identify biological pathways that are potentially relevant to the etiology of frailty.  The major goal of this core is to promote molecular and biological studies of aging and frailty-relevant pathways, and to translate these findings into relevant diagnostic, preventive and treatment strategies. Building on our prior cycles, mitochondrial biology, chronic inflammation, renin angiotensin system, and genetics continue to be a core expertise content offered to investigators from within the core.  We have also gained expertise and collaborators at Johns Hopkins who have considerable “omics” and in computational biology expertise.   These technologies have provided a logical basis for searching and identifying specific biomarkers associated with human phenotypes and diseases; they can not only provide markers for human disease that are useful for nosology in heterogeneous clinical phenotypes but, more importantly, provide deep insight into pathophysiology and disease mechanisms that will form the bases for future diagnostics and treatments.   Consequently, the rationale for RC-2 is to provide the expertise, technology access and infrastructure, mentoring, and training necessary to facilitate the highest quality etiologic research in frailty.

Resource Core 3 (RC3): Clinical Translation and Recruitment Core (RC3)
Leader 1:    Todd Brown, MD
In order to more effectively meet JHU OAIC’s goal of translating frailty-related etiological discoveries into clinical studies that help maintain independence in older adults, and to overcome the substantial barriers to success in clinical investigation for junior investigators,  the leadership of this OAIC made a strategic decision to develop this resource core.  RC-3 provides to supported OAIC investigators: 1) comprehensive training and mentorship in clinical research that spans from study design through implementation through outcome interpretation, 2) clinical research space and assistance with all aspects of forms and protocol development, data collection, and recruitment of human subjects,  3) an active registry of more than 1000 older adults who have consented to be contacted for aging and frailty related studies, and 4) synergy with other cores in order to optimize all aspects of frailty-related study design, data collection, and biological measurement and junior faculty training.  This synergy is greatly augmented by our core leaders, Dr. Robert Wise, who has considerable expertise in the development, implementation, and conduct of clinical physiological studies and clinical trials and who ended his tenure as leader in 2018. Dr. Todd Brown, an endocrinologist with considerable human subjects research expertise and who plays a leading role in the ICTR at Johns Hopkins, now leads RC-3.  The daily operations are led by a highly skilled and experienced research program manager with expertise in the measurement of frailty, mobility, and cognition, as well as expertise in protocol development and implementation and in subject recruitment and retention, in coordination with our OAIC administrator and Drs. Brown and Walston.  This initiative, which is closely aligned with the JHU Division of Geriatric Medicine and Gerontology goals of better integrating clinical practice with clinical research, is funded in part by philanthropic resources. 

  B. RESEARCH (28 Projects Listed)
  Leader(s): GROSS, ALDEN L.
    NIH K01AG050699 / (2016-2021)
  DESCRIPTION (provided by applicant): Alden L. Gross is an Assistant Professor in the Department of Epidemiology at the Johns Hopkins Bloomberg School of Public Health. He seeks a mentored career development award to obtain critical knowledge skills in the biology of aging, particularly as it relates to frailty in older adults, and necessary research experience foran independent career as an epidemiologist in aging. The training application details a five year plan of formal and informal instruction in the physiological basis of frailty and aging consisting f mentored research by an established team of experts, coursework, seminars, guided study in frailty by mentors, collaborations in richly educational working groups, national and local meetings, and mentored research informed by the training. Short-term career goals include to complete coursework in the biology of aging and practice, disseminate high-quality mentored research through publications and presentations, engage in career development activities, and apply for independent R01 funding beginning in the fourth year of the award period. Long-term career goals are to be an independent psychiatric epidemiologist with content expertise in the biology of aging, particularly as it relates to frailty in older adults. The specific aims of the research proposed are to develop and validate an objective method for measuring physiological frailty using combinations of physiological markers of dysregulation across multiple body systems in an integrative data analysis of three longitudinal datasets, to determine whether physiological frailty or cognitive impairment predicts subsequent change in the other, and to evaluate reciprocal relationship between changes in physiological frailty and cognitive decline with attention to implications for future public health interventions. An ancillary study is proposd to enrich existing biomarker data. Completion of the proposed aims will provide preliminary findings that will lay the groundwork for mounting interventions to establish frailty as a window o opportunity for intervention or screening of subsequent cognitive decline.
    NIH K01AG052640 / (2017-2022)
  ABSTRACTThis is an application for a K01 Research Career Development Award. The goal of the proposed project is toprovide the candidate with advanced skills needed to establish an independent research program examiningthe relationship between vision loss and cognitive decline in older individuals. To facilitate this long-term goalthe candidate will: (1) characterize the longitudinal relationship between objective measures of visual functionand cognition in older adults, (2) determine the relationship between vision loss and brain volume and corticalthickness in older adults, and the role brain volume and thickness may play in the vision-cognition relationship,and (3) assess the association between vision loss and participation in cognitively stimulating activities,exploring this participation as a mediator of the vision-cognition relationship. The candidate proposes acomprehensive training plan, combining formal coursework, meetings and tutorials overseen by her mentors,participation in applied training experiences, and involvement in seminars and workshops. Specific traininggoals include: (1) receive training in the neuropsychological and clinical assessment of older individuals, (2)develop neuroimaging analyses skills, (3) receive training in the neuroscience of vision, (4) gain advancedknowledge of mediation and experimental study design and analyses, and (5) continued training in theresponsible conduct of research. The training plan will be executed in coordination with the set of researchactivities, mentioned above, that are based on preliminary data collected by the applicant. The preliminary datashow that reduced visual functioning is associated cross-sectionally with: (1) lower executive function, memory,and language test scores, and (2) reduced gray and white matter volumes, in the visual cortex and frontallobes. The candidate will expand on these findings, using longitudinal data from participants in the BaltimoreLongitudinal Study on Aging (BLSA) who are 60 years and older. The aim of the project is to test the `sensoryloss consequence hypothesis', using a multi-domain approach to examine the vision-cognition relationship.The primary hypotheses to be examined are that: (1) reduced visual function is associated with greaterdeclines in executive function, memory, and language test scores, and an increased risk of incident dementia,(2) reduced visual function is associated with reduced brain volume and thickness in regions of interest withinthe frontal cortex and visual pathways, which mediate the vision-cognition relationship, and (3) age-relatedvision loss is associated with a reduction in the frequency and variety of participation in cognitively stimulatingactivities, which also influences the vision-cognition relationship in older adults. Results from this research willbe used to develop a subsequent R01 research proposal that will facilitate the candidate's transition to anindependent researcher.
  Leader(s): CHUNG, TAE HWAN
    NIH K08AG058483 / (2018-2023)
  PROJECT SUMMARY Decline in skeletal muscle function with aging is a major determinant of disability and morbidity in late life.However, the neurobiology of such decline in skeletal muscle function in normal aging is poorly understood.The proposed K08 project is a critical step towards to understanding the underlying mechanism of age-relateddecline of skeletal muscle function. This study uniquely focuses on the intersection between kynureninemetabolic pathway, motor neuron, neuromuscular junction (NMJ), and skeletal muscle function. Kynureninepathway is a major route to the synthesis of Nicotinamide adenine dinucleotide (NAD), a critical coenzyme thatbalances redox status of all living cells. Many intermediate metabolites of kynurenine pathway are known to bepotent neurotoxins, and involved in various age-related neurodegenerative diseases. The preliminary studiesof this project showed alterations of kynurenine pathway in aging peripheral neuromuscular system. Herein, itis hypothesized that age-related alterations in kynurenine pathway contributes to neurodegeneration in spinalmotor neurons, eventually causing age-associated muscle weakness. Aim1 propose to identify key alterationsin the kynurenine pathway in the aging spinal motor neurons, using mass spectrometry, PCR, and Westernblot techniques. Aim2 propose to determine the neurotoxicity of kynurenine pathway in aging neuromuscularsystem both in vitro and in vivo models. Finally, Aim3 tests the effects of pharmacological inhibition of akynurenine metabolite synthesis. The findings from this study will likely identify molecular targets for age-associated muscle weakness, and used for future translational study. The proposal will take place in the Johns Hopkins School of Medicine under the mentorship of JeremyWalston, MD, Ahmet Hoke, MD, PhD, and Robert Schwarcz, PhD. An integrated career development andmentoring plan has been also proposed to ensure Dr. Chung?s successful transition to independence. Thetraining goals are focused on development of Dr. Chung?s expertise in kynurenine neurobiology, variousmolecular techniques in neuroscience research, and translational gerontology. The strength of the proposalcomes from the collaboration between all of his mentors who have world-renowned expertise in aging frailty(Dr. Walston), peripheral neurodegeneration (Dr. Hoke), and kynurenine neurobiology (Dr. Schwarcz).
  Leader(s): MATHUR, AARTI
    NIH K23AG053429 / (2017-2022)
  Project SummaryThis project aims to evaluate the association of frailty with post-operative changes in voice, swallowing, andquality of life following thyroidectomy in older adults. Specifically, Aim 1 is to evaluate the effect ofthyroidectomy on voice, swallowing, and quality of life in older adults. The literature suggests that thesealterations occur at a relatively high frequency in younger patients. We aim to quantify frequency andmagnitude of changes in voice, swallowing, and QOL using subjective assessment with surveys and semi-structured patient interviews. Additionally we aim to correlate this with objective data obtained from speech-language pathology evaluations using videostroboscopy and videofluoroscopy. In Aim 2, we will explore theassociations between a frailty phenotype with pre-operative findings, thyroid-specific markers, and post-thyroidectomy alterations in voice, swallowing or decline in QOL. In addition to exploring the role of frailty topredict these alterations and identify a high-risk group, we will also explore the utility of thyroid or laryngealspecific markers to augment the predictive power of frailty. In Aim 3, we hope to investigate the role of pre-operative interventions including tracheal traction exercises and voice therapy to reduce the incidence ofimpact of post-operative alterations. We will randomize patients to intervention or usual care and evaluate thefrequency of alterations after thyroidectomy. This work represents an interdisciplinary approach to establishalterations in voice and swallowing that occur after thyroidectomy in older individuals, the impact of thesechanges on quality of life, and an attempt to reduce post-surgical disability. Findings from this study will informthe design of 2 future clinical trials aimed at 1) evaluating pre-operative interventions to reduce surgicaldisability after thyroidectomy and 2) creating a patient-reported outcome measurement tool specifically forolder adults undergoing thyroidectomy.
    NIH K24AG056578 / (2017-2022)
  Project SummaryThe aims of this proposal are to 1) develop the candidate's capacity for research, leadership, and mentorshipthrough career development in clinical trials, building and leading national collaborations, and mentoring, 2) toexpand her mentorship of promising junior investigators in patient-oriented aging research, and 3) to pursue aninnovative research direction to develop and evaluate person-centered interventions to optimize medicationuse in older people with multiple chronic conditions that will serve as a platform to engage an expanding groupof mentees. The candidate, a geriatrician who practices in a primary care clinic, has established a nationally-and internationally-recognized, high impact, well-funded independent clinical research program with anoutstanding publication record. In the 14 years since completing her geriatrics fellowship, she has establishedherself as a successful mentor of trainees from all levels who have published high-impact research, obtainedfunding and necessary research skills, and continue to conduct patient-oriented research. The candidate hasdeveloped a robust research portfolio focused on patient-centered care for older adults, particularly those withmultiple chronic conditions. The candidate's work to date has been transformative both within aging and inother fields by shifting attention from a disease-specific approach to care to one that recognizes that most olderadults live with multiple chronic conditions. The candidate has a strong track record of research funding fromAHRQ, PCORI and the NIA to improve the generation and synthesis of evidence to better inform the care ofpeople with multiple chronic conditions, and to develop patient- and family-centered approaches to care ofolder adults with multiple chronic conditions. This proposal will provide the candidate with protected time toincrease her expertise, expand her mentoring program, and develop new research focused on optimalmedication prescribing to improve patient-centered outcomes for this population. The candidate will furtherdevelop a formal mentoring program for the engagement and development of high-caliber mentees who willserve as the next generation of leaders in patient-oriented research for aging populations. She will work witheach mentee to implement a focused career development plan in which they complete research projects anddevelop skills including grant and scientific writing, study design, and presentation skills necessary to besuccessful independent patient-oriented investigators. The outstanding environment for aging research andclinical research training at Johns Hopkins is fundamental to this proposal.
    NIH K76AG057020 / (2017-2021)
  PROJECT SUMMARY/ABSTRACTBackground: Surgery for hip fracture can be devastating for older adults, with complications includingdelirium, increased risk of dementia, and inability to walk. As an anesthesiologist and clinician-scientist, I havefocused on reducing delirium after surgery. In this proposal, I will build the foundation for a research careerfocused on the broader goals of reducing neurocognitive and functional decline after surgery in older adults. Iwill specifically focus on the role of optimizing intraoperative cerebral perfusion, because of pilot datasuggesting that reduced cerebral perfusion during surgery is a modifiable risk factor for delirium.Career Development Plan: I am proposing specific educational goals that address gaps in my currentknowledge. First, I will develop expertise in cerebrovascular physiology and monitoring under the mentorshipof Dr. Koehler, an expert in cerebral blood flow regulation. Second, I will develop expertise in neurocognitivetesting and dementia assessment under the mentorship of Dr. Kamath, a neuropsychologist, and Dr.Gottesman, an expert in dementia adjudication in the research setting. Third, I will gain expertise in clinicaltrials and measuring functional status through the mentorship of Drs. Sieber and Neuman (experts inperioperative clinical trials in older adults), and Dr. Walston (a geriatrician with expertise in functional status).Finally, I will develop as a leader through interactions with my mentors, courses, and leadership opportunities.Research Proposal: During hip fracture surgery, extreme variations in blood pressure are common in olderadults, who are susceptible to cerebral ischemia and vulnerable to consequences of hypotension. However,there is no standard of care as to what constitutes adequate blood pressure during surgery. Our group haschampioned methodology to define optimal blood pressure in individual patients by real-time monitoring ofcerebral autoregulation. Using these methods in cardiac surgery, we have shown that mean arterial pressure(MAP) below the limits of cerebral autoregulation is associated with postoperative morbidity, and that anintervention to target intraoperative MAP based on this monitoring may reduce delirium. Although promising,these results in cardiac surgery may not apply in hip fracture surgery. To address this gap in knowledge, I willextend these methods to hip fracture surgery patients. I will characterize (a) the extent of, and (b) risk factorsfor intraoperative MAP variation above and below the limits of cerebral autoregulation during hip fracturesurgery (Aim 1). I will also examine associations of MAP variation with neurocognitive and functionaloutcomes (Aim 2). Based on these results, I will design a pilot feasibility/safety trial to determine whethertargeting MAP within the limits of autoregulation could improve neurocognitive/functional outcomes (Aim 3).Summary: Promising results from this proposal would support a definitive trial, which would have the potentialto fundamentally alter anesthetic strategies across a wide range of surgical populations. The educational planin this proposal will support my career goal of improving outcomes for older adults after surgery.
    NIH K76AG059984 / (2018-2022)
  PROJECT SUMMARYBackground: Cancer screening can lower cancer-related mortality and morbidity but may be associated withsignificant harms and burdens in older adults. There is often a lag-time of 10 years before patients screenedfor breast, colorectal, or prostate cancers actually benefit. On the other hand, multiple harms from screeningcan occur in the short-term. Older adults with limited life expectancy continue to receive cancer screening athigh rates even though it exposes them to the harms of screening with little chance of benefit. Clinicians are amajor driver of over-screening but why they often continue to recommend cancer screening in older adults withlimited life expectancy is unknown. This proposal aims to improve the cancer screening of older adults by 1)identifying the factors that facilitate or hinder clinician recommendations to stop routine screening in olderadults with limited life expectancy, and 2) better supporting clinicians to appropriately incorporate lifeexpectancy in their screening recommendations.Research proposal: Aim 1 will use qualitative methods to understand the range of factors that facilitate orhinder clinicians from recommending screening cessation in older adults with limited life expectancy. Aim 2 willtest these factors in a national physician survey to determine and quantify their effects on physicians'screening recommendations in older adults with limited life expectancy. Aim 3 will then develop and pilot test anovel multi-modal intervention to target the factors that significantly contribute to over-screening. Theintervention will be developed with input from clinicians and older adults and will use multiple, overlappingstrategies that may include decision support, communication coaching, and clinician feedback.Career development plan: The candidate is a geriatrician who has already demonstrated national andinstitutional leadership in research and a strong track record of academic scholarship with numerous highimpact publications and early investigator grants. Her long-term career goal is to be a research leader focusedon incorporating life expectancy to inform patient-centered, individualized preventive care decisions for olderadults. She has laid out a comprehensive, feasible career development plan that will enable her to transitioninto an independent investigator and research leader. She proposes to learn new skills in decision support,clinical trial design, and implementation science, in addition to continued development of leadership skills. Shehas assembled an exemplary mentoring team with expertise in the subject area and the relevant researchmethods and works in a rich research environment with tremendous resources to support her development.Summary: The proposal addresses an important research gap and produces a novel intervention that mayhave major impact to improve the cancer screening of older adults. The results from this proposal will support asubsequent large-scale clinical trial to test the intervention. This proposal will also further foster the careerdevelopment of the candidate into a research leader focused on individualized preventive care in older adults.
    NIH P30AG059298 / (2018-2023)
  The Schools of Medicine, Nursing, and Public Health of the Johns Hopkins University areproposing a new Alzheimer's-related Resources Center for Minority Aging Research (AD-RCMAR) in response to RFA-AG-18-002. The aims of this application are to: (1) mentor early-stage investigators from underrepresented backgrounds in minority aging and health disparitiesresearch, with a focus on Alzheimer's disease and related disorders (ADRD), using a life courseperspective encompassing biological, behavioral, and community factors contributing tocognitive impairment and dementia in older minority adults; (2) conduct epidemiological,preventive, and intervention research that addresses ADRD in later life within a multi-levelframework that encompasses individuals, families, social networks, and communities; and 3)engage communities and health care providers ? especially family caregivers, primary carepractices, communities of faith, and community organizations ? as our partners in recognizingdementia and developing interventions with the potential to prevent cognitive decline andreduce ADRD dementia risk and disparities in minority older adults. The Johns Hopkins AD-RCMAR consists of: (1) an Administrative Core whose function is to provide governance and anadministrative structure, to support research, to foster interactions between Cores and otherCenters, and to ensure RCMAR Scientists develop mentoring relationships across the affiliateddepartments, schools, the intramural program at NIA in Baltimore, and nationally; (2) aResearch Education Component to foster diverse junior investigators and mid-careerinvestigators transitioning into ADRD-relevant research through support for individual pilotprojects, career mentoring, scholar-to-scholar interactions, and role modeling; (3) a Community-Liaison and Recruitment Core to ensure the relevance of the ADRD research and to increaseknowledge of engagement of community members in the research enterprise with the creationof a Community Resource Institute as a venue for community-investigator interaction; and (4) anAnalysis Core as a foundation for methodological and statistical mentoring, including educationand mentoring in mixed-methods research. An Executive Committee includes communityrepresentatives and a Scientific Advisory Panel consists of distinguished investigators withrelevant expertise in minority aging, disparities, and ADRD. A pilot project program supportedby all Cores to facilitate the development of RCMAR Scientists includes three initial pilotprojects focusing on recruitment of minority populations for ADRD research, early diagnoses ofdementia, and intervention development related to ADRD-related driving disparities.
    NIH R01AG055404 / (2018-2022)
  The role of modifiable risk factors (RF), like physical activity (PA), sleep quality, social engagement, andcardiovascular (CV) risk is receiving greater attention to promote the cognitive health of an aging populationand reduce risk of Alzheimer's disease. Each of these risk factors is known to be influenced by environmentalsources, such as neighborhood walkability, safety, noise, and access to low-cost transportation, retail, andhealthy food sources. However, little is known about the role of neighborhood factors as drivers of cognitiveaging and risk for Alzheimer's disease. If neighborhood matters, adaptations in the use of availableinfrastructures have the potential to impact thousands at a time. Those neighborhood factors that most impactindividual RF and cognitive health to reduce Alzheimer's disease risk may further differ by race and sex.Evaluating the role of neighborhood characteristics on cognitive health is difficult to interpret from more widelyused cross-sectional data due to residual confounding. Therefore, investigating how residentially stable olderadults are affected by their local stable and changing contexts and how older adults who relocate to a newneighborhood may respond to their new context by changing health behaviors requires long-term study duringthe last 1/3 of life years prior to the onset of Alzheimer's disease. The Cardiovascular Health Study (CHS)represents an ideal cohort for studying interactions between individual health and neighborhood risk factors forvarious reasons. First, participants were well characterized for key modifiable RF, above, as well as cognition,and mobility. Second, the cohort is nationally representative, bi-racial and spans socioeconomically diverse,urban and rural neighborhoods, allowing us to examine the relation between individual risk and variability inneighborhood factors. Third, our proposal seeks to address the research challenges and opportunitiesarticulated in the NIA Health Disparities Research Framework by examining interactions between environment,biology and behavior. We hypothesize that long-term exposure to neighborhood disadvantage may serve asa common cause of individual risk factors and neurocognitive and functional health, particularly insocio-demographically at-risk groups. Specific aims are to characterize associations between long-termneighborhood exposures and: 1) individual rates of decline and impairment in cognition and physical function;2) individual risk factors (PA, sleep quality, social engagement and CV burden) for Alzheimer's disease, whichmay mediate neighborhood differences in cognitive and functional risk, and; 3) whether specific neighborhoodexposures account for racial and sex differences in cognitive and functional risk. Addressing these questions inthe CHS provides an unmatched opportunity to examine the influence of a range of neighborhood factors onlong-term trajectories of cognitive and functional aging prior to the onset of Alzheimer's disease. This work willinform future design of multi-level approaches to target those neighborhood factors impacting multiple RF tooptimize healthful activity, reduce health disparities, and help adults remain active and age in place.1
  Leader(s): LIN, FRANK R; CORESH, JOSEF ;
    NIH R01AG055426 / (2017-2022)
  Novel approaches to reduce the risk of age-related cognitive decline, Alzheimer?s disease (AD), and otherdementias in older adults are urgently needed given the aging of the population. Epidemiologic studiesdemonstrate that peripheral hearing loss in older adults is strongly and independently associated withaccelerated cognitive decline and incident dementia. Hypothesized mechanistic pathways underlying thisobserved association include the effects of poor hearing and distorted peripheral encoding of sound oncognitive load, brain structure/function, and/or reduced social engagement. Importantly, these pathways maybe modifiable with comprehensive hearing loss treatment consisting of the use of hearing technologies(hearing aids, other integrated hearing assistive devices) and rehabilitative training. To date, however, therehas never been a randomized trial that has investigated whether such therapies could reduce cognitive declineand the risk of Alzheimer?s disease and other dementias in older adults. Over the past two years, we havedeveloped the Aging, Cognition, and Hearing Evaluation in Elders (ACHIEVE) randomized trial. The ACHIEVEtrial will recruit 750 70-84 year-old cognitively-normal older adults with hearing loss who will be randomized 1:1to the hearing intervention (hearing needs assessment, fitting of hearing devices, education/counseling) orcontrol intervention (individualized successful aging education sessions with a health educator coveringhealthy aging topics). The trial will be powered to detect a minimum of a 0.30 standard deviation (SD)difference in the annual rate of cognitive decline between the hearing intervention and the successful agingintervention arms over a 3-year follow-up period. The ACHIEVE study brings together a multidisciplinary groupof investigators and leverages the existing research infrastructure, scientific expertise, and well-characterizedparticipant cohort of the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS). TheACHIEVE trial has the following aims: Aim 1 To determine the effect of hearing rehabilitative interventionversus a successful aging control intervention on rates of cognitive decline (primary outcome measure) in 70-84 year-old cognitively-normal older adults with hearing loss. Aim 2 To determine the effect of hearingrehabilitative intervention versus a successful aging control intervention on secondary outcome measures ofadjudicated incident dementia, physical and social functioning, health-related quality of life, and physicalactivity. Secondary Aims: 1) To investigate whether hearing rehabilitative intervention alters establishedtrajectories of cognitive decline in participants recruited from ARIC-NCS. 2) To investigate the effect of hearingrehabilitative intervention on rates of cognitive decline in persons with Alzheimer?s disease risk factors andbiomarkers. Given that nearly two-thirds of all adults 70 years and older have a clinically-significant hearingloss, conducting the ACHIEVE study to determine if existing hearing rehabilitative interventions can reduce therate of cognitive decline in older adults is of substantial public health importance.
    NIH R01AG055781 / (2017-2022)
  Older adults with end stage renal disease (ESRD) who receive kidney transplantation (KT) double their lifeexpectancy. The new kidney allocation system, designed to better match longevity of recipients and allografts,has been in effect for 2 years. During this time, access to KT among older adults has plummeted; with ratesdeclining 10% for candidates aged 61-70 and 24% for those aged >70. The core problem is that the UnitedNetwork for Organ Sharing (UNOS) decided that longevity matching for the new allocation system would bebased on Estimated Post-Transplant Survival (EPTS), a simple model that only includes chronologic age,diabetes, time on dialysis, and prior transplant. EPTS has poor predictive power among older recipients; the c-statistic of EPTS for older recipients is 0.59, which is lower than the c-statistic of 0.67 for younger recipients.We hypothesize that a measure of physiologic reserve will more accurately stratify risk among older KTrecipients than chronologic age. Our preliminary work suggests that the Fried frailty phenotype, is associatedwith poor post-KT outcomes. While our findings are encouraging, it is unlikely that this construct captures allthe dimensions of physiologic reserve associated with ESRD. It is likely that some attributes of the Fried frailtyphenotype are not even relevant for this population. We believe an ESRD-specific measure of physiologicreserve, beyond frailty and/or other conventional measures, would greatly improve risk stratification.UNOS and the transplant community might be reluctant to add a new variable to the purposefully parsimoniousEPTS score, which was debated for 15 years. Our novel approach, supported by the upcoming UNOSpresident, is to replace chronologic age with physiologic age in the model. The overarching goal of ourresearch will be to develop a physiologic age calculator and test whether replacing chronologic age withphysiologic age improves prognostication for older adults with ESRD.To achieve these goals, we will leverage existing data and collect new data within an ongoing longitudinalcohort study of 5,500 ESRD patients. We will abstract new data on components of physiologic reserve from theparent study and enroll an additional 2,342 new ESRD patients in an ancillary study which will directly measurethe physiologic reserve components that cannot be abstracted. We will test the following aims: 1) To elicit andevaluate novel constructs that might quantify physiologic reserve in older ESRD patients; 2) To create a valid,reliable, and generalizable measure of physiologic reserve for ESRD patients; 3) To test if replacingchronologic age with physiologic age improves prognostication in older recipients.This work would improve prognostication for older adults with ESRD, which would benefit patient selection,informed consent, and case-mix adjusted transplant center report cards. Our novel approach to replacingchronologic age with physiologic age has the support of UNOS leadership and could have an immediateimpact on organ allocation and prioritization, possibly improving access for older KT candidates.
  Leader(s): AGRAWAL, YURI
    NIH R01AG057667 / (2018-2023)
  Project summaryThis project investigates whether vestibular loss predicts falls in patients with Alzheimer?s disease (AD).The proposed research is an observational study of 150 patients with AD to evaluate the associationbetween baseline vestibular function and 2-year incidence of falls. We will also explore whether vestibularfunction is associated with balance and gait function, as well as spatial cognitive function, as potentialmechanisms by which vestibular function contributes to fall risk. Specifically, Aim 1 is to determinewhether vestibular loss predicts falls in patients with mild-moderate AD. We hypothesize that poorervestibular function at baseline predicts a higher 2-year incidence of falls. Additionally, we hypothesize thatthe attributable risk of falls associated with vestibular loss will be substantial enough (>~10%) to warrantfurther investigation of vestibular therapy as a clinically significant modifier of fall risk. Aim 2 is to evaluatewhether vestibular loss in AD predicts impaired static and dynamic balance, measured using the BergBalance Scale (BBS) and the Timed-Up-and-Go (TUG) test. We hypothesize that greater reduction investibular function over the 2-year follow-up period predicts greater decline in BBS and TUG performance.Aim 3 is to evaluate whether vestibular loss in AD predicts impaired spatial cognitive skills. We willadminister cognitive tests of spatial cognition (including the Money Road Map test, the Card Rotationstest, the Visual Form Discrimination test and the Clock Drawing test), and we will also query participantsand caregivers about difficulty with driving, losing objects, getting lost and wandering behaviors asfunctional manifestations of impaired spatial cognition in AD patients. We hypothesize that greaterreduction in vestibular function over the 2-year follow-up period predicts greater decline in spatial cognitivetest scores, and a higher incidence of functional spatial cognitive impairment. Moreover, we hypothesizethat impaired balance measures (from Aim 2) and impaired spatial cognitive skills will both be independentmediators of the association between vestibular loss and incident falls. To accomplish these aims, we willleverage well-established resources at Johns Hopkins including the Johns Hopkins Alzheimer?s DiseaseResearch Center and the Memory and Alzheimer?s Treatment Center. Falls are a major source ofmorbidity in AD and current interventions are not uniformly effective. If our observational studiesdemonstrate that vestibular loss is associated with poorer balance and spatial cognition and incident falls,these results will inform the design of interventional trials to prevent falls in AD patients.
  Leader(s): PIGGOTT, DAMANI
    NIH R01AG060825 / (2018-2023)
  PROJECT SUMMARY/ABSTRACTWith effective antiretroviral therapy (ART), life expectancy for HIV-infected persons has markedly improved, yetmarked deficits in survival remain for HIV-infected persons with a history of injecting drugs (PWID). Disparitiesamong PWID have been attributed in part to a shifting spectrum of disease to aging-associated conditionsdriven by persistent inflammation even with ART. Frailty is an important aging-related state of vulnerability tostress, with an increased burden in HIV infection, strongly associated with heightened inflammation, andpredictive of premature mortality and aging-related morbidity among PWID. Injecting drugs itself can increasethe severity of inflammation in HIV. The human gut microbial ecosystem (gut microbiome) critically regulatesinflammation and immunity. Alterations in the gut microbiome (gut dysbiosis) together with associateddisruptions of gut structure and immune integrity constitute an inflammatory-microbiome signature (gutdysbiosis, increased gut permeability, translocation of microbial products, immune activation, heightenedinflammation) linked to adverse aging-associated inflammatory conditions and disease. Proposed is asystematic investigation of the role of HIV infection and injection drug use (IDU) in defining the inflammatory-microbiome signature and determination of the relationship of this signature to frailty. Through assessments ofthe fecal and mucosal microbiome in the AIDS Linked to the IntraVenous Experience (ALIVE) cohort of HIV-infected and epidemiologically comparable HIV-uninfected PWID, we will determine how HIV infection andactive IDU alter microbiome composition and function and the relationship of these changes to inflammationand frailty progression over time. Using a germ free murine model, we will further define the frail humanmicrobial communities and gene products that precipitate inflammation. These studies will facilitate elucidationof gut microbial determinants of frailty among HIV-infected PWID and could significantly inform microbiotamodulation strategies to reduce frailty-associated inflammation beyond ART. Understanding the role of the gutmicrobiome in relation to HIV, injection drug use, and frailty remains a critical next step to reducing the markeddisparities in clinical outcomes among HIV-infected PWID.
    NIH R01AG061786 / (2019-2023)
  PROJECT SUMMARYAlzheimer's disease (AD) is the most common cause of dementia. Underlying pathological and physiologicalchanges related to the onset and progression of AD are believed to emerge several years prior to clinicalmanifestations. Sensory impairments, gait abnormalities, and motor slowing may precede the diagnosis of ADby a decade or more, presenting the exciting possibility that changes in sensorimotor functioning may act asearly noninvasive biomarkers for AD. Previous work by our group has identified links between cognitiveperformance and sensory impairment and gait speed and variability, making them potential preclinical markersof early AD pathology. We propose to use up to 10 years of existing longitudinal data, and ongoing/new datacollection in approximately 1,000 older adults in the Baltimore Longitudinal Study of Aging (BLSA), to examinethe roles of sensory function, gait speed and variability, and free-living measures of daily physical activity (PA)as precursors to cognitive impairment. We will also determine the link between sensorimotor measures andbiomarkers of AD pathology, including A? deposition using [11C]-Pittsburgh compound B positron emissiontomography, brain atrophy using structural magnetic resonance imaging (MRI), Tau and pTau from cerebrospinalfluid, and cognitive performance. We will further utilize the rich data resources of the BLSA to develop aparsimonius prediction model for risk of progression to MCI/AD, and validate its performance in theAtherosclerosis Risk in Communities (ARIC) study. A better understanding of the associations amongsensorimotor changes, subclinical AD pathology, and cognitive performance may elucidate a high-risk phenotypethat is associated with increased risk of poor cognitive outcomes over time and increase our understanding ofthe complex associations among declines in sensory, physical, and cognitive functioning with age. To this end,future intervention studies of AD prevention might screen for sensorimotor impairments as a high-risk phenotypereflective of increased risk for developing AD, which could serve as surrogate outcomes in clinical trials.Moreover, sensorimotor impairments may present feasible and modifiable targets for AD prevention byidentifying critical threshold(s) for implementation of assistive and rehabilitative technologies such as hearingaids, corrective lenses, surgical or pharmacologic procedures to correct hearing and/or vision impairment (e.g.,cataract surgery, cochlear implants), and physical therapy/timing and coordination of movement training tocorrect gait abnormalities.
  Leader(s): WEISS, ROBERT G
    NIH R01AG063661 / (2019-2024)
  People living with HIV infection (PLWH) are living longer but with advancing age experienceaccelerated functional decline (decreased strength, slowed gait, reduced exercise tolerance) and increasedfrailty, as compared to non-infected individuals. The syndromes of functional decline and frailty are associatedwith impaired quality of life, increased vulnerability to superimposed stresses, and the likelihood of prematuremorbidity and mortality. The mechanisms underlying this accelerated dysfunction and disability, however, arepoorly understood. The proposed project examines the contribution of altered skeletal muscle (SM)mitochondrial function and high energy phosphate metabolism to the related, but distinct syndromes of fatigue,exercise intolerance, and frailty often present in older PLWH. Considerable pre-clinical data and our pilotclinical studies using a 31P magnetic resonance spectroscopy (MRS) fatigability test during and following lower-extremity exercise suggest an ?energetic myopathy? as a possible basis for the fatigue and decreasedperformance in older PLWH individuals. However the extent, underlying responsible factors, and functionalsignificance of altered SM mitochondrial bioenergetics in this population have not been characterized. Inaddition, two potential mechanisms responsible for altered SM high energy phosphate metabolism in otherpopulations, increased inflammation and SM lipid accumulation, have not been examined and related tomuscle energetics in PLWH and so these too will be examined. The central hypothesis is that impaired SMmitochondrial energy metabolism, initiated by aging and accelerated in the setting of contemporary HIV, is acentral contributor to the geriatric syndromes of fatigue, exercise intolerance, and frailty in older PLWH. Wepropose to use state-of-the art 31P MRS exercise testing, detailed muscle and whole body compositionmeasures, functional assessments during observed and free-living conditions, and biomarkers of inflammationand immune activation in 200 older (age>=60) women and men derived from four local NIH-sponsored cohortsto address these questions. The specific aims are 1) to define the scope of SM metabolic changes in olderwomen and men living with HIV, 2) to probe whether inflammation, skeletal fat and other underlying factors arerelated to the energetic abnormalities in older PLWH and 3) to determine the functional significance of SMenergetic changes in older PLWH by examining the relationships between the energetic changes and exercisetolerance and other functional assessments as well as the frailty phenotype. Fatigue, exercise intolerance, andfrailty are common in older PLWH and the underlying mechanisms remain poorly understood These novel,timely studies will provide new insights and guide future intervention strategies designed to attenuate orreverse mitochondrial and bioenergetic decline and thereby reduce the personal and societal toll of thesegeriatric conditions in older women and men living with HIV.
    NIH R01DK114074 / (2018-2022)
  ABSTRACTOver 640,000 US adults suffer from ESRD, >95% of whom receive hemodialysis (HD) for the rest of their life oruntil transplantation. Kidney disease and HD significantly impact cognitive function, especially higher-orderexecutive function. Only 13% of HD patients have normal cognition; HD patients experience executive functionimpairment at a rate 3-fold higher than the general population, leading to hospitalization, disability, and death.Studies of older adults suggest that the only effective interventions for preserving executive function arecognitive training (CT) and/or exercise training (ET). These modalities have not been tested for executivefunction preservation in HD patients; even younger HD patients suffer substantial executive functionimpairment and could benefit from these interventions. HD frequency (3 sessions a week) and duration (4-6hours/session) makes HD patients a ?captive audience? for intradialytic CT and/or ET to mitigate executivefunction decline. In preliminary studies, HD patients reported spending most of their time watching TV;intradialytic CT and/or ET could replace these passive activities. In preliminary studies, 87% of nephrologyproviders believed that their patients would be interested in intradialytic CT and 83% believed that theirpatients would be interested in intradialytic ET. Among HD patients, 67% wanted to improve their cognitionthrough CT and 71% wanted to improve their strength and cognition through ET while undergoing HD.To test the feasibility of intradialytic interventions, we conducted a pilot RCT of 20 HD patients, comparingstandard of care to CT or ET; even in this pilot, we found that intradialytic CT and ET preserved executivefunction. As expected, executive function in patients receiving standard of care declined substantially by 3months (difference=47.4 seconds, P=0.006); however, this decline was not seen among those receiving CT orET. Compared with standard of care, the difference in mean change was -46.72 seconds (95% CI: -91.12, -2.31; P=0.04) for CT and -56.21 seconds (95% CI: -105.86, -6.56; P=0.03) for ET. In just 3 months, CT and ETpreserved executive function compared to a striking decline with standard of care.To properly test the impact of intradialytic CT and/or ET, on the executive function decline associated with HD,we propose the following aims: 1) To conduct an RCT to evaluate executive function decline in the setting ofintradialytic CT and/or ET, 2) To quantify the effects of intradialytic CT and/or ET on ESRD-specific clinicaloutcomes, 3) To quantify the effects of intradialytic CT and/or ET, on patient-centered outcomes.Through this RCT, we will learn the impact of two potential non-pharmacological interventions, cognitive andexercise training, in preserving executive function during HD. If successful, this will improve HD outcomes of>640,000 adults with ESRD. For the first time, we will have validated, beneficial activities replace the typicalpassive activities of HD patients. Our findings will be implementable in dialysis centers across the country tohelp reduce the decline in executive function.
    NIH R01DK120518 / (2018-2022)
  ABSTRACT>400,000 older adults (age =55) suffer from end-stage renal disease (ESRD). There has been a 5-foldincrease in the number of kidney transplants (KT) in this age group. Older recipients are a distinct group due toimpaired homeostasis, higher comorbidity burden, and immune system attenuation. These physiologic factorsinfluence older KT recipients? response to immunosuppression (IS) medications, a lifelong treatment.The balance between short-term benefits and long-term adverse outcomes of IS can be challenging in olderKT recipients. Excellent short-term outcomes (1-year allograft survival>95% and acute rejection [AR]<15%) areachieved in younger patients with modern IS, but our preliminary findings suggest that older KT recipients areat 1.5x increased risk of poor IS tolerance. Older KT recipients are also more susceptible to long-term adverseoutcomes associated with the modern IS regimens like infections, malignancy, and new-onset diabetes aftertransplantation (NODAT) resulting in part from an attenuated immune response. Our preliminary findingssuggest that IS regimens with calcineurin inhibitors increase an older recipient?s dementia risk. Yet, ourpreliminary data suggest that IS is not personalized; center practices account for 46% of IS regimen variation.While KT has been found to be cost saving for ESRD patients, the total KT cost is influenced by accumulatinglong-term adverse outcomes of IS in this population. IS is not chosen in a cost-blind environment; if the risksand benefits are similar, then cost-effectiveness is an important adjunct to IS regimen choice. The risks,benefits, and cost-effectiveness for an older KT recipient cannot simply be inferred from studies of youngerrecipients or from clinical trials that largely excluded older recipients. A comprehensive dataset with all keydata elements is needed to develop personalized IS for older KT recipients.To develop a personalized approach to IS for older KT recipients, we will integrate 3 novel datasets with>78,800 older KT recipients KT recipients (2005-2019): (1) national data from the Scientific Registry ofTransplant Recipients (SRTR); (2) Medicare claims to identify post-KT outcomes and costs; (3) pharmacyclaims to identify not only IS agents used but also novel lab data of metabolized IS levels (for 14,000 olderrecipients). Using this integrated data, we will: 1) compare the effects of IS regimens on efficacy, morbidity,and mortality for older KT recipients; 2) develop Markov models and calculate cost-effectiveness for ISregimens for older KT recipients; and 3) generate individualized reports of predicted efficacy, morbidity, andmortality along with IS regimen cost for practitioners to use for the clinical counseling of older KT recipients.Our goal is to provide evidence and communication tools to help move the field of transplantation away fromcenter-based protocols for IS to personalized IS for older KT recipients. The ability to predict trade-offs in ARand graft survival against long-term adverse outcomes for specific IS regimens in older KT recipients will allowpatients and physicians to customize IS choices in a cost-effective and more informed manner.!
  Leader(s): ARKING, DAN E
    NIH R01HL131573 / (2016-2021)
  DESCRIPTION (provided by applicant): Coronary heart disease (CHD) continues to be a leading cause of mortality and morbidity worldwide. Age-related decline in mitochondrial function is a novel mechanism that may underlie multiple biological changes that increase the risk of atherosclerosis and CHD in the general population. We determined mtDNA copy number (mtDNA-CN) in whole blood, one of the primary relevant biological tissues for atherosclerosis, in 16,401 participants from 2 prospective community-based cohorts, the Atherosclerosis Risk in Communities (ARIC) study and the Cardiovascular Health Study (CHS). mtDNA-CN was significantly associated with age and was a robust predictor of overall mortality. The age-, sex-, and collection site-adjusted hazard ratio comparing mortality in the lowest to the highest quintiles of mtDNA-CN was 1.47 (P=4.24x10-14). Furthermore, lower mtDNA-CN at baseline was associated with an increased incidence of CHD (hazard ratio for a 1-SD decrease in mtDNA-CN 1.21, P=3.89x10-19) independent of traditional CHD risk factors. To establish the role of mtDNA-CN in CHD, we first propose to validate our findings in two additional longitudinal cohorts, the Multiethnic Study of Atherosclerosis (MESA) and the Rotterdam Study (RS), and together with ARIC and CHS, combine the rich clinical and genetic data available from these cohorts to comprehensively evaluate the role of mtDNA-CN in CHD, including determining whether mtDNA-CN is associated with subclinical atherosclerosis or with the development of traditional CHD risk factors. Second, we will use DNA from the baseline and 2 follow-up visits in ARIC to assess how longitudinal changes in mtDNA-CN influence future CHD risk. Third, we will conduct a GWAS, using both common and rare variants, to identify genetic determinants of mtDNA-CN in ~90,000 participants from ARIC, CHS, MESA, RS and additional CHARGE cohorts. Associated genetic variants will be used to determine whether decreased mtDNA-CN is causative for CHD using Mendelian randomization. Finally, we will functionally identify, characterize, and determine the downstream consequences of GWAS-identified genes that alter mtDNA-CN through a combination of mitochondrial functional assays, RNAseq, and computational network/pathway analysis. Computational analysis will identify shared patterns of dysregulation, interactions between regulatory genes, and pathways responsible for specific physiological changes. Given the preliminary data suggesting widespread phenotypic variation associated with altered mtDNA-CN, understanding the regulatory network associated with mtDNA-CN will be critical to elucidating the mechanisms that both regulate mtDNA-CN and/or drive the downstream phenotypic consequences. This proposal brings together unique expertise in GWAS, cardiovascular health, and mitochondrial function, and capitalizes on 4 well-established cohorts with ~5,800 cases of prevalent and incident CHD in over 20 years of follow-up, to elucidate the causal role of mtDNA-CN in CHD. More importantly, mtDNA-CN represents a potential novel etiology of CHD not captured by any established or proposed CHD risk factors.
    NIH R21AG060243 / (2019-2021)
  ABSTRACTThe goal of the proposed project is to determine if estimates of cognitive impairment and Alzheimer?s diseaseand related dementias (ADRD) are biased among older adults with hearing or vision impairment. The impact ofthis this potential bias could be significant, as over 55% of Americans 60 years and older have either hearingor vision impairment. The specific aims of this research are to: (1) Identify and adjust for potential bias inestimates of cognitive function due to hearing or vision impairment, and (2) Quantify the across-study variationin methods used to collect and analyze cognitive data in older adults with hearing or vision loss. For aim 1,data from the Baltimore Longitudinal Study on Aging (BLSA) and the Atherosclerosis Risk in CommunitiesStudy (ARIC) will be used, as both studies used standard measures of hearing, vision, and cognition. Analyseswill use cross-sectional data and an item response theory (IRT) modeling approach to: (1) disentangle the trueeffect of sensory impairment on cognitive function from the potential bias that sensory impairment may have oncognitive test performance; and (2) if present, correct for this potential bias and re-estimate cognitiveimpairment and ADRD prevalence. This aim will test the hypothesis that, after accounting for the level ofcognitive ability (indexed using historical, longitudinal cognitive test data assessed in the BLSA and ARIC inyears prior to the development of sensory impairment), older adults with hearing impairment systematicallyperform worse on cognitive tests that rely on hearing stimuli, and that older adults with vision impairmentsystematically perform worse on cognitive tests that rely or vision stimuli, compared to participants withoutthese impairments. Aim 2 includes three steps: (1) Systematically identifying longitudinal cohort studies ofolder adults that collect cognitive testing data; (2) Administering a survey collecting information on studyprotocols and perform protocol abstraction to assess how cognitive function is measured and analyzed in olderadults with sensory loss; and (3) Comparing the data abstracted from these protocols to assess the variationacross studies in: (a) the assessment of hearing or vision, (b) exclusions from cognitive testing and analysesbased on sensory impairment, (c) accommodations for sensory loss made during cognitive testing, and (d)adjustment for sensory loss in the analysis of cognitive data. We hypothesize that fewer than 50% of cohortstudies surveyed use protocols for collecting and analyzing cognitive data in older adults with hearing or visionloss. The overall results of this project have crosscutting impact, as correct estimates of the prevalence andincidence of ADRD are paramount for public health planning, and etiologic research aimed at identifyingapproaches to reduce ADRD risk. This work will support: (1) a U13 to develop standard protocols/tools forcollecting and analyzing cognitive data in older adults with sensory impairment, and (2) an R01 to implementmethodological approaches to ?adjust? estimates of cognitive function for sensory impairment using longitudinaldata, and a large scale effort to re-calculate these estimates.
    NIH R42AG054322 / (2017-2021)
  The metabolic syndrome (MetS) is a cluster of factors that increases the risks for cardiovascular disease, type 2diabetes mellitus, and mortality, and currently affects > 40% of US adults. MetS is associated with endothelialdysfunction, decreased circulating endothelial progenitor cells (EPCs), and a pro-inflammatory state. We havemade the exciting discovery that therapy with allogeneic mesenchymal stem cells (MSCs) restores endothelialdysfunction and circulating EPCs towards normal the levels, and reduces markers of inflammation. Endothelialfunction represents a key driver of cardiovascular morbidity and mortality in MetS, and as such, restoringendothelial function could lead to clinical benefits in this patient population. We will conduct a clinical trial usingLongeveron-produced allogeneic mesenchymal stem cells (LMSCs) delivered to subjects with MetS. In PhaseI of this study, we will perform a dose-escalation Safety Run-In to first establish safety of LMSC therapy insubjects with MetS. After a safety review and approval from an independent data safety monitoring board(DMSB), Phase II of this Fast-Track Study will commence. This will entail a Randomized, Double-Blinded,Placebo-Controlled Phase on 40 subjects with MetS. The following specific aims will be examined. Specific Aim #1: To test the hypothesis that LMSCs are safe to intravenously-administer to subjects with MetS. We will examine for incidence of treatment-emergent serious adverse events (TE-SAEs); blood chemistry, hematology, coagulation, and urinalysis; and alloimmune reaction and T and B cell subsets to examine levels of immune activation. Specific Aim #2: To test the hypothesis that intravenously-administered LMSCs will improve endothelial dysfunction and increase circulating EPCs in subjects with MetS. We will examine endothelial dysfunction using flow-mediated vasodilation (FMD), and circulating EPCs by colony assays and flow cytometry. Specific Aim #3: To test the hypothesis that intravenously-administered LMSCs will improve systemic markers of inflammation in subjects with MetS. We will use ELISA to examine panels of inflammatory markers. Specific Aim #4: To test the hypothesis that intravenously-administered LMSCs will lead to clinical improvement in subjects with MetS. We will examine for changes in glucose control (hemoglobin A1c, fasting glucose, fasting insulin, HOMA), lipid profile (HDL, LDL, triglycerides, cholesterol), blood pressure and cardiac function, physical performance, and subject quality of life.We anticipate that the results of this study will lead to a much needed therapeutic for subjects with MetS.Longeveron is positioned to rapidly advance this program to a pivotal phase III trial if the results prove positive,and to bring this technology to market.
  Leader(s): ROTH, DAVID L
    NIH RF1AG050609 / (2016-2021)
  DESCRIPTION (provided by applicant): The growth of the older adult population, increased prevalence of many disabling conditions, and high costs of institutional care are placing heavy demands on family members to provide informal caregiving services to adults with disabilities. Many previous studies have characterized caregiving as a chronic stress experience associated with poorer health and biomarker indicators of inflammation and compromised immunity. However, the vast majority of existing studies have been based on convenience samples and cross-sectional comparisons, and relatively few studies of caregiving have used population-based samples or prospectively examined transitions into the caregiving role within individual participants. The proposed study will identify individuals who have transitioned from a non-caregiving role into a family caregiving relationship while participating in a large, prospective, epidemiological study. The REasons for Geographic And Racial Differences in Stroke (REGARDS) project is an ongoing epidemiological study with over 17,800 active middle-aged and older participants as of May 31, 2015. Pilot data suggest that over 1,200 of these participants have transitioned from a non-caregiving role at REGARDS baseline (8-12 years ago) into an informal family caregiving role at the present time. Serum samples were collected and stored from an initial REGARDS in-home assessment, and follow-up serum samples are now being collected as part of a 2nd REGARDS in-home assessment. We propose to identify and enroll 300 participants from REGARDS who have transitioned into a family caregiving role between these two REGARDS in-home assessments and who continue to be caregivers at the 2nd in- home assessment. We will compare these caregivers to 300 individually-matched non-caregivers. A multi- step matching and covariate-adjustment procedure will be used to control for many potential confounding variables including demographics, socioeconomic status, prior health status, and family relationship factors. Changes over a 10-year period on a set of inflammatory biomarkers (e.g., CRP, IL-6, d-dimer, TNF-R1), health biomarkers (e.g., lipids, HgA1c), and self-reported health outcome measures (e.g., health-related quality of life, depressive symptoms, health behaviors) will be compared between incident caregivers and matched non- caregivers. Important subgroup comparisons will include a focus on the 30% of caregivers who are expected to be caring for a family member with Alzheimer's disease or another form of dementia. The proposed Caregiving Transitions Project will be the first population-based study ever conducted on the impact of transitioning into a caregiving role on serum-based biomarkers and other important health-related outcomes. Critical new knowledge will be provided for better understanding the health impact of informal caregiving, which will be an even more critical healthcare resource in the coming years.
    NIH RF1AG055151 / (2017-2022)
  PROJECT SUMMARY/ABSTRACTRecent estimates suggest that almost two-thirds of the individuals diagnosed with Alzheimer?s disease [AD]are women. The National Institutes of Health and the Alzheimer?s Association have highlighted the critical needto understand sex differences in the risk factors and clinical progression of AD. Reproductive and hormonalfactors may be particularly important for women. Hypertensive pregnancy disorders [HPD] have beenassociated with subjective cognitive complaints or white matter lesions five to ten years after the HPD, but thelong-term effects of HPD on brain structure and cognitive function are unknown. Population-based studies areneeded to assess the contribution of HPD and subtype (i.e., preeclampsia) to the risk of cognitive decline, AD,and neuroimaging measures of amyloid-beta [A?], neurodegeneration, and cerebrovascular pathologies.Further, observational studies and clinical trials have examined the effects of early menopause (natural orsurgically-induced) and hormonal therapy [HT] on the risk of AD and other dementias. However, it is notcurrently known whether the effects of early menopause, HT use, and their interactions with APOE genotype,are associated with specific type(s) of brain pathology (i.e., A?, neurodegeneration, cerebrovascular) becausemulti-modal imaging studies have not been conducted. The overall aims of this proposal are to elucidate theimpact of two hormonally-related sex-specific factors for women, pregnancy (e.g., number of pregnancies,HPD) and menopause (surgically-induced or natural), on the risk of cognitive decline, AD, and neuroimagingmeasures of A?, neurodegeneration, and cerebrovascular pathologies. Because the literature and ourpreliminary data suggest that risk scores for cardiovascular disease and dementia are less predictive in womencompared to men, we also propose to incorporate these sex-specific factors to develop a more predictive riskscore of mild cognitive impairment and AD for women. To accomplish our goals, we will utilize two existinginfrastructures at the Mayo Clinic: the Mayo Clinic Study of Aging (MCSA; U01 AG006786) and the RochesterEpidemiology Project medical records-linkage system (REP; R01 AG034676). Using the REP, we will newlyabstract information on pregnancy and menopause for 2,370 women enrolled in the MCSA. Because fewstudies assessing pregnancy and menopause have also adjusted for putative confounding variables, we willalso abstract this data using the REP to determine whether these sex-specific conditions are independentpredictors of cognitive decline, AD, and neuroimaging measures of specific brain pathologies. Successfulcompletion of these aims will be a key step towards understanding whether these sex-specific factors areassociated with the risk of AD in women, to understanding whether these factors are related to a specific typeof brain pathology (i.e., A?, neurodegeneration, cerebrovascular), and to developing a better risk score forpredicting cognitive impairment, dementia, and specific brain changes in women.
    NIH U01AG047837 / (2014-2020)
  DESCRIPTION (provided by applicant): The public health burden of falls in older persons is substantial. Several lines of evidence suggest that vitamin D supplements might substantially reduce the risk of falls, potentially by > 25% in persons with low serum 25-hydroxyvitamin D [25(OH)D] levels. However, trial evidence is insufficient to guide policy. The proposed study is a seamless, two stage, Bayesian response-adaptive randomized trial for dose-ranging and efficacy confirmation. The trial is designed to identify the best overall dose of vitamin D supplementation and confirm the level of efficacy of that dose for fall prevention. Participants wil be community-dwelling adults, aged 70+ (~40% black, ~60% women), with a baseline serum 25(OH)D level of 10-29 ng/ml, who report at least one fall in the prior year. After an initial pilt phase to evaluate recruitment strategies and finalize data collection procedures, participants willbe randomly assigned to 1 of 4 vitamin D3 (cholecalciferol) test doses: 200IU, 1000IU, 2000IU and 4000IU/d. Participants will take their assigned pills for 2 years with extended follow-up off therapy for 1 more year. Stage 1 of this design will select the best dose of vitamin D for prevention of falls over a 6m follow-up period. Participants in the control (200IU) and best dose group will continue seamlessly into Stage 2 with additional recruitment and continued follow-up of all participants. The principal outcome (Stage 2) is time to first fall (or death) over 2 years f therapy. Secondary outcomes are fall rates, patterns of falling, gait speed, balance, muscle strength, frailty, SPPB score, and, in a sample of participants, 400m walk time and accelerometry. Falls will be ascertained from fall calendars completed daily by participants. Follow-up visits will occur at 3, 12, 24 and 36m. Subgroups with potential for differential benefitfrom vitamin D supplementation are pre- specified as: a) race (blacks vs others), b) baseline vitamin D levels (10-19 vs 20-29ng/ml), and c) frailty status (frail, pre-frail, not frail). Our prven capacity to recruit a diverse population, including large numbers of blacks, allows us to test the effects of vitamin D supplementation in key subgroups. Strengths of the study include a team of interdisciplinary investigators who have vast experience and an exceptional track record in the design, conduct, analysis and dissemination of clinical trials, many of which have guided policy. The investigative team includes individuals with expertise in vitamin D metabolism, endocrinology, geriatrics, assessment of physical function and falls, biostatistics, epidemiology, central laboratory procedures, adaptive designs, community engagement, and recruitment. Building on our record in previous community-based trials, we expect that trial results will be timely, rigorous, and directly relevant to public health guidelines and will immediately influence fall prevention policies related to vitamin D supplementation in older persons.
    NIH U01AG057545 / (2017-2022)
  PROJECT SUMMARYAlzheimer?s disease (AD) is the most common cause of dementia. Underlying pathological and physiologicalchanges related to the onset and progression of AD are believed to emerge several years prior to clinicalmanifestations. Gait abnormalities and motor slowing typically precede the diagnosis of AD by a decade ormore, presenting the exciting possibility that changes in gait may act as early noninvasive biomarkers for AD.Previous work by our group has identified key markers of impending and/or accelerated gait speed declinebased on physiological measures of the energy cost of slow walking, peak energy capacity, and quantities andpatterns of objectively measured free-living physical activity (PA), making them potential preclinical markers ofearly AD pathology. We propose to use 8 years of existing longitudinal data, and ongoing/new data collectionin nearly 1,000 older adults in the Baltimore Longitudinal Study of Aging (BLSA), to examine the roles ofaltered energy reserves, and reduced and fragmented daily PA as precursors to clinical markers of Alzheimer?sdisease and neuronal injury, which include A? deposition using [11C]-Pittsburgh compound B positron emissiontomography, brain atrophy using structural magnetic resonance imaging (MRI), and cognitive performance. Wewill also explore potential vascular mechanisms linking energy reserves and PA to these outcomes, includingcerebral blood flow, ankle brachial index, and pulse wave velocity, as well as the role of mediating or modifyingfactors such as inflammation and the apolipoprotein E genotype. The BLSA is a continuously enrolled cohortstudy of aging that already contains repeated measures of cognition and adjudication of cognitive status, inwhich a subset completes repeated MRI and PiB PET scans. Importantly, our preliminary cross-sectional datafrom the BLSA indicate strong associations among energy reserves, cognitive performance, b-amyloid burden,and diurnal patterns of daily PA. We propose to investigate the longitudinal associations among thesevariables to identify physiological thresholds of poor energy reserve and reduced and fragmented patterns ofdiurnal PA as early precursors to the onset and progression of AD pathology. A better understanding of theassociation between energy reserves/PA, subclinical AD pathology, and cognitive performance may elucidatea physiological threshold of diminished energy reserve that is associated with increased risk of poor cognitiveoutcomes over time, and increase our understanding of the complex association between declines in physicaland cognitive functioning with age. Moreover, uncovering patterns of daily free-living PA most commonlyassociated with this threshold will help define a phenotype of reduced and/or fragmented PA that signifiesimpending emergence and progression of AD. Given the proliferation of wearable devices to monitor PA in theconsumer and research markets, identifying changes in PA consistent with the development of AD pathologycould provide evidence for future wide-scale screening for early detection of persons at high risk of AD.
  Leader(s): WIRTZ, DENIS
    NIH U01AG060903 / (2018-2023)
  AbstractAlterations in the nuclear protein lamin and associated structures in the nucleus have beenidentified as a source of nuclear morphology changes that markedly impact overall cellularfunction. These changes in nuclear morphology are thought to drive molecular changes thatinfluence a wide range of aging-related phenotypes and chronic disease states. Importantly, wehave recently used high-throughput measurements of nuclear morphology to identify outstandingbiomarkers of chronological age. We hypothesize that these age-related changes in nuclearmorphology are highly correlated with chronological age in healthy individuals, and that a specificage-related biological change in lamin underlies this phenomenon. Building on our priordevelopment of these high-throughput and accurate measures of nuclear morphology, we proposehere to further develop this biological discovery and technology as a valid and reliable biomarkerof aging-related biological mechanisms. We hypothesize that changes in nuclear morphology canbe rapidly measured and that age-related alterations correlate with aging-related phenotypes anddisease states independently of chronological age, consistent with a measure of cellular biologicalage. To test these hypotheses and move results toward clinical utility, we have assembled a highlysynergistic, interdisciplinary team propose the following specific aims:Aim 1. Using our validated single-cell technologies, we will develop a mechanistic understandingof how descriptors of nuclear morphology in human dermal fibroblasts and B-lymphocytes arerobust biomarkers of aging in healthy individuals. Aim 2. Establish the accuracy and precisionwith which our proposed biomarkers identify chronological age for individuals with varyingdemographic, behavioral, and health characteristics. Aim 3. We will examine the strength withwhich morphological biomarkers discriminate individuals with adverse phenotypes and outcomesof aging, and at risk for the development of these, from healthy older adults, above and beyondchronological age.
  Leader(s): PUNJABI, NARESH M
    NIH U34DK120051 / (2018-2020)
  ABSTRACTThis application is in response to the National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK)program announcement PAR-18-423 for implementing a multi-center randomized clinical trial to test thehypothesis that treatment of obstructive sleep apnea (OSA) with positive airway pressure (PAP) therapy inpeople with prediabetes will reduce the progression to type 2 diabetes mellitus (T2DM). For the U34 planningphase, we have established a network of ten clinical sites guided by an experienced team of investigators withan extensive background in conducting multicenter randomized trials. To provide leadership for the trial, we havebuilt a consortium of exceptional investigators and include the following: (a) The Center for Clinical Trials at theJohns Hopkins University Bloomberg School of Public Health to establish a central Data Coordinating Center;(b) The Clinical Research Center for Sleep at the University of Pennsylvania to organize a Sleep Reading Centerfor home sleep testing; (c) a PAP adherence core; (d) a weight loss core at Brown University; and (e) a bioassaycore laboratory at the University of Minnesota. In this application, we describe our record of conducting andmanaging multi-center research programs; strategies for assembling and managing a complex research network;and the talented team of coinvestigators with expertise in pulmonary and sleep medicine, endocrinology, clinicaltrials methodology, weight loss interventions, epidemiology, and biostatistics. The Specific Aims for the U34planning period are to: (1) refine the organizational structure and the leadership plan for the trial; (2) finalize thestudy protocol and associated source documents, provide clinical site training, and develop a manual ofoperations for the Sleep Reading Center, the PAP Adherence Core, and the Clinical Sites; (3) construct a datamanagement system, establish methods of data quality assurance, and develop a manual of operations for theDCC; (4) outline plans for data analysis and handling of study-related publications and presentations; and (5)obtain human subjects and regulatory approvals from a central IRB. The U34 consortium will develop a U01grant application for a multi-center clinical trial on the utility of PAP therapy in preventing T2DM in people withOSA and prediabetes. The Specific Aims of the U01 trial are as follows. Aim 1: To determine whether, in peoplewith prediabetes and moderate-to-severe OSA, the addition of PAP therapy to a lifestyle intervention isassociated with lower rate of progression from prediabetes to T2DM. Aim 2: To assess whether, in people withprediabetes and moderate-to-severe OSA, the addition of PAP therapy to a lifestyle intervention program isassociated with greater improvements than with lifestyle intervention alone in: (a) insulin sensitivity, as assessedby the homeostasis model assessment index (HOMA-IR); (b) hemoglobin A1c modeled as a continuous variable;(c) sympathetic nervous system activity; (d) inflammatory markers including C-reactive protein (CRP) andinterleukin-6 (IL-6); (e) resting blood pressure; (f) body weight and measures of central obesity (i.e., waistcircumference); and (g) OSA-related symptoms and quality of life.
  Leader(s): KLEIN, SABRA L.
    NIH U54AG062333 / (2018-2023)
  SEX AND AGE DIFFERENCES IN IMMUNITY TO INFLUENZA (SADII) SUMMARYThe NIH Office of Research on Women?s Health (ORWH) should support a Specialized Center of ResearchExcellence (SCORE) on sex differences in influenza immunity because despite having antivirals and vaccines,influenza remains a significant public health threat, causing approximately 100,000 hospitalizations, 30,000deaths, and approximately $7 billion in lost productivity in the United States, alone. Sex and age are emergingas two host variables that significantly impact the pathogenesis of influenza virus infection and responses toinfluenza vaccines. The Sex and Age Differences in Immunity to Influenza (SADII, pronounced sade) SCOREwill leverage the internationally recognized research, resources, and educational opportunities at JohnsHopkins University to transform women?s health and impact the development of and policy decisions aboutinfluenza vaccine programs, including universal influenza vaccines. The overarching hypothesis being testedthrough the SADII SCORE Research Projects is that female-biased vaccine-induced immunity to influenzaviruses is age-dependent and reflects both hormonal and genetic differences between the sexes that impactimmune responses (i.e., both effector and memory) to influenza vaccine antigens. SADII will bring togetherinvestigators focused on 1) seasonal influenza vaccination in an existing age and sex stratified humanpopulation; 2) animal models that can test hypotheses and mechanisms of action that are inferred from studiesin human populations; and 3) the contributions of age, frailty, sex, and gender to vaccine outcomes usingquantitative and qualitative statistical models. By using the combined expertise in our research groups, SADIIis uniquely positioned to identify the biological basis behind sex and age differences in immune responses toinfluenza vaccination and disseminate those findings to the broader research, clinical, and public healthcommunities. The overarching mission of the SADII SCORE will be achieved through the following SpecificAims: 1) To provide leadership and oversight of the SADII SCORE and collaboration with other entities atJohns Hopkins and elsewhere to develop a translational research program focused on sex and age differencesin immunology and infectious diseases; 2) To systematically evaluate sex differences in vaccine-inducedimmune responses across the life course using translational approaches involving human studies andmechanistic animal models; and 3) To meet the career enhancement needs of diverse translational scientistsstudying sex differences at Johns Hopkins and beyond. We are prepared to transform women?s health, sex,and gender research into a signature initiative at Johns Hopkins and in the fields of microbiology andimmunology.
    NIH UH3AG056933 / (2019-2022)
  Project SummaryWhen confronted with a major physical stressor, some older adults are able to recover, with minimal decline,their physical and cognitive function, while others suffer precipitous, irreversible declines in function. This is thecentral notion behind resiliency. Little is known about the intrinsic (e.g., physiologic and molecular processes)and extrinsic (e.g., health behaviors) factors that impact resiliency. A two-phase study is proposed here toaddress this gap in our understanding. In phase 1, data will be generated to characterize age-related changesin physical resiliencies, their determinants, and their outcomes. Phase 2 will involve construction and validationof measures of resiliency; assessment of their predictive and clinical value; and investigation of age-relatedbiological mechanisms determining specific resiliencies.Phase 1 Specific Aims:1. To define, develop and refine phenotypic measures of resiliency responses to three pre-defined physical stressors: hip replacement surgery, initiation of hemodialysis, and bone marrow transplantation for hematologic malignancy.2. To develop and pilot test candidate indicators of physical resiliency to include static and dynamic, as well as global and stressor-specific, measures.3. To identify pre-stressor determinants of resilience, including measures of disease states, psychosocial factors, and molecular measures, and to characterize their measurement and statistical properties.4. To synthesize data developed in Aims 1-3 to inform the design of Phase 2 studies.Phase 2 Specific Aims:1. For each of clinical stressor to be studied: To build and evaluate assessments of resiliency incorporating measures identified in phase 1. Promising candidate measures will be cross-validated and their accuracy in predicting short- and long-term resilient stressor response rigorously characterized. The relative predictive value of global vs. specific, static vs. dynamic, and solely EHR-based versus broader resiliency measures will be assessed.2. To characterize and assess age-related biological mechanisms that contribute to resilience or lack thereof that are specific to each clinical stressor, as well as mechanisms that are common across three specific physical stressors in older adults.3. In preparation for the conduct of intervention studies: to cross-validate measures of resiliency at an external institution and to design pilot studies of strategies to bolster resiliencies based on clinical findings and biological mechanisms identified in Phase 1.
  C. PILOT/EXPLORATORY PROJECTS (5 Pilot Projects Listed)
1. Project Title: Pilot Behavioral Intervention to Address Pain and Frailty in Older African-American Women
  Leader: Janiece Taylor, PhD, RN, Mary Catherine Beach, PhD; Sarah L. Szanton PhD, ANP, FAAN, Roland J. Thorpe Jr., PhD

Older African American women are crucial to target for intervention not only because of their heightened frailty prevalence, but because they are at higher risk of pain than other racial/ethnic groups and African American men and have exacerbated relationship and outcomes of frailty and pain. They often experience difficulties communicating with health care providers, moreover, that may interfere with treatment of symptoms related to pain and frailty: Communication intervention has well documented potential to lessen these difficulties and result in better disease management. Specific aims of this study are: 1) To pilot a tailored behavioral activation intervention focused on improving frailty, chronic pain, and depressive symptoms among community dwelling older African American women and collect summary data needed to design a confirmatory intervention trial. Strategies will be non-pharmacologic and aim to improve communication, physical activity and education. 2) To determine a) feasibility and acceptability of the intervention b) if strategies and evaluation techniques were appropriate. 

2. Project Title: Exploratory Study of Metabolomics Energy Signatures in Frailty
  Leader: Anne Le, MD, Reyhan Westbrook, PhD

Building on a small PES awarded to Drs. Le and Westbrook that utilized a frail mouse model previously characterized in RC-2, altered metabolomics signatures were identified that suggest that TCA cycle processes are a component of dysregulated energy utilization in frailty. Given this background, we hypothesize that specific patterns of altered energy metabolites linked to glucose metabolism through mitochondrial bioenergetics, biosynthesis, and redox homeostasis pathways can help to distinguish frail from non-frail older adults, and that the circulating concentrations of metabolites related to glucose metabolism are measurably different between frail and non-frail older adults. Utilizing research resources from all three resource cores, and Dr. Le’s established metabolomics measurement infrastructure (Metabolomics facility) and expertise in energy metabolism measurement, the following specific aims were proposed: 1) To utilize metabolomics measurement to reconstruct the relevant metabolic pathways of glucose metabolism related to bioenergetics, biosynthesis, and redox homeostasis, and determine differences between frail and non-frail participants, and 2) To identify the most promising biomarkers for a frailty-related energetic signature and plan for a future targeted validation study of diagnostic utility and biological discovery. 

3. Project Title: Association between Sleep Deficiency and Frailty: What harms most?
  Leader: Naresh Punjabi, MD, PhD, Jiawei Bai, PhD

Epidemiologic surveys show that at least 50% of adults over 65 years in age have sleep-related complaints. Sleep disturbance has been associated with neurohormonal, circadian, and homeostatic alterations: As many such changes have been evidenced by this OAIC and others to also underlie frailty, it reasonable to expect interconnections between sleep quality and frailty. We hypothesize that disordered sleep heightens risk for frailty onset and believe that intervention to improve sleep can prevent or buffer frailty. Prior studies indicate that poor sleep quality is associated with frailty. These predominantly have assessed sleep, however, by either self-report or relatively crude summaries (e.g. time in sleep states) of actigraphy or polysomnography data. This project uses data from the community-based Sleep Heart Health Study (SHHS) to extract power spectral “curves” summarizing the history of the overnight sleep EEG, by functional principal components analysis (fPCA), and identify sleep EEG signatures highly associated with frailty prevalence, incidence and transitions, and vice versa. 

4. Project Title: PCSK9 Links Age and Frailty Inflammation to Endothelial Cell Dysfunction
  Leader: Thorsten Leucker, MD, PhD, Gary Gerstenblith, MD.

One of the most significant aspects of aging is the marked increase in mortality and significant lifelong disability due to coronary vascular and cerebrovascular disease respectively. There is heterogeneity in that risk with a significant increase in older individuals with frailty and those with the prediabetes, both of which are increased with age and independently associated with vascular disease. Many preclinical and clinical studies indicate that inflammation is a common predisposing factor but the link between inflammation and vascular disease in older adults and particularly in those with frailty and pre-diabetes is not well characterized. Decreased endothelial cell (EC) production and release of nitric oxide (NO), which has potent anti-atherosclerotic effects is a driver of the development and progression of atherosclerotic vascular disease. Beyond its role in cholesterol homeostasis, proprotein convertase subtilisin/kexin type 9 (PCSK9, is associated with the future risk of cardiovascular diseases. Laboratory studies of isolated ECs demonstrate that inflammatory stimuli increase EC PCSK9 and, in separate experiments, that increased PCSK9 decreases endothelial nitric oxide synthase (eNOS) and NO bioavailability, decreases which indicate EC dysfunction independent of low-density lipoprotein cholesterol (LDL-C).


This research will examine whether PCSK9 links proinflammatory stimuli with EC dysfunction by studying in vivo endothelial- dependent vascular function and in vitro basic studies of ECs. A comparison of the in vivo and in vitro results will also provide information regarding the extent to which vascular dysfunction in the older groups is related to systemic, circulating factors and to mitochondrial dysfunction. In addition to association, we will examine causality by using PCSK9 targeted small interfering RNA in the above basic studies. The significance of the research to the field of aging, therefore, is the opportunity it offers to understand whether EC PCSK9 is one mediator of the known cardiovascular risk associated with inflammation in older individuals, which then would provide a target of intervention as PCSK9 antibodies are available for clinical use.

5. Project Title: Daily physical activity patterns and the modifying role of inflammatory markers in frailty
  Leader: Amal Wanigatunga, PhD, MPH, Jennifer A. Schrack, PhD, Lawrence J. Appel, MD, MPH, Dr. Robert H. Christenson, PhD

Frailty is a common medical syndrome of increased vulnerability in adults aged 70 years and older that is often accompanied by low daily physical activity (PA) and high chronic inflammation. Currently, the method by which low PA is quantified and defined relies on coarse measures of self-reported time spent in a few daily activities, leaving a large knowledge gap regarding the true manifestation of PA decrements in frailty. Moreover, chronic inflammatory markers such as interleukin-6 (IL-6) and C-reactive protein (CRP) have been linked to components of frailty, including high fatigability and functional decline, making it plausible that degradation of daily PA patterns may be connected to rising circulation of both IL-6 and CRP. This warrants further investigation into inflammation as a possible underlying mechanism connecting detailed measures of PA and the onset and progression of frailty with aging. Findings from such investigation would lay the groundwork towards building the clinical utility of measuring physical activity in non-laboratory, community-dwelling settings to detect and intervene on trajectories towards frailty and accelerated aging in ever-expanding older adult populations.


The proposed research aims to examine (1) whether total daily PA and patterns of daily PA accumulation differ by frailty status (non-frail, pre-frail, and frail), and (2) whether chronic inflammation modifies this association. We hypothesize that free-living PA patterns are deteriorated and diminished in those who exhibit pre-frail and frail phenotypes, compared to non-frail individuals. Further, we hypothesize that these sophisticated measures of PA are sensitive to rising chronic inflammation (IL-6 and CRP) typically present in frail older adults. The proposed research provides an exciting opportunity to use cutting-edge methods to extract unique patterns of PA accumulation from objectively measured PA and assess whether greater deterioration in these PA patterns are seen with higher inflammation and frailty states. 

  D. DEVELOPMENT PROJECTS (3 Development Projects Listed)
1. Project Title: Characterizing Longitudinal Interdependence among Multiple Multi-System Dysregulation (MSD) Biomarkers
  Leader: Karen Bandeen-Roche, PhD

MSD has long been hypothesized as a determinant of frailty but rarely has been assessed other than through counts of dysregulated systems taken cross-sectionally. This DP lays groundwork for its study as a dynamic process through specific aims to: (1) Characterize longitudinal interdependence among biomarkers of systems thought to underlie frailty; (2) Derive summary measures of longitudinal dysregulation in multiple systems; (3) Validate measures resulting from (2) by assessing their associations with frailty and mortality, and whether they are stronger predictors of frailty than the count measure.  

2. Project Title: Development of an aptamer to selectively target the angiotensin autoantibody
  Leader: Peter Abadir, MD, Neal Fedarko, PhD

Prior RC-2 studies have focused on the angiotensin system as a potential contributor to frailty and as a target for intervention development. A recent publication in part supported by RC-1, 2, and 3 described agonistic autoantibodies (aAbs) against the Angiotensin Type 1 Receptor (AT1R) whose serum levels increased in older
adults and were associated with inflammatory cytokines, hypertension, adverse health outcomes and frailty. Aptamers are oligonucleotides that bind their targets with high affinity and specificity and are currently used for
in vitro diagnostics, biosensor technologies, and targeted therapies. RNA aptamer agents can be engineered as allosterically modulated ribozymes - where binding to the targeted aAb activates the selfcleaving ribozyme domain and a fluorescence quencher is removed, yielding a fluorescent signal. This DP seeks to develop the lead agents necessary for creating a unique high throughput diagnostic/prognostic quantitative assay.  

3. Project Title: Development and Validation of Age-, Sex-, and Race-specific Thresholds for the Physical Frailty Phenotype Criteria Among Kidney Transplant Candidates and Recipients
  Leader: Nadia M. Chu, PhD

The physical frailty phenotype (PFP) is a measure of frailty recognized for its clinical utility. Frailty, based on the current PFP criteria, is common and associated with adverse outcomes among adult kidney transplant (KT) candidates and recipients. However, older and African American candidates/recipients are disproportionately impacted by frailty. Despite differences found between age and racial subgroups in KT, recent studies in community-dwelling older adults suggest that these variations may be partially due to measurement error, such that PFP criteria may assess frailty differentially between subgroups, resulting in potential misclassification. Given that KT populations comprise of a wider age-range and a greater prevalence of males and minority groups, this potential misclassification of individuals as frail could make it especially challenging for clinicians to identify candidates that can withstand surgery and benefit from KT. Our overall goal for this study will be to generate age-, sex-, and race-specific PFP criteria thresholds for KT candidates and recipients by leveraging an ongoing, prospective, multi-center NIA-funded R01 on frailty and aging in ESRD of 7,803 candidates and 1,383 recipients (aged ?18) linked to the national registry of all KT candidates and recipients. Specifically, we will aim to (1) test if age-, sex-, and race-specific thresholds for PFP criteria are needed among KT candidates and recipients; (2) calculate nationally-representative thresholds for continuous PFP components among KT candidates and recipients and create an updated PFP; and (3) compare predictive validity of the original PFP and the updated PFP (incorporating new nationally-representative thresholds) against adverse outcomes including waitlist mortality, longer length of stay, graft loss and post-KT mortality. Linkage to the national registry provides the unique opportunity to translate measures that were collected at the cohort-level and project them to the national-level in order to calculate nationally-representative thresholds for the PFP criteria using creative statistical methodologies. By doing so, we will reduce misclassification in future studies examining predictors, mechanisms, and consequences of frailty, which can have a direct impact on clinical practice by improving risk stratification, identifying frail candidates for prehabilitation, and improving equitable access to KT, particularly for older, robust candidates. Findings from this study will support the American Society of Transplantation’s goal to establish a standard, validated measure of frailty in solid organ transplantation. Additionally, with expert guidance from the OAIC Biostatistics Core, study findings will provide a benchmark for the operationalization of frailty and a blueprint for gerontologists on how to identify appropriate thresholds to improve geriatric assessments.  

REC Scholar, Research & Grants Funded During Pepper Supported Time Years Publications
Alden Gross, PhD
Associate Professor / Epidemiology
Intersection of Domain-specific Cognitive Performance and Frailty: An Integrative Data Analysis
  • NIA K01 (2016)

2014-2016  2 (2 1st/Sr)
Charles H. Brown IV, MD
Associate Professor / Anesthesiology and Critical Care Medicine
The association between baseline frailty and postoperative delirium or functional decline after cardiac surgery, and a potential intervention to improve outcomes.
  • NIA K76 Beeson (2018)

2014-2016  5 (1 1st/Sr)
Charles H. Brown IV, MD
Associate Professor / Anesthesiology and Critical Care Medicine
The association between baseline frailty and postoperative delirium or functional decline after cardiac surgery, and a potential intervention to improve outcomes.
  • NIA K76 Beeson (2018)

2014-2016  5 (1 1st/Sr)
Rani Hasan, MD, MHS
Assistant Professor / Cardiology
Frailty in Elderly Patients Undergoing Transcatheter Aortic Valve Replacement (TAVR) for Symptomatic Severe Aortic Valve Stenosis (AS): Impact on Outcomes, Effect of TAVR on the Frailty Phenotype, and Association with Inflammation
2015-2018  2 (0 1st/Sr)
Tae Chung, MD
Assistant Professor / Physical Medicine and Rehabilitation
Involvement of Kynurenine and NAD Pathways in Frailty
  • NIA K08 (2018)

2016-2018  2 (2 1st/Sr)
Abdulla Damluji, MD, PhD
Assistant Professor / Cardiology
Consequences of Frailty in Older Adults after Acute Coronary Syndrome
  • K23 submitted

2017-2019  5 (5 1st/Sr)
Orla Sheehan, MD, PhD
Assistant Professor / Geriatric Medicine
Frailty and compensatory mechanisms for managing treatment burden, treatment adherence, and adverse outcomes in homebound older adults
  • K23 submitted.

2018-2020  2 (1 1st/Sr)
Pei-Hsun Wu, PhD
Associate Research Professor / Institute for NanoBioTechnology
Biophysical cellular characteristics in frail and non-frail older adults
2018-2020  2 (1 1st/Sr)
Bharath Ambale-Venkatesh, PhD
Assistant Professor / Radiology and Radiological Science
Pathways leading to frailty: a study of muscle, cardiovascular tissue, and energy utilizing whole-body magnetic resonance imaging
  • K01 submitted.

2018-2020  0 (0 1st/Sr)
Reyhan Westbrook, PhD
Instructor / Geriatric Medicine
Metabolomic differences in energy utilization and Kyn/Trp metabolism pathways in mouse models of frailty: evidence-based implication for translational studies in humans
  • K01 submitted

2018-2020  2 (1 1st/Sr)
Keenan Walker, PhD
Assistant Professor / Neorology
Examining the bidirectional relationship between physical frailty and neurodegenerative pathways
  • K23 award, “Systemic- and Neuro-Inflammation and the Progression of Alzheimer’s Disease”, August 2019

2019-2019  2 (2 1st/Sr)

  1. Derivation of a measure of physiological multisystem dysregulation: Results from WHAS and health ABC.
    Gross AL, Carlson MC, Chu NM, McAdams-DeMarco MA, Mungas D, Simonsick EM, Varadhan R, Xue QL, Walston J, Bandeen-Roche K
    Mech Ageing Dev, 2020 May 11, 188: 111258 | PMID: 32423871
    Citations: | AltScore: 5.05
  2. Clinically Meaningful Change for Physical Performance: Perspectives of the ICFSR Task Force.
    Guralnik J, Bandeen-Roche K, Bhasin SAR, Eremenco S, Landi F, Muscedere J, Perera S, Reginster JY, Woodhouse L, Vellas B
    J Frailty Aging, 2020, 9(1): 9-13 | PMID: 32150208 | PMCID: PMC7286121
    Citations: | AltScore: 28.35
  3. The Association between Frailty and Uncorrected Refractive Error in Older Adults.
    Lee MJ, Varadaraj V, Tian J, Bandeen-Roche K, Swenor BK
    Ophthalmic Epidemiol, 2020 Jun, 27(3): 219-225 | PMID: 31952461 | PMCID: PMC7080595
    Citations: | AltScore: NA
  4. Stable ischemic heart disease: how to keep it that way.
    Leucker TM, Schulman SP, Gerstenblith G
    J Clin Invest, 2020 Mar 2, 130(3): 1055-1057 | PMID: 31985489 | PMCID: PMC7269554
    Citations: | AltScore: 8.65
  5. Linking early life risk factors to frailty in old age: evidence from the China Health and Retirement Longitudinal Study.
    Li Y, Xue QL, Odden MC, Chen X, Wu C
    Age Ageing, 2020 Feb 27, 49(2): 208-217 | PMID: 31957780 | PMCID: PMC7047816
    Citations: 1 | AltScore: 11.05
  6. Evaluation of mitochondrial DNA copy number estimation techniques.
    Longchamps RJ, Castellani CA, Yang SY, Newcomb CE, Sumpter JA, Lane J, Grove ML, Guallar E, Pankratz N, Taylor KD, Rotter JI, Boerwinkle E, Arking DE
    PLoS One, 2020, 15(1): e0228166 | PMID: 32004343 | PMCID: PMC6994099
    Citations: | AltScore: 1.5
  7. IL10 deficiency promotes alveolar enlargement and lymphoid dysmorphogenesis in the aged murine lung.
    Malinina A, Dikeman D, Westbrook R, Moats M, Gidner S, Poonyagariyagorn H, Walston J, Neptune ER
    Aging Cell, 2020 Apr, 19(4): e13130 | PMID: 32170906 | PMCID: PMC7189990
    Citations: 2 | AltScore: 0.25
  8. Perceptions and Practices Regarding Frailty in Kidney Transplantation: Results of a National Survey.
    McAdams-DeMarco MA, Van Pilsum Rasmussen SE, Chu NM, Agoons D, Parsons RF, Alhamad T, Johansen KL, Tullius SG, Lynch R, Harhay MN, Rao MK, Berger J, Cooper M, Tan JC, Cheng XS, Woodside KJ, Parajuli S, Lentine KL, Kaplan B, Segev DL, Kobashigawa JA, Dadhania D, AST Kidney Pancreas Community of Practice Workgroup.
    Transplantation, 2020 Feb, 104(2): 349-356 | PMID: 31343576 | PMCID: PMC6834867
    Citations: | AltScore: 6.4
  9. Functional Outcomes of Frail Patients After Cardiac Surgery: An Observational Study.
    Nakano M, Nomura Y, Suffredini G, Bush B, Tian J, Yamaguchi A, Walston J, Hasan R, Mandal K, Schena S, Hogue CW, Brown CH 4th
    Anesth Analg, 2020 Jun, 130(6): 1534-1544 | PMID: 32384343
    Citations: | AltScore: NA
  10. Frailty transitions, inflammation and mortality among persons aging with HIV infection and injection drug use.
    Piggott DA, Bandeen-Roche K, Mehta SH, Brown TT, Yang H, Walston JD, Leng SX, Kirk GD
    AIDS, 2020 Apr 13, 34(8): 1217-1225 | PMID: 32287069
    Citations: | AltScore: 4.5
  11. Visual Impairment and Frailty: Examining an Understudied Relationship.
    Swenor BK, Lee MJ, Tian J, Varadaraj V, Bandeen-Roche K
    J Gerontol A Biol Sci Med Sci, 2020 Feb 14, 75(3): 596-602 | PMID: 31419280
    Citations: 1 | AltScore: 1
  12. Dissecting the Racial/Ethnic Disparity in Frailty in a Nationally Representative Cohort Study with Respect to Health, Income, and Measurement.
    Usher T, Buta B, Thorpe RJ, Huang J, Samuel LJ, Kasper JD, Bandeen-Roche K
    J Gerontol A Biol Sci Med Sci, 2020 Mar 9
    pii: glaa061. | PMID: 32147727
    Citations: | AltScore: 11.4
  13. Perceptions, Barriers, and Experiences With Successful Aging Before and After Kidney Transplantation: A Focus Group Study.
    Van Pilsum Rasmussen SE, Warsame F, Eno AK, Ying H, Covarrubias K, Haugen CE, Chu NM, Crews DC, Harhay MN, Schoenborn NL, Segev DL, McAdams-DeMarco MA
    Transplantation, 2020 Mar, 104(3): 603-612 | PMID: 31283666 | PMCID: PMC6930354
    Citations: | AltScore: 2.7
  14. Association of peripheral inflammatory markers with connectivity in large-scale functional brain networks of non-demented older adults.
    Walker KA, Gross AL, Moghekar AR, Soldan A, Pettigrew C, Hou X, Lu H, Alfini AJ, Bilgel M, Miller MI, Albert MS, Walston J
    Brain Behav Immun, 2020 Jan 11
    pii: S0889-1591(19)31061-X. | PMID: 31935468
    Citations: | AltScore: 9.5
  15. Single-cell morphology encodes metastatic potential.
    Wu PH, Gilkes DM, Phillip JM, Narkar A, Cheng TW, Marchand J, Lee MH, Li R, Wirtz D
    Sci Adv, 2020 Jan, 6(4): eaaw6938 | PMID: 32010778 | PMCID: PMC6976289
    Citations: 1 | AltScore: 64.45
  16. Discrepancy in Frailty Identification: Move Beyond Predictive Validity.
    Xue QL, Tian J, Walston JD, Chaves PHM, Newman AB, Bandeen-Roche K
    J Gerontol A Biol Sci Med Sci, 2020 Jan 20, 75(2): 387-393 | PMID: 30789645 | PMCID: PMC7176056
    Citations: 1 | AltScore: 2.2
  1. Novel missense alleles of SIGMAR1 as tools to understand emerin-dependent gene silencing in response to cocaine.
    Arun AS, Eddings CR, Wilson KL
    Exp Biol Med (Maywood), 2019 Nov, 244(15): 1354-1361 | PMID: 31324122 | PMCID: PMC6880142
    Citations: 1 | AltScore: NA
  2. Principles and Issues for Physical Frailty Measurement and its Clinical Application.
    Bandeen-Roche K, Gross AL, Varadhan R, Buta B, Carlson MC, Huisingh-Scheetz M, McAdams-DeMarco M, Piggott DA, Brown TT, Hasan RK, Kalyani RR, Seplaki CL, Walston JD, Xue QL
    J Gerontol A Biol Sci Med Sci, 2019 Jul 9, 75(6): 1107-1112
    pii: glz158. | PMID: 31287490 | PMCID: PMC7243579
    Citations: | AltScore: 3.45
  3. Hierarchical Development of Frailty and Cognitive Impairment: Clues Into Etiological Pathways.
    Chu NM, Bandeen-Roche K, Tian J, Kasper JD, Gross AL, Carlson MC, Xue QL
    J Gerontol A Biol Sci Med Sci, 2019 Oct 4, 74(11): 1761-1770 | PMID: 31120105 | PMCID: PMC6777087
    Citations: | AltScore: NA
  4. Dynamic Frailty Before Kidney Transplantation: Time of Measurement Matters.
    Chu NM, Deng A, Ying H, Haugen CE, Garonzik Wang JM, Segev DL, McAdams-DeMarco MA
    Transplantation, 2019 Aug, 103(8): 1700-1704 | PMID: 31348438 | PMCID: PMC6679826
    Citations: 6 | AltScore: NA
  5. Authors' Reply.
    Chu NM, Gross AL, Shaffer AA, Haugen CE, Norman SP, Xue QL, Sharrett AR, Carlson M, Bandeen-Roche K, Segev DL, McAdams-DeMarco MA
    J Am Soc Nephrol, 2019 Aug, 30(8): 1548-1549 | PMID: 31300483 | PMCID: PMC6683707
    Citations: | AltScore: NA
  6. Frailty and Changes in Cognitive Function after Kidney Transplantation.
    Chu NM, Gross AL, Shaffer AA, Haugen CE, Norman SP, Xue QL, Sharrett AR, Carlson MC, Bandeen-Roche K, Segev DL, McAdams-DeMarco MA
    J Am Soc Nephrol, 2019 Feb, 30(2): 336-345 | PMID: 30679381 | PMCID: PMC6362628
    Citations: 10 | AltScore: 51.1
  7. Percutaneous Coronary Intervention in Older Patients With ST-Segment Elevation Myocardial Infarction and Cardiogenic Shock.
    Damluji AA, Bandeen-Roche K, Berkower C, Boyd CM, Al-Damluji MS, Cohen MG, Forman DE, Chaudhary R, Gerstenblith G, Walston JD, Resar JR, Moscucci M
    J Am Coll Cardiol, 2019 Apr 23, 73(15): 1890-1900 | PMID: 30999991 | PMCID: PMC7185801
    Citations: 2 | AltScore: 75.05
  8. Frailty Among Older Adults With Acute Myocardial Infarction and Outcomes From Percutaneous Coronary Interventions.
    Damluji AA, Huang J, Bandeen-Roche K, Forman DE, Gerstenblith G, Moscucci M, Resar JR, Varadhan R, Walston JD, Segal JB
    J Am Heart Assoc, 2019 Sep 3, 8(17): e013686 | PMID: 31475601 | PMCID: PMC6755849
    Citations: 1 | AltScore: 4.7
  9. Reply: Benefit of Primary Percutaneous Coronary Intervention in Elderly Patients With Cardiogenic Shock.
    Damluji AA, Moscucci M
    J Am Coll Cardiol, 2019 Aug 13, 74(6): 824-825 | PMID: 31395138
    Citations: | AltScore: NA
  10. Temporal Trends of Percutaneous Coronary Interventions in Older Adults With Acute Myocardial Infarction.
    Damluji AA, Resar JR, Gerstenblith G, Gross AL, Forman DE, Moscucci M
    Circ Cardiovasc Interv, 2019 May, 12(5): e007812 | PMID: 31010297 | PMCID: PMC6488214
    Citations: | AltScore: 32
  11. Accuracy of Samsung Gear S Smartwatch for Activity Recognition: Validation Study.
    Davoudi A, Wanigatunga AA, Kheirkhahan M, Corbett DB, Mendoza T, Battula M, Ranka S, Fillingim RB, Manini TM, Rashidi P
    JMIR Mhealth Uhealth, 2019 Feb 6, 7(2): e11270 | PMID: 30724739 | PMCID: PMC6386649
    Citations: | AltScore: NA
  12. Rare <i>BANF1</i> Alleles and Relatively Frequent <i>EMD</i> Alleles Including 'Healthy Lipid' Emerin p.D149H in the ExAC Cohort.
    Dharmaraj T, Guan Y, Liu J, Badens C, Gaborit B, Wilson KL
    Front Cell Dev Biol, 2019, 7: 48 | PMID: 31024910 | PMCID: PMC6459885
    Citations: 2 | AltScore: 0.5
  13. Frailty, body composition and the risk of mortality in incident hemodialysis patients: the Predictors of Arrhythmic and Cardiovascular Risk in End Stage Renal Disease study.
    Fitzpatrick J, Sozio SM, Jaar BG, Estrella MM, Segev DL, Parekh RS, McAdams-DeMarco MA
    Nephrol Dial Transplant, 2019 Feb 1, 34(2): 346-354 | PMID: 29868775 | PMCID: PMC6365769
    Citations: 8 | AltScore: 1
  14. Lisinopril Preserves Physical Resilience and Extends Life Span in a Genotype-Specific Manner in Drosophila melanogaster.
    Gabrawy MM, Campbell S, Carbone MA, Morozova TV, Arya GH, Turlapati LB, Walston JD, Starz-Gaiano M, Everett L, Mackay TFC, Leips J, Abadir PM
    J Gerontol A Biol Sci Med Sci, 2019 Nov 13, 74(12): 1844-1852 | PMID: 31197356
    Citations: | AltScore: 7.1
  15. Targeted Metabolomics Shows Low Plasma Lysophosphatidylcholine 18:2 Predicts Greater Decline of Gait Speed in Older Adults: The Baltimore Longitudinal Study of Aging.
    Gonzalez-Freire M, Moaddel R, Sun K, Fabbri E, Zhang P, Khadeer M, Salem N Jr, Ferrucci L, Semba RD
    J Gerontol A Biol Sci Med Sci, 2019 Jan 1, 74(1): 62-67 | PMID: 29788121 | PMCID: PMC6298185
    Citations: 3 | AltScore: 1.75
  16. Plasma Markers of Inflammation Linked to Clinical Progression and Decline During Preclinical AD.
    Gross AL, Walker KA, Moghekar AR, Pettigrew C, Soldan A, Albert MS, Walston JD
    Front Aging Neurosci, 2019, 11: 229 | PMID: 31555121 | PMCID: PMC6742958
    Citations: | AltScore: 10
  17. Measuring Aging and Identifying Aging Phenotypes in Cancer Survivors.
    Guida JL, Ahles TA, Belsky D, Campisi J, Cohen HJ, DeGregori J, Fuldner R, Ferrucci L, Gallicchio L, Gavrilov L, Gavrilova N, Green PA, Jhappan C, Kohanski R, Krull K, Mandelblatt J, Ness KK, O'Mara A, Price N, Schrack J, Studenski S, Theou O, Tracy RP, Hurria A
    J Natl Cancer Inst, 2019 Dec 1, 111(12): 1245-1254 | PMID: 31321426
    Citations: 1 | AltScore: 23.7
  18. How Do Older Adults Consider Age, Life Expectancy, Quality of Life, and Physician Recommendations When Making Cancer Screening Decisions? Results from a National Survey Using a Discrete Choice Experiment.
    Janssen EM, Pollack CE, Boyd C, Bridges JFP, Xue QL, Wolff AC, Schoenborn NL
    Med Decis Making, 2019 Aug, 39(6): 621-631 | PMID: 31226903 | PMCID: PMC7080208
    Citations: | AltScore: 1
  19. Association Between Adiposity and Perceived Physical Fatigability in Mid- to Late Life.
    Martinez-Amezcua P, Simonsick EM, Wanigatunga AA, Urbanek JK, Chiles Shaffer N, Ferrucci L, Schrack JA
    Obesity (Silver Spring), 2019 Jul, 27(7): 1177-1183 | PMID: 31127707 | PMCID: PMC6591054
    Citations: 1 | AltScore: 8.9
  20. Frailty and Long-Term Post-Kidney Transplant Outcomes.
    McAdams-DeMarco MA, Chu NM, Segev DL
    Curr Transplant Rep, 2019 Mar, 6(1): 45-51 | PMID: 31768307 | PMCID: PMC6876846
    Citations: | AltScore: NA
  21. Prehabilitation prior to kidney transplantation: Results from a pilot study.
    McAdams-DeMarco MA, Ying H, Van Pilsum Rasmussen S, Schrack J, Haugen CE, Chu NM, Gonz?lez Fern?ndez M, Desai N, Walston JD, Segev DL
    Clin Transplant, 2019 Jan, 33(1): e13450 | PMID: 30462375 | PMCID: PMC6342659
    Citations: 8 | AltScore: 0.85
  22. Observational Study Examining the Association of Baseline Frailty and Postcardiac Surgery Delirium and Cognitive Change.
    Nomura Y, Nakano M, Bush B, Tian J, Yamaguchi A, Walston J, Hasan R, Zehr K, Mandal K, LaFlam A, Neufeld KJ, Kamath V, Hogue CW, Brown CH 4th
    Anesth Analg, 2019 Aug, 129(2): 507-514 | PMID: 30540612 | PMCID: PMC7243370
    Citations: | AltScore: 13.05
  23. Comorbidity, Frailty, and Waitlist Mortality among Kidney Transplant Candidates of All Ages.
    P?rez Fern?ndez M, Mart?nez Miguel P, Ying H, Haugen CE, Chu NM, Rodr?guez Puyol DM, Rodr?guez-Ma?as L, Norman SP, Walston JD, Segev DL, McAdams-DeMarco MA
    Am J Nephrol, 2019, 49(2): 103-110 | PMID: 30625489 | PMCID: PMC6374203
    Citations: 4 | AltScore: 5.95
  24. Association Between Cardiovascular Risk and Perceived Fatigability in Mid-to-Late Life.
    Qiao Y, Martinez-Amezcua P, Wanigatunga AA, Urbanek JK, Simonsick EM, Ferrucci L, Schrack JA
    J Am Heart Assoc, 2019 Aug 20, 8(16): e013049 | PMID: 31409206 | PMCID: PMC6759892
    Citations: 1 | AltScore: 27
  25. Is Family Caregiving Associated With Inflammation or Compromised Immunity? A Meta-Analysis.
    Roth DL, Sheehan OC, Haley WE, Jenny NS, Cushman M, Walston JD
    Gerontologist, 2019 Sep 17, 59(5): e521-e534 | PMID: 30852588 | PMCID: PMC6857696
    Citations: 1 | AltScore: 105.85
  26. Transcatheter Aortic Valve Replacement in a Sinus of Valsalva Aneurysm: The Evolving Role of Structural Cardiac Imaging.
    Rout A, Madianos EF, Pfeffer BJ, Damluji AA
    Circ Cardiovasc Imaging, 2019 Sep, 12(9): e009386 | PMID: 31451007 | PMCID: PMC7099850
    Citations: | AltScore: 0.5
  27. Fractures and Subsequent Graft Loss and Mortality among Older Kidney Transplant Recipients.
    Salter ML, Liu X, Bae S, Chu NM, Miller Dunham A, Humbyrd C, Segev DL, McAdams-DeMarco MA
    J Am Geriatr Soc, 2019 Aug, 67(8): 1680-1688 | PMID: 31059126 | PMCID: PMC6684377
    Citations: 1 | AltScore: 6.95
  28. Examining Generalizability of Older Adults' Preferences for Discussing Cessation of Screening Colonoscopies in Older Adults with Low Health Literacy.
    Schoenborn NL, Crossnohere NL, Janssen EM, Pollack CE, Boyd CM, Wolff AC, Xue QL, Massare J, Blinka M, Bridges JFP
    J Gen Intern Med, 2019 Nov, 34(11): 2512-2519 | PMID: 31452029 | PMCID: PMC6848333
    Citations: | AltScore: NA
  29. Demographic, health, and attitudinal factors predictive of cancer screening decisions in older adults.
    Schoenborn NL, Xue QL, Pollack CE, Janssen EM, Bridges JFP, Wolff AC, Boyd CM
    Prev Med Rep, 2019 Mar, 13: 244-248 | PMID: 30719405 | PMCID: PMC6350222
    Citations: | AltScore: 0.5
  30. Active-to-Sedentary Behavior Transitions, Fatigability, and Physical Functioning in Older Adults.
    Schrack JA, Kuo PL, Wanigatunga AA, Di J, Simonsick EM, Spira AP, Ferrucci L, Zipunnikov V
    J Gerontol A Biol Sci Med Sci, 2019 Mar 14, 74(4): 560-567 | PMID: 30357322 | PMCID: PMC6417447
    Citations: 5 | AltScore: 11.65
  31. Low plasma lysophosphatidylcholines are associated with impaired mitochondrial oxidative capacity in adults in the Baltimore Longitudinal Study of Aging.
    Semba RD, Zhang P, Adelnia F, Sun K, Gonzalez-Freire M, Salem N Jr, Brennan N, Spencer RG, Fishbein K, Khadeer M, Shardell M, Moaddel R, Ferrucci L
    Aging Cell, 2019 Apr, 18(2): e12915 | PMID: 30719830 | PMCID: PMC6413748
    Citations: 2 | AltScore: 0.5
  32. Frailty Tools are Not Yet Ready for Prime Time in High-Risk Identification.
    Sheehan OC, Leff B, Ritchie CS
    J Hosp Med, 2019 Jul, 14(7): 450 | PMID: 31251723
    Citations: | AltScore: NA
  33. Racial differences in inflammation and outcomes of aging among kidney transplant candidates.
    Shrestha P, Haugen CE, Chu NM, Shaffer A, Garonzik-Wang J, Norman SP, Walston JD, Segev DL, McAdams-DeMarco MA
    BMC Nephrol, 2019 May 17, 20(1): 176 | PMID: 31101015 | PMCID: PMC6524264
    Citations: | AltScore: 0.5
  34. Chronic Systemic Inflammation Is Associated With Symptoms of Late-Life Depression: The ARIC Study.
    Sonsin-Diaz N, Gottesman RF, Fracica E, Walston J, Windham BG, Knopman DS, Walker KA
    Am J Geriatr Psychiatry, 2020 Jan, 28(1): 87-98 | PMID: 31182350 | PMCID: PMC6868307
    Citations: | AltScore: 9.2
  35. Warfarin use and the risk of stroke, bleeding, and mortality in older adults on dialysis with incident atrial fibrillation.
    Tan J, Bae S, Segal JB, Zhu J, Alexander GC, Segev DL, McAdams-DeMarco M
    Nephrology (Carlton), 2019 Feb, 24(2): 234-244 | PMID: 29219209 | PMCID: PMC5993567
    Citations: 2 | AltScore: 3.5
  36. A note on proposed estimation procedures for claims-based frailty indexes.
    Van Domelen DR, Bandeen-Roche K
    Am J Epidemiol, 2019 Nov 1
    pii: kwz247. | PMID: 31673711
    Citations: | AltScore: 0.75
  37. Near Vision Impairment and Frailty: Evidence of an Association.
    Varadaraj V, Lee MJ, Tian J, Ramulu PY, Bandeen-Roche K, Swenor BK
    Am J Ophthalmol, 2019 Dec, 208: 234-241 | PMID: 31465753 | PMCID: PMC6888870
    Citations: | AltScore: 12.6
  38. Midlife Systemic Inflammation Is Associated With Frailty in Later Life: The ARIC Study.
    Walker KA, Walston J, Gottesman RF, Kucharska-Newton A, Palta P, Windham BG
    J Gerontol A Biol Sci Med Sci, 2019 Feb 15, 74(3): 343-349 | PMID: 29534173 | PMCID: PMC6376088
    Citations: 6 | AltScore: 58.6
  39. Moving Frailty Toward Clinical Practice: NIA Intramural Frailty Science Symposium Summary.
    Walston J, Bandeen-Roche K, Buta B, Bergman H, Gill TM, Morley JE, Fried LP, Robinson TN, Afilalo J, Newman AB, L?pez-Ot?n C, De Cabo R, Theou O, Studenski S, Cohen HJ, Ferrucci L
    J Am Geriatr Soc, 2019 Aug, 67(8): 1559-1564 | PMID: 31045254 | PMCID: PMC6830521
    Citations: 6 | AltScore: 38.05
  40. Reply to From Frailty to Gerastenia.
    Walston J, Bandeen-Roche K, Ferrucci L
    J Am Geriatr Soc, 2019 Oct, 67(10): 2210-2211 | PMID: 31441501
    Citations: | AltScore: 2.5
  41. Physical activity fragmentation as a potential phenotype of accelerated aging.
    Wanigatunga AA, Ferrucci L, Schrack JA
    Oncotarget, 2019 Jan 25, 10(8): 807-809 | PMID: 30783511 | PMCID: PMC6368227
    Citations: 1 | AltScore: NA
  42. Effect of Hospitalizations on Physical Activity Patterns in Mobility-Limited Older Adults.
    Wanigatunga AA, Gill TM, Marsh AP, Hsu FC, Yaghjyan L, Woods AJ, Glynn NW, King AC, Newton RL Jr, Fielding RA, Pahor M, Manini TM, Lifestyles Intervention and Independence for Elders Study Investigators.
    J Am Geriatr Soc, 2019 Feb, 67(2): 261-268 | PMID: 30452084 | PMCID: PMC6613645
    Citations: 1 | AltScore: 8.25
  43. Longitudinal Relationship Between Interleukin-6 and Perceived Fatigability Among Well-Functioning Adults in Mid-to-Late Life.
    Wanigatunga AA, Varadhan R, Simonsick EM, Carlson OD, Studenski S, Ferrucci L, Schrack JA
    J Gerontol A Biol Sci Med Sci, 2019 Apr 23, 74(5): 720-725 | PMID: 29846512 | PMCID: PMC6941496
    Citations: 2 | AltScore: 7.3
  44. Limited health literacy and adverse outcomes among kidney transplant candidates.
    Warsame F, Haugen CE, Ying H, Garonzik-Wang JM, Desai NM, Hall RK, Kambhampati R, Crews DC, Purnell TS, Segev DL, McAdams-DeMarco MA
    Am J Transplant, 2019 Feb, 19(2): 457-465 | PMID: 29962069 | PMCID: PMC6312744
    Citations: 7 | AltScore: 14
  45. Integrating Frailty and Cognitive Phenotypes: Why, How, Now What?
    Xue QL, Buta B, Ma L, Ge M, Carlson M
    Curr Geriatr Rep, 2019 Jun, 8(2): 97-106
    PMID: 31815092 | PMCID: PMC6897328
    Citations: 1 | AltScore: NA

Harvey J. Cohen, M.D.
Division Chief of Geriatrics, Director of the Center for the Study of Aging and Human Development, Duke University Medical Center
Serving since 2003 (17 years)

Luigi Ferrucci, M.D., Ph.D.
NIA Scientific Director, Senior Investigator and Chief, Longitudinal Studies Section
Serving since 2003 (17 years)

Joan E. Bailey-Wilson, Ph.D.
Head, Statistical Genetics Section; Co-Branch Chief, Inherited Disease Research Branch; National Human Genome Research Institute; National Institutes of Health
Serving since 2008 (12 years)

Gerald Beck, Ph.D.
Section Head, Clinical Trials; Design and Analysis, Department of Quantitative Health Sciences, Cleveland Clinic Foundation
Serving since 2013 (7 years)

Howard Bergman, M.D.
Chair, Department of Family Medicine, Professor of Family Medicine, Medicine and Oncology, Dr. Joseph Kaufmann Professor of Geriatric Medicine, McGill University
Serving since 2013 (7 years)

  Karen Bandeen-Roche (2019)
  • Dr. Bandeen-Roche was recognized with two awards in the field of Statistics during the last year—she was re-elected to the Executive Director board for the International Biometric Society, and she was the Distinguished Women in Statistics keynote lecturer (Vanderbilt University, April, 2019): work from this OAIC was featured prominently in this lecture.
Reyhan Westbrook (2019)
  • REC investigator, Dr. Reyhan Westbrook, won the W. Leigh Thompson Excellence in Research Award, Basic Research Faculty, for his work on “Altered Metabolome in Frailty Link Chronic Inflammation to Functional Decline” at the 2019 Johns Hopkins Department of Medicine Research Retreat.

General Brief Description of Minority Activities:

Janiece Taylor, PhD: Pilot Study. "Pilot Behavioral Intervention to Address Pain and Frailty in Older African-American Women."

Karen Bandeen-Roche, PhD: RC1 Development Project: includes analyses of frailty measurement variance by race in the National Health and Aging Trends Study.

Minority Trainee(s):
  • Janiece Taylor, PhD, Assistant Professor
    Janiece Taylor, PhD: Pilot Study. "Pilot Behavioral Intervention to Address Pain and Frailty in Older African-American Women."
Minority Grant(s):