HARC Pilot Awardees

Dr. Peng Li obtained his PhD in Biomedical Engineering from Shandong University, China, in 2014; he received multidisciplinary postdoctoral trainings first focusing on nonlinear dynamics in physiology at Shandong University (2014-2015), then in sleep/circadian physiology and neurophysiology at Brigham and Women’s Hospital, Harvard Medical School (2015-2018). In 2019, Dr. Li was promoted to the Instructor in Medicine at the Harvard Medical School and Associated Physiologist at the Brigham and Women’s Hospital. He now also serves as the Research Director of the Medical Biodynamics Program, a multidisciplinary research and training program aiming to promote translation and interdisciplinary research in sleep medicine. Since his PhD, Dr. Li has been fascinated by how complex patterns in spontaneous fluctuations of physiological output can be linked to innate physiological or bodily functions such as autonomic function and circadian system, and associated with health outcomes. He has developed and applied many nonlinear algorithms for harnessing changes in physiological signals that are better connected to adverse outcomes than traditional analytical approaches. For example, Dr. Li has shown that the scale invariant patten (i.e., fractal pattern) in spontaneous rest-activity recordings (i.e., actigraphy) degrades with aging that exacerbates with the clinical progression of Alzheimer’s dementia (Li et al. 2019 Neurobiol Aging), is associated with incident Alzheimer’s dementia (Li et al. 2018 Alzheimer Dement), and predicts frailty, disability, and death (Li et al. 2019 Sci Transl Med) independent of many known risk factors. His study has also demonstrated that various circadian function degradations predict the risk of Alzheimer’s dementia years ahead of cognitive symptoms occur and progress in parallel with cognitive decline (Li et al. 2020 Lancet Healthy Longev). Dr. Li is keen to apply his expertise to promote a proactive strategy for early detection of individuals with elevated risk of cognitive symptoms or brain pathology, to achieve healthy aging especially healthy cognitive aging, which means even more in vulnerable populations such as people living with HIV infection (PLWH). Dr. Li has become more and more interested in studying PLWH after learning that they are more prone to experience cognitive impairment. To obtain advance research training in HIV and aging, he has applied and successfully secured a Developmental Award from the Harvard University Center for AIDS Research to study changes in daily activity patterns in PLWH and their relationship with cognitive performance. Inspired by his prior research, in this Pilot Project sponsored by the HIV and Aging Research Consortium, he proposed to utilize a novel data-adaptive analytical tool, namely empirical mode decomposition that is better suited for analyzing nonstationary and nonlinear physiological data and has been shown to be able to extract intrinsic oscillation mode representing rest-activity circadian rhythms, to study actigraphy of 100 PLWH in the UK Biobank cohort. He will investigate rest-activity circadian rhythm changes in PLWH using this novel approach and whether it links to cognitive performance. He will also explore the potential mechanism in terms of multimorbidity that contributes to the association between circadian dysfunction and cognitive deficits.

Associations between rest activity circadian rhythm and cognition in PLWH
Cognitive impairment is an increasing clinical concern as people living with HIV infection (PLWH) age. It leads to poor adherence of the older PLWH to complex medical regimens that are necessary for independent living. Responding to this potential crisis affecting quality of life within PLWH, the PI Dr. Peng Li’s research focuses on the identification of biomarkers and modifiable risk factors for cognitive impairment, and the application of lifestyle modifications that can improve cognitive performance. This proposed Pilot Project is focused on circadian function, a fundamental driver of physiological homeostasis. In the general population, prior work including ours showed that circadian disturbance appears in preclinical Alzheimer’s disease. It further deteriorates with cognitive decline. In animals, circadian deficiency is shown to be associated with greater susceptibility to virus infection; virus infection also interferes with circadian clock, leading to impaired circadian rhythms (such as in activity, body temperature, and circulating biomarkers including cortisol and growth hormone etc.). In PLWH, there is indirect evidence for circadian deficiency including disturbed sleep and sleep-wake rhythms. PLWH are also found to have blunted day-night systolic blood pressure dipping and morning-evening CD4+ lymphocytes oscillation. To prepare data for in-laboratory examination of the endogenous circadian function of PLWH, this Pilot Project aims to characterize the circadian rest-activity patterns in PLWH by analyzing rest-activity data from actiwatch using a novel data adaptive approach (namely empirical mode decomposition, EMD), examine the association between circadian variations and cognition, and understand the potential mechanisms underlying this association in PLWH. We propose to study 100 PLWH and 500 uninfected controls (extracted from over 100,000 participants) of 40-69 years old in the UK Biobank cohort. Two hypotheses will be tested: (Hypothesis 1) There are greater variations in circadian patterns in PLWH compared to uninfected controls that adversely influence cognitive performance. We will perform the EMD to extract cyclic components in actigraphy. The EMD has no assumption of the cycle length, allowing the examination of potential deviation in the rest-activity period from being exactly 24 hours. We will calculate the amplitude, phase, and length of each circadian cycle across seven days of actigraphy data. We expect (1a) PLWH have lower mean amplitude (MA) and greater variances in phase (PV) and cycle length (LV) and (1b) the MA, PV, and LV are associated with cognitive performance, which is stronger in PLWH than in uninfected controls. (Exploratory Hypothesis 2) Multimorbidity (e.g., inflammation, CVD) in PLWH contributes to dysregulation in circadian rhythms and deficits in cognitive performance. We will explore these potential pathways based on blood C-reactive protein level for inflammation and a 10-year cardiovascular risk score calculated based on several known risk factors for cardiovascular diseases. Achieving the aims will provide key preliminary data for larger research grants such as R01 to formally examine changes in the endogenous circadian patterns, to understand the causal relationship between circadian function and cognitive decline, and to test whether circadian intervention can help improve cognitive performance in PLWH.

Dr. Vitor Oliveira is a Research Associate at the Frances Payne Bolton School of Nursing at Case Western Reserve University. He is an exercise scientist studying the relationship between HIV and physical function, as well as the effects of exercise interventions on health outcomes of people aging with HIV. Dr. Oliveira completed his education in Brazil, which included a master’s and a doctoral training at the Londrina State University. During this time, he was involved in two main research studies: one study analyzing the effects of a combined exercise training on different health outcomes of adults with HIV and another study aiming to investigate different aspects of sarcopenia in this population. Here in the U.S., he completed a 7-months pre-doctoral training under the mentoring of Dr. Allison Webel in 2018. He is currently involved in the PROSPER-HIV study (Impact of Physical Activity Routines and Dietary Intake on the Longitudinal Symptom Experience of People Living with HIV) and the HEALTH study (The High-Intensity Exercise Study to Attenuate Limitations and Train Habits in Older Adults with HIV). Despite his early-stage investigator status, he has contributed to papers in high-impact HIV, nutrition, and exercise journals. Dr. Oliveira’s career goals are to lead multidisciplinary research projects examining how to improve physical function and quality of life of people aging with HIV, as well as to continue examining changes that occur on physical function over the lifespan in this population.

Relationship between body fat and functional status among adults aging with HIV
Nearly half of people living with HIV (PWH) in the U.S. today are 50 years or older. A major obstacle to achieving an increased healthspan (i.e., the length of time that a person is healthy, and not just alive) in this population is the decline in physiological function that occurs with advancing age, culminating in disability, frailty and ultimately, death. Importantly, PWH experience reduced muscle strength and physical function when compared to people without HIV; these impairments are observed up to 10 years earlier among PWH. These data demonstrate that HIV infection, in conjunction with normal aging, imposes additional challenges to an extended healthspan in this population. Another challenge aging PWH face is a rapid increase in obesity, which may affect skeletal muscle through multiple pathways, including hormone changes, inflammation, and local deposits of fat. These changes can lead to reduced muscle strength, impaired physical function, sarcopenia, and frailty. Although the negative association between body fat and functional status has been demonstrated in older adults without HIV, little is known about how body fat contributes to muscle and physical function impairments in aging PWH. To our knowledge, the few studies addressing these issues are limited in their design, leaving inconclusive results. This knowledge is likely to lead to new insights on the prevention and treatment of functional impairments and frailty in PWH, resulting in a higher quality of life and increased healthspan. While PWH experience normal age-associated physiologic changes such as loss in skeletal muscle and gains in body fat, their changes may be compounded by decades of HIV infection and antiretroviral therapy use.

In this study, the associations of body fat and functional status will be investigated in 150 PWH (≥40 years) enrolled in the ongoing PROSPER-HIV Study, which is being conducted in four CNICS sites across the country. Nesting this pilot study within PROSPER-HIV allows us access to a representative sample of the people aging with HIV in the U.S. The PROSPER-HIV study is collecting rigorous data on physical activity and diet intake, positioning us well to explore the importance of these modifiable lifestyle behaviors on the healthspan of PWH. The aims of this proposal are to:
Aim 1) Examine the relationship between body mass index, abdominal visceral adiposity, handgrip strength and physical function in aging PWH.
Aim 2) Explore the potential influence of lifestyle factors (i.e., physical activity and diet quality), inflammation, sex hormones, and sex differences on the relationship between body mass index, abdominal visceral adiposity, handgrip strength, and physical function in aging PWH. We will examine the senescence-associated secretory phenotype (SASP) chemokines as biomarkers of aging and frailty and sex hormones: total testosterone (Total T), estradiol (E2), sex hormone binding globulin (SHBG), and dehydroepiandrostenedione (DEHA). Despite having access to better HIV treatments and increased life expectancy, PWH experience many comorbidities and complications across the lifespan. Our ultimate goal is to inform clinically relevant, personalized biobehavioral interventions to help PWH age well.

Dr. S. Kathleen Bandt, MD is an Assistant Professor of Neurological Surgery at Northwestern University. She completed residency training in Neurological Surgery at Washington University in Saint Louis followed by the Epilepsy & Functional Neurosurgery Fellowship at Yale University. She then earned the prestigious Van Wagenen International Research Fellowship investigating brain network interactions using MRI data in France prior to joining Northwestern in 2017. Dr Bandt, together with Pierre Besson, PhD, founded the ANISE Lab at Northwestern were they jointly develop novel computational tools for advancing neuroscientific knowledge using MRI data.

Surface based deep learning to define HIV-related brain aging
The purpose of our research is to advance our understanding of how HIV infection affects brain aging. In order to achieve this purpose, we will use our newly developed method, surface-based deep learning (SBDL), which harnesses the computational power of deep learning using convolutional neural network architectures applied to surface meshes of geometric surfaces of the brain. This method provides a data-driven approach to determine an individual’s “brain age” using T1 weighted brain MRI data. Given the similarities between cognitive decline in aging and the similar phenotype observed in PLWH, we hypothesize that SBDL prediction of brain age can serve as a valuable surrogate biomarker of individual differences in cognitive status in the setting of HIV infection. To test our hypotheses we will implement SBDL brain age prediction in imaging data that has been acquired in the NIH-funded Chicago Early HIV Infection Study. Identification of factors associated with accelerated brain aging in HIV infection will help illuminate potential pathophysiologic mechanisms and inform new therapeutic targets and interventions to minimize long-term cognitive complications and preserve quality of life in PLWH.

Dr. Andrew Hahn is a member of the Division of General Internal Medicine based at Harborview Medical Center and a UW clinical instructor of medicine. As a hospital-based internist, he is an expert in the acute care and safe discharge of medically complex adult and pediatric inpatients. He earned his bachelor’s degree from Pomona College and MD from the University of Washington School of Medicine undergoing internal medicine and pediatrics residency at Baylor College of Medicine in Houston before returning to UW to complete a fellowship in Infectious Diseases. His areas of research interest center around substance use, addiction, and aging among people living with HIV (PLWH). He is partnered with and mentored by Drs. Paul and Heidi Crane as well as Chris Delaney on projects and analyses related to behavioral risks and biomarkers among PLWH using CNICS data.

Determination of the impact of abnormal glucose levels on the progression to frailty among people living with HIV Higher glucose levels in people without and with diabetes are associated with higher risk of aging-related outcomes including frailty and cognitive changes. People with HIV (PWH) experience accelerated or accentuated aging through several proposed mechanisms and are likely to be highly susceptible to the effects of elevated glucose on metabolic and inflammatory pathologic processes. We suspect that PWH experience accelerated or accentuated aging related to direct viral effects, altered immune function, behavioral factors, and medication effects. PWH are thus more likely than the general population to experience greater impact of altered metabolism and inflammation on frailty. This is a crucial area of clinical relevance given the concern for increased rates of both hyperglycemia and frailty among the aging population of PWH. Frailty is an important clinical and epidemiologic concept that has repeatedly been shown to predict morbidity and mortality among PWH. It is a composite variable incorporating unintentional weight loss, exhaustion, low physical activity, and low mobility/slower walking speed. While numerous prior studies have described the high incidence and prevalence of frailty among PWH and several have explored both HIV-specific and non-HIV-specific risk factors in progression to frailty, this is the first time, to our knowledge, that elevated cumulative glycemia—regardless of abnormal levels or a diagnosis of diabetes—has been assessed for impact on aging-related comorbidities in this high-risk population.

This project aims to describe the impact of elevated glucose and other biomarkers on the risk of frailty among PWH using complex and robust statistical methods. We will determine the incidence and prevalence of frailty and pre-frailty over time among PWH with and without diabetes. Then, using competing risk and marginal structural Cox models, we will examine associations between cumulative glycemia and progression to frailty. Cumulative glycemia will be constructed by incorporating clinical HbA1c and random and fasting glucose values in a longitudinal hierarchical Bayesian model which accounts for the different measurement properties, including timeframes of these glycemic indicators. We will also evaluate diabetes-associated conditions (such as cardiovascular disease and chronic kidney disease) as potential mediators of the relationship between glycemia and frailty. Finally, we will conduct exploratory analyses to characterize the impact of biomarkers for inflammation or altered metabolism on progression to frailty among PWH. There may be other processes related to inflammation and metabolism contributing to accelerated aging among PWH, which may improve our ability to predict progression to frailty. We will use a similar Bayesian modeling approach to determine which biomarkers, such as C-reactive protein or tumor necrosis factor-alpha, have a high probability of adding information to the cumulative glycemia model. This project will help elucidate the role of elevated glucose, corrected for other risk factors and comorbidities, on progression to frailty among PWH.