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.