Tuhina Neogi, Ph.D. - US grants

DESCRIPTION (provided by applicant): I am a rheumatologist who is undertaking research training under the mentorship of Dr. David T. Felson at Boston University School of Medicine. I am also pursuing a doctoral degree in Epidemiology. My immediate career goals are to pursue further clinical research training to establish myself as an independent investigator. My long-term goals are to continue in an academic position as a clinician scientist, with a research career focused on epidemiologic study of rheumatic diseases. At present, my interests lie in studying pathophysiologic contributors to osteoarthritis (OA), and in particular, factors related to bone health in OA. Dr. Felson and his research team have a proven track-record in OA research and have made numerous important contributions to the field. In this research environment, I've already begun to explore the association of vitamin K, a nutritional factor with bone effects, with OA in collaboration with Dr. Sarah Booth, a collaborator on this proposed study. This proposed study will extend this collaboration to study additional aspects of OA by focusing on factors that are associated with subchondral bone attrition in OA, which is a depression of the subchondral bony surface unrelated to gross fracture. Subchondral bone is thought to play an important role in both the pain and progression of OA. The altered properties of subchondral bone likely reflect both mechanical and systemic factors. We propose examining the relation of subchondral bone attrition on knee MRI with limb alignment/bone mineral density, and nutritional factors related to bone health measured in blood (vitamins D and K), and the interaction of these factors, using data from 1600 participants of the Multicenter OA Study (MOST), a large 30-month prospective cohort. We also propose examining the relation of subchondral bone attrition with cartilage defects on MRI, and with knee pain. Thus, this study proposes to examine potential contributors to the development and progression of OA, and identify potential targets for therapeutic strategies. Relevance: OA is the most common form of arthritis with no proven therapies for its management. Given our aging population, this constitutes a major public health concern. If we determine that mechanical and systemic factors interact to produce bony abnormalities in OA, this would suggest that both systemic and mechanical aspects must be targeted to successfully treat OA, including possibly antiresorptive therapy and vitamins D and K supplements in combination with knee braces.

Knee osteoarthritis (OA) is the leading cause of lower extremity disability among older adults in the United States. Inadequate pain relief with knee replacement (KR), the only definitive therapy for knee OA, occurs in ~20-30% of patients. Central sensitization (CS), which is an abnormal excitability of neurons in the central nervous system, causes heightened pain sensitivity and therefore may contribute to ongoing pain after KR. CS can occur for a variety of reasons, including mechanical and inflammatory inputs from diseased tissue, such as may be seen in knee OA, and therefore OA itself may be a risk factor for CS. Pilot data support an association of CS with severe pain post-KR, and with radiographic knee OA. The objective of this study is to comprehensively study the association of: 1) CS with pain post-KR; 2) duration and severity of radiographic knee OA, and specific features of inflammation (synovitis, effusion) and mechanical load (bone marrow lesions) with CS. These studies will provide insight into potential pathophysiologic mechanisms underlying post-KR and knee OA pain, and occurrence of CS. The study will be conducted within the NIH-funded Multicenter Osteoarthritis (MOST) Study, which is a cohort of ~3000 older adults with knee OA of varying severity and duration, as well as persons who are at high risk for knee OA, who have had longitudinal standardized assessments of disease, pain, and function over 7 years to date, with >600 KRs to date. This study will extend the evaluation of persons with KRs to enable greater assessments of CS pre- and post-KR. Two measures of CS will be evaluated: 1) temporal summation and 2) pressure pain threshold, which is a marker of peripheral and/or central sensitization at sites of disease/inflammation, or of CS when assessed at an otherwise normal area. The evaluation of these associations will occur in the context of other pertinent factors associated with poor KR pain outcomes that are comprehensively collected in this cohort. Insight into the role of CS in pain post-KR, and the pathology of OA that may contribute to CS will offer opportunity to develop rational new targets for improving pain outcomes in knee OA earlier in the disease process, as well as improving pain outcomes post-KR, which is currently the only definitive therapy available for knee OA.

PROJECT SUMMARY/ABSTRACT I am a rheumatologist and PhD-trained epidemiologist who has devoted my career to patient-oriented research (POR) focused on osteoarthritis (OA) and gout, two of the most common rheumatologic conditions, which contribute to pain, functional limitations, and diminished quality of life. My training has not only positioned me well to pursue high quality POR, but has also provided me with the necessary skills to train the next generation of clinical scientists. Over the past decade, I have demonstrated a strong commitment to mentorship though mentoring or co-mentoring 21 trainees in POR. These mentoring activities have led to successful funding for the majority of those mentees, including a junior faculty with a fundable K23 score. Further, all continue to perform clinical research, with all but one conducting Rheumatology-related research, and 4 current medical resident mentees are interested in pursuing clinical research careers in Rheumatology. This K24 award would enable me to expand and extend these successful mentoring endeavors so that I may serve as primary mentor to a greater number of mentees by ensuring that I have protected time and relief from future clinical and administrative duties. The broad goals of this K24 grant are to: 1) support my continued development and impact as a primary mentor in POR with a new focus on junior faculty, particularly K applicants and awardees, and those transitioning from K to R awards; 2) establish a new formal research mentor training program for POR in Rheumatology at Boston University School of Medicine (BUSM); and 3) enhance my own POR in a novel direction so that I continue to conduct scientifically rigorous and meaningful POR. With my commitment to POR and mentoring to date, the rich resources available at BUSM and the Clinical Epidemiology Unit, and strong institutional support, the K24 provides an invaluable opportunity to expand my mentoring capacity of junior faculty as primary mentor, with a special emphasis on women clinical researchers, and to establish a specialized structured POR and mentor training curriculum in Rheumatology with formal evaluation of mentees and mentors. In addition to mentoring, one of my long-term goals is to continue advancing my recognized research capabilities. The research proposed leverages my established expertise in OA and gout, and collaboration with experts in the field who have complementary proficiencies to strengthen my research program. Supported by strong biologic rationale, I propose to study the interrelationship between urate (the pathophysiologic culprit in gout) and OA using novel technologies. I will examine the relation of local urate deposition within the knee joints of 3000 subjects in a large NIH-funded cohort study using a novel imaging technology, dual-energy CT, which enables differentiation of urate from other forms of crystal deposition such as calcium, to OA pathology on MRI and to pain. I will also conduct a state-of-the-art proteomic analysis of synovial fluid to discern the impact of urate on inflammatory mediators in knee OA synovial fluid, and the relation to inflammatory features in OA, such as synovitis. The knowledge gap to be addressed by the proposed research will provide novel insights into a potentially new therapeutic target in OA, a disease for which there are currently no therapies available. Moreover, the proposed research will provide excellent mentoring opportunities. This K24 grant would greatly augment my existing research mentoring program in POR by enabling me to recruit and act as primary mentor to 2-3 new trainees and junior faculty annually, with the ultimate goal of developing the next generation of patient-oriented rheumatic disease clinical investigators and research mentors.

Chronic pain affects over 100 million American adults and >40% of older adults age ?65, with estimated costs of >$500 billion to $1 trillion annually. Older adults are at increased risk of having multiple painful conditions and are living longer with the negative impacts of chronic pain. Chronic pain, regardless of anatomy or diagnosis involved (e.g., back pain, migraine), is the leading cause of disability worldwide. Limited insights into whether common mechanisms underlie all pain conditions, regardless of diagnosis, has contributed to inadequate pain management options, and in turn, to the opioid epidemic. Health care providers who treat one pain condition (e.g., joint pain) typically do not manage symptoms in other parts of the body (e.g., abdominal pain), and patients are often referred from one specialist to another. Studying commonalities of various chronic overlapping pain conditions (COPC) in community-based cohorts unselected for pain conditions can provide novel insights into causes and consequences of chronic pain as a disease itself. For example, neurophysiologic alterations in pain processing such as pain sensitization (assessing ascending pain pathways) and conditioned pain modulation (CPM) (assessing descending pain modulation) may be common mechanisms underlying all chronic pain. Such knowledge would spur development of novel pain management approaches for all types of pain regardless of anatomy or diagnosis involved. Despite the substantial public health burden of chronic pain, little is known about the epidemiology and evolution of COPC in older adults, nor of the impact of COPC on physical function, risk of nursing home admission, and mortality in older adults. We propose to evaluate chronic pain in the upcoming study visit of a thoroughly-characterized community-based older adult cohort unselected for any pain complaints, the Framingham Heart Study (FHS) (N~1874, mean age 76, 84% ?age 70). We aim to understand the epidemiology of COPC, regardless of anatomy or diagnosis involved, the evolution of COPC over time, neurophysiologic alterations in pain processing as risk factors for COPC and its evolution, and consequences of COPC and altered pain processing in older adults. We propose acquiring objective quantitative sensory testing (QST) measures of pain sensitization and CPM, which are associated with pain severity and response to treatment in experimental settings of subjects selected for particular pain conditions. However, whether QST- assessed neurophysiologic alterations may be common underlying risk factors for all forms of chronic pain, and for functional limitations, institutionalization, and mortality in a community-based cohort of older adults unselected for pain is unknown. We will collect data regarding a multitude of chronic pain conditions, QST, self-report and performance-based physical function, and nursing home admissions during the next planned study visit, as well as two follow-up assessments to obtain longitudinal data, and leverage the ongoing FHS surveillance of mortality. Our work will address several knowledge gaps, and insights gained may ultimately facilitate new preventive and therapeutic approaches to relieving chronic pain and its consequences, regardless of underlying diagnosis.

Knee osteoarthritis (KOA) is a major public health problem that has high prevalence and is associated with increased morbidity and premature mortality. It has been identified as the biggest unmet medical need among musculoskeletal conditions. It is typically described as a slowly progressive disease, though some individuals have rapid structural progression. There are currently no treatments available to prevent the disease or halt its progression, due in part to challenges in identifying knees at highest risk for structural progression. The standard for assessing structural progression following development of KOA is loss of joint space width (JSW), however there is limited information regarding normal age-related changes vs. disease-related changes in JSW, potential differences by sex and race, or consequences for pain and function. The distinction between normal age-related decline in organ function and JSW loss characteristic of progressive KOA is not known and represents an important knowledge gap. The current proposal is a critical first step in evaluating the clinical relevance of change in JSW in terms of pain and function, as well as evaluation of risk factors. It uses pooled data from three of the largest and most diverse longitudinal observational studies of KOA: the Johnston County Osteoarthritis Project (JoCoOA), a population-based cohort; and the Multicenter Osteoarthritis Study (MOST) and the Osteoarthritis Initiative (OAI), two cohorts of individuals with or at risk of developing symptomatic KOA. Over multiple visits, these three cohorts, together comprising ~10,500 participants, collected comparable data on demographics, risk factors, patient-reported outcomes, and identical weightbearing fixed flexion knee radiographs scored for OA severity. The specific aims are to 1.) Describe the natural history of healthy knee aging in disease-free knees; 2.) Identify subgroups of knees based on longitudinal changes in knee structure, pain and function across the spectrum from healthy knee aging to rapid OA progression; and 3.) Evaluate the clinical relevance of JSW changes for an individual knee based on concurrent risk of increased pain and functional limitations, and for future knee replacement. These aims will be addressed separately for men and women, and separately for whites and African Americans.

Chronic pain affects over 100 million American adults, with an estimated cost of $560-635 billion annually, yet this major burden is relatively understudied in African Americans (AAs). Older adults are at increased risk of having multiple painful conditions and are living longer with the negative impacts of chronic pain. Chronic pain, regardless of anatomy or diagnosis involved (e.g., back pain, migraine), is the leading cause of disability worldwide. Limited insights into whether common mechanisms underlie all pain conditions, regardless of diagnosis, has contributed to inadequate pain management options. Health care providers who treat one pain condition (e.g., joint pain) typically do not manage symptoms in other parts of the body (e.g., abdominal pain), and patients are often referred from one specialist to another. Studying commonalities of various chronic overlapping pain conditions (COPC) in community-based cohorts unselected for pain conditions can provide novel insights into causes and consequences of chronic pain as a disease itself. For example, neurophysiologic alterations in pain processing such as pain sensitization (assessing ascending pain pathways) and conditioned pain modulation (CPM) (assessing descending pain modulation) may be common mechanisms underlying all chronic pain. Such knowledge would spur development of novel pain management approaches for all types of pain regardless of anatomy or diagnosis involved. Despite the substantial public health burden of chronic pain, little is known about the epidemiology and evolution of COPC in older AA adults, nor of the impact of COPC on physical or psychosocial function, risk of nursing home admission, and mortality in older AAs. We propose to evaluate chronic pain in the upcoming study visit of a thoroughly-characterized community-based older AA cohort unselected for any pain complaints, the Jackson Heart Study (JHS) (N~2540, two-thirds ?age 65). We aim to understand the epidemiology of COPC, regardless of anatomy or diagnosis involved, the evolution of COPC over time, neurophysiologic alterations in pain processing, healthy lifestyle factors and psychosocial factors as risk factors for COPC, and consequences of COPC and altered pain processing in older adults. We propose acquiring objective quantitative sensory testing (QST) measures of pain sensitization and CPM, which are associated with pain severity in experimental settings. Whether QST-assessed neurophysiologic alterations may be common underlying risk factors for all forms of chronic pain, and for poor physical and psychosocial functioning, institutionalization, and mortality in a community-based cohort of older AAs unselected for pain is unknown. We will collect data regarding a multitude of chronic pain conditions, QST, healthy lifestyle factors, physical and psychosocial function, and nursing home admissions during the next planned study visit, as well as two follow-up assessments to obtain longitudinal data, and leverage the ongoing JHS surveillance of mortality. Our work will address several knowledge gaps, and insights gained may ultimately facilitate new preventive and therapeutic approaches to relieving chronic pain and its consequences, regardless of underlying diagnosis.

Chronic pain affects >100 million American adults with estimated costs of up to $1 trillion annually. Older adults are at increased risk of having multiple painful conditions and are living longer with the negative impacts of chronic pain. Chronic pain, regardless of anatomy or diagnosis involved (e.g., back pain, migraine), is the leading cause of disability worldwide. Limited insights into whether common mechanisms underlie all pain conditions, regardless of diagnosis, has contributed to inadequate pain management options, and in turn, to the opioid epidemic. Health care providers who treat one pain condition (e.g., joint pain) typically do not manage symptoms in other parts of the body (e.g., abdominal pain), and patients are often referred from one specialist to another. Studying commonalities of various chronic overlapping pain conditions (COPC) in community-based cohorts unselected for pain conditions can provide novel insights into causes of chronic pain as a disease itself, and into shared risk factors that may be promising targets to help ameliorate chronic pain regardless of diagnosis. Alterations in nociceptive signaling such as pain sensitization assessed by quantitative sensory testing (QST) may commonly underlie chronic pain, but why such alterations occur is not known, and whether such nociceptive signaling changes are heritable is also not known. Beyond nociception, there may be broader nervous system dysfunction underlying chronic pain. Generalized heightened sensitivity to external stimuli (e.g., light, sound) and impaired autonomic nervous system functioning, reflected by diminished heart rate variability (HRV), are associated with chronic pain, but it is unclear if they contribute to COPC, QST-assessed abnormalities, or development of chronic pain. Treatments targeting these potential risk factors could represent new avenues for pain management. Another untapped potential is in understanding whether positive factors such as resilience, sleep quality, and physical activity can be harnessed to alter risk of COPC or QST abnormalities. We propose evaluating COPC in the upcoming study visit of a community-based middle age and older adult cohort unselected for any pain complaints, the 3rd Generation of the Framingham Heart Study (FHS) (N~3374, mean age 60). We aim to understand the relation of multisensory sensitivity, autonomic function, resilience, sleep, and physical activity to COPC, QST-assessed pain processing and evolution of chronic pain over time; and to study heritability of QST abnormalities. Understanding the relation of these novel factors to COPC and QST would spur development of novel pain management approaches for all types of pain regardless of diagnosis involved. We will collect data regarding common chronic pain complaints, QST (to assess pain sensitization), and proposed risk factors, and conduct two follow-up assessments to obtain longitudinal data. We will leverage the ongoing FHS Offspring (2nd Generation) Exam in which we are collecting the same QST measures to assess heritability of pain processing abnormalities. Our work will address several knowledge gaps, and insights gained may facilitate new approaches to relieving chronic pain and its consequences, regardless of underlying diagnosis.