PROJECT SUMMARY Osteoarthritis (OA) is a leading cause of pain and disability worldwide and results in a reduced quality of life due to pain from common tasks such as walking or climbing and descending stairs. A particular challenge of OA is detection of disease at an early and reversible stage before irreversible structural damage has occurred. However, current imaging methods are performed in a static fashion and have limited sensitivity to joint function or the tissue response to loading. There is a major need to evaluate the joint response from everyday loading tasks, and how this response is altered in OA. Further, as age is a key risk factor of osteoarthritis, which predominantly affects older adults, the role of aging in tissue changes and response to loading stress is of particular interest. PET-MRI offers simultaneous evaluation of multiple early markers of OA in all joint tissues. In particular, [18F]NaF uptake can quantitatively evaluate bone metabolism, including bone perfusion and deposition of [18F] ions into the bone matrix. Further, we have observed that joint loading acutely alters the bone physiology affecting [18F]NaF uptake. This suggests that [18F]NaF uptake may be sensitive to increases in the metabolic response of bone where there is breakdown of the whole-joint unit that results in focal increases in bone loading. This project aims to develop a novel imaging “stress test”, based on [18F]NaF PET-MRI, that is able to evaluate at a single time point, both the function of the whole-joint unit after physiological joint loading and multiple early markers of OA. Our Specific Aims are to (1) develop a rapid, quantitative, dose- and time-minimized [18F]NaF PET-MRI protocol to evaluate joint function from a stair ascent/descent exercise “stress” test ; (2) evaluate [18F]NaF PET-MRI imaging to detect and characterize differences in joint function associated with age and between sexes; and (3) evaluate tissue response to loading stresses measured with PET-MRI in early OA and whether abnormal response is predictive of OA disease progression. The innovation of this project is the development of novel PET and MRI methods to assess the whole-joint response to loading and evaluation of early degenerative disease changes affecting joint function and future OA progression. The significance of this work is an imaging method that is able to rapidly assess joint function in response to physiological loads, and evaluation of how this joint response evolves with age and between genders, as well as the role of altered joint physiology in OA. This may allow us to detect early joint dysfunction at a single time point, to not only study OA pathophysiology, risk factors, and phenotypes, but also to develop targeted interventions.