MR Biomarkers of Inflammation in Knee Osteoarthritis

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Osteoarthritis (OA) is highly prevalent in U.S. military service members and Veterans due to the impact of joint trauma and overuse injury. Its socioeconomic impact is substantial, estimated to approach $60 billion per year, and no disease-modifying treatments exist. Collaborative programs (such as CaRe-AP) have been proposed to develop a treatment for post-traumatic osteoarthritis (PTOA) that will relieve pain and improve function. The hypothesis that PTOA is caused by maladaptive repair responses including activation of the pro-inflammatory pathways of innate immunity that in turn result in pain, loss of function and structural decline have been broadly accepted. To this end, OA has long been characterized as a ‘wear and tear’ disease but is now considered a cell-mediated condition involving low-grade innate inflammation affecting all tissues of the joint (cartilage, bone, synovium, fat pads). Inflammatory processes increase the risk of knee OA (kOA) onset and progression, though the role of inflammation in the kOA, and as a determinant in successful treatments is unclear. Further, correlation of structural changes that result in progression of degeneration in kOA with those that serve as pain generators in this disease is crucial. Opioid prescriptions due to acute and chronic musculoskeletal pain visits increased by 50% between 2006 and 2010. MRI of kOA has historically focused on tissue specific drivers of OA, most notably cartilage evaluation. Our past work has pioneered a whole-joint approach to kOA, taking into consideration interactions between cartilage, meniscus and subchondral bone. The current MRI literature on the synovium, synovial fluid, infrapatellar fat pad (IFP) and bone marrow are limited, presenting a significant gap in MRI evaluation of kOA. The overwhelming majority of MRI literature addressing synovitis/effusion involves intravenous contrast-based protocols. In a patient population prone to peripheral vascular disease (affecting contrast delivery) and requiring longitudinal follow-up, contrast administration is suboptimal. Given the histologic elements of the inflammatory pathway in synovium, IFP and bone marrow, non-invasive identification and characterization of cellular infiltrates as well as their distinction from synovial hyperplasia, fibrosis and vascularity in tissues would represent a revolutionary step in understanding the role of inflammation in OA progression and response to therapy. Restriction Spectrum Imaging (RSI) is a novel diffusion-weighted technique that has been used to distinguish restricted diffusion within cells from other water compartments, has higher resolution than standard diffusion sequences, and has the potential to be standardized across institutions. Ultrashort Echo Time Dual Echo Steady State (UTE-DESS) combines UTE and DESS to characterize tissues with a range of intrinsic MR properties and allows quantitative evaluation of those properties (T1 and T2) as well as diffusion data. We hypothesize that these techniques can be used to identify cellular infiltrates (RSI) and distinguish them from regions of fibrosis and vascularity (UTE-DESS) in synovium, IFP and bone marrow in the setting of kOA. The overall goal of this project is to optimize and validate novel non-invasive (RSI and UTE-DESS) MRI biomarkers of joint inflammation that can identify and characterize inflammatory changes of cellular infiltrates, fibrosis and vascularity in synovium, IFP and bone marrow. We will deploy these MR biomarkers of inflammation in a preclinical animal model (mild, moderate and severe kOA) and translate optimized sequences to assess conservative therapy in kOA subjects. We will develop a multi-variate statistical model that incorporates outcomes from clinical morphologic MRI, novel optimized MR biomarkers of inflammation, MR spectroscopy to create a structural/ biochemical framework to correlate with kOA pain/function.