Osteoarthritis (OA) is the leading cause of disability in the US, affecting more than 27 million Americans, and represents a dramatically increasing financial burden as a consequence of population aging. The huge budgetary impact of OA is largely due to the absence of approved therapies for the treatment of OA. Though new disease modifying OA drugs (DMOADs) have been proposed over the last several years, their clinical evaluation faces many difficulties, which result in high drop out rates of clinical trials for DMOADs. Many of these difficulties trace back to the standard for imaging diagnosis, which is as for 50 years plane radiographs. Plane radiographs cannot detect early stages of OA, where the DMOAD can be more effective, show slow progression in OA patients and provide a crude patient staging since only indirect measurement of changes in articular cartilage and menisci is possible. Articular cartilage is a key tissue for the early diagnosis of OA, since biochemical degradation of the components of cartilage matrix (proteoglycan [PG] and collagen) are among the first signs of OA. Detection of changes in PG and collagen in articular cartilage would significantly improve our ability for patient diagnosis, grading and prognosis. Although few magnetic resonance imaging (MRI) parameters are sensitive either to PG content, the assessment of the collagen remains elusive with only some parameters partially sensitive to collagen. To overcome this problem we propose to use diffusion tensor imaging (DTI) as biomarker for OA. DTI is sensitive to both PG content (through the mean diffusivity (MD)) and the collagen architecture (through the fractional anisotropy (FA)) of cartilage matrix. Recently, we have developed a novel technique for DTI of articular cartilage at 3 T: a radial spin-echo diffusion tensor imaging (RAISED) sequence. In the proposed project we will validate DTI of articular cartilage at 3 T for OA diagnosis, OA staging and prognosis of OA progression. In aim 1 we will validate the optimized RAISED sequence on knee cadaver samples using histology as a standard of reference. In aim 2 we will conduct an in vivo cross- sectional study to validate DTI in vivo for OA diagnosis, OA staging. We will focus of OA patients with unilateral OA. These subjects will have Kellgern Lawrence (KL) score II in one knee and KL=I in the contralateral knee, we will include also a control group with KL 0. In the baseline examination we will test the ability of DTI to detect and grade early phases of the disease In aim 3 we will perform a 3-year longitudinal study in which we will examine the KL 1 knee of patients with unilateral OA for a period of three years. According to data form the Osteoarthritis initiative (OAI) subjects with unilateral OA and KL=1 have a progression to KL 2 over three years of 26.1%. We will test whether the patients showing progression in 3 years have increased DTI at baseline or 1.5 years and X-ray and clinical assessment in year 3. By validating the proposed methodologies in vivo, the results from this proposal will profoundly improve our ability to detect, stage and monitor OA and help guide clinical trials for the development of new DMOADs.