Diffusion Tensor Imaging as a Biomarker for the Early Diagnosis, Staging and Progression of Osteoarthritis

 描述(由申请人提供)：骨关节炎(OA)是美国残疾的主要原因，影响着2700多万美国人，并代表着由于人口老龄化而急剧增加的经济负担。骨性关节炎的巨大预算影响在很大程度上是由于缺乏治疗骨质疏松症的已获批准的疗法。尽管在过去的几年里已经提出了新的治疗疾病的OA药物(DMOADs)，但它们的临床评价面临着许多困难，导致DMOADs的临床试验失败率很高。这些困难中的许多可以追溯到成像诊断的标准，就像50年来的平面射线照片一样。由于只能间接测量关节软骨和半月板的变化，平面X线片不能发现早期OA，DMOAD可能更有效，显示OA患者进展缓慢，并提供一个粗略的患者分期。关节软骨是早期诊断骨性关节炎的关键组织，因为软骨基质成分(蛋白多糖和胶原蛋白)的生化降解是骨性关节炎的早期征兆之一。检测关节软骨中PG和胶原的变化将显著提高对患者的诊断、分级和预后的能力。虽然很少有磁共振成像(MRI)参数对PG含量敏感，但对胶原的评估仍然很难，只有一些参数对胶原部分敏感。为了克服这一问题，我们建议使用扩散张量成像(DTI)作为OA的生物标志物。DTI对软骨基质的PG含量(通过平均弥散率(MD))和胶原结构(通过分数各向异性(FA))都很敏感。最近，我们开发了一种用于关节软骨3T弥散张量成像的新技术：径向自旋回波扩散张量成像(RAISTED)序列。在拟议的项目中，我们将验证关节软骨3T弥散张量成像在骨关节炎诊断、骨关节炎分期和骨关节炎进展预后中的作用。在目标1中，我们将以组织学为参考标准，在膝关节身体标本上验证优化的隆起序列。在目标2中，我们将进行一项体内横断面研究，以验证体内DTI对OA诊断、OA分期的有效性。我们将重点关注单侧骨性关节炎患者。这些受试者的一侧膝关节Kellgern Lawrence(KL)评分为II，对侧膝关节KL=I，我们还将包括一个KL为0的对照组。在基线检查中，我们将在目标3中测试DTI对疾病早期阶段的发现和分级能力，我们将进行为期3年的纵向研究，其中我们将检查单侧骨性关节炎患者的KL 1膝关节，为期3年。根据骨关节炎倡议(OAI)的数据，单侧OA和KL=1的患者在三年内进展到KL2的比例为26.1%。我们将测试在3年内出现进展的患者是否在基线或1.5年内增加了DTI，并在第3年增加了X光和临床评估。通过在体内验证所建议的方法，这项建议的结果将显著提高我们检测、分期和监测OA的能力，并有助于指导临床试验开发新的DMOADs。

 DESCRIPTION (provided by applicant): 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.