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，影响超过2700万美国人，并且由于人口老龄化而造成经济负担急剧增加。OA的巨大预算影响主要是由于缺乏用于治疗OA的批准疗法。尽管近年来不断有新的疾病修饰OA药物（DMOAD）被提出，但其临床评价面临诸多困难，导致DMOAD临床试验的高脱落率。这些困难中的许多可以追溯到影像诊断的标准，这是50年来的平面X线片。平面X线片不能检测OA的早期阶段，其中DMOAD可以更有效，显示OA患者的缓慢进展，并提供粗略的患者分期，因为只能间接测量关节软骨和关节软骨的变化。关节软骨是早期诊断OA的关键组织，因为软骨基质组分（蛋白聚糖[PG]和胶原蛋白）的生化降解是OA的最初体征之一。检测关节软骨中PG和胶原的变化，可显著提高对患者的诊断、分级和预后的判断能力。尽管很少有磁共振成像（MRI）参数对PG含量敏感，但胶原蛋白的评估仍然难以捉摸，只有一些参数对胶原蛋白部分敏感。为了克服这个问题，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（通过平均扩散率（MD））和胶原结构（通过分数各向异性（FA））敏感。最近，我们开发了一种新的技术，在3T的关节软骨DTI：径向自旋回波扩散张量成像（RAISED）序列。在本项目中，我们将验证3T下关节软骨的DTI用于OA诊断、OA分期和OA进展的预后。在目标1中，我们将使用组织学作为参考标准，在膝关节尸体样本上验证优化的RAISED序列。在目标2中，我们将进行一项体内横断面研究，以验证DTI在体内用于OA诊断、OA分期。我们将重点关注单侧OA患者。这些受试者的一个膝关节的Kellgern Lawrence（KL）评分为II，对侧膝关节的KL=I，我们还将纳入KL 0的对照组。在基线检查中，我们将测试DTI检测和分级疾病早期阶段的能力。在目标3中，我们将进行一项为期3年的纵向研究，其中我们将检查单侧OA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的受试者在3年内有26.1%进展至KL 2。我们将测试3年内显示进展的患者是否在基线或1.5年时增加了DTI，并在第3年进行X线和临床评估。通过在体内验证所提出的方法，该提案的结果将大大提高我们检测、分期和监测OA的能力，并有助于指导新DMOAD开发的临床试验。

 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.