EARLY DETECTION: HETEROTOPIC OSSIFICATION IN CNS INJURY

异位骨化（HO）发生在脊髓损伤（SCI）后1 - 3个月内，严重限制了康复。 HO发展迅速，并且通常直到创伤后相对较晚和康复期间才被识别，此时该过程难以逆转。 吲哚美辛和依替膦酸二钠可延缓HO的发展。 然而，预防性治疗通常以次优剂量给予，并且患者可能耐受不良。 在诊断出HO后，制定了全强度剂量，然而，现在在预防HO发展方面效果较差，因为该过程已发展到更严重的阶段。 最好的解决方案是在早期诊断，在生理预承诺阶段，这是可逆的最佳剂量的治疗。 因此，本研究的主要目的是验证以下假设：1）通过测量HO相关的早期生理事件，可以识别出有发生HO倾向的SCI患者（SCI后一周内检测）;以及2）在所述预处理中发生的生理活动的假设量。通过核医学SPECT扫描可以检测到骨化发展的特定阶段，这将与三个月时的HO实际体积相关。 这些假设将通过以下具体目标进行检验：1）确定适当的核医学成像方法和损伤后的成像时间，以允许早期检测HO，患者将在SCI后1周、4周和12周通过铊-201和Tc-99 m MDP进行研究。 这将导致一个最佳的单一筛选测试协议的验证，以准确地识别SCI患者谁将发展为HO。 2)在同一时间点通过MRI进行解剖成像，以确定位置和体积; 3）确定康复临床数据与核医学和MRI扫描之间的相关性。 通过已建立的三维参考系统（可填充不同的造影剂并在核医学SPECT扫描和MRI扫描期间使用），可提高准确性。 这允许与通过MRI检测到的HO体积相关的早期生理活动的共定位和精确体积评估。 预计脊髓损伤患者康复的以下益处：1）核成像扫描的成本效益和最佳时机，以检测早期可逆阶段的HO发展; 2）Tc-99 m成像，铊-201成像和MRI成像将揭示不同时间HO发展过程的基本知识。 这些信息将有助于阐明HO启动和形成的病理生理学基础; 3）HO形成的速率和幅度将被精确定量，并与脊髓损伤和康复的参数相关;四、在此开发的成像方案可用于快速确定未来治疗试验或康复方案的功效，以减少导致HO形成的生理事件在SCI后的第一周内。 当HO形成过程处于可逆阶段时，可以使用这些HO形成的早期生理预测因子来监测未来的早期药物治疗方案的功效。

Heterotopic ossification (HO)occurs within one to three months of spinal cord injury (SCI), and severely limits rehabilitation. HO develops rapidly and is often not recognized until relatively late after trauma and during rehabilitation, when the process is difficult to reverse. Development of HO can be retarded by indomethacin and disodium etidronate. However, prophylactic treatment is often given in suboptimal doses and may not be well tolerated by the patient. After diagnosis of HO, full strength doses are instituted, however, are now less effective in preventing HO development since the process has developed to a more committed stage. The best solution is to establish the diagnosis very early, at a physiological pre-commitment stage, which is reversible by optimal doses of therapy. Therefore, the major purpose of this proposal will test the hypothesis that: 1) SCI patients predisposed to develop HO can be identified by measuring early physiological events involved in HO (detected within one week after SCI); and 2) a hypothetical volume of physiologic activities occurring in the pre-committed stage of ossification development can be detected by nuclear medicine SPECT scanning which will correlate with the actual volume of HO at three months. These hypothesis will be tested by the following specific aims: 1) determine the appropriate nuclear medicine imaging methodologies and imaging times after injury to allow early detection of HO, patients will be studied at one, four and 12 weeks after SCI by Thallium-201 and Tc-99m MDP. This will lead to the validation of an optimum single screening test protocol to accurately identify SCI patients who will progress to develop HO. 2) conduct anatomic imaging by MRI at the same time points to determine the location and volume of; and 3) to determine correlations between rehabilitation clinical data and nuclear medicine and MRI scans. Accuracy will be facilitated by an established three dimensional reference system that can be filled with different contrast agents and used during both the nuclear medicine SPECT scans and MRI scanning. This allows co- localization and precise volume assessment of early physiologic activity correlated to the volume of HO detected by MRI. The following benefits to rehabilitation of spinal cord injury patients are anticipated: 1) cost effective and optimal timing of nuclear imaging scans to detect HO development at an early reversible stage; 2) fundamental knowledge regarding the developmental process of HO at different times will be revealed by Tc-99m imaging, Thallium-201 imaging, and MRI imaging. This information will help clarify the pathophysiology underlying HO initiation and commitment to formation; 3) the rate and magnitude of HO formation will be precisely quantitated, and correlated with parameters of spinal cord injury, and rehabilitation; 4) the imaging protocols developed here can be used to rapidly determine the efficacy of future therapeutic trials or rehabilitation protocols to decrease physiological events leading to formation of HO within the first week after SCI. Future early drug therapy protocols can be monitored for efficacy using these early physiologic predictors of HO formation, when the process is in a reversible stage.