EARLY DETECTION: HETEROTOPIC OSSIFICATION IN CNS INJURY

异位骨化（HO）发生在脊髓损伤（SCI）后一至三个月内，严重限制康复。HO发展迅速，通常直到创伤后较晚和康复期间才被发现，此时这一过程难以逆转。吲哚美辛和地屈酸二钠可延缓HO的发展。然而，预防性治疗通常以次优剂量给予，并且患者可能不能很好地耐受。在诊断出HO后，由于该过程已经发展到一个更坚定的阶段，因此现在制定了全强度剂量，但在预防HO发展方面效果较差。最好的解决办法是尽早诊断，在生理上的前承诺阶段，这是可逆的最佳剂量的治疗。因此，本提案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（在SCI后一周内检测到），可以识别具有HO易感性的SCI患者；2)通过核医学SPECT扫描可以检测到骨化发展前阶段发生的生理活动的假设体积，这将与三个月时HO的实际体积相关联。这些假设将通过以下具体目的进行验证：1)确定适当的核医学成像方法和损伤后成像次数，以便早期发现HO，将在SCI后1周，4周和12周对患者进行铊-201和Tc-99m MDP研究。这将导致最佳单一筛选测试方案的验证，以准确识别将发展为HO的SCI患者。2)在同一时间点进行MRI解剖成像，确定肿瘤的位置和体积；3)确定康复临床数据与核医学和MRI扫描之间的相关性。准确性将通过建立三维参考系统来促进，该系统可以填充不同的造影剂，并在核医学SPECT扫描和MRI扫描期间使用。这允许共定位和精确的体积评估早期生理活动与MRI检测到的HO体积相关。预计对脊髓损伤患者康复的以下益处：1)成本效益和核成像扫描的最佳时机，以检测早期可逆阶段的HO发展；2)通过Tc-99m显像、铊-201显像、MRI显像揭示不同时期HO发育过程的基础知识。这一信息将有助于阐明HO发生和形成的病理生理学基础；3) HO形成的速度和大小将被精确量化，并与脊髓损伤和康复参数相关；4)这里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有效性，以减少脊髓损伤后第一周内导致HO形成的生理事件。未来的早期药物治疗方案可以使用这些HO形成的早期生理预测指标来监测其疗效，当该过程处于可逆阶段时。

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.