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，严重限制康复。HO发展迅速，通常直到创伤后和康复过程中相对较晚的时候才被认识到，当时这一过程很难逆转。消炎痛和依替磷酸二钠可延缓HO的发生。然而，预防性治疗的剂量往往不是最理想的，患者可能无法很好地耐受。然而，在诊断出HO后，全强度剂量现在在预防HO发展方面不那么有效，因为这一过程已发展到更坚定的阶段。最好的解决方案是尽早确定诊断，在生理性的预承诺阶段，通过最佳剂量的治疗是可逆的。因此，这项建议的主要目的将检验以下假设：1)通过测量脊髓损伤后一周内发生的与HO有关的早期生理事件，可以识别出易发生HO的脊髓损伤患者；以及2)通过核医学SPECT扫描，可以检测到在成骨发育的预先承诺阶段发生的假设量的生理活动，这将与三个月时的实际HO量相关联。这些假设将通过以下具体目标进行验证：1)确定合适的核医学成像方法和损伤后的成像时间为早期检测HO，患者将在脊髓损伤后1、4和12周进行Thallium-201和Tc-99mMDP的研究。这将导致验证最佳的单项筛查测试方案，以准确地识别将发展为HO的脊髓损伤患者。2)在同一时间点进行MRI解剖成像，确定病灶的位置和体积；3)确定康复临床资料与核医学和MRI扫描的相关性。建立的三维参考系统可以填充不同的造影剂，并在核医学SPECT扫描和MRI扫描中使用，将有助于提高准确性。这使得可以对MRI检测到的HO体积相关的早期生理活动进行共同定位和精确的体积评估。预计对脊髓损伤患者的康复有以下好处：1)具有成本效益和最佳时机的核成像扫描，以在早期可逆阶段检测HO的发展；2)关于HO在不同时间的发育过程的基本知识将通过TC-99m成像、Thal2 0 1成像和MRI成像来揭示。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形成的速度和幅度将被精确量化，并与脊髓损伤和康复的参数相关；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，以减少导致脊髓损伤后第一周内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早期HO形成的生理学预测因子来监测疗效，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.