Noninvasive Assessment of Traumatic Brain Injury with PET using 64CuCl2

描述(申请人提供)：本研究的目的是确定以氯化铜-(64CuCl2)为示踪剂(铜-正电子发射断层扫描)无创性评估创伤性脑损伤神经炎症的可行性。脑外伤是死亡和发病的主要原因，特别是在45岁以下的人群中。在临床前动物模型中，旨在调节兴奋性神经传递、氧化应激和神经营养因子等的治疗方法在限制继发性神经变性和改善神经预后方面一直有效。然而，这些干预措施在第三阶段的人体临床试验中并未被证明有效。需要有足够的方法对脑外伤进行非侵入性评估，并为治疗试验选择患者。越来越多的证据表明，神经炎症在脑外伤的发病机制中起着重要作用。PET具有较高的灵敏度和适合于定量分析的特点，因此在神经炎症成像方面具有很大的吸引力。虽然[11C](R)-PK11195可用于脑组织神经炎症的正电子发射计算机断层扫描，但C-11放射性核素的短半衰期限制了其在具有现场回旋加速器的成像中心的使用。寻找更多的示踪剂用于PET对神经炎症的成像具有重要意义。已知炎症与炎症细胞对铜的摄取增加有关。我们假设：1)脑外伤后神经炎症与铜摄取增加有关，铜-PET可对此进行无创性评估；2)铜-PET可用于筛选神经炎症活动期患者进行抗炎药物的临床试验；3)铜-PET可根据抗炎药物治疗后小鼠脑组织铜摄取量的减少来监测抗炎药物对脑损伤的治疗效果。为了验证我们的假设，我们将使用64CuCl2作为示踪剂，对小鼠进行皮层受控撞击(CCI)后的实验性PET，以评估创伤脑组织中的神经炎症。本项目的具体目的是：目的1：确定铜-PET能否无创性定量评价小鼠脑损伤后的神经炎症反应；目的2：确定铜-PET能否监测抗炎药物对脑损伤的治疗效果。在这项拟议的研究中，我们将使用米诺环素，一种有效的抗炎药物。这项新的铜-PET技术有望对脑外伤患者的临床治疗产生重大影响：1)铜-PET有望用于脑外伤患者神经炎症的定位和定量评估；2)铜-PET有望用于筛选脑损伤患者神经炎症活动性的患者进行抗炎药物临床试验；3)铜-PET有望用于监测脑损伤患者的抗炎治疗。

DESCRIPTION (provided by applicant): The purpose of this study is to determine feasibility of noninvasive assessment of neuroinflammation in traumatic brain injury (TBI) with positron emission tomography (PET) using copper-64 chloride (64CuCl2) as a tracer (Cu-64 PET). TBI is a major cause of mortality and morbidity, particularly among persons below the age of 45. In pre- clinical animal models, therapies aimed at modulating excitatory neurotransmission, oxidative stress, and neurotrophic factors, among others, have been effective in limiting secondary neurodegeneration and improving neurological outcome. These interventions, however, have not proved effective in Phase III human clinical trials. There is a need for methods adequate for noninvasive assessment of TBI and selection of patients for treatment trials. Emerging evidence indicates that neuroinflammation plays an important role in the pathogenesis of TBI. PET is attractive for imaging neuroinflammation based on its high sensitivity and suitability for quantitative analysis. Although [11C] (R)-PK11195 is useful for PET of neuroinflammation in brain tissues, but the short-half life of C-11 radionuclide restrict its use to imaging centers with an onsite cyclotron. It is significant to search for additional tracers for imaging neuroinflammation with PET. It has been known that Inflammation is associated with increased uptake of copper by the inflammatory cells. We hypothesize that: 1) neuroinflammation in TBI is associated with increased uptake of copper, which may be assessed non-invasively with Cu-64 PET; 2) Cu-64 PET may be used to select patients with active neuroinflammation for clinical trials of anti-inflammatory drugs; 3) therapeutic effects of anti-inflammatory drugs on TBI may be monitored with Cu-64 PET, based on reduction of copper uptake in the brain tissues of TBI mice treated with anti-inflammation drugs. To test our hypothesis, we will conduct experimental PET of mice post Cortical Controlled Impact (CCI) to assess neuroinflammation in the traumatized brain tissues, using 64CuCl2 as a tracer. The Specific aims of this proposed project are: AIM 1: To determine whether neuroinflammation in mice with TBI post can be assessed noninvasively and quantitatively with Cu-64 PET; AIM 2: To determine whether therapeutic effects of anti-inflammatory drugs on TBI can be monitored with Cu- 64 PET. We will use minocycline, a potent anti-inflammatory drug, in this proposed study. This new Cu-64 PET technology is expected to have significant impact on clinical management of the patients with TBI: 1) Cu-64 PET is expected to be useful for localization and quantitative assessment of neuroinflammation in the patients with TBI; 2) Cu-64 PET is expected to be useful for selection of the TBI patients with active neuroinflammation for anti-inflammation drug clinical trials; 3) Cu-64 PET is expected to be useful for monitoring anti-inflammatory therapies in patients with TBI.