Noninvasive Assessment of Traumatic Brain Injury with PET using 64CuCl2

描述（由申请人提供）：本研究的目的是确定使用Cu-64氯化铜（64CuCl2）作为示踪剂（Cu-64 PET）的正电子发射断层扫描（PET）无创性评估创伤性脑损伤（TBI）神经炎症的可行性。脑外伤是造成死亡和发病的一个主要原因，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在限制继发性神经变性和改善神经预后方面是有效的。然而，这些干预措施尚未在III期人体临床试验中证明有效。有必要有足够的方法对创伤性脑损伤进行无创评估和选择患者进行治疗试验。新的证据表明，神经炎症在创伤性脑损伤的发病机制中起重要作用。PET因其高灵敏度和定量分析的适用性，在神经炎症成像中具有重要的应用价值。虽然[11C] (R)-PK11195可用于脑组织神经炎症的PET检查，但由于C-11放射性核素的半衰期短，限制了其在现场回旋加速器成像中心的应用。寻找其他示踪剂用于PET成像神经炎症具有重要意义。众所周知，炎症与炎症细胞对铜的吸收增加有关。我们假设：1)创伤性脑损伤的神经炎症与铜摄取增加有关，这可以用Cu-64 PET无创评估；2) Cu-64 PET可用于筛选活动性神经炎症患者进行抗炎药物的临床试验；3)利用Cu-64 PET检测抗炎药对TBI小鼠脑组织铜摄取的减少，可以监测抗炎药对TBI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，对小鼠皮质控制性撞击（CCI）后进行实验性PET，以评估创伤脑组织的神经炎症。本项目的具体目的是：目的1：确定Cu-64 PET是否可以无创定量评估TBI后小鼠的神经炎症；目的2：探讨Cu- 64 PET是否可以监测抗炎药物对TBI的治疗效果。在这项研究中，我们将使用米诺环素，一种有效的抗炎药物。这种新型Cu-64 PET技术有望对TBI患者的临床管理产生重大影响：1)Cu-64 PET有望用于TBI患者神经炎症的定位和定量评估；2) Cu-64 PET有望用于选择活动性神经炎症的TBI患者进行抗炎药物临床试验；3) Cu-64 PET有望用于监测TBI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. PUBLIC HEALTH RELEVANCE: 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). Cu-64 PET is expected to be useful for localization and quantitative assessment of neuroinflammation in the traumatized brain tissues, selection of patients with TBI for anti-inflammation drug trials, and monitoring therapeutic effects of anti-inflammatory drugs in patients with TBI.