Noninvasive Assessment of Traumatic Brain Injury with PET using 64CuCl2

使用 64CuCl2 通过 PET 对脑外伤进行无创评估

• 批准号: 8326063
• 负责人: FANGYU PENG
• 金额: $ 20.83万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8326063
• 关键词: Accounting; Age; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Cell Proliferation; Cells; Cerebrum; Chloride Ion; Chlorides; Clinical Management; Clinical Trials; Copper; Cyclotrons; Failure; Functional disorder; Half-Life; Homeostasis; Human; Image; Immune response; Inflammation; Inflammatory; Intervention; Knowledge; Metabolism; Methods; Microglia; Minocycline; Molecular Chaperones; Monitor; Morbidity - disease rate; Mus; Nerve Degeneration; Neurological outcome; Oxidative Stress; Pathogenesis; Patient Selection; Patients; Persons; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Physiological; Physiological Processes; Play; Positron-Emission Tomography; Pre-Clinical Model; Radioactivity; Radioisotopes; Role; TBI Patients; Technology; Testing; Therapeutic; Therapeutic Effect; Tissues; Tracer; Traumatic Brain Injury; Wilson disease protein; Wound Healing; base; brain tissue; candidate identification; controlled cortical impact; copper transporter 1; design; glucose metabolism; improved; innovation; mortality; neuroinflammation; neurotransmission; neurotrophic factor; pre-clinical; treatment trial; uptake

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.

描述（由申请方提供）：本研究的目的是确定使用氯化铜（64 CuCl 2）作为示踪剂（Cu-64 PET）通过正电子发射断层扫描（PET）对创伤性脑损伤（TBI）中的神经炎症进行无创评估的可行性。 TBI是死亡和发病的主要原因，特别是在45岁以下的人中。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疗法在限制继发性神经变性和改善神经学结果方面是有效的。然而，这些干预措施在III期人体临床试验中尚未证明有效。有必要的方法足以无创评估TBI和选择患者的治疗试验。新的证据表明，神经炎症在TBI的发病机制中起着重要作用。PET是有吸引力的成像神经炎症基于其高灵敏度和适用于定量分析。虽然[11 C]（R）-PK 11195可用于脑组织中神经炎症的PET，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。因此，寻找更多的示踪剂用于PET神经炎症成像具有重要意义。 已知炎症与炎性细胞对铜的摄取增加有关。我们假设：1）TBI中的神经炎症与铜的摄取增加相关，这可以用Cu-64 PET非侵入性地评估; 2）Cu-64 PET可以用于选择具有活动性神经炎症的患者用于抗炎药物的临床试验;（3）Cu-64 PET可用于监测抗炎药物对TBI的治疗效果，基于用抗炎药物治疗的TBI小鼠脑组织中铜摄取的减少。为了验证我们的假设，我们将使用64 CuCl 2作为示踪剂，对皮质控制撞击（CCI）后的小鼠进行实验PET，以评估创伤脑组织中的神经炎症。本项目的具体目标是：目的1：确定是否可以用Cu-64 PET无创定量评估TBI后小鼠的神经炎症;目的2：确定是否可以用Cu- 64 PET监测抗炎药物对TBI的治疗效果。我们将使用米诺环素，一种有效的抗炎药，在这项拟议的研究。 这种新的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有望用于选择具有活动性神经炎症的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。