In Vivo Imaging of Post-Traumatic Cerebral Amyloid Deposition

描述(申请人提供)：越来越多的证据表明，大脑淀粉样β蛋白(Abeta)沉积，在创伤性脑损伤(TBI)后迅速开始，发生于对轴突和氧化损伤的反应。我们的长期目标是验证使用一种新的分子探针[18F]FDDNP的正电子发射断层扫描(PET)成像来显示急性脑外伤患者体内的Abeta斑块。我们假设[18F]FDDNP的结合量将与脑脊液中可扩散的Abeta浓度和患者预后相关。其具体目的是：1)利用脑标本放射自显影和免疫组织化学方法，证实脑内[18F]FDDNP对脑Abeta沉积的特异性；2)通过[18F]FDDNP-PET显像，确定脑Abeta斑块沉积与脑脊液Abeta浓度之间的关系。[18F]FDDNP-PET已成功地用于对阿尔茨海默病患者的淀粉样蛋白病理进行成像，从而实现早期诊断和提高对疾病的了解。我们相信，在广泛的颅脑损伤严重程度范围内，利用正电子发射计算机断层扫描(PET)显示体内淀粉样蛋白沉积的能力，将使我们能够第一次评估脑损伤的发生率、时间进程和区域分布。更重要的是，它还可能提供一种非侵入性工具来监测旨在减少淀粉样蛋白沉积(包括神经炎症调节剂)的治疗效果。简而言之，研究设计需要对一系列轻度到重度颅脑损伤患者在受伤后(3-10天)进行FDDNP-PET的急性研究。这一结果可能具有重要的公共卫生意义，因为对大脑淀粉样蛋白沉积的病理后果的更好的理解可能会导致药物治疗，从而改善脑外伤后的预后。

DESCRIPTION (provided by applicant): Accumulating evidence suggests that cerebral amyloid beta (Abeta) deposition, which begins rapidly following traumatic brain injury (TBI), occurs in response to axonal and oxidative damage. Our long-term goal is to validate the use of positron emission tomography (PET) imaging with a novel molecular probe, [18F]FDDNP, for visualizing Abeta plaques, in vivo, in the setting of acute TBI. We hypothesize that the amount of [18F]FDDNP binding will correlate with both the concentration of diffusible Abeta in the cerebrospinal fluid and patient outcome. The Specific Aims are to 1) confirm the specificity of [18F]FDDNP for cerebral Abeta deposition [18F]FDDNP uptake following TBI using autoradiography and immunohistochemistry of brain specimens and, 2) determine the relationship between cerebral Abeta plaque deposition, assessed by [18F]FDDNP-PET imaging, and CSF Abeta concentration acutely following TBI. [18F]FDDNP-PET has been used successfully in imaging amyloid pathology in Alzheimer's disease patients, allowing early diagnosis and improved understanding of the disease. We believe that the ability to visualize amyloid deposition in vivo with PET, in a broad range of TBI injury severity, will allow us for the first time to assess the incidence, time course, and regional distribution. More importantly, it may also offer a noninvasive tool to monitor the efficacy of treatments aimed at decreasing amyloid deposition (including neuro-inflammation modulators). In brief, the research design entails studying a range of mild to severely head-injured patients acutely after injury (3-10 days) with FDDNP-PET. The results may have important public health implications in that improved understanding of the pathological consequences of cerebral amyloid deposition may lead to medical treatments that will improve outcome following TBI.