Name: pet imaging of neuroinflammation using [11c]dpa-713 in a mouse model of ischemic stroke
Uploaded: 2018-06-14T13:00:00.000+00:00
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Description: Watch this Scientific Journal Video about PET Imaging of Neuroinflammation Using [11C]DPA-713 in a Mouse Model of Ischemic Stroke at JoVE.com

作者感谢 Buckwalter 实验室 (特别是托德. 彼得森博士) 提供老鼠模型和执行 dMCAO 和假手术。此外, 我们还要感谢 Invicro 的托马斯 Liguori 为他的技术援助与 VivoQuant 图像分析软件, Tim 道尔博士, 劳拉 Pisani, Frezghi 博士 Habte 从 SCi3 小动物成像设施在斯坦福的意见和协助开发这一成像协议, 和放射化学设施 (特别是钧博士公园) 为他们的帮助与综合 [11C] DPA-713。

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作者声明没有利益冲突。

该协议描述了使用 [11C] DPA-713-PET 对 dMCAO 和假鼠 neuroinflammation 进行量化的方法。TSPO PET 是目前最广泛研究的影像生物标志物, 用于可视化和测量 neuroinflammation。TSPO 表达是上调在脑胶质细胞炎症允许无创检测和量化的 neuroinflammation。此外, 它是一种高度翻译的技术, 使它成为一个宝贵的工具, 在临床和临床前的研究。该协议和代表性的结果突出了使用 [11C] DPA-713 PET 检测和监测中风和其他神经系统疾病在体内的 neuroinflammatory 改变的适用性。
本研究采用3月大的 C57BL/6 雌性小鼠进行 dMCAO 手术。这一模型的选择, 因为它导致一个高度可重现性梗塞局限于体感皮层, 提供了一个永久性局灶缺血的模型与其他中风模型 (如大脑中动脉, 低变异性)闭塞 (MCAO) 灯丝法)14。脑卒中模型的 PET 成像具有在大脑中包含一个内部参考区域的优势, 每个动物使用 ROIs 在对侧半球。由于手术后会产生一些炎症, 因此在研究设计中包括接受假手术的小鼠是很重要的, 即在没有动脉闭塞的情况下, 对脑膜进行开颅和手法治疗。单开颅手术可能会导致潜在的神经组织中断, 并引入病原体, 导致免疫应答独立于中风20。因此, 假手术后的一些炎症是预期的, 应该与 dMCAO 平行评估, 以排除仅因手术而导致信号的可能性。为了避免在 dMCAO 队列分析中包括没有中风的手术引起的炎症, mr 成像必须进行, 以确认成功的中风手术和梗塞的发展。MRI 也提供了一个结构参考框架, 这是必不可少的准确绘制梗死和对侧 ROIs。此外, 还需要准确的图像处理, 包括图像配准和 ROI 定义, 以确保可靠的量化。
当与 C-11 标记 radiotracers 进行 PET 和显影研究时, 必须牢记额外的限制。必须考虑短半衰期 (20.33 分钟) 的 C-11, 其使用一般限于研究机构, 现场回旋接入。必须事先确定适当的放射性运输路线、剂量管理和采集时间点, 并预先准备好实验工作流程的详细计划, 使团队能够快速有效地工作。这项研究的设计和建立已经概述, 以适应4小鼠的成像同时增加数据输出时, 使用 C-11 示踪剂。如果可能的话, 最好在 C-11 示踪器到达成像设备时, 让所有的老鼠空心化, 并在 CT 扫描中进行, 以确保注射前的放射性衰减最小。这一步步协议最好是由至少3位研究人员进行, 以便在重大放射性衰变之前快速插管、剂量测量、示踪剂注射、PET 扫描和脑切片。这需要两个人进行 PET 扫描和注射所有4只老鼠同时进行。在注射前开始 PET 采集的原因是为了保证血液和感兴趣区域的示踪剂分布的药代动力学和动力学得到准确和完全的捕获。许多步骤可能需要进行有力的训练和练习, 以确保实验的顺利运行。特别是, 这个协议依赖于成功的尾静脉插管的 C57BL/6 小鼠, 这可能是困难的, 因为深色的头发呈现在他们的尾巴上, 可能会变得更具挑战性的中风后发生或如果在多个时间点成像相同的老鼠.
PET 成像的另一个考虑因素包括仔细记录放射性剂量和残余活动测量, 包括确切的测量时间。这对于在扫描时注入剂量的精确衰减校正是必不可少的, 并且用于获得对每个 ROI 的示踪剂摄取量 (即% ID/g) 的精确测量。在扫描时, 要知道每只老鼠的放射性确切量, 以确保准确的图像分析。因此, 最好同步扫描仪计算机上的时钟和剂量校验仪, 以避免在使用 C-11 等短命同位素时出现错误。
精确的 PET 图像量化也可以被扫描仪的精度和设置所限制。因此, 为了确保准确量化的 PET/ct 图像, 重要的是进行质量控制检查的 CT 和 pet 部件的扫描仪。CT 质量控制检查包括 x 射线源调节, 暗/光, 和中心关闭设置校准。这些校准措施和正确的系统噪音, 必须在收购之前按照扫描仪制造商的建议执行。对 PET 扫描仪也应进行校准。这通常包括扫描 "标准/宠物幻影" 扫描, 其中包含已知的放射性浓度。在制定标准时, 最好使用与研究中使用的放射性同位素相同的放射性核素, 这一剂量与老鼠体内的一只小鼠相比, 与动物成像的采集参数相同。在本议定书中, 用放射性稀释的20毫升注射器作为标准, 随后的 PET 成像结果用于根据校准探测器测量的实际剂量计算校正系数。该校正比可应用于实验获得的成像数据, 以确保对 PET 图像感兴趣区域的示踪剂摄取进行准确量化。除了考虑扫描当天出现的任何背景活动外, 这也说明了放射性核素的正电子范围。由于剂量校验仪是这一校正因子生成的一个组成部分, 因此必须根据制造商指南定期校准该设备。
在进行体外显影时, 选择注射后安乐死的最佳时间点是很重要的, 以确保感兴趣区域的高信号到背景。三十分钟后注射是选择 [11C] DPA-713 显影使用在动态 PET 成像中获得的数据-即, 在体内动态口香糖作为指导, 同时也考虑到 C-11 的短半衰期和时间参与切片并在提取后暴露脑组织。考虑到这一点, [11C] DPA-713 显影必须在单独的一组小鼠上进行, 以允许注射更高的 [11C] DPA-713 剂量和30分钟的时间点用于麻醉下灌注和安乐死。在进行体外显影前对3-4 只小鼠进行小体内 PET 试验研究将有助于确定显影的最佳时间点。另外一个考虑的是体内显影是在注射后恢复小鼠, 还是将其麻醉直到安乐死。让他们麻醉模仿扫描的条件, 并确保放射性分布或排泄动力学不改变的恢复。此外, 这可以防止对小鼠的额外压力, 避免恢复和随后的诱导。最后, 一个有用的补充, 在前体协议将是评估的区域损害的脑切片用于显影通过免疫组化染色 (放射性衰变后), 以产生高分辨率图像的梗塞地点和体积。
由于使用基于 C-11 的跟踪器有限制, 因此可以很容易地修改此协议, 以便使用 F-18 (半衰期为109.77 分钟) 的 TSPO 跟踪程序, 这可能更适用于没有现场回旋加速器的位置。此外, 此协议还描述了使用4鼠标映像设置的情况。虽然这种高通量方法在使用 C-11 示踪器时是最佳的, 但对于使用单鼠标成像床的那些协议也可能进行修改。对本议定书所概述的技术进行周密的规划和一致的培训将导致使用 [11C] DPA-713 生成大量数据, 这可以很容易地用于探讨 neuroinflammation 在疾病表现中的作用和神经系统疾病的其他啮齿动物模型的进展。此外, 这项技术可以用来评估在体内对小胶质细胞的免疫调节疗法的反应。

中风是第五大死因, 也是美国1残疾的主要原因。缺血性中风是绝大多数这些病例 (87%), 发生在血液流向大脑的局部中断 (例如,由血块或脂肪堆积)。随后减少了对受影响地区的氧气和养分供应, 并启动了复杂的病理级联, 导致脑卒中核心 (梗塞) 内的神经元死亡, 除了周围地区。Neuroinflammation 是导致这种损害的途径中的一个关键组成部分, 包括居民脑免疫细胞和浸润性外周免疫细胞 (中性粒细胞、T 细胞、B 细胞和单核巨噬细胞), 认为这有助于破坏性级联2,3。活化小胶质细胞和巨噬菌是这 neuroinflammatory 反应的中心, 报告的有害和有益的影响后, 缺血性中风2。因此, 必须评估这些细胞在中风后的体内贡献。
PET 是一种强大的3维分子成像技术, 通过使用标记为正电子 (β +) 放射放射性核素的特定分子 (如11C、 13N), 可以在体内可视化生物过程, 15O 和18F。这种非侵入性方法比体外方法 (如免疫组化) 有许多优点, 因为它允许实时获取分子信息, 在活着的完整的主题, 并允许纵向调查。PET 成像的 TSPO, 一个标记的活化小胶质细胞和外周髓系体细胞, 提供了一种手段, 以量化和跟踪体内的先天免疫细胞反应, 并可用于评估中风后炎症和反应治疗干预。TSPO, 以前称为外周型苯二氮受体, 是一个 18 kDa 蛋白, 被认为是在胆固醇运输和合成神经甾体4的作用。此外, 证据表明, TSPO 参与了 neuroinflammation 和神经元存活5,6, 报告说, 在许多神经系统疾病包括中风7的表达增加,痴呆症8, 帕金森病9和多发性硬化症10。TSPO 位于外线粒体膜上, 在周围有高度表达, 特别是在类固醇相关组织 (如腺体) 中, 以及在心脏、肾脏和肺部10中可见的中层水平。然而在健康的大脑中, TSPO 水平低, 主要受限于胶质细胞6,11。在脑卒中观察到的神经元损伤后, 中枢神经系统 (CNS) TSPO 水平显著增加。这种观察到的上调 TSPO 可以被利用在体内图像 neuroinflammation, 表达水平提供了准确的炎症严重性指标。因此, 该方法的目的是准确量化 neuroinflammation 在小鼠脑缺血性中风模型中的作用, TSPO PET。
针对 neuroinflammation 的 PET 成像, 研制了多种 TSPO 示踪剂。在这里, TSPO-PET 成像被描述使用 [11C] DPA-71312, 一个有希望的第二代 TSPO 示踪器, 它显示了增强信号的噪声和较低的非特定绑定比历史上使用 [11C] PK11195 13.以此方法为例, 选择了 dMCAO 小鼠中风模型14。该模型包括颞侧开颅术和远端大脑中动脉的永久性结扎, 导致体感皮层局灶性缺血。这有利于临床前中风的研究, 由于缺血性损伤的高重现性和低死亡率相关的模型。到目前为止, TSPO PET 成像研究尚未在 dMCAO 啮齿动物模型中报道。然而, 以往的 PET 成像研究使用大脑中动脉闭塞 (MCAO) 模型, 一个更严重和可变中风模型, 在小鼠和大鼠, 报告 TSPO 表达增加从3天和峰值7天后中风15, 16,17,18。因此, 我们进行了6天后 dMCAO 的 PET 成像与高 TSPO 表达一致。[11C]在同侧 (梗塞) 和对侧半球评估脑 DPA-713 吸收。TSPO-PET 结合结构 MRI, 可精确划定梗死和对侧区域的兴趣 (ROIs)。在这里, 我们描述了基于 atlas 和 MRI 驱动的 ROI 方法来计算 [11C] DPA-713 的吸收。放射性在脾脏中的摄取量也被评估以调查组间炎症的周围水平。这种方法有可能为脑卒中和其他神经系统疾病的时空动力学和特定 neuroimmune 交互作用提供重要的洞察力。

<table><tbody><tr><td>Inveon PET/CT scanner</td><td>Siemens</td><td>Version 4.2</td><td></td></tr><tr><td>MRI scanner</td><td>Varian</td><td></td><td>7 Telsa</td></tr><tr><td>ParaVision software</td><td>Bruker</td><td>Version 6.0.1</td><td>MRI operating software</td></tr><tr><td>VivoQuant software</td><td>InVicro</td><td>Version 2.5</td><td>Image analysis software</td></tr><tr><td>Inveon Research Workspace software</td><td>Siemens</td><td>Version 4.2</td><td>Scanner operating software. Includes microQView, the post-processing managing software</td></tr><tr><td>Dose calibrator</td><td>Capintech</td><td></td><td>CRC-15 PET</td></tr><tr><td>Typhoon phosphor imager 9410</td><td>GE Healthcare</td><td>8149-30-9410</td><td></td></tr><tr><td>Butterfly catheters</td><td>SAI Infusion Technologies</td><td>BFL-24</td><td>27.5 G needle</td></tr><tr><td>1 mL syringes</td><td>BD</td><td></td><td></td></tr><tr><td>Insulin syringes</td><td>BD</td><td>329461</td><td>0.5 mL insulin syringes with needle</td></tr><tr><td>20 mL syringe&amp;nbsp;</td><td>VWR</td><td>BD302831</td><td>BD Syringe Slip Tip Graduated</td></tr><tr><td>Tissue glue</td><td>Santa Cruz Animal Health</td><td>sc-361931</td><td>3 mL</td></tr><tr><td>Heat lamp</td><td>Fluker</td><td>27002</td><td>5.5&quot; reptile heat lamp with clamp and switch</td></tr><tr><td>0.9% sterile saline</td><td>Pfizer</td><td>00409-4888-10</td><td>0.9% sodium chloride for injection, 10 mL</td></tr><tr><td>Eye lubricant</td><td>Watson Rugby</td><td>PV926977</td><td>Artificial Tears Lubricant Eye Ointment, 1/8 oz</td></tr><tr><td>Chux absorbent sheets</td><td>ThermoFisher Scientific</td><td>1420662</td><td>Disposable absorbent padding</td></tr><tr><td>Iris scissors</td><td>World Precision Instruments</td><td>503708-12</td><td>11.5 cm, Straight, 12-pack</td></tr><tr><td>Surgical tape</td><td>3M Durapore</td><td>1538-0</td><td>1/2&quot; x 10 yard roll, silk, hypoallergenic</td></tr><tr><td>Mouse PET bed</td><td>In house</td><td></td><td>4 mouse PET bed</td></tr><tr><td>Lighter</td><td>Bic</td><td>UDP2WMDC</td><td></td></tr><tr><td>Isoflurane</td><td>Henry Schein</td><td>NDC 11695-6776-2</td><td>Isothesia, inhalation anesthetic, 250 mL</td></tr><tr><td>Oxygen</td><td>Praxiar</td><td>UN1072</td><td>Compressed gas</td></tr><tr><td>Autoradiography cassette</td><td>Cole Palmer</td><td>EW-21700-34</td><td>Aluminum, 8&quot; x 10&quot;</td></tr><tr><td>Autoradiography film</td><td>GE Life Sciences</td><td>28-9564-78</td><td>Storage Phosphor Screen BAS-IP SR 2025 E Super Resolution, 20 &amp;times; 25 cm, screen only</td></tr><tr><td>Microtome blades</td><td>ThermoFisher Scientific</td><td>30-508-35</td><td>MB35 Premier Disposable, 34&amp;deg; cutting angle</td></tr><tr><td>Microtome</td><td>Microm</td><td></td><td>HM 550</td></tr><tr><td>Microscope slides</td><td>Fisher Scientific</td><td>12-550-15</td><td>Superfrost&amp;trade; Plus Microscope Slides</td></tr><tr><td>OCT liquid</td><td>VWR</td><td>25608-930</td><td>Formulation of water-soluble glycols and resins for cryostat sectioning at temperatures of -10&amp;deg;C (14&amp;deg;F) and below</td></tr><tr><td>Freezing molds</td><td>Poly sciences</td><td>18646A-1</td><td>Disposable paraffin molds</td></tr><tr><td>Saran wrap</td><td>Saran</td><td>25700001300</td><td></td></tr><tr><td>Disinfectant</td><td>Virkon S</td><td></td><td></td></tr></tbody></table>

pet imaging of neuroinflammation using [11c]dpa-713 in a mouse model of ischemic stroke

Neuroinflammation 是缺血性中风后病理级联的中心。非侵入性分子成像方法有可能对脑卒中某些 neuroimmune 相互作用的时间动力学和角色提供重要的洞察力。具体地说, 正电子发射断层扫描 (PET) 成像的转运体蛋白 18 kDa (TSPO), 一个标记的活化小胶质细胞和外周髓系体细胞, 提供了检测和跟踪 neuroinflammation在体内的手段。在这里, 我们提出了一个方法, 以准确量化 neuroinflammation 使用 [11C] N, n-二乙基-2-[2-(4-甲氧基苯基)-57-dimethylpyrazolo [15-a] 嘧啶-3-基] 乙酰胺 ([11C] DPA-713), 一个有希望的第二代 TSPO-PET放射性, 在大脑中动脉闭塞 (dMCAO) 与假手术小鼠相比。MRI 进行2天后 dMCAO 手术, 以确认中风和定义梗死的位置和体积。PET/计算机断层扫描 (CT) 成像术后6天 dMCAO, 以捕捉峰值增加的 TSPO 水平后中风。对 PET 图像进行定量测定, 以评估 dMCAO 和假鼠大脑和脾脏中 [11C] DPA-713 的摄取量, 以评估中枢和周围炎症水平。体内[11C]DPA-713 脑吸收是通过体内显影证实的。

小鼠进行 MRI 检查成功的中风, 并通过扫描4小鼠同时进行 [11C] DPA-713 PET。PET、CT 和 MR 图像在手动绘制脑 ROIs 和执行半自动分裂脑图谱分析之前进行了联合注册, 以调查同侧和对侧区域的示踪物摄取情况 (图 2)。
PET/CT 图像和时间活动曲线 (口香糖-放射性活动作为时间的函数) 显示增加 [11C] DPA-713 吸收在同侧半球 (图 3a)。定量的动态 PET 脑图像, 使用总结数据从50-60 分钟, 显示显着增加的示踪剂摄取 (% ID/g) 在同侧半球 (梗死) 相比, 在 dMCAO, 但不是在假鼠使用人工绘制ROI 方法 (图 3B)。dMCAO 和假鼠在同侧半球也观察到了增加的摄取量。使用 atlas 方法观察到同侧半球之间没有显著差异, 可能是由于 atlas ROIs 大于梗塞的大小 (通常限于体感皮层), 因此稀释了信号。然而, 所有 ROIs 对 dMCAO 的总摄取量比假的增加, 这与以前使用 MCAO 模型小鼠的报告一致, 表明在梗塞19以外地区的 TSPO 表达增加。dMCAO 与假鼠同时使用两种方法增加同侧/对侧比值;然而, 由于 ROI 方法的差异较大, 这种差异仅在大脑皮层使用大脑图谱方法时才显著。这可以通过增加每组老鼠的数量来克服。定量的 [11C] DPA-713 的摄取在脾脏显示没有显著差异组 (图 4)。
脑 dMCAO 小鼠 PET 成像结果经活体高分辨率数字显影证实 (图 5)。增加 [11C] DPA-713 的摄取在梗死组织中观察到, 在周围健康的脑组织中可忽略的信号。这些图像的定量显示与对侧比从1.4 到2.09 的 dMCAO 小鼠。
<img alt="Figure 1" class="xfigimg" src="/files/ftp_upload/57243/57243fig1.jpg"> 图 1:PET 扫描仪和工作区设置.所有工作区都覆盖在保护性吸收填料, 以创造一个无菌环境。(a)校准后, 一张 3 d-打印的小鼠床, 同时配有4只小鼠的成像设备, 用于所有4只麻醉小鼠的扫描仪和鼻锥。(B)预先准备了 PET 成像所需的设备, 包括含盐水的27.5 克导管、眼润滑剂、乙醇拭子、热灯、外科胶带、组织胶水、0.5 毫升注射器、剪刀和打火机。(C)放射性注射时, 将盐水冲洗注射器和剪刀放在扫描仪背面。<a href="https://cloudflare.jove.com/files/ftp_upload/57243/57243fig1large.jpg" target="_blank">请单击此处查看此图的较大版本.</a>
<img alt="Figure 2" class="xfigimg" src="/files/ftp_upload/57243/57243fig2.jpg"> 图 2:同侧/对侧 ROI 和右/左分裂半球脑图谱的 PET 图像分析过程.利用人工绘制的 ROIs 和半自动化3D 分裂脑图谱方法, 利用图像分析软件确定了同侧和对侧区域的示踪物摄取量 (ROIs)。自动 3D PET/CT 注册后进行人工注册的大脑 MRI 在相应的鼠标头骨定义的 CT 图像。3D ROI 工具用于手动绘制同侧 (红色) 和对侧 (绿色) ROIs 使用 MRI 梗塞作为参考。对于分裂大脑的方法, 3D 左/右分裂小鼠大脑图谱被加载和安装在头骨中的 CT 图像定义。脑 ROIs 用于定量在这个3D 鼠标大脑图谱包括左皮层 (深灰色), 左海马体 (矢车菊蓝色), 左纹状体 (深粉红色), 右皮层 (番茄红色), 右海马 (绿色), 右 Striatium (青色)。在每一个区域获得 [11C] DPA-713 的吸收, 并随后转换为%ID/g 通过正常化的衰减校正剂量时, 每只老鼠扫描。<a href="https://cloudflare.jove.com/files/ftp_upload/57243/57243fig2large.jpg" target="_blank">请单击此处查看此图的较大版本.</a>
<img alt="Figure 3" class="xfigimg" src="/files/ftp_upload/57243/57243fig3.jpg"> 图 3: 代表体内[11C] DPA-713 DMCAO 和假鼠的脑吸收。(A)动态 PET/CT 图像和口香糖显示增加 [11C] DPA-713 在小鼠的同侧皮层接受 DMCAO (n = 3) 和轻微增加假 (n = 3) 操作小鼠, 与 DMCAO 小鼠表现显着更大的与脑梗塞和对侧侧的比例注射剂量的对比 (%ID/g)。(B) PET 量化 (50-60 分钟总结) 显示, 使用 ROI 方法和在皮质 (Ctx) 使用分裂脑图谱方法显著增加了同侧 roi 的吸收。海马 (HC) 或纹状体 (Str) 无明显差异。使用两种分析方法均能提高同侧比对侧比, 但 Ctx 使用脑图谱方法在统计学上有显著意义。* (p < 0.05), ** (p < 0.001)<a href="https://cloudflare.jove.com/files/ftp_upload/57243/57243fig3large.jpg" target="_blank">请单击此处查看此图的较大版本.</a>
<img alt="Figure 4" class="xfigimg" src="/files/ftp_upload/57243/57243fig4v2.jpg"> 图 4:代表体内[11C] DPA-713 dMCAO 和假鼠的脾吸收。(A) [11C] DPA-713 动态 PET/CT 图像显示脾脏 ROIs 在 dMCAO (n = 3) 和假 (n = 3) 小鼠。(B)定量结果表明, dMCAO 和假鼠在脾脏摄取方面没有显著的结果。<a href="https://cloudflare.jove.com/files/ftp_upload/57243/57243fig4v2large.jpg" target="_blank">请单击此处查看此图的较大版本.</a>
<img alt="Figure 5" class="xfigimg" src="/files/ftp_upload/57243/57243fig5v2.jpg"> 图 5: 代表显影结果.数字显影图像显示增加 [11C] DPA-713 吸收在同侧半球相比。<a href="https://cloudflare.jove.com/files/ftp_upload/57243/57243fig5v2large.jpg" target="_blank">请单击此处查看此图的较大版本.</a>

Watch this Scientific Journal Video about PET Imaging of Neuroinflammation Using [11C]DPA-713 in a Mouse Model of Ischemic Stroke at JoVE.com

PET Imaging of Neuroinflammation Using [11C]DPA-713 in a Mouse Model of Ischemic Stroke

正电子发射层析成像 (PET) 转运体蛋白 18 kDa (TSPO) 提供了一种非侵入性的手段来可视化 neuroinflammation 在脑疾病的发展和进展中的动态作用。本协议描述 TSPO-PET 和前体显影在小鼠缺血性中风模型中检测 neuroinflammation。

Neuroinflammation 的 PET 成像 [11C] DPA-713 在小鼠缺血性中风模型中的应用

Neuroinflammation is central to the pathological cascade following ischemic stroke. Non-invasive molecular imaging methods have the potential to provide ...

pet-imaging-neuroinflammation-using-11cdpa-713-mouse-model-ischemic

Research

JoVE Journal

Medicine

PET Imaging of Neuroinflammation Using [11C]DPA-713 in a Mouse Model of Ischemic Stroke

12.5K 次观看.  Stanford University. 正电子发射层析成像 (PET) 转运体蛋白 18 kDa (TSPO) 提供了一种非侵入性的手段来可视化 neuroinflammation 在脑疾病的发展和进展中的动态作用。本协议描述 TSPO-PET 和前体显影在小鼠缺血性中风模型中检测 neuroinflammation。

视频: PET Imaging of Neuroinflammation Using [11C]DPA-713 in a Mouse Model of Ischemic Stroke

MRI and PET in Mouse Models of Myocardial Infarction

Myocardial infarction is one of the leading causes of death in the Western world. The similarity of the mouse heart to the human heart has made it an ideal model for testing novel therapeutic strategies.
In vivo magnetic resonance imaging (MRI) gives excellent views of the heart noninvasively with clear anatomical detail, which can be used for accurate functional assessment. Contrast agents can provide basic measures of tissue viability but these are nonspecific. Positron emission tomography (PET) is a complementary technique that is highly specific for molecular imaging, but lacks the anatomical detail of MRI. Used together, these techniques offer a sensitive, specific and quantitative tool for the assessment of the heart in disease and recovery following treatment.
In this paper we explain how these methods are carried out in mouse models of acute myocardial infarction. The procedures described here were designed for the assessment of putative protective drug treatments. We used MRI to measure systolic function and infarct size with late gadolinium enhancement, and PET with fluorodeoxyglucose (FDG) to assess metabolic function in the infarcted region. The paper focuses on practical aspects such as slice planning, accurate gating, drug delivery, segmentation of images, and multimodal coregistration. The methods presented here achieve good repeatability and accuracy maintaining a high throughput.

We describe how to perform MRI and PET imaging of the mouse heart. The protocol is tailored to assess treatment efficacy in models of myocardial infarction and heart failure.

MRI和PET心肌梗死小鼠模型

Myocardial infarction is one of the leading causes of death in the Western world. The similarity of the mouse heart to the human heart has made it an ...

科研

医学

Non-invasive Imaging and Analysis of Cerebral Ischemia in Living Rats Using Positron Emission Tomography with 18F-FDG

Stroke is the third leading cause of death among Americans 65 years of age or older1. The quality of life for patients who suffer from a stroke fails to return to normal in a large majority of patients2, which is mainly due to current lack of clinical treatment for acute stroke. This necessitates understanding the physiological effects of cerebral ischemia on brain tissue over time and is a major area of active research. Towards this end, experimental progress has been made using rats as a preclinical model for stroke, particularly, using non-invasive methods such as 18F-fluorodeoxyglucose (FDG) coupled with Positron Emission Tomography (PET) imaging3,10,17. Here we present a strategy for inducing cerebral ischemia in rats by middle cerebral artery occlusion (MCAO) that mimics focal cerebral ischemia in humans, and imaging its effects over 24 hr using FDG-PET coupled with X-ray computed tomography (CT) with an Albira PET-CT instrument. A VOI template atlas was subsequently fused to the cerebral rat data to enable a unbiased analysis of the brain and its sub-regions4. In addition, a method for 3D visualization of the FDG-PET-CT time course is presented. In summary, we present a detailed protocol for initiating, quantifying, and visualizing an induced ischemic stroke event in a living Sprague-Dawley rat in three dimensions using FDG-PET.

Non-invasive Imaging and Analysis of Cerebral Ischemia in Living Rats Using Positron Emission Tomography with 18F-FDG

Brain damage resulting from cerebral ischemia may be non-invasively imaged and studied in rats using pre-clinical positron emission tomography coupled with the injectable radioactive probe, 18F-fluorodeoxyglucose. Further, the use of modern software tools that include volume of interest (VOI) brain templates dramatically increase the quantitative information gleaned from these studies.

无创成像和脑缺血分析生活中的大鼠使用正电子发射断层扫描<sup&gt; 18</sup&gt; F-FDG

Stroke is the third leading cause of death among Americans 65 years of age or older1. The quality of life for patients who suffer from a stroke fails to ...

Simultaneous PET/MRI Imaging During Mouse Cerebral Hypoxia-ischemia

Dynamic changes in tissue water diffusion and glucose metabolism occur during and after hypoxia in cerebral hypoxia-ischemia reflecting a bioenergetics disturbance in affected cells. Diffusion weighted magnetic resonance imaging (MRI) identifies regions that are damaged, potentially irreversibly, by hypoxia-ischemia. Alterations in glucose utilization in the affected tissue may be detectable by positron emission tomography (PET) imaging of 2-deoxy-2-(18F)fluoro-&#7429;-glucose ([18F]FDG) uptake. Due to the rapid and variable nature of injury in this animal model, acquisition of both modes of data must be performed simultaneously in order to meaningfully correlate PET and MRI data. In addition, inter-animal variability in the hypoxic-ischemic injury due to vascular differences limits the ability to analyze multi-modal data and observe changes to a group-wise approach if data is not acquired simultaneously in individual subjects. The method presented here allows one to acquire both diffusion-weighted MRI and [18F]FDG uptake data in the same animal before, during, and after the hypoxic challenge in order to interrogate immediate physiological changes.

The method presented here uses simultaneous positron emission tomography and magnetic resonance imaging. In the cerebral hypoxia-ischemia model, dynamic changes in diffusion and glucose metabolism occur during and after injury. The evolving and irreproducible damage in this model necessitates simultaneous acquisition if meaningful multi-modal imaging data are to be acquired.

同时PET / MRI成像在小鼠脑缺氧缺血

Dynamic changes in tissue water diffusion and glucose metabolism occur during and after hypoxia in cerebral hypoxia-ischemia reflecting a bioenergetics ...

A Versatile Murine Model of Subcortical White Matter Stroke for the Study of Axonal Degeneration and White Matter Neurobiology

Stroke affecting white matter accounts for up to 25% of clinical stroke presentations, occurs silently at rates that may be 5-10 fold greater, and contributes significantly to the development of vascular dementia. Few models of focal white matter stroke exist and this lack of appropriate models has hampered understanding of the neurobiologic mechanisms involved in injury response and repair after this type of stroke. The main limitation of other subcortical stroke models is that they do not focally restrict the infarct to the white matter or have primarily been validated in non-murine species. This limits the ability to apply the wide variety of murine research tools to study the neurobiology of white matter stroke. Here we present a methodology for the reliable production of a focal stroke in murine white matter using a local injection of an irreversible eNOS inhibitor. We also present several variations on the general protocol including two unique stereotactic variations, retrograde neuronal tracing, as well as fresh tissue labeling and dissection that greatly expand the potential applications of this technique. These variations allow for multiple approaches to analyze the neurobiologic effects of this common and understudied form of stroke.

Here we present methodology for the production of a focal stroke in murine white matter by local injection of an irreversible endothelial nitric oxide synthase (eNOS) inhibitor (L-Nio). Presented are two stereotactic variations, retrograde neuronal tracing, and fresh tissue labeling and dissection that expand the potential applications of this technique.

皮层下的多功能小鼠模型白质行程轴索变性和白质神经生物学的研究

Stroke affecting white matter accounts for up to 25% of clinical stroke presentations, occurs silently at rates that may be 5-10 fold greater, and ...

Autoradiographic Measurements of [14C]-Iodoantipyrine in Rat Brain Following Central Post-Stroke Pain

Approximately 8% of stroke patients present symptoms of central post-stroke pain (CPSP). CPSP is associated with allodynia and hypersensitivity to nociceptive stimuli. Although some studies have shown that neuropathic pain may involve the dorsolateral prefrontal cortex, rostral anterior cingulate cortex, amygdala, hippocampus, periaqueductal gray, rostral ventromedial medulla, and medial thalamus, the neural substrates and their connections that mediate CPSP remain unclear. [14C]-Iodoantipyrine (IAP) uptake can be measured to evaluate spontaneously active pain. It can be used to assess the activation of neural substrates that may be involved in CPSP in an animal model. The [14C]-IAP method in rats is less expensive to perform compared with other brain mapping techniques. The present [14C]-IAP protocol is used to measure the activation of neural substrates that are involved in CPSP that is induced by lesions of the ventral basal nucleus (VB) of the thalamus in a rodent model.

Autoradiographic Measurements of [14C]-Iodoantipyrine in Rat Brain Following Central Post-Stroke Pain

We present a protocol to measure [14C]-iodoantipyrine (IAP) uptake and assess the activation of neural substrates that are involved in central post-stroke pain (CPSP) in a rodent model.

的放射自显影测量[<sup&gt; 14</sup&gt; J] -Iodoantipyrine大鼠脑继中央脑卒中后疼痛

Approximately 8% of stroke patients present symptoms of central post-stroke pain (CPSP). CPSP is associated with allodynia and hypersensitivity to ...

Induction of Ischemic Stroke and Ischemia-reperfusion in Mice Using the Middle Artery Occlusion Technique and Visualization of Infarct Area

Cerebrovascular disease is highly prevalent in the global population and encompasses several types of conditions, including stroke. To study the impact of stroke on tissue injury and to evaluate the effectiveness of therapeutic interventions, several experimental models in a variety of species were developed. They include complete global cerebral ischemia, incomplete global ischemia, focal cerebral ischemia, and multifocal cerebral ischemia. The model described in this protocol is based on the middle cerebral artery occlusion (MCAO) and is related to the focal ischemia category. This technique produces consistent focal ischemia in a strictly defined region of the hemisphere and is less invasive than other methods. The procedure described is performed on mice, given the availability of several genetic variants and the high number of tests standardized for mice to aid in the behavioral and neurodeficit evaluation.

We describe a mouse model of stroke induced by the occlusion of the middle cerebral artery using a silicone coated suture. The protocol can be applied to induce permanent occlusion or a temporary ischemia, followed by reperfusion.

缺血性中风和缺血再灌注小鼠的诱导使用梗塞区的中心动脉闭塞技术和可视化

Cerebrovascular disease is highly prevalent in the global population and encompasses several types of conditions, including stroke. To study the impact of ...

A Fibrin-Enriched and tPA-Sensitive Photothrombotic Stroke Model

An ideal thromboembolic stroke model requires certain properties, including relatively simple surgical procedures with low mortality, a consistent infarction size and location, precipitation of platelet:fibrin intermixed blood clots similar to those in patients, and an adequate sensitivity to fibrinolytic treatment. The rose bengal (RB) dye-based photothrombotic stroke model meets the first two requirements but is highly refractory to tPA-mediated lytic treatment, presumably due to its platelet-rich, but fibrin-poor clot composition. We reason that combination of RB dye (50 mg/kg) and a sub-thrombotic dose of thrombin (80 U/kg) for photoactivation aimed at the proximal branch of middle cerebral artery (MCA) may produce fibrin-enriched and tPA-sensitive clots. Indeed, the thrombin and RB (T+RB)-combined photothrombosis model triggered mixed platelet:fibrin blood clots, as shown by immunostaining and immunoblots, and maintained consistent infarct sizes and locations plus low mortality. Moreover, intravenous injection of tPA (Alteplase, 10 mg/kg) within 2 h post-photoactivation significantly decreased the infarct size in T+RB photothrombosis. Thus, the thrombin-enhanced photothrombotic stroke model may be a useful experimental model to test novel thrombolytic therapies.

Traditional photothrombotic stroke (PTS) models mainly induce dense platelet aggregates of a high resistance to tissue plasminogen activator (tPA)-lytic treatment. Here a modified murine PTS model is introduced by co-injecting thrombin and photosensitive dye for photoactivation. The thrombin-enhanced PTS model produces mixed platelet:fibrin clots and is highly sensitive to tPA-thrombolysis.

纤维蛋白富集和 tPA 敏感的光血栓形成卒中模型

An ideal thromboembolic stroke model requires certain properties, including relatively simple surgical procedures with low mortality, a consistent ...

神经科学

Positron Emission Tomography Imaging for In Vivo Measuring of Myelin Content in the Lysolecithin Rat Model of Multiple Sclerosis

Multiple sclerosis (MS) is a neuroinflammatory disease with expanding axonal and neuronal degeneration and demyelination in the central nervous system, leading to motor dysfunctions, psychical disability, and cognitive impairment during MS progression. Positron emission tomography (PET) is an imaging technique able to quantify in vivo cellular and molecular alterations.
Radiotracers with affinity to intact myelin can be used for in vivo imaging of myelin content changes over time. It is possible to detect either an increase or decrease in myelin content, what means this imaging technique can detect demyelination and remyelination processes of the central nervous system. In this protocol we demonstrate how to use PET imaging to detect myelin changes in the lysolecithin rat model, which is a model of focal demyelination lesion (induced by stereotactic injection) (i.e., a model of multiple sclerosis disease). 11C-PIB PET imaging was performed at baseline, and 1 week and 4 weeks after stereotaxic injection of lysolecithin 1% in the right striatum (4 &#181;L) and corpus callosum (3 &#181;L) of the rat brain, allowing quantification of focal demyelination (injection site after 1 week) and the remyelination process (injection site at 4 weeks).
Myelin PET imaging is an interesting tool for monitoring in vivo changes in myelin content which could be useful for monitoring demyelinating disease progression and therapeutic response.

Positron Emission Tomography Imaging for In Vivo Measuring of Myelin Content in the Lysolecithin Rat Model of Multiple Sclerosis

This protocol has the aim of monitoring in vivo myelin changes (demyelination and remyelination) by positron emission tomography (PET) imaging in an animal model of multiple sclerosis.

多发性硬化症的莱索莱西汀鼠模型中用于测量骨髓含量的 体内 发射断层扫描成像

Multiple sclerosis (MS) is a neuroinflammatory disease with expanding axonal and neuronal degeneration and demyelination in the central nervous system, ...

Imaging CD19+ B Cells in an Experimental Autoimmune Encephalomyelitis Mouse Model using Positron Emission Tomography

Multiple sclerosis (MS) is the most common demyelinating central nervous system (CNS) disease affecting young adults, often resulting in neurological deficits and disability as the disease progresses. B lymphocytes play a complex and critical role in MS pathology and are the target of several therapeutics in clinical trials. Currently, there is no way to accurately select patients for specific anti-B cell therapies or to non-invasively quantify the effects of these treatments on B cell load in the CNS and peripheral organs. Positron emission tomography (PET) imaging has enormous potential to provide highly specific, quantitative information regarding the in vivo spatiotemporal distribution and burden of B cells in living subjects.
This paper reports methods to synthesize and employ a PET tracer specific for human CD19+ B cells in a well-established B cell-driven mouse model of MS, experimental autoimmune encephalomyelitis (EAE), which is induced with human recombinant myelin oligodendrocyte glycoprotein 1-125. Described here are optimized techniques to detect and quantify CD19+ B cells in the brain and spinal cord using in vivo PET imaging. Additionally, this paper reports streamlined methods for ex vivo gamma counting of disease-relevant organs, including bone marrow, spinal cord, and spleen, together with high-resolution autoradiography of CD19 tracer binding in CNS tissues.

Imaging CD19+ B Cells in an Experimental Autoimmune Encephalomyelitis Mouse Model using Positron Emission Tomography

This paper details methodology for radiolabeling a human-specific anti-CD19 monoclonal antibody and how to use it to quantify B cells in the central nervous system and peripheral tissues of a mouse model of multiple sclerosis using in vivo PET imaging, ex vivo gamma counting, and autoradiography approaches.

使用正电子发射断层扫描对实验性自身免疫性脑脊髓炎小鼠模型中的 CD19+ B 细胞进行成像

Multiple sclerosis (MS) is the most common demyelinating central nervous system (CNS) disease affecting young adults, often resulting in neurological ...

缺血性卒中的无创综合 PAUSAT 全脑成像

Integrated Photoacoustic, Ultrasound, and Angiographic Tomography (PAUSAT) for NonInvasive Whole-Brain Imaging of Ischemic Stroke

Presented here is an experimental ischemic stroke study using our newly developed noninvasive imaging system that integrates three acoustic-based imaging technologies: photoacoustic, ultrasound, and angiographic tomography (PAUSAT). Combining these three modalities helps acquire multi-spectral photoacoustic tomography (PAT) of the brain blood oxygenation, high-frequency ultrasound imaging of the brain tissue, and acoustic angiography of the cerebral blood perfusion. The multi-modal imaging platform allows the study of cerebral perfusion and oxygenation changes in the whole mouse brain after stroke. Two commonly used ischemic stroke models were evaluated: the permanent middle cerebral artery occlusion (pMCAO) model and the photothrombotic (PT) model. PAUSAT was used to image the same mouse brains before and after a stroke and quantitatively analyze both stroke models. This imaging system was able to clearly show the brain vascular changes after ischemic stroke, including significantly reduced blood perfusion and oxygenation in the stroke infarct region (ipsilateral) compared to the uninjured tissue (contralateral). The results were confirmed by both laser speckle contrast imaging and triphenyltetrazolium chloride (TTC) staining. Furthermore, stroke infarct volume in both stroke models was measured and validated by TTC staining as the ground truth. Through this study, we have demonstrated that PAUSAT can be a powerful tool in noninvasive and longitudinal preclinical studies of ischemic stroke.

作者聚焦：用于缺血性卒中的无创全脑成像的集成光声、超声和血管造影断层扫描 （PAUSAT）  

This work demonstrates the use of a multimodal ultrasound-based imaging platform for noninvasive imaging of ischemic stroke. This system allows for the quantification of blood oxygenation through photoacoustic imaging and impaired perfusion in the brain through acoustic angiography.

集成光声、超声和血管造影断层扫描 （PAUSAT） 用于缺血性卒中的无创全脑成像

Presented here is an experimental ischemic stroke study using our newly developed noninvasive imaging system that integrates three acoustic-based imaging ...

Neuroinflammation 的 PET 成像 [¹¹C] DPA-713 在小鼠缺血性中风模型中的应用

摘要

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此视频中的章节

MRI和PET心肌梗死小鼠模型

无创成像和脑缺血分析生活中的大鼠使用正电子发射断层扫描

同时PET / MRI成像在小鼠脑缺氧缺血

皮层下的多功能小鼠模型白质行程轴索变性和白质神经生物学的研究

的放射自显影测量[

缺血性中风和缺血再灌注小鼠的诱导使用梗塞区的中心动脉闭塞技术和可视化

纤维蛋白富集和 tPA 敏感的光血栓形成卒中模型

多发性硬化症的莱索莱西汀鼠模型中用于测量骨髓含量的体内发射断层扫描成像

使用正电子发射断层扫描对实验性自身免疫性脑脊髓炎小鼠模型中的 CD19⁺ B 细胞进行成像

集成光声、超声和血管造影断层扫描（PAUSAT）用于缺血性卒中的无创全脑成像

Neuroinflammation 的 PET 成像 [11C] DPA-713 在小鼠缺血性中风模型中的应用

摘要

探索更多视频

此视频中的章节

MRI和PET心肌梗死小鼠模型

无创成像和脑缺血分析生活中的大鼠使用正电子发射断层扫描

同时PET / MRI成像在小鼠脑缺氧缺血

皮层下的多功能小鼠模型白质行程轴索变性和白质神经生物学的研究

的放射自显影测量[

缺血性中风和缺血再灌注小鼠的诱导使用梗塞区的中心动脉闭塞技术和可视化

纤维蛋白富集和 tPA 敏感的光血栓形成卒中模型

多发性硬化症的莱索莱西汀鼠模型中用于测量骨髓含量的 体内 发射断层扫描成像

使用正电子发射断层扫描对实验性自身免疫性脑脊髓炎小鼠模型中的 CD19+ B 细胞进行成像

集成光声、超声和血管造影断层扫描 （PAUSAT） 用于缺血性卒中的无创全脑成像

Neuroinflammation 的 PET 成像 [¹¹C] DPA-713 在小鼠缺血性中风模型中的应用

多发性硬化症的莱索莱西汀鼠模型中用于测量骨髓含量的体内发射断层扫描成像

使用正电子发射断层扫描对实验性自身免疫性脑脊髓炎小鼠模型中的 CD19⁺ B 细胞进行成像

集成光声、超声和血管造影断层扫描（PAUSAT）用于缺血性卒中的无创全脑成像