Towards a novel small animal quantitative perfusion MRI reference standard

磁共振灌注成像是治疗中风、心肌缺血或肿瘤等疾病的一种重要的临床成像技术。血流灌注参数的绝对量化对于最客观地做出治疗决策是非常必要的。小动物磁共振灌注成像在定量方面远远落后于临床扫描。这一不足限制了临床前灌流实验向临床研究的转化。缺乏量化的主要原因是无法精确测量动态动脉血浓度--所谓的动脉输入函数(AIF)--这是定量灌注MRI的关键前提。特别是在老鼠身上，考虑到图像的分辨率，例如，颅内动脉血管通常太小，无法测量来自纯血液的信号。在之前的前期工作中，我们开发了一种新的技术来测量小动物的AIF：动物的血液被分流并通过体外循环产生人工灌流的血池，可以放置在成像平面内。我们可以证明这种新的装置在小鼠的核磁共振灌注成像中收集AIF的潜力，具有以前没有达到的质量和定量稳健性。此外，该设置允许同时测量放射性示踪剂血液浓度，从而实现独特的多模式验证方法。在这个项目中，我们的目标是(1)证明我们的实验装置可以作为评估传统AIF测量方法的量化基础事实。(2)我们将建立一个特定的AIF和血流参数的参考数据集，作为未来研究的量化标准。(3)比较动态对比增强(DCE)和动态磁化率对比(DSC)-MRI这两种最常见的磁共振灌注成像方法的定量潜力。(4)我们将验证最近发表的快速MR灌注磁共振成像技术的定量潜力。为了实现这些目标，我们使用我们新的体外循环设置在荷有脑胶质母细胞瘤的小鼠脑中进行了DCE和DSC灌注MRI，这是一种常见的临床前和临床前研究灌注的场景。我们将通过对MR衍生的造影剂浓度和灌注参数进行广泛的多模式验证来实现我们的目标，包括：(1)将同时测量标准Gd造影剂的共注射放射性标记变体，以验证AIF的整个动态范围。(2)激光消融电离耦合等离子体质谱(LA-ICPMS)将用于评价组织中造影剂的浓度。(3)[99mTc]标记的放射性示踪剂将通过SPECT/CT和放射自显影对脑血流量和血流进行定量研究，从而有望使定量临床前灌注MRI赶上临床扫描的定量能力，最终改善临床前和翻译研究。

Perfusion MRI is a clinically important imaging technique in the management of e.g. stroke, cardiac ischemia or tumors. Absolute quantification of perfusion parameters is highly desirable to take treatment decisions most objectively. Small animal perfusion MRI falls far behind from clinical scanning in terms of quantification. This insufficiency limits the translation of preclinical perfusion experiments into clinical studies. The lack of quantification mainly derives from the inability to precisely measure the dynamic arterial blood concentration - the so-called arterial input function (AIF) – a critical prerequisite for quantitative perfusion MRI. Especially in mice, given the image resolution, e.g. intracranial arterial vessels are typically too small to measure signals from pure blood. In previous preliminary work, we developed a novel technique for measuring AIFs in small animals: The animals’ blood is shunted and lead through an extracorporeal circulation to generate an artificial perfused blood reservoir that can be positioned inside the imaging plane. We could demonstrate the potential of the novel setup to gather AIFs in perfusion MRI in mice with previously unmet quality and quantitative robustness. Moreover, the setup allows to simultaneously measure radiotracer blood concentrations allowing unique multimodal validation approaches. In this project, we aim (1) to demonstrate that our experimental setup can serve as a quantitative ground truth to evaluate conventional methods of AIF measurements. (2) We will establish a specific reference dataset of AIFs and perfusion parameters serving as a quantitative standard for future studies. (3) We will compare the quantitative potential of the two most common perfusion MRI methods: dynamic contrast-enhanced (DCE) and dynamic susceptibility contrast (DSC)-MRI. (4) We will validate the quantitative potential of recently published rapid MR imaging techniques of perfusion MRI.To fulfill these objectives, we perform DCE and DSC perfusion MRI using our novel extracorporeal circulation setup in mouse brains bearing intracranial glioblastoma, a frequent preclinical and clinical scenario to study perfusion. We will target our objectives by extensive multimodal validation of the MR-derived contrast agent concentration and perfusion parameters including: (1) A co-Injected radioactive labelled variant of a standard Gadolinium contrast agent will be simultaneously measured to validate the whole dynamic range of the AIF. (2) Laser-ablation ionizing coupled plasma mass spectrometry (LA-ICP-MS) will serve to evaluate contrast agent concentration in tissue. (3) [99mTc]-labeled radiotracers will be co-injected for quantitatively mapping cerebral blood volume and flow by SPECT/CT and autoradiography.We thereby expect a significant advance for quantitative preclinical perfusion MRI to catch up with the quantitative abilities of clinical scanning finally improving preclinical and translational studies.