The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, 600N. Wolfe Street, Park 326, Baltimore, MD 21287, USA; F. M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Research Institute, Baltimore, MD, USA.
Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 600 North Wolfe Street, CMSC 8-121, Baltimore, MD 21287, USA.
Neuroimage. 2023 Mar;268:119870. doi: 10.1016/j.neuroimage.2023.119870. Epub 2023 Jan 11.
Blood-brain barrier (BBB) plays a critical role in protecting the brain from toxins and pathogens. However, in vivo tools to assess BBB permeability are scarce and often require the use of exogenous contrast agents. In this study, we aimed to develop a non-contrast arterial-spin-labeling (ASL) based MRI technique to estimate BBB permeability to water in mice. By determining the relative fraction of labeled water spins that were exchanged into the brain tissue as opposed to those that remained in the cerebral veins, we estimated indices of global BBB permeability to water including water extraction fraction (E) and permeability surface-area product (PS). First, using multiple post-labeling delay ASL experiments, we estimated the bolus arrival time (BAT) of the labeled spins to reach the great vein of Galen (VG) to be 691.2 ± 14.5 ms (N = 5). Next, we investigated the dependence of the VG ASL signal on labeling duration and identified an optimal imaging protocol with a labeling duration of 1200 ms and a PLD of 100 ms. Quantitative E and PS values in wild-type mice were found to be 59.9 ± 3.2% and 260.9 ± 18.9 ml/100 g/min, respectively. In contrast, mice with Huntington's disease (HD) revealed a significantly higher E (69.7 ± 2.4%, P = 0.026) and PS (318.1 ± 17.1 ml/100 g/min, P = 0.040), suggesting BBB breakdown in this mouse model. Reproducibility studies revealed a coefficient-of-variation (CoV) of 4.9 ± 1.7% and 6.1 ± 1.2% for E and PS, respectively. The proposed method may open new avenues for preclinical research on pathophysiological mechanisms of brain diseases and therapeutic trials in animal models.
血脑屏障（BBB）在保护大脑免受毒素和病原体侵害方面起着至关重要的作用。然而，目前用于评估 BBB 通透性的体内工具非常有限，并且通常需要使用外源性对比剂。在这项研究中，我们旨在开发一种无需对比剂的动脉自旋标记（ASL）MRI 技术来评估水在小鼠 BBB 中的通透性。通过确定标记水自旋中进入脑组织的相对比例与仍留在脑静脉中的比例，我们可以估计水的全局 BBB 通透性指数，包括水提取分数（E）和渗透表面积乘积（PS）。首先，通过多次标记后延迟 ASL 实验，我们估计标记自旋到达 Galen 大静脉（VG）的标记到达时间（BAT）为 691.2 ± 14.5 ms（N = 5）。接下来，我们研究了 VG ASL 信号对标记持续时间的依赖性，并确定了具有 1200 ms 标记持续时间和 100 ms PLD 的最佳成像方案。在野生型小鼠中，定量 E 和 PS 值分别为 59.9 ± 3.2%和 260.9 ± 18.9 ml/100 g/min。相比之下，亨廷顿病（HD）小鼠的 E 值（69.7 ± 2.4%，P = 0.026）和 PS 值（318.1 ± 17.1 ml/100 g/min，P = 0.040）显著升高，表明该小鼠模型中 BBB 破裂。重复性研究显示，E 和 PS 的变异系数（CoV）分别为 4.9 ± 1.7%和 6.1 ± 1.2%。该方法可能为脑疾病的病理生理机制的临床前研究和动物模型中的治疗试验开辟新途径。
