Division of Psychology, Communication and Human Neuroscience, School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Zochonis Building, Oxford Road, Manchester, M13 9PL, UK.
Geoffrey Jefferson Brain Research Centre, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
Fluids Barriers CNS. 2023 Apr 3;20(1):25. doi: 10.1186/s12987-023-00422-7.
Blood-brain barrier (BBB) dysfunction occurs in many brain diseases, and there is increasing evidence to suggest that it is an early process in dementia which may be exacerbated by peripheral infection. Filter-exchange imaging (FEXI) is an MRI technique for measuring trans-membrane water exchange. FEXI data is typically analysed using the apparent exchange rate (AXR) model, yielding estimates of the AXR. Crusher gradients are commonly used to remove unwanted coherence pathways arising from longitudinal storage pulses during the mixing period. We first demonstrate that when using thin slices, as is needed for imaging the rodent brain, crusher gradients result in underestimation of the AXR. To address this, we propose an extended crusher-compensated exchange rate (CCXR) model to account for diffusion-weighting introduced by the crusher gradients, which is able to recover ground truth values of BBB water exchange (k) in simulated data. When applied to the rat brain, k estimates obtained using the CCXR model were 3.10 s and 3.49 s compared to AXR estimates of 1.24 s and 0.49 s for slice thicknesses of 4.0 mm and 2.5 mm respectively. We then validated our approach using a clinically relevant Streptococcus pneumoniae lung infection. We observed a significant 70 ± 10% increase in BBB water exchange in rats during active infection (k = 3.78 ± 0.42 s) compared to before infection (k = 2.72 ± 0.30 s; p = 0.02). The BBB water exchange rate during infection was associated with higher levels of plasma von Willebrand factor (VWF), a marker of acute vascular inflammation. We also observed 42% higher expression of perivascular aquaporin-4 (AQP4) in infected animals compared to non-infected controls, while levels of tight junction proteins remain consistent between groups. In summary, we propose a modelling approach for FEXI data which removes the bias in estimated water-exchange rates associated with the use of crusher gradients. Using this approach, we demonstrate the impact of peripheral infection on BBB water exchange, which appears to be mediated by endothelial dysfunction and associated with an increase in perivascular AQP4.
血脑屏障（BBB）功能障碍发生在许多脑部疾病中，越来越多的证据表明，它是痴呆症的早期过程，可能会因外周感染而加重。过滤交换成像（FEXI）是一种测量跨膜水交换的 MRI 技术。FEXI 数据通常使用表观交换率（AXR）模型进行分析，得出 AXR 的估计值。破碎机梯度通常用于在混合期内消除来自纵向存储脉冲的不需要的相干路径。我们首先证明，在使用薄切片进行啮齿动物大脑成像时，破碎机梯度会导致 AXR 的低估。为了解决这个问题，我们提出了一个扩展的破碎机补偿交换率（CCXR）模型，以解释破碎机梯度引入的扩散加权，该模型能够恢复模拟数据中 BBB 水交换（k）的真实值。当应用于大鼠大脑时，使用 CCXR 模型获得的 k 估计值分别为 3.10 s 和 3.49 s，而对于切片厚度为 4.0 mm 和 2.5 mm，AXR 估计值分别为 1.24 s 和 0.49 s。然后，我们使用一种临床相关的肺炎链球菌肺部感染来验证我们的方法。我们观察到，在活跃感染期间，大鼠 BBB 的水交换显著增加了 70±10%（k=3.78±0.42 s），而在感染前，k=2.72±0.30 s（p=0.02）。感染期间的 BBB 水交换率与血浆血管性血友病因子（VWF）水平升高有关，VWF 是急性血管炎症的标志物。我们还观察到，与非感染对照相比，感染动物的血管周 aquaporin-4（AQP4）表达增加了 42%，而两组之间的紧密连接蛋白水平保持一致。总之，我们提出了一种用于 FEXI 数据的建模方法，可以消除与使用破碎机梯度相关的估计水交换率的偏差。使用这种方法，我们证明了外周感染对 BBB 水交换的影响，这似乎是由内皮功能障碍引起的，并与血管周 AQP4 的增加有关。
