Water-exchange MRI detects subtle blood-brain barrier breakdown in Alzheimer's disease rats
Water-exchange MRI detects subtle blood-brain barrier breakdown in Alzheimer's disease rats
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DOI：
10.1016/j.neuroimage.2018.09.030
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发表时间：
2019-01-01
期刊：
影响因子：
5.7
通讯作者：
Parker, Geoff J. M.
中科院分区：
文献类型：
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作者：
Dickie, Ben R.;Vandesquille, Matthias;Parker, Geoff J. M.
血脑屏障（BBB）的破坏被认为在阿尔茨海默病（AD）的发生和发展中起着关键作用。然而，AD本身是否导致BBB完整性丧失的问题仍然不确定，因为许多体内研究未能检测到AD相关BBB破坏的迹象。我们假设AD相关的BBB损伤是微妙的，并且这些阴性结果是由于缺乏测量灵敏度而产生的。为了开发一种更灵敏的测量BBB破坏的方法，我们设计了一种新的MRI扫描方案来量化内源性水的trans-BBB交换。使用这种方法，我们在AD大鼠模型中检测到BBB水渗透性增加，这与紧密连接蛋白occludin的表达减少有关。使用动态对比增强（DCE）-MRI评估的BBB对MRI造影剂的渗透性在转基因动物和野生型动物之间没有差异，并且与occludin表达无关。我们的数据支持AD相关的血脑屏障破坏的发生，并表明这种血脑屏障病理是微妙的，使用现有的“示踪剂渗漏”方法可能无法检测到。我们验证的水交换MRI方法提供了一个新的强大的工具，研究血脑屏障损伤在体内。
Blood-brain barrier (BBB) breakdown has been hypothesized to play a key role in the onset and progression of Alzheimer's disease (AD). However, the question of whether AD itself contributes to loss of BBB integrity is still uncertain, as many in-vivo studies have failed to detect signs of AD-related BBB breakdown. We hypothesize AD-related BBB damage is subtle, and that these negative results arise from a lack of measurement sensitivity. With the aim of developing a more sensitive measure of BBB breakdown, we have designed a novel MRI scanning protocol to quantify the trans-BBB exchange of endogenous water. Using this method, we detect increased BBB water permeability in a rat model of AD that is associated with reduced expression of the tight junction protein occludin. BBB permeability to MRI contrast agent, assessed using dynamic contrast-enhanced (DCE)-MRI, did not differ between transgenic and wild-type animals and was uncorrelated with occludin expression. Our data supports the occurrence of AD-related BBB breakdown, and indicates that such BBB pathology is subtle and may be undetectable using existing 'tracer leakage' methods. Our validated water-exchange MRI method provides a new powerful tool with which to study BBB damage in-vivo.