Department of Neurology, Cedars-Sinai Medical Center, 127 S. San Vicente Blvd., AHSP Building, Suite A6600, A8103, Los Angeles, CA, 90048, USA.
Department of Neurosurgery, Cedars-Sinai Medical Center, 127 S. San Vicente Blvd., AHSP Building, Suite A6600, A8103, Los Angeles, CA, 90048, USA.
Crit Care. 2019 Feb 22;23(1):63. doi: 10.1186/s13054-019-2356-2.
Mechanical ventilation is strongly associated with cognitive decline after critical illness. This finding is particularly evident among older individuals who have pre-existing cognitive impairment, most commonly characterized by varying degrees of cerebral amyloid-β accumulation, neuroinflammation, and blood-brain barrier dysfunction. We sought to test the hypothesis that short-term mechanical ventilation contributes to the neuropathology of cognitive impairment by (i) increasing cerebral amyloid-β accumulation in mice with pre-existing Alzheimer's disease pathology, (ii) increasing neurologic and systemic inflammation in wild-type mice and mice with pre-existing Alzheimer's disease pathology, and (iii) increasing hippocampal blood-brain barrier permeability in wild-type mice and mice with pre-existing Alzheimer's disease pathology.
We subjected double transgenic Alzheimer's disease (APP/PSEN1) and wild-type mice to mechanical ventilation for 4 h and compared to non-mechanically ventilated Alzheimer's disease model and wild-type mice. Cerebral soluble/insoluble amyloid-β/amyloid-β and neurological and systemic markers of inflammation were quantified. Hippocampal blood-brain barrier permeability was quantified using a novel methodology that enabled assessment of small and large molecule permeability across the blood-brain barrier.
Mechanical ventilation resulted in (i) a significant increase in cerebral soluble amyloid-β (p = 0.007) and (ii) significant increases in neuroinflammatory cytokines in both wild-type and Alzheimer's disease mice which, in most cases, were not reflected in the plasma. There were (i) direct correlations between polymorphonuclear cells in the bronchoalveolar fluid and cerebral soluble amyloid-β (p = 0.0033), and several Alzheimer's disease-relevant neuroinflammatory biomarkers including cerebral TNF-α and IL-6; (iii) significant decreases in blood-brain barrier permeability in mechanically ventilated Alzheimer's disease mice and a trend towards increased blood-brain barrier permeability in mechanically ventilated wild-type mice.
These results provide the first evidence that short-term mechanical ventilation independently promotes the neuropathology of Alzheimer's disease in subjects with and without pre-existing cerebral Alzheimer's disease pathology. Future studies are needed to further clarify the specific mechanisms by which this occurs and to develop neuroprotective mechanical ventilation strategies that mitigate the risk of cognitive decline after critical illness.
机械通气与危重病后认知功能下降密切相关。这一发现尤其在有既往认知障碍的老年人中更为明显，最常见的表现为不同程度的脑淀粉样蛋白-β（amyloid-β）蓄积、神经炎症和血脑屏障功能障碍。我们试图通过以下方法来验证假说：即短期机械通气通过（i）增加预先存在阿尔茨海默病病理的小鼠脑内淀粉样蛋白-β的蓄积，（ii）增加野生型小鼠和预先存在阿尔茨海默病病理的小鼠的神经和全身炎症，以及（iii）增加野生型小鼠和预先存在阿尔茨海默病病理的小鼠的海马血脑屏障通透性，导致认知障碍的神经病理学改变。
我们对双转基因阿尔茨海默病（APP/PSEN1）和野生型小鼠进行 4 小时机械通气，并与未进行机械通气的阿尔茨海默病模型和野生型小鼠进行比较。定量分析了脑可溶性/不溶性淀粉样蛋白-β/淀粉样蛋白-β以及神经和全身炎症标志物。采用一种新的方法学来定量评估血脑屏障中小分子和大分子的通透性，以评估海马血脑屏障的通透性。
机械通气导致（i）脑可溶性淀粉样蛋白-β显著增加（p=0.007），（ii）野生型和阿尔茨海默病小鼠的神经炎症细胞因子显著增加，在大多数情况下，这些细胞因子在血浆中并未反映出来。（i）肺泡灌洗液中的多形核细胞与脑可溶性淀粉样蛋白-β之间存在直接相关性（p=0.0033），并且与几个阿尔茨海默病相关的神经炎症生物标志物（包括脑 TNF-α 和 IL-6）存在直接相关性；（iii）机械通气的阿尔茨海默病小鼠的血脑屏障通透性显著降低，而机械通气的野生型小鼠的血脑屏障通透性有增加的趋势。
这些结果首次提供了证据，表明短期机械通气可独立促进有和无预先存在脑内阿尔茨海默病病理的患者的阿尔茨海默病神经病理学。未来的研究需要进一步阐明其发生的具体机制，并制定神经保护的机械通气策略，以降低危重病后认知功能下降的风险。
