Effect of Increasing Age on Brain Dysfunction in Cirrhosis.
Effect of Increasing Age on Brain Dysfunction in Cirrhosis.
复制标题
年龄增长对肝硬化脑功能障碍的影响。
DOI：
10.1002/hep4.1286
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发表时间：
2019
影响因子：
5.1
通讯作者：
Bajaj,JasmohanS
中科院分区：
文献类型：
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作者：
Liu,Runping;Ahluwalia,Vishwadeep;Kang,JasonD;Ghosh,SiddharthaS;Zhou,Huiping;Li,Yunzhou;Zhao,Derrick;Gurley,Emily;Li,Xiaojiaoyang;White,MelanieB;Fagan,Andrew;Lippman,HRobert;Wade,JamesB;Hylemon,PhillipB;Bajaj,JasmohanS
肝硬化患者年龄越来越大，这可能会对肝性脑病以外的脑功能障碍产生影响。我们的目的是通过人类和动物实验来研究伴随衰老和肝硬化对脑炎症和变性的影响。在人类研究中，年龄匹配的肝硬化患者和65 - 85岁的对照组接受了认知测试、生活质量（QOL）评估、脑磁共振（MR）光谱和静息状态功能磁共振成像（rs - fMRI）分析。组间数据比较。在动物研究中，幼龄（10 - 12周龄）和老年（1.5岁）C57BL/6小鼠分别给予ccl4灌胃以发展为肝硬化或对照组，并随访12周。研究人员分析了炎症介质（白细胞介素[IL]‐6、IL‐1β、转化生长因子β [TGF‐β]和单核细胞化学诱导蛋白1）、sirtuin‐1和γ -氨基丁酸(GABA) -能突触可塑性（神经素‐2 [NLG2]、大同源物4 [DLG4]、GABA受体、亚基γ 1/亚基B1 [GABRG1/B1]）的皮质信使RNA （mRNA）表达，并比较了年轻/年老对照和肝硬化小鼠。人体研究包括46名受试者（23人/组）。肝硬化患者的生活质量和认知能力较差。在磁共振光谱上，肝硬化患者与氨和低乙酰天冬氨酸相关的变化更严重，而rs - fMRI分析显示，与对照组相比，这些患者在额顶叶皮质区表现出功能连接的变化。动物研究结果表明，老年小鼠需要较低的ccl4才能达到肝硬化。年龄较大的小鼠，尤其是肝硬化小鼠，表现出更高的皮层炎性IL - 6、IL - 1β和TGF - β mRNA表达；高级胶质细胞和小胶质细胞活化；与年轻小鼠相比，sirtuin‐1的表达更低。老年小鼠的兴奋性突触组织者DLG4表达较低，NLG2和GABRG1/B1受体表达较高，表明突触组织以抑制性为主。结论：衰老可调节肝硬化患者脑功能改变；这会影响生活质量、认知和大脑连接。皮质炎症、小胶质细胞激活和GABA能突触可塑性的改变可能是原因之一。
Patients with cirrhosis are growing older, which could have an impact on brain dysfunction beyond hepatic encephalopathy. Our aim was to study the effect of concomitant aging and cirrhosis on brain inflammation and degeneration using human and animal experiments. For the human study, age‐matched patients with cirrhosis and controls between 65 and 85 years underwent cognitive testing, quality of life (QOL) assessment, and brain magnetic resonance (MR) spectroscopy and resting state functional MR imaging (rs‐fMRI) analysis. Data were compared between groups. For the animal study, young (10‐12 weeks) and old (1.5 years) C57BL/6 mice were given either CCl4gavage to develop cirrhosis or a vehicle control and were followed for 12 weeks. Cortical messenger RNA (mRNA) expression of inflammatory mediators (interleukin [IL]‐6, IL‐1β, transforming growth factor β [TGF‐β], and monocyte chemoattractant protein 1), sirtuin‐1, and gamma‐aminobutyric acid (GABA)‐ergic synaptic plasticity (neuroligin‐2 [NLG2], discs large homolog 4 [DLG4], GABA receptor, subunit gamma 1/subunit B1 [GABRG1/B1]) were analyzed and compared between younger/older control and cirrhotic mice. The human study included 46 subjects (23/group). Patients with cirrhosis had worse QOL and cognition. On MR spectroscopy, patients with cirrhosis had worse changes related to ammonia and lower N‐acetyl aspartate, whereas rs‐fMRI analysis revealed that these patients demonstrated functional connectivity changes in the frontoparietal cortical region compared to controls. Results of the animal study showed that older mice required lower CCl4to reach cirrhosis. Older mice, especially with cirrhosis, demonstrated higher cortical inflammatory mRNA expression of IL‐6, IL‐1β, and TGF‐β; higher glial and microglial activation; and lower sirtuin‐1 expression compared to younger mice. Older mice also had lower expression of DLG4, an excitatory synaptic organizer, and higher NLG2 and GABRG1/B1 receptor expression, indicating a predominantly inhibitory synaptic organization.Conclusion:Aging modulates brain changes in cirrhosis; this can affect QOL, cognition, and brain connectivity. Cortical inflammation, microglial activation, and altered GABA‐ergic synaptic plasticity could be contributory.