Culley Deborah J, Snayd Mary, Baxter Mark G, Xie Zhongcong, Lee In Ho, Rudolph James, Inouye Sharon K, Marcantonio Edward R, Crosby Gregory
Department of Anesthesia, Harvard Medical School, Brigham and Women's Hospital , Boston, MA , USA.
Department of Neuroscience, Icahn School of Medicine at Mount Sinai , New York, NY , USA.
Front Aging Neurosci. 2014 Jun 10;6:107. doi: 10.3389/fnagi.2014.00107. eCollection 2014.
Delirium is a common and morbid condition in elderly hospitalized patients. Its pathophysiology is poorly understood but inflammation has been implicated based on a clinical association with systemic infection and surgery and preclinical data showing that systemic inflammation adversely affects hippocampus-dependent memory. However, clinical manifestations and imaging studies point to abnormalities not in the hippocampus but in cortical circuits. We therefore tested the hypothesis that systemic inflammation impairs prefrontal cortex function by assessing attention and executive function in aged animals. Aged (24-month-old) Fischer-344 rats received a single intraperitoneal injection of lipopolysaccharide (LPS; 50 μg/kg) or saline and were tested on the attentional set-shifting task (AST), an index of integrity of the prefrontal cortex, on days 1-3 post-injection. Plasma and frontal cortex concentrations of the cytokine TNFα and the chemokine CCL2 were measured by ELISA in separate groups of identically treated, age-matched rats. LPS selectively impaired reversal learning and attentional shifts without affecting discrimination learning in the AST, indicating a deficit in attention and cognitive flexibility but not learning globally. LPS increased plasma TNFα and CCL2 acutely but this resolved within 24-48 h. TNFα in the frontal cortex did not change whereas CCL2 increased nearly threefold 2 h after LPS but normalized by the time behavioral testing started 24 h later. Together, our data indicate that systemic inflammation selectively impairs attention and executive function in aged rodents and that the cognitive deficit is independent of concurrent changes in frontal cortical TNFα and CCL2. Because inattention is a prominent feature of clinical delirium, our data support a role for inflammation in the pathogenesis of this clinical syndrome and suggest this animal model could be useful for studying that relationship further.
谵妄是老年住院患者中常见的一种病态情况。其病理生理学尚不清楚，但基于与全身感染和手术的临床关联以及临床前数据表明全身炎症会对海马体依赖的记忆产生不利影响，炎症被认为与之有关。然而，临床表现和影像学研究指出异常并非出现在海马体，而是在皮质回路。因此，我们通过评估老年动物的注意力和执行功能，来检验全身炎症会损害前额叶皮质功能这一假设。24月龄的Fischer-344大鼠腹腔注射一次脂多糖（LPS；50μg/kg）或生理盐水，并在注射后第1至3天进行注意力转换任务（AST）测试，该任务是前额叶皮质完整性的指标。在单独一组经过相同处理、年龄匹配的大鼠中，通过酶联免疫吸附测定法（ELISA）测量细胞因子TNFα和趋化因子CCL2的血浆和额叶皮质浓度。LPS选择性地损害了AST中的逆向学习和注意力转换，而不影响辨别学习，这表明存在注意力和认知灵活性缺陷，但并非整体学习能力缺陷。LPS可使血浆TNFα和CCL2急性升高，但在24 - 48小时内恢复正常。额叶皮质中的TNFα没有变化，而LPS注射2小时后CCL2增加了近三倍，但在24小时后开始行为测试时恢复正常。总之，我们的数据表明全身炎症会选择性地损害老年啮齿动物的注意力和执行功能，并且认知缺陷与额叶皮质TNFα和CCL2的同时变化无关。由于注意力不集中是临床谵妄的一个突出特征，我们的数据支持炎症在这种临床综合征发病机制中的作用，并表明该动物模型可能有助于进一步研究这种关系。
