术后认知功能障碍的研究进展

1徐志慧 2李斌飞通讯作者

术后认知功能障碍( Postoperative Cognitive Dysfunction,POCD)是指发生在术后的长期认知受损,主要表现为人格、记忆、定向、思维等改变。在非心脏手术中，术后3个月POCD的发生往往与死亡率相关⁽¹⁾。大量研究表明年龄、术前受教育水平、手术时长等是目前确定的危险因素⁽²⁾⁽³⁾。随着逐步进入老龄化社会,老年人择期手术也越来越常见,本文拟从POCD的机制、诊断及治疗方面阐述POCD的研究进展,也为在围术期如何预防及诊治奠定了基础。

一．机制

关于POCD的机制,近年来得到了许多研究如:炎症学说、免疫损害、突触及神经元功能改变等。其中炎症反应尤其是海马区的炎症反应被证实与学习记忆障碍相关。这一过程与损伤血脑屏障、小胶质细胞调节等相关^(2)(4)(5)。下文将具体阐述。

1.POCD的炎症学说

1.1老年人的慢性炎症:对于术后认知功能障碍POCD,多项研究表明年龄是其危险因素之一⁽²⁾⁽³⁾。这可能与老年人的慢性炎症、神经突触功能改变等相关。在一系列研究中,可发现衰老动物的基础行为、细胞因子、免疫特性等与年轻小鼠不同^(6-9):在手术、感染、创伤等不同刺激下,可在高龄组中观察到更强的炎症反应,如IL-1、IL-1β、IL-6、THF-α等炎症因子明显增加且持续时间较长。但在另一项模拟脑外伤的动物研究中发现,受伤后7-10天后方能观察到明显的炎症反应,这可能提示老年人的中枢炎症反应是缓慢发生⁽¹⁰⁾。当炎症因子在海马区浸润时，尤其是IL-1β。机体的学习、记忆往往受到影响。敲除IL-1基因或是予IL-1β拮抗剂能够改善术后记忆^(6-8)(11)。

目前普遍认为小胶质细胞的异常激活参与了老年人中的慢性炎症通。小胶质细胞, 是连接外周与中枢炎症反应大的关键物质,起源于髓系细胞且周转率低。相关研究表明,正常老年人中的小胶质细胞处于过度激活状态(尤其在海马体中)，使得促炎因子增加而抗炎因子减少^(6)(12)。此外在外伤或手术中，如Cao等人发现进行部分肝切除术的部分小鼠，在术后发生了学习、记忆的下降,同时可以观察到术后第一天海马区促炎细胞因子增加，且老年大鼠的炎症反应甚至可延长至第3天⁽¹³⁾。而预先给与小胶质细胞耗竭剂CSF-1,可明显改善小鼠的记忆障碍、炎症反应^(14)（15）。

1.2炎症反应:手术及麻醉引起的损伤,可以导致炎症反应并释放炎症介质。如IL-1β、IL-2、IL-6、TNF-α等^(2)(7)(9)。那么周围炎症是如何引起中枢炎症的产生呢?近年来血脑屏障的改变逐步进入了人们的视野。血脑屏障是由脑微血管内皮细胞、连接蛋白、星形胶质细胞等组成,在中枢稳态维持方面发挥着重要的作用:可防止一些有毒的物质进入中枢,还可参与炎症、神经退行性病变的调控^(16-18)。在一项动物剖腹手术(2h)、1.4%异氟醚麻醉实验中,采用右旋糖酐示踪法可观察到18月龄小鼠的血脑屏障的通透性明显高于9月龄的小鼠,这说明手术/麻醉能够破坏血脑屏障的完整性,并且是与年龄相关⁽⁶⁾。IL-2激活NF-kB、减少BBB黏附蛋白蛋白酪氨酸磷酸酶2的生成⁽¹⁹⁾。IL-6能够减少BBB中连接蛋白claudin-5、occludin含量⁽⁶⁾进而破坏血脑屏障的完整性。

那么炎症反应是如何影响认知功能的呢?首先炎症反应具有自我反馈与调节作用,如IL-1β可诱导单核细胞趋化蛋白1(MCP1)的聚集、通过激活CXCR2而导致中枢内中性粒细胞的浸润,参与一些慢性神经炎症疾病⁽²⁰⁾。IL-1β还可通过促进活性氧的生成进而抑制长时程增强LTP。TNF-a可由小胶质细胞和星形胶质细胞以及某些神经元群产生的。敲除TNF-α基因后,可观察小鼠得学习、记忆受损,神经生长因子(NGF)的生成受到抑制^(21-23)，予TNF-α拮抗剂后能改善周围炎症及POCD⁽²⁴⁾。IL-6,属糖蛋白130(gp130)激活因子。在小鼠中风模型中,可促进脑室内神经元的生长、血管的生成和功能恢复^(25-26)。其他一些炎症标志物如IL-4、IL-10、CRP、HMGB1、S-100β蛋白均发现与POCD的病理过程相关^(27)(28)。

1.3免疫系统的调节:

1.3.1小胶质细胞：小胶质细胞,是中枢神经系统内的巨噬细胞,对神经元的分化及突触具有调节作用,抑制神经炎症,维护中枢系统的稳态，也被证实可参与其他神经退行性病变（29-31）。和巨噬细胞类似,小胶质细胞可通过其表面的M1/M2表型转化对炎症反应进行调节。如M1型表型被认为是促炎表型^(32-34),而M2则被认为是抗炎表型。生理状态下，小胶质细胞被认为是神经元的保护因子。如在一项用NMDA诱导小鼠海马区神经元死亡的实验中,发现小胶质细胞的减少会加重神经损伤^(35)(36

⁾。Chen等人^(37)(38)发现当用膦酸酯多糖LPS诱导的小鼠中枢中,可观察到小胶质细胞能够取代轴体细胞抑制性突触,从而发挥神经保护作用。小胶质细胞的增值与分化可受集落刺激因子1受体CSF1R,调控⁽¹⁵⁾。予小鼠CSF1R,可明显观察到海马内小胶质细胞的减少、M2表型转化的增加,在缺血、炎症方面有着保护作用⁽³⁴⁾。这也部分提示我们小胶质细胞的异常激活往往与疾病进展相关。可能机制有(1).炎症小体的激活：小胶质细胞表型转为M1表型（促炎型）⁽³⁴⁾；(2).通过细胞表面的钾离子通道、嘌呤能受体调节细胞因子的释放^(39)(40)；(3).与TLR4结合、激活NF-从而放大炎症反应、增强自噬能力⁽⁴¹⁾。

1.3.2星形胶质细胞：作为中枢神经系统内最多的胶质细胞群，部分星形胶质细胞参与了血脑屏障的构成，维持中枢稳态，并可作为外周与中枢的媒介⁽⁴²⁾。此外，星形胶质细胞也参与了一些神经退行性病变的病理过程⁽⁴³⁾。如在小鼠胫骨骨折术后可观察到星形胶质细胞数量减少、代谢障碍进而影响神经功能。而这可能是因为星形胶质细胞可调节突触结构与功能，也可以通过内质网应激激活小胶质细胞放大中枢炎症进而导致认知功能障碍^(44-45)。

2.POCD的其他机制：除上述所提到的神经炎症，其他如氧化应激、突触改变也得到了人们广泛研究，认为其参与了神经退行性病变的病理过程^{(4)(9)(46-47)}。手术外伤可导致机体氧化应激增强^(48)(49)。如在一项模拟老鼠胫骨骨折手术中，可在发生POCD的小鼠中观察到术后24小时、7天海马区抗氧化酶减少⁽⁵⁰⁾。Qiu等研究者在进行剖腹探查的小鼠海马中，可以发现由Nox2及炎症因子IL-1β增高，而前者可以产生ROS，造成氧化应激损伤。最终导致记忆障碍⁽⁴⁹⁾。关于氧化应激与POCD的联系，主要有以下机制：(1)氧化应激可以通过激活小胶质细胞进而放大炎症反应;(2)损伤线粒体呼吸链中的关键成分造成脑代谢障碍(3)突触损伤及神经元的凋亡等^(49-50)。突触，主要是由突触前膜、突触间隙、突触后膜组成，是部分神经元连接之间的功能单位。在一项模拟脑外伤的动物实验中可以观察到小胶质细胞自噬增强并导致突触减少⁽¹⁰⁾,在小鼠开腹手术中，可见海马区突触标记物：后突触后密度蛋白95 (PSD-95）和突触素的水平下降并与术后认知功能障碍相关⁽⁵¹⁾。Xiao等人也发现手术麻醉引起的记忆障碍可能与海马突触可塑性改变有关⁽⁵²⁾。增强强突触密度、改善突触间传递可改善老年人的认知功能^(53-54)这提示这突触改变在POCD发生机制中有着重要作用。

在上述所提到的机制中，氧化应激、突触改变等均与炎症反应的发生似乎均有某种炎症通路的调控。为此，本文着重于POCD的炎症学说来系统阐述其机制及治疗。

二．诊断方法:

1.神经心理学测验:目前还没有专门用于POCD诊断的方法,较为大家理解和认可的是在术前、术后对人们进行神经心理学测验,并依据术前、术后检测改变情况来判断是否发生了POCD。但该类检测易受测试者主观的影响,常常需要经过专门的培训,也易患者教育程度、疼痛、情绪等因素的影响。常见的检测方法如下:

1.1简易智能量表MMSE:是目前国内最广泛使用的检测POCD的量表。主要内容包括方向、记忆、语言、注意力和视觉空间技能。目前认为未接受教育(文盲）<17分、小学以下<20分、初中以上<24可诊断为认知功能障碍。MMSE量表简单易行,为大家广泛接受。但该量表本身也有不足,如易受术前教育程度的影响、对轻度的认知障碍检出率不高。

1.2蒙特利尔MoCA:主要内容有学习、定位、语言、计算、注意、记忆和空间结构等。总分为30分,得分越高,认知功能越好。若低于26分,则认为有认知功能损害。MoCA≥17分检测出大多数轻度认知功能障碍MCI病例(96.3%）,而MMSE下限为≥24分(98.3%）相似。相较于MMSE,MoCA对POCD的检出率更高^(55)(56)。并推荐优先选择MoCA⁽⁵⁷⁾;

1.3国际多种心POCD研究小组ISPOCD

1.3.1组成:视觉语言学习测试: the visual verbal learning test,概念转换测试the concept shifting test;斯特鲁普颜色词干扰测试the Stroop colour word interferencetest;字母-数字编码the letter-digitCoding。

1.3.2如何诊断:可靠变量指数法(reliablechangeindex,RCI）:即"Z值计分法",以非手术组作为对照组。Z=(术后较术前的变化值-非手术正常对照组变化值的均数）/非手术正常对照组变化值的标准差。如果在各项测试中至少有两个Z值或总Z值≥1.96,则认为认知障⁽⁵⁸⁾。

1.4影像学:

磁共振检查MRI:MRI可以观察到脑实质与血管的变化,提供了研究大脑病理或生理疾病机制的机会。一项回顾性研究发现神经血管改变(如白质高强度和脑梗死)与认知改变具有一定相关性⁽⁵⁹⁾。且在MRI上可观察到海马体体积的变化,海马体是人类认知、记忆的重要结构。其体积、血流的减少往往与POCD的发生具有一定相关性^(60)(61)。但是对大脑特定结构的观察及对脑血流得检测需更专业的仪器来获得,此外如何针对脑白质及血管结构改变进行定量及定性,仍需未来进一步探索。所以关于MRI在POCD的诊断只是作为一种辅助性措施。

2.生物指标:

2.1炎症介质:上文提到，神经炎症是POCD的潜在发展机制之。在手术/麻醉术后引起的POCD中，往往伴随着炎症介质的改变^(5)(6)(14)。在IL-6基因敲除的小鼠中，未见BBB通透性、认知改变⁽¹⁰⁾。这提示我们IL--6在POCD的发生过程中占据重要位置⁽¹⁴⁾。其他炎症介质如IL-1、IL-1β、IL-2、TNF-α、CRP等也均证实了与POCD具有一定相关性^(4)(49)。并且在一项关于POCD的系统评价中，发现IL-6与POCD的发生较其他炎症介质更具有相关性⁽²⁸⁾。

2.2神经损伤标记物：

S-100蛋白，钙结合蛋白，有24种亚型，在炎症产生于调控中发挥重要作用⁽⁶²⁾。其中S-100β主要由星形胶质细胞表达。低浓度时具有神经保护作用如诱导神经突的生长;而当浓度超过1um时,可以与晚期糖基化终产物受体RAGE结合,促进小胶质细胞内COX-2表达增加,也可通过NFκB 而进一步扩大炎症反应,从而加重细胞毒作用^(27)(63)。在一项meta分析中指出,S-100β蛋白与POCD的发生具有相关性,可以作为预测指标⁽²⁸⁾。S100B蛋白，作为血脑屏障、星形胶质细胞损伤标志物。术后6h、24h的血清S-100B蛋白可以作为冠状动脉旁路移植术后POCD的预测因子(⁶⁴⁾。在一项前瞻性研究中，证实了S-100B可以作为危重症患者远期术后认识功能障碍的血清标志物⁽⁶⁵⁾。NSE主要存在神经元中，可在缺血性脑损伤、心脏骤停、脑外伤中发现其血液中浓度升高并且NSE可以作为急性脑卒中的预测因子，心脏骤停后48小时其浓度也与远期死亡率相关^(66-69)。但在关于POCD的预测方面NSE的特异性不如S100B蛋白⁽⁶⁴⁾。此外，在一项非心脏手术中，未能发现术后S-100B蛋白、NSE与POCD具有明确的相关性⁽⁷⁰⁾。未来关于脑损伤标志物即POCD预测因子仍需进一步的探索。

除了上述所提到的炎性因子、神经损伤蛋白，近年一些其他标志物也逐渐进入了人们的视野，脑特异性蛋白胶质纤维酸蛋白(GFAP），是星形胶质细胞内的一种的蛋白，与脑损伤具有一定相关性⁽⁶⁹⁾。已有相关研究证实，其在非心脏手术术后对术后1个月POCD的预测作用⁽⁷⁰⁾。淀粉样蛋白-β（1-42）（Aβ（1-42））可通过干扰海马去胰岛素信号而导致认知功能障碍^(71)(72)。

3.未来展望-治疗

关于POCD的治疗，目前尚没有明确的建议，本文拟从上述提到的发病机制来阐述具有一些前景的治疗药物。

3.1右美托咪定:一种选择性α2肾上腺素受体激动剂,关于右美托咪定在POCD中的应用，得出了许多令人鼓舞的研究结果。如在一项针对年龄大于65岁行非心脏手术的单中心研究结果显示:术中使用负荷剂量(1ug/kg）、术后立即使用PCA 400ug的右美托咪定能够减少术后早期(7天）POCD的发生⁽⁷³⁾。在一项模拟小鼠脊髓缺血的实验中,预先24小时连续注入右美托咪定对神经元的结构与功能均具有保护作用，可能时右美托咪定可增加环AMP反应元件结合蛋白(CREB）的磷酸化、神经源性营养因子BDNF表达增加。神经元中CREB磷酸化可增加机体对缺血的耐受,且在病理和行为上都有保护作用⁽⁷⁴⁾。BDNF,属于神经营养蛋白,增强神经元的可塑性、抑制细胞凋亡⁽⁷⁵⁾。此外,右美托咪定也可促进海马体细胞外信号调节激酶(ERK)1/2的磷酸化,后者参与记忆生成，也促进了小胶质细胞表型转化而参与神经炎症调控^(76)(77)。尽管目前关于右美托咪定在减少POCD的发生率已经在部分临床研究得到了证实。但是近期也有部分文章提出了质疑,认为POCD的诊断及观察时间点未明确,未来仍需进一步的大规模临床研究^(78-81)。

3.2利多卡因:利多卡因,是一种局麻药也是一种抗心律失常药物。在神经保护作用方面也有相关研究，认为较高浓度的利多卡因可以减少心脏术后认知功能障碍的发生⁽⁸²⁾。如:在一项模拟空气栓塞的动物实验中,预先注入利多卡因,可以部分保留体感诱发电位并降低颅内压⁽⁸³⁾;术中给与一定剂量的利多卡因，能够减少麻醉所引起的线粒体结构、呼吸链损伤及改善小鼠术后认知功能障碍⁽⁸⁴⁾。然而最近有部分研究未能发现利多卡因与POCD的必然联系

⁽⁸⁵⁾,在一项针对480名心脏术后患者,术中及术后持续使用利多卡因48小时,进行了术后6周的随访,并未发现利多卡因对POCD有积极影响。这提示未来进一步的验证。

3.3肠道微生物的调节:近年来,肠道微生物的对人体的调节作用得到了广泛研究,出现了许多新的词汇,如肺-肠轴、脑-肠轴等。已有多项研究结果表示,肠道微生物可通过脑肠轴调节神经炎症、影响血脑屏障^(40)(86)(87)。在一项小鼠腹部手术中,预先给与益生元可以降低海马区IL-1β并且改善小鼠的学习记忆功能,与此同时,还能观察到小胶质细胞M1型表面标志物的减少⁽⁴⁹⁾。此外,肠道微生物可对其他神经退行性变也有着积极作用^(87)(88)(89)。但是关于脑肠轴的具体机制以及不同微生物对其的影响尚未明确,目前仍无具体的临床研究,未来仍需进一步的探讨。

3.4氯胺酮:是一种常见的静脉麻醉药物，且具有镇痛作用。近年来,关于氯胺酮的神经保护功能更是打破了人们对它传统的认知。具体的神经保护主要体现在抗炎、抑制氧化应激、减少细胞凋亡等。研究发现氯胺酮可通过激活PI3K/AKT/GSK-3信号通路抑制细胞凋亡⁽⁹⁰⁾;也可阻断钙离子通道从而抑制氧化应激⁽⁹¹⁾;;阻断TLR2/4,NF-KB ,P65信号通路等抗炎、调节情绪⁽⁹²⁾，并减少细胞因子如IL-6、CRP、S100β的产生^(93-94)。一些临床研究表明能够减少心脏、腹部、骨科手术术后POCD的产生^(4)(94-96)。但关于氯胺酮对POCD的临床疗效证据不足,现有的研究也有矛盾结果,未来仍需更多得前瞻性研究。

3.5其他药物:环加氧酶(COX)抑制剂如帕瑞昔布、塞来昔布等、n-乙酰半胱氨酸、他汀类药物等^(97-100),主要与其抑制炎症、抑制小胶质细胞激活、抗氧化应激等作用相关,尽管已有相关研究得出了阳性结果,但部分结果互相矛盾,未来仍需更大、纵向的随机对照试验。

4.总结

术后认知功能障碍,是一种远期的并发症,增加社会负担与患者家庭经济。关于POCD的机制目前仍未有明确的结论,本文就炎症学说展开了阐述,重点强调了外周炎症-血脑屏障-中枢炎症在认知方面的作用,以及免疫系统的调控功能。关于POCD的诊断,本文所建议的是采用生化指标及不同量表,其中ISPOCD所推荐的一系列认知测量方法可信度、特异度、敏感度均较高,但需经过规范的培训,未来可能需进一步推广。在治疗方面,更多的是针对炎症、氧化应激、神经保护等方面,虽然右美托咪定、利多卡因等在治疗方面初步取得了一些令人满意的结果,但也有研究结果得出了相反的结论,未来仍需进一步的研究与探索。

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