術(shù)后認(rèn)知功能障礙發(fā)病機(jī)制的研究進(jìn)展*

周 陽(yáng) 綜述 王 軍 郭向陽(yáng) 審校

(北京大學(xué)第三醫(yī)院麻醉科，北京 100191)

?

·文獻(xiàn)綜述·

術(shù)后認(rèn)知功能障礙發(fā)病機(jī)制的研究進(jìn)展*

周 陽(yáng) 綜述 王 軍 郭向陽(yáng)**審校

(北京大學(xué)第三醫(yī)院麻醉科，北京 100191)

術(shù)后認(rèn)知功能障礙(post-operative cognitive dysfunction，POCD)是術(shù)后常見(jiàn)的中樞神經(jīng)系統(tǒng)并發(fā)癥，目前POCD的發(fā)病機(jī)制尚不明確。本文就POCD的幾種可能的發(fā)病機(jī)制進(jìn)行綜述，通過(guò)進(jìn)一步的研究以闡明POCD的發(fā)病機(jī)制，在臨床工作中對(duì)POCD進(jìn)行早期預(yù)防、診斷和治療，具有重要的醫(yī)學(xué)、社會(huì)和經(jīng)濟(jì)意義。

術(shù)后認(rèn)知功能障礙； 發(fā)病機(jī)制

1955年，Bedford對(duì)1193例老年全麻手術(shù)患者回顧分析時(shí)觀察到，患者術(shù)后出現(xiàn)了認(rèn)知困難或不同程度的癡呆，這種認(rèn)知功能損害是術(shù)后常見(jiàn)的中樞神經(jīng)系統(tǒng)并發(fā)癥，通常稱為術(shù)后認(rèn)知功能障礙(postoperative cognitive dysfunction，POCD)[1]。POCD主要表現(xiàn)為患者人格、社交能力、認(rèn)知能力和技巧的變化，可應(yīng)用神經(jīng)心理學(xué)評(píng)估，包括韋氏成人記憶量表(Wechsler Adult Memory Scale，WMS)、明尼蘇達(dá)多項(xiàng)人格調(diào)查表(Minnesota Multiphasic Personality Inventory，MMPI)、簡(jiǎn)易智能狀態(tài)檢查量表(Mini-Mental State Examination，MMSE)等多項(xiàng)測(cè)試[2～4]。由于定義、測(cè)試方法的不同，POCD的發(fā)生率報(bào)道不一。國(guó)際POCD研究小組(the International Study of Post-Operative Cognitive Dysfunction，ISPOCD)的研究[2]表明，65歲以上非心臟手術(shù)患者術(shù)后1周POCD的發(fā)生率為26%，術(shù)后3個(gè)月發(fā)生率為10%。心臟手術(shù)后POCD的發(fā)生率較高，術(shù)后幾周發(fā)生率為30%～80%，術(shù)后3～6個(gè)月發(fā)生率為10%～60%[5,6]。隨著社會(huì)老齡化的發(fā)展，人類平均壽命的延長(zhǎng)和人們對(duì)生活質(zhì)量的要求不斷提高，每年接受外科手術(shù)的老年患者越來(lái)越多。盡管外科手術(shù)和麻醉管理的技術(shù)在不斷提高，發(fā)生POCD的人數(shù)越來(lái)越多卻是不容忽視的問(wèn)題。POCD可使患者住院時(shí)間延長(zhǎng)，術(shù)后并發(fā)癥增多，并導(dǎo)致遠(yuǎn)期并發(fā)癥發(fā)生率和死亡率增加[3,7]，是影響術(shù)后轉(zhuǎn)歸的重要原因，給社會(huì)造成了嚴(yán)重的醫(yī)療和經(jīng)濟(jì)負(fù)擔(dān)[4]。

POCD發(fā)生的危險(xiǎn)因素主要有[8]：①患者因素，如老齡，合并心腦血管疾病，術(shù)前認(rèn)知功能損害，教育水平低以及酗酒史；②手術(shù)因素，如長(zhǎng)時(shí)間或大型手術(shù)，術(shù)中或術(shù)后并發(fā)癥，二次手術(shù)；③麻醉因素，如長(zhǎng)效麻醉劑，顯著的內(nèi)環(huán)境紊亂，低氧低灌注導(dǎo)致的器官缺血，術(shù)中或術(shù)后麻醉相關(guān)并發(fā)癥。老齡是POCD發(fā)生的獨(dú)立危險(xiǎn)因素[2,9]。目前的研究認(rèn)為，麻醉方式與POCD的發(fā)生無(wú)相關(guān)性[10]。

盡管過(guò)去幾十年進(jìn)行了大量研究，但POCD的發(fā)病機(jī)制仍不明確。一旦患者發(fā)生POCD，將影響手術(shù)治療效果，不利于麻醉手術(shù)后康復(fù)，對(duì)外科及麻醉科醫(yī)護(hù)人員造成額外工作負(fù)擔(dān)和精神壓力。本文對(duì)目前較為公認(rèn)的易感基因、膽堿能系統(tǒng)、神經(jīng)遞質(zhì)或受體異常、應(yīng)激以及中樞神經(jīng)系統(tǒng)炎癥反應(yīng)等幾個(gè)POCD的可能發(fā)病機(jī)制進(jìn)行綜述，希望在臨床工作中對(duì)術(shù)前篩查、術(shù)中手術(shù)操作和麻醉管理、術(shù)后康復(fù)治療的圍術(shù)期多個(gè)層面進(jìn)行干預(yù)，降低POCD的發(fā)生率，提高圍術(shù)期醫(yī)療安全及質(zhì)量。

1 易感基因

載脂蛋白E(apolipoprotein E，apoE)基因位于19號(hào)染色體長(zhǎng)臂，有3個(gè)常見(jiàn)的等位基因(ε2、ε3、ε4)。apoE不僅在調(diào)節(jié)脂質(zhì)代謝、維持膽固醇平衡方面起重要作用，也參與神經(jīng)系統(tǒng)的正常生長(zhǎng)和損傷后修復(fù)過(guò)程。apoE攜帶與腦皮質(zhì)及海馬區(qū)β淀粉樣變、神經(jīng)纖維纏結(jié)的發(fā)生有關(guān)，從而容易出現(xiàn)阿爾茨海默病(Alzheimer’s disease，AD)的臨床癥狀[11]。ε4等位基因攜帶者的海馬容積趨向縮小，能增加AD發(fā)生的風(fēng)險(xiǎn)[12]。AD以進(jìn)行性認(rèn)知功能障礙和記憶力損害為主要表現(xiàn)，與POCD存在很多相似之處，因而推測(cè)apoEε4等位基因?qū)OCD的發(fā)生也可能起重要作用。國(guó)內(nèi)Cai等[13]比較了吸入或全靜脈兩種麻醉方式下POCD的發(fā)生與apoEε4等位基因的關(guān)系，結(jié)果表明，apoEε4等位基因與全靜脈麻醉術(shù)后發(fā)生的POCD關(guān)系不大，而與異氟烷吸入麻醉術(shù)后發(fā)生的POCD有密切關(guān)系。2014年Cao等[14]的Meta分析認(rèn)為，apoEε4等位基因能顯著增加術(shù)后1周POCD的發(fā)生風(fēng)險(xiǎn)，而與術(shù)后1～3個(gè)月及術(shù)后1年P(guān)OCD的關(guān)系不大。臨床中能否通過(guò)術(shù)前基因篩查、術(shù)中用全憑靜脈麻醉代替靜吸復(fù)合麻醉等措施，減少apoEε4等位基因攜帶患者POCD的發(fā)生率，值得進(jìn)一步研究。

2 膽堿能系統(tǒng)功能下降

中樞膽堿能系統(tǒng)在學(xué)習(xí)、記憶和注意力等認(rèn)知功能的調(diào)節(jié)中起重要作用。乙酰膽堿(acetylcholine，Ach)是腦內(nèi)廣泛分布的調(diào)節(jié)型神經(jīng)遞質(zhì)。Ach有2種受體，分別為煙堿樣受體(nAChRs)和毒蕈堿樣受體(mAChRs)。nAChRs參與調(diào)節(jié)海馬學(xué)習(xí)與記憶的神經(jīng)生理學(xué)過(guò)程，同時(shí)與注意力有關(guān)[15,16]。中樞神經(jīng)系統(tǒng)膽堿能神經(jīng)傳遞功能下降，nAChRs表達(dá)下調(diào)，會(huì)導(dǎo)致神經(jīng)退行性變，出現(xiàn)認(rèn)知功能異常。通過(guò)特異性蛋白結(jié)合nAChRs調(diào)節(jié)神經(jīng)可塑性可以改善認(rèn)知功能[17]。

β淀粉樣蛋白(amyloid β protein，Aβ)的產(chǎn)生和聚集在AD的發(fā)病過(guò)程中起著重要作用，對(duì)認(rèn)知功能有很大影響。研究表明術(shù)后中樞膽堿能系統(tǒng)功能改變與Aβ蛋白有很大關(guān)系，而nAChRs是Aβ神經(jīng)毒性的主要靶點(diǎn)。較低濃度的Aβ就會(huì)顯著減少細(xì)胞系nAChRs結(jié)合位點(diǎn)的數(shù)目，而長(zhǎng)時(shí)間的Aβ作用會(huì)產(chǎn)生細(xì)胞毒性作用。老年人海馬Aβ水平增高，Ach釋放受抑制，使膽堿能神經(jīng)元更容易受損[18]。淀粉樣前體蛋白(amyloid precursor protein，APP)與Aβ的過(guò)度表達(dá)，導(dǎo)致海馬容積明顯縮小，最終影響學(xué)習(xí)和記憶功能，因而老年患者更容易發(fā)生POCD。麻醉藥物對(duì)中樞膽堿能系統(tǒng)的作用不一。臨床濃度的異氟烷能引起APP加工異常，導(dǎo)致人類神經(jīng)膠質(zhì)瘤和小鼠腦細(xì)胞內(nèi)Aβ生成增加[19,20]，提示術(shù)中麻醉藥物引起的Aβ水平異常升高可能是POCD的發(fā)病機(jī)制之一。抗膽堿藥作為術(shù)前用藥可減少氣道黏膜和唾液腺體分泌物，目前認(rèn)為，臨床使用抗膽堿能藥物可能會(huì)增加老年患者發(fā)生POCD的風(fēng)險(xiǎn)，但仍需進(jìn)一步研究[21,22]，因此，對(duì)手術(shù)患者，特別是老年患者，盡量避免或減少抗膽堿藥物作為常規(guī)用藥，對(duì)減少POCD的發(fā)生可能具有重要作用。另一方面，可應(yīng)用擬膽堿藥及膽堿酯酶抑制劑如多奈哌齊、利凡斯的明、加蘭他敏等增加膽堿能物質(zhì)的合成轉(zhuǎn)運(yùn)和釋放，對(duì)已存在的認(rèn)知功能障礙進(jìn)行治療[23]。

3 神經(jīng)遞質(zhì)或受體異常

神經(jīng)元之間的信息傳遞大部分是通過(guò)神經(jīng)遞質(zhì)及其相應(yīng)受體的功能實(shí)現(xiàn)的。這些神經(jīng)遞質(zhì)或受體功能異常，可導(dǎo)致不同程度的認(rèn)知功能障礙。

中樞神經(jīng)系統(tǒng)遞質(zhì)多是氨基酸類，根據(jù)其對(duì)神經(jīng)元的作用不同而分為興奮性氨基酸(excitatory amino acids，EAA)如谷氨酸(glutamic acid，Glu)、天冬氨酸，和抑制性氨基酸(inhibitory amino acids，IAA)如γ-氨基丁酸(gamma amino butyric acid，GABA)、甘氨酸。Glu是中樞神經(jīng)系統(tǒng)中重要的興奮性神經(jīng)遞質(zhì)，作用于N-甲基-D-天冬氨酸(N-methyl-D-aspartic acid，NMDA)受體和非NMDA受體。Glu神經(jīng)元功能低下將導(dǎo)致認(rèn)知功能下降，而Glu含量異常增高時(shí)，可引起“興奮性毒性”，即腦缺血缺氧造成的能量代謝障礙直接抑制細(xì)胞質(zhì)膜上的Na+-K+-ATP酶活性，使細(xì)胞外K+濃度增高，神經(jīng)元去極化，EAA在突觸間隙大量釋放，使EAA受體過(guò)度激活，導(dǎo)致突觸后神經(jīng)元過(guò)度興奮并最終死亡[24]。NMDA受體是神經(jīng)元突觸可塑性及大腦皮層和海馬神經(jīng)元長(zhǎng)時(shí)程增強(qiáng)(long-term potentiation，LTP)的主要調(diào)控者，構(gòu)成了中樞神經(jīng)系統(tǒng)學(xué)習(xí)和記憶功能的基礎(chǔ)[25,26]。外源性刺激可通過(guò)下調(diào)Glu與GABA的比例，減少NMDA受體表達(dá)，引起海馬神經(jīng)元退變，突觸間隙模糊、突觸后密度增加，最終導(dǎo)致學(xué)習(xí)和記憶能力障礙[27]。年齡增長(zhǎng)使海馬和腦皮質(zhì)的氧化還原狀態(tài)改變，導(dǎo)致NMDA受體功能下降，神經(jīng)突觸功能減弱，導(dǎo)致注意力受損[28]。同時(shí)，年齡增長(zhǎng)引起的NMDA信號(hào)通路功能下調(diào)，突觸關(guān)鍵性蛋白生成減少，可導(dǎo)致認(rèn)知功能下降，而且apoEε4等位基因的存在會(huì)加重這種病生理改變[29]。

中樞神經(jīng)系統(tǒng)兒茶酚胺水平對(duì)認(rèn)知功能也有很大的影響。多巴胺(dopamine，DA)可直接作用于海馬CA1區(qū)或間接作用于內(nèi)嗅皮質(zhì)區(qū)，對(duì)調(diào)節(jié)行為決策、注意力調(diào)控與學(xué)習(xí)記憶功能發(fā)揮重要作用。前額葉皮質(zhì)和海馬區(qū)DA調(diào)節(jié)障礙導(dǎo)致的記憶受損與年齡呈線性相關(guān)[30]。DA有5種受體亞型，即D1、D2、D3、D4和D5，不同受體亞型在認(rèn)知和執(zhí)行的不同階段發(fā)揮著不同的作用，如通過(guò)調(diào)節(jié)D2樣受體可改善或者損害認(rèn)知功能[31]。去甲腎上腺素(norepinephrine，NE)是另一類重要的神經(jīng)遞質(zhì)，通過(guò)α1、α2和β受體發(fā)揮作用。一般認(rèn)為，腦中α2受體激動(dòng)與維持正常的認(rèn)知功能有關(guān)，而α1受體持續(xù)、過(guò)度激活可導(dǎo)致認(rèn)知異常。合適劑量的NE能通過(guò)作用于原肌球蛋白受體激酶B(tropomyosin receptor kinase B，TrkB)保護(hù)原皮質(zhì)及藍(lán)斑免受β-淀粉樣變的毒性作用，保護(hù)認(rèn)知功能[32]。動(dòng)物研究[33]表明，老齡化的腦組織NE缺乏，LTP功能受損，更容易出現(xiàn)空間記憶以及認(rèn)知障礙。然而，應(yīng)激狀態(tài)下NE大量釋放，也可引起認(rèn)知功能下降和意識(shí)障礙。此外，5-羥色胺(5-hydroxy tryptamine，5-HT)與情感認(rèn)知和學(xué)習(xí)記憶等神經(jīng)功能也有很大關(guān)系。臨床上可應(yīng)用興奮性氨基酸如美金剛拮抗NMDA受體，調(diào)節(jié)Glu的異常水平，同時(shí)激動(dòng)DA受體，改善患者的認(rèn)知行為和臨床癥狀[23]。

4 應(yīng)激與腎上腺皮質(zhì)激素過(guò)度分泌

應(yīng)激反應(yīng)是機(jī)體對(duì)外來(lái)刺激產(chǎn)生的內(nèi)環(huán)境改變，包括腎上腺皮質(zhì)激素、兒茶酚胺和其他激素水平的改變以及由此導(dǎo)致的代謝變化。長(zhǎng)期應(yīng)激作用使血漿中腎上腺皮質(zhì)激素水平升高，激活海馬及其他部位(如前額葉皮層)的激素受體，從而誘導(dǎo)樹(shù)突狀重組和谷氨酸能活性改變，出現(xiàn)海馬神經(jīng)元損害，導(dǎo)致認(rèn)知功能障礙。老年人腎上腺皮質(zhì)激素水平升高與海馬體積減小有關(guān)[34]。庫(kù)欣綜合征患者受激素長(zhǎng)期作用，較健康人群更容易發(fā)生類似腦萎縮和海馬神經(jīng)元退行性變的注意力、空間記憶等多種認(rèn)知功能損害。

手術(shù)是圍術(shù)期造成患者機(jī)體發(fā)生應(yīng)激反應(yīng)的最強(qiáng)烈的因素。創(chuàng)傷程度不同的手術(shù)對(duì)術(shù)后患者認(rèn)知功能的影響不同。大型手術(shù)后患者更容易出現(xiàn)行為活動(dòng)障礙。另一方面，手術(shù)后腎上腺皮質(zhì)激素水平晝夜節(jié)律的紊亂也與POCD的發(fā)生有關(guān)。術(shù)前加強(qiáng)患者心理疏導(dǎo)和護(hù)理，減緩其精神壓力，避免患者情緒過(guò)度變化，外科手術(shù)過(guò)程中減少可能增加創(chuàng)傷的不必要操作，同時(shí)圍術(shù)期合理應(yīng)用腎上腺皮質(zhì)激素，可能有助于減少術(shù)后認(rèn)知并發(fā)癥的發(fā)生，值得進(jìn)一步研究。

5 中樞神經(jīng)系統(tǒng)炎癥

近年來(lái)，越來(lái)越多的研究指出，中樞神經(jīng)系統(tǒng)炎癥反應(yīng)(neuroinflammation)在POCD的發(fā)生機(jī)制中發(fā)揮了重要作用。

衰老、手術(shù)創(chuàng)傷和感染等多種因素均可激活免疫系統(tǒng)，使炎癥因子表達(dá)水平增加，引起外周炎癥反應(yīng)。傳統(tǒng)觀點(diǎn)認(rèn)為，中樞神經(jīng)系統(tǒng)是“免疫特赦器官”，一方面是因?yàn)榇嬖谘X屏障(blood-brain barrier，BBB)的保護(hù)作用，另一方面是神經(jīng)膠質(zhì)細(xì)胞處于生理靜息狀態(tài)，抗原呈遞被抑制，免疫活性較低。然而，研究證實(shí)，外周炎癥反應(yīng)大量生成的炎癥因子可以作用于腦脈管系統(tǒng)處內(nèi)皮細(xì)胞，弱化細(xì)胞間的緊密連接，使BBB通透性發(fā)生改變，同時(shí)破壞了BBB的完整性，使白細(xì)胞更容易向腦部遷移，從而產(chǎn)生中樞神經(jīng)系統(tǒng)炎癥反應(yīng)，最終造成突觸結(jié)構(gòu)破壞，神經(jīng)元死亡，導(dǎo)致一系列腦功能受損的表現(xiàn)[35]。也有觀點(diǎn)認(rèn)為，外周炎癥因子可通過(guò)迷走神經(jīng)直接傳入中樞神經(jīng)系統(tǒng)，導(dǎo)致中樞炎癥反應(yīng)，出現(xiàn)腦功能損害[36]。

生理狀態(tài)下，腦內(nèi)適度存在的白介素1β(interleukin-1 beta，IL-1β)、腫瘤壞死因子α(tumor necrosis factor alpha，TNF-α)等炎癥因子可促進(jìn)LTP形成，對(duì)記憶和認(rèn)知功能有益，而異常升高的炎癥因子水平則可通過(guò)c-Jun氨基末端激酶(c-Jun N-terminal kinase，JNK)和p38絲裂素活化蛋白激酶(p38-mitogen activated protein kinase，p38 MAPK)等途徑抑制LTP的誘導(dǎo)形成，從而造成認(rèn)知功能損害[37～39]。研究[40,41]表明，IL-1β可激活神經(jīng)膠質(zhì)細(xì)胞，進(jìn)一步釋放相關(guān)炎癥因子，這種炎癥反應(yīng)的惡性循環(huán)能造成腦組織不可逆的破壞和神經(jīng)退行性變。同時(shí)IL-1β作用于突觸前和突觸后的NMDA受體，使其對(duì)Glu反應(yīng)敏感，減少突觸連接，破壞突觸可塑性，最終導(dǎo)致記憶和認(rèn)知功能障礙[42]，因而IL-1β可能在POCD的發(fā)病機(jī)制中起著關(guān)鍵作用。而其他炎癥因子在POCD的發(fā)生發(fā)展過(guò)程中也起著重要作用。

創(chuàng)傷較大的手術(shù)引起的炎癥反應(yīng)更強(qiáng)，更容易導(dǎo)致認(rèn)知功能障礙，如心臟手術(shù)后患者血漿TNF-α、IL-6、CRP等因子水平增高與認(rèn)知功能下降有關(guān)[43,44]。臨床研究表明，IL-6、S100β蛋白水平增加可作為POCD發(fā)生的預(yù)測(cè)參數(shù)[45]。動(dòng)物實(shí)驗(yàn)也證實(shí)，海馬組織IL-1β和IL-6的表達(dá)水平與認(rèn)知功能障礙的受損程度呈正相關(guān)[46]。即使不行手術(shù)，單純吸入麻醉也能導(dǎo)致腦組織炎癥因子表達(dá)水平增加，但這種炎癥反應(yīng)是否導(dǎo)致認(rèn)知功能障礙尚需進(jìn)一步研究[47]。

目前已有觀察圍術(shù)期抗炎處理對(duì)認(rèn)知功能影響的研究。非甾體類抗炎藥(non-steroidal anti-inflammatory drugs，NSAIDs)被認(rèn)為對(duì)認(rèn)知功能存在潛在的保護(hù)作用。環(huán)氧化酶1(cyclooxygenases，COX-1)表達(dá)于小膠質(zhì)細(xì)胞，COX-2表達(dá)于神經(jīng)元，因而COX-1受體抑制劑可能對(duì)減少中樞神經(jīng)系統(tǒng)炎癥反應(yīng)更有利。確實(shí)，阿司匹林(不可逆的COX-1抑制劑)可通過(guò)降低前列腺素，增加抗炎脂氧素水平抑制中樞炎癥和氧化反應(yīng)[48,49]。雖然NSAIDs能減少中樞神經(jīng)系統(tǒng)炎癥反應(yīng)，可能對(duì)認(rèn)知功能障礙存在治療作用，但是目前仍缺乏應(yīng)用NSAIDs可以改善認(rèn)知功能的循證醫(yī)學(xué)證據(jù)[50,51]。羥甲基戊二酰輔酶A(hydroxy methylglutaryl coenzyme A，HMG-CoA)還原酶抑制劑，如他汀類藥物具有抗炎和免疫調(diào)節(jié)功能，同時(shí)可通過(guò)在炎癥環(huán)境下穩(wěn)定內(nèi)皮細(xì)胞，維持BBB的完整性。此外，他汀類藥物還可抑制神經(jīng)膠質(zhì)細(xì)胞的激活，減少小膠質(zhì)細(xì)胞釋放TNF-α、IL-1β、IL-6等炎癥因子干預(yù)中樞炎癥反應(yīng)。動(dòng)物研究[52]表明，他汀類藥物可通過(guò)減少海馬IL-1β和COX-2生成，使糖原合成酶激酶3(glycogen synthase kinase 3，GSK3)通路失活，對(duì)認(rèn)知功能起保護(hù)作用。臨床已有前瞻研究觀察到應(yīng)用他汀類藥物能顯著降低術(shù)后譫妄的發(fā)生，但仍缺乏其對(duì)中樞炎癥反應(yīng)作用機(jī)制的文獻(xiàn)支持[53]。

盡管國(guó)內(nèi)外對(duì)POCD從流行病學(xué)、病理生理學(xué)變化到臨床干預(yù)進(jìn)行了大量研究，但POCD臨床表現(xiàn)多樣，涉及因素眾多，發(fā)病機(jī)制復(fù)雜，可能與易感基因、膽堿能系統(tǒng)、神經(jīng)遞質(zhì)、應(yīng)激和中樞神經(jīng)系統(tǒng)炎癥反應(yīng)有關(guān)。本綜述顯示，在術(shù)前篩查、術(shù)中外科手術(shù)和麻醉管理、術(shù)后治療的圍術(shù)期多個(gè)層面進(jìn)行干預(yù)，都有可能減少術(shù)后認(rèn)知并發(fā)癥的發(fā)生。今后仍需多學(xué)科、多因素進(jìn)一步聯(lián)合研究，闡明POCD的具體發(fā)病機(jī)制，做到早期預(yù)防、診斷和治療，增強(qiáng)圍術(shù)期安全，改善患者的生存質(zhì)量。

1 Bedford PD.Adverse cerebral effects of anaesthesia on old people.Lancet,1955,269(6884):259-263.

2 Moller JT,Cluitmans P,Rasmussen LS,et al.Long-term postoperative cognitive dysfunction in the elderly ISPOCD1 study.ISPOCD investigators.International Study of Post-Operative Cognitive Dysfunction.Lancet,1998,351(9106):857-861.

3 Krenk L,Rasmussen LS,Kehlet H.New insights into the pathophysiology of postoperative cognitive dysfunction.Acta Anaesthesiol Scand,2010,54(8):951-956.

4 Monk TG,Price CC.Postoperative cognitive disorders.Curr Opin Crit Care,2011,17(4):376-381.

5 Silbert BS,Evered LA,Scott DA.Incidence of postoperative cognitive dysfunction after general or spinal anaesthesia for extracorporeal shock wave lithotripsy.Br J Anaesth,2014,113(5):784-791.

6 van Harten AE,Scheeren TW,Absalom AR.A review of postoperative cognitive dysfunction and neuroinflammation associated with cardiac surgery and anaesthesia.Anaesthesia,2012,67(3):280-293.

7 Holroyd-Leduc JM,Khandwala F,Sink KM.How can delirium best be prevented and managed in older patients in hospital?CMAJ,2010,182(5):465-470.

8 Rundshagen I.Postoperative cognitive dysfunction.Dtsch Arztebl Int,2014,111(8):119-125.

9 Scott DA,Evered LA,Silbert BS.Cardiac surgery, the brain, and inflammation.J Extra Corpor Technol,2014,46(1):15-22.

10 Mason SE, Noel-Storr A,Ritchie CW.The impact of general and regional anesthesia on the incidence of post-operative cognitive dysfunction and post-operative delirium: a systematic review with meta-analysis.J Alzheimers Dis,2010,22 Suppl 3:67-79.

11 Kumar NT,Liestol K,Loberg EM,et al.Apolipoprotein E allelotype is associated with neuropathological findings in Alzheimer’s disease.Virchows Arch,2015,Apr 22.[Epub ahead of print]

12 Harwood DG,Barker WW,Ownby RL,et al.Apolipoprotein E polymorphism and age of onset for Alzheimer’s disease in a bi-ethnic sample.Int Psychogeriatr,2004,16(3):317-326.

13 Cai Y,Hu H,Liu P,et al.Association between the apolipoprotein E4 and postoperative cognitive dysfunction in elderly patients undergoing intravenous anesthesia and inhalation anesthesia.Anesthesiology,2012,116(1):84-93.

14 Cao L,Wang K,Gu T,et al.Association between APOE epsilon 4 allele and postoperative cognitive dysfunction:a meta-analysis.Int J Neurosci,2014,124(7):478-485.

15 Kutlu MG,Gould TJ.Nicotinic receptors,memory,and hippocampus.Curr Top Behav Neurosci,2015,23:137-163.

16 Hahn B.Nicotinic receptors and attention.Curr Top Behav Neurosci,2015,23:103-135.

17 Jensen MM,Arvaniti M,Mikkelsen JD,et al.Prostate stem cell antigen interacts with nicotinic acetylcholine receptors and is affected in Alzheimer’s disease.Neurobiol Aging,2015,36(4):1629-1638.

18 Kar S,Slowikowski SP,Westaway D,et al.Interactions between beta-amyloid and central cholinergic neurons: implications for Alzheimer’s disease.J Psychiatry Neurosci,2004,29(6):427-441.

19 Xie Z,Dong Y,Maeda U,et al.The common inhalation anesthetic isoflurane induces apoptosis and increases amyloid beta protein levels.Anesthesiology,2006,104(5):988-994.

20 Xie Z,Culley DJ,Dong Y,et al.The common inhalation anesthetic isoflurane induces caspase activation and increases amyloid beta-protein level in vivo.Ann Neurol,2008,64(6):618-627.

21 Shoair OA,Grasso IM,Lahaye LA,et al.Incidence and risk factors for postoperative cognitive dysfunction in older adults undergoing major noncardiac surgery:a prospective study.J Anaesthesiol Clin Pharmacol,2015,31(1):30-36.

22 Ruxton K,Woodman RJ,Mangoni AA.Drugs with anticholinergic effects and cognitive impairment,falls and all-cause mortality in older adults:a systematic review and meta-analysis.Br J Clin Pharmacol,2015,Mar 2.[Epub ahead of print]

23 田小生，周 婷，崔德華，等.術(shù)后認(rèn)知功能障礙.神經(jīng)疾病與精神衛(wèi)生,2012,12(1):1-5.

24 Rasmussen LS,Moller JT.Central nervous system dysfunction after anesthesia in the geriatric patient.Anesthesiol Clin North America,2000,18(1):59-70.

25 Riedel G,Platt B,Micheau J.Glutamate receptor function in learning and memory.Behav Brain Res,2003,140(1-2):1-47.

26 Rezvani AH.Involvement of the NMDA System in Learning and Memory.Animal Models of Cognitive Impairment.Boca Raton: CRC Press,2006.Chapter 4.

27 Wang H,Peng R,Zhao L,et al.The relationship between NMDA receptors and microwave-induced learning and memory impairment:a long-term observation on Wistar rats.Int J Radiat Biol,2015,91(3):262-269.

28 Guidi M,Kumar A,Foster TC.Impaired attention and synaptic senescence of the prefrontal cortex involves redox regulation of NMDA receptors.J Neurosci,2015,35(9):3966-3977.

29 Liu DS,Pan XD,Zhang J,et al.APOE4 enhances age-dependent decline in cognitive function by down-regulating an NMDA receptor pathway in EFAD-Tg mice.Mol Neurodegener,2015,10(1):7.

30 Abdulrahman H,Fletcher PC,Bullmore E,et al.Dopamine and memory dedifferentiation in aging.Neuroimage,2015,Mar 21.[Epub ahead of print]

31 Reeves S,Mehta M,Howard R,et al.The dopaminergic basis of cognitive and motor performance in Alzheimer’s disease.Neurobiol Dis,2010,37(2):477-482.

32 Liu X,Ye K,Weinshenker D.Norepinephrine protects against amyloid-beta toxicity via TrkB.J Alzheimers Dis,2015,44(1):251-260.

33 Mei Y,Jiang C,Wan Y,et al.Aging-associated formaldehyde-induced norepinephrine deficiency contributes to age-related memory decline.Aging Cell,2015,Apr 11.[Epub ahead of print]

34 Sudheimer KD,O’Hara R,Spiegel D,et al.Cortisol,cytokines,and hippocampal volume interactions in the elderly.Front Aging Neurosci,2014,6:153.

35 Terrando N,Eriksson LI,Ryu JK,et al.Resolving postoperative neuroinflammation and cognitive decline.Ann Neurol,2011,70(6):986-995.

36 Fung A,Vizcaychipi M,Lloyd D,et al.Central nervous system inflammation in disease related conditions: mechanistic prospects.Brain Res,2012,1446:144-155.

37 Cumiskey D,Curran BP,Herron CE,et al.A role for inflammatory mediators in the IL-18 mediated attenuation of LTP in the rat dentate gyrus.Neuropharmacology,2007,52(8):1616-1623.

38 Butler MP,O’Connor JJ,Moynagh PN.Dissection of tumor-necrosis factor-alpha inhibition of long-term potentiation (LTP) reveals a p38 mitogen-activated protein kinase-dependent mechanism which maps to early-but not late-phase LTP.Neuroscience,2004,124(2):319-326.

39 Belarbi K,Jopson T,Tweedie D,et al.TNF-alpha protein synthesis inhibitor restores neuronal function and reverses cognitive deficits induced by chronic neuroinflammation.J Neuroinflammation,2012,9:23.

40 Cibelli M,Fidalgo AR,Terrando N,et al.Role of interleukin-1beta in postoperative cognitive dysfunction.Ann Neurol,2010,68(3):360-368.

41 Wan Y,Xu J,Ma D,et al.Postoperative impairment of cognitive function in rats: a possible role for cytokine-mediated inflammation in the hippocampus.Anesthesiology,2007,106(3):436-443.

42 Mishra A,Kim HJ,Shin AH,et al.Synapse loss induced by interleukin-1beta requires pre- and post-synaptic mechanisms.J Neuroimmune Pharmacol,2012,7(3):571-578.

43 Parolari A,Camera M,Alamanni F,et al.Systemic inflammation after on-pump and off-pump coronary bypass surgery: a one-month follow-up.Ann Thorac Surg,2007,84(3):823-828.

44 Ramlawi B,Rudolph JL,Mieno S,et al.C-Reactive protein and inflammatory response associated to neurocognitive decline following cardiac surgery.Surgery,2006,140(2):221-226.

45 Li YC,Xi CH,An YF,et al.Perioperative inflammatory response and protein S-100beta concentrations-relationship with post-operative cognitive dysfunction in elderly patients.Acta Anaesthesiol Scand,2012,56(5):595-600.

46 Cao XZ, Ma H,Wang JK, et al.Postoperative cognitive deficits and neuroinflammation in the hippocampus triggered by surgical trauma are exacerbated in aged rats.Prog Neuropsychopharmacol Biol Psychiatry,2010,34(8):1426-1432.

47 Wu X,Lu Y,Dong Y,et al.The inhalation anesthetic isoflurane increases levels of proinflammatory TNF-alpha, IL-6, and IL-1beta.Neurobiol Aging,2010,33(7):1364-1378.

48 Arfi A,Richard M,Gandolphe C,et al.Neuroinflammatory and oxidative stress phenomena in MPS IIIA mouse model: the positive effect of long-term aspirin treatment.Mol Genet Metab,2011,103(1):18-25.

49 Wu Y,Zhai H,Wang Y,et al.Aspirin-triggered lipoxin A(4) attenuates lipopolysaccharide-induced intracellular ROS in BV2 microglia cells by inhibiting the function of NADPH oxidase.Neurochem Res,2012,37(8):1690-1696.

50 Jaturapatporn D,Isaac MG,Mccleery J,et al.Aspirin,steroidal and non-steroidal anti-inflammatory drugs for the treatment of Alzheimer’s disease.Cochrane Database Syst Rev,2012,2:D6378.

51 Lee M,Sparatore A,Del SP,et al.Hydrogen sulfide-releasing NSAIDs attenuate neuroinflammation induced by microglial and astrocytic activation.Glia,2010,58(1):103-113.

52 Vizcaychipi MP,Watts HR,O’Dea KP,et al.The therapeutic potential of atorvastatin in a mouse model of postoperative cognitive decline.Ann Surg,2014,259(6):1235-1244.

53 Katznelson R,Djaiani GN,Borger MA,et al.Preoperative use of statins is associated with reduced early delirium rates after cardiac surgery.Anesthesiology,2009,110(1):67-73.

(修回日期：2015-05-26)

(責(zé)任編輯：王惠群)

Research Progress of Pathogenesis Mechanisms of Postoperative Cognitive Dysfunctions

ZhouYang,WangJun,GuoXiangyang.

DepartmentofAnesthesiology,PekingUniversityThirdHospital,Beijing100191,China

Correspondingauthor:GuoXiangyang,E-mail:puthmzk@163.com

【Summary】 Postoperative cognitive dysfunction (POCD) is a common central nervous system complication after anesthesia and surgery. The mechanisms of POCD are not clear yet. The article reviewed several potential mechanisms that have been reported. Further researches are needed to identify the pathophysiologic progress of POCD, which have great clinical and economic values.

Postoperative cognitive dysfunction; Mechanisms

國(guó)家自然科學(xué)基金(30972835,81371205)

R614.1

A

1009-6604(2015)07-0658-05

10.3969/j.issn.1009-6604.2015.07.023

2015-05-11)

** 通訊作者，E-mail：puthmzk@163.com