李艷,賀電,李婭,楚蘭,劉芳,方旭明,田田

·論著·

腦活素治療Alzheimer’s病的Meta分析

李艷,賀電,李婭,楚蘭,劉芳,方旭明,田田

目的 評(píng)價(jià)腦活素治療Alzheimer’s病(AD)的絕對(duì)有效性和安全性。方法 檢索CENTRAL、MEDLINE、EMBASE、PsycINFO、CBMdisc(檢索截至2015年9月30日)關(guān)于腦活素單藥治療AD癡呆或AD源性輕度認(rèn)知障礙的隨機(jī)、安慰劑平行對(duì)照臨床試驗(yàn)。采用Cochrane協(xié)作網(wǎng)的偏倚風(fēng)險(xiǎn)評(píng)價(jià)工具評(píng)價(jià)原始研究方法學(xué)質(zhì)量，GRADEpro 3.2軟件評(píng)價(jià)原始研究的局限性、結(jié)果的不一致性和不精確性、證據(jù)的間接性、發(fā)表偏倚對(duì)主體證據(jù)質(zhì)量的影響。結(jié)果 共納入6項(xiàng)研究，共950例AD癡呆患者。亞組分析結(jié)果顯示腦活素30 ml可改善輕中度AD癡呆患者隨訪1月時(shí)或隨訪6個(gè)月時(shí)認(rèn)知功能[標(biāo)準(zhǔn)均數(shù)差(SMD)=-0.360,95%CI：-0.600 ～ -0.130，P=0.003；SMD=-0.350，95%CI：-0.590～-0.100，P=0.005)]。隨訪6個(gè)月時(shí)精神行為癥狀改善(SMD=-0.290，95%CI：-0.540～-0.050，P=0.020)。腦活素不能改善隨訪1個(gè)月時(shí)或隨訪6個(gè)月時(shí)日常能力(SMD=-0.160，95%CI：-0.350～0.040，P=0.120；SMD=-0.210，95%CI：-0.450～0.030，P=0.080)。隨訪1個(gè)月和6個(gè)月時(shí)腦活素組和安慰劑組不良事件的發(fā)生率無差異，無嚴(yán)重不良事件發(fā)生。所有研究均存在方法學(xué)局限性，主要缺陷為測(cè)量偏倚風(fēng)險(xiǎn)不清楚，且制藥企業(yè)資助或參與研究，潛在偏倚風(fēng)險(xiǎn)較高。絕大多數(shù)結(jié)局指標(biāo)的總樣本量不足，并且部分結(jié)果的95%CI過寬，導(dǎo)致證據(jù)質(zhì)量下降。結(jié)論 低/極低級(jí)別證據(jù)表明，腦活素對(duì)輕中度AD癡呆患者的認(rèn)知功能和精神行為癥狀有輕微的改善作用，但不能改善患者的日常能力。

Alzheimer’s病；腦活素；隨機(jī)對(duì)照試驗(yàn)；Meta分析

Alzheimer’s病(AD)是癡呆最常見的病因，目前全球范圍內(nèi)約有20×106例患者，預(yù)計(jì)到2050年，全球?qū)⒂?.35×108例患者[1]。AD的病理生理學(xué)過程始于臨床診斷為癡呆前多年，疾病過程可以分為無癥狀的臨床前期[2]、有癥狀的癡呆前期[輕度認(rèn)知障礙(MCI)期][3]和臨床癡呆期3個(gè)階段[4]。目前尚無有效治療方法。隨著對(duì)AD分子生物學(xué)研究的深入，治療方向逐漸從單一的認(rèn)知功能改善轉(zhuǎn)為疾病修正治療，目的在于防止或減少β-淀粉樣蛋白(Aβ)和tau蛋白形成、集聚或沉積，減輕神經(jīng)炎癥程度，減緩神經(jīng)變性過程，阻止認(rèn)知功能惡化。腦活素是一種多肽混合物的水溶液，具有多種生物學(xué)活性，如神經(jīng)營(yíng)養(yǎng)[5]、抗Aβ[6]和抗tau蛋白[7]。迄今已有多項(xiàng)臨床試驗(yàn)評(píng)價(jià)腦活素療效，但樣本量較小且結(jié)果不盡一致。Wei 等[8]的Meta分析顯示，腦活素可以顯著改善輕中度AD患者總體印象評(píng)分。Gauthier等[9]的Meta分析顯示，腦活素可以改善輕中度AD患者總體印象評(píng)分和認(rèn)知功能。然而，上述兩項(xiàng)研究未充分考慮各研究間的異質(zhì)性和潛在偏倚，且未全面分析和評(píng)價(jià)證據(jù)質(zhì)量，有必要再次對(duì)這些臨床試驗(yàn)進(jìn)行系統(tǒng)評(píng)價(jià)，以探討腦活素治療AD的絕對(duì)有效性和安全性。

1 對(duì)象與方法

1.1 對(duì)象 (1)AD癡呆患者的診斷符合國(guó)際疾病分類法-10(ICD-10)[10]、美國(guó)精神障礙診斷與統(tǒng)計(jì)手冊(cè)第3版修訂版(DSM-Ⅲ-R)和第4版(DSM-Ⅳ)[11-12]、美國(guó)國(guó)立神經(jīng)病學(xué)、語言障礙和卒中研究所-AD及相關(guān)疾病協(xié)會(huì)(NINCDS-ADRDA)[4，13]制定的很可能癡呆標(biāo)準(zhǔn)。(2)AD源性MCI患者的診斷符合Petersen等[14]、Winblad等[15]和NINCDS-ADRDA制定的標(biāo)準(zhǔn)[3]，同時(shí)須有證據(jù)支持系A(chǔ)D所致，且有認(rèn)知功能隨年齡增長(zhǎng)逐漸下降的證據(jù)；排除腦血管病、顱腦創(chuàng)傷或其它疾病所致的認(rèn)知功能下降，排除其它神經(jīng)變性疾病。

1.2 方法

1.2.1 文獻(xiàn)檢索 以“cerebrolysin”“cerebroprotein hydrolysate”“Alzheimer” “dementia”“mild cognitive impairment”為英文檢索詞；以“腦活素”“腦蛋白水解物” “阿爾茨海默病” “老年性癡呆”“輕度認(rèn)知障礙”為中文檢索詞。計(jì)算機(jī)檢索CENTRAL、MEDLINE、EMBASE、PsycINFO、CBMdisc(檢索截至日期：2015年9月30日)等國(guó)內(nèi)外數(shù)據(jù)庫(kù)關(guān)于腦活素單藥治療AD癡呆或MCI的隨機(jī)、安慰劑平行對(duì)照臨床試驗(yàn)，并查閱相關(guān)綜述和研究的參考文獻(xiàn)以補(bǔ)充可能遺漏的相關(guān)臨床試驗(yàn)。

1.2.2 文獻(xiàn)納入及排除標(biāo)準(zhǔn) 選擇腦活素單藥治療AD癡呆或AD源性MCI的隨機(jī)、安慰劑平行對(duì)照試驗(yàn)。試驗(yàn)組為腦活素靜脈滴注，給藥頻率和治療時(shí)間無限制。對(duì)照組為安慰劑靜脈滴注，給藥頻率和治療時(shí)間與試驗(yàn)組一致。主要結(jié)局包括：(1)認(rèn)知功能，采用AD評(píng)估量表-認(rèn)知分量表(ADAS-Cog)[16-17]、MMSE[18]、連線測(cè)驗(yàn)(TMT)[19]。(2)臨床總體印象：采用臨床醫(yī)師整體印象變化量表(CGI)[20]、 臨床醫(yī)師訪談時(shí)對(duì)病情變化的印象補(bǔ)充量表(CIBIC+)[21]。(3)基線時(shí)為AD源性MCI的患者，隨訪中進(jìn)展為AD癡呆的病例數(shù)。(4)不良事件的病例數(shù)、發(fā)生嚴(yán)重不良事件的病例數(shù)。次要結(jié)局包括：(1)日常能力：采用日常生活活動(dòng)能力量表(ADL)[22]、工具性日常生活活動(dòng)能力量表(IADL)[23]、癡呆殘疾評(píng)估(DAD)[24]、紐倫堡活動(dòng)問卷(NAI)[25]。(2)精神行為癥狀：采用神經(jīng)精神癥狀問卷(NPI)[26]、AD病理行為評(píng)定量表(BEHAVE-AD)[27]、AD評(píng)估量表-非認(rèn)知分量表(ADAS-nonCog)[16]。

1.2.3 文獻(xiàn)質(zhì)量評(píng)價(jià) 根據(jù)Cochrane 系統(tǒng)評(píng)價(jià)手冊(cè)5.1.0版[28]，由兩位評(píng)價(jià)員采用Cochrane協(xié)作網(wǎng)的偏倚風(fēng)險(xiǎn)評(píng)價(jià)工具對(duì)各項(xiàng)研究的方法學(xué)質(zhì)量獨(dú)立進(jìn)行評(píng)價(jià)，包括隨機(jī)分配方法、分配方案隱藏方法、受試者和研究人員設(shè)盲情況，結(jié)局測(cè)量者的設(shè)盲情況、結(jié)局?jǐn)?shù)據(jù)的完整性、選擇性報(bào)告研究結(jié)果和其他偏倚情況。如果一項(xiàng)研究退出率>20%或干預(yù)組組間退出原因不平衡，則該項(xiàng)研究判定為具有較高的隨訪偏倚。采用GRADEpro軟件[29]進(jìn)一步評(píng)價(jià)各項(xiàng)臨床試驗(yàn)設(shè)計(jì)和實(shí)施過程中的局限性和偏倚風(fēng)險(xiǎn)、研究結(jié)果的不一致性(研究結(jié)果間無法解釋的異質(zhì)性)和不精確性(總樣本量過小或95%CI過寬)、研究證據(jù)的間接性，以及發(fā)表偏倚對(duì)證據(jù)質(zhì)量的影響。

1.2.4 資料提取 由兩位評(píng)價(jià)員獨(dú)立篩選研究、提取資料，包括研究基本信息、研究方法和可能存在的偏倚、研究對(duì)象特征、干預(yù)措施、結(jié)局指標(biāo)、研究結(jié)果、資助機(jī)構(gòu)以及潛在利益沖突等。

1.2.5 統(tǒng)計(jì)學(xué)方法 采用RevMan 5.3.3[30]進(jìn)行數(shù)據(jù)合成，選擇腦活素30 ml組與安慰劑對(duì)照組進(jìn)行Meta分析，并分析隨訪短期(≤1個(gè)月)、中期(1～6個(gè)月)、長(zhǎng)期(>6個(gè)月)的結(jié)局?jǐn)?shù)據(jù)。若異質(zhì)性檢驗(yàn)顯示存在中度或中度以上統(tǒng)計(jì)學(xué)異質(zhì)性(I2>30.000%)，根據(jù)癡呆嚴(yán)重程度、同一結(jié)局所測(cè)量的量表差異、偏倚風(fēng)險(xiǎn)程度進(jìn)行亞組分析，以分析異質(zhì)性來源。根據(jù)一種假設(shè)(可能情況)進(jìn)行敏感性分析，以評(píng)價(jià)退出病例對(duì)主要結(jié)局的影響。

2 結(jié) 果

2.1 文獻(xiàn)檢索和研究質(zhì)量評(píng)價(jià) 初篩共獲得相關(guān)文獻(xiàn)95篇，經(jīng)閱讀文題和摘要篩選出10篇文獻(xiàn)，進(jìn)一步閱讀原文，剔除1項(xiàng)開放性臨床試驗(yàn)[31]，最終納入9篇文獻(xiàn)[32-40]共6項(xiàng)隨機(jī)對(duì)照臨床試驗(yàn),共950例輕中度AD癡呆患者。特征見表1；研究質(zhì)量和偏倚風(fēng)險(xiǎn)評(píng)價(jià)結(jié)果見表2。

2.2 效應(yīng)量的合并

2.2.1 認(rèn)知功能 有5項(xiàng)研究[32-36]報(bào)道了隨訪1個(gè)月時(shí)的認(rèn)知功能，其中3項(xiàng)研究[33-35]間無明顯的異質(zhì)性(P=0.300，I2=16.000%)，采用隨機(jī)效應(yīng)模型進(jìn)行合并，結(jié)果顯示，腦活素治療輕中度AD癡呆患者，可改善隨訪1個(gè)月時(shí)認(rèn)知功能[標(biāo)準(zhǔn)均數(shù)差(SMD)=-0.360，95%CI：-0.600～-0.130，P=0.003)]。有3項(xiàng)研究[35-37]報(bào)道隨訪6個(gè)月時(shí)的認(rèn)知功能，其中2項(xiàng)[35,37]研究間無異質(zhì)性(P=0.690，I2=0.000%)，用隨機(jī)效應(yīng)模型進(jìn)行合并顯示，腦活素治療可改善輕中度AD癡呆患者隨訪6個(gè)月時(shí)認(rèn)知功能(SMD=-0.350，95%CI：-0.590～-0.100，P=0.005)。

2.2.2 臨床總體印象 有5項(xiàng)研究[32-36]報(bào)道隨訪1個(gè)月時(shí)臨床總體印象；3項(xiàng)研究[35-37]報(bào)道隨訪6個(gè)月時(shí)臨床總體印象，各研究間均存在異質(zhì)性，故未進(jìn)行數(shù)據(jù)合并。

表1 所納入6項(xiàng)研究的特征(x±s，例，%)研究 例數(shù) 女性 年齡(歲) 基線MMSE 評(píng)分 干預(yù)措施 隨訪時(shí) 間(個(gè)月)結(jié)局指標(biāo)Rüether等[32](1994)1SCAG、CGI、ZVT、NAI、bf?S 腦活素組6038(63．3)71．6±8．821．6±1．330ml腦活素，靜脈輸注，1次/d，周一至周五，共四周 對(duì)照組6041(68．3)71．3±7．821．6±1．3安慰劑Bae等[33](2000)1ADAS?Cog、CGI、GDS、MMSE、ADL、IADL 腦活素組3423(67．6)73．1±9．716．3±4．830ml腦活素，靜脈輸注，1次/d，周一至周五，共四周 對(duì)照組1912(63．2)69．0±9．114．6±5．5安慰劑Xiao等[34](2000)1MMSE、CGI、ZVT、SCAG、ADL、NAI 腦活素組7434(45．9)69．8±8．118．8±3．230ml腦活素，靜脈輸注，1次/d，周一至周五，共四周 對(duì)照組8345(54．2)70．9±7．319．1±3．2安慰劑Rüether等[35](2001)6ADAS?Cog、CGI、MADR?S、NAI、ADAS?nonCog、SKT 腦活素組7649(64．5)72．5±7．917±3．930ml腦活素，靜脈輸注，1次/d，每周連續(xù)給藥5d，共四周，間隔8周后再次按上述給藥方案給藥 對(duì)照組7338(52．1)73．5±7．617．5±4．4安慰劑Panisset等[36](2002)6ADAS?Cog、CIBIC+、MMSE、DAD、CORNELL、PSMS、IADL、BEHAVE?AD、CDR 腦活素組9758(59．8)73．2±6．120．2±3．330ml腦活素，靜脈輸注，1次/d，每周連續(xù)給藥5d，共四周 對(duì)照組9553(55．8)75．2±6．220．9±3．2安慰劑Alvarez等[37](2006)6ADAS?Cog+、CIBIC+、MMSE、NPI、ZVT、DAD 腦活素10ml組6949(71．0)72．2±9．919．7±3．9腦活素10ml，靜脈輸注，1次/d，每周給藥5d，給藥四周，之后每周給藥2d，給藥8周 腦活素30ml組7053(75．7)73．4±8．719．7±3．2腦活素30ml 腦活素60ml組7150(70．4)74．6±7．319．6±4．1腦活素60ml 對(duì)照組6945(65．2)73．9±9．819．8±3．8安慰劑 注：ADAS?Cog+：ADAS?Cog量表修訂版；bf?S：Zerssen自評(píng)量表；CDR：臨床癡呆評(píng)定量表；CORNELL：康奈爾抑郁量表；GDS：老年抑郁量表；MADR?S：蒙哥馬利抑郁量表；PSMS：軀體生活自理量表；SCAG：老年臨床評(píng)定量表；SKT：簡(jiǎn)短認(rèn)知功能測(cè)驗(yàn)；ZVT：TMT

表2 所納入6項(xiàng)研究的方法學(xué)質(zhì)量與偏倚風(fēng)險(xiǎn)評(píng)價(jià)(例，%)研究隨機(jī)分配方法(選擇性偏倚)分配方案隱藏(選擇性偏倚)受試者和研究人員的設(shè)盲(實(shí)施偏倚)結(jié)果測(cè)量者的設(shè)盲(測(cè)量偏倚)結(jié)果數(shù)據(jù)的完整性(隨訪偏倚)腦活素組安慰劑組選擇性報(bào)告研究結(jié)果(報(bào)告偏倚)其他偏倚來源Rüether等[32](1994)不清楚偏倚風(fēng)險(xiǎn)低偏倚風(fēng)險(xiǎn)低不清楚00偏倚風(fēng)險(xiǎn)低偏倚風(fēng)險(xiǎn)高Bae等[33](2000)不清楚偏倚風(fēng)險(xiǎn)低偏倚風(fēng)險(xiǎn)低不清楚00偏倚風(fēng)險(xiǎn)低偏倚風(fēng)險(xiǎn)高Xiao等[34](2000)偏倚風(fēng)險(xiǎn)低偏倚風(fēng)險(xiǎn)低偏倚風(fēng)險(xiǎn)低不清楚2(2．7)0偏倚風(fēng)險(xiǎn)低偏倚風(fēng)險(xiǎn)高Ruether等[35](2001)偏倚風(fēng)險(xiǎn)低偏倚風(fēng)險(xiǎn)低偏倚風(fēng)險(xiǎn)低不清楚6(7．9)7(9．6)偏倚風(fēng)險(xiǎn)低偏倚風(fēng)險(xiǎn)高Panisset等[36](2002)偏倚風(fēng)險(xiǎn)高偏倚風(fēng)險(xiǎn)低偏倚風(fēng)險(xiǎn)低不清楚9(9．3)12(12．6)偏倚風(fēng)險(xiǎn)低偏倚風(fēng)險(xiǎn)高Alvarez等[37](2006)偏倚風(fēng)險(xiǎn)低不清楚偏倚風(fēng)險(xiǎn)低不清楚腦活素10ml：11(15．9)腦活素30ml：9(12．9)腦活素60ml：6(8．6)16(23．2)偏倚風(fēng)險(xiǎn)低偏倚風(fēng)險(xiǎn)高

2.2.3 精神行為癥狀 有3項(xiàng)研究[35-37]報(bào)道隨訪6個(gè)月時(shí)精神行為癥狀，其中2項(xiàng)[35，37]研究間無異質(zhì)性(P=0.870，I2=0.000%)，采用隨機(jī)效應(yīng)模型進(jìn)行合并，結(jié)果顯示，腦活素治療輕中度AD癡呆患者，可改善隨訪6個(gè)月時(shí)精神行為癥狀(SMD=-0.290，95%CI：-0.540～-0.050，P=0.020)。

2.2.4 日常能力 有5項(xiàng)研究[32-36]報(bào)道隨訪1個(gè)月時(shí)日常能力，其中3項(xiàng)[34-36]研究間無明顯異質(zhì)性(P=0.300，I2=16.000%)，采用隨機(jī)效應(yīng)模型進(jìn)行合并，結(jié)果顯示，腦活素治療輕中度AD癡呆患者，不能改善隨訪1個(gè)月時(shí)日常能力(SMD=-0.160，95%CI：-0.350～0.040，P=0.120)。有3項(xiàng)研究[35-37]報(bào)道隨訪6個(gè)月日常能力，其中2項(xiàng)[35,37]研究間無異質(zhì)性(P=0.580，I2=0.000%)，采用隨機(jī)效應(yīng)模型進(jìn)行合并顯示，腦活素治療輕中度AD癡呆患者，不能改善隨訪6個(gè)月時(shí)日常能力(SMD=-0.210，95%CI：-0.450～0.030，P=0.080)。

2.2.5 安全性 有3項(xiàng)[32-34]報(bào)道隨訪1個(gè)月時(shí)不良事件發(fā)生率，各研究間無異質(zhì)性(P=0.710，I2=0.000%)，采用隨機(jī)效應(yīng)模型進(jìn)行合并，結(jié)果顯示，與安慰劑比較，腦活素治療輕中度AD癡呆不增加隨訪1個(gè)月時(shí)不良事件發(fā)生率(RR=2.940，95%CI：0.720～11.990；P=0.130)。3項(xiàng)研究[32-34]報(bào)道隨訪1個(gè)月時(shí)無一例發(fā)生嚴(yán)重不良事件。3項(xiàng)研究[35-37]報(bào)道隨訪6個(gè)月時(shí)不良事件和嚴(yán)重不良事件發(fā)生率，各項(xiàng)研究間無異質(zhì)性(P=0.430，I2=0.000%；P=0.790，I2=0.000%)，采用隨機(jī)效應(yīng)模型進(jìn)行合并，結(jié)果顯示，與安慰劑比較，腦活素治療輕中度AD癡呆不增加隨訪6個(gè)月時(shí)不良事件和嚴(yán)重不良事件發(fā)生率(RR= 0.920，95%CI：0.790～1.070，P=0.280 ；RR= 1.090，95%CI：0.620～1.910，P=0.760)。

2.3 主要結(jié)局的證據(jù)質(zhì)量 所有經(jīng)Meta分析的結(jié)局證據(jù)等級(jí)因原始研究局限性或(和)結(jié)果的不精確性而降低，評(píng)為極或極低級(jí)別證據(jù)。由于本系統(tǒng)評(píng)價(jià)納入的研究數(shù)目較少，未能進(jìn)行發(fā)表偏倚評(píng)價(jià)。

3 討 論

本系統(tǒng)評(píng)價(jià)共納入6項(xiàng)腦活素單藥治療AD的隨機(jī)、安慰劑平行對(duì)照臨床試驗(yàn)，所有試驗(yàn)在方法學(xué)上均存在局限性，主要為測(cè)量偏倚風(fēng)險(xiǎn)不清楚，并且制藥企業(yè)資助或參與了研究。因此，所有試驗(yàn)均判定為高偏倚風(fēng)險(xiǎn)的研究。其中1項(xiàng)研究使用計(jì)算機(jī)產(chǎn)生隨機(jī)化序列，但因區(qū)組長(zhǎng)度過大，導(dǎo)致兩組患者在年齡和病程上不具有可比性，選擇性偏倚風(fēng)險(xiǎn)較高。

本研究結(jié)果顯示，靜脈滴注腦活素30 ml治療輕中度AD癡呆可改善患者短中期認(rèn)知功能；此外，精神行為癥狀亦有所改善；但不能改善日常能力。腦活素30 ml治療輕中度AD癡呆安全性較好。

然而，由于所納入研究方法學(xué)的缺陷(主要為測(cè)量偏倚風(fēng)險(xiǎn)不清楚、制藥企業(yè)資助或參與研究)或/和結(jié)果的不精確性(由于總樣本量不足或/和結(jié)果95%CI過寬)，上述結(jié)果的真實(shí)性受影響，證據(jù)質(zhì)量降低。總的來說，使用量表評(píng)估的結(jié)局，包括認(rèn)知功能、精神行為癥狀以及日常能力，受測(cè)量偏倚的影響較大。本系統(tǒng)評(píng)價(jià)所納入試驗(yàn)的測(cè)量偏倚風(fēng)險(xiǎn)不清楚，并且制藥企業(yè)資助或參與了所有研究，潛在偏倚風(fēng)險(xiǎn)較高，上述量表評(píng)估結(jié)局的證據(jù)質(zhì)量下調(diào)2個(gè)等級(jí)，此外，除隨訪1個(gè)月日常能力外，其余結(jié)局總樣本量均不足400例，并且部分結(jié)果的95%CI過寬，證據(jù)質(zhì)量進(jìn)一步下調(diào)1個(gè)等級(jí)，被評(píng)定為極低級(jí)別證據(jù)。雖不良事件結(jié)局的證據(jù)受測(cè)量偏倚影響小，但仍受潛在高偏倚風(fēng)險(xiǎn)(制藥企業(yè)資助或參與研究)的影響，因此，證據(jù)質(zhì)量下調(diào)1個(gè)等級(jí)。此外，不良事件結(jié)局的證據(jù)質(zhì)量還因樣本量不足或/和結(jié)果95%CI過寬進(jìn)一步下調(diào)1個(gè)等級(jí)，被評(píng)定為低級(jí)別證據(jù)。在臨床總體印象方面，由于各項(xiàng)研究間存在統(tǒng)計(jì)學(xué)異質(zhì)性，未能進(jìn)行Meta分析。

低/極低級(jí)別證據(jù)表明，腦活素對(duì)輕中度AD癡呆患者的認(rèn)知功能和精神行為癥狀有輕微的改善作用，但不能改善患者的日常能力。

[1]Alzheimer ’s Association. 2014 Alzheimer’s disease facts and figures[J]. Alzheimers Dement, 2014, 10:e47.

[2]Sperling RA, Aisen PS, Beckett LA, et al. Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the national institute on aging- Alzheimer’s association workgroups on diagnostic guidelines for Alzheimer’s disease[J]. Alzheimers Dement, 2011, 7:280.

[3]Albert MS, DeKosky ST, Dickson D, et al. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease[J]. Alzheimers Dement, 2011, 7:270.

[4]McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the national institute on aging-Alzheimer’s association workgroups on diagnostic guidelines for Alzheimer’s disease[J]. Alzheimers Dement, 2011, 7:263.

[5]Ubhi K, Rockenstein E, Vazquez-Roque R, et al. Cerebrolysin modulates pronerve growth factor/nerve growth factor ratio and ameliorates the cholinergic deficit in a transgenic model of Alzheimer’s disease[J]. J Neurosci Res, 2013, 91:167.

[6]Rockenstein E, Torrance M, Mante M, et al. Cerebrolysin decreases amyloid-beta production by regulating amyloid protein precursor maturation in a transgenic model of Alzheimer’s disease[J]. J Neurosci Res, 2006, 83:1252.

[7]Rockenstein E, Ubhi K, Trejo M, et al. CerebrolysinTMefficacy in a transgenic model of tauopathy: role in regulation of mitochondrial structure[J]. BMC Neurosci, 2014,15:90.

[8]Wei ZH, He QB, Wang H, et al. Meta-analysis: the efficacy of nootropic agent Cerebrolysin in the treatment of Alzheimer’s disease[J]. J Neural Transm (Vienna), 2007, 114:629.

[9]Gauthier S, Proao JV, Jia J, et al. Cerebrolysin in mild-to-moderate Alzheimer’s disease: a meta-analysis of randomized controlled clinical trials[J]. Dement Geriatr Cogn Disord, 2015, 39:332.

[10]World Health Organization. The ICD-10 classification of mental and behavioural disorders: clinical description and diagnostic guidelines[M]. Geneva: World Health Organization, Division of Mental Health, 1992.

[11]American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders[M]. Third Edition, Revised. American Psychiatric Association, 1989.

[12]American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders[M]. 4th Edition. American Psychiatric Association, 1994.

[13]McKhann G, Drachman D, Folstein M, et al. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA work group under the auspices of department of health and human services task force on Alzheimer’s disease[J]. Neurology, 1984, 4:939.

[14]Petersen RC, Smith GE, Waring SC, et al. Mild cognitive impairment: clinical characterization and outcome[J]. Arch Neurol,1999,56:303.

[15]Winblad B, Palmer K, Kivipelto M, et al. Mild cognitive impairment-beyond controversies, towards a consensus: report of the international working group on mild cognitive impairment[J]. J Intern Med, 2004,256:240.

[16]Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer’s disease[J]. Am J Psychiatry, 1984,141:1356.

[17]Mohs RC, Knopman D, Petersen RC, et al. Development of cognitive instruments for use in clinical trials of antidementia drugs: additions to the Alzheimer’s disease assessment scale that broaden its scope. The Alzheimer’s disease cooperative study[J]. Alzheimer Dis Assoc Disord, 1997,11:s13.

[18]Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician[J]. J Psychiatr Res,1975,12:189.

[19]Oswald WD. Der Zahlen-Verbindungs-Test im hoheren lebensalter[M]. In: Aspekte Psychologischer Forschung. Hogrefe, Gottingen: 1986.

[20]Guy W. Clinical Global Impressions (CCI)[M]. In: ECDEU Assessment Manual for Psychopharmacology. Rockville, MD: US Department of Health and Human Services, 1976.

[21]Knopman DS, Knapp MJ, Gracon SI, et al. The Clinician Interview-Based Impression (CIBI): a clinician’s global change rating scale in Alzheimer’s disease[J]. Neurology, 1994,44:2315.

[22]Katz S, Ford AB, Moskowitz RW, et al. Studies of illness in aged. The index of ADL: a standardized measure of biological and psychosocial funtion[J]. JAMA, 1963, 185:914.

[23]Lawton MP, Brody EM. Assessment of older people: self-maintaining andinstrumental activities of daily living[J]. Gerontologist, 1969, 9:179.

[24]Gélinas I, Gauthier L, McIntyre M, et al. Development of a functional measure for persons with Alzheimer’s disease: the disability assessment for dementia[J]. Am J Occup Ther, 1999,53:471.

[25]Oswald WD, Fleischmann UM. Nürnberger-Alters-Inventar NAI[M]. Testkasten und Manual, 3. Aufl. Universit?t Erlangen-Nürnberg, Nürnberg. Hogrefe (Testzentrale Stuttgart), G?ttingen. 1992.

[26]Cummings JL, Mega M, Gray K, et al. The neuropsychiatric inventory: comprehensive assessment of psychopathology in dementia[J]. Neurology, 1994,44:2308.

[27]Reisberg B, Borenstein J, Salob SP, et al. Behavioral symptoms in Alzheimer’s disease: phenomenology and treatment[J]. J Clin Psychiatry,1987,48:9.

[28]Higgins JPT, Green S (editors). Cochrane handbook for systematic reviews of interventions Version 5.1.0 [updated March 2011][DB/OL]. Available at: www.cochrane-handbook.org.

[29]Schünemann H, Brozek J, Oxman A, editors. GRADE handbook for grading quality of evidence and strength of recommendation. Version 3.2 [updated March 2009][DB/OL]. Available at: http://www.cc-ims.net/gradepro.

[30]Review Manager (RevMan). Version 5.3 [CP]. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.

[31]Muresanu DF, Rainer M, Moessler H. Improved global function and activities of daily living in patients with AD: a placebo-controlled clinical study with the neurotrophic agent Cerebrolysin[J]. J Neural Transm Suppl, 2002,62:277.

[32]Rüether E, Ritter R, Apecechea M, et al. Efficacy of the peptidergic nootropic drug cerebrolysin in patients with senile dementia of the lzheimer type (SDAT) [J]. Pharmacopsychiatry,1994,27:32.

[33]Bae CY, Cho CY, Cho K, et al. A double-blind, placebo-controlled, multicenter study of erebrolysin for Alzheimer’s disease[J]. J Am Geriatr Soc,2000,48:1566.

[34]Xiao SF, Yan HQ, Yao PF, et al. Efficacy of FPF 1070 (Cerebrolysin) in atients with Alzheimer ’s disease: A multicentre, randomised, double-blind, lacebo-controlled trial[J]. Clin Drug Invest, 2000,9:43.

[35]Rüether E, Husmann R, Kinzler E, et al. A 28-week, double-blind, placebo-controlled study with cerebrolysin in patients with mild to moderate Alzheimer’s disease[J]. Int Clin Psychopharmacol, 2001,16:253.

[36]Panisset M, Gauthier S, Moessler H, et al. Cerebrolysin in Alzheimer’s disease: a randomized, double-blind, placebo-controlled trial with a neurotrophic agent[J]. J Neural Transm (Vienna),2002,109:1089.

[37]Alvarez XA, Cacabelos R, Laredo M, et al. A 24-week, double-blind, placebo-controlled study of three dosages of cerebrolysin in patients with mild to moderate Alzheimer’s disease[J]. Eur J Neurol,2006, 13:43.

[38]Rüether E, Ritter R, Apecechea M, et al.Sustained improvements in patients with dementia of Alzheimer’s type (DAT) 6 months after termination of cerebrolysin therapy[J]. J Neural Transm (Vienna),2000,107:815.

[39]Rüether E, Alvarez XA, Rainer M, et al. Sustained improvement of cognition and global function in patients with moderately severe Alzheimer’s disease: a double-blind, placebo-controlled study with the neurotrophic agent cerebrolysin[J]. J Neural Transm Suppl, 2002,62:265.

[40]Alvarez XA, Cacabelos R, Sampedro C, et al. Efficacy and safety of cerebrolysin in moderate to moderately severe Alzheimer’s disease: results of a randomized, double-blind, controlled trial investigating three dosages of cerebrolysin[J]. Eur J Neurol, 2011,18:59.

Meta-analysis of cerebrolysin for Alzheimer’s disease

LIYan，HEDian，LIYa，etal.

DepartmentofNeurology，AffiliatedHospitalofGuizhouMedicalUniversity，Guiyang550004,China

Objective To assess the absolute efficacy and safety of cerebrolysin for patients with Alzheimer’s disease(AD). Methods CENTRAL, MEDLINE、EMBASE, PsycINFO, CBMDisc(up to September 30，2015) were searched for the randomized, placebo-controlled, parallel-group clinical trials evaluating cerebrolysin as monotherapy for patients with AD dementia or mild cognitive impairment due to AD. The methodological quality of the original studies were evaluated by using the Cochrane collaboration’s tool. The influences of study limitations, inconsistency of results, imprecision of effect estimates, indirectness of evidence and publication bias on the quality of the body of evidence were assessed by using GRADEpro software (version 3.2).Results Six studies were included, involving 950 patients with AD dementia. Subgroup analyses indicated cerebrolysin at a dose of 30 ml improved cognitive function in patients with mild-to-moderate AD dementia at one month or six months of follow-up [standard mean difference (SMD)=-0.360,95%CI：-0.600--0.130，P=0.003；SMD =-0.350，95%CI：-0.590--0.100，P=0.005)]. There was improvement in behavioural and psychiatric symptoms at six months of follow-up(SMD=-0.290,95%CI：-0.540--0.050,P=0.020).Cerebrolysin did not improve activities of daily living at one month or six months of follow-up (SMD=-0.160，95%CI：-0.350-0.040，P=0.120；SMD=-0.210，95%CI：-0.450-0.030，P=0.080). The incidence of adverse events (AEs) at one month or six month of follow-up was not different between the cerebrolysin group and the placebo group. No serious AEs occurred in both groups. All studies had methodological limitations, mainly on an unclear risk of detection bias. The pharmaceutical company funded or participated in the clinical trials， therefore，the potential risk of bias was high.Furthermore, the total sample size for most outcomes was insufficient, and the 95%CIof most results was wide. All these factors contributed to a decreased quality level of the evidence.Conclusions There is low/very low-quality evidence to show that cerebrolysin has slight effects in improving cognitive function and behavioural and psychiatric symptoms in patients with mild-to-moderate AD dementia. It has no effects in improving activities of daily living.

Alzheimer’s disease; cerebrolysin; randomized controlled trial; meta-analysis

貴州省科技計(jì)劃項(xiàng)目(黔科合重大專項(xiàng)字[2014]6008號(hào))

550004 貴陽，貴州醫(yī)科大學(xué)附屬醫(yī)院神經(jīng)內(nèi)科

賀電

R749.1

A

1004-1648(2017)03-0179-06

2016-03-29

2016-05-19)