拓西平
老年人認(rèn)知功能障礙研究進(jìn)展
拓西平
(第二軍醫(yī)大學(xué)附屬長(zhǎng)海醫(yī)院老年病科,上海 200433)
隨著社會(huì)老齡化的迅速進(jìn)展,認(rèn)知功能障礙和癡呆患者日益增多,如何進(jìn)行早期診斷及干預(yù)是老年醫(yī)學(xué)研究在新世紀(jì)面臨的重要課題。近些年,隨著對(duì)老年人認(rèn)知功能障礙及癡呆的定義和分類(lèi)的規(guī)范,采用針對(duì)性和實(shí)踐性強(qiáng)的神經(jīng)心理學(xué)測(cè)查量表,使得大量回顧性及前瞻性流行病學(xué)研究具有了可比性,對(duì)包括輕度認(rèn)知功能障礙在內(nèi)的老年認(rèn)知功能障礙及癡呆的危險(xiǎn)因素進(jìn)行了系統(tǒng)的分析,從而為臨床藥物及行為干預(yù)提供了靶點(diǎn),同時(shí)為基礎(chǔ)研究及藥物開(kāi)發(fā)提供了方向。
老年人;認(rèn)知功能障礙;癡呆
隨著人口老齡化在全球范圍迅速進(jìn)展,以認(rèn)知功能障礙為主要表現(xiàn)的老年性癡呆成為繼腫瘤、心腦血管病、糖尿病之后,嚴(yán)重影響老年人生活質(zhì)量,給家庭和社會(huì)帶來(lái)沉重負(fù)擔(dān)的重要疾病。國(guó)內(nèi)早期的抽樣調(diào)查研究顯示,嚴(yán)重認(rèn)知功能障礙及輕度認(rèn)知功能障礙的發(fā)病率分別為4.1%和14.4%[1]。隨著神經(jīng)心理學(xué)測(cè)查量表的不斷完善以及流行病學(xué)調(diào)查的廣泛開(kāi)展,目前普遍認(rèn)為國(guó)內(nèi)老年人認(rèn)知功能障礙的發(fā)病率遠(yuǎn)高于此,癡呆和輕度認(rèn)知功能障礙的發(fā)病率分別達(dá)5.2%~7.0%和15.7%~26.2%[2?6]。2010年中國(guó)人口調(diào)查報(bào)告顯示,全國(guó)總?cè)丝?3.39億中≥60歲的人口占13.26%,以此為基數(shù)計(jì)算,保守估計(jì)老年癡呆及認(rèn)知功能障礙的人數(shù)在>3 000萬(wàn)。本期專(zhuān)欄苗振春等[7]對(duì)上海地區(qū)400名軍隊(duì)離退休干部認(rèn)知功能障礙和血脂進(jìn)行了流行病學(xué)調(diào)查,發(fā)現(xiàn)在年齡≥60歲的軍隊(duì)離退休干部中,患認(rèn)知功能障礙的比例高達(dá)22.55%,而在認(rèn)知功能障礙的老年人中,其心腦血管疾病、糖尿病的發(fā)生率也相對(duì)較高。所以老年人認(rèn)知功能障礙相關(guān)性疾病,已成為21世紀(jì)老齡化社會(huì)醫(yī)療工作的重要內(nèi)容。
正確認(rèn)識(shí)老年人認(rèn)知功能障礙相關(guān)的概念,是啟動(dòng)老年人認(rèn)知相關(guān)臨床和基礎(chǔ)研究的先決條件。認(rèn)知是人腦對(duì)事物信息的接收、儲(chǔ)存、分析、使用、執(zhí)行、反饋、調(diào)整等的綜合反映,是感覺(jué)輸入的變換、減少、解釋、儲(chǔ)存、恢復(fù)和使用等復(fù)雜過(guò)程。認(rèn)知功能則包含了多個(gè)認(rèn)知域,例如記憶、計(jì)算、時(shí)空間定向、結(jié)構(gòu)能力、執(zhí)行能力、語(yǔ)言理解和表達(dá)及應(yīng)用等方面,可以表現(xiàn)為感知覺(jué)、記憶力、語(yǔ)言、抽象思維、表達(dá)等功能,綜合反映了大腦的功能狀況。認(rèn)知功能障礙泛指各種原因?qū)е碌某潭炔灰坏恼J(rèn)知功能損害,可表現(xiàn)為學(xué)習(xí)和記憶障礙、失語(yǔ)、失認(rèn)、失用及視空間障礙等,以及由此伴隨的焦慮、抑郁、激越、沖動(dòng)等情感障礙,程度從輕度認(rèn)知功能損害到癡呆。輕度認(rèn)知功能損害指有記憶障礙和(或)其他輕度認(rèn)知功能障礙,但個(gè)體的社會(huì)職業(yè)或日常生活功能未受影響,亦不能由已知的醫(yī)學(xué)或神經(jīng)精神疾病解釋?zhuān)墙橛谡@匣c輕度癡呆之間的一種臨床狀態(tài),臨床上分為遺忘型和非遺忘型。癡呆指器質(zhì)性疾病引起的一組嚴(yán)重認(rèn)知功能缺陷或衰退的臨床綜合征,如進(jìn)行性思維、記憶、行為和人格障礙等,可伴隨精神和運(yùn)動(dòng)功能癥狀,損害達(dá)到影響職業(yè)、社會(huì)功能或日常生活能力的程度,臨床上常分為阿爾茨海默?。ˋlzheimer’s disease,AD)型癡呆、血管源型癡呆(vascular dementia,VD)、混合型癡呆及其他類(lèi)型[8]。目前,無(wú)論采用世界衛(wèi)生組織的《國(guó)際疾病分類(lèi)》第10版(International Classification of Disease,ICD-10),還是美國(guó)精神病聯(lián)合會(huì)的《精神障礙診斷和統(tǒng)計(jì)手冊(cè)》第4版(The Diagnostic and Statistical Manual of Mental Disorders,DSM-Ⅳ)中關(guān)于癡呆的診斷標(biāo)準(zhǔn),均要求以下4點(diǎn):(1)記憶力減退;(2)其他認(rèn)知能力減退;(3)認(rèn)知衰退足以影響社會(huì)功能;(4)排除意識(shí)障礙、譫妄等導(dǎo)致的上述癥狀[9]。
基于以上定義和分類(lèi),神經(jīng)科醫(yī)師和精神科醫(yī)師不斷完善并制定了用于不同環(huán)境、診斷不同類(lèi)型及程度認(rèn)知功能障礙的各種神經(jīng)心理學(xué)測(cè)查量表,正確選擇并合理選用這些量表,是進(jìn)行流行病學(xué)調(diào)查和診斷疾病的重要依據(jù)。目前將認(rèn)知功能障礙最常見(jiàn)的神經(jīng)心理學(xué)表現(xiàn)分為3類(lèi):(1)單純認(rèn)知功能障礙;(2)合并精神行為癥狀;(3)伴隨社會(huì)和日常能力減退[10],各種量表也主要圍繞這3方面而設(shè)定。
認(rèn)知功能評(píng)估包括總體認(rèn)知功能、記憶力、執(zhí)行、功能、語(yǔ)言、運(yùn)用、視空間和結(jié)構(gòu)能力等。目前總體認(rèn)知評(píng)估推薦簡(jiǎn)易智力狀態(tài)檢查(Mini-Mental State Examination,MMSE),建議作為癡呆的篩查,應(yīng)用最為廣泛[11,12];Mattis癡呆評(píng)估量表(Mattis Dementia Rating Scale,DRS)常常用于額葉、皮質(zhì)下型癡呆的評(píng)定和隨訪(fǎng)[13];阿爾茨海默病評(píng)估量表認(rèn)知部分(Alzheimer’s Disease Assessment Scale-cog,ADAS-cog)主要用于AD型癡呆和血管源型癡呆藥物的療效評(píng)價(jià)[14]。記憶力評(píng)估是癡呆診斷和鑒別診斷的重要環(huán)節(jié),因此盡可能對(duì)所有患者進(jìn)行記憶力評(píng)估;執(zhí)行功能是鑒別皮質(zhì)性癡呆和皮質(zhì)下性癡呆的重要指標(biāo),因此盡可能對(duì)所有癡呆患者進(jìn)行執(zhí)行功能評(píng)估。語(yǔ)言障礙、失用、視空間結(jié)構(gòu)功能障礙均是癡呆認(rèn)知癥狀的主要表現(xiàn)之一,盡可能采用相應(yīng)量表對(duì)所有患者進(jìn)行相關(guān)功能的評(píng)估。
癡呆患者經(jīng)常出現(xiàn)的紊亂的知覺(jué)、思維內(nèi)容、心境及行為等,稱(chēng)為癡呆行為心理癥狀(behavioral and psychological symptoms of dementia,BPSD)。常見(jiàn)的表現(xiàn)有焦慮、抑郁、淡漠、激越、妄想、幻覺(jué)、睡眠障礙、沖動(dòng)攻擊、怪異行為、飲食障礙、性行為異常等。按癥狀群可分為神經(jīng)癥性、情感性、精神病性、人格改變和譫妄癥狀等。評(píng)估心理行為癥狀有利于癡呆的鑒別診斷和療效評(píng)價(jià),推薦對(duì)所有的患者進(jìn)行。其中AD行為病理評(píng)定量表(BEHAVE-AD)[15],Cohen- Mansfield激越調(diào)查表(Cohen-Mansfield Agitation Inventory,CMAI)[16]和神經(jīng)精神病學(xué)調(diào)查表(Neuropsychiatric Inventory,NPI)[17,18]等量表,通常需要依賴(lài)知情者提供的信息進(jìn)行評(píng)定,同時(shí)應(yīng)當(dāng)考慮到伴隨的軀體疾病或藥物副作用可能是導(dǎo)致精神行為癥狀的原因。
日常生活能力包括兩個(gè)方面:基本日常生活能力(basic activities of daily living,BADL)和工具輔助性日常生活能力(instrumental activities of daily living,IADL),前者指獨(dú)立生活所必須的基本功能,如穿衣、吃飯、如廁等,后者包括復(fù)雜的日常或社會(huì)活動(dòng)能力,如出訪(fǎng)、工作、家務(wù)能力等,需要更多認(rèn)知功能的參與。日常能力減退是癡呆的核心癥狀之一,是診斷癡呆的必須條件,復(fù)雜日常能力的減退亦有助于輕度認(rèn)知功能障礙的早期診斷。評(píng)價(jià)日常能力常用的量表包括阿爾茨海默病合作研究日常生活能力量表(Alzheimer’s Disease Cooperative Study ADL,ADCS-ADL)[19]、Lawton工具輔助性日常生活能力量表(Instrumental ADL Scale of Lawton)[20]、功能活動(dòng)問(wèn)卷(Functional Activities Questionnaire,F(xiàn)AQ)[21]、進(jìn)行性惡化評(píng)分(Progressive Deterioration Scale,PDS)[22]和癡呆殘疾評(píng)估(Disability Assessment for Dementia,DAD)[23]等。其中FAQ和IADL量表涉及復(fù)雜的社會(huì)功能和日?;顒?dòng),適用于較輕患者的評(píng)價(jià)。重癥癡呆患者應(yīng)該另選相應(yīng)的評(píng)定量表,如重癥AOCS-ADL量表(ADCS-ADL-severe)[24]。應(yīng)當(dāng)對(duì)所有患者進(jìn)行日常能力的評(píng)定,并定期復(fù)查(6個(gè)月),以了解病情的進(jìn)展及評(píng)價(jià)干預(yù)效果。
一般而言,進(jìn)行較大規(guī)模的流行病學(xué)調(diào)查研究,所采用的量表要求相對(duì)簡(jiǎn)單,可操作性強(qiáng),具有相應(yīng)的區(qū)分度即可;但針對(duì)某一項(xiàng)危險(xiǎn)因素評(píng)估,或?qū)δ骋惶囟ōh(huán)節(jié)進(jìn)行詳細(xì)判斷和分析,則需要采用不同的量表,綜合應(yīng)用和分析。本期專(zhuān)欄收錄的第二軍醫(yī)大學(xué)附屬長(zhǎng)海醫(yī)院對(duì)老年認(rèn)知功能相關(guān)性系列研究中,根據(jù)不同研究目的,對(duì)不同量表進(jìn)行了靈活應(yīng)用。例如苗振春等[7]在對(duì)上海地區(qū)軍隊(duì)離退休干部老年高脂血癥患者認(rèn)知功能現(xiàn)況調(diào)查時(shí),采用MMSE進(jìn)行篩查,隨后應(yīng)用蒙特利爾認(rèn)知評(píng)估量表(Montreal Cognitive Assessment,MoCA)[25]對(duì)認(rèn)知功能的各個(gè)方面進(jìn)行測(cè)量,分析和血脂間的關(guān)系;羅鑭等[26]在對(duì)胱抑素C基因(cystatin C gene,CST3)多態(tài)性與2型糖尿病患者輕度認(rèn)知損害的相關(guān)性研究中,在采用MMSE、MoCA之后,進(jìn)一步采用了日常生活能力量表(Activity of Daily Living Scale,ADL)和全面衰退量表(Global Deterioration Scale,GDS)進(jìn)行評(píng)分,同時(shí)為了排除器質(zhì)性疾病的影響,還采用流行病學(xué)調(diào)查用抑郁自評(píng)量表,即流行病學(xué)研究中心抑郁量表(Center for Epidemiogic Studies-Depression Scale,CES-D)、焦慮自評(píng)量表(Self-rating Anxiety Scale,SAS)、帕金森病篩查量表(Screening Scale for Parkinson’s Disease,SSPD),對(duì)抑郁、焦慮、帕金森病等情況進(jìn)行了分析。
臨床工作中建立認(rèn)知功能障礙或癡呆診斷時(shí),應(yīng)注意鑒別病因[27],神經(jīng)影像學(xué)檢查對(duì)于診斷和鑒別診斷很重要,應(yīng)常規(guī)進(jìn)行頭顱MRI檢查,其優(yōu)于CT檢查,有條件者可行SPECT、PET和功能性MRI檢查。應(yīng)常規(guī)檢查血常規(guī)、肝腎功能、甲狀腺功能,檢測(cè)葉酸及維生素B12水平。腦脊液中的tau蛋白和APP[28,29]等有助于診斷,神經(jīng)病理學(xué)檢查和基因?qū)W檢查可以提高診斷的準(zhǔn)確性,尤其是體液或腦脊液中的生物標(biāo)志物,可用于診斷認(rèn)知功能障礙及癡呆。本期專(zhuān)欄中羅鑭等[26]將156例老年2型糖尿病患者,分為輕度認(rèn)知功能障礙組和認(rèn)知功能正常組,對(duì)CST3多態(tài)性與其發(fā)生輕度認(rèn)知損害的關(guān)系進(jìn)行分析發(fā)現(xiàn),CST3攜帶B等位基因是老年2型糖尿病患者發(fā)生輕度認(rèn)知功能障礙的危險(xiǎn)因素,檢測(cè)CST3多態(tài)性將可能有利于老年2型糖尿病患者認(rèn)知損害的早期診斷,為發(fā)現(xiàn)新的生物標(biāo)志物用于診斷和評(píng)價(jià)提供了思路。
大量流行病學(xué)調(diào)查研究顯示,導(dǎo)致認(rèn)知功能障礙的主要危險(xiǎn)因素包括:人口學(xué)因素(年齡、性別、家族史等)、遺傳學(xué)因素(載脂蛋白E4、早老素1、早老素2、tau蛋白、β淀粉樣肽前體及Notch3基因等)、生活方式(吸煙、不合理飲食、缺乏鍛煉及社會(huì)退縮等)及個(gè)人史(教育水平低下、頭部創(chuàng)傷、精神疾?。┑取F渲心挲g是影響認(rèn)知功能障礙發(fā)病率的最主要因素,隨著年齡增加,人體功能如感覺(jué)、知覺(jué)、視覺(jué)等下降,導(dǎo)致認(rèn)知功能障礙的發(fā)病率迅速上升[30]。本期專(zhuān)欄中白潔等[31]對(duì)上海地區(qū)90名離退休干部的聽(tīng)力下降情況和認(rèn)知功能進(jìn)行了調(diào)查,發(fā)現(xiàn)認(rèn)知功能在聽(tīng)力障礙未治療組患者中明顯下降,聽(tīng)力障礙是老年認(rèn)知功能障礙的重要危險(xiǎn)因素之一,助聽(tīng)器輔助治療可能對(duì)認(rèn)知功能有改善作用。前瞻性研究也發(fā)現(xiàn),聽(tīng)力下降是導(dǎo)致老年人進(jìn)行性癡呆的獨(dú)立危險(xiǎn)因素[32,33]。近年來(lái)的調(diào)查研究顯示,各種血管性危險(xiǎn)因素不僅是血管源性癡呆的獨(dú)立危險(xiǎn)因素,而且也是AD和輕度認(rèn)知功能障礙的獨(dú)立危險(xiǎn)因素[34]。苗振春等[7]調(diào)查了上海地區(qū)軍隊(duì)離退休干部中高脂血癥患者與認(rèn)知功能障礙的關(guān)系,發(fā)現(xiàn)軍隊(duì)離休干部高脂血癥組認(rèn)知功能改變的患病率為29.00%,高于正常血脂組認(rèn)知功能改變的患病率(16.11%,<0.001)。高脂血癥組MMSE量表分?jǐn)?shù)、MoCA量表分?jǐn)?shù)均較正常血脂組低(<0.001)。認(rèn)知功能分項(xiàng)指標(biāo)提示,高脂血癥組老年人的地點(diǎn)定向力、延遲回憶能力、注意力和計(jì)算力均較正常血脂組下降(<0.05)。隨訪(fǎng)發(fā)現(xiàn),輕度認(rèn)知功能障礙的患者,轉(zhuǎn)化為癡呆的危險(xiǎn)性遠(yuǎn)遠(yuǎn)大于認(rèn)知正常的人群[35],因此對(duì)輕度認(rèn)知功能障礙的防治,將作為以后工作的重點(diǎn)。
由于認(rèn)知功能障礙的根本病因尚不明確,因此治療方法尚缺乏針對(duì)性。
5.1.1 指南推薦藥物 目前推薦明確診斷為輕-中度阿爾茨海默病患者可以選用膽堿酯酶抑制劑[多奈哌齊(donepezil)、重酒石酸卡巴拉?。╮ivastigmine)、加蘭他敏(galantamine)]治療,其中多奈哌齊還可用于治療確診的中-重度阿爾茨海默病,血管源型癡呆患者可以選用美金剛(memantine)或美金剛與多奈哌齊、卡巴拉汀聯(lián)合治療。當(dāng)應(yīng)用某一膽堿酯酶抑制劑治療無(wú)效或因不良反應(yīng)不能耐受時(shí),可根據(jù)患者病情及出現(xiàn)不良反應(yīng)程度,選擇停藥或調(diào)換其他膽堿酯酶抑制劑進(jìn)行治療。輕-中度阿爾茨海默病患者還可以選用尼麥角林(nicergoline)、尼莫地平(nimodipine)、吡拉西坦(piracetam)或奧拉西坦(oxiracetam)、維生素E等作為膽堿酯酶抑制劑、興奮性氨基酸受體拮抗劑的協(xié)同治療藥物[36]。
5.1.2 相關(guān)藥物研究 近年來(lái)有大量針對(duì)老年認(rèn)知功能障礙的相關(guān)藥物研究,但多止步于臨床藥物試驗(yàn),有的是因?yàn)榘悬c(diǎn)選擇錯(cuò)誤,有的是因?yàn)樗幬锊涣挤磻?yīng),而有專(zhuān)家認(rèn)為,還可能與試驗(yàn)人群所處的疾病階段有關(guān)。近年有以胰島素鼻腔噴霧和皮下注射生長(zhǎng)激素釋放激素為代表的老藥新用,證實(shí)對(duì)AD或輕度認(rèn)知功能障礙患者認(rèn)知功能有改善。采用免疫球蛋白治療AD的被動(dòng)免疫研究及采用腺相關(guān)病毒介導(dǎo)的神經(jīng)生長(zhǎng)因子移植治療AD的臨床研究均令人期待。而干細(xì)胞移植,似乎是未來(lái)的方向[37]。本期收錄的一些研究,提供了阿司匹林緩解認(rèn)知功能障礙的動(dòng)物學(xué)證據(jù)及機(jī)制研究,表明其通過(guò)調(diào)節(jié)腦組織中白細(xì)胞介素-6、白細(xì)胞介素-1β和腫瘤壞死因子的表達(dá),影響AD模型大鼠學(xué)習(xí)記憶能力[38]。中國(guó)傳統(tǒng)中藥因可作用于多環(huán)節(jié)、多途徑、多系統(tǒng),且具有成本低廉,毒副作用小的優(yōu)點(diǎn),在國(guó)內(nèi)有較多研究。銀杏葉制劑或鼠尾草提取物可能對(duì)治療AD有效,尚待進(jìn)一步驗(yàn)證。筆者前期系列研究表明,具有抗氧化作用的中成藥物,例如五味子,對(duì)AD樣大鼠的學(xué)習(xí)和記憶能力有一定程度的改善,主要通過(guò)抑制小膠質(zhì)細(xì)胞的炎癥反應(yīng)以及氧化應(yīng)激對(duì)神經(jīng)元的損傷[39,40]。
對(duì)于輕度認(rèn)知功能障礙,近期的薈萃分析發(fā)現(xiàn)目前常用的藥物似乎效果還不十分明確[41],而非藥物治療的干預(yù)手段反而凸顯其重要作用[42]。所以,對(duì)于輕度認(rèn)知功能障礙患者,目前更加強(qiáng)調(diào)有效地控制各種血管性危險(xiǎn)因素,包括高血壓、糖尿病、高脂血癥、動(dòng)脈粥樣硬化、高同型半胱氨酸血癥、肥胖、代謝綜合征、吸煙及大量飲酒[43]。目前已知的保護(hù)性因素包括常喝綠茶,適度運(yùn)動(dòng),休閑活動(dòng)、保護(hù)性飲食(富含維生素B12、葉酸)、多咀嚼等,但以上尚缺乏統(tǒng)一量化標(biāo)準(zhǔn)。有研究對(duì)受試者進(jìn)行短期(5~6周)認(rèn)知訓(xùn)練及隨后加強(qiáng)訓(xùn)練,發(fā)現(xiàn)可使認(rèn)知功能略有改善,5年后年齡相關(guān)認(rèn)知減退程度減輕,工具性日常生活活動(dòng)能力略改善,是目前值得研究推廣的方向。
總之,認(rèn)知功能障礙的發(fā)展是個(gè)長(zhǎng)期的過(guò)程,可能在臨床前數(shù)十年即已開(kāi)始。在疾病進(jìn)展的后期,特別是發(fā)生癡呆后再開(kāi)始治療,雖仍可能延緩認(rèn)知功能衰退的進(jìn)程,但已有的損害多不能逆轉(zhuǎn)。因此早期干預(yù)具有重要意義,輕度認(rèn)知功能障礙是早期發(fā)現(xiàn)和早期干預(yù)的切入點(diǎn),具體干預(yù)措施仍在探索之中。雖然對(duì)各種癡呆已有了一定的治療手段,但仍然存在療效不突出和費(fèi)用昂貴等問(wèn)題。預(yù)防應(yīng)成為最重要的措施,在各種危險(xiǎn)因素中,血管性危險(xiǎn)因素是可以被發(fā)現(xiàn)和控制的,因此要特別重視對(duì)高危人群的篩查和干預(yù)。凡有高血壓病、腦動(dòng)脈粥樣硬化、腦血管病、糖尿病及冠心病的患者,均應(yīng)進(jìn)行記憶及智能的測(cè)查,以便早期發(fā)現(xiàn)、早期治療。
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(編輯: 王雪萍)
Cognitive dysfunction in the elderly in China: Research progress
TUO Xi-Ping
(Department of Geriatrics, Affiliated Changhai Hospital, the Second Military Medical University, Shanghai 200433, China)
Along with the coming of aging society, there are more and more people suffering from cognitive dysfunction or dementia. How to make early diagnosis and intervention for these diseases is an important subject in geriatric study in the new century. In recent years, new and standardized definitions and classifications for the elderly cognitive dysfunction and dementia were achieved, and the specific and practical neuropsychological scales were applied. Many retrospective and prospective epidemiological studies were carried out and then analyzed comparably. Systematic analysis was performed on the risk factors for the elderly cognitive dysfunction and dementia, including mild cognitive impairment. The results provided therapeutic targets for clinical drugs and behavior intervention, and also for research direction on fundamental study and drug development.
elderly; cognitive dysfunction; dementia
R749; R592
A
10.3724/SP.J.1264.2014.00075
2014?04?30;
2014?05?05
拓西平, E-mail: xptuo_01@126.com