樊東瓊 李 銳 雷 旭 喻 婧

(1西南大學(xué)心理學(xué)部,重慶 400715)(2中國科學(xué)院心理研究所心理健康重點(diǎn)實(shí)驗(yàn)室老年心理研究中心,北京 100101)

1 引言

阿爾茲海默癥(Alzheimer’s disease,AD)是老年期癡呆中最常見的一種類型。據(jù)預(yù)測到2050年,每80個人中就有一位AD患者(Brookmeyer,Johnson,Ziegler-Graham,&Arrighi,2007)。AD發(fā)病隱匿,影響大腦結(jié)構(gòu)和功能連接的改變(Sorg et al.,2007),因此也被稱為“失連接綜合癥”(disconnection syndrome)(Delbeuck,van der Linden,&Collette,2003;Liu et al.,2014)。以連續(xù)體看待AD的病程發(fā)展,可將其劃分為前臨床期(preclinical)、輕度認(rèn)知障礙(mild cognitive impairment,MCI)和癡呆(dementia)三個階段(Sperling et al.,2011)。其中高危人群MCI又根據(jù)其是否涉及記憶損傷分為遺忘型 MCI(amnestic MCI,aMCI)和非遺忘型 MCI(non-amnestic MCI,naMCI)(Petersen et al.,2009)。這兩類MCI又根據(jù)損傷是否僅限于某一認(rèn)知維度進(jìn)一步區(qū)分為單維(single domain)和多維(multiple domains)兩個亞型(Petersen,2011)。aMCI個體隨著病程的發(fā)展有部分會轉(zhuǎn)歸為AD,其年轉(zhuǎn)歸率顯著高于正常老年人和naMCI(Castaneda et al.,2003;Hahn et al.,2013;Liu et al.,2014;Petersen,2011)。與AD類似,研究發(fā)現(xiàn)腦功能連接的損傷是MCI神經(jīng)退行性病變在皮層水平的主要特征(Bai et al.,2011)。

靜息態(tài)功能磁共振成像(resting-state functional magnetic resonance imaging,rs-fMRI)作為非侵入性可視化成像方法,不需要刺激呈現(xiàn)和患者反應(yīng)(Fleisher et al.,2009)。AD患者認(rèn)知受損嚴(yán)重,在掃描狀態(tài)下讓其完成認(rèn)知任務(wù)相對困難,因此rs-fMRI為考察AD的腦功能提供了一個有效途徑(Dosenbach et al.,2010)。在靜息狀態(tài)下,血氧依賴水平(blood oxygen level dependency,BOLD)信號中的低頻振蕩反應(yīng)出腦中神經(jīng)元的基線活動,代表人類大腦神經(jīng)元在沒有外部輸出和目標(biāo)導(dǎo)向活動時(shí)的狀態(tài),這些低頻振幅的整體協(xié)同活動構(gòu)成了功能相關(guān)的靜息態(tài)網(wǎng)絡(luò)(resting state networks,RSNs)(Damoiseaux et al.,2006;Sch?lvinck,Maier,Ye,Duyn,&Leopold,2010)。根據(jù)靜息狀態(tài)下BOLD低頻信號的同步性劃分出默認(rèn)網(wǎng)絡(luò)(default mode network,DMN)、額頂網(wǎng)絡(luò)(fronto-parietal network,FPN)、執(zhí)行網(wǎng)絡(luò)(executive network,EN)、突顯網(wǎng)絡(luò)(salience network,SN)等。其中FPN、EN和SN又被統(tǒng)稱為額葉認(rèn)知網(wǎng)絡(luò)(frontal cognitive network,FCN)(Agosta et al.,2012)。RSNs的概念被研究者們所采納,并應(yīng)用到AD的相關(guān)研究中(Brier et al.,2012;Mantini,Perrucci,Del Gratta,Romani,&Corbetta,2007;Sheline&Raichle,2013;Song et al.,2013;Zamboni et al.,2013)。

AD和MCI患者的RSNs發(fā)生了哪些變化,以及這些變化與病程發(fā)展是怎樣的關(guān)系？同時(shí),大尺度腦網(wǎng)絡(luò)功能連接的改變與個體大腦結(jié)構(gòu)改變,以及表現(xiàn)出來的認(rèn)知損傷有何聯(lián)系？提出這些問題將有助于整合現(xiàn)有發(fā)現(xiàn),進(jìn)一步加深對AD病理機(jī)制的理解,提出可能的早期識別和診療監(jiān)測模型。

2 AD/MCI靜息態(tài)腦網(wǎng)絡(luò)的改變

rs-fMRI技術(shù)對于AD患者功能連接的改變、疾病早期鑒定、后續(xù)治療效果評定以及藥物追蹤有重要的臨床意義(Sheline&Raichle,2013),是目前針對AD等神經(jīng)退行性疾病的有效生物學(xué)標(biāo)記(Thomas et al.,2014)。研究者將全腦分出116個感興趣區(qū)域(region of interest,ROIs),使用大尺度網(wǎng)絡(luò)(large-scale network,LSN)分析ROIs功能連接改變與行為表現(xiàn)之間的關(guān)系,發(fā)現(xiàn)LSN區(qū)分AD、aMCI以及正常老年人具有較高的敏感性和特異性(Chen et al.,2011)。早期研究認(rèn)為DMN是反映AD病理特征的核心網(wǎng)絡(luò)(Bai et al.,2008;Greicius,Srivastava,Reiss,& Menon,2004;Raichle&Snyder,2007;Zhong et al.,2014)。隨著研究的深入,研究者逐漸發(fā)現(xiàn),除DMN外還有其它腦網(wǎng)絡(luò)對AD病程同樣敏感(Brier et al.,2012),即AD和大尺度腦網(wǎng)絡(luò)改變有關(guān)(Bai et al.,2011;Borgheresi et al.,2008;Brier et al.,2012;McLaren,Sperling,&Atri,2014;Sheline&Raichle,2013;Song et al.,2013;Sorg et al.,2007;Zamboni et al.,2013)。下文將從默認(rèn)網(wǎng)絡(luò)和額葉認(rèn)知網(wǎng)絡(luò)(包括額頂網(wǎng)絡(luò)、執(zhí)行網(wǎng)絡(luò)和突顯網(wǎng)絡(luò))受AD/MCI影響的研究分別進(jìn)行評述。

2.1 默認(rèn)網(wǎng)絡(luò)DMN的改變

大腦中存在著這樣的腦區(qū),在執(zhí)行外部任務(wù)或目標(biāo)指向時(shí)受到抑制表現(xiàn)為負(fù)激活,而在清醒靜息時(shí)神經(jīng)活動高度活躍(Raichle et al.,2001),構(gòu)成的網(wǎng)絡(luò)被認(rèn)為與內(nèi)省行為和狀態(tài)有關(guān)(Buckner,Andrews-Hanna,&Schacter,2008;Greicius et al.,2007)。DMN的核心腦區(qū)包括后扣帶回/楔前葉(posterior cingutate cortex/precuneus cortex,PCC/PCu)、海馬、前扣帶回腹側(cè)(ventral anterior cingulate cortex,vACC)、內(nèi)側(cè)前額葉(medial prefrontal cortex,MPFC)、角回(angular gyrus,AG)、外側(cè)顳葉等(Binnewijzend et al.,2012)。隨著AD的發(fā)生與發(fā)展DMN中的額頂通路(fronto-parietal pathway)、顳額通路(temporo-frontal pathway)和顳頂通路(temporo-parietal pathway)發(fā)生顯著改變(Li et al.,2013),具體表現(xiàn)為PCC/PCu和海馬等腦區(qū)域功能連接顯著下降,而這些腦區(qū)對于情節(jié)記憶的編碼與提取、言語認(rèn)知以及言語產(chǎn)生有重要作用(Zhong et al.,2014;Zhou et al.,2008)。

具體而言,從正常對照到MCI,再到AD,PCC/PCu功能連接強(qiáng)度呈遞減趨勢,其中在MCI早期PCC就已發(fā)生病理性改變(Binnewijzend et al.,2012;Song et al.,2013)。提示PCC/PCu對于解釋MCI到AD的轉(zhuǎn)歸以及疾病的早期識別具有重要意義(Rombouts,Barkhof,Goekoop,Stam,&Scheltens,2005)。PCC是DMN加工信息的重要節(jié)點(diǎn),來自其它區(qū)域的信息通過PCC整合后完成功能的表達(dá)(Dunn et al.,2014)。aMCI患者PCC與顳葉皮層功能連接減弱,與額葉皮層功能連接增加(Bai et al.,2009)。連接減弱導(dǎo)致aMCI患者在行為上顯示出認(rèn)知損傷,使其進(jìn)一步向AD發(fā)展;而連接增強(qiáng)表明在PFC區(qū)域可能進(jìn)行著認(rèn)知神經(jīng)資源的重新分配,以彌補(bǔ)其它腦區(qū)的功能損傷(Qi et al.,2010)。與aMCI患者相比,AD患者DMN功能連接損傷更為廣泛,包括PCC/PCu、右頂下小葉(緣上回)和左頂下小葉(角回)功能連接的顯著下降(Agosta et al.,2012)。

除PCC/PCu外,海馬也是DMN中與AD病程極其相關(guān)的腦區(qū)(Wang,Liang,et al.,2011)。aMCI患者首先表現(xiàn)為情景記憶能力下降,逐步發(fā)展為更廣泛的記憶損傷以及認(rèn)知功能障礙,因此研究與記憶相關(guān)的海馬腦區(qū)對于理解AD、aMCI患者隨病程發(fā)生的腦功能連接異常具有重要意義。在aMCI時(shí)期海馬就表現(xiàn)出功能損傷(De Vogelaere,Santens,Achten,Boon,&Vingerhoets,2012),以及與全腦網(wǎng)絡(luò)功能連接的下降(Zhou et al.,2008)。追蹤研究發(fā)現(xiàn)aMCI患者3年內(nèi)海馬、海馬旁回和楔葉功能連接顯著下降,且沒有發(fā)現(xiàn)功能連接增強(qiáng)(Wang,Liang,et al.,2011)。同時(shí),研究發(fā)現(xiàn)AD患者也表現(xiàn)出海馬與全腦功能連接的下降(Allen et al.,2007),并且從正常老化到aMCI,再到AD,海馬及海馬旁回在內(nèi)的后內(nèi)側(cè)皮質(zhì)功能連接呈現(xiàn)線性下降趨勢(Zhou et al.,2008)。

綜上,DMN的功能連接對AD相關(guān)的早期神經(jīng)退行性改變敏感(De Vogelaere et al.,2012)。總體而言：1)MCI、AD患者DMN功能連接下降集中在PCC/PCu、海馬等網(wǎng)絡(luò)的中后部區(qū)域。這些腦區(qū)在病程早期就對淀粉樣蛋白沉積、灰質(zhì)萎縮以及神經(jīng)元纖維纏結(jié)非常敏感,因此對于病程的早期識別具有重要意義;2)AD患者較之MCI患者表現(xiàn)出更為廣泛的病理性改變。研究顯示AD患者DMN前部和后部(anterior DMN,aDMN;posterior DMN,pDMN)功能連接下降,預(yù)示其網(wǎng)絡(luò)內(nèi)部整體連接的減弱(Liu et al.,2014;Toussaint et al.,2014)。結(jié)果提示DMN改變的彌散程度對于病程監(jiān)控具有一定參考價(jià)值。

2.2 額葉認(rèn)知網(wǎng)絡(luò)FCN的改變

FCN包括額頂網(wǎng)絡(luò)、執(zhí)行網(wǎng)絡(luò)和突顯網(wǎng)絡(luò)(Agosta et al.,2012)。

2.2.1 額頂網(wǎng)絡(luò)FPN的改變

FPN有左額頂網(wǎng)絡(luò)(left FPN,LFP)和右額頂網(wǎng)絡(luò)(right FPN,RFP)之分,兩者在功能上存在差異。RFP主要負(fù)責(zé)活動抑制、軀體感知覺和痛覺處理;LFP則與記憶、語言、注意以及視覺加工相關(guān)(Chang et al.,2014)。主要腦區(qū)包括背外側(cè)前額葉(dorsolateral prefrontal cortex,DLPFC)、頂下小葉(inferior parietal lobule,IPL)、顳中回等腦區(qū)(Agosta et al.,2012;Fox et al.,2005)。

研究發(fā)現(xiàn)aMCI患者FPN功能連接與正常對照組差異不顯著(Agosta et al.,2012;Song et al.,2013),而AD患者表現(xiàn)出左顳下回、右緣上回(Agosta et al.,2012)以及左頂上小葉(superior parietal lobule,SPL)(Song et al.,2013)功能連接下降。SPL是視覺注意的重要腦區(qū),該腦區(qū)功能連接的下降可以解釋AD患者出現(xiàn)的視覺注意能力損傷。更多研究顯示,aMCI和AD會導(dǎo)致FPN功能連接增強(qiáng)。研究發(fā)現(xiàn)aMCI患者LFP中PFC和內(nèi)側(cè)顳葉(medial temporal lobe,MTL)功能連接強(qiáng)于正常對照組(Zamboni et al.,2013)。AD患者LFP中IPL(Agosta et al.,2012)、PFC以及頂葉功能連接增強(qiáng),RFP中DLPFC和腹外側(cè)前額葉皮質(zhì)(ventral lateral PFC,VLPFC)功能連接增強(qiáng)。因?yàn)轭~葉負(fù)責(zé)高級認(rèn)知處理以及情緒的調(diào)控,這些增強(qiáng)的額頂葉連接也可能反映AD/MCI患者對焦慮、憤怒等情緒的異常敏感(Zamboni et al.,2013)。

綜上,FPN在AD/MCI患者上更多的表現(xiàn)為功能連接增強(qiáng),而在部分腦區(qū)域出現(xiàn)功能連接的下降。代償理論認(rèn)為增加的功能連接可以平衡大腦的整體效益,這種平衡在MCI時(shí)期開始顯現(xiàn),并且持續(xù)到AD早期。除了代償理論之外,另一種解釋為病理性改變導(dǎo)致患者對于情緒的異常敏感,這些對于情緒的反應(yīng)體現(xiàn)在功能連接上顯示為FPN連接增強(qiáng)。

2.2.2 執(zhí)行網(wǎng)絡(luò)EN的改變

EN主要定位于PFC內(nèi)外側(cè)腦區(qū)(Agosta et al.,2012),這些腦區(qū)與活動抑制、情緒加工等認(rèn)知過程相關(guān)。aMCI患者ACC和DLPFC功能連接下降,這兩個腦區(qū)與執(zhí)行功能相關(guān)。除此之外,aMCI患者VLPFC和前額葉前部皮層功能連接增加,預(yù)示大腦資源的重新分配,即aMCI患者的腦網(wǎng)絡(luò)正在經(jīng)歷重塑(Wu et al.,2014)。AD患者EN功能連接減弱(Agosta et al.,2012),但在特定腦區(qū),如DMPFC和DLPFC,也存在功能連接增強(qiáng)(Weiler et al.,2014)。對于MCI患者,EN中增強(qiáng)的功能連接比AD患者更加廣泛(Agosta et al.,2012)。

EN隨MCI/AD病程發(fā)展而改變的特性提示,在認(rèn)知損傷早期,大腦嘗試著調(diào)用其它區(qū)域的資源來平衡腦區(qū)損傷帶來的影響,并且病程越早,這種資源調(diào)用效果越好。換言之,隨著病程的推移,那些原先承擔(dān)“替補(bǔ)”功能的腦區(qū)也可能逐漸發(fā)生損傷,無法進(jìn)行原有的“替補(bǔ)”工作。因此我們在AD患者上觀察到EN功能連接的增加少于MCI患者。

2.2.3 突顯網(wǎng)絡(luò)SN的改變

SN由額島皮層(frontoinsular cortex,FIC)、背側(cè)前扣帶回(dorsal ACC,dACC)和DLPFC等腦區(qū)域組成,包括背側(cè)注意控制SN和腹側(cè)情緒控制SN(Agosta et al.,2012),主要負(fù)責(zé)辨別內(nèi)外環(huán)境刺激完成注意捕獲(Jilka et al.,2014),調(diào)節(jié)執(zhí)行網(wǎng)絡(luò)EN和DMN之間的關(guān)系,根據(jù)外部任務(wù)需求完成EN和DMN之間的切換(Di&Biswal,2014;Goulden et al.,2014;He et al.,2014)。研究顯示SN相應(yīng)腦區(qū)(dACC、FIC、DLPFC、MPFC)灰質(zhì)體積隨正常老化、MCI、AD遞減(Xie et al.,2012)。同時(shí),SN對年齡敏感,正常老人SN的結(jié)構(gòu)和功能已經(jīng)出現(xiàn)損傷(He et al.,2014)。其中,FIC可以從連續(xù)的感覺輸入中辨別突顯刺激(salient stimuli),其結(jié)構(gòu)和功能的損傷會影響CEN與DMN之間的功能轉(zhuǎn)換、刺激分辨和社會情感信息加工的能力。因此FIC下降的功能連接不僅是區(qū)分正常對照組和AD患者的重要指標(biāo),也是區(qū)分不同年齡段的重要特征(He et al.,2014)。AD患者SN功能連接的增加主要定位于腹側(cè)區(qū)域,這一區(qū)域主要負(fù)責(zé)社會情感和內(nèi)臟自主活動過程(Agosta et al.,2012)。AD患者在該區(qū)域的功能連接增加顯示其為了保證機(jī)體正常運(yùn)轉(zhuǎn)所采取的代償措施(He et al.,2014)。aMCI患者SN結(jié)構(gòu)和功能連接改變介于正常對照組與AD患者之間,進(jìn)一步證實(shí)aMCI的過渡屬性(He et al.,2014)。

綜上,突顯網(wǎng)絡(luò)是辨別環(huán)境刺激并且完成大腦狀態(tài)轉(zhuǎn)換的重要腦區(qū),在機(jī)體內(nèi)外活動中承擔(dān)“監(jiān)控”功能?？傮w而言：1)在正常老年人群體中SN的結(jié)構(gòu)和功能已經(jīng)出現(xiàn)損傷,提示該網(wǎng)絡(luò)不僅對病理老化敏感,同樣受生理老化的作用;2)AD/MCI患者SN的損傷不僅體現(xiàn)在網(wǎng)絡(luò)內(nèi)部功能連接發(fā)生病理性改變,還體現(xiàn)在對其它網(wǎng)絡(luò)的調(diào)節(jié)能力上,其損傷間接導(dǎo)致DMN和CEN兩大網(wǎng)絡(luò)的大尺度連接減弱。SN內(nèi)部功能連接和其調(diào)節(jié)效率的減弱將加速認(rèn)知損傷,主要體現(xiàn)為辨別環(huán)境刺激能力的減弱和廣泛的注意功能障礙。

上述AD/MCI患者靜息態(tài)下不同腦網(wǎng)絡(luò)功能連接改變匯總見表1。

3 AD/MCI患者腦功能連接和腦結(jié)構(gòu)改變的關(guān)系

AD認(rèn)知損傷的腦機(jī)制除了腦功能連接異常以外,還體現(xiàn)在腦結(jié)構(gòu)萎縮、白質(zhì)改變、神經(jīng)纖維纏結(jié),以及淀粉樣蛋白沉積等多個方面(Bozzali,Padovani,Caltagirone,&Borroni,2011)。AD 患者腦結(jié)構(gòu)和腦功能連接的改變是疾病診斷非常重要的兩個方面,兩者結(jié)合可以增加診斷的效力(Wee,Yap,Zhang,et al.,2012)。

腦結(jié)構(gòu)是腦功能的基礎(chǔ),有研究者認(rèn)為腦功能連接依賴于腦結(jié)構(gòu)連接(Hahn et al.,2013),因此一般假設(shè)結(jié)構(gòu)連接可以直接或者間接反映功能連接(van den Heuvel,Mandl,Kahn,&Pol,2009)。彌散張量成像(diffusion tensor imaging,DTI)結(jié)合rs-fMRI研究發(fā)現(xiàn)AD/MCI患者病理性老化使得原先由海馬旁回作為中介連接后扣帶和海馬之間的間接通路,轉(zhuǎn)變?yōu)楹罂蹘c海馬的直接通路聯(lián)系,提示海馬旁回的病理性損傷(Soldner et al.,2012)。Zhu等(2013)發(fā)現(xiàn)扣帶回峽部(isthmus of the cingulate cortex,ICC)與DMN中其它腦區(qū)域的結(jié)構(gòu)和功能連接的減弱,與DMN代謝活動以及萎縮情況一致。除此之外,研究發(fā)現(xiàn)AD患者腦島、dACC、MPFC、DLPFC灰質(zhì)體積顯著下降,這些下降的灰質(zhì)體積與相應(yīng)腦區(qū)功能連接的改變基本對應(yīng)(He et al.,2014)。

然而,另一些研究者指出腦結(jié)構(gòu)和腦功能連接這二者之間并不是簡單的一對一關(guān)系,大部分RSNs的差異不能簡單的用諸如皮層萎縮、白質(zhì)損傷這樣的結(jié)構(gòu)改變來解釋(Agosta et al.,2012)。首先,隨著年齡增長,大腦會出現(xiàn)萎縮,這種自然老化并不一定和病理有關(guān)(He et al.,2014),即一定范圍內(nèi)的結(jié)構(gòu)改變并不會導(dǎo)致相應(yīng)腦區(qū)域功能的病變;其次,在大腦網(wǎng)絡(luò)中鄰近腦區(qū)之間存在著結(jié)構(gòu)聯(lián)系,而距離很遠(yuǎn)的腦區(qū)之間雖然沒有直接的結(jié)構(gòu)聯(lián)系,卻存在功能聯(lián)系,相互協(xié)同工作(Honey et al.,2009;van den Heuvel&Pol,2010);再次,有研究顯示灰質(zhì)體積矯正并沒有改變腦區(qū)功能分析的結(jié)果(De Vogelaere et al.,2012;Wang,Yan,et al.,2011)。AD的一些腦區(qū)域中,比如邊緣系統(tǒng)中的扣帶皮層(Bozzali et al.,2011)代謝減退/功能分離先于灰質(zhì)萎縮;最后,研究發(fā)現(xiàn)AD/MCI患者DMN區(qū)域淀粉樣蛋白沉積(amyloid deposition)與功能連接的改變并不相關(guān)(Adriaanse et al.,2014),間接支持了功能連接的改變不能簡單的由腦結(jié)構(gòu)的改變來解釋的觀點(diǎn)(Song et al.,2013)。

因此,AD的功能連接損傷不能單純由下降的灰質(zhì)體積、白質(zhì)損傷,以及淀粉樣蛋白沉積等結(jié)構(gòu)改變來解釋,AD還和更廣泛、更復(fù)雜的大尺度腦網(wǎng)絡(luò)功能連接損傷相關(guān)(Song et al.,2013)。根據(jù)現(xiàn)有研究結(jié)果,我們推測有些功能連接的改變可能獨(dú)立于結(jié)構(gòu)的改變,尤其是那些不存在直接結(jié)構(gòu)聯(lián)系距離較遠(yuǎn)的腦區(qū)域。雖然腦結(jié)構(gòu)是腦功能執(zhí)行的基礎(chǔ),但腦功能連接并不完全等同于結(jié)構(gòu)連接,即大腦功能在已有結(jié)構(gòu)的基礎(chǔ)上進(jìn)行著靈活的協(xié)調(diào)和分配,以完成復(fù)雜任務(wù)、應(yīng)對變化。病理改變帶來的結(jié)構(gòu)損傷可以通過功能連接的代償作用得到彌補(bǔ)。隨著病程的惡化,腦功能網(wǎng)絡(luò)的代償功能也將隨著腦結(jié)構(gòu)的損傷加重而逐漸減弱,甚至?xí)催^來抑制原有功能表達(dá),加速病程的發(fā)展。

表1 近年來關(guān)于AD/MCI/NC的靜息態(tài)fMRI研究總結(jié)

4 討論與展望

功能磁共振成像能有效探索大腦“黑箱”,靜息態(tài)功能核磁共振是研究阿爾茲海默癥的有力途徑。靜息態(tài)功能連接(resting state functional connectivity)反映的是大腦的本征連接(intrinsic connectivity),與任務(wù)態(tài)功能連接(task-evoked functional connectivity)相對應(yīng)。任務(wù)態(tài)下的腦網(wǎng)絡(luò)可以理解為靜息態(tài)下的本征網(wǎng)絡(luò)與任務(wù)引發(fā)的特異性網(wǎng)絡(luò)的疊加(Cole,Bassett,Power,Braver,&Petersen,2014)。靜息態(tài)功能連接可以通過fMRI、腦電圖(electroencephalography,EEG)、腦磁圖(magnetoencephalography,MEG)等方式進(jìn)行獲取和分析。不同數(shù)據(jù)模態(tài)反應(yīng)的是不同信號獲取方式下的功能腦網(wǎng)絡(luò)模式。靜息態(tài)功能連接的fMRI基于BOLD信號中低頻振幅的同步性,按照功能整合原則,利用血氧依賴水平信號的變化間接反應(yīng)腦網(wǎng)絡(luò)功能連接的變化。EEG/MEG通過直接獲取神經(jīng)元放電產(chǎn)生的微弱電/磁信號,在多個頻率波段的基礎(chǔ)上構(gòu)建靜息態(tài)功能腦網(wǎng)絡(luò),屬于直接方法。EEG/MEG有較好的時(shí)間分辨率,但空間分辨率較差;fMRI則與之相反有較好的空間分辨率,而時(shí)間分辨率較差。因此,數(shù)據(jù)融合分析(multimodal data fusion)將有效提高研究的時(shí)空分辨率(Babajani&Soltanian-Zadeh,2006)。

4.1 診斷的標(biāo)記性神經(jīng)通路

在靜息態(tài)功能磁共振成像中AD/MCI患者的大腦功能連接存在廣泛改變。已有研究結(jié)果顯示隨著MCI向AD轉(zhuǎn)歸,功能腦網(wǎng)絡(luò)的改變可能存在三方面特異性改變：1)腦區(qū)損傷主要表現(xiàn)在PCC/PCu和海馬區(qū)域(Greicius et al.,2004);2)“PCC--MTL通路”在病程發(fā)展中損傷顯著。研究發(fā)現(xiàn)PCC和其它腦區(qū)(主要是顳葉皮層)連接損傷的代償在MCI階段開始顯現(xiàn)。然而隨著病程加劇,這些補(bǔ)償機(jī)制也慢慢瓦解,并且由于病理的改變帶來更多的損傷(Wang,Yan,et al.,2011)。PCC--MTL功能連接對于理解和監(jiān)控AD前臨床期病程進(jìn)展具有重要意義(Bai et al.,2009);3)長時(shí)程連接的減弱與全腦網(wǎng)絡(luò)連接效率的降低密切相關(guān)。認(rèn)知損傷程度與腦功能連接的減弱程度成正相關(guān),尤其是遠(yuǎn)距離的功能連接(Liu et al.,2014),如DMN內(nèi)前后子網(wǎng)絡(luò)之間的長距離連接(Song et al.,2013)。此外,研究發(fā)現(xiàn)大腦左半球的損傷先于右半球(Wee,Yap,Denny,et al.,2012),提示左半球在病程監(jiān)控中可能更加敏感。

結(jié)合前人研究成果,后續(xù)關(guān)于靜息態(tài)下標(biāo)志性神經(jīng)通路的研究可以考慮從下4點(diǎn)展開：1)DMN是較早發(fā)現(xiàn)功能連接改變的區(qū)域,有研究者進(jìn)一步將DMN細(xì)分為dMPFC子系統(tǒng)和MTL子系統(tǒng)(Andrews-Hanna,2012)。兩個子系統(tǒng)隨AD/MCI病程的進(jìn)展變化模式是否同質(zhì)改變有待進(jìn)一步探討;2)腦網(wǎng)絡(luò)的改變不僅局限于AD,任何疾病都可能導(dǎo)致腦部功能與結(jié)構(gòu)改變,探索AD在功能腦網(wǎng)絡(luò)的特異性改變對于研究結(jié)果的推廣性非常重要。因此,為了得到更為準(zhǔn)確的特異性指標(biāo),與腦成像技術(shù)相關(guān)的進(jìn)一步研究需要結(jié)合AD與其它疾病作辨別區(qū)分,這也是認(rèn)識其標(biāo)記性神經(jīng)通路的重要手段之一;3)AD/MCI本身存在著異質(zhì)性問題(Lehmann et al.,2013),不同分型反映大腦的特異性損傷和病變,準(zhǔn)確區(qū)分其中差異有助于把握AD/MCI的病理特征;4)另外,目前腦網(wǎng)絡(luò)的分類并不確定,RSNs很大程度依賴于研究者對成分?jǐn)?shù)量的預(yù)先定義,包括頻譜分析、空間模式和先前的研究等(Binnewijzend et al.,2012;Zhong et al.,2014),因此這種心理學(xué)上的概念與可測性之間的關(guān)系有待于進(jìn)一步的研究確證。

4.2 診療的腦網(wǎng)絡(luò)標(biāo)記

腦功能連接隨AD病程的發(fā)展而變化,因此研究其大尺度腦網(wǎng)絡(luò)功能連接改變模式對于理解AD/MCI的病理機(jī)制很重要。在MCI階段,DMN和FCN都存在功能連接減弱,并且隨著病程推移,逐步表現(xiàn)出更加廣泛的連接損傷。增加的功能連接集中在內(nèi)側(cè)前額葉皮質(zhì),是一些距離相對較近的腦區(qū)(Liu et al.,2014)。對于MCI患者,LPFC和MTL,DLPFC和APFC,后顳上回和枕中回組成的視聽通路以及位于頂葉區(qū)域的角回功能連接增加,大腦可能嘗試通過認(rèn)知資源的重新分配平衡腦區(qū)功能。轉(zhuǎn)歸為AD后,增加的功能連接進(jìn)一步擴(kuò)展到DMPFC和DLPFC,說明大腦資源的動態(tài)分配過程有一定程度的可塑性。隨著病程發(fā)展,增強(qiáng)的連接也同時(shí)呈現(xiàn)下降趨勢,預(yù)示著代償作用受病理惡化的影響,削弱其承擔(dān)新功能的能力。

整體而言,DMN表現(xiàn)出功能連接下降而FCN功能連接增加,這種模式是疾病病理的結(jié)果,并且促使患者在病程早期可以調(diào)用更多大腦前部的區(qū)域(Song et al.,2013;Zamboni et al.,2013)。這一功能腦網(wǎng)絡(luò)指標(biāo)經(jīng)過進(jìn)一步研究確證之后,不僅可用于疾病的識別,對于治療反饋也有重要意義。有效的治療方案可以促使異常腦網(wǎng)絡(luò)向常態(tài)回歸,這也就為早期治療手段的有效性評定提供了很好的綜合性指標(biāo)。MCI或輕度AD患者DMN和FCN在有效治療前后功能連接的改變預(yù)測如圖1所示,即有效治療手段可以促使下降的DMN功能連接隨之增加,而增加的FCN功能連接隨之下降,最后趨于一個正常而穩(wěn)定的水平。

圖1 MCI或輕度AD患者DMN和FCN(EN)有效治療前后功能連接改變預(yù)測(腦網(wǎng)絡(luò)節(jié)點(diǎn)參考Agosta et al.,2012)

4.3 AD/MCI亞型的異質(zhì)性

最新診斷標(biāo)準(zhǔn)將AD視為一個包括MCI在內(nèi)的連續(xù)過程(Albert et al.,2011)。由于AD病因不明,并且在病程發(fā)展過程中本身就存在著異質(zhì)性,不同的癡呆類型表現(xiàn)癥狀不同,常見的AD分型如早發(fā)型AD(early-onset AD),發(fā)病年齡小于65歲,主要表現(xiàn)為記憶和執(zhí)行功能受損;logopenic變型原發(fā)進(jìn)行性失語型(logopenic variant primary progressive aphasia)主要表現(xiàn)為語言的損傷;后皮質(zhì)萎縮型(posterior cortical atrophy)則主要表現(xiàn)為視覺空間能力受損(Lehmann et al.,2013)。早發(fā)型AD的病理特異性功能連接變化在突顯網(wǎng)絡(luò)前部和執(zhí)行網(wǎng)絡(luò)右側(cè),logopenic變型原發(fā)進(jìn)行性失語型為語言網(wǎng)絡(luò),而后皮質(zhì)萎縮型則與視覺網(wǎng)絡(luò)相關(guān)(Lehmann et al.,2013)。此外,研究發(fā)現(xiàn)多維aMCI較單維aMCI而言,表現(xiàn)為更多灰質(zhì)萎縮以及低頻振幅(ALFF)的改變,揭示多維aMCI是更可能發(fā)展成為AD的前驅(qū)癥狀階段(Li et al.,2014)。研究結(jié)果提示我們除了探討認(rèn)知相關(guān)的核心網(wǎng)絡(luò)以外,未來研究還應(yīng)該從AD/MCI的異質(zhì)性角度出發(fā),探討不同分型在其特異性網(wǎng)絡(luò)上的改變。細(xì)化不同類型的AD/MCI有助于對不同亞型的病人進(jìn)行更好的診斷和病程監(jiān)控。

5 結(jié)語

阿爾茲海默癥嚴(yán)重威脅老年人身心健康和晚年生活質(zhì)量,對其認(rèn)識、診斷和治療上的突破對于人類的健康和發(fā)展非常重要。易感人群和前臨床期的監(jiān)控和干預(yù),是阻止疾病惡化、延緩病程的重要手段,因此早期篩查和技術(shù)手段的革新是戰(zhàn)勝阿爾茲海默癥的有效途徑。靜息態(tài)功能磁共振成像技術(shù)的無創(chuàng)、可視化、采樣便利等優(yōu)勢,使其成為當(dāng)前研究阿爾茲海默癥的重要手段?，F(xiàn)有研究顯示隨著病程的推進(jìn),AD/MCI患者顯示出默認(rèn)網(wǎng)絡(luò)連接逐漸減弱以及額葉認(rèn)知網(wǎng)絡(luò)連接先增強(qiáng)后減弱的整體趨勢。同時(shí)指出,認(rèn)知障礙的發(fā)生是腦結(jié)構(gòu)和腦功能改變交互作用的結(jié)果,二者可能不是單一的孰先孰后?？茖W(xué)發(fā)展帶動技術(shù)手段的革新,未來研究需要從網(wǎng)絡(luò)的精細(xì)化入手,配合探討與病程相關(guān)的大腦的階段性變化特征,以期找到識別和監(jiān)控疾病的腦連接標(biāo)記。

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