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主觀認知減退影像學(xué)研究進展

2018-01-20 21:00趙志蓮齊志剛李坤成
關(guān)鍵詞:顳葉皮層皮質(zhì)

樊 響,趙志蓮,齊志剛,李坤成*

(1.首都醫(yī)科大學(xué)宣武醫(yī)院放射科,北京 100053;2.磁共振成像腦信息學(xué)北京市重點實驗室,北京 100053)

阿爾茨海默病(Alzheimer disease, AD)是以進行性認知功能障礙和記憶力損害為特征的神經(jīng)系統(tǒng)變性疾病。隨著診斷階段前移,主觀認知減退(subjective cognitive decline, SCD)的概念被引入。2014年,SCD概念啟動組(Subjective Cognitive Decline Initiative, SCD-I)成立,Jessen等[1]提出SCD概念框架:SCD是患者主訴有記憶障礙而無相應(yīng)客觀臨床表現(xiàn)的階段,可檢測到相關(guān)生物標(biāo)志物證據(jù),但尚未達到輕度認知障礙(mild cognitive impairment, MCI)程度。SCD是最終進展為AD的高危群體,但AD并非是引起主觀認知損害的唯一原因,某些精神疾病或正常老化等均可導(dǎo)致認知損害。AD患者尚未出現(xiàn)認知障礙臨床表現(xiàn)時,生物學(xué)標(biāo)記即可出現(xiàn)異常。生物學(xué)標(biāo)記主要分為體液標(biāo)志物和影像學(xué)生物標(biāo)志物,其中影像學(xué)生物標(biāo)志物近年發(fā)展迅速,可檢測β-淀粉樣蛋白(amyloid β-protein, Aβ)沉積,評估神經(jīng)退行性改變,故可用來預(yù)測SCD是否進展為AD。本文對SCD的影像學(xué)研究進展進行綜述。

1 MRI

1.1 結(jié)構(gòu)MRI(structural MRI, SMRI) SMRI可觀察皮質(zhì)萎縮情況。AD患者皮層萎縮具有一定分布特點和發(fā)展規(guī)律,而SCD患者皮質(zhì)萎縮特點與AD具有相似性。SCD患者海馬、內(nèi)嗅皮層、后扣帶回及內(nèi)顳葉等可較正常老年人更早出現(xiàn)萎縮[2],以顳葉為著[3],但是否具有診斷及預(yù)測意義尚存爭議。Cantero等[4]發(fā)現(xiàn)SCD患者海馬CA1區(qū)、CA2區(qū)及齒狀回區(qū)的分子層體積較小,且血漿Aβ42水平較高;但海馬特定區(qū)域體積與血漿Aβ42是否可作為組合標(biāo)志物還需進一步觀察。既往研究[5]認為神經(jīng)變性晚期杏仁核體積減小,但Schultz等[6]發(fā)現(xiàn)SCD患者皮層萎縮也可發(fā)生于杏仁核,且皮層萎縮患者神經(jīng)心理檢查分數(shù)更易減低。Zanchi等[7]發(fā)現(xiàn)右側(cè)杏仁核(及雙層海馬)體積減小可早于認知下降。

1.2 fMRI

1.2.1 靜息態(tài)fMRI 靜息態(tài)BOLD自發(fā)性低頻振蕩信號可反映神經(jīng)自發(fā)活動[8]。靜息態(tài)腦功能網(wǎng)絡(luò)研究[9]發(fā)現(xiàn),默認網(wǎng)絡(luò)(default mode network, DMN)是一組腦區(qū),在執(zhí)行認知任務(wù)時表現(xiàn)為負激活,靜息時存在同步低頻振蕩,與Aβ沉積區(qū)域高度重疊。DMN不同腦區(qū)活動在AD病程中變化各異,前側(cè)及腹側(cè)先增強后下降,而后側(cè)較早出現(xiàn)下降[10]。近年來,fMRI已廣泛被應(yīng)用于AD研究中,但相對較少用于SCD。Wang等[11]發(fā)現(xiàn)SCD患者右側(cè)海馬功能連接下降,程度輕于MCI患者。Edelman等[12]發(fā)現(xiàn)認知正常老年人執(zhí)行海馬記憶任務(wù)時,內(nèi)顳葉激活與Aβ沉積相關(guān),提出AD臨床前期中內(nèi)顳葉激活可能是神經(jīng)變性的早期生物學(xué)標(biāo)記。

1.2.2 任務(wù)態(tài)fMRI SCD患者腦激活在工作記憶時與正常人無明顯差異,而進行情景記憶再認時其右側(cè)海馬活性減低,同時右背外側(cè)前額葉皮質(zhì)活性增強[13]。在編碼任務(wù)時,SCD患者與正常人均有左側(cè)前額葉皮質(zhì)及小腦激活,且完成任務(wù)的表現(xiàn)無明顯差異,但SCD患者左側(cè)前額葉皮質(zhì)激活強度與任務(wù)表現(xiàn)有關(guān),提示可能存在代償機制[14]。在注意分散任務(wù)時,SCD患者左側(cè)內(nèi)顳葉、雙側(cè)丘腦、后扣帶回和尾狀核激活增強[15]。在跨時決定任務(wù)時,SCD患者可出現(xiàn)延時折扣,即更傾向于選擇即刻獎賞;而正常人傾向選擇未來更多獎賞,可能與額葉前極皮層、右側(cè)島葉皮質(zhì)和扣帶回前部皮質(zhì)激活有關(guān)[16]。上述研究表明,SCD患者執(zhí)行不同認知任務(wù)時腦區(qū)激活表現(xiàn)各異。

1.3 擴散成像

1.3.1 DTI DTI由DWI發(fā)展而來,可三維顯示神經(jīng)纖維束改變及走行方向;測量指標(biāo)包括各向異性分數(shù)(fractional anisotropy, FA)、平均擴散率(mean diffusivity, MD)、軸向擴散系數(shù)和徑向擴散系數(shù)。研究[17]表明,AD和MCI患者多個部位白質(zhì)纖維束受損,包括胼胝體、扣帶回、海馬旁纖維束、顳葉、頂葉及額葉等腦區(qū)纖維束;而SCD患者內(nèi)嗅皮層、內(nèi)顳葉、海馬旁纖維及后扣帶回白質(zhì)纖維束易受損害[18],且進展為MCI的SCD患者胼胝體、內(nèi)顳葉、內(nèi)嗅皮層、楔前葉及緣上回等部位的纖維束更易受累。SCD在DTI測量指標(biāo)上主要表現(xiàn)為FA下降、徑向擴散系數(shù)及MD升高。Doan等[19]發(fā)現(xiàn)SCD患者穹窿、鉤狀束、胼胝體和主要感覺運動通路中存在雙向改變,提示白質(zhì)微觀結(jié)構(gòu)在AD進展全程中存在連續(xù)性改變。正常老年人也常出現(xiàn)腦白質(zhì)高信號(white matter hyperintensities, WMHs),致進展為MCI及AD的風(fēng)險增加。有學(xué)者[20]采用DTI與腦脊液(cerebrospinal fluid, CSF)觀察具有WMHs的SCD及MCI患者,發(fā)現(xiàn)以DTI測量的指標(biāo)差異均無統(tǒng)計學(xué)意義,而CSF中Aβ42(+)患者DA、DR和MD值較Aβ42(-)患者更高。還有學(xué)者[21]提出SCD患者腦白質(zhì)網(wǎng)絡(luò)結(jié)構(gòu)全局及局部效率均明顯下降,且主要集中于雙側(cè)眶額區(qū)及左側(cè)丘腦等腦區(qū)。DTI發(fā)生改變的部位無法與皮層萎縮部位相對應(yīng),提示白質(zhì)纖維束損害的病理生理基礎(chǔ)可能與皮層萎縮不同。此外,有學(xué)者[22]提出DTI比CSF更能預(yù)測認知功能減退,提示DTI可能發(fā)展為獨立預(yù)測AD風(fēng)險的標(biāo)志物[23]。

1.3.2 擴散峰度成像(diffusion kurtosis imaging, DKI) DKI是基于DTI技術(shù)的延伸,DTI理論前提為水分子擴散呈正態(tài)分布,而DKI可量化非正態(tài)分布水分子擴散,以描繪組織微觀結(jié)構(gòu)。DKI主要參數(shù)包括平均峰度(mean kurtosis, MK)、徑向峰度(radial kurtosis, RK)及峰度各向異性(kurtosis anisotrop, KA)。有學(xué)者[24]發(fā)現(xiàn)AD、MCI及正常對照組胼胝體壓部及放射冠MK明顯不同;還有學(xué)者[25]發(fā)現(xiàn),與正常對照組相比,AD患者胼胝體膝部、扣帶束,顳葉及額葉體素數(shù)量在MK上高于FA及MD,提示MK較FA和MD更敏感。Gong等[26]發(fā)現(xiàn)早期MCI患者深部灰質(zhì)有大量異常MK區(qū)域,提示MK可作為補充指標(biāo),用于檢測深部灰質(zhì)微觀結(jié)構(gòu)變化。

1.4 動脈自旋標(biāo)記(arterial spin labeling, ASL) ASL可無創(chuàng)測量腦血流,無需注射對比劑即可獲得血流絕對值,可重復(fù)性較好。采用3D ASL測量的腦血流量值有助于檢測AD前驅(qū)期功能變化,可作為提示AD嚴重程度的標(biāo)志[27]。Collij等[28]發(fā)現(xiàn),ASL灌注圖基于多元模式分析的方法鑒別SCD與AD的準確率較高,但鑒別SCD與MCI的準確率較低。對于ASL診斷SCD的價值尚需進一步觀察。

2 PET

18F-FDG PET可通過測定腦葡萄糖代謝率而反映腦功能變化。目前對于SCD患者18F-FDG PET代謝變化尚無定論。Scheef等[29]發(fā)現(xiàn)SCD患者右側(cè)楔前葉表現(xiàn)為低代謝,同時右側(cè)內(nèi)顳葉為高代謝。Ewers等[30]提出內(nèi)顳葉和頂葉低代謝可較準確地預(yù)測正常老年人是否進展為AD。還有學(xué)者[29,31]發(fā)現(xiàn),SCD患者縱向記憶力下降與右側(cè)楔前葉葡萄糖代謝減低在基線水平相關(guān)。Jeong等[32]發(fā)現(xiàn)SCD患者左側(cè)顳上回、右側(cè)扣帶回、左側(cè)海馬旁回、右側(cè)舌回及右側(cè)角回早期代謝易下降,執(zhí)行功能變化與右側(cè)扣帶回后部代謝率呈正相關(guān)。

11C-匹茨堡化合物(11C-PIB)PET可用于顯示Aβ沉積。認知功能正常的記憶門診患者Aβ沉積高于正常健康對照組[33]。與18F-FDG PET與臨床癥狀相關(guān)不同,11C-PIB可于臨床癥狀出現(xiàn)前達到平臺期,沉積量與臨床癥狀嚴重程度不一定相關(guān)。SCD患者Aβ沉積與特定區(qū)域皮質(zhì)萎縮相關(guān),而正常人無此相關(guān)性[34]。Dore等[3]提出Aβ沉積并非正常過程,伴Aβ沉積的老年人海馬及顳葉皮層萎縮較不伴Aβ沉積的老年人更快。有學(xué)者[35]發(fā)現(xiàn),伴有Aβ沉積的受試者主訴常有認知功能下降。此外,半量淀粉樣蛋白PET比CSF標(biāo)志物更能指導(dǎo)AD分級及預(yù)后判斷,其標(biāo)準化攝取率(standardised uptake value ratio, SUVr)可作為確定認知程度的獨立因素[36]。既往研究通常認為Aβ沉積是導(dǎo)致AD的重要原因[37],而Kumar等[38-39]提出Aβ是一種對腦細胞具有保護作用的抗菌肽,為Aβ的研究提出了新方向。

Tau PET與CSF標(biāo)志物檢查的一致性較高[40],且Tau PET可監(jiān)測AD病理進展程度[41]。有學(xué)者[42]發(fā)現(xiàn)正常老年人無論是否伴有有Aβ沉積,其顳葉均易出現(xiàn)Tau聚集。目前關(guān)于Tau PET與SCD相關(guān)性的研究較少見,SCD患者腦內(nèi)Tau聚集是否較正常老人更多還有待進一步證實。

3 展望

SCD亞臨床特征于個體水平較難發(fā)現(xiàn)[43]。SCD自身表現(xiàn)具有異質(zhì)性,國內(nèi)外研究的入組標(biāo)準及診斷也具有異質(zhì)性,可能導(dǎo)致研究結(jié)果差異及偏倚。統(tǒng)一入組標(biāo)準和診斷標(biāo)準,建立大樣本多中心研究和數(shù)據(jù)庫十分必要。近年來,AD神經(jīng)影像學(xué)計劃已取得許多重要突破,可推動未來AD大樣本多中心研究。此外,中國人群的腦成像與西方腦圖譜存在差異,國內(nèi)AD影像學(xué)研究采用中國人3D結(jié)構(gòu)腦圖譜(Chinese2020)[44],可獲得更準確的結(jié)果。隨著大數(shù)據(jù)時代來臨,多元模式分析(multivariate pattern analysis, MVPA)用途廣泛,其中,支持向量機是AD研究中較常用的MVPA方法,且多項研究[45-46]表明支持向量機診斷及鑒別AD的準確率較高。Peter等[2]提出多元模式識別可敏感、有效鑒別SCD;Collij等[28]基于多元模式分析表明ASL灌注圖可用于鑒別SCD與AD。另有研究[47]認為老年患者主觀認知下降與抑郁癥狀相關(guān),而與客觀認知無關(guān),故對于SCD的研究須排除抑郁因素的干擾,并通過隨訪加以證實。

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本刊可以直接使用的英文縮略語(一)

計算機體層攝影術(shù)(computed tomography, CT)

多層螺旋CT(multiple-slice CT, MSCT)

高分辨率CT(high resolution CT, HRCT)

容積CT(volumetric computed tomography, VCT)

CT血管造影(computed tomographic angiography, CTA)

CT靜脈造影(CT venography, CTV)

磁共振成像(magnetic resonance imaging, MRI)

功能磁共振成像(functional magnetic resonance imaging, fMRI)

擴散(彌散)加權(quán)成像(diffusion weighted imaging, DWI)

磁敏感加權(quán)成像(susceptibility-weighted imaging, SWI)

擴散(彌散)張量成像(diffusion tensor imaging, DTI)

灌注加權(quán)成像(perfusion weighted imaging, PWI)

磁共振血管造影(magnetic resonance angiography, MRA)

磁共振波譜(magnetic resonance spectroscopy, MRS)

氫質(zhì)子磁共振波譜(proton magnetic resonance spectroscopy,1H-MRS)

表觀擴散(彌散)常數(shù)(apparent diffusion coefficient, ADC)

數(shù)字減影血管造影(digtal subtraction angiography, DSA)

經(jīng)導(dǎo)管動脈化療栓塞術(shù)(transcatheter arterial chemoembolization, TACE)

經(jīng)頸靜脈肝內(nèi)門-體分流術(shù)(transjugular intrahepatic porto-systemic shunt, TIPS)

冠狀動脈血管造影術(shù)(coronary angiography, CAG)

最大密度投影(maximum intensity projection, MIP)

容積再現(xiàn)技術(shù)(volume rendering technique, VRT)

表面陰影成像(surface shaded displace, SSD)

最小密度投影(minimum intensity projection, MinIP)

多平面重建(multi-planar reconstruction, MPR)

多平面重組(multi-planar reformation, MPR)

容積再現(xiàn)(volume rendering, VR)

容積重建(volume reconstruction, VR)

曲面重組(curved planar reformation, CPR)

曲面重建(curved planar reconstruction, CPR)

自旋回波(spin echo, SE)

快速自旋回波(fast spin echo, FSE)或者(turbo spin echo, TSE)

快速場回波(fast field echo, FFE)

平面回波成像(echo planar imaging, EPI)

梯度回波(gradient echo, GRE)

信噪比(signal noise ratio, SNR)

對比噪聲比(contrast noise ratio, CNR)

血氧水平依賴(blood oxygenation level dependent, BOLD)

視野(field of view, FOV)

時間飛躍法(time of flight, TOF)

激勵次數(shù)(number of excitation, NEX)

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