主觀認知減退影像學研究進展

樊 響，趙志蓮，齊志剛，李坤成*

(1.首都醫科大學宣武醫院放射科，北京 100053；2.磁共振成像腦信息學北京市重點實驗室，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系統變性疾病。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客觀臨床表現的階段，可檢測到相關生物標志物證據，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致認知損害。AD患者尚未出現認知障礙臨床表現時，生物學標記即可出現異常。生物學標記主要分為體液標志物和影像學生物標志物，其中影像學生物標志物近年發展迅速，可檢測β-淀粉樣蛋白(amyloid β-protein, Aβ)沉積，評估神經退行性改變，故可用來預測SCD是否進展為AD。本文對SCD的影像學研究進展進行綜述。

1 MRI

1.1 結構MRI(structural MRI, SMRI) SMRI可觀察皮質萎縮情況。AD患者皮層萎縮具有一定分布特點和發展規律，而SCD患者皮質萎縮特點與AD具有相似性。SCD患者海馬、內嗅皮層、后扣帶回及內顳葉等可較正常老年人更早出現萎縮[2]，以顳葉為著[3]，但是否具有診斷及預測意義尚存爭議。Cantero等[4]發現SCD患者海馬CA1區、CA2區及齒狀回區的分子層體積較小，且血漿Aβ42水平較高；但海馬特定區域體積與血漿Aβ42是否可作為組合標志物還需進一步觀察。既往研究[5]認為神經變性晚期杏仁核體積減小，但Schultz等[6]發現SCD患者皮層萎縮也可發生于杏仁核，且皮層萎縮患者神經心理檢查分數更易減低。Zanchi等[7]發現右側杏仁核(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fMRI 靜息態BOLD自發性低頻振蕩信號可反映神經自發活動[8]。靜息態腦功能網絡研究[9]發現，默認網絡(default mode network, DMN)是一組腦區，在執行認知任務時表現為負激活，靜息時存在同步低頻振蕩，與Aβ沉積區域高度重疊。DMN不同腦區活動在AD病程中變化各異，前側及腹側先增強后下降，而后側較早出現下降[10]。近年來，fMRI已廣泛被應用于AD研究中，但相對較少用于SCD。Wang等[11]發現SCD患者右側海馬功能連接下降，程度輕于MCI患者。Edelman等[12]發現認知正常老年人執行海馬記憶任務時，內顳葉激活與Aβ沉積相關，提出AD臨床前期中內顳葉激活可能是神經變性的早期生物學標記。

1.2.2 任務態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海馬活性減低，同時右背外側前額葉皮質活性增強[13]。在編碼任務時，SCD患者與正常人均有左側前額葉皮質及小腦激活，且完成任務的表現無明顯差異，但SCD患者左側前額葉皮質激活強度與任務表現有關，提示可能存在代償機制[14]。在注意分散任務時，SCD患者左側內顳葉、雙側丘腦、后扣帶回和尾狀核激活增強[15]。在跨時決定任務時，SCD患者可出現延時折扣，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、右側島葉皮質和扣帶回前部皮質激活有關[16]。上述研究表明，SCD患者執行不同認知任務時腦區激活表現各異。

1.3 擴散成像

1.3.1 DTI DTI由DWI發展而來，可三維顯示神經纖維束改變及走行方向；測量指標包括各向異性分數(fractional anisotropy, FA)、平均擴散率(mean diffusivity, MD)、軸向擴散系數和徑向擴散系數。研究[17]表明，AD和MCI患者多個部位白質纖維束受損，包括胼胝體、扣帶回、海馬旁纖維束、顳葉、頂葉及額葉等腦區纖維束；而SCD患者內嗅皮層、內顳葉、海馬旁纖維及后扣帶回白質纖維束易受損害[18]，且進展為MCI的SCD患者胼胝體、內顳葉、內嗅皮層、楔前葉及緣上回等部位的纖維束更易受累。SCD在DTI測量指標上主要表現為FA下降、徑向擴散系數及MD升高。Doan等[19]發現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，提示白質微觀結構在AD進展全程中存在連續性改變。正常老年人也常出現腦白質高信號(white matter hyperintensities, WMHs)，致進展為MCI及AD的風險增加。有學者[20]采用DTI與腦脊液(cerebrospinal fluid, CSF)觀察具有WMHs的SCD及MCI患者，發現以DTI測量的指標差異均無統計學意義，而CSF中Aβ42(+)患者DA、DR和MD值較Aβ42(-)患者更高。還有學者[21]提出SCD患者腦白質網絡結構全局及局部效率均明顯下降，且主要集中于雙側眶額區及左側丘腦等腦區。DTI發生改變的部位無法與皮層萎縮部位相對應，提示白質纖維束損害的病理生理基礎可能與皮層萎縮不同。此外，有學者[22]提出DTI比CSF更能預測認知功能減退，提示DTI可能發展為獨立預測AD風險的標志物[23]。

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

1.4 動脈自旋標記(arterial spin labeling, ASL) ASL可無創測量腦血流，無需注射對比劑即可獲得血流絕對值，可重復性較好。采用3D ASL測量的腦血流量值有助于檢測AD前驅期功能變化，可作為提示AD嚴重程度的標志[27]。Collij等[28]發現，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]發現SCD患者右側楔前葉表現為低代謝，同時右側內顳葉為高代謝。Ewers等[30]提出內顳葉和頂葉低代謝可較準確地預測正常老年人是否進展為AD。還有學者[29,31]發現，SCD患者縱向記憶力下降與右側楔前葉葡萄糖代謝減低在基線水平相關。Jeong等[32]發現SCD患者左側顳上回、右側扣帶回、左側海馬旁回、右側舌回及右側角回早期代謝易下降，執行功能變化與右側扣帶回后部代謝率呈正相關。

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與臨床癥狀相關不同，11C-PIB可于臨床癥狀出現前達到平臺期，沉積量與臨床癥狀嚴重程度不一定相關。SCD患者Aβ沉積與特定區域皮質萎縮相關，而正常人無此相關性[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。有學者[35]發現，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標志物更能指導AD分級及預后判斷，其標準化攝取率(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標志物檢查的一致性較高[40]，且Tau PET可監測AD病理進展程度[41]。有學者[42]發現正常老年人無論是否伴有有Aβ沉積，其顳葉均易出現Tau聚集。目前關于Tau PET與SCD相關性的研究較少見，SCD患者腦內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現[43]。SCD自身表現具有異質性，國內外研究的入組標準及診斷也具有異質性，可能導致研究結果差異及偏倚。統一入組標準和診斷標準，建立大樣本多中心研究和數據庫十分必要。近年來，AD神經影像學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AD影像學研究采用中國人3D結構腦圖譜(Chinese2020)[44]，可獲得更準確的結果。隨著大數據時代來臨，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，而與客觀認知無關，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。

[1] Jessen F, Amariglio RE, van Boxtel M, et al. A conceptual framework for research on subjective cognitive decline in preclinical Alzheimer's disease. Alzheimers Dement, 2014,10(6):844-852.

[2] Peter J, Scheef L, Abdulkadir A, et al. Gray matter atrophy pattern in elderly with subjective memory impairment. Alzheimers Dement, 2014,10(1):99-108.

[3] Dore V, Villemagne VL, Bourgeat PA, et al. Cross-sectional and longitudinal analysis of the relationship between a beta deposition, cortical thickness, and memory in cognitively unimpaired individuals and in Alzheimer disease. JAMA Neurol, 2013,70(7):903-911.

[4] Cantero JL, Iglesias JE, Van Leemput KA. Regional hippocampal atrophy and higher levels of plasma amyloid-beta are associated with subjective memory complaints in nondemented elderly subjects. J Gerontol A Biol Sci Med Sci, 2016,71(9):1210-1215.

[5] 袁強，鄒翎，陳芹.Alzheimer病患者基于體素的腦結構特征研究.四川大學學報(醫學版)，2008，39(3)：496-499.

[6] Schultz SA, Oh JM, Koscik RL, et al. Subjective memory complaints, cortical thinning, and cognitive dysfunction in middle-aged adults at risk for AD. Alzheimers Dement (Amst), 2015,1(1):33-40.

[7] Zanchi D, Giannakopoulos P, Borgwardt S, et al. Hippocampal and amygdala gray matter loss in elderly controls with subtle cognitive decline. Front Aging Neurosci, 2017,9:50.

[8] Biswal B, Yetkin FZ, Haughton VM, et al. Functional connectivity in the motor cortex of resting human brain using echo-planar MRI. Magn Reson Med, 1995,34(4):537-541.

[9] Buckner RL, Sepulcre J, Talukdar T, et al. Cortical Hubs revealed by intrinsic functional connectivity: Mapping, assessment of stability, and relation to Alzheimer's disease. J Neurosci, 2009,29(6):1860-1873.

[10] Damoiseaux JS, Prater KE, Miller BL, et al. Functional connectivity tracks clinical deterioration in Alzheimer's disease. Neurobiol Aging, 2012,33(4):828.e19-828.e30.

[11] Wang Y, Risacher SL, West JD, et al. Altered default mode network connectivity in older adults with cognitive complaints and amnestic mild cognitive impairment. J Alzheimers Dis, 2013,35(4):751-760.

[12] Edelman K, Tudorascu DL, Agudelo C, et al. Amyloid-Beta deposition is associated with increased medial temporal lobe activation during memory encoding in the cognitively normal elderly. Am J Geriatr Psychiatry, 2017,25(5):551-560.

[13] Erk S, Spottke A, Meisen A, et al. Evidence of neuronal compensation during episodic memory in subjective memory impairment. Arch Gen Psychiatry, 2011,68(8):845-852.

[14] Rodda JE, Dannhauser TM, Cutinha DJ, et al. Subjective cognitive impairment: Increasedprefrontal cortex activation compared to controls during an encoding task. Int J Geriatr Psychiatry, 2009,24(8):865-874.

[15] Rodda J, Dannhauser T, Cutinha DJ, et al. Subjective cognitive impairment: Functional MRI during a divided attention task. Eur Psychiatry, 2011,26(7):457-462.

[16] Hu X, Uhle F, Fliessbach K, et al. Reduced future-oriented decision making in individuals with subjective cognitive decline: A functional MRI study. Alzheimers Dement (Amst), 2017,6:222-231.

[17] Radanovic M, Silvestre Pereira FR, Stella F, et al. White matter abnormalities associated with Alzheimer's disease and mild cognitive impairment: A critical review of MRI studies. Expert Rev Neurother, 2013,13(5):483-493.

[18] Ryu SY, Lim EY, Na S, et al. Hippocampal and entorhinal structures in subjective memory impairment: A combined MRI volumetric and DTI study. Int Psychogeriatr, 2017,29(5):785-792.

[19] Doan NT, Engvig A, Persson K, et al. Dissociable diffusion MRI patterns of white matter microstructure and connectivity in Alzheimer's disease spectrum.Sci Rep, 2017,7:45131. doi: 10.1038/srep45131.

[20] Kalheim LF, Bjornerud A, Fladby T, et al. White matter hyperintensity microstructure in amyloid dysmetabolism. J Cereb Blood Flow Metab, 2017,37(1):356-365.

[21] Shu N, Wang X, Bi Q, et al. Disrupted topologic efficiency of white matter structural connectome in individuals with subjective cognitive decline. Radiology, 2018,286(1):229-238.

[22] Selnes P, Aarsland D, Bjornerud A, et al. Diffusion tensor imaging surpasses cerebrospinal fluid as predictor of cognitive decline and medial temporal lobe atrophy in subjective cognitive impairment and mild cognitive impairment. J Alzheimers Dis, 2013,33(3):723-736.

[23] Gold BT, Zhu Z, Brown CA, et al. White matter integrity is associated with cerebrospinal fluid markers of Alzheimer's disease in normal adults. Neurobiol Aging, 2014,35(10):2263-2271.

[24] Struyfs H, Van Hecke W, Veraart J, et al. Diffusion kurtosis imaging: A possible MRI biomarker for AD diagnosis? J Alzheimers Dis, 2015,48(4):937-948.

[25] Yuan L, Sun M, Chen Y, et al. Non-Gaussian diffusion alterations on diffusion kurtosis imaging in patients with early alzheimer's disease. Neurosci Lett, 2016,616:11-18.

[26] Gong NJ, Chan CC, Leung LM, et al. Differential microstructural and morphological abnormalities in mild cognitive impairment and alzheimer's disease: Evidence from cortical and deep gray matter. Hum Brain Mapp, 2017,38(5):2495-2508.

[27] Binnewijzend MA, Kuijer JP, Benedictus MR, et al. Cerebral blood flow measured with 3D pseudocontinuous arterial spin-labeling MR imaging in Alzheimer disease and mild cognitive impairment: A marker for disease severity. Radiology, 2013,267(1):221-230.

[28] Collij LE, Heeman F, Kuijer JP, et al. Application of machine learning to arterial spin labeling in mild cognitive impairment and Alzheimer disease. Radiology, 2016,281(3):865-875.

[29] Scheef L, Spottke A, Daerr M, et al. Glucose metabolism, gray matter structure, and memory decline in subjective memory impairment. Neurology, 2012,79(13):1332-1339.

[30] Ewers M, Brendel M, Rizk-Jackson AA, et al. Reduced FDG-PET brain metabolism and executive function predict clinical progression in elderly healthy subjects. Neuroimage Clin, 2014,4:45-52.

[31] 段小藝，劉翔，葉佳俊，等.阿爾茨海默病及輕度認知損傷患者PET與MRI分析.中國醫學影像技術，2017，33(11):1624-1629.

[32] Jeong HS, Park JS, Song IU, et al. Changes in cognitive function and brain glucose metabolism in elderly women with subjective memory impairment: A 24-month prospective pilot study. Acta Neurol Scand, 2017,135(1):108-114.

[33] Snitz BE, Lopez OL, Mcdade E, et al. Amyloid-beta imaging in older adults presenting to a memory clinic with subjective cognitive decline: A Pilot Study.J Alzheimers Dis, 2015,48(Suppl 1):S151-S159.

[34] Chetelat G, Villemagne VL, Pike KE, et al. Larger temporal volume in elderly with high versus low beta-amyloid deposition. Brain, 2010,133(11):3349-3358.

[35] Alegret M, Rodriguez O, Espinosa A, et al. Concordance between subjective and objective memory impairment in volunteer subjects. J Alzheimers Dis, 2015,48(4):1109-1117.

[36] Ben Bouallegue F, Mariano-Goulart D, Payoux P, et al. Comparison of CSF markers and semi-quantitative amyloid PET in Alzheimer's disease diagnosis and in cognitive impairment prognosis using the ADNI-2 database. Alzheimers Res Ther, 2017,9(1):32.

[37] Cummings JL. Alzheimer's disease. N Engl J Med， 2004,351(1):56-67.

[38] Kumar DK, Eimer WA, Tanzi RE, et al. Alzheimer's disease: The potential therapeutic role of the natural antibiotic amyloid-beta peptide. Neurodegener Dis Manag, 2016,6(5):345-348.

[39] Kumar DK, Choi SH, Washicosky KJ, et al. Amyloid-beta peptide protects against microbial infection in mouse and worm models of Alzheimer's disease. Sci Transl Med, 2016,8(340): 340ra72.

[40] Mo Y, Stromswold J, Wilson K, et al. A multinational study distinguishing Alzheimer's and healthy patients using cerebrospinal fluid tau/Aβ42 cutoff with concordance to amyloid positron emission tomography imaging. Alzheimers Dement (Amst), 2017,6:201-209.

[41] Cho H, Choi JY, Hwang MS, et al. Tau PET in alzheimer disease and mild cognitive impairment. Neurology, 2016,87(4):375-383.

[42] Lockhart SN, Scholl M, Baker SL, et al. Amyloid and tau PET demonstrate region-specific associations in normal older People. Neuroimage, 2017,150:191-199.

[43] Kielb S, Rogalski E, Weintraub S, et al. Objective features of subjective cognitive decline in a US National database.Alzheimers Dement, 2017,13(12):1337-1344.

[44] Liang P, Shi L, Chen N, et al. Construction of brain atlases based on a multi-center MRI dataset of 2020 Chinese adults. Sci Rep, 2015,5:18216.

[45] 齊志剛，錢天翼，安彥紅，等．聯機測量灰質皮層體積在阿爾茨海默病診斷中的應用．中國醫學影像技術，2016,32(8)：1165-1169．

[46] 李昕，童隆正，周曉霞，等．基于MR圖像三維紋理特征的阿爾茨海默病和輕度認知障礙的分類．中國醫學影像技術，2011，27(5)：1047-1051．

[47] Zlatar ZZ, Muniz M, Galasko D, et al. Subjective cognitive decline correlates with depression symptoms and not with concurrent objective cognition in a clinic-based sample of older adults. J Gerontol B Psychol Sci Soc Sci, 2017,doi: 10.1093/geronb/gbw207. [Epub ahead of print].

本刊可以直接使用的英文縮略語(一)

計算機體層攝影術(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)加權成像(diffusion weighted imaging, DWI)

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

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

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

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

磁共振波譜(magnetic resonance spectroscopy, MRS)

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

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

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

經導管動脈化療栓塞術(transcatheter arterial chemoembolization, TACE)

經頸靜脈肝內門-體分流術(transjugular intrahepatic porto-systemic shunt, TIPS)

冠狀動脈血管造影術(coronary angiography, CAG)

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

容積再現技術(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(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(number of excitation, NEX)