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抑郁症核医学脑功能显像的进展

时间:2024-09-03

李金明,杨渊,陈璟

(华中科技大学同济医学院附属同济医院,湖北武汉430030)

抑郁症核医学脑功能显像的进展

李金明,杨渊,陈璟

(华中科技大学同济医学院附属同济医院,湖北武汉430030)

抑郁症是目前临床上常见的精神性疾病之一。核医学显像是最早应用于抑郁症脑功能显像的影像学手段,能为临床提供抑郁症行为缺陷相关的影像学依据,包括脑血流灌注的改变、脑代谢的异常以及脑受体的表达和活性信息等。伴随核医学仪器的更新,多模态显像技术的发展,核医学脑功能显像在抑郁症病因探索、早期诊断以及治疗监测方面将发挥越来越大的作用。

抑郁症;脑;核医学

抑郁症以持久自发性情绪低落,对日常活动丧失兴趣和愉快感为主要临床特征。迄今,抑郁症的病因并不清楚,目前认为个体遗传基因片段异常所致局部脑血供、代谢、神经活动等改变,以及易患性格特征是抑郁症发病的生理和心理基础[1]。流行病学调查[2]显示抑郁症全球患病率约为8%~12%,且呈逐年增高的趋势,已成为全球性主要精神问题之一。

Hamilton抑郁量表评分是目前临床评估抑郁严重程度的主要方法,但受测评者个体差异影响较大。通过脑功能显像探索抑郁症患者脑血供、代谢以及神经活动的异常规律将有助于推进抑郁症的早期鉴别诊断以及个体化治疗[3]。脑功能显像主要手段包括核医学显像(单光子发射计算机断层显像(SPECT)和正电子发射计算机断层显像(PET))和磁共振显像(MRI)。其中前者在抑郁症研究方面发展较早,且伴随核医学仪器的发展,SPECT/CT、PET/CT和PET/MRI同机图像融合显像仪的出现,在抑郁症病因探索、早期诊断以及治疗监测方面将发挥越来越大的作用。

1 脑血流灌注显像

由于显像剂进入脑细胞的量与局部脑血流灌注正相关,而后者影响脑功能及代谢,因此,脑血流灌注显像在一定程度上可以反映局部脑功能状态。脑血流灌注SPECT显像常用显像剂有99mTc-ECD、99mTc-HMPAO、123I-IMP和133Xe等;PET显像常用显像剂为13N-NH3·H2O和15O-H2O。

1.1 脑血流灌注减低

大量核医学脑血流灌注显像研究均发现抑郁症患者存在不同程度的脑血流灌注减低,但各文献报道的灌注减低区域及程度略有不同:①大脑皮层血流灌注减低。按照出现异常的频率依次为额叶、颞叶、枕叶和顶叶[4-6]。前额叶皮质是边缘系统情绪环路(Papez环路)向新皮层输送感觉和情绪信息的重要部位[7]。Goodwin等[8]研究认为前额叶皮质不同部位受累时,患者可表现欣快冲动或情绪淡漠,即当背侧前额叶皮质,尤其是背侧前额叶中央皮质受累时,患者表现情绪淡漠;当腹侧前额叶皮质,尤其是腹侧前额叶中央皮质和眶额回皮质受累时,患者表现欣快冲动。Nagafusa等99mTc-ECD SPECT显像显示抑郁症患者双侧前额叶皮质和双侧枕叶以左侧受累严重[4]。②边缘系统血流灌注减低[4-6]。边缘系统通过Papez环路相互联系,并与新皮层、丘脑和脑干发生广泛联系,参与调解本能和情感行为。其中扣带回的前部特别的牵扯到情绪,尤其对负面情绪起作用;海马区域主要负责记忆和学习,二者在脑血流灌注显像中常与眶额回皮质或前额叶皮质一同呈现异常结果。单、双相抑郁症脑血流灌注SPECT显像对比研究[9]发现两组均存在双侧颞叶、额叶、海马血流灌注减低;且血流灌注减低程度与患者学习和判断能力的损伤、注意力和记忆力的减退存在相关性。③小脑血流灌注减低[4,6]。PET和fMRI脑显像研究[10]显示抑郁症患者小脑和丘脑血流灌注减低。推测小脑参与悲观情绪的识别和表达,长期的严重抑郁可能通过损伤小脑与额叶的功能联系而累及小脑。但目前尚没有资料证实小脑血流灌注减低是罹患抑郁症的危险因素或者是抑郁症病程进展的结果。

1.2 脑血流灌注增加

Goodwin等[8]研究脑血流灌注显像发现存在抑郁症家族史的年轻患者扣带回皮质和背侧前额叶皮质血流灌注增加;年轻抑郁症患者扣带回后部和基底节区血流灌注的增加与认知功能的损伤相关;而老年抑郁症患者扣带回后部血流灌注的增加与并存焦虑症状有关。推测脑血流灌注增加可能关联频繁的消极思考,而脑血流灌注减低可能关联淡漠的情感表现。Savitz等[11]研究未经治疗的双相抑郁症患者15O-H2O PET脑显像,发现左腹侧额叶和左侧杏仁核血流灌注增加,且Hamilton抑郁量表评分与左侧杏仁核血流灌注正相关,与左腹侧额叶血流灌注负相关。而Videbech等[12]研究15O-H2O PET脑显像,发现中-重度抑郁症患者右侧海马和左侧小脑血流灌注增加。冀二妮等[9]发现双相抑郁症患者双侧基底节血流灌注增加,推测可能为双相抑郁症患者躁狂发作的生理基础。

抑郁症患者局部脑血流灌注改变存在个体差异,在一定程度上可以反映患者行为缺陷和抑郁严重程度,并可预测临床治疗效果,但目前尚无权威性结论。Monkul等[13]研究未经治疗的抑郁症患者15O-H2O脑PET显像,发现右侧扣带回前部、额中回和额下回血流灌注减低;双侧扣带回后部、右侧尾状核、左侧海马旁回血流灌注增加;Hamilton抑郁量表评分与双侧额中回、左侧额下回、右侧扣带回前部血流灌注负相关,与右侧丘脑和左侧壳核正相关。Videbech等[14]研究提示抑郁严重程度与双侧背外侧额叶和眶额回皮质血流灌注负相关,与海马血流灌注正相关。Monkul等[13]发现抑郁症患者焦虑情绪与双侧扣带回后部和顶下小叶血流灌注正相关;抑郁情绪与左背外侧前额皮层和左侧角回血流灌注负相关;认知功能损伤与左内侧前额叶皮层血流灌注正相关。Brockmann等[15]研究5-羟色胺再摄取抑制剂(SSRI)治疗后的抑郁症患者99mTc-HMPAO SPECT脑显像,发现治疗有效者早期前额叶、颞叶和扣带回血流灌注增加;伴随治疗进程,额下回血流灌注减低,中央前回血流灌注增加。Kohn等99mTc-HMPAO SPECT脑显像[16]发现三环类和SSRI类抗抑郁药物治疗有效者可恢复正常脑血流灌注;而电休克治疗有效者原血流灌注减低区血供改善并不明显,同时双侧颞顶部和小脑出现血流灌注减低。

2 脑代谢显像

核医学脑代谢显像包括脑葡萄糖代谢显像、氧代谢显像和蛋白质代谢显像。其中脑葡萄糖代谢和氧代谢显像已运用于抑郁症的研究。

2.1 脑葡萄糖代谢显像

葡萄糖几乎是脑组织的唯一能源物质。18F-FDG PET脑显像[17-19]已发现抑郁症患者存在广泛脑区葡萄糖代谢异常。Drevets等[20]发现未经治疗的抑郁症患者双侧眶额回、双腹侧额叶、左侧杏仁核和扣带回后部葡萄糖代谢增加;膝下前额叶皮质、背外侧额叶前中部葡萄糖代谢减低;且左背外侧前额叶皮质葡萄糖代谢与Hamilton抑郁量表评分负相关。

McGrath等[21]研究SSRI治疗或认知行为治疗的抑郁症患者,发现岛叶葡萄糖代谢减低关联认知行为治疗后的抑郁缓解或SSRI治疗的不敏感;预示岛叶葡萄糖代谢可能成为抑郁症治疗评价的生物标记物,指导抑郁症初始治疗的选择。Baeken等[22]研究高频经颅磁刺激(HF-rTMS)治疗药物抵抗难治型单相抑郁症患者时发现,抑郁缓解者膝下前扣带回皮质葡萄糖代谢明显下降。

2.2 脑氧代谢显像

正常人脑耗氧量占全身的20%。Ottowitz等[23]利用15O-PET显像研究抑郁症患者的记忆加工过程,发现抑郁症患者语言学习中右侧扣带回前部、左腹侧前额皮质、双侧海马和左侧眶额回皮质氧代谢增高;右侧扣带回前部氧代谢与语言组织有关,左腹侧前额皮质氧代谢与语言加工有关。

3 脑神经递质受体显像

抑郁症发病机制目前尚不明确,现阶段较为公认的假说有单胺递质假说和受体假说[24]。核医学脑神经递质受体显像可反映脑区单胺类神经递质及受体水平和活性,现已应用于抑郁症的病因探索、治疗监测以及新药开发的基础和临床研究中[24]。

3.1 5-羟色胺(5-HT)受体显像

3.1.1 5-HT1A受体显像

5-HT1A受体主要分布于脑干中缝核突触前膜和边缘区突触后膜。Savitz等[24]认为抑郁症患者颞叶内侧皮质和边缘区5-HT1A受体活性下降,且受糖皮质激素水平的影响;中缝核不同亚区5-HT1A受体结合活性可能存在差异。Boldrini等[25]发现中缝核喙部、腹外侧和背侧区域5-HT1A受体活性增强;中缝核尾部区域5-HT1A受体活性减弱。Fisher等[26]联合11CWAY100635 PET和fMRI脑显像发现抑郁症患者中缝核5-HT1A受体活性减弱关联杏仁核血氧水平依赖(BOLD)信号的增强。

3.1.2 5-HT2A受体显像

5-HT2A受体广泛分布于人脑组织中,额叶和颞叶密度最高,其次为基底节、顶叶、中央前回、丘脑等。Baeken等[27-28]进行123I-5-I-R91150 SPECT脑显像发现药物抵抗的单相抑郁症患者背侧额叶(右侧为著)和扣带回前部5-HT2A受体活性降低;左侧海马区5-HT2A受体活性增高;HF-rTMS疗效与双背外侧前额叶皮质5-HT2A受体活性正相关,与右侧海马5-HT2A受体活性负相关。常用5-HT2A受体PET显像剂包括18F-Altanserin、11C-MDL、18F-FESP和18F-Setoperone,其中18FFESP和18F-Setoperone同时可结合多巴胺(DA)受体。虽然多数5-HT2A受体PET显像显示抑郁症患者5-HT2A受体活性下降,但尸检和临床前研究暗示抑郁症患者5-HT2A受体活性可能上调。Savitz等[24]认为矛盾结果可能与显像前患者的抗抑郁治疗干预有关。此外,抑郁症患者行为缺陷上的差异也是显像结果不一致的原因之一。

3.1.3 5-HT1B受体显像

5-HT1B受体主要分布于基底节。Murrough等11C-P943 PET显像[29]发现未经治疗的抑郁症患者纹状体腹侧5-HT1B受体活性降低。Anisman等[30]发现自杀幸存的抑郁症患者前额叶皮质、眶额皮质外侧和海马5-HT1BmRNA表达减少。

3.1.4 5-HT转运体(5-HTT)显像

伴随5-HTT抑制剂在抑郁症治疗中作用的认同,5-HTT成为抑郁症研究热点之一。然而5-HTT脑显像结果迥异[31]。研究[32]显示5-HTT活性受配体显像剂类型、显像季节和受检者体质量影响。常用5-HTT SPECT显像剂包括非选择性显像剂123I-β-CIT和选择性显像剂123I-ADAM。常用5-HTT PET显像剂有11C-(+)McN5652和11C-DASB。Amsterdam等123I-ADAM SPECT显像发现抑郁症患者中脑、颞叶及基底节区5-HTT活性降低,暗示可用于抑郁症的鉴别诊断[33]。Hsieh等[34]研究发现抑郁症患者后代中脑5-HTT活性下降,暗示抑郁症遗传易感性归因于抑郁症的病理生理。Miller等11CDASB PET显像发现有自杀倾向的抑郁症患者5-HTT活性明显低于轻度抑郁症患者和健康对照组,预示5-HTT活性可能反映抑郁症病情严重程度[35]。

3.2 DA受体显像

3.2.1 DA1受体显像

DA1受体主要分布于纹状体、伏隔核、视束、前额叶皮质、中央前回、扣带回、海马和杏仁核。11C-SCH23390和11CNNC-112是常用DA1受体PET显像剂。Dougherty等11CSCH23390 PET显像[36]发现抑郁症患者发怒时纹状体DA1受体活性下降13%。Cannon等11C-NNC-112 PET显像[37]发现抑郁症患者左侧尾状核中部DA1受体活性下降14%。由于11C-NNC-112可同时结合DA1受体和5-HT2A受体,所以显像结果有可能受干扰。

3.2.2 DA2受体显像

DA2受体主要分布于纹状体。Yang等[38]和de Kwaasteniet等[39]131I-IBZM SPECT脑显像发现抑郁症患DA2受体活性与健康对照组无明显差异。而Lehto等[40]研究发现抑郁症患者颞叶DA2受体活性增高。常用DA2受体PET显像剂包括靶向DA2/DA3受体的11C-Raclopride、18F-Fallypride和11CFLB-457;靶向DA2/DA4受体的11C-NMSP。Meyer等11CRaclopride PET显像发现抑郁症患者双侧壳核DA2/DA3受体活性增高[41]。Kobiella等研究18F-Fallypride PET和fMRI脑显像,发现抑郁症患者BOLD信号与纹状体DA2/DA3受体活性负相关,与杏仁核、岛叶和扣带回前部DA2/DA3受体活性正相关[42]。Savitz等[24]还发现吸烟和显像剂类型影响显像结果。

3.2.3 DA转运体(DAT)显像

常用的DAT SPECT显像剂有123I-β-CIT、123I-FP-CIT和99mTc-TRODAT-1。Di Giuda等123I-FP-CIT SPECT显像发现抑郁症患者基底节区(以纹状体为著)DAT活性增高[43]。Amsterdam等99mTc-TRODAT-1 SPECT显像[44]发现抑郁症患者纹状体DAT活性增高。11C-CFT和11C-RTI-32是常用DAT PET显像剂。Meyer等[45]发现未经治疗的抑郁症患者纹状体DAT活性下降14%。

此外,Conway等[46]利用FDOPA作为显像剂进行PET显像,也发现抑郁症患者脑部纹状体多巴胺能系统活性减低。

3.3 单胺氧化酶-A(MAO-A)活性显像

MAO-A可催化代谢5-HT,去甲肾上腺素和DA。Meyer等11C-Harmine PET显像[47]发现抑郁症患者广泛脑区MAOA活性增高;SSRI治疗不敏感的抑郁症患者MAO-A活性增高;复发的抑郁症患者前额皮层和扣带回前部MAO-A活性增高。暗示MAO-A活性增高可能是抑郁症的特征性标志之一。

3.4 乙酰胆碱受体显像

Hannestad等123I-5IA-85380 SPECT脑显像[48]发现双相抑郁症患者额叶、颞叶、顶叶、扣带回前部、海马、杏仁核、丘脑和纹状体β2*-烟碱型N受体活性减低。

3.5 去甲肾上腺素转运体显像

Remy等11C-RTI-32 PET显像[49]发现有抑郁病史的帕金森病患者边缘系统去甲肾上腺素转运体活性减低,暗示帕金森病患者出现抑郁与边缘系统中去甲肾上腺素能系统受损有关。

综上所述,核医学脑功能显像为抑郁症病因探索、临床诊断、治疗和预防提供了一定依据。5-HT受体、DA受体和转运体蛋白显像有望未来开发新型抑郁症诊断显像剂。多模态脑功能显像联合将为了解抑郁症的病理生理提供新视角。然而,受研究对象、方法等诸多条件的影响,各种核医学脑功能显像均未形成统一的观点,仍然需要更多深入细致的研究,包括健康自愿者脑功能显像对照;抑郁症患者异常的脑功能显像与其临床特征、治疗选择和监测的联系等。

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Progress of nuclear medicine brain functional imaging in depression

LI Jin-ming,YANG Yuan,CHEN Jing (Tongji Hospital of Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430030,China)

Depression is a globally prevalent psychiatric disorder.Nuclear medicine functional imaging of the brain is the first imaging method applied in depression research,which can demonstrate the abnormalities of cerebral blood flow perfusion, cerebral metabolism,and the distribution and function of neuroreceptors,etc.With the development of nuclear medicine device and the appearance of multimodal imaging system,nuclear medicine imaging will play an even more important role in exploring pathogenesis,developing new technologies for early diagnosis and therapy monitoring of depression.

Depressive disorder;Brain;Nuclear medicine

R749.4;R817.4

A

1008-1062(2016)10-0739-05

2016-01-18

李金明(1990-),男,安徽六安人,在读硕士研究生。E-mail:ljming0518@163.com

陈璟,华中科技大学同济医学院附属同济医院核医学科,430030。E-mail:lindaxcx@vip.163.com

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