Volume 43 Issue 6
Jan.  2020
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Application of PET/CT in depression and related research advances

  • Depression is a common mood disorder, which seriously affects the quality of life of patients. Accurate diagnosis and timely treatment are important. However, the pathogenesis of depression is incomplete clear, and there is also a lack of specific examination methods are lacking. Conventional examinations face various technical bottlenecks in the diagnosis and treatment effect of depression. However, molecular imaging research provides new research ideas and methods for depression. The author reviews the research progress of PET/CT in term of neuronal mechanism, diagnosis and detection of depression.
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    [10] Li H, Sagar AP, Kéri S. Microglial markers in the frontal cortex are related to cognitive dysfunctions in major depressive disorder[J]. J Affect Disord, 2018, 241: 305−310. DOI: 10.1016/j.jad.2018.08.021.
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    [13] Holmes SE, Hinz R, Conen S, et al. Elevated Translocator Protein in Anterior Cingulate in Major Depression and a Role for Inflammation in Suicidal Thinking: A Positron Emission Tomography Study[J]. Biol Psychiatry, 2018, 83(1): 61−69. DOI: 10.1016/j.biopsych.2017.08.005.
    [14] Owen DR, Narayan N, Wells L, et al. Pro-inflammatory activation of primary microglia and macrophages increases 18 kDa translocator protein expression in rodents but not humans[J]. J Cereb Blood Flow Metab, 2017, 37(8): 2679−2690. DOI: 10.1177/0271678X17710182.
    [15] Tóth M, Doorduin J, Häggkvist J, et al. Positron Emission Tomography studies with [11C] PBR28 in the Healthy Rodent Brain: Validating SUV as an Outcome Measure of Neuroinflammation[J/OL]. PLoS One, 2015, 10(5): e0125917 [2019-02-27]. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0125917. DOI: 10.1371/journal.pone.0125917.
    [16] 付畅, 张红菊, 史大鹏, 等. 首发抑郁症前额叶静息态葡萄糖代谢和血流灌注改变及其与临床症状的相关性[J]. 中华医学杂志, 2015, 95(37): 3017−3022. DOI: 10.3760/cma.j.issn.0376−2491.2015.37.005.Fu C, Zhang HJ, Shi DP, et al. Correlation of region blood perfusion and glucose metabolism of the prefrontal lobes with clinical features in patients with first-episode depression[J]. Natl Med J China, 2015, 95(37): 3017−3022. DOI: 10.3760/cma.j.issn.0376−2491.2015.37.005.
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    [18] Wei K, Xue HL, Guan YH, et al. Analysis of glucose metabolism of 18F-FDG in major depression patients using PET imaging: Correlation of salivary cortisol and α-amylase[J]. Neurosci Lett, 2016, 629: 52−57. DOI: 10.1016/j.neulet.2016.06.039.
    [19] Ohgi Y, Futamura T, Hashimoto K. Glutamate Signaling in Synaptogenesis and NMDA Receptors as Potential Therapeutic Targets for Psychiatric Disorders[J]. Curr Mol Med, 2015, 15(3): 206−221. DOI: 10.2174/1566524015666150330143008.
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    [21] Esterlis I, DellaGioia N, Pietrzak RH, et al. Ketamine-induced reduction in mGluR5 availability is associated with an antidepressant response: an [11C] ABP688 and PET imaging study in depression[J]. Mol Psychiatry, 2018, 23(4): 824−832. DOI: 10.1038/mp.2017.58.
    [22] Carlson PJ, Diazgranados N, Nugent AC, et al. Neural Correlates of Rapid Antidepressant Response to Ketamine in Treatment-Resistant Unipolar Depression: A Preliminary Positron Emission Tomography Study[J]. Biol Psychiatry, 2013, 73(12): 1213−1221. DOI: 10.1016/j.biopsych.2013.02.008.
    [23] Lally N, Nugent AC, Luckenbaugh DA, et al. Neural correlates of change in major depressive disorder anhedonia following open-label ketamine[J]. J Psychopharmacol, 2015, 29(5): 596−607. DOI: 10.1177/0269881114568041.
    [24] Li CT, Chen MH, Lin WC, et al. The effects of low-dose ketamine on the prefrontal cortex and amygdala in treatment-resistant depression: A randomized controlled study[J]. Hum Brain Mapp, 2016, 37(3): 1080−1090. DOI: 10.1002/hbm.23085.
    [25] Lener MS, Niciu MJ, Ballard ED, et al. Glutamate and Gamma-Aminobutyric Acid Systems in the Pathophysiology of Major Depression and Antidepressant Response to Ketamine[J]. Biol Psychiatry, 2017, 81(10): 886−897. DOI: 10.1016/j.biopsych.2016.05.005.
    [26] Chen MH, Li CT, Lin WC, et al. Persistent antidepressant effect of low-dose ketamine and activation in the supplementary motor area and anterior cingulate cortex in treatment-resistant depression: A randomized control study[J]. J Affect Disord, 2018, 225: 709−714. DOI: 10.1016/j.jad.2017.09.008.
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Application of PET/CT in depression and related research advances

    Corresponding author: Lihong Bu, bulihongs@126.com
  • PET Center, Renmin Hospital of Wuhan University, Wuhan 430060, China

Abstract: Depression is a common mood disorder, which seriously affects the quality of life of patients. Accurate diagnosis and timely treatment are important. However, the pathogenesis of depression is incomplete clear, and there is also a lack of specific examination methods are lacking. Conventional examinations face various technical bottlenecks in the diagnosis and treatment effect of depression. However, molecular imaging research provides new research ideas and methods for depression. The author reviews the research progress of PET/CT in term of neuronal mechanism, diagnosis and detection of depression.

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1.   背景
  • 抑郁症是一种以情感低落和意志活动减退为主要特征的常见且易复发的心境障碍性精神疾病[1]。抑郁症发病年龄跨越区间大,并逐渐出现低龄化趋势,全球终身患病率约为29.9%[2];且患病率及自杀率逐年上升[3]。抑郁症发病机制尚不完全明确,其病因与许多因素有关,如遗传、神经内分泌、社会环境等[4]。目前,尚无诊断抑郁症的特异性检查项目。迄今为止,抑郁症的临床诊断标准是基于“临床症状体征”的分析,主要依靠临床症状进行诊断。而分子影像为抑郁症的研究独辟蹊径,在体内细胞水平可以无创地获得有关抑郁症的代谢信息,进而反映各个神经核团的功能变化,体现其相对活性。PET/CT分子显像所提供的这些信息将有助于其机制的研究、更加准确地诊断以及治疗反应的监测,进一步推动抑郁症精准诊断以及个性化治疗的发展。

2.   PET/CT在抑郁症神经元机制中的应用
  • 抑郁症是一种异质性疾病,其引起疾病的神经元机制尚不完全清楚。早期的研究一直以单胺假说为核心,却无重大突破。目前,神经免疫机制已成为研究抑郁症的热点。不少研究结果显示抑郁症的发生可能与细胞因子密切相关[5]。在正常情况下,细胞因子可以为神经元提供辅助作用,但其过度和长期的激活则会适得其反,不但影响单胺类递质的代谢,而且可使神经元细胞损伤或凋亡、出现功能异常并导致认知功能下降等。而这些又将成为抑郁症发生的危险因素,如轻度认知障碍患者的抑郁率高达25%~40%[6]。还有研究结果表明,银屑病这类慢性炎症疾病患者并发抑郁症的风险大大增加[7-8]

    此外,最近有研究者通过PET显像检测大鼠小胶质细胞的活化和海马神经炎症的发生,结果表明小胶质细胞被激活可诱导抑郁和焦虑样行为[9]。该结果提示神经元机制不仅伴有神经炎症,其过程还涉及小胶质细胞的激活。

    在正常生理环境下,小胶质细胞有高效监测等作用,一旦出现炎症、感染或创伤等异常应激情况,小胶质细胞将迅速被激活并发挥其吞噬功能,清除受损细胞并修复有关组织,但是持续过度激活的小胶质细胞会释放神经毒性因子及促炎症因子,从而引起神经细胞的退行性改变和凋亡。转位蛋白(translocator protein,TSPO)是位于小胶质细胞外线粒体膜上的蛋白质,当小胶质细胞被激活时,TSPO的表达也会增加。有研究者使用PET/CT显像来监测重度抑郁症患者转位蛋白总分布容积(translocator protein total distribution volume,TSPO VT)、小胶质细胞密度和炎症的标志物,从而研究重度抑郁症的病理生理学的发病机制,研究结果显示未经治疗的重度抑郁症(major depressive disorder,MDD)患者的认知功能障碍可能与额叶皮层的小胶质细胞病变有关[10-11]。而Setiawan等[12]使用同样的方法监测TSPO VT,结果发现MDD患者的皮质和皮质下的广泛区域相对于健康对照受试者显著升高;同时该研究结果还发现在前扣带回皮质中TSPO VT越高,其抑郁症状越严重,相似的情况在其他抑郁症相关的脑区如岛叶与前额叶也存在。这些研究结果表明抑郁症发病与其相关脑区的小胶质细胞的密度及活性密切相关。

    随后一项研究应用显像监测中度至MDD患者发作期间前扣带皮质中异位蛋白增加的情况,同时也发现MDD患者前扣带皮层的TSPO VT明显高于对照组,特别是在有自杀倾向的患者中表现得尤为明显[13]。这项研究结果不仅提示了抑郁症发病机制与小胶质细胞被激活有关,并且进一步评估了MDD的抗炎治疗的重要性。

    但是TSPO对原发性神经炎症和小胶质细胞激活的特异性并不是唯一的[14-15]。TSPO也可以由星形胶质细胞和内皮细胞表达,但是TSPO的表达增加可能表明的是小胶质细胞和巨噬细胞的密度而不是激活数量,所以,该研究具有一定的局限性。

3.   PET/CT在抑郁症诊断方面的应用
  • 目前对抑郁症的诊断取决于其临床症状,而不是任何实验室的检查结果,建立诊断抑郁症的生物学标志物是精神病学实践中需要解决的重要问题。

    然而,PET/CT对抑郁症的诊断有何作用呢?付畅等[16]将首发抑郁症患者及健康者分为两组,应用18F-FDG PET/CT分析首次发病的抑郁症患者前额叶脑功能的改变,结果表明,与健康人相比,抑郁症一组双侧额叶代谢均减低;同时与MRI相比,PET/CT可以更灵敏地检测出患者脑区病变位置。

    另外有研究者通过三维动脉自旋标记MRI技术和18F-FDG PET/CT探索MDD患者脑血流灌注与糖代谢的关系,并分析这些功能变化与抑郁症之间的相关性[17]。研究结果表明,18F-FDG PET/CT在识别前额叶功能异常时比三维动脉自旋标记MRI技术更加灵敏。还有研究结果显示,与健康对照组相比,MDD患者组在几个脑区显示出较高的唾液皮质醇、血清淀粉样蛋白A水平和较低的18F-FDG代谢[18],因此采用唾液皮质醇、血清淀粉样蛋白A水平及18F-FDG PET/CT的代谢情况联合检测作为临床上抑郁症的诊断手段,从而增加诊断的准确率。

    虽然18F-FDG PET/CT能为抑郁症的诊断提供一定的信息,但是,PET显像的空间分辨率低,无法分清更加精确的解剖结构。另外,PET显像的准确性易受其他因素干扰,所以并不能完全满足临床诊断的要求,但目前还没有其他显像剂应用于抑郁症临床诊断的相关报道。

4.   PET/CT在监测抑郁症治疗效果方面的应用
  • 目前多数抗抑郁药物治疗面临缓解率低、复发风险高等问题,所以及时了解治疗效果是迫切需要的。但是由于缺乏对抑郁症潜在神经病理生理机制的了解,所以可通过观察的症状指导抑郁症的治疗决策。越来越多的研究结果表明,谷氨酸能神经传递异常在抑郁症发展过程中和治疗抵抗性抑郁症中起重要作用[19-20]

    迄今为止,虽然仍难以测量人脑中的谷氨酸能神经传递,但是可通过有些技术计算谷氨酸水平来探索谷氨酸能神经传递,其中就包括分子影像技术。有研究者利用促代谢型谷氨酸受体5(metabotropic glutamate receptor 5,mGluR5)的放射性配体11C-ABP688进行PET显像,评估健康受试者和MDD患者的谷氨酸水平[21]。但是,11C-ABP688 PET显像在临床环境中测量谷氨酸受体受限于其半衰期短,缺乏实际可用性。由于神经元中产生的谷氨酸是来自葡萄糖衍生的三羧酸循环中间体和支链氨基酸,突触间隙中的谷氨酸的再摄取以及伴有神经元去极化和谷氨酸从突触前囊泡释放到突触间隙的过程所需要的能量均与葡萄糖的应用有关,所以,18F-FDG作为临床上应用广泛且成熟的显像剂,可以通过测量脑葡萄糖的摄取间接测量谷氨酸能水平。18F-FDG PET/CT显像可能成为评估谷氨酸能神经传递水平的最有希望的工具。

    PET/CT不仅用于了解谷氨酸能神经传递机制,还用于评估抑郁症治疗疗效。如氯胺酮可作用于谷氨酸系统,抑制中枢神经谷氨酸受体或减少谷氨酸含量,有望作为新一代快速抗抑郁药物而成为研究热点。最近有研究者利用18F-FDG PET/CT研究抵抗性抑郁症患者注射氯胺酮后脑功能代谢的前后变化。如Carlson等[22]通过测量18F-FDG PET/CT基线和观察注射氯胺酮后2 h患者脑的葡萄糖代谢,结果发现抑郁症症状有所改善直接与右上颞回和中颞回的葡萄糖代谢的变化相关。另一项研究结果通过PET测量基线和观察注射氯胺酮2 h后患者脑葡萄糖代谢发现,若快感缺失这一抑郁症的核心症状减少,海马和背侧前方扣带回皮质的葡萄糖代谢显著增加[23]。Li等[24]通过PET/CT测量基线和注射氯胺酮(患者组)和生理盐水(对照组)40 min后评估脑功能的变化发现,注射低剂量氯胺酮患者的前额叶皮层、辅助运动区和背侧前方扣带回皮质的标准化吸收值高于对照组,该结果还证实前额皮质中葡萄糖代谢增加与抑郁症状改善显著相关。此外,最近的临床研究表明,氯胺酮的抗抑郁作用不仅发生在注射数小时后,也可能持续数天甚至2周之后[25]。正如前面研究中所提到的注射0.5 mg/kg氯胺酮可以在几小时内迅速减轻抑郁症状。但在进一步研究中发现了注入0.5 mg/kg氯胺酮持久的抗抑郁作用远远超过了氯胺酮及其活性代谢产物的半衰期的原因在于其与辅助运动区和前扣带皮层持续增加的活动有关[26]。这些研究结果对诠释抑郁症临床症状快速改善的潜在机制有重大意义。

    另外,Yang等[27]反复在5周龄雄性小鼠皮质中注射皮质酮诱导其产生抑郁症,然后予以5周的抗抑郁药物治疗,然后通过PET/CT对小鼠前额叶皮层、颞叶和海马相关脑区的能量代谢进行分析,结果显示小鼠经治疗后病情显著改善,应用18F-FDG PET/CT显像可以了解治疗效果。有研究数据也表明,18F-FDG PET/CT可以显示抑郁症患者和对照组在不同类型的干预前后,大脑区域特别是前扣带回皮层葡萄糖代谢的变化[28]。有研究曾报道1例对药物治疗有抵抗力的抑郁症患者,应用了多种抗抑郁药和非典型抗精神病药,患者症状没有改善,但其大脑葡萄糖代谢弥漫性增高,而患者继续治疗7周后症状改善,PET显像发现大脑的前扣带回皮层经治疗后代谢与正常脑实质区域代谢相仿[29]。这些研究结果提示前扣带回皮层的代谢变化将可能是评估治疗反应的预测因子。

5.   小结和展望
  • PET/CT可以识别抑郁症的生化标志物及大脑结构性变化,增加诊断准确率,评估疗效,但在临床具体实施中仍存在一定的局限性。近年来,PET/MR除了可以同时收集抑郁症患者的功能和代谢信息,还具有低辐射、多参数、分清更加精确的解剖结构等优点,可以与PET/CT互补,所以未来的研究对于应用PET/MR检查抑郁症相关的变化及脑功能是必要的,将进一步推动对抑郁症的神经元机制的研究。虽然PET/CT在抑郁症各方面的研究中取得了很大的进展,但是18F-FDG特异度不高,易受其他因素干扰,所以,未来的努力更应扩展到抑郁症理想生物标志物的研究上。理想的生物标志物应符合高灵敏度、高特异度、可重复性,易获取且价格低廉,并提供监测疾病进展的能力,且不受年龄、补偿机制或治疗的影响。虽然有一定的挑战,但是相信随着未来分子影像技术的发展,研发出针对抑郁症的精准探针指日可待。

    利益冲突 本研究由署名作者按以下贡献声明独立开展,不涉及任何利益冲突。

    作者贡献声明 李雪蓉负责论文的撰写;卜丽红负责论文的审阅。

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