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摘要：随着年龄增长，脑白质病变发生率越来越高。研究发现，脑白质病变不仅与脑卒中的发生及预后、认知功能障碍、语言障碍及行为等相关，还与抑郁密切相关；脑白质病变引起抑郁障碍的病理生理基础可能是传导束受损导致功能障碍；脑白质病变部位、严重程度均与抑郁的发生及严重程度相关；干预脑白质病变的危险因素可能延缓抑郁障碍的发生。本文就脑白质病变引起抑郁障碍的可能机制及二者的相互关系予以综述。
关键词：脑白质病变；抑郁障碍；发病机制；严重程度
本文引用格式：田春娥,李伟,王琰,等.脑白质病变与抑郁障碍的相关性研究[J].世界最新医学信息文摘,2019,19(76):102-103,117.
Correlation between White Matter Lesions and Depression
TIAN Chun-e1，LI Wei2，WANG Yan1，MA Min-jiang1,ZHANG Mi-juan1
(1.Xi’an Medical University,Xi’an Shaanxi;2.Shaanxi People’s Hospital,Xi’an Shaanxi)
ABSTRACT:With the increase of age，the incidence of white matter lesions is getting higher and higher.The study found that white matter lesions are not only related to the occurrence and outcome of stroke,cognitive dysfunction,language disorders and behavior,but also closely related to depression;The pathophysiological basis of depression caused by leukoencephalopathy may be dysfunction caused by impaired conduction bundle;the location and severity of white matter lesions are related to the occurrence and severity of depression;Interfering with the risk factors of white matter lesions may delay the occurrence of depression.This article reviews the possible mechanism of depression caused by white matter lesions and their correlation.
KEY WORDS:White matter lesions;Depression disorders;Pathogenesis;The severity
0引言
脑白质病变(White matter lesions，WMLs）亦称脑白质疏松（Leukoaraiosis，LA），1987年由加拿大学者Hachinski首先提出，表现为脑室旁和/或深部白质的斑点状或斑片状改变，CT呈低密度改变，MRIT2加权像及Flair呈高信号。抑郁障碍是由各种原因引起的情绪低落、兴趣缺乏等为主要表现的临床综合征[1]。国内外多项研究表明，WMLs与抑郁相关，国外一项关于WMLs与抑郁障碍研究的荟萃分析，发现不同部位脑白质病变与抑郁的相关性不同[2]。本文就WMLs与抑郁障碍的相关性研究予以综述。
1WMLs的特点
WMLs的危险因素有年龄、高血压、糖尿病、高脂血症、吸烟、高同型半胱氨酸（Homocysteine,HCY）、低血红蛋白水平等，其中年龄、高血压是其独立危险因素[3]。有研究进一步探讨WMLs病人的危险因素，发现HCY、血肌酐亦是WMLs的独立危险因素，高血压伴高水平HCY,易出现WMLs[4]。此外，还有研究表明盐摄入通过对内皮细胞的作用在WMLs的形成中起关键作用[5]。发病机制主要包括:低灌注所致缺血缺氧[6]、血-脑屏障受损[7]、脑室周围静脉胶原增生沉积[8]、氧化应激与炎症反应[9,10]、细胞凋亡[11]以及基因遗传学[12,13]等。脑白质的血液供应主要来自脑表面穿通动脉，侧枝循环差，导致大脑深部白质容易发生慢性低灌注损伤。从而血脑屏障受损导致大分子物质进入血管、血管周围空间和神经组织中导致轴突退化、髓鞘脱失，从而影响白质的完整性[14]。此外血管周围间隙异常[15]、反常血栓形成[16]、维生素D缺乏[17]及神经生物学机制[18]等也会损害白质完整性。影像学方面，磁共振弥散张量成像（Diffusion Tensor Imaging，DTI）可以无创性重建脑白质纤维束的三维成像，观察白质纤维束的走行及其微观结构的改变[19]。此外，增强MRI可用来测量血脑屏障的渗透性，评估局部的脑血流量和脑血容量；磁化传递成像(magnetizationtransferratio,MTR)作为脑白质病变的又一核磁标志，可以反映细胞膜上炎症或脱髓鞘等白质病理改变；核磁灌注对早期白质损害也具有重要意义。WMLs起病隐匿，临床表现主要为认知、情感、自主神经功能及运动功能障碍等[20]。
2WMLs与抑郁障碍相关的可能发病机制
WMLs引起抑郁障碍的发病机制尚不明确，目前多认为调节情感的边缘系统及前额叶二者之间的上下行投射经基底节区形成环路，并与其他皮质及皮质下结构形成广泛的联系受损导致血管性抑郁[21]。环路损害可通过额叶、背外侧额叶及前扣带回神经纤维通路直接受损、脑干上行到纹状体-苍白球-丘脑皮质环路中的单胺类神经递质纤维受破坏及基底节区神经节损害导致眶额通路、前额叶的5-羟色胺功能紊乱导致抑郁障碍。当脑白质病变累及这一环路时，可能会导致神经纤维联络中断，这与抑郁患者的临床表现和神经心理学方面的表现是一致的，如老年抑郁患者执行功能的减退。Taylor等对血管性抑郁假说进一步解释[22]：血管抑郁假说是建立在抑郁与血管病理或血管危险因素及其行为相关关系的基础上的。脑血管疾病导致白质受损，进而破坏额叶-纹状体的连接，可能使抑郁疾病易感、促进老年抑郁症状慢性迁延。此外[23]，抑郁可能通过行为或遗传机制，使下丘脑-垂体-肾上腺轴失调、血管内皮功能障碍或自主神经失调进而影响WMLs进展。
3WMLs与抑郁障碍的关系
3.1WMLs解剖部位与抑郁障碍的关系
额叶、颞叶及边缘系统等调控情绪的部位受WMLs影响时，则易出现抑郁症状[24]。研究发现大范围皮层病变、严重皮层下白质病变及基底节区小病灶亦与抑郁发生相关。重症抑郁障碍患者额叶、顶叶及上纵束白质完整性受损明显。Guo等[25]研究证实青少年抑郁症患者海马旁回的白质纤维素完整性减少与迟发型抑郁症的病理生理学机制相关。Zhu等[26]运用全脑空间统计分析研究青少年首发重症抑郁症患者左侧内囊前肢、左侧扣带回、右侧海马旁回白质纤维的完整性受损；还发现抑郁症患者双侧钩束的各向异性分数（fractional anisotrophy,FA值）较对照组明显减低，从而钩束的FA值减小可能成为诊断抑郁症的一个重要依据；抑郁症患者的胼胝体、丘脑这些部位白质纤维FA值并无异常。这与以往一些研究结果相反，因此还需进一步研究证实。此外，深部WMLs的严重程度与卒中3个月后焦虑和抑郁的发生有关，严重的深部WMLs是迟发抑郁及焦虑的危险因素[27]。
3.2WMLs严重程度与抑郁障碍的关系
WMLs体积与其严重程度相关，较大的WMLs体积与抑郁症状的严重程度呈正相关。一项包含1658例老年抑郁患者的研究，随访4年后发现观察组人群的WMLs体积明显增大，非抑郁组WMLs体积越大的人群未来发展为抑郁的风险越高。Potter等人发现，伴有WMLs的抑郁障碍患者年龄大于无WMLs的抑郁障碍患者[28]。Krishman等[29]研究发现，WMLs的严重程度与抑郁症状及老年抑郁症患者的自杀未遂相关。以上均提示WMLs严重程度与抑郁障碍之间密切相关。
3.3WMLs与抑郁障碍的双向关系
WMLs可能导致抑郁障碍，因为已经证明WMLs进展可预测抑郁事件的发生[30]和较差的预后，并且抑郁严重程度与WMLs的特异性定位相关[31]。Krishman等[32]研究发现，抑郁症患者常见WMLs。采用老年抑郁量表对脑室周围和皮层下两个类型的脑白质损害进行研究，单变量分析发现抑郁症状与两个类型的脑白质损害相关。Logistic回归分析发现，老年抑郁严重程度能够预测皮层下白质病变的发生。总之，抑郁症与WMLs之间存在双向关系已被证实。然而其他研究认为，调整吸烟、生理残疾及认知障碍等因素后，WMLs与抑郁的相关性明显降低甚至消失，故二者的相互关系及作用机制有待进一步研究[32]。
3.4WMLs所致抑郁障碍的治疗和预后判断
目前尚无前瞻性试验用于指导WMLs的治疗，主要是控制危险因素。一些研究表明，降脂治疗可能对WML有防治作用[33,34]。已有研究表明抑郁症发生、发展和转归与额叶、扣带回、海马、杏仁核等多个部位脑组织结构和功能的变化有关。仍有研究[35]发现胼胝体及白质纤维束的投射区可作为抑郁症靶向治疗的解剖基础。关于电刺激治疗抑郁症的研究[36]发现，电刺激治疗使参与情绪调节的背侧边缘通路纤维完整性增加。此外，脑白质完整性与电休克治疗反应显著相关，这可能支持未来寻找一种临床适用的预测电休克治疗反应的生物标志物[37]。此外，Korgaonkar等[38]动态分析经规范治疗重症抑郁症患者的扣带回、海马旁回、穹窿、终纹床核及钩束5个脑区白质的FA值，发现扣带回和终纹床核的FA值变化可以较好预测抗抑郁治疗的疗效。Zhu等[39]研究提示检测白质完整性的改变，特别是在皮层和皮质下神经回路中，有可能成为评价治疗抑郁症疗效的病理生理学基础。Taylor等人[40]对11名接受抗抑郁药物治疗后的抑郁老年人行颅脑3T MRI，分析MRI以测量WMLs占据的每个纤维束体积的分数，统计分析通过二分类法在控制年龄和基线抑郁严重程度后，纤维束WMLs严重程度对三个月和六个月抑郁严重程度的影响。该试验研究支持这样的假设：对于扣带束的局灶性损伤可能导致短期抗抑郁反应不良；这些研究结果值得进一步研究。关于WMLs导致抑郁障碍的防治策略主要有：(1)控制危险因素；(2)减缓、阻止或逆转已存在病变；(3)改善疾病相关临床症状。
4结语
人口老龄化使WMLs的发病率增加，随着影像学技术的发展，WMLs的检出率增加，其引起的临床症状不仅导致患者预后不良、生活质量下降，而且给社会带来沉重负担。WMLs与抑郁障碍明显相关，明确可能的发病机制及影响因素可能为今后脑白质病变引起的抑郁障碍的临床预防、诊断及治疗提供帮助。
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