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Advances in Clinical Medicine
Vol. 12  No. 09 ( 2022 ), Article ID: 56125 , 7 pages
10.12677/ACM.2022.1291248

阿尔茨海默病伴抑郁患者血清指标与 认知的相关性

雷小晶1，江秀丽2，王晶3，李加梅2，郑加平2*

1潍坊医学院临床医学院，山东 潍坊

2日照市人民医院神经内科，山东 日照

3丽水市中心医院康复科，浙江 丽水

收稿日期：2022年8月21日；录用日期：2022年9月15日；发布日期：2022年9月22日

摘要

目的：分析血清脑源性神经营养因子(BDNF)、炎症因子在阿尔茨海默病(AD)伴抑郁患者中的表达及其与认知功能的相关性。方法：选取65例AD患者为研究组，其中AD伴抑郁患者为AD + D组，AD不伴抑郁患者为AD组，另选取45例健康体检者为NC组，采用简易智力检查量表(MMSE)评估受试者的认知功能，检测三组血清BDNF、IL-1β、IL-6和TNF-α水平。结果：与NC组和AD组相比，AD + D组血清BDNF显著降低，血清IL-1β、IL-6和TNF-α显著升高，差异有统计学意义(P < 0.05)。AD组MMSE评分与血清IL-6水平呈负相关(r = 0.481, P < 0.05)，但是与IL-1β、TNF-α和BDNF水平无明显相关性(r = −0.194, −0.212, −0.324, P > 0.05)；AD + D组MMSE评分与血清IL-1β、IL-6和TNF-α水平呈负相关(r = −0.469, −0.603, −0.499, P < 0.05)，与血清BDNF呈正相关(r = 0.738, P < 0.05)。AD组血清BDNF与IL-6呈负相关(r = −0.497, P < 0.05)，与IL-1β和TNF-α无明显相关性(r = −0.233, −0.087, P > 0.05)；AD + D组血清BDNF水平与IL-1β、IL-6和TNF-α水平呈负相关(r = −0.426, −0.741, −0.481, P < 0.05)。结论：阿尔茨海默病伴抑郁患者血清BDNF与炎症因子有一定的相关性，并且可能与认知功能障碍存在紧密联系。

关键词

阿尔茨海默病，抑郁，炎症因子，脑源性神经营养因子

Correlation between Serum Markers and Cognition in Alzheimer’s Disease Patients with Depression

Xiaojing Lei1, Xiuli Jiang2, Jing Wang3, Jiamei Li2, Jiaping Zheng2*

1School of Clinical Medicine, Weifang Medical University, Weifang Shandong

2Department of Neurology, People’s Hospital of Rizhao, Rizhao Shandong

3Department of Rehabilitation, Lishui Municipal Central Hospital, Lishui Zhejiang

Received: Aug. 21st, 2022; accepted: Sep. 15th, 2022; published: Sep. 22nd, 2022

ABSTRACT

Objective: To analyze the expressions of serum brain-derived neurotrophic factor (BDNF) and inflammatory factors in Alzheimer’s disease patients with depression and their correlation with cognitive function. Methods: A total of 65 Alzheimer’s disease patients were selected as the research group, divided into Alzheimer’s disease group and Alzheimer’s disease with depression group according to whether or not with depression, and 45 healthy subjects were selected as the control group during the same period. The subjects’ cognitive function was assessed using the Mini-Mental State Examination Scales (MMSE). Serum levels of BDNF, IL-1β, IL-6 and TNF-α were detected in all subjects. Results: Compared with the control group and Alzheimer’s disease group, the serum BDNF in the Alzheimer’s disease with depression group was significantly decreased, and the serum IL-1β, IL-6 and TNF-α were significantly increased, and the differences were statistically significant (P < 0.05). The MMSE score in Alzheimer’s disease group was negatively correlated with serum IL-6 level (r = 0.481, P < 0.05), but not significantly correlated with serum IL-1β, TNF-α and BDNF levels (r = −0.194, −0.212, 0.324, P > 0.05). The MMSE score in Alzheimer’s disease with depression group was negatively correlated with serum IL-1β, IL-6 and TNF-α levels (r = −0.469, −0.603, −0.499, P < 0.05), and positively correlated with serum BDNF (r = 0.738, P < 0.05). Serum BDNF in Alzheimer’s disease group was negatively correlated with IL-6 (r = −0.497, P < 0.05), but not significantly correlated with IL-1β and TNF-α (r = −0.233, −0.087, P > 0.05). The serum BDNF level in Alzheimer’s disease with depression group was negatively correlated with the levels of IL-1β, IL-6 and TNF-α (r = −0.426, −0.741, −0.481, P < 0.05). Conclusion: Serum BDNF in patients with Alzheimer’s disease and depression may have a certain correlation with inflammatory factors, and may be closely related to cognitive dysfunction.

Keywords:Alzheimer’s Disease, Depression, Inflammatory Factors, BDNF

Copyright © 2022 by author(s) and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

http://creativecommons.org/licenses/by/4.0/

1. 引言

阿尔茨海默病(Alzheimer’s disease, AD)是一种以进行性认知功能障碍为临床表现的神经退行性疾病，中国60岁以上人群痴呆患病率为6%，约1500万，其中AD患病率为3.9%，约1000万 [1]，给社会和家庭带来了沉重的负担。一些痴呆患者会伴随各种精神症状 [2]，其中抑郁症状较为常见。越来越多的证据表明常规抗抑郁药对与AD相关的抑郁症无效 [3]，因此迫切需要了解AD相关抑郁的神经生理学机制，来指导进一步的治疗。有学者提出，AD和抑郁症可能存在相似的生理学机制 [4]，两者均有神经炎症反应的存在和脑源性神经营养因子(Brain Derived Neurotropic Factor, BDNF)的降低 [5]。已经注意到AD患者IL-1β、IL-6和TNF-α等炎症因子普遍升高，IL-6和TNF-α也被认为与抑郁症密切相关 [6]，并通过刺激下丘脑–垂体–肾上腺皮质(HPA)轴来参与抑郁症的发生。因此，本研究旨在探究AD伴抑郁患者外周炎症因子和BDNF水平及其与认知的关系。

2. 资料与方法

2.1. 一般资料

选取2021年1月至2022年3月来我院就诊的65例AD患者。其中AD不伴抑郁的患者设为AD组，AD伴抑郁的患者设为AD + D组。纳入标准：1) 年龄55~80岁，性别不限；2) 符合美国国家衰老研究所(NIA)和阿尔茨海默病学会(AA)提出的“NIA-AA诊断标准”；3) Hachinski缺血分级评分 < 4分；4)能配合完成神经心理量表评估；5) 签署知情同意书。排除标准：1) 合并严重心脑血管疾病、肝、肾、甲状腺、肿瘤及其他系统性疾病；2) 近3个月内服用过影响代谢类的药物；3) 有药物成瘾、脑外伤、癫痫及其他原因所致的认知障碍及精神类疾病；4) 正在参与其它药物临床研究者。采用汉密尔顿抑郁量表对入组资料再次分组，汉密尔顿抑郁量表(HAMD) ≤ 7分为AD组，汉密尔顿抑郁量表(HAMD) > 17分为AD + D组；另选取同期健康体检者45例为NC组；采用简易智力检查量表(MMSE)评估所有受试者的认知功能。本研究经日照市人民医院伦理委员会审核通过(伦审号：2021-KY-伦审-33)，所有受试者均由本人或家属签署知情同意书。

2.2. 研究方法

2.2.1. 血清BDNF及炎症因子的检测

采集受试者清晨空腹肘静脉血3 ml，4℃下静置30 min，低温分离(4℃)后提取上清液至EP管内−80℃保存，采用酶联免疫吸附方法(ELISA)检测血清白细胞介素-1β (IL-1β)、白细胞介素-6 (IL-6)和肿瘤坏死因子-α (TNF-α)水平，试剂盒由深圳普门科技股份有限公司提供。同采用酶联免疫吸附方法(ELISA)检测血清BDNF的含量，试剂盒由武汉博士德生物工程有限公司提供，严格按照说明书进行操作。

2.2.2. 统计方法

采用SPSS25.0统计学软件进行数据处理，计数资料之间的比较采用卡方检验；计量资料以均数 ±标准差表示，多组间的比较采用单因素方差分析；各变量间关系采用Pearson相关分析。认为P < 0.05差异有统计学意义。

3. 结果

3.1. 一般临床资料比较

本研究共纳入AD患者65例，根据是否合并抑郁分为AD组和AD + D组，另选取同期健康体检者为NC组：① AD组，共35例，男18例，女17例；平均年龄(65.96 ± 9.02)岁；教育年限(6.23 ± 4.05)年；高血压12例(34.3%)；糖尿病5例(14.3%)；吸烟11例(31.4%)；饮酒9例(25.7%)。② AD + D组，共30例，男16例，女14例；平均年龄(65.63 ± 8.50)岁；教育年限(4.97 ± 3.87)年；高血压8例(26.7%)；糖尿病例(20.0%)；吸烟7例(23.3%)；饮酒5例(16.7%)。③ NC组，共45例，男25例，女20例；平均年龄(69.38 ± 7.89)岁；教育年限(5.89 ± 3.89)年；高血压15例(33.3%)；糖尿病9例(20.0%)；吸烟8例(22.9%)；饮酒7例(20.0%)。三组基线各项指标间差异均无统计学意义(均P > 0.05)。

3.2. 血清指标及MMSE评分比较

与NC组相比，AD组和AD + D组MMSE评分、血清BDNF均显著降低，血清IL-1β、IL-6和TNF-α均显著升高，差异有统计学意义(P < 0.001)。与AD组相比，AD + D组MMSE评分、血清BDNF均显著降低，血清IL-1β、IL-6和TNF-α均显著升高，差异有统计学意义(P < 0.001)。见表1。

Table 1. Comparison of serum index and MMSE score

表1. 血清指标及MMSE评分比较

注：BDNF：脑源性神经营养因子；IL-1β：白细胞介素-1β；IL-6：白细胞介素-6；TNF-α：肿瘤坏死因子-α；与正常组相比，*P < 0.05；与AD组比较，#P < 0.05。

3.3. MMSE评分与IL-1β、IL-6、TNF-α和BDNF水平的相关性分析

AD组MMSE评分与血清IL-6水平呈负相关(r = 0.481, P < 0.05)，与血清IL-1β、TNF-α和BDNF水平无显著相关性(r = −0.194, −0.212, 0.324, P > 0.05)。AD + D组MMSE评分与血清IL-1β、IL-6和TNF-α水平呈负相关(r = −0.469, −0.603, −0.499, P < 0.05)，与血清BDNF呈正相关(r = 0.738, P < 0.05)。见表2。

3.4. 血清BDNF水平与IL-1β、IL-6和TNF-α水平的相关性分析

AD组血清BDNF与IL-6呈负相关(r = −0.497, P < 0.05)，与IL-1β和TNF-α无显著相关性(r = −0.233、−0.087, P > 0.05)。AD + D组血清BDNF水平与IL-1β、IL-6和TNF-α水平呈负相关(r = −0.426、−0.741、−0.481, P < 0.05)。见表3。

Table 2. Correlation of MMSE score with IL-1β, IL-6, TNF-α and BDNF

表2. MMSE评分与IL-1β、IL-6、TNF-α和BDNF的相关性

Table 3. Correlation of BDNF with IL-1β, IL-6 and TNF-α

表3. BDNF与IL-1β、IL-6和TNF-α的相关性

4. 讨论

抑郁症是阿尔茨海默病(AD)的危险因素和早期临床表现 [7] [8]，大量研究提示AD和抑郁相关，且炎性反应在其病理生理机制中起着关键作用 [4] [5]。炎症反应是AD的发病机制之一，AD患者大脑中存在大量活化的小胶质细胞，参与重要的生理作用，如突触发生、突触可塑性和神经元支持，但当反应过度时，会诱导促炎神经胶质表型的转变，导致促炎因子的持续产生 [9]；细胞炎症因子可以通过加剧炎症反应或者氧化应激障碍等促进神经元的凋亡、神经纤维的损伤和β淀粉样蛋白的沉积，进而加剧AD的病情进展 [10]；当小胶质细胞衍生的炎症因子影响AD相关脑区如前额叶皮层和海马的功能时，可能导致AD患者出现抑郁症状 [4] [5]。

有文献表明IL-1β、IL-6和TNF-α在AD患者和抑郁症患者体内均显著升高 [11] [12] [13]，本研究发现AD组外周血IL-1β、IL-6和TNF-α水平较NC组显著升高，而AD + D组外周血IL-1β、IL-6和TNF-α水平较AD组显著升高，与既往的研究一致 [13]，这提示伴有抑郁的AD患者外周免疫系统被激活，炎症因子可能过度释放。已有研究证实外周免疫系统激活和促炎细胞因子水平升高可导致的大脑情感和认知功能的改变，炎症反应可以通过刺激下丘脑–垂体–肾上腺(HPA)轴，引起糖皮质激素的增高 [14]，而血液循环中高浓度的糖皮质激素会导致海马神经元发生和树突的减少，并增加神经元对氧自由基和β淀粉样蛋白的脆弱性，这些均可能导致情绪障碍和认知障碍的发生 [15]。另外，有研究表明，重度抑郁症患者外周炎症因子升高，可能是引起抑郁的慢性压力激活外周免疫系统、影响小胶质细胞的活性，从而导致促炎因子、白介素和趋化因子的释放 [4]。此外，血脑屏障的损伤可导致外周炎症因子渗透到中枢神经系统 [16]，进而增强神经炎症，导致组织损伤。本研究发现，AD + D组MMSE评分较AD组显著降低(P < 0.05)，因此，在本研究背景下，我们推测抑郁症患者可能通过炎症反应来促进AD的进展，加重AD患者的认知障碍损伤程度。随后我们分析了AD组和AD + D组MMSE评分与血清BDNF、IL-1β、IL-6和 TNF-α水平的相关性。我们发现AD组MMSE评分与血清IL-6水平呈负相关，与IL-1β、TNF-α、BDNF水平无显著相关性，这表明IL-6与AD患者的认知障碍严重程度呈正相关，与之前的研究一致 [17]。而AD + D组MMSE评分与血清IL-1β、IL-6、TNF-α水平呈负相关，与BDNF水平呈正相关，表明AD伴抑郁患者的认知障碍严重程度可能与IL-1β、IL-6、TNF-α水平呈负相关，与BDNF水平呈正相关 [18]。有研究表明，炎症引起的BDNF减少可能导致长期记忆和突触可塑性破坏，且炎症因子与BDNF有一定的相关性 [19] [20]，因此，我们进一步探索了AD组和AD + D组血清BDNF水平与IL-1β、IL-6、TNF-α水平的相关性。

BDNF是中枢神经系统中分布最广泛的神经营养因子，对神经元的发育和正常生理功能起重要作用，可调节突触的传递和可塑性，促进树突和轴突的生长，因此BDNF对大脑的发育至关重要，在学习和记忆中发挥重要的生理功能，提高BDNF水平可以对认知功能包括记忆和学习产生一定的影响 [21] [22]。除此之外，BDNF还可以通过突触可塑性的破坏引起抑郁症，是抑郁症及一些心理障碍疾病的生物学标志物 [23]。Curto [24] 等认为AD伴抑郁患者血清BDNF水平与AD患者相比并无显著差异。本研究检测到AD + D组血清BDNF较AD组显著降低，炎症因子水平较AD组显著升高，这与Curto等人的研究并不一致。AD + D组血清BDNF水平除了与血清IL-6水平呈正相关外，还与血清IL-1β、TNF-α水平呈负相关，这在AD组中并未体现。我们猜测，炎症介质水平的升高会降低BDNF的表达 [20]，这也许可以解释为什么我们的结果与既往的研究有差异。Cortese [19] 等研究发现，当大脑中的IL-1受体被选择性拮抗剂阻断时，mBDNF和磷酸化的TrkB将不再减少，这表明IL-1可以调控mBDNF水平；而在外周神经损伤导致的记忆缺陷中，TNF-α的过量产生可调节BDNF的表达 [25]；也有文献表明，PolyI:C诱导的神经炎症反应可使炎症因子(如IL-1β、TNF-α)增加并使BDNF和TrkB的表达下降 [26]；这些均提示炎症因子对BDNF水平有一定的调控能力。AD伴抑郁患者血清IL-1β、IL-6、TNF-α水平的升高和BDNF水平的下降均与MMSE评分密切相关，显示出抗炎药对AD伴抑郁患者的治疗前景。AD伴抑郁患者中血清BDNF与IL-1β、TNF-α存在一定相关性，这在不伴有抑郁的AD患者中并未体现，因此，血清BDNF和IL-1β、TNF-α之间的联系值得我们进一步探索，这在缺乏针对性治疗AD伴抑郁患者的情况下，为这部分患者的临床治疗提供一个新的思路。

综上所述，AD伴抑郁患者血清BDNF水平下降、炎症因子水平升高，均与认知存在紧密联系，提示BDNF和炎症因子可能参与AD伴抑郁的病理过程。有效调控BDNF和炎症因子水平，或对AD伴抑郁患者的治疗有着重要意义。

但是本研究仍有一定的局限性，首先，本研究测量的为血清中的标志物，并未进行脑脊液中相关指标的检测；其次，本研究为横断面研究并未进行跟踪随访，且样本量较小，仍需大样本、前瞻性研究等证实。

文章引用

雷小晶,江秀丽,王 晶,李加梅,郑加平. 阿尔茨海默病伴抑郁患者血清指标与认知的相关性
Correlation between Serum Markers and Cognition in Alzheimer’s Disease Patients with Depression[J]. 临床医学进展, 2022, 12(09): 8640-8646. https://doi.org/10.12677/ACM.2022.1291248

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    27. NOTES

    *通讯作者。

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