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Chinese Journal of Alzheimer's Disease and Related Disorders

Abbreviation (ISO4): Chinese Journal of Alzheimer's Disease and Related Disorders      Editor in chief: Jun WANG

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Chinese Journal of Alzheimer's Disease and Related Disorders >

2021 , Vol. 4 >Issue 3: 231 - 236

DOI: https://doi.org/10.3969/j.issn.2096-5516.2021.03.012

Research Articles

Quantifying Extrapyramidal Iron Deposition in Patients with Alzheimer's disease using Quantitative Susceptibility Mapping

  • DONG Jun-yi ,
  • LIU Yang-ying-qiu ,
  • GAO Bing-bing ,
  • TIAN Shi-yun ,
  • SONG Qing-wei ,
  • MIAO Yan-wei
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  • Department of Radiology, First Affiliated Hospital of Dalian Medical University, DaLian Liaoning 116011, China

Received date: 2021-05-13

  Revised date: 2021-06-28

  Online published: 2021-09-25

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Abstract

Objective: To quantitative the iron deposition of extrapyramidal nuclei in patients with Alzheimer's disease (AD) by quantitative susceptibility mapping(QSM) and to analyze the correlation between magnetic sensitivity values(MSV) and clinical laboratory indicators and cognitive scores. Methods: Fifty-nine patients with AD (AD group) and 22 aged volunteers without cognitive impairment (CON group) underwent routine MRI and ESWAN examination. SPIN software was used for image post-processing. MSV of bilateral head of caudate nucleus(HCN), globus pallidus(GP), putamen(PUT), thalamus(THA), red nucleus(RN), substantia nigra(SN) and dentate nucleus(DN) were measured respectively, and correlation analysis was conducted with cognitive scores and general data. The area under ROC curve was used to evaluate the effectiveness of MSV values in diagnosing AD. Results: The MSV of all nuclei in AD group were higher than CON group, and there were significant differences in bilateral HCN, bilateral GP, bilateral THA, right RN, right SNand left DN (P< 0.05). The MSV of bilateral HCN and bilateral PUT had a significant negative correlation with the MMSE score. There was a significant negative correlation between the MSV of bilateral HCN, bilateral PUT and MoCA scores. The MSV of bilateral HCN, bilateral PUT had a significant negative correlation with CDT scores (all P< 0.05). The MSV of right GP was positively correlated with the course of the disease; The MSV of bilateral THA were inversely related to triglyceride content(all P< 0.05). ROC analysis showed that MSV of the left GP had the largest AUC. Conclusion: Increasing iron deposition of extrapyramidal nuclei in AD patients may affect cognitive status.

Key words： Alzheimer's disease; extrapyramidal; iron deposition; quantitative magnetic susceptibility; magnetic sensitivity values

Cite this article

DONG Jun-yi , LIU Yang-ying-qiu , GAO Bing-bing , TIAN Shi-yun , SONG Qing-wei , MIAO Yan-wei . Quantifying Extrapyramidal Iron Deposition in Patients with Alzheimer's disease using Quantitative Susceptibility Mapping[J]. Chinese Journal of Alzheimer's Disease and Related Disorders, 2021 , 4(3) : 231 -236 . DOI: 10.3969/j.issn.2096-5516.2021.03.012

阿尔茨海默病(Alzheimer's disease, AD)是常见的神经变性疾病,其特征在于逐渐进展的认知功能障碍以及行为改变。AD的神经病理特征包括神经原纤维缠结(neurofibrillary tangles, NFTs)导致的神经细胞丧失以及β淀粉样蛋白(β-amyloid protein, Aβ)在脑内沉积形成神经炎性斑块[1]。
铁代谢异常被认为是AD早期发病的重要标志之一。然而,铁沉积与AD病理之间的联系尚未确定[2]。有研究对AD患者进行尸检后发现脑内老年斑和神经纤维缠结中有过多铁沉积,Aβ斑块和神经原纤维缠结具有活性铁,是催化反应的重要部位[2],以上均提示铁参与了AD的病理生理过程[3]。此外,铁结合蛋白如转铁蛋白、铁蛋白和铁调节蛋白2(iron regulatory protein 2, IRP2)被证实与AD中神经变性有关[2]。定量磁敏感成像(quantitative susceptibility mapping, QSM)是新兴的MRI技术,对组织之间的磁化率差异十分敏感。近年来有人提出,与其他MR方法相比,QSM在检测脑铁含量方面具有最高的灵敏度和特异性[4,5]。利用QSM对脑铁定量已经较广泛应用于临床研究,如多发性硬化[6]、AD[7,8]、帕金森病(Parkinson's disease, PD)等[9]。
本研究旨在利用QSM磁化率对AD患者锥体外系核团铁沉积进行量化评估,并进一步分析其影响因素及对认知功能的影响,以期对AD患者锥体外系核团铁沉积的变化机制有所了解,找到监测AD患者病情演变的影像学指标。

1 材料与方法

1.1 一般资料

2015年9月至2018年12月大连医科大学附属第一医院临床诊断为AD的患者59例（AD组）,其中男性21例,女性38例;年龄在53~85岁,平均年龄(71.12±9.21)岁;受教育程度：文盲2人,小学11人,初中21人,高中及中专17人,大专及大学本科8人;病程0.5~14年,平均病程(3.68±2.42)年。本组患者符合美国国立神经及交流疾病研究所和阿尔茨海默病及相关疾病协会(NINCDS-ADRDA)标准（修订版）[10],并除外其它病因导致的痴呆,无神经功能缺损表现,无合并严重内科急症,无烟、酒精或药物依赖史。同时收集了22名年龄及性别均与AD组相匹配的无认知障碍的老年人作为对照组（Controls, CON组）;其中男性12例,女性10例;年龄在51~91岁,平均年龄(67.86±8.60)岁;受教育程度：文盲1人,小学7人,初中4人,高中及中专8人,大专2人。本组患者MRI扫描脑白质高信号均符合脑白质损害评定量表(Fazekas-scale)2级以下或脑内存在≤2个静止性腔隙性脑梗死。AD组和CON组均为右利手。同时收集所有病例入院时的临床资料及实验室检查结果,包括年龄、性别、病程、受教育程度、血压情况、总胆固醇、甘油三酯、高密度脂蛋白(high-density lipoprotein, HDL)、低密度脂蛋白(low-density lipoprotein, LDL)及同型半胱氨酸含量。本研究获得医院伦理委员会审核批准。

1.2 设备和扫描参数

所有受试者采用美国GE Signa HDXT 3.0T超导MRI扫描仪,取仰卧位,采用8通道相控阵头表面线圈,行常规MRI序列及ESWAN序列扫描。所有扫描序列参数设置相同。扫描范围覆盖全脑,从上颅顶开始,逐一向下,至枕骨大孔水平,为保证扫描结果具有可比性,选择统一的解剖学定位标志,即以前-后联合连线为扫描基线。具体扫描序列及参数如表1所示。
表1 MRI扫描参数

Tab. 1 MR scanning parameters

名称 TR(ms) TE(ms) 层厚(mm) 层间距(mm) FOV(cm×cm) 矩阵 翻转角（°） 带宽（kHz）
T1WI 2500 25 6 1 22×19.8 320×256 / 31.25
T2WI 5000 118 6 1 22×19.8 320×256 / 31.25
T2 Flair 9000 172 6 1 22×22 256×192 / 31.25
ESWAN 36 3.6;7.8;11.9;16.1;
20.3;24.4;28.6;32.8		 1 0 24×24 256×256 20 31.25

1.3 图像后处理

将ESWAN原始数据以DICOM格式保存及传输至个人电脑,采用美国韦恩州立大学馈赠的核磁共振信号处理(signal processing in nuclear magneticresonance, SPIN)软件进行图像后处理。首先利用SPIN软件中SWIM(susceptibility weighted imaging mapping, SWIM)模块对ESWAN原始相位图和幅度图进行进一步处理,获得QSM。处理步骤为：(1) 进行颅骨剥离及算法,采用复合阈值消除相位图上非组织区域的伪影：BET=0.2;(2)相位展开;(3)阶段质量图：颗粒大小=6,阈值=0.05; (4)背景场去除：采用复杂谐波伪影去除法(sophisticated harmonic artifact reduction for phase data, SHARP);(5)对高通滤波相位图的傅里叶转换过程中施加标准反转滤波。

1.4 感兴趣区设定

采用SPIN软件定量测量磁敏感图中感兴趣区(region of interest, ROI)的磁敏感值(magnetic sensitivity value, MSV)。ROI包括双侧尾状核头（图A）、苍白球（图A）、壳核（图A）、丘脑腹外侧核（图A）、红核（图B）、黑质（图B）及齿状核（图C）。各个核团ROI的选择标准：参考各个核团的解剖结构,同时避开因核团周围铁的双极效应产生的高信号,根据QSM上显示的核团边界的最大层面,沿着核团边缘手动勾画ROI,在同一位置的三个连续层面测量,取平均值,因部分患者的丘脑腹外侧核解剖结构较小,则在显示的最大层面测量三次,取平均值。

1.5 认知评分量表

由一名神经内科副主任医师对所有AD患者进行神经功能及认知功能评分,包括简易智力状态检查量表(mini-mental state examination, MMSE)评分、蒙特利尔认知评估量表(montreal cognitive assessment, MoCA)评分、画钟试验(clock drawing task, CDT)评分及日常生活能力量表(activity of daily living scale, ADL)评分。
图1 灰质核团ROI选取示意图。图A：从前至后分别为尾状核头（红色）、壳核（绿色）、苍白球（紫色）、丘脑腹外侧核（橙色）;图B：内侧为红核（蓝色）、外侧为黑质（亮黄色）;图C：齿状核（粉红色）。

Fig.1 Gray matter nucleus ROI selection schematic diagram. A: HCN (red), PUT (green), GP (purple), THA (orange). B: RN (blue) and SN (bright yellow). C: DN (pink).

1.6 统计学分析

应用社会科学统计软件包(statistics package for social science, SPSS)17.0版进行数据分析,计量资料符合正态分布者以均数±标准差(x±s)表示,非正态分布者以中位数（ML,QU）表示,计数资料以百分数表示;所有数据是否符合正态分布采用One-Sample K-S检验。因AD组与CON组病例相差较多,两组间所有MSV值及一般资料（年龄、受教育程度、总胆固醇、甘油三酯、高密度脂蛋白、低密度脂蛋白、同型半胱氨酸）比较采用非参数检验。对AD组MSV值与MMSE评分、MoCA评分及ADL评分进行Pearson相关分析, AD组MSV值与CDT评分进行Spearman相关分析, AD组一般资料与MSV值进行Pearson相关分析;AD组一般资料与各认知评分进行Spearman相关分析,计算相关系数;相关性用热点图表示。采用ROC曲线下面积(Area under Curve, AUC)评价各诊断AD的效能,各MSV值的AUC间差异采用Delong检验。以P <0.05为差异具有统计学意义。

2 结果

2.1 AD组与CON组间锥体外系核团MSV值比较

AD组各核团MSV值均高于CON组（图2）,但在双侧尾状核头、双侧苍白球、双侧丘脑腹外侧核、右侧红核、右侧黑质、左侧齿状核具有统计学差异（P<0.05,详见表2）。
图2 AD组及CON组各核团的MSV值比较。标★者为两组间差异具有统计学意义（P<0.05）。

Fig.2 Comparison of MSV values of nuclei in AD and CON groups. Marked with "★" means difference between the two groups was statistically significant (P < 0.05).

表2 AD组与CON组各脑灰质核团MSV值比较（x±s）

Tab. 2 Comparison of MSV values of gray matter nuclei in AD and CON group(x±s)

部位 AD组 HC组 P值
Left-HCN 87.95±18.14 79.28±15.86 0.013①
Right-HCN 92.22±25.06 77.61±20.75 0.018①
Left-GP 142.85±44.28 119.72±27.06 0.036①
Right-GP 148.19±40.73 125.00±28.07 0.011①
Left-PUT 93.93±29.16 89.39±23.91 0.420
Right-PUT 100.02±28.46 91.97±21.45 0.531
Left-THA 42.42±18.94 34.29±8.33 0.033①
Right-THA 52.63±22.97 39.47±9.91 0.019①
Left-RN 98.34±31.95 83.32±14.85 0.071
Right-RN 101.44±33.63 85.36±20.18 0.035①
Left-SN 139.11±34.86 128.50±32.09 0.167
Right-SN 138.66±36.76 119.81±27.86 0.035①
Left-DN 103.02±31.77 88.21±26.45 0.039①
Right-DN 103.82±35.80 88.58±31.65 0.085

Note: Marked with “①” were statistically significant (P < 0.05).

2.2 AD组锥体外系核团MSV值与各认知评分间相关性

双侧尾状核头(rL=-0.488, P=0.000; rR=-0.436, P=0.001)、双侧壳核(rL=-0.290, P=0.027; rR=-0.347,P=0.008)的MSV值与MMSE评分间具有负相关性,其中双侧尾状核头、右侧壳核MSV值与MMSE评分间为低度负相关（图3A）;双侧尾状核头(rL=-0.388, P=0.003; rR=-0.438, P=0.001)、双侧壳核(rL=-0.317, P=0.015; rR=-0.348, P=0.007)与MoCA评分间具有低度负相关性（图3B）;双侧尾状核头(rL=-0.366, P=0.007; rR=-0.538, P=0.000)、双侧壳核(rL=-0.343, P=0.011; rR=-0.366, P=0.007)与CDT评分间具有负相关性,其中右侧尾状核头MSV值与CDT评分间为中度负相关,左侧尾状核头、双侧壳核为低度负相关（图3C）;双侧各核团MSV值与ADL评分间无显著相关性(P>0.05)。
图3 A为AD组各脑灰质核团MSV值与MMSE评分间相关性分析热点图;B为AD组各脑灰质核团MSV值与MoCA评分间相关性分析热点图;C为AD组各脑灰质核团MSV值与CDT评分间相关性分析热点图;D为AD组各核团MSV值与各一般资料相关性分析热点图。标“*”者为两者存在相关性。

Fig.3 A shows the hot spot of correlation analysis between MSV values of gray matter nuclei and MMSE score in AD group. B: The hot spot diagram of correlation analysis between MSV values of gray matter nuclei and MoCA score in AD group; C: The hot spot diagram of correlation analysis between MSV values of gray matter nuclei and CDT score in AD group; D: The hotspot diagram of correlation analysis between MSV values of each nucleus in AD group and general data. Those marked with "*" indicate correlation between the two.

2.3 AD组锥体外系核团MSV值与一般资料相关性分析

右侧苍白球的MSV值与病程正相关(r=0.302, P=0.049)（图3D）;双侧丘脑腹外侧核的MSV值与甘油三酯含量负相关(rL=-0.347,P=0.008;rR=-0.280, P=0.033)（图3D）;各核团与总胆固醇、HDL、LDL及同型半胱氨酸含量均无相关性(P>0.05)。

2.4 锥体外系核团MSV值诊断AD的效能

ROC曲线显示,在各核团中,右侧苍白球MSV值的AUC最大,为0.685,在阈值为139.29时,敏感度为62.7%,特异度为72.7%（图4）。经Delong检验得出,各核团ROC曲线的AUC间差异无统计学意义(P>0.05)。
图4 ROC曲线图。紫色为右侧苍白球MSV值的曲线。

Fig.4 ROC curve. The curve of the MSV of right GP(purple).

3 讨论

3.1 QSM及MSV值与铁沉积的关系

QSM是一种测量物体的磁化率分布的非侵入式磁共振成像技术,是一种基于磁敏感成像(susceptibility weighted imaging, SWI)发展起来的一种新成像方法和技术,它能够定量测量局部组织的磁化率特性。
脑组织磁化率的变化可以有几个不同的生物物理起源。目前认为灰质的磁化率主要由铁蛋白大分子中储存的组织铁主导[11]。铁蛋白复合物是铁的球状储存蛋白,具有顺磁性,因此铁可以增加组织的磁化率[12]。Bilgic等在正常对照组中进行的实验表明,QSM评估的组织磁敏感性与铁浓度之间存在较高相关性[13]。Haacke等也证实QSM可以定量计算磁化率[14],且其与脑铁浓度有很强的正相关性。因此,我们有充分的理由相信,灰质核团的MSV值越高,铁沉积越多。

3.2 AD锥体外系核团铁沉积改变病理机制及临床意义

脑铁水平的改变是AD患者的重要特征,但是,目前尚不清楚具体的大脑结构在何处发生变化。本研究对锥体外系不同核团之间的铁沉积进行了比较,结果显示AD组各核团铁沉积均高于CON组,但仅在双侧尾状核头、双侧苍白球、双侧丘脑腹外侧核、右侧红核、右侧黑质、左侧齿状核差异具有统计学意义,提示AD患者锥体外系核团存在局限性的铁含量增多,并且有理由相信皮质-纹状体系及皮质-脑桥-小脑系核团均存在病理性损伤。Moon 等及Acosta-Cabronero 等研究均发现AD患者尾状核及壳核的铁沉积明显增多[8,15]。此外,Zhu等研究证实,与年龄和性别匹配的健康对照组相比[16],AD患者海马、顶叶皮层、尾状核和壳核以及小脑齿状核中的铁含量明显更高。结合既往对于AD患者的研究[17],提示铁稳态的破坏可能与AD的病理生理相关,并且可能发生在AD的早期。AD组与CON组铁沉积存在差异的可能原因包括：1）脑中铁的积累与神经原纤维缠结和淀粉样斑块密切相关;2）铁还可以影响激酶活性,干扰tau蛋白磷酸化从而加重斑块聚集,导致小胶质细胞激活,进一步加重AD患者脑内铁沉积[18];3）研究显示过氧化物也可以导致小胶质细胞释放储存的铁,使得AD患者脑内的铁沉积进一步加重[19];（4）AD患者中存在线粒体的结构功能障碍,其溶酶体的降解也可导致铁含量的增加[20]。本研究结果中铁沉积的量存在区域性差异,造成这种差异的原因可能为,在AD状态下脑内各核团铁沉积的病理生理机制不同,不同结构对铁的需求量亦不同。随着年龄的增长,铁在中脑和基底神经节的沉积速度不同,随之铁沉积的量也不同[21]。本研究得出,在各核团中,右侧苍白球MSV值的AUC最大,是鉴别AD患者与正常人的最佳指标。
许多研究已经报道了AD患者皮质特定区域内存在铁沉积[22⇓~24]。有学者认为这种沉积在AD和其他神经变性疾病中具有病理意义[22,23]。在AD脑的尸检研究中,报道了皮质铁沉积与额叶皮质Aβ和tau病理负荷以及Braak评分之间的高度相关性[25],因而在以后的工作中,我们将对脑皮层铁沉积的改变模式进行进一步的研究,并探讨核团及脑皮层的铁沉积改变是否存在一定的关联性。
Sun等利用QSM检测皮层下血管轻度认知障碍患者脑铁沉积[26],并研究脑铁沉积与认知障碍的严重程度之间的相关性,发现血管轻度认知障碍患者在双侧海马和右侧壳核内的磁敏感值升高;右侧海马的磁敏感值与记忆z-分数呈负相关,与语言z-分数呈正相关,右壳核磁敏感值与注意执行z-score呈负相关。并且,Liu等人利用SWI的高通滤波相位图像研究血管性痴呆患者脑铁沉积及其与认知障碍严重程度的相关性[27],结果显示血管性痴呆患者双侧海马、尾状核头、壳核、右侧苍白球和左侧黑质相位值明显增加,并且左侧海马、右侧尾状核头的相位值与神经心理评分密切相关,以上研究均显示脑铁沉积可能是血管性痴呆的一个生物标志物,在其病理生理机制中发挥重要作用,并在作为认知的生物标志物方面具有临床意义,但血管性认知障碍在AD的诊断中是无法回避的,因此在后续的研究工作中,我们也将进一步利用磁化率的检测对两者进行鉴别。
此外,本研究探讨了QSM评估的锥体外系核团MSV值与脑认知功能相关评分之间的相关性,结果显示双侧尾状核头、双侧壳核的MSV值与MMSE、MoCA及CDT评分间均具有负相关性,即MSV值越高,铁沉积越多,MMSE评分、MoCA评分及CDT评分越低,认知水平越差;Du等研究发现MMSE评分和MoCA评分的下降与左侧尾状核磁化率的增加显著相关[28];Wang等利用SWI分析AD患者铁沉积与MMSE评分之间的相关性[29],他们发现磁化率与双侧苍白球的MMSE评分呈负相关;Zhu等研究也证实AD患者顶叶皮质[16]、海马、壳核的铁浓度与认知功能损害程度呈正相关;以上均与本研究的结果一致。由此我们推测双侧尾状核头、双侧壳核中的铁含量与AD患者认知功能下降的严重程度相关,而双侧尾状核头及双侧壳核的MSV值有可能成为基于MR成像的判断AD严重程度的生物标志物。苍白球、壳核和尾状核头是构成锥体外系核团的主要结构,在AD患者的认知功能中发挥重要作用。铁负荷过多以及随后在这些核团中自发释放的神经毒性游离铁可能导致神经元死亡和记忆衰退。此外,双侧尾状核头和壳核损害可引起包括认知功能障碍在内的一系列功能障碍,这也可能是双侧尾状核头、双侧壳核铁含量与认知功能相关的原因。右侧苍白球的MSV值与病程正相关,说明病程越长,右侧苍白球铁沉积量越多,这因为AD的发展是一个不可逆的病理过程,因此,病程越长,病情越严重,而核团的铁沉积与病情的恶化呈正相关。双侧丘脑腹外侧核的MSV值与甘油三酯含量负相关,说明甘油三酯含量越高,双侧丘脑腹外侧核的铁沉积越低。

4 局限性

4.1 本研究为回顾性研究,样本均为住院患者,多因症状较明显时方来院就诊,也因此病程均比较长,症状相对较重,而轻度认知障碍的患者较少,未纳入本研究,还需要进一步分析。
4.2 样本量较小,在以后的研究中会相应增加样本量。
4.3 本研究对象均为老年人,灰质核团中除了铁的沉积,还存在生理性钙盐的沉积,目前的研究手段尚无法区分两者,这将会对研究的准确性产生一些影响。

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