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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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Evaluation on acupuncture treatment in mild Alzheimer’s disease by 3D-ASL

  • MA Tian ,
  • LI Hui ,
  • FAN Xiang ,
  • NI Hong ,
  • QI Zhigang ,
  • LI Kuncheng
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  • Department of Radiology, Xuanwu Hospital, Capital Medical University, Beijing Key Lab of MRI and Brain Informatics

Received date: 2019-07-18

  Revised date: 2019-07-26

  Online published: 2019-12-25

Abstract

Objective: To investigate the changes of cerebral blood flow perfusion in patients with mild Alzheimer’s disease (AD) by three-dimensional arterial spin labeling (3D-ASL), and to evaluate the therapeutic effect of ad acupuncture at “siguan point”. Methods: Twenty mild AD patients (AD group) diagnosed by the neurological memory disorders clinic of Xuanwu Hospital, Capital Medical University from June 2016 to April 2018 and twenty normal volunteers matched with age, gender and education level of AD group were recruited as control group. 20 patients were randomly divided into two groups: “siguan" conventional acupuncture group (10 patients), and “siguan" sham acupuncture group (10 patients). All subjects underwent 3D-ASL scanning to get relative cerebral blood flow data at the time of enrollment, and neuropsychological scale examination was conducted. 3D-ASL scanning was performed again after intervention of acupuncture. The images were processed and analyzed using the software package SPM12. Results: In the “siguan" conventional acupuncture group, 2 cases were excluded because of the significant head movement artifacts. ①There was no statistical difference in age, gender and level of education between the mild AD group and NC group (P> 0.05). The scores of MMSE and MoCA in mild AD group was significantly lower than that of NC group; ② Compared with the NC group, decreased perfusion areas were observed in the bilateral precuneus and posterior cingulate cortex in the mild AD group (cluster number was 878, P< 0.05); (3) ③After 6 months of acupuncture intervention, 3D-ASL was reexamined. It was found that, the perfusion of left anterior cuneiform lobe and posterior cingulate cortex was increased, in addition, the perfusion of bilateral middle frontal cortex, superior frontal cortex, putamen nucleus, caudate nucleus, rectus muscles, left inferior frontal cortex, insula, right thalamus, superior temporal cortex central sulcus were also increased in the conventional acupuncture group. while that of the shallow acupuncture group was decreased in corresponding areas.(cluster number was 11 279, P< 0.05). Conclusion: 3D-ASL discovered that the perfusion of bilateral anterior cuneiform lobe and posterior cingulate cortex was decreased in mild AD and acupuncturing “siguan" point increased the cerebral perfusion (including the original hypoperfusion brain area) in mild AD patients.

Cite this article

MA Tian , LI Hui , FAN Xiang , NI Hong , QI Zhigang , LI Kuncheng . Evaluation on acupuncture treatment in mild Alzheimer’s disease by 3D-ASL[J]. Chinese Journal of Alzheimer's Disease and Related Disorders, 2019 , 2(4) : 481 -487 . DOI: 10.3969/j.issn.2096-5516.2019.04.003

阿尔茨海默病(Alzheimer’s disease, AD)属于神经退行性疾病,临床隐匿发病,通常以记忆力减退为首发症状,病情逐渐加重,最终导致痴呆,是老年痴呆的最常见类型[1]。AD的临床表现复杂,除记忆、认知、语言障碍及人格改变等症状外,还可伴发精神症状,使其早期诊断、预后判断极为困难。目前AD发病后尚无治愈手段,新药研发均以失败而告终,只能寄希望于早期诊断,早期干预,以延缓AD病情的进展。
除脑脊液Aβ和τ蛋白含量检验外,寻找新的影像学诊断指标是当前AD研究的热点,而脑磁共振成像(magnetic resonance imaging, MRI)和正电子发射体层显像(positron emission tomography, PET)已经不断取得进展,例如MRI脑结构测量显示海马萎缩是诊断AD的主要指标,FDG-PET显示脑葡萄糖代谢减低,Aβ斑块和τ蛋白显像也与腰穿脑脊液Aβ和τ蛋白含量检验相关,成为AD的重要诊断指标。有数学模型估计,仅对AD实现早期诊断,即可节省高达7.9万亿美元的医疗和护理费用[2]
本研究应用三维动脉自旋标记扫描评价轻度AD患者的脑血流灌注,并初步用于针刺治疗轻度AD的疗效评价。

1 资料与方法

1.1 研究对象

搜集2016年6月至2018年4月间20例就诊于首都医科大学宣武医院神经内科记忆障碍门诊,并诊断为轻度AD患者(AD组)和在社区招募的20例年龄、性别和受教育程度与之相匹配的正常老年人作为对照(normal control, NC)组。

1.1.1 轻度AD患者入组标准

年龄50~80岁,右利手。AD诊断符合美国国立脑老化研究所及阿尔茨海默病协会(National Institute on Aging-Alzheimer’s Association, NIA- AA)2011 年推出的阿尔茨海默病诊断标准,临床痴呆评定量表(clinical dementia rating, CDR)得分不大于1分。

1.1.2 轻度AD组患者排除标准

经神经内科系统检查、病史询问、实验室血液检查、MRI常规扫描排除甲减、维生素缺乏及缺血性脑血管病等其他原因所致痴呆,排除患有高血压、高血脂、糖尿病等基础疾病者。

1.1.3 正常老年人入组

无记忆障碍或认知能力下降等主诉,无神经和精神疾病史,常规头颅MRI检查无异常改变。简易精神状态量表(mini-mental state examination, MMSE)总分≥28分。

1.2 方法

每位被试的详细病史均由神经内科记忆门诊医生采集。神经心理学量表检查由同一名有多年量表测评工作经验的神经内科医师完成,检查时间与MRI检查大致接近;量表包括MMSE、蒙特利尔认知评估量表(montreal cognitive assessment, MoCA)、临床痴呆评定量表(clinical dementia rating, CDR)、Hachinski缺血量表、老年抑郁量表。至少2名神经内科医师综合被试的临床资料做出轻度AD的临床诊断。

1.2.1 针刺干预方法

将 20例轻度AD患者随机分为2组,每组 10例,分别接受常规针刺“四关穴”(常规针刺组)、针刺“四关穴”假穴(针刺假穴组)。两组均由同一名经验丰富的针灸医师进行手针针刺操作。

1.2.2 穴位选择

“四关穴”定位参照中华人民共和国国家标准《腧穴名称与定位》(GB /T12346-2006),即双侧合谷穴(LI4,在手背,位于第2掌骨桡侧的中点处)和双侧太冲穴(LR3,在足背,位于第1和2跖骨之间,跖骨底结合部前凹陷,或触摸到动脉搏动)。

1.2.3 针刺方法

在安静环境中进行针刺,针灸医师在针刺前取穴、消毒,采用1寸无菌银针(直径0.3 mm,长度25 mm)。(1)“四关穴”常规针刺:银针垂直刺入皮肤,进针至理想深度施以平补平泻的捻转手法,达到“得气”效果(被试有酸麻胀痛感、针灸医师感觉银针被裹紧),捻转银针频率为60次/min,持续捻转5 min,间歇1 min,留针共20 min; (2)针刺“四关穴”假穴:使用银针针尖刺入皮部,5 min后针灸医师再次轻触银针,无捻转动作,重复3次后取下银针,共计20 min; (3)针刺次数:每周3次,12次(即4周)为1个疗程,间歇2周,再继续下一个疗程,共4个疗程,累计6个月。

1.2.4 三维动脉自旋标记扫描

使用首都医科大学宣武医院超导型3.0T高场磁共振扫描仪(GE Discovery MR750)及8通道相控阵头线圈。三维动脉自旋标记(3D arterial spin labeling, 3D-ASL)扫描具体参数为:TR/TE=4 886 ms/10.5 ms, TI=2025ms,层厚3 mm, 240 mm视野,获取46层图像覆盖从顶部头皮至颅底范围。
所有被试均在入组时行MRI的3D-ASL 扫描,采集相对脑血流量(relative cerebral blood flow, rCBF)数据,常规针刺组和针刺假穴组经干预6个月后行3D-ASL复查。扫描过程中要求被试保持清醒状态,平卧于扫描仪内,尽可能保持头部静止不动。

1.2.5 数据预处理

通过3D-ASL序列扫描获得全脑灌注图像, MR仪器自带软件自动生成CBF图。采用第12版统计参数图(statistical parametric mapping, SPM)对所有被试rCBF图进行预处理,步骤包括空间标准化、数据归一化和平滑,将rCBF标准化至加拿大蒙特利尔神经研究所(Montreal neurological institute, MNI)标准脑空间上,且每个体素的CBF值均经过Z变换,用8mm窗宽的高斯核来平滑rCBF图像,最终得到每个被试预处理后的rCBF图像。

1.3 统计学处理

采用第16版统计产品与服务解决方案(Statistical Product and Service Solutions, SPSS)统计软件对轻度AD组和NC组的年龄、受教育年限、MMSE评分、MoCA评分均行独立样本t检验分析;常规针刺组和针刺假穴组患者6个月随访前后的MMSE和MoCA评分变化差值,采用独立样本t检验分析,以P< 0.05为具有统计学差异的阈值。
rCBF数据采用SPM进行统计分析。应用双样本t检验比较基线状态轻度AD和NC组的rCBF数据,观察轻度AD组脑血流灌注改变,差异有统计学意义的阈值定为P< 0.05, FWE校正的协变量为年龄、性别和受教育程度。采用2×2灵活因素设计(flexible factor design)比较常规针刺组与针刺假穴组治疗前后脑血流灌注改变的差异,探索针刺治疗对全脑血流的调节作用,阈值设定为P< 0.05, FWE校正。应用xjview软件将结果显示在MNI坐标系中,生成三维脑表面渲染图。

2 结果

常规针刺组有2例因头动伪影多而被去除,剩余8例数据纳入分析,10例针刺假穴组图像质量好。

2.1 轻度AD组与正常对照组的基本资料比较。

轻度AD组与NC组的年龄、性别、受教育年限均无统计学差异(P> 0.05),但MMSE评分、MoCA评分值的差异有统计学意义(P< 0.05)。与NC组相比,轻度AD组MMSE和MoCA评分值均显著降低,而MoCA评分值降低得更为显著(表1)。6个月后复查发现,常规针刺组和针刺假穴组MMSE评分和MoCA评分值与其基线比较,差异无统计学意义(P> 0.05)。
表1 轻度AD组与正常对照组的基本临床资料比较( $\bar{x}±s$
组别 例数 性别 年龄/岁 受教育年限/年 MMSE评分/分
MoCA评分/分
轻度AD组 20 6 14 70.0±8.3 13.7±3.0 21.3±4.2 17.5±4.4
正常对照组 20 7 13 67.2±6.2 12.5±2.6 28.9±0.8 26.3±2.1
t -1.243 -1.267 7.600 8.051
P 0.221 0.263 0.000 0.001

2.2 轻度AD组与正常对照组的相对脑血流比较

与NC组相比,轻度AD组的双侧楔前叶和后扣带回脑灌注减低(体素数目为987,P< 0.05),见表2图1
表2 轻度AD组rCBF降低脑区
脑区
(AAL)
左/右/双侧 MNI坐标/mm 簇大小 F
X轴 Y轴 Z轴
楔前叶 -6 -46 14 582 7.279 3
后扣带回 223
楔前叶 51
后扣带回 22
图1 轻度AD组与正常对照组脑灌注比较

注:蓝色和绿色区域为轻度AD组的rCBF值减低区,累及双侧楔前叶和后扣带回,以左侧为著。

2.3 常规针刺组针刺前后相对脑血流值的变化

常规针刺组行针刺干预6个月后复查3D-ASL,原低灌注脑区(即左侧楔前叶及左侧后扣带回)的灌注改善(rCBF值增加),此外,左侧距状裂周围皮层、舌回、梭状回、颞中回、颞下回、额上回、枕中回、枕上回、海马旁回、丘脑、海马、枕下回等区域的rCBF值亦增加,见图2
图2 常规针刺四关穴组rCBF值变化

注:红色区域为灌注增加(rCBF值增高)脑区,包括左侧楔前叶和后扣带回。

2.4 常规针刺组与针刺假穴组的相对脑血流变化比较

常规针刺组和针刺假穴组行针刺干预6个月后分别复查3D-ASL,两组检出部分存在灌注差异脑区,共3簇,簇1为右侧额中回、额上回、壳核、额下回、脑岛、尾状核、直回,簇2为左侧额中回、壳核、额上回、尾状核、直回及右侧丘脑,簇3为右侧颞上回、中央沟盖,见表3图3
表3 常规针刺组与针刺假穴组的rCBF差异脑区比较
序号 脑区(AAL) MNI坐标/mm 簇大小 F
X轴 Y轴 Z轴
簇1 右侧额中回、额上回、壳核、额下回、脑岛、尾状核、直回 34 62 16 7 141 689.092
簇 2 左侧额中回、壳核、额上回、尾状核、直回及右侧丘脑 -32 62 16 3 491 807.545
簇 3 右侧颞上回、中央沟盖 44 -18 6 647 662.307
图3 常规针刺组和针刺假穴组6个月后随访脑灌注差异

注:A-C图的红色和黄色区为常规针刺组与针刺假穴组的灌注差异脑区,分别对应表中簇1-簇3。

行事后分析发现,常规针刺组在前述簇1、簇2、 簇3区域(双侧额中回、额上回、壳核、尾状核、直回,左侧额下回、脑岛,右侧丘脑、颞上回、中央沟)脑灌注增加,针刺假穴组则见脑灌注减低(体素数目为11279,P< 0.05),见图4
图4 脑灌注差异脑区事后分析

注:A-C图对应簇1-簇3,簇1、簇2、簇3常规针刺组脑灌注增加、针刺假穴组脑灌注减低。

3 讨论

随着研究不断深入,尤其发现载脂蛋白E中冠心病易感基因型APOE4与AD发病有相关性,脑神经血管性机能损伤(如微血管减少、血脑屏障破坏等)已被确定是影响AD发生发展的一个重要因素[3]。有临床研究指出存在多重血管危险因素老年人患AD的风险显著高于无血管危险因素者[4]。有证据表明AD患者脑灌注改变早在临床症状出现之前、甚至在Aβ沉积或脑萎缩之前就已出现,这不仅提示血管因素在AD发病机制中的作用,还显示脑灌注成像作为临床前期诊断指标的应用价值。应用脑灌注成像探索血管因素与AD的关系,或许对其诊断及疗效评价均有所帮助[5-6]

3.1 动脉自旋标记技术在AD中的应用价值

脑灌注成像可以获取脑血流动力学特性相关参数,定量分析脑组织灌注情况,评价脑神经血管机能。AD发病有血管因素是一种共识,已有研究者发现AD患者脑血流灌注减低,且rCBF值与MMSE和MoCA相关[7-8]。AD不仅在前驱期至终末期持续存在脑灌注异常,且微血管系统损伤在疾病终末期可能造成更大影响[9]
3D-ASL灌注成像对动脉血中的质子进行标记,与借助外源性对比剂的灌注成像比较,无需对比剂,操作简便,其硬件要求低、但图像质量相对较好,在临床应用逐年增多[10]。有文献报道3D- ASL与称为脑灌注“金标准”PET比较,二者相关性良好[11-12]。与SPECT比较,3D-ASL显示脑灌注异常改变更为敏感[13]
有研究显示AD痴呆前I期患者(仅Aβ异常、而τ无异常改变)的颞叶和顶叶CBF值下降,II期患者(Aβ和τ均有异常改变)者颞叶CBF值下降,CBF持续下降可能反映病情进展,该指标可用于预测人群罹患AD的风险、判断病情严重程度,有助于筛选治疗AD的药物[14]

3.2 AD脑灌注改变

本研究显示与NC组相比,轻度AD组在双侧楔前叶及后扣带回见灌注减低区域,提示AD患者有与认知相关脑区的灌注不足。且轻度AD患者的脑灌注减低有偏侧性,即左侧半球比右侧半球的脑灌注减低更为显著。这也许与本研究被试均为右利手有关。随病程发展,优势半球的血流灌注需求量较对侧大,逐渐出现主动正向调节能力下降,失去优势的偏侧化。
放宽统计校正标准后,与NC组相比,除双侧楔前叶和后扣带回外,轻度AD组的双侧扣带旁回、左侧角回、距状裂周围皮层、楔叶、缘上回、颞中回亦见灌注减低区。文献报道经典AD为双侧颞顶叶代谢减低[15-17],后扣带回低灌注为AD的特征性改变[18],本研究结果支持上述观点。由于双侧楔前叶负责情景记忆,上述脑区灌注不足提示其与患者认知功能损害有关[19]

3.3 针刺干预阿尔茨海默病的理论基础与疗效评价

国内研究发现,仅施行针刺或作为药物治疗的辅助方法,对AD患者都有一定疗效。有研究应用功能磁共振成像寻找针刺穴位与特定脑功激活区的相关性,推测针刺可调节AD患者大脑某些认知相关脑区的激活和功能连接,而且针刺健康人和AD患者的作用不相同,针刺对健康人和AD患者均有双向调节作用,在脑功能状态方面表现为“激活”和“去激活”并存[20-22]
双侧合谷穴和太冲穴古称“四关穴”,具有安神定志,疏肝理气,开窍醒神的功能,本课题组对针刺“四关穴”开展系列研究,已经发现针刺AD患者的激活脑区与AD典型受累部位一致,这也许是针刺疗效的基础。
本研究常规针刺“四关穴”组和针刺“四关穴”假穴组经6个月治疗后复查3D-ASL,发现前者多个脑区的灌注增加,尤其轻度AD患者出现左楔前叶和左后扣带回灌注减低,而针刺“四关穴”后上述区域的脑灌注增加的意义重大。
比较常规针刺“四关穴”组和针刺“四关穴”假穴组干预前后全脑rCBF值发现,二组在部分脑区存在差异,常规针刺“四关穴”组表现为脑灌注增加,而针刺“四关穴”假穴组表现为脑灌注减低,提示针刺“四关穴”干预对轻度AD患者脑灌注产生正向调节作用。比较常规针刺“四关穴”组与针刺“四关穴”假穴组,干预前后患者的MMSE、MoCA评分值,未发现差异有统计学意义,或因针刺干预及随访时间较短,未能显示二者的显著区别。
本研究存在一定局限性,如针刺干预患者的样本量较少,随访时间短,今后如能扩大样本量、增加随访次数,可进一步证实结果的可靠性。

4 小结

3D-ASL显示轻度AD患者的双侧楔前叶和后扣带回灌注减低,针刺“四关穴”可使轻度AD患者的脑灌注增加(包括原来的低灌注脑区)。
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