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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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Research progress of peripheral blood biomarkers of Alzheimer’s disease

  • QIAO Xinyi 1, 2 ,
  • YUE Ling 1, 2 ,
  • XIAO Shifu , 1, 2
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  • 1 Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine
  • 2 Alzheimer’s Disease and Related Disorders Center

Received date: 2019-08-01

  Revised date: 2019-08-09

  Online published: 2019-12-25

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressivecognitive impairment. With the rapid aging of China, the disease burden is becoming heavier. In order to early prevent and treat the disease, researchers committed to find effective and easily detectable biomarkers for early recognition of AD. Among them, the peripheral blood biomarkers detection is a potential method for early screening and follow-up in the community population because of its convenient collection and little trauma. In this paper, the research progress of peripheral blood biomarkers of AD was reviewed.

Cite this article

QIAO Xinyi , YUE Ling , XIAO Shifu . Research progress of peripheral blood biomarkers of Alzheimer’s disease[J]. Chinese Journal of Alzheimer's Disease and Related Disorders, 2019 , 2(4) : 548 -555 . DOI: 10.3969/j.issn.2096-5516.2019.04.016

前言

阿尔茨海默病(Alzheimer’s disease, AD),即老年痴呆,是一种表现为认知功能障碍进行性加重的神经变性疾病。AD的特征性病理改变包括β淀粉样蛋白(Aβ)沉积形成的细胞外老年斑,和Tau蛋白过度磷酸化形成的神经细胞内神经原纤维缠结。
随着中国快速老龄化,AD的疾病负担越发沉重,因此,寻找有效且便于检测的标志物,以早期识别AD及其所致的认知功能减退,对疾病的治疗和预防具有重要意义。目前AD生物标志物研究主要聚焦于脑脊液、神经影像及外周血。其中,留取脑脊液的腰穿操作属于有创操作,可接受度有限,神经影像学检查价格高昂,难以在社区人群中普及,而外周血标志物采集方便、创伤小,是具有潜力的早期筛查和随诊手段。
在外周血中能够检测到早期识别AD的生物标志物,其机制与AD的血脑屏障(brain-blood barrier, BBB)损伤[1]有关。大脑通过BBB与血液系统隔离,两者之间通过各种转运蛋白维持少量、必须的物质交换,以限制病原体和无关细胞进入大脑,BBB的存在对维持正常的神经功能和信息处理至关重要。而AD相关的病理研究显示,患者存在BBB损伤,使大脑中的病理相关蛋白得以进入血液系统。一项使用了动态增强MRI的研究发现,BBB损伤与年龄相关,最早发生于海马,并可能与认知功能减退有关[2]。本文就AD的外周血生物标志物研究进展进行综述。

1 β淀粉样蛋白(Aβ)

淀粉样蛋白级联假说是AD发病机制的主流假说之一,Aβ的构象变化使其易于聚集,形成可溶性寡聚体,并可以继续播散,在别处继续发挥突触毒性作用。而胞外的清除细胞,如小胶质细胞、星形胶质细胞、寡突胶质细胞等,在病理条件下对Aβ的清除作用减弱,使得Aβ生成与清除之间不平衡,导致了Aβ的过度沉积。目前大量研究证实,脑脊液中Aβ对AD诊断的准确率较高,而脑内Aβ沉积在导致脑脊液中Aβ含量降低的同时,也能导致血浆Aβ含量降低,使得血浆Aβ成为潜在的早期AD生物标志物。
作为形成老年斑的重要成分,Aβ40和Aβ42是目前研究最多的两种Aβ亚型。一项纵向研究显示,血浆Aβ42浓度升高的个体,AD患病风险增加[3]。另外,还有纵向研究纳入了34名健康老人,并在4年后对他们进行随访发现,基线血浆Aβ42水平增加及随访时血浆Aβ42下降程度,与认知测试得分减低有关[4]。而一项前瞻性队列研究则认为,AD患病风险的增加与血浆Aβ40浓度,而不是血浆Aβ42浓度升高有关[5]。既往相关研究显示,Aβ42沉积在AD病理过程中发生于Aβ40沉积之前[6],提示Aβ在AD发病机制的不同阶段所产生的不同作用是导致上述结果差异的可能原因。一项纳入了13项研究共10 303例受试者的meta分析也显示,单独使用Aβ40或Aβ42作为标志物的研究,其结果一致性不佳,而Aβ42/Aβ40值降低,与AD疾病发展及认知功能下降存在显著关联[7]。一项横断面研究发现,Aβ42/Aβ40值与脑内Aβ沉积相关(P< 0.001)[8]。另一项多中心研究也得出类似结论,研究者将匹兹堡化合物B正电子发射断层扫描(pittsburgh compound-B PET, PIB-PET)所示的Aβ沉积程度作为标准,发现淀粉样前体蛋白片段APP669-711/ Aβ42、Aβ40/Aβ42值以及它们的复合生物标志物在预测Aβ沉积方面表现良好,并且与PIB-PET所示的Aβ沉积程度以及脑脊液Aβ42水平均相关,其中复合生物标志物的AUC值最高(96.7%,n=121; 94.1%,n=111)[9]。另外,还有少量研究发现Aβ38可以在脑内引起微血管损伤,通过炎症、氧化应激及细胞凋亡过程增加痴呆的易感性,血浆Aβ38水平降低与AD患病风险增加相关[10-11]。一项纳入39例AD患者、61例对照的研究,先使用血浆Aβ标志物对AD患者进行初筛,再用脑脊液Aβ及Tau蛋白标志物进行复核诊断,其敏感度为90%,特异性达97%[12],提示了血浆Aβ标志物在早期筛查AD中的应用价值。尽管单独的Aβ亚型并不是一个理想的AD早期识别生物标志物,然而不同亚型及其相关蛋白相结合所形成的复合标志物在临床应用方面具有潜力。

2 Tau蛋白

脑脊液Tau蛋白升高是另一种被广泛认同的AD诊断标志物,Tau蛋白可发生裂解,进而释放入外周血中,近年来超敏检测方法的发展使得外周血Tau蛋白的检测成为可能[13]。许多研究均发现,与健康对照相比,血浆Tau蛋白水平在轻度认知缺损(mild congnitive impairment, MCI)和AD患者中升高[14,15]。一项meta分析纳入了22组AD患者共1872例和20组健康对照共3 855例,对血浆或血清中包括Aβ40、总Tau蛋白(T-tau)在内的6种标志物进行详细分析,只有血浆T-tau显示出显著组间差异(P=0.02)[16]。Zetterberg等[17]对54例AD、75例MCI及25例健康对照进行了平均8.4年的随访发现,与MCI及健康对照相比,AD患者血浆Tau蛋白明显升高,然而进展为AD的MCI患者血浆Tau蛋白水平,与维持原MCI诊断的患者及健康对照相比无明显差异,提示Tau蛋白在预测疾病进展方面表现不佳,在其水平明显升高之前可能需要大量的轴突损伤。较高的血浆T-tau蛋白水平与认知功能下降显著相关,包括记忆、注意力、视空间、执行功能等方面[18],并且这一结论在一项包含458例受试者、中位随访期为3年的纵向研究中得到了进一步证实[19]。另外,血浆Tau蛋白水平还与灰质、海马、杏仁核体积呈负相关[20]。在一项横断面研究中,虽然未发现血浆Tau蛋白在MCI和AD患者中的组间差异,但将血浆Aβ42和Tau蛋白的乘积当作一种复合标志物时,其在鉴别MCI和AD方面敏感度和特异性分别为80%和82%[21]。总之,血浆Tau蛋白及其与其他标志物的复合标志物,是有前景的AD早期筛查、识别生物标志物,需更多的大样本随访研究及高灵敏度检测方法进一步验证其临床应用的可靠性。

3 载脂蛋白

中年时总胆固醇水平升高是AD及其他类型痴呆的危险因素之一[22],而载脂蛋白是一组与胆固醇和脂质代谢有关的蛋白质,其可能参与神经退行性疾病病理过程的研究结论,使其成为了AD生物标志物研究热点之一[23]。编码载脂蛋白E(ApoE)的等位基因4(APOEε4)与AD发病风险显著相关,参与了Aβ聚集和清除、Tau病理学、突触可塑性、神经炎症、脂代谢、线粒体功能障碍和血脑屏障通透性等AD发病机制中的各个环节,使ApoE成为了目前研究最多的载脂蛋白[24]。但研究结果并不一致,一部分研究发现AD患者血浆ApoE水平降低,而另一些研究得出了相反的结果[27-28]。同时,APOEε4携带者与血浆ApoE水平的关系也存在争议[28-29]。这种结果的差异可能与样本量、实验设计、测量方法等因素有关。一项纵向队列研究对664例被试进行了为期2年的随访,并未发现基线ApoE水平与认知功能下降之间的关联[30]。提示尽管APOEε4基因在AD中的作用已被广泛认同,但血浆ApoE可能并不是一个良好的标志物。
ApoJ又称为簇蛋白(clusterin, CLU),是一种参与抵抗细胞外蛋白质错误折叠的伴侣蛋白,在AD的病理过程中,ApoJ在抑制Aβ聚集沉积、增加小胶质细胞对Aβ的清除以及抑制补体激活方面发挥作用[31-32]。多项全基因组关联研究证实,CLU基因是AD强有力的遗传位点之一,使得许多研究将ApoJ视为一种有潜力的AD外周标志物[33-34]。一项多中心研究分析了包括ApoJ在内的7种与海马萎缩相关以及5种与AD快速进展相关的蛋白,只有ApoJ在研究的验证部分被证明与AD患者的内嗅皮质萎缩、疾病严重程度及临床进展有关,且血浆ApoJ浓度增加可以预测内侧颞叶Aβ负荷的增加[35]。其他研究也得出了类似的结论,表明血浆ApoJ水平增高是MCI患者进展为AD的危险因素,并能预测进行性认知功能减退[36-37]。而一项横断面研究有不同的发现,血浆ApoJ水平高的MCI患者,其易受AD病理影响的脑区,如颞上回、海马旁回、扣带回等萎缩率更小[38],提示在MCI患者中血浆ApoJ水平增高可能是一种保护性因素,然而在遗传风险、不利环境因素等各方面危险因素共同影响下,这项保护性因素并不能阻止疾病的进展。
其他关于载脂蛋白的研究还发现,在MCI和AD患者中,低水平的ApoA1、ApoA2、ApoH、ApoC3和高水平的ApoB、ApoB/ApoA1比值与认知功能减退相关[39-42]。总之,载脂蛋白是一种具有前景的AD早期诊断及预测标志物,但仍需继续探索。

4 炎症及补体相关

炎症在AD早期病理过程中起重要作用,研究发现临床常用的炎症指标C反应蛋白(CRP)与全因性痴呆风险增加有关,与健康对照相比,AD患者外周血CRP水平降低,而超敏CRP与AD的关系与年龄成正相关[43-45]。另一种常见的炎症相关痴呆标志物是白细胞介素6(IL-6),它由小胶质细胞和星型胶质胞释放,加速了神经退行性变的进程,与AD和全因性痴呆均相关[46-47]。一项跨欧洲队列研究发现,血浆IL-6和肿瘤坏死因子-α(TNF-α)水平下降与AD患者全脑体积减小显著相关,IL-4和IL-10水平下降与AD患者快速认知功能下降相关[48]
炎症由补体途径激活,多项研究表明补体成分、调节因子和活化产物均会在AD中发生改变,并可能成为AD发病及进展的预测指标。有研究发现在AD和MCI患者血浆中,补体因子H(CFH)和α2微球蛋白浓度升高[49]。这一结论在另一项研究中得到证实,但在改变检测方法后并不能重复该结果,同时该研究还发现补体成分C3、C4、补体因子B(CFB)以及补体C1抑制剂在AD患者和对照组血浆中存在差异表达[50]。另一种补体因子CFI和末端补体复合物(terminal complement complex, TCC)与对照组相比,在MCI患者血浆中明显减少,但血浆TCC水平在AD和对照组之间无明显差异[51]。另外,补体成分C2、C9的血浆浓度增加与AD患者快速认知功能下降相关[52]。近年来通过蛋白质组学技术发现了越来越多炎症相关标志物,但可重复性有限,并且受各种躯体疾病影响较多,目前并不能作为诊断AD的特异性指标,但监测其水平波动可能能够应用于预测疾病进展及严重程度。

5 miRNA

miRNA是一组长度约为22个核苷酸的非编码小分子RNA,参与了AD的细胞变化[53]。它们通过与靶信使RNA(mRNA)的3’-非翻译区结合,干扰基因的调控和翻译,导致mRNA不稳定或降解[54]。多项研究在筛查后通过实时定量聚合酶链反应(RT- qPCR)进行验证,有多种miRNA被发现在AD或MCI患者中失调,与健康对照相比,AD患者血清miR-455-3p水平升高(AUC=0.79),miR-29c-3p、miR-19b-3p、miR-501-3p(AUC=0.82)、miR-223(AUC=0.786)水平下降,且血清miR-223与miR- 125b相结合时识别AD的性能比单独使用miR-223更好(AUC=0.879)[55-58]。在血浆中也检测到了miRNA水平的变化,血浆miR-502-3p和miR-483-5p水平上调可以较好的区分AD和HC以及MCI和HC(AUC> 0.9)[59]。与MCI和健康对照相比,AD患者血浆miR-411水平明显升高,但在轻、中、重度AD 3组间及MCI和HC组间差异不明显[60]。而将不同miRNA结合为复合标志物后,区分MCI和健康对照的AUC值最高可达0.962(miR-191/miR-101和miR-103/miR- 222),miR-191、miR-125b和miR-590-5p的复合标志物也能较好的区分MCI和健康对照(AUC> 0.95)[61],这种复合标志物在区分MCI和健康对照上的优势在其他研究中也得到了证实[62]。以上结论提示,在AD中,miRNAs的调控失调可能有助于早期发现疾病,并可能持续监测疾病的进展,并使治疗干预措施得以评估。

6 外泌体

外泌体是一种纳米级细胞外囊泡,普遍存在于外周血液中,携带大量特异性蛋白质及生物活性物质,起调控目标基因的蛋白质、脂类和miRNA的作用,因此被认为是重要的疾病诊断标志物。现有研究发现,外泌体中的P-tau和Aβ42蛋白,与AD疾病进程——由aMCI转为AD密切相关,可作为疾病的早期诊断标志物[63]。最近宣武医院贾建平教授团队的研究发现,在外周血神经源性外泌体中,AD与MCI患者和对照组相比,Aβ42、T-tau和P-tau水平均具有显著差异,能够清楚对三者进行区分。对外周血神经源性外泌体和脑脊液生物标志物进行相关性分析发现,神经源性外泌体中Aβ42、T-tau和P-tau的水平与其在脑脊液中的水平高度相关[64],表明外泌体生物标志物可能反映了大脑的病理生理变化,且等同于脑脊液生物标志物的诊断效力,是用于AD诊断的潜在生物标志物。

7 神经纤维丝轻链

神经纤维丝轻链(neurofilament light chain, NfL)是细胞骨架的一个组成部分,主要表达于大直径有髓鞘轴突,脑脊液中的NfL是一种敏感的神经轴突损伤生物标志物[65]。体液中NfL的变化与小鼠模型脑损伤、脑萎缩以及包括神经退行性疾病在内的多种神经系统疾病有关。前期研究发现,脑脊液中的NfL与血液中的NfL紧密相关[66],引发了通过监测NfL变化从而预测AD神经变性和疾病进展的讨论。Fox团队的研究探讨了血清NfL对距离AD发病的预测年限、认知功能评估和脑萎缩程度的判断作用,纳入PSEN1或APP突变家系的48名成员,在单分子阵列(Simoa)平台使用超敏免疫测定法检测血清NfL,并对受试者进行认知测试和MRI检查(计算脑萎缩比率)。结果显示,突变携带者血清NfL浓度升高,且升高程度与疾病分期和症状严重程度相关,提示血清NfL可能是早期AD相关神经变性的可行生物标志物[67]。之后Preische等[68]进一步扩大样本量,利用DIAN数据(存在显性突变的家族性AD成员)和生物样本来研究症状前、症状性AD患者血液中的NfL变化。研究者连续测量血清NfL发现,NfL变化率相比某一横截面的血清NfL数值,能够早10年区分非突变携带者和突变携带者,并且在患者由症状前发展为症状性AD时达到高峰。该研究中检测的抗原是NfL的核心结构域,这是一种短而稳定的片段(约10 kD)。研究者认为NfL的这种稳定片段可以作为血液生物标志物,用于监测脑中缓慢的神经变性过程。另一项共纳入1 583例被试的纵向研究发现,与健康对照相比,血浆NfL在MCI和AD患者中明显升高,且MCI患者的血浆NfL水平的快速增加,与脑脊液中神经元损伤的生物标志物快速增加、海马萎缩更快、葡萄糖代谢率更低以及整体认知更快恶化有关[69]。总之,血清NfL与AD的进展相关,其可作为临床试验入组筛选标志物:症状前的AD突变携带者,NfL变化率越大,则越接近症状性AD。血浆NfL可作为AD患者神经变性的无创生物标志物,并可能能够用于疾病药物试验中的疗效监测。

8 其他血浆标志物

除了上述几大类标志物以外,还有免疫球蛋白、支架蛋白、糖蛋白及白蛋白家族等均被发现在AD患者中存在浓度改变。转甲状腺素(TTR)在AD病理中可作为支架蛋白与Aβ结合,防止Aβ沉积和老年斑形成[70],一项动物研究发现TTR水平升高是阻止斑块病理发展到其他AD病理特征的保护性因素之一[71],支持了上述观点。与健康对照相比,血浆TTR水平在AD和aMCI患者中显著下降,并且女性受TTR水平下降的影响更大[72],这与AD患病风险的性别差异一致,表现了TTR在AD早期筛查中的潜力。凝溶胶蛋白(GSN)是一种肌动蛋白结合蛋白,能够抑制Aβ纤维化,以及Aβ诱导的细胞毒性作用[73-74]。在AD转基因小鼠模型研究中,血浆GSN水平升高可降低脑Aβ水平和淀粉样蛋白负荷,进一步证明了GSN在AD病理过程中的保护性作用[75]。血浆GSN水平在AD患者中显著降低这一结论,在几项研究中均得到了证实[76-77]。另外,AD或MCI患者中还发现有浓度升高的血清维生素D结合蛋白(DBP)、血浆纤维蛋白原γ链、血浆激肽释放酶8以及浓度降低的维生素E结合蛋白(DEP)等多种蛋白,均可能成为有潜力的标志物之一[78-80],但仍需更多研究加以验证。

9 总结及展望

随着蛋白质组学、脂质组学等更多高敏度新技术的发展,在外周血中有越来越多的蛋白被发现在AD或MCI患者中有浓度变化,见表1。然而由于样本量、研究方案、检测方法、统计方法等的差异,各项研究之间的结果不尽相同。另外,外周血中蛋白质含量高,混杂因素较多,许多潜在标志物会受到基础躯体疾病的影响,以上因素均会对结果产生负面影响,导致了在外周血中寻找稳定、可靠的AD早期识别标志物的研究进展不尽如人意。但众多的研究仍然表明外周血标志物在早期筛查AD方面具有一定优势,并且复合标志物相较于单一标志物在敏感度与特异性上都更胜一筹,提示复合标志物的研究与验证可能是未来进一步研究更具有潜力的方向。
表1 外周血生物标志物
种类 标志物 检测标本 浓度变化 疾病阶段 参考文献
42 血浆 升高 AD [3-4]
40 血浆 升高 AD [5]
38 血浆 降低 AD [11]
42/Aβ40 血浆 降低 AD/MCI [7⇓-9]
Tau蛋白 T-Tau 血浆 升高 AD/MCI [14-15,19]
载脂蛋白 ApoE 血浆 升高 AD [27-28]
降低 [25-26]
ApoJ 血浆 升高 AD/MCI [35⇓-37]
ApoA1 血浆 降低 AD/MCI [39-40]
ApoA2, ApoH 血浆 降低 AD/MCI [39]
ApoC3 血浆 降低 AD/MCI [41]
ApoB, ApoB/ApoA1 血浆 升高 AD/MCI [39,42]
炎症相关 CRP 血浆 降低 AD [44]
IL-6 血浆 降低 AD [47]
IL-4, IL-10, TNF-α 血浆 降低 AD [48]
补体途径 CFH 血浆 升高 AD/MCI [49]
CFI, TCC 血浆 降低 MCI [51]
C3, C4, CFB 血浆 升高 AD [50]
miRNA miR-455-3p 血清 升高 AD [55]
miR-29c-3p,
miR-19b-3p
血清 降低 AD [56]
miR-501-3p 血清 降低 AD [57]
miR-223 血清 降低 AD [58]
miR-502-3p,
miR-483-5p
血浆 升高 AD/MCI [59]
miR-411 血浆 升高 AD [60]
外泌体 42,
T-Tau, P-Tau
血浆外泌体 升高 AD [64]
NfL NfL 血浆 升高 AD/MCI [67,69]
其他蛋白 TTR 血浆 降低 AD/MCI [72]
GSN 血浆 降低 AD [76-77]
DBP 血清 升高 AD/MCI [78]
纤维蛋白原γ链 血浆 升高 AD [79]
激肽释放酶8 血浆 升高 AD [80]
DEP 血浆 降低 AD [79]
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