精华荟萃:神经科学火热的神经丝轻链,是何物?

2021-11-15 Freeman MedSci原创

NfL在脑脊液(CSF)和血液中的水平与各种神经系统疾病(包括炎症性、神经退行性、创伤性和脑血管疾病)中轴突损伤的程度成比例地增加。

在神经系统疾病的管理中,迫切需要可靠的生物标志物,以提高鉴别诊断和预后评估的准确性,并预测对治疗的反应。这适用于所有原因引起的中枢神经系统(CNS)疾病,包括炎症性、神经退行性、创伤性和血管性疾病。

生物标志物在神经系统疾病中的另一个应用可能是识别或排除神经退行性过程的存在,这对随后的临床管理很有用。

在与轴突损伤或变性有关的中枢神经系统和周围神经系统疾病中,已经发现脑脊液(CSF)和血液中的神经丝轻链(NfL)浓度增加。

在过去的二十年中,越来越多的研究表明,CSF和血液中的NfL水平在中枢神经系统疾病中发生改变,并与疾病特征相关。此外,作为对正在进行的轴突损伤的定量测量,NfL水平的增加对各种神经系统疾病有预后价值。由于测量NfL在血液中的浓度是可行的,它可能是监测中枢神经系统疾病病程的一个有前途的生物标志物,最好是评估患者对治疗的反应。

藉此,这里总结了NfL的结构、功能和释放机制,以及可以测量NfL浓度的方法。然后回顾了它在各种中枢神经系统疾病中的潜在诊断和预后价值。


 NfL的结构、功能和测量


NfL是神经丝(Nfs)的一个亚单位,它是专门位于神经元细胞质中的圆柱形蛋白。 Nfs赋予神经元结构稳定性,存在于树突和神经元体部,以及轴突中,它们的表达量特别高。由于Nfs能使轴突呈放射状生长,较大的有髓轴突大量表达Nfs和NfL。

在正常情况下,低水平的NfL不断地从轴突中释放出来,在年老时释放出更高水平的NfL。然而,在中枢神经系统轴突因炎症、神经退行性、创伤或血管损伤而受损时,NfL的释放急剧增加。释放的NfL到达与CSF自由交流的间质和血液中,其浓度大约比CSF低40倍。

在Nfs亚单位中,神经丝重链(NfH)广泛进行翻译后磷酸化(pNfH),这影响了Nfs沿轴突运输的动态,因此也影响了轴突的稳定性。 虽然对NfL的研究较少,但CSF中pNfH的增加可作为轴突损伤的生物标志物,特别是在肌萎缩性脊髓侧索硬化症(ALS)中,pNfH对其特别有针对性。

然而,由于NfL是Nfs的骨架,它是最丰富的亚单位,也是最可溶性的亚单位,这使NfL成为生物液体中最可靠的可测量的Nfs亚单位。

在CSF中,NfL可以通过Sandwich ELISA技术进行检测。 然而,ELISA测量血液中NfL浓度的灵敏度是不够的。单分子阵列(Simoa)技术已被用于血液中NfL的定量,甚至在年轻健康对照组(HC)的样本中也是如此。这种超灵敏的技术使其有可能在群体水平上检测血液中NfL的纵向变化,而且当其增长超过分析变异时,也可以在个人水平上检测,而分析变异仍然是6%左右。


NfL的潜在诊断价值

神经系统疾病患者CSF中NfL的浓度高于HCs,最近也有关于血液NfL的类似发现。NfL作为生物标志物在多发性硬化症(MS)、阿尔茨海默病(AD)、额颞叶痴呆(FTD)、ALS、非典型帕金森病(APD)和脑外伤(TBI)中的作用已被广泛报道。

另外,NfL已被研究用于克雅氏病和HIV感染的神经系统并发症(在CSF中达到非常高的浓度)、亨廷顿氏病(HD)和正常压力脑积水(NPH)中。

由于NfL是一个敏感但非特异性的轴突损伤标志物,其潜在的诊断价值不在于区分以类似轴突损失程度为特征的神经系统疾病的能力,而在于区分具有不同程度的大髓鞘轴突损伤和/或具有不同进展速度或疾病强度的CNS疾病,或区分神经退行性疾病和非神经退行性疾病。

因此,NfL在临床上的潜在诊断作用应辅以其他神经学评估,以及更多的疾病特异性生物标志物和脑成像结果。


NfL和神经系统疾病

NfL和多发性硬化

在多发性硬化症及其首次临床表现,即临床孤立综合征(CIS)中,CSF NfL浓度都会增加。

从没有神经系统疾病的对照组中,CSF NfL可用于识别患者,准确率很高。血清NfL也有类似的发现。测量NfL的时间可能影响其浓度,特别是与最后一次急性炎症发作的时间点有关。

复发性多发性硬化症(RRMS)患者的CSF和血清NfL往往比临床稳定的RRMS患者高。CSF NfL在复发后的2-3个月内保持较高的水平,然后下降到较低的水平

因此,在最后一次复发后的3个月内,CSF NfL可能具有最高的诊断准确性。这可能也适用于血液中的NfL,其浓度似乎与CSF NfL的动态变化相同。

NfL和痴呆

在AD患者中,CSF和血液中的NfL高于HCs(对照)。

就CSF NfL而言,AD患者与HCs的区分具有良好的准确性(AUC高达0.77,95% CI 0.64至0.89)。

同样,血液中的NfL也显示出很好的准确性(AUC=0.87)。

此外,血液中NfL的变化似乎比AD的第一个临床表现要早16年,这在对AD突变携带者的纵向研究中得到了证明。

 

NfL和渐冻症

NfL在ALS诊断中的作用 与健康人和神经系统对照组相比,ALS患者的CSF NfL较高,与其他运动神经元疾病(MND)(即原发性侧索硬化症、脊髓性肌萎缩症和肯尼迪病)的患者相比也是如此。

CSF NfL在区分ALS患者和HCs时表现出最高的准确性(AUC=0.99,敏感性97%,特异性95%,P<0.0001),但其在区分早期症状期(6个月内发病)的ALS患者和其他神经系统疾病(AUC=0.95,95% CI 0.91至0.99)的准确性仍然很高。

这些结果高度相关,即使在对疑似MND患者进行首次临床评估时,NfL也可能具有诊断效用。

此外,在ALS中,CSF和血清NfL有很强的相关性(r=0.78,p<0.0001)。

相关性在HCs中较弱(r=0.57,p<0.01),因此,与HCs相比,ALS中CSF NfL较高的持续轴索损伤可能与NfL通过血脑屏障从CSF到血液的更快再分配有关。

NfL和运动障碍疾病

NfL的预后价值已在PD和PSP中得到评估,但对MSA和CBS的预后价值尚无数据。

就PD而言,基线CSF NfL值与痴呆评分表分数每年的平均变化有关(相关系数=-0.25,P=0.03)。

此外,它们还能预测随后5-9年内转化为PDD的风险(CSF NfL >1100 pg/mL的HR=高达2.6,95% CI 1.1至5.9,p=0.03),但加入其他生物标志物,如CSF Aβ42(CSF NfL/Aβ42比率>1的HR=高达6. 25。

在PSP(进行性核上麻痹)中,较高的基线CSF和血液NfL值似乎与运动和认知症状的快速恶化有关。

例如,基线血浆NfL水平≥36.7 pg/mL的患者比基线血浆NfL水平<36.7 pg/mL的患者在1年内有更严重的PSP评分表的恶化(平均增加36.5%,95%CI为44.3%)。

NfL与其他生物标志物(即CSF NfL/p-tau比值)的结合进一步提高了预测PSP评分表分数年度变化的能力(p=0.003)。

此外,CSF NfL 1年的纵向变化与1年内小脑上行区体积的变化呈反比(相关系数=-0.45,p=0.04)。

NfL和脑外伤

TBI是短期(如脑震荡后综合症和创伤后癫痫)和长期神经系统后遗症(如AD和慢性创伤性脑病)的风险因素,但到目前为止,还没有发现可靠的TBI预后标志物。

CSF和血清NfL已被证明是良好的预后标志物,能够预测临床和神经放射学结果。

54对于轻度TBI患者,在创伤后1小时和36小时测量的血清NfL值可用于区分症状迅速缓解的患者和脑震荡后综合征延长的患者(1小时AUC=0.82,95%CI 0.6至1;36小时AUC=0.83,95%CI 0.6至1)。

此外,休息14天后,CSF NfL浓度高的拳击手在评估信息处理速度的测试中表现出更差的认知能力。

在冰球运动员中,基线CSF NfL似乎与以前的轻度TBI事件的数量相关,并且在有长期昏迷后综合症病史的运动员中往往更高。

此外,在与运动有关的TBI发生1小时后,发现血清NfL对于区分脑震荡后在10天内恢复比赛的运动员和延迟较长时间才恢复比赛的运动员有很高的准确性(AUC=0.82,P<0.0001)。

血清NfL(在与运动有关的TBI后6天测量)在识别因长时间脑震荡后综合症而辞职的冰球运动员方面显示出更高的准确性(AUC=0.89,p=0.005)。

值得注意的是,血清NfL在TSCI中也显示出潜在的预后价值,其在创伤后24小时的数值与3-12个月后的运动结果显示出良好的相关性(r=-0.72,p<0.001)。


结语:

在神经系统疾病的管理中,对轴索损伤的识别和量化是非常重要的。

NfL是一种神经元胞质蛋白,在大口径髓鞘轴突中高度表达。

它在脑脊液(CSF)和血液中的水平与各种神经系统疾病(包括炎症性、神经退行性、创伤性和脑血管疾病)中轴突损伤的程度成比例地增加。

新的免疫测定法能够在超低水平上检测生物标志物,允许在血液中测量NfL,从而有可能轻松和重复地测量NfL以监测疾病的进程。

脑脊液和血液中的NfL可以作为神经系统疾病的诊断、预后和监测的生物标志物,而且NfL是未来最有希望用于临床和研究的生物标志物之一。

 

参考文献:

1 Olsson B, Portelius E, Cullen NC, et al. Association of cerebrospinal fluid neurofilament light protein levels with cognition in patients with dementia, motor neuron disease, and movement disorders. JAMA Neurol 2018:1–8.


2 Disanto G, Barro C, Benkert P, et al. Serum neurofilament light: a biomarker of neuronal damage in multiple sclerosis. Ann Neurol 2017;81:857–70. 3 Poesen K, De Schaepdryver M, Stubendorff B, et al. Neurofilament markers for ALS correlate with extent of upper and lower motor neuron disease. Neurology 2017;88:2302–9.

 

4 Kuhle J, Plattner K, Bestwick JP, et al. A comparative study of CSF neurofilament light and heavy chain protein in MS. Mult Scler 2013;19:1597–603. 5 Kuhle J, Gaiottino J, Leppert D, et al. Serum neurofilament light chain is a biomarker of human spinal cord injury severity and outcome. J Neurol Neurosurg Psychiatry 2015;86:273–9.


6 S M, A F, S M, et al. Serum neurofilament light chain in NMOSD and related disorders: comparison according to aquaporin-4 and myelin oligodendrocyte glycoprotein antibodies status. Mult Scler J Exp Transl Clin 2017;3:2055217317743098.


7 Mattsson N, Andreasson U, Zetterberg H, et al. Association of plasma neurofilament light with neurodegeneration in patients with Alzheimer disease. JAMA Neurol 2017;74:557–66.


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9 Mattsson N, Insel PS, Palmqvist S, et al. Cerebrospinal fluid tau, neurogranin, and neurofilament light in Alzheimer’s disease. EMBO Mol Med 2016;8:1184–96. 10 Alcolea D, Vilaplana E, Suárez-Calvet M, et al. CSF sAPPβ, YKL-40, and neurofilament light in frontotemporal lobar degeneration. Neurology 2017;89:178–88. 11 Rohrer JD, Woollacott IOC, Dick KM, et al. Serum neurofilament light chain protein is a measure of disease

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  2. [GetPortalCommentsPageByObjectIdResponse(id=1935027, encodeId=040f193502e6c, content=<a href='/topic/show?id=df6ee41476f' target=_blank style='color:#2F92EE;'>#神经丝轻链#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=55, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=74147, encryptionId=df6ee41476f, topicName=神经丝轻链)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=0bed488, createdName=jktdtl, createdTime=Tue Aug 23 18:13:04 CST 2022, time=2022-08-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1221348, encodeId=dc371221348df, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=51, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20210905/47d873f313bc47fe9d5d7a69b86d877f/545be3203f2745cab07fbf19b980c439.jpg, createdBy=bea65467125, createdName=ms2000000544679768, createdTime=Sat May 21 09:45:49 CST 2022, time=2022-05-21, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1681443, encodeId=450516814434c, content=<a href='/topic/show?id=366b8e2299e' target=_blank style='color:#2F92EE;'>#荟萃#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=39, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=87229, encryptionId=366b8e2299e, topicName=荟萃)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=c12d27855367, createdName=venlin, createdTime=Sat Aug 20 13:13:04 CST 2022, time=2022-08-20, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1801695, encodeId=c9a8180169572, content=<a href='/topic/show?id=91f1e4142bd' target=_blank style='color:#2F92EE;'>#神经丝#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=46, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=74142, encryptionId=91f1e4142bd, topicName=神经丝)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=1d01326, createdName=lizhou0204, createdTime=Fri Mar 25 00:13:04 CST 2022, time=2022-03-25, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1070921, encodeId=8b7e10e092182, content=认真学习了, beContent=null, objectType=article, channel=null, level=null, likeNumber=55, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo6EF3hKja8nER8RMzxQdria9eCYFhgLTLsDOeqnvIYdeLDz5eP6EnicLuE5gibiawgno4zUA0jAR7Nbtp2llQ9fs3Mk/0, createdBy=278f1986883, createdName=医鸣惊人, createdTime=Tue Nov 16 22:19:16 CST 2021, time=2021-11-16, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1443693, encodeId=40d914436930f, content=<a href='/topic/show?id=5b78e4414c7' target=_blank style='color:#2F92EE;'>#神经科#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=33, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=74414, encryptionId=5b78e4414c7, topicName=神经科)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=9a4e5108341, createdName=12498f1em09(暂无昵称), createdTime=Tue Nov 16 21:13:04 CST 2021, time=2021-11-16, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1570137, encodeId=134415e0137b7, content=<a href='/topic/show?id=c65ee4421c4' target=_blank style='color:#2F92EE;'>#神经科学#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=23, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=74421, encryptionId=c65ee4421c4, topicName=神经科学)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=ce0115632498, createdName=pandamao2015, createdTime=Tue Nov 16 21:13:04 CST 2021, time=2021-11-16, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1070508, encodeId=bd6610e05081d, content=好, beContent=null, objectType=article, channel=null, level=null, likeNumber=60, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://thirdwx.qlogo.cn/mmopen/vi_32/ykGRcou2PxnPQC5twzEHcKBEDM3ib9lUhTSrkFjLcOKfmcyPIfMddkzeIVnkIaZlVCutkibqf9AUTYHzhOiavelQg/132, createdBy=d2f05306482, createdName=测血压, createdTime=Mon Nov 15 20:09:26 CST 2021, time=2021-11-15, status=1, ipAttribution=)]
    2022-05-21 ms2000000544679768

    学习

    0

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    2022-08-20 venlin
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    2021-11-16 医鸣惊人

    认真学习了

    0

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    2021-11-15 测血压

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