散发型克雅病脑脊液tau蛋白的改变

Changes of tau protein in cerebrospinal fluid of sporadic Creutzfeldt-Jakob disease

目的探索脑脊液标志物,尤其是总tau蛋白(T-tau)及磷酸化tau蛋白(P-tau)对Creutzfeldt-Jakob病(Creutzfeldt-Jakob disease,CJD)的诊断与鉴别诊断价值。方法按2009年Brain标准及2018年Neurology改良版标准选取2018—2019年北京协和医院脑脊液生物标志物研究队列中的散发性CJD(sporadic CJD,sCJD)患者。按2011年美国国立老化研究所与阿尔茨海默病(AD)协会标准选择年龄、性别相对匹配的AD患者以及认知功能正常的其他神经系统疾病患者作为对照病例,应用其脑脊液标本进行分组对照研究。共收集了12例sCJD患者入组,同时收集49例AD患者以及14名认知正常者入对照组。所有脑脊液标本均为腰椎穿刺时直接滴落收集,-80℃保存,由专门实验室及指定实验员进行T-tau蛋白、P-tau蛋白测定。同时收集sCJD患者影像学及脑电图资料,并按规定将sCJD病例报送中国疾病预防控制中心,检测14-3-3蛋白及相关的基因。结果通过非参数秩和检验对比3组人群脑脊液tau蛋白含量,结果显示sCJD组T-tau水平达1211(448,2227)pg/ml,AD组T-tau水平达549(314,1078)pg/ml,均显著高于对照组[127(79,192)pg/ml,U=20、73,P<0.01]。sCJD组的T-tau蛋白水平升高更明显,显著高于AD患者(U=178,P=0.0349)。在AD患者中,P-tau水平达72(58,109)pg/ml,较对照组[27(15,42)pg/ml]显著升高(U=82,P<0.01),但在sCJD患者[32(24,47)pg/ml]无明显升高。sCJD患者的T-tau/P-tau比值[29.77(20.01,54.53)]高于AD[7.45(4.79,10.43);U=87,P<0.01]。12例sCJD头颅MRI均存在"花边征",5例存在脑电图三相波改变。9例sCJD患者被上报至中国疾病防治中心,其中4例14-3-3蛋白阳性;9例朊蛋白PRNP基因均无突变,129位密码子均为M/M型,219位密码子均为E/E型。结论sCJD患者脑脊液tau蛋白、T-tau/P-tau显著增高,对于sCJD的诊断及鉴别具有一定价值。

Objective To evaluate the value of cerebrospinal fluid markers expecially total-tau protein(T-tau),phosphorylated-tau protein(P-tau)in diagnosis and differentiation of sporadic Creutzfeldt-Jakob disease(sCJD).Methods sCJD(according to 2009 Brain criteria,2018 Neurology amended criteria),Alzheimer's disease(AD;the National Institute on Aging at National Institutes of Health and the Alzheimer's Association revised guidelines 2011 criteria)and other patients without cognitive impairment,matched for sex and age,in the Department of Neurology,Peking Union Medical College Hospital from 2018 to 2019 were enrolled.Twelve sCJD patients,49 AD patients and 14 normal controls were enrolled.Cerebrospinal fluid(CSF)specimens were collected through gravity dropping directly,and further stored in-80℃and disposed according to widely used standards.The levels of T-tau and P-tau were measured by ELISA.The data on electroencephalogram and neuroimaging findings of sCJD patients were recorded.Moreover,specimens of sCJD patients were sent to the Chinese Center for Disease Control and Prevention to test 14-3-3 protein and PRNP genotype.Results Using Mann-Whitney U test,T-tau concentrations were found higher in patients with sCJD(1211(448,2227)pg/ml)than in AD patients(549(314,1078)pg/ml;U=178,P=0.0349),and both groups had higher T-tau than the control group(127(79,192)pg/ml;U=20,73,P<0.01).The level of P-tau was significantly increased in AD patients(72(58,109)pg/ml)compared to the control group(27(15,42)pg/ml;U=82,P<0.01),but not in sCJD patients(32(24,47)pg/ml).The T-tau/P-tau ratio was higher in sCJD patients(29.77(20.01,54.53))than in AD patients(7.45(4.79,10.43);U=87,P<0.01).Twelve sCJD patients had cotical hyperintensity on diffusion weighted imaging and five had periodic three-phase waves on electroencephalogram.Nine sCJD patients,whose CSF samples were tested in the Chinese Center for Disease Control and Prevention,carried an M/M genotype at codon 129 and E/E at codon 219.Conclusion The CSF tau level and T-tau/P-tau ratio are significantly increased in sCJD,which may promote the diagnosis and differentiation of sCJD in routine clinical setting.