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阿尔茨海默病(Alzheimer disease,AD)是一种常见的神经退行性疾病,占痴呆总数的60%~80%,其给患者家庭及社会带来了沉重的负担[1]。AD的病理学特征为β淀粉样蛋白(amyloid-β protein,Aβ)沉积导致的老年斑、tau蛋白高度磷酸化引起的神经原纤维缠结以及其他神经退行性改变,如突触减少和神经元丢失[2]。目前,常用于AD诊断的脑脊液生物标志物包括反映脑Aβ沉积的Aβ42和Aβ40,以及反映皮层纤维原缠结的t-tau和p-tau,这些标志物对AD具有较高的诊断率,但其异常也可能在其他痴呆患者中出现[2-3]。研究结果表明,脑脊液中t-tau/Aβ42水平的比值(the level ratio of t-tau to Aβ42,t-tau/Aβ42)和Aβ42/Aβ40水平的比值(the level ratio of Aβ42 to Aβ40,Aβ42/Aβ40)相比单独的t-tau、p-tau、Aβ42和Aβ40可能是更为有效的AD诊断生物标志物[3-4]。此外,AD患者脑脊液中α突触核蛋白(α-synuclein,α-syn)的水平高于轻度认知障碍患者和健康者[5]。11C-匹兹堡化合物B(Pittsburgh compound-B,PIB)对纤维状Aβ具有高亲和力,是Aβ沉积的特异性标志物;11C-PIB PET/CT可提供不同临床阶段Aβ沉积的信息,并与尸检结果显示的Aβ沉积区域密切相关,故其可作为AD早期诊断的可靠影像学手段[6]。本研究经计算得出脑脊液生物标志物α-syn、Aβ40、Aβ42、t-tau、p-tau、t-tau/Aβ42和Aβ42/Aβ40诊断AD的最佳临界值,并分析它们与11C-PIB PET/CT显像诊断AD的准确率及相关性,探讨临床应用中最具预测性的脑脊液生物标志物,从而为AD的诊断提供参考。
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由表1可知,AD患者组和健康对照组在性别、年龄和教育年限方面的差异均无统计学意义(均P>0.05),组间具有同质性;2组受试者MMSE和CDR评分的差异均有统计学意义(均P<0.001);AD患者组脑脊液标志物α-syn、t-tau和p-tau水平及t-tau/Aβ42均高于健康对照组(均P<0.01),而Aβ42水平和Aβ42/Aβ40均低于健康对照组(均P<0.05);AD患者组11C-PIB PET/CT显像的阳性率为82.0%,其典型病例的图像见图1。
项目 AD患者组(n=50) 健康对照组(n=16) 检验值 P值 男性/女性(例) 26/24 6/10 χ2=1.020 0.312 年龄(岁) 70.0±4.8 71.0±5.7 t=2.668 0.612 教育年限(年) 7.1±6.4 8.4±6.1 t=3.021 0.505 CDR(分) 1.33±0.45 0 t=6.001 <0.001 MMSE(分) 20.1±3.8 29.3±2.1 t=3.986 <0.001 α-syn(pg/mL) 560±194 410±85 t=2.315 0.001 Aβ40(pg/mL) 9621±614 9897±1802 t=−4.223 0.082 Aβ42(pg/mL) 589±405 895±392 t=−5.443 0.020 t-tau(pg/mL) 679±302 345±102 t=4.001 0.008 p-tau(pg/mL) 99±41 55±22 t=2.336 <0.001 t-tau/Aβ42 1.061±0.697 0.262±0.137 t=3.291 <0.001 Aβ42/Aβ40 0.065±0.014 0.099±0.028 t=−3.487 0.013 11C-PIB PET/CT阳性率 82.0%(41/50) 12.5%(2/16) χ2=25.787 <0.001 注:α-syn、Aβ40、Aβ42、t-tau、p-tau均为脑脊液生物标志物。AD为阿尔茨海默病;CDR为临床痴呆评定量表;MMSE为简易精神状态量表;α-syn为α突触核蛋白;Aβ为β淀粉样蛋白;t-tau/Aβ42为t-tau/Aβ42水平的比值;Aβ42/Aβ40为Aβ42/Aβ40水平的比值;PIB为匹兹堡化合物B;PET为正电子发射断层显像术;CT为计算机体层摄影术 表 1 2组受试者临床资料的比较
Table 1. Comparison of clinical data in two groups
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由ROC曲线的AUC可判断脑脊液生物标志物对AD患者的诊断准确率,AUC越大,诊断准确率越高。脑脊液生物标志物对AD患者的诊断准确率由高到低依次为t-tau/Aβ42、Aβ42/Aβ40、α-syn、Aβ42、t-tau、p-tau和Aβ40。t-tau/Aβ42和Aβ42/Aβ40诊断AD的最佳临界值分别为0.509和0.072,α-syn诊断AD的最佳临界值为465 pg/mL(表2)。
脑脊液生物标志物 AUC 最佳临界值 灵敏度(%) 特异度(%) 95%CI P值 α-syn(pg/mL) 0.795 465 74.0 68.8 0.628~0.851 0.004 Aβ40(pg/mL) 0.601 8562 42.3 54.0 0.402~0.732 0.074 Aβ42(pg/mL) 0.703 623 70.1 68.5 0.613~0.823 0.010 t-tau(pg/mL) 0.644 542 57.8 82.9 0.496~0.805 0.006 p-tau(pg/mL) 0.621 62 72.9 48.1 0.499~0.791 0.009 t-tau/Aβ42 0.892 0.509 80.0 81.2 0.801~0.949 < 0.001 Aβ42/Aβ40 0.865 0.072 76.0 75.0 0.658~0.900 < 0.001 注:ROC为受试者工作特征;AUC为曲线下面积;CI为可变区间;α-syn为α突触核蛋白;Aβ为β淀粉样蛋白;t-tau/Aβ42为t-tau/Aβ42水平的比值;Aβ42/Aβ40为Aβ42/Aβ40水平的比值 表 2 脑脊液生物标志物ROC曲线的指标结果
Table 2. Index results of receiver opertor characteristic curve of cerebrospinal fluid biomarkers
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由表2可知,t-tau/Aβ42、Aβ42/Aβ40和α-syn的诊断准确率较高,故分别分析三者与11C-PIB PET/CT显像联合诊断的价值。由表3可知,t-tau/Aβ42与11C-PIB PET/CT显像联合诊断的灵敏度和准确率均高于两者单独诊断(均P<0.05);Aβ42/Aβ40和α-syn分别与11C-PIB PET/CT显像联合诊断的灵敏度均高于其单独诊断(均P<0.05);其他各项指标的比较,差异均无统计学意义(均P>0.05)。
诊断项目 灵敏度(%) 特异度(%) 准确率(%) t-tau/Aβ42 80.0(40/50)a 81.2(13/16) 80.3a Aβ42/Aβ40 76.0(38/50)b 75.0(12/16) 75.8 α-syn 74.0(37/50)c 68.8(11/16) 72.7 11C-PIB PET/CT 78.0(39/50)abc 75.0(12/16) 77.2a 11C-PIB PET/CT+t-tau/Aβ42 96.0(48/50) 87.5(14/16) 93.9 11C-PIB PET/CT+Aβ42/Aβ40 94.0(47/50) 81.2(13/16) 90.9 11C-PIB PET/CT+α-syn 94.0(47/50) 75.0(12/16) 89.4 注:a表示与11C-PIB PET/CT+t-tau/Aβ42比较,灵敏度和准确率均较低(χ2=6.061、5.469、7.162、7.439,均P<0.05);b表示与11C-PIB PET/CT+Aβ42/Aβ40比较,灵敏度均较低(χ2=6.353、5.316,均P<0.05);c表示与11C-PIB PET/CT+α-syn比较,灵敏度均较低(χ2=7.440、5.316,均P<0.05)。PIB为匹兹堡化合物B;PET为正电子发射断层显像术;CT为计算机体层摄影术;t-tau/Aβ42为t-tau/Aβ42水平的比值;Aβ42/Aβ40为Aβ42/Aβ40水平的比值;Aβ为β淀粉样蛋白;α-syn为α突触核蛋白。t-tau、Aβ42、Aβ40和α-syn均为脑脊液生物标志物 表 3 脑脊液生物标志物、11C-PIB PET/CT及其联合诊断的效能
Table 3. The diagnostic efficacy of cerebrospinal fluid biomarkers, 11C-Pittsburgh compound-B PET/CT and their combined diagnosis
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由图2可见,t-tau/Aβ42、Aβ42/Aβ40和α-syn与11C-PIB PET/CT显像的SUVR有显著相关性(r=0.555、−0.451、0.445,均P<0.01);t-tau/Aβ42、Aβ42/Aβ40和α-syn与11C-PIB PET/CT诊断一致性的Kappa值分别为0.769、0.623、0.587,均P<0.001,其中t-tau/Aβ42与11C-PIB PET/CT诊断的一致性较好;α-syn和Aβ42/Aβ40与11C-PIB PET/CT诊断的一致性一般。
脑脊液生物标志物与11C-PIB PET/CT显像对阿尔茨海默病的诊断准确率及相关性研究
Diagnostic accuracy and correlation between cerebrospinal fluid biomarkers and 11C-PIB PET/CT imaging in Alzheimer disease
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摘要:
目的 探讨脑脊液生物标志物与11C-匹兹堡化合物B(PIB)PET/CT显像在阿尔茨海默病(AD)中的诊断准确率及相关性,确定脑脊液生物标志物诊断AD的最佳临界值。 方法 回顾性分析2011年1月至2020年3月在北部战区总医院行11C-PIB PET/CT显像和腰椎穿刺的66名受试者的临床资料,其中男性32名、女性34名,年龄61~82(71.0±3.4)岁。根据诊断标准分为AD患者组(50例)和健康对照组(16名)。采用酶联免疫吸附测定法检测脑脊液生物标志物α突触核蛋白(α-syn)、β淀粉样蛋白(Aβ)40、Aβ42、t-tau、p-tau水平,并计算t-tau/Aβ42水平的比值(t-tau/Aβ42)、Aβ42/Aβ40水平的比值(Aβ42/Aβ40)。采用受试者工作特征(ROC)曲线分析脑脊液生物标志物诊断AD的最佳临界值、灵敏度和特异度。分析11C-PIB PET/CT图像,计算平均Aβ沉积标准化摄取值比(SUVR),分析2组受试者脑脊液生物标志物与11C-PIB PET/CT显像诊断AD的准确率及相关性。2组间脑脊液生物标志物水平的比较采用独立样本t检验,计数资料的比较采用χ2检验,相关性采用Pearson相关性分析,一致性分析采用Kappa检验。 结果 AD患者组脑脊液生物标志物α-syn、t-tau、p-tau水平及t-tau/Aβ42均高于健康对照组(t=2.315、4.001、2.336、3.291,均P<0.01),而Aβ42水平和Aβ42/Aβ40均低于健康对照组(t=−5.443、−3.487,均P<0.05)。t-tau/Aβ42诊断AD的准确率最高(AUC=0.892,P<0.001),其次为Aβ42/Aβ40和α-syn(AUC=0.865、0.795,均P<0.01)。t-tau/Aβ42和Aβ42/Aβ40诊断AD的最佳临界值分别为0.509和0.072,α-syn诊断AD的最佳临界值为465 pg/mL。t-tau/Aβ42、Aβ42/Aβ40、α-syn和11C-PIB PET/CT显像诊断的灵敏度分别为80.0%(40/50)、76.0%(38/50)、74.0%(37/50)和78.0%(39/50),前三者分别与后者联合诊断AD的灵敏度为96.0%(48/50)、94.0%(47/50)和94.0%(47/50),均高于其单独诊断(χ2=5.316~7.440,均P<0.05);t-tau/Aβ42与11C-PIB PET/CT显像联合诊断的准确率均高于其单独诊断(93.9%对80.3%,93.9%对77.2%),且差异有统计学意义(χ2=5.469、7.439,均P<0.05)。t-tau/Aβ42、Aβ42/Aβ40和α-syn与11C-PIB PET/CT显像的SUVR有显著相关性(r=0.555、−0.451、0.445,均P<0.01);t-tau/Aβ42、Aβ42/Aβ40和α-syn与11C-PIB PET/CT显像诊断一致性的Kappa值分别为0.769、0.623、0.587,均P<0.001,其中t-tau/Aβ42与11C-PIB PET/CT显像诊断的一致性较好。 结论 t-tau/Aβ42、Aβ42/Aβ40和α-syn均为理想的AD诊断标准,结合11C-PIB PET/CT显像可提高对AD诊断的准确率。 -
关键词:
- 阿尔茨海默病 /
- 淀粉样蛋白 /
- tau蛋白质类 /
- 正电子发射断层显像术 /
- 体层摄像术,X线计算机 /
- 11C-匹兹堡化合物B
Abstract:Objective To investigate the diagnostic accuracy and correlation between cerebrospinal fluid biomarkers and 11C-Pittsburgh compound-B (PIB) PET/CT imaging in Alzheimer disease (AD). The optimal cut-off values of cerebrospinal fluid biomarkers are also determined. Methods The clinical data of 66 subjects who underwent 11C-PIB PET/CT imaging and lumbar puncture at the General Hospital of Northern Theater Command from January 2011 to March 2020 were retrospectively analyzed. The participants included 32 males and 34 females aged 61–82 (71.0±3.4) years and were divided into the AD patient group (n=50) and the healthy control group (n=16) according to established criteria. Enzyme-linked immunosorbent assay was used to detect levels of the cerebrospinal fluid biomarkers α-synuclein (α-syn), β-amyloid (Aβ) 40, Aβ42, t-tau and p-tau. The level ratios of t-tau to Aβ42 (t-tau/Aβ42) and Aβ42 to Aβ40 (Aβ42/Aβ40) were calculated. The receiver operator characteristic (ROC) curve was used to analyze the diagnostic optimal cut-off value, sensitivity, and specificity of the cerebrospinal fluid biomarkers. 11C-PIB PET/CT images were analyzed. The average Aβ deposition standardized uptake value ratio (SUVR) was calculated, and the accuracy and correlation between the two groups of cerebrospinal fluid biomarkers and 11C-PIB PET/CT imaging in the diagnosis of AD were analyzed. The levels of cerebrospinal fluid biomarkers between the two groups was compared by independent-sample t test, and the count data were compared by χ2 test. Pearson correlation coefficients were calculated for correlation analysis, and consistency was determined using the Kappa test. Results The levels of cerebrospinal fluid biomarkers α-syn, t-tau andp-tau as well as t-tau/Aβ42 in the AD patient group were higher than those in the healthy control group (t=2.315, 4.001, 2.336, 3.291, all P<0.01), while the Aβ42 level and Aβ42/Aβ40 were lower than those in the healthy control group (t=−5.443, −3.487, both P<0.05). T-tau/Aβ42 revealed the highest diagnostic accuracy for AD (AUC=0.892, P<0.001), followed by Aβ42/Aβ40 and α-syn (AUC=0.865, 0.795, both P<0.01). The optimal cut-off values of t-tau/Aβ42 and Aβ42/Aβ40 were 0.509 and 0.072, respectively, and the aptimal cut-off value of α-syn was 465 pg/mL. The sensitivities of t-tau/Aβ42, Aβ42/Aβ40, α-syn and 11C-PIB PET/CT imaging for predicting AD were 80.0% (40/50), 76.0% (38/50), 74.0% (37/50) and 78.0% (39/50), respectively. The sensitivities of the first three methods in combination with 11C-PIB PET/CT imaging for predicting AD were 96.0% (48/50), 94.0% (47/50) and 94.0% (47/50), respectively, which were all higher than a single method (χ2=5.316–7.440, all P<0.05). The combined diagnostic accuracy of t-tau/Aβ42 and 11C-PIB PET/CT imaging was greater than that of a single diagnostic method (93.9% vs. 80.3%, 93.9% vs. 77.2%), and the difference noted was statistically significant (χ2=5.469, 7.439, both P<0.05). T-tau/Aβ42, Aβ42/Aβ40 and α-syn level were significantly correlated with 11C-PIB PET/CT SUVR (r=0.555, −0.451, 0.445, all P<0.01). The Kappa value of diagnostic consistencies of t-tau/Aβ42, Aβ42/Aβ40 and α-syn with 11C-PIB PET/CT imaging were 0.769, 0.623 and 0.587, respectively (all P<0.001). Among the criteria considered, t-tau/Aβ42 demonstrated great diagnostic consistency with 11C-PIB PET/CT. Conclusions T-tau/Aβ42, Aβ42/Aβ40 and α-syn are ideal diagnostic criteria for AD. Combining these parameters with 11C-PIB PET/CT imaging could improve the accuracy of AD diagnosis. -
表 1 2组受试者临床资料的比较
Table 1. Comparison of clinical data in two groups
项目 AD患者组(n=50) 健康对照组(n=16) 检验值 P值 男性/女性(例) 26/24 6/10 χ2=1.020 0.312 年龄(岁) 70.0±4.8 71.0±5.7 t=2.668 0.612 教育年限(年) 7.1±6.4 8.4±6.1 t=3.021 0.505 CDR(分) 1.33±0.45 0 t=6.001 <0.001 MMSE(分) 20.1±3.8 29.3±2.1 t=3.986 <0.001 α-syn(pg/mL) 560±194 410±85 t=2.315 0.001 Aβ40(pg/mL) 9621±614 9897±1802 t=−4.223 0.082 Aβ42(pg/mL) 589±405 895±392 t=−5.443 0.020 t-tau(pg/mL) 679±302 345±102 t=4.001 0.008 p-tau(pg/mL) 99±41 55±22 t=2.336 <0.001 t-tau/Aβ42 1.061±0.697 0.262±0.137 t=3.291 <0.001 Aβ42/Aβ40 0.065±0.014 0.099±0.028 t=−3.487 0.013 11C-PIB PET/CT阳性率 82.0%(41/50) 12.5%(2/16) χ2=25.787 <0.001 注:α-syn、Aβ40、Aβ42、t-tau、p-tau均为脑脊液生物标志物。AD为阿尔茨海默病;CDR为临床痴呆评定量表;MMSE为简易精神状态量表;α-syn为α突触核蛋白;Aβ为β淀粉样蛋白;t-tau/Aβ42为t-tau/Aβ42水平的比值;Aβ42/Aβ40为Aβ42/Aβ40水平的比值;PIB为匹兹堡化合物B;PET为正电子发射断层显像术;CT为计算机体层摄影术 表 2 脑脊液生物标志物ROC曲线的指标结果
Table 2. Index results of receiver opertor characteristic curve of cerebrospinal fluid biomarkers
脑脊液生物标志物 AUC 最佳临界值 灵敏度(%) 特异度(%) 95%CI P值 α-syn(pg/mL) 0.795 465 74.0 68.8 0.628~0.851 0.004 Aβ40(pg/mL) 0.601 8562 42.3 54.0 0.402~0.732 0.074 Aβ42(pg/mL) 0.703 623 70.1 68.5 0.613~0.823 0.010 t-tau(pg/mL) 0.644 542 57.8 82.9 0.496~0.805 0.006 p-tau(pg/mL) 0.621 62 72.9 48.1 0.499~0.791 0.009 t-tau/Aβ42 0.892 0.509 80.0 81.2 0.801~0.949 < 0.001 Aβ42/Aβ40 0.865 0.072 76.0 75.0 0.658~0.900 < 0.001 注:ROC为受试者工作特征;AUC为曲线下面积;CI为可变区间;α-syn为α突触核蛋白;Aβ为β淀粉样蛋白;t-tau/Aβ42为t-tau/Aβ42水平的比值;Aβ42/Aβ40为Aβ42/Aβ40水平的比值 表 3 脑脊液生物标志物、11C-PIB PET/CT及其联合诊断的效能
Table 3. The diagnostic efficacy of cerebrospinal fluid biomarkers, 11C-Pittsburgh compound-B PET/CT and their combined diagnosis
诊断项目 灵敏度(%) 特异度(%) 准确率(%) t-tau/Aβ42 80.0(40/50)a 81.2(13/16) 80.3a Aβ42/Aβ40 76.0(38/50)b 75.0(12/16) 75.8 α-syn 74.0(37/50)c 68.8(11/16) 72.7 11C-PIB PET/CT 78.0(39/50)abc 75.0(12/16) 77.2a 11C-PIB PET/CT+t-tau/Aβ42 96.0(48/50) 87.5(14/16) 93.9 11C-PIB PET/CT+Aβ42/Aβ40 94.0(47/50) 81.2(13/16) 90.9 11C-PIB PET/CT+α-syn 94.0(47/50) 75.0(12/16) 89.4 注:a表示与11C-PIB PET/CT+t-tau/Aβ42比较,灵敏度和准确率均较低(χ2=6.061、5.469、7.162、7.439,均P<0.05);b表示与11C-PIB PET/CT+Aβ42/Aβ40比较,灵敏度均较低(χ2=6.353、5.316,均P<0.05);c表示与11C-PIB PET/CT+α-syn比较,灵敏度均较低(χ2=7.440、5.316,均P<0.05)。PIB为匹兹堡化合物B;PET为正电子发射断层显像术;CT为计算机体层摄影术;t-tau/Aβ42为t-tau/Aβ42水平的比值;Aβ42/Aβ40为Aβ42/Aβ40水平的比值;Aβ为β淀粉样蛋白;α-syn为α突触核蛋白。t-tau、Aβ42、Aβ40和α-syn均为脑脊液生物标志物 -
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