CSF Biomarkers and Incipient Alzheimer Disease in Patients With Mild Cognitive Impairment
CSF Biomarkers and Incipient Alzheimer Disease in Patients With Mild Cognitive Impairment
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DOI：
10.1001/jama.2009.1064
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发表时间：
2009-07-22
影响因子：
120.7
通讯作者：
Blennow, Kaj
中科院分区：
文献类型：
--
作者：
Mattsson, Niklas;Zetterberg, Henrik;Blennow, Kaj
背景小规模的单中心研究表明，脑脊液（CSF）生物标志物可能有助于识别轻度认知障碍（MCI）患者的早期阿尔茨海默病（AD），但尚未进行大规模的多中心研究。目的确定CSF β-淀粉样蛋白（1-42）诊断的准确性（A β 42）、总tau蛋白（T-tau）和在位置苏氨酸181磷酸化的tau（P-tau）用于预测MCI患者中的初期AD。1990-2007年进行的一项涉及AD患者和对照组的横断面研究，以确定临界点，随后是一项涉及MCI患者的前瞻性队列研究。在欧洲和美国的12个中心共招募了750名MCI患者，529名AD患者和304名对照。MCI患者随访至少2年或直至症状进展为临床dementia.Main Outcome Measures的敏感性，特异性，阳性和阴性似然比（LRs）的CSF A β 42，T-tau，和P-tau识别初期AD。结果在随访期间，271例MCI患者被诊断为AD和59例其他痴呆。特别是A β 42测定具有相当大的研究中心间变异性。发生AD的患者中位A β 42（356;范围，96-1075 ng/L）和较高的P-tau（81;范围，15-183纳克/升）和T-tau蛋白（582;范围，83-2174 ng/L）水平高于随访期间未发生AD的MCI患者（579; A β 42的范围为1211420 ng/L; 53; P-tau的范围为15-163 ng/L;和294; T-tau的范围为31-2483 ng/L，P < .001）。A β 42、P-tau和T-tau的受试者工作特征曲线下面积分别为0.78（95%置信区间[CI]，0.75-0.82）、0.76（95% CI，0.72-0.80）和0.79（95% CI，0.76-0.83）。在AD组和对照组中定义敏感性设定为85%的临界值，并在MCI组中进行测试，其中A β 42/P-tau比值和T-tau的组合以83%的敏感性鉴定早期AD。（95% CI，78%-88%），特异性72%（95% CI，68%-76%），阳性LR，3.0（95% CI，2.5-3.4），阴性LR，0.24（95% CI，0.21-0.28）。结论多中心研究发现，CSF A β 42、T-tau和P-tau对早期AD的诊断准确性较高，但与单中心研究相比，准确性较低。研究中心间检测变异性突出了分析技术和临床程序标准化的必要性。JAMA. 2009;302（4）：385-393
Context Small single-center studies have shown that cerebrospinal fluid (CSF) biomarkers may be useful to identify incipient Alzheimer disease (AD) in patients with mild cognitive impairment (MCI), but large-scale multicenter studies have not been conducted.Objective To determine the diagnostic accuracy of CSF beta-amyloid(1-42) (A beta 42), total tau protein (T-tau), and tau phosphorylated at position threonine 181 (P-tau) for predicting incipient AD in patients with MCI.Design, Setting, and Participants The study had 2 parts: a cross-sectional study involving patients with AD and controls to identify cut points, followed by a prospective cohort study involving patients with MCI, conducted 1990-2007. A total of 750 individuals with MCI, 529 with AD, and 304 controls were recruited by 12 centers in Europe and the United States. Individuals with MCI were followed up for at least 2 years or until symptoms had progressed to clinical dementia.Main Outcome Measures Sensitivity, specificity, positive and negative likelihood ratios (LRs) of CSF A beta 42, T-tau, and P-tau for identifying incipient AD.Results During follow-up, 271 participants with MCI were diagnosed with AD and 59 with other dementias. The A beta 42 assay in particular had considerable intersite variability. Patients who developed AD had lower median A beta 42 (356; range, 96-1075 ng/L) and higher P-tau (81; range, 15-183 ng/L) and T-tau (582; range, 83-2174 ng/L) levels than MCI patients who did not develop AD during follow-up (579; range, 1211420 ng/L for A beta 42; 53; range, 15-163 ng/L for P-tau; and 294; range, 31-2483 ng/L for T-tau, P < .001). The area under the receiver operating characteristic curve was 0.78 (95% confidence interval [CI], 0.75-0.82) for A beta 42, 0.76 (95% CI, 0.72-0.80) for P-tau, and 0.79 (95% CI, 0.76-0.83) for T-tau. Cut-offs with sensitivity set to 85% were defined in the AD and control groups and tested in the MCI group, where the combination of A beta 42/P-tau ratio and T-tau identified incipient AD with a sensitivity of 83% (95% CI, 78%-88%), specificity 72% (95% CI, 68%-76%), positive LR, 3.0 (95% CI, 2.5-3.4), and negative LR, 0.24 (95% CI, 0.21-0.28). The positive predictive value was 62% and the negative predictive value was 88%.Conclusions This multicenter study found that CSF A beta 42, T-tau, and P-tau identify incipient AD with good accuracy, but less accurately than reported from single-center studies. Intersite assay variability highlights a need for standardization of analytical techniques and clinical procedures. JAMA. 2009;302(4):385-393