Department of Psychiatry, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Alzheimers Dement. 2010 Sep;6(5):367-77. doi: 10.1016/j.jalz.2010.07.004.
Low cerebrospinal fluid (CSF) amyloid-beta(1-42) concentration and high total-tau/Abeta(1-42) ratio have been recommended to support the diagnosis of prodromal Alzheimer's disease (AD) in patients with amnestic mild cognitive impairment (aMCI) and also to select patients for clinical trials (Shaw et al, Ann Neurol 2009;65:403-13; Dubois et al, Lancet Neurol 2007;6:734-46).
We tested this recommendation with clinical trials simulations using patients from the Alzheimer Disease Neuroimaging Initiative who fulfilled the following entry criteria: (1) aMCI, (2) aMCI with CSF Abeta(1-42) <or=192 mg/mL, (3) and aMCI with total-tau/Abeta(1-42) >0.39. For each criterion, we randomly resampled the database obtaining samples for 1000 trials for each trial scenario, planning for 1 or 2 year trials with samples from 50 to 400 patients per treatment or placebo group, with up to 40% dropouts, outcomes after using the AD assessment scale-cognitive subscale and clinical dementia rating scale with effect sizes ranging from 0.15 to 0.75, and calculated statistical power.
Approximately 70% to 74% of aMCI patients with CSF measures met biomarker criteria. The addition of the low Abeta(1-42) or high tau/Abeta(1-42) requirement resulted in minimal or no increase in the power of the trials compared with enrolling aMCI without requiring the biomarker criteria. Slightly larger mean differences between the placebo and treatment groups fulfilling biomarker criteria were offset by increased outcome variability within the groups.
Although patients with aMCI or patients with prodromal AD meeting CSF biomarkers criteria were slightly more cognitively impaired and showed greater decline than patients with aMCI diagnosed without considering the biomarkers, the requirement of biomarker-positive patients would most likely not result in more efficient clinical trials, and trials would take longer because fewer patients would be available. A CSF Abeta(1-42) marker, however, could be useful as an explanatory variable or covariate when warranted by the action of a drug.
低脑脊髓液（CSF）β淀粉样蛋白（1-42）浓度和高总 tau/Abeta（1-42）比值已被推荐用于支持有遗忘型轻度认知障碍（aMCI）的前驱性阿尔茨海默病（AD）患者的诊断，并且还用于选择临床试验的患者（Shaw 等人，Ann Neurol 2009；65:403-13；Dubois 等人，Lancet Neurol 2007；6:734-46）。
我们使用符合以下纳入标准的阿尔茨海默病神经影像学倡议（Alzheimer Disease Neuroimaging Initiative）患者进行临床试验模拟来测试这一建议：（1）aMCI，（2）CSF Abeta（1-42）<或=192mg/mL 的 aMCI，（3）和总 tau/Abeta（1-42）>0.39 的 aMCI。对于每个标准，我们随机重新采样数据库，为每个试验方案获得 1000 个试验的样本，计划进行 1 或 2 年的试验，每个治疗或安慰剂组有 50 至 400 名患者的样本，有高达 40%的脱落率，使用 AD 评估量表认知分量表和临床痴呆评定量表进行结果评估，效应大小范围为 0.15 至 0.75，并计算统计功效。
大约 70%至 74%的有 CSF 测量的 aMCI 患者符合生物标志物标准。与招募没有生物标志物标准的 aMCI 相比，添加低 Abeta（1-42）或高 tau/Abeta（1-42）要求只会使试验的功效略有增加或没有增加。符合生物标志物标准的安慰剂和治疗组之间的平均差异略大，但组内的结果变异性增加。
虽然符合 CSF 生物标志物标准的 aMCI 患者或前驱性 AD 患者比未考虑生物标志物的 aMCI 患者认知障碍略严重，并且表现出更大的衰退，但生物标志物阳性患者的要求不太可能导致更有效的临床试验，并且试验时间会更长，因为可用于试验的患者较少。但是，当药物作用需要时，Abeta（1-42）脑脊液标志物可以作为解释变量或协变量。
