Laboratory of Neuroimaging and Alzheimer's Epidemiology, IRCCS Istituto Centro San Giovanni diDio Fatebenefratelli, Brescia, Italy.
Unit of Statistics, IRCCS Istituto Centro San Giovanni diDio Fatebenefratelli, Brescia, Italy.
J Alzheimers Dis. 2019;69(1):3-14. doi: 10.3233/JAD-180152.
Early Alzheimer's disease (AD) detection using cerebrospinal fluid (CSF) biomarkers has been recommended as enrichment strategy for trials involving mild cognitive impairment (MCI) patients.
To model a prodromal AD trial for identifying MRI structural biomarkers to improve subject selection and to be used as surrogate outcomes of disease progression.
APOE ɛ4 specific CSF Aβ42/P-tau cut-offs were used to identify MCI with prodromal AD (Aβ42/P-tau positive) in the WP5-PharmaCog (E-ADNI) cohort. Linear mixed models were performed 1) with baseline structural biomarker, time, and biomarker×time interaction as factors to predict longitudinal changes in ADAS-cog13, 2) with Aβ42/P-tau status, time, and Aβ42/P-tau status×time interaction as factors to explain the longitudinal changes in MRI measures, and 3) to compute sample size estimation for a trial implemented with the selected biomarkers.
Only baseline lateral ventricle volume was able to identify a subgroup of prodromal AD patients who declined faster (interaction, p = 0.003). Lateral ventricle volume and medial temporal lobe measures were the biomarkers most sensitive to disease progression (interaction, p≤0.042). Enrichment through ventricular volume reduced the sample size that a clinical trial would require from 13 to 76%, depending on structural outcome variable. The biomarker needing the lowest sample size was the hippocampal subfield GC-ML-DG (granule cells of molecular layer of the dentate gyrus) (n = 82 per arm to demonstrate a 20% atrophy reduction).
MRI structural biomarkers can enrich prodromal AD with fast progressors and significantly decrease group size in clinical trials of disease modifying drugs.
使用脑脊液（CSF）生物标志物早期检测阿尔茨海默病（AD）已被推荐为涉及轻度认知障碍（MCI）患者的试验的富集策略。
建立一个前驱 AD 试验模型，以识别 MRI 结构生物标志物，从而改善受试者选择，并作为疾病进展的替代终点。
使用 APOE ɛ4 特异性 CSF Aβ42/P-tau 截断值在 WP5-PharmaCog（E-ADNI）队列中识别有前驱 AD（Aβ42/P-tau 阳性）的 MCI。线性混合模型分别进行了 1）以基线结构生物标志物、时间和生物标志物×时间交互作用作为因素，预测 ADAS-cog13 的纵向变化；2）以 Aβ42/P-tau 状态、时间和 Aβ42/P-tau 状态×时间交互作用作为因素，解释 MRI 测量的纵向变化；3）根据选定的生物标志物计算试验的样本量估计。
只有基线侧脑室容积能够识别出进展较快的前驱 AD 患者亚组（交互作用，p = 0.003）。侧脑室容积和内侧颞叶测量值是对疾病进展最敏感的生物标志物（交互作用，p≤0.042）。通过脑室容积进行富集，可以将临床试验所需的样本量减少 13%至 76%，具体取决于结构结局变量。需要最小样本量的生物标志物是海马亚区 GC-ML-DG（齿状回分子层的颗粒细胞）（每组 82 例，以证明萎缩减少 20%）。
MRI 结构生物标志物可以富集快速进展的前驱 AD 患者，并显著减少疾病修饰药物临床试验的组间规模。
