Janssen Research and Development, LLC, Raritan, New Jersey, USA.
Neuropsychiatr Dis Treat. 2014 May 24;10:929-52. doi: 10.2147/NDT.S62323. eCollection 2014.
The objective of this analysis was to develop a nonlinear disease progression model, using an expanded set of covariates that captures the longitudinal Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) scores. These were derived from the Alzheimer's Disease Neuroimaging Initiative ADNI-1 study, of 301 Alzheimer's disease and mild cognitive impairment patients who were followed for 2-3 years.
The model describes progression rate and baseline disease score as a function of covariates. The covariates that were tested fell into five groups: a) hippocampal volume; b) serum and cerebrospinal fluid (CSF) biomarkers; c) demographics and apolipoprotein Epsilon 4 (ApoE4) allele status; d) baseline cognitive tests; and e) disease state and comedications.
Covariates associated with baseline disease severity were disease state, hippocampal volume, and comedication use. Disease progression rate was influenced by baseline CSF biomarkers, Trail-Making Test part A score, delayed logical memory test score, and current level of impairment as measured by CDR-SB. The rate of disease progression was dependent on disease severity, with intermediate scores around the inflection point score of 10 exhibiting high disease progression rate. The CDR-SB disease progression rate in a typical patient, with late mild cognitive impairment and mild Alzheimer's disease, was estimated to be approximately 0.5 and 1.4 points/year, respectively.
In conclusion, this model describes disease progression in terms of CDR-SB changes in patients and its dependency on novel covariates. The CSF biomarkers included in the model discriminate mild cognitive impairment subjects as progressors and nonprogressors. Therefore, the model may be utilized for optimizing study designs, through patient population enrichment and clinical trial simulations.
本分析旨在建立一个非线性疾病进展模型，使用一组扩展的协变量来捕捉纵向临床痴呆评定量表-总和评分（CDR-SB）的变化。这些协变量来自阿尔茨海默病神经影像学倡议 ADNI-1 研究，该研究纳入了 301 名阿尔茨海默病和轻度认知障碍患者，随访时间为 2-3 年。
该模型将进展速度和基线疾病评分描述为协变量的函数。测试的协变量分为五类：a）海马体积；b）血清和脑脊液（CSF）生物标志物；c）人口统计学和载脂蛋白 Epsilon 4（ApoE4）等位基因状态；d）基线认知测试；和 e）疾病状态和合并用药。
与基线疾病严重程度相关的协变量是疾病状态、海马体积和合并用药。疾病进展速度受到基线 CSF 生物标志物、连线测试 A 部分得分、延迟逻辑记忆测试得分以及 CDR-SB 测量的当前损害水平的影响。疾病进展速度取决于疾病严重程度，拐点 10 分左右的中间评分表现出较高的疾病进展速度。一个患有晚期轻度认知障碍和轻度阿尔茨海默病的典型患者的 CDR-SB 疾病进展速度估计分别约为 0.5 和 1.4 分/年。
总之，该模型根据患者的 CDR-SB 变化及其对新型协变量的依赖性来描述疾病进展。纳入模型的 CSF 生物标志物可区分轻度认知障碍患者的进展者和非进展者。因此，该模型可用于通过患者人群富集和临床试验模拟来优化研究设计。
