背景:临床痴呆评分(CDR)全局(CDR-G)和框评分总和(CDR-SB)通常用作主要结果变量,以衡量症状性阿尔茨海默病(AD)临床试验中的进展或治疗效果。
目的:我们试图确定CDR是否对症状前AD的变化敏感,以及在多年的抗淀粉样蛋白在无症状阿尔茨海默病(A4)二级预防研究中是否存在动态的特定CDR盒。
方法:所有参与者进入研究的CDR-G为0。框得分被单独检查,并作为认知的复合(记忆,定位和判断/解决问题)和功能(社区事务和家庭/爱好)。仅当在两次连续访问中发生变化时,才列出框得分的进展。
方法:A4研究在澳大利亚的67个地点进行,加拿大,日本和美国。
方法:1,147个人,年龄在65~85岁之间的患者被随机分为安慰剂组(n=583)和索兰珠单抗组(n=564).所有参与者都接受了基线flobetapirPET扫描,年度CDR,在240周的过程中,每6个月进行一次认知测试,使用原发性阿尔茨海默氏症认知综合指数(PACC)。
方法:使用广义估计方程和广义最小二乘模型来探索CDR-G中的建模平均进展率,CDR-SB,单个CDR盒,solanezumab和安慰剂组的CDR综合评分。模型进行了改装,以探索在基线时淀粉样蛋白的厘状三元组中CDR进展的概率(<46.1CL,46.1至77.2CL,>77.2CL)。所有型号都包括年龄效应,教育,APOEε4载波状态,基线淀粉样蛋白与flobetapirPET,治疗,和治疗时间。
结果:在CDR-G中,安慰剂组和solanezumab组之间没有统计学差异,CDR-SB,试验过程中特定的CDR框或CDR复合评分。判断/解决问题的变化存在于基线,并随着时间的推移而持续。但CDR存储盒和CDR认知复合的进展很快占主导地位。社区事务和家庭/爱好几乎没有进展。个人护理保持稳定。CDR框的认知和功能进展的概率开始于中等或晚期淀粉样蛋白水平(46.1至77.2CL,>77.2CL),而最低水平的淀粉样蛋白(<46.1CL)显示相对较少的CDR进展。
结论:研究结果表明,CDR记忆盒和CDR认知复合物在240周内进展,并与基线时淀粉样蛋白的中晚期相关。社区事务和家庭/爱好的功能变化相对稳定。这些发现表明,特定的CDR框评分变化可能有助于完善我们在未来AD预防试验中对预期治疗效果的测量。
BACKGROUND: Clinical Dementia Rating (CDR) global (CDR-G) and sum of box scores (CDR-SB) are commonly used as primary outcome variables to measure progression or treatment effects in symptomatic Alzheimer disease (AD) clinical trials.
OBJECTIVE: We sought to determine whether the CDR is sensitive to change in pre-symptomatic AD and whether there are specific CDR boxes that are dynamic during the multi-year Anti-Amyloid in Asymptomatic Alzheimer\'s Disease (A4) secondary prevention
study.
METHODS: All participants entered the
study with a CDR-G of 0. Box scores were examined individually and as composites of cognition (memory, orientation and judgment /problem solving) and function (community affairs and home/ hobbies). A progression in box score was tabulated only when the change occurred at two consecutive visits.
METHODS: The A4
study took place at 67 sites in Australia, Canada, Japan and the United States.
METHODS: 1,147 individuals, ages 65-85, were randomized to either placebo (n= 583) or solanezumab (n= 564). All participants received a baseline flobetapir PET scan, an annual CDR, and cognitive testing every 6 months with the Primary Alzheimer Cognitive Composite (PACC) over the course of 240 weeks.
METHODS: Generalized estimating equations and generalized least square models were used to explore the modeled mean progression rate in the CDR-G, CDR-SB, individual CDR boxes, and CDR composite scores in the combined solanezumab and placebo groups. Models were refitted to explore the probability of CDR progression in centiloid tertiles of amyloid at baseline (< 46.1 CL, 46.1 to 77.2 CL, > 77.2 CL). All models included effects for age, education, APOEε4 carrier status, baseline amyloid with flobetapir PET, treatment, and time-by-treatment.
RESULTS: There were no statistical differences between the placebo or solanezumab groups in CDR-G, CDR-SB, specific CDR boxes or CDR composite scores over the course of the
trial. Changes in judgment/ problem solving were present at baseline and persisted over time, but progression on the CDR memory box and the CDR cognitive composite quickly predominated. Community affairs and home/ hobbies showed little progression. Personal care remained stable. The probability of cognitive and functional progression in CDR boxes began either at the intermediate or advanced amyloid level (46.1 to 77.2 CL, > 77.2 CL), while amyloid at the lowest level (< 46.1 CL) showed relatively little CDR progression.
CONCLUSIONS: The findings suggest that the CDR memory box and the CDR cognitive composite progressed over 240 weeks and were associated with intermediate and advanced stages of amyloid at baseline. Functional changes in community affairs and home/hobbies were relatively stable. These finding suggest that specific CDR box score changes may help refine our measurement of expected treatment effects in future AD prevention trials.