Chengjie Xiong, Division of Biostatistics, Campus Box 8067, 4523 Clayton Ave., St. Louis, MO, 63110-1093, Phone: 314-362-3635; Fax: 314-362-2693, Email:
J Prev Alzheimers Dis. 2018;5(2):110-119. doi: 10.14283/jpad.2018.16.
Clinical trials of investigational drugs for Alzheimer disease (AD) increasingly focus on the prodromal (symptomatic) stage of the illness and now its preclinical (asymptomatic) stage. Sensitive and specific cognitive and functional endpoints are needed to track subtle cognitive and functional changes in the early and preclinical stages to minimize sample sizes in these trials.
To identify informative items in a standard clinical assessment protocol and a psychometric battery that are predictive of onset of dementia symptom.
Longitudinal retrospective study.
Washington University (WU) Knight Alzheimer Disease Research Center (ADRC).
A total of 735 individuals at least 65 years old and cognitively normal at baseline from a longitudinal clinical cohort at the WU Knight ADRC.
The annual clinical assessment included a wide spectrum of functional and cognitive domains; a comprehensive psychometric battery was completed about 2 weeks after the clinical evaluation. Psychometricians are blinded to the results of the clinical evaluation and to the prior performance of the participants on the psychometric tests.
The mean age at baseline of the 735 participants was 74.30 and 62.31% were female. 240 individuals developed prodromal dementia symptoms (consistent with mild cognitive impairment due to AD and with very mild AD dementia) during longitudinal follow-up (mean follow-up=6.79 years). Among a total of 562 items in the clinical and cognitive assessments under analysis, 292 (52%) were identified as informative because their longitudinal changes were predictive of symptomatic onset. When these items were used to form the functional and cognitive composites, the longitudinal rates of changes were free of a learning effect and captured subtle longitudinal progression prior to symptomatic onset. The rates of change were much greater right after the symptomatic onset than those from the functional and cognitive composites formed using non-informative items. Although the sample sizes for prevention trials (prior to symptomatic onset) using the informative items still yield large numbers, the sample sizes for early treatment trial (after symptomatic onset) was much smaller than those derived from all the items or from the non-informative items alone.
The antecedent longitudinal changes in nearly half of the items in a clinical assessment protocol and a comprehensive cognitive battery did not show statistically significant ability to predict the dementia symptom onset, and hence may be non-informative to track the preclinical functional and cognitive progression of AD. The remaining items, on the other hand, captured some of the preclinical changes prior to the symptom onset, but performed much better right after the symptom onset. Currently ongoing prevention trials on preclinical AD of elderly individuals may need to re-assess the sample sizes and statistical power.
针对阿尔茨海默病（AD）的研究性药物临床试验越来越关注疾病的前驱期（有症状）和临床前期（无症状）。需要敏感和特异的认知和功能终点来跟踪早期和临床前期的细微认知和功能变化，以最小化这些试验的样本量。
确定标准临床评估方案和心理计量学测试中能预测痴呆症状发生的有意义项目。
纵向回顾性研究。
华盛顿大学（WU）Knight 阿尔茨海默病研究中心（ADRC）。
WU Knight ADRC 纵向临床队列中至少 65 岁且基线时认知正常的 735 名个体。
每年的临床评估包括广泛的功能和认知领域；大约在临床评估后 2 周完成全面的心理计量学测试。心理计量学家对临床评估的结果以及参与者在心理计量测试中的先前表现均不知情。
735 名参与者的基线平均年龄为 74.30 岁，62.31%为女性。240 名个体在纵向随访期间出现前驱期痴呆症状（符合 AD 导致的轻度认知障碍和非常轻度 AD 痴呆）（平均随访时间=6.79 年）。在分析的临床和认知评估中共有 562 个项目，其中 292 个（52%）被确定为有意义项目，因为它们的纵向变化可以预测症状发生。当这些项目被用于形成功能和认知综合指标时，纵向变化率没有学习效应，并且可以在症状发生前捕捉到细微的纵向进展。症状发生后，变化率远高于使用无意义项目形成的功能和认知综合指标。虽然使用有意义项目的预防试验（在症状发生前）的样本量仍然很大，但早期治疗试验（在症状发生后）的样本量要小得多，小于从所有项目或仅从无意义项目获得的样本量。
临床评估方案和全面认知测试中近一半项目的纵向变化没有显示出预测痴呆症状发生的统计学能力，因此可能无法用于跟踪 AD 的临床前期功能和认知进展。另一方面，其余项目在症状发生前捕捉到了一些临床前期变化，但在症状发生后表现更好。目前正在进行的老年人群临床前期 AD 的预防试验可能需要重新评估样本量和统计功效。
