Raschetti Roberto, Albanese Emiliano, Vanacore Nicola, Maggini Marina
National Center for Epidemiology, Surveillance and Health Promotion, National Institute of Health, Rome, Italy.
PLoS Med. 2007 Nov 27;4(11):e338. doi: 10.1371/journal.pmed.0040338.
Mild cognitive impairment (MCI) refers to a transitional zone between normal ageing and dementia. Despite the uncertainty regarding the definition of MCI as a clinical entity, clinical trials have been conducted in the attempt to study the role of cholinesterase inhibitors (ChEIs) currently approved for symptomatic treatment of mild to moderate Alzheimer disease (AD), in preventing progression from MCI to AD. The objective of this review is to assess the effects of ChEIs (donepezil, rivastigmine, and galantamine) in delaying the conversion from MCI to Alzheimer disease or dementia.
The terms "donepezil", "rivastigmine", "galantamine", and "mild cognitive impairment" and their variants, synonyms, and acronyms were used as search terms in four electronic databases (MEDLINE, EMBASE, Cochrane, PsycINFO) and three registers: the Cochrane Collaboration Trial Register, Current Controlled Trials, and ClinicalTrials.gov. Published and unpublished studies were included if they were randomized clinical trials published (or described) in English and conducted among persons who had received a diagnosis of MCI and/or abnormal memory function documented by a neuropsychological assessment. A standardized data extraction form was used. The reporting quality was assessed using the Jadad scale. Three published and five unpublished trials met the inclusion criteria (three on donepezil, two on rivastigmine, and three on galantamine). Enrolment criteria differed among the trials, so the study populations were not homogeneous. The duration of the trials ranged from 24 wk to 3 y. No significant differences emerged in the probability of conversion from MCI to AD or dementia between the treated groups and the placebo groups. The rate of conversion ranged from 13% (over 2 y) to 25% (over 3 y) among treated patients, and from 18% (over 2 y) to 28% (over 3 y) among those in the placebo groups. Only for two studies was it possible to derive point estimates of the relative risk of conversion: 0.85 (95% confidence interval 0.64-1.12), and 0.84 (0.57-1.25). Statistically significant differences emerged for three secondary end points. However, when adjusting for multiple comparisons, only one difference remained significant (i.e., the rate of atrophy in the whole brain).
The use of ChEIs in MCI was not associated with any delay in the onset of AD or dementia. Moreover, the safety profile showed that the risks associated with ChEIs are not negligible. The uncertainty regarding MCI as a clinical entity raises the question as to the scientific validity of these trials.
轻度认知障碍（MCI）是正常衰老与痴呆之间的过渡阶段。尽管MCI作为一种临床实体的定义尚不确定，但已开展临床试验，旨在研究目前已获批用于轻至中度阿尔茨海默病（AD）症状性治疗的胆碱酯酶抑制剂（ChEIs）在预防MCI进展为AD方面的作用。本综述的目的是评估ChEIs（多奈哌齐、卡巴拉汀和加兰他敏）在延缓MCI转化为阿尔茨海默病或痴呆方面的效果。
使用“多奈哌齐”“卡巴拉汀”“加兰他敏”和“轻度认知障碍”及其变体、同义词和首字母缩略词作为检索词，在四个电子数据库（MEDLINE、EMBASE、Cochrane、PsycINFO）和三个登记处进行检索：Cochrane协作试验登记处、当前对照试验登记处和ClinicalTrials.gov。纳入已发表和未发表的研究，条件为：以英文发表（或描述）的随机临床试验，且研究对象为已确诊MCI和/或经神经心理学评估记录有异常记忆功能的人群。使用标准化的数据提取表。采用Jadad量表评估报告质量。三项已发表和五项未发表的试验符合纳入标准（三项关于多奈哌齐，两项关于卡巴拉汀，三项关于加兰他敏）。各试验的纳入标准不同，因此研究人群并不同质。试验持续时间为24周至3年。治疗组与安慰剂组在MCI转化为AD或痴呆的概率上未出现显著差异。治疗患者的转化率在13%（2年以上）至25%（3年以上）之间，安慰剂组患者的转化率在18%（2年以上）至28%（3年以上）之间。仅两项研究能够得出转化相对风险的点估计值：0.85（95%置信区间0.64 - 1.12）和0.84（0.57 - 1.25）。三个次要终点出现了统计学显著差异。然而，在进行多重比较校正后，仅一项差异仍具有显著性（即全脑萎缩率）。
在MCI中使用ChEIs与AD或痴呆发病的延迟无关。此外，安全性分析表明，与ChEIs相关的风险不可忽视。MCI作为一种临床实体的不确定性引发了对这些试验科学有效性的质疑。
