去甲肾上腺素能治疗对阿尔茨海默病的认知和神经精神影响：系统评价与荟萃分析

Cognitive and neuropsychiatric effects of noradrenergic treatment in Alzheimer's disease: systematic review and meta-analysis.

作者信息

David Michael C B, Del Giovane Martina, Liu Kathy Y, Gostick Benjamin, Rowe James Benedict, Oboh Imafidon, Howard Robert, Malhotra Paresh A

机构信息

Imperial College London and the University of Surrey, UK Dementia Research Institute Care Research and Technology Centre, London, UK

Brain Sciences, Imperial College London, London, UK.

出版信息

J Neurol Neurosurg Psychiatry. 2022 Jul 5;93(10):1080-90. doi: 10.1136/jnnp-2022-329136.

BACKGROUND

Dysfunction of the locus coeruleus-noradrenergic system occurs early in Alzheimer's disease, contributing to cognitive and neuropsychiatric symptoms in some patients. This system offers a potential therapeutic target, although noradrenergic treatments are not currently used in clinical practice.

OBJECTIVE

To assess the efficacy of drugs with principally noradrenergic action in improving cognitive and neuropsychiatric symptoms in Alzheimer's disease.

METHODS

The MEDLINE, Embase and ClinicalTrials.gov databases were searched from 1980 to December 2021. We generated pooled estimates using random effects meta-analyses.

RESULTS

We included 19 randomised controlled trials (1811 patients), of which six were judged as 'good' quality, seven as 'fair' and six 'poor'. Meta-analysis of 10 of these studies (1300 patients) showed a significant small positive effect of noradrenergic drugs on global cognition, measured using the Mini-Mental State Examination or Alzheimer's Disease Assessment Scale-Cognitive Subscale (standardised mean difference (SMD): 0.14, 95% CI: 0.03 to 0.25, p=0.01; I=0%). No significant effect was seen on measures of attention (SMD: 0.01, 95% CI: -0.17 to 0.19, p=0.91; I=0). The apathy meta-analysis included eight trials (425 patients) and detected a large positive effect of noradrenergic drugs (SMD: 0.45, 95% CI: 0.16 to 0.73, p=0.002; I=58%). This positive effect was still present following removal of outliers to account for heterogeneity across studies.

DISCUSSION

Repurposing of established noradrenergic drugs is most likely to offer effective treatment in Alzheimer's disease for general cognition and apathy. However, several factors should be considered before designing future clinical trials. These include targeting of appropriate patient subgroups and understanding the dose effects of individual drugs and their interactions with other treatments to minimise risks and maximise therapeutic effects.

PROSPERO REGISTERATION NUMBER

CRD42021277500.

背景

蓝斑 - 去甲肾上腺素能系统功能障碍在阿尔茨海默病早期就会出现，导致部分患者出现认知和神经精神症状。该系统是一个潜在的治疗靶点，尽管目前去甲肾上腺素能治疗尚未应用于临床实践。

目的

评估主要具有去甲肾上腺素能作用的药物在改善阿尔茨海默病认知和神经精神症状方面的疗效。

方法

检索1980年至2021年12月的MEDLINE、Embase和ClinicalTrials.gov数据库。我们使用随机效应荟萃分析生成汇总估计值。

结果

我们纳入了19项随机对照试验（1811例患者），其中6项被判定为“高质量”，7项为“中等质量”，6项为“低质量”。对其中10项研究（1300例患者）的荟萃分析显示，使用简易精神状态检查表或阿尔茨海默病评估量表 - 认知分量表测量，去甲肾上腺素能药物对整体认知有显著的小的正向作用（标准化均数差（SMD）：0.1, 95%置信区间：0.03至0.25，p = 0.01；I² = 0%）。在注意力测量方面未观察到显著作用（SMD：0.01, 95%置信区间： - 0.17至0.19，p = 0.91；I² = 0%）。对淡漠的荟萃分析纳入了8项试验（425例患者），并检测到去甲肾上腺素能药物有较大的正向作用（SMD：0.45, 95%置信区间：0.16至0.73，p = 0.002；I² = 58%）。在去除异常值以解释研究间的异质性后，这种正向作用仍然存在。