From the The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Australia.
Neurology. 2023 May 16;100(20):e2114-e2124. doi: 10.1212/WNL.0000000000207156. Epub 2023 Mar 27.
To evaluate brain volume changes caused by different subclasses of anti-β-amyloid (Aβ) drugs trailed in patients with Alzheimer disease.
PubMed, Embase, and ClinicalTrials.gov databases were searched for clinical trials of anti-Aβ drugs. This systematic review and meta-analysis included adults enrolled in randomized controlled trials of anti-Aβ drugs (n = 8,062-10,279). The inclusion criteria were as follows: (1) randomized controlled trials of patients treated with anti-Aβ drugs that have demonstrated to favorably change at least one biomarker of pathologic Aβ and (2) detailed MRI data sufficient to assess the volumetric changes in at least one brain region. MRI brain volumes were used as the primary outcome measure; brain regions commonly reported include hippocampus, lateral ventricle, and whole brain. Amyloid-related imaging abnormalities (ARIAs) were investigated when reported in clinical trials. Of the 145 trials reviewed, 31 were included in the final analyses.
A meta-analysis on the highest dose of each trial on hippocampus, ventricle, and whole brain revealed drug-induced acceleration of volume changes that varied by anti-Aβ drug class. Secretase inhibitors accelerated atrophy to the hippocampus (Δ placebo - Δ drug: -37.1 µL [19.6% more than placebo]; 95% CI -47.0 to -27.1) and whole brain (Δ placebo - Δ drug: -3.3 mL [21.8% more than placebo]; 95% CI -4.1 to 2.5). Conversely, ARIA-inducing monoclonal antibodies accelerated ventricular enlargement (Δ placebo - Δ drug: +2.1 mL [38.7% more than placebo]; 95% CI 1.5-2.8) where a striking correlation between ventricular volume and ARIA frequency was observed ( = 0.86, = 6.22 × 10). Mild cognitively impaired participants treated with anti-Aβ drugs were projected to have a material regression toward brain volumes typical of Alzheimer dementia ∼8 months earlier than if they were untreated.
These findings reveal the potential for anti-Aβ therapies to compromise long-term brain health by accelerating brain atrophy and provide new insight into the adverse impact of ARIA. Six recommendations emerge from these findings.
评估不同类别的抗β-淀粉样蛋白（Aβ）药物治疗阿尔茨海默病患者后引起的脑容量变化。
检索 PubMed、Embase 和 ClinicalTrials.gov 数据库，以寻找抗 Aβ 药物的临床试验。本系统评价和荟萃分析纳入了在抗 Aβ 药物随机对照试验中入组的成年人（n = 8062-10279）。纳入标准如下：（1）抗 Aβ 药物治疗的患者随机对照试验，该试验已证明至少有一个病理性 Aβ 的生物标志物发生有利变化；（2）有足够详细的 MRI 数据评估至少一个脑区的体积变化。MRI 脑容量作为主要结局测量指标；常报告的脑区包括海马体、侧脑室和全脑。当临床试验报告淀粉样相关成像异常（ARIAs）时，对其进行了研究。在审查的 145 项试验中，有 31 项最终纳入分析。
对每个试验的最高剂量进行荟萃分析，发现不同的抗 Aβ 药物类别对脑容量变化有不同的药物诱导加速作用。 蛋白酶体抑制剂加速了海马体（Δ安慰剂-Δ药物：-37.1µL [比安慰剂多 19.6%]；95%CI-47.0 至-27.1）和全脑（Δ安慰剂-Δ药物：-3.3mL [比安慰剂多 21.8%]；95%CI-4.1 至 2.5）的萎缩。相反，诱导 ARIA 的单克隆抗体加速了脑室扩大（Δ安慰剂-Δ药物：+2.1mL [比安慰剂多 38.7%]；95%CI 1.5-2.8），观察到脑室体积与 ARIA 频率之间存在显著相关性（=0.86，=6.22×10）。用抗 Aβ 药物治疗的轻度认知障碍患者预计会比未治疗的患者更早地向阿尔茨海默病痴呆症的典型脑容量回归约 8 个月。
这些发现揭示了抗 Aβ 疗法通过加速脑萎缩来损害长期脑健康的潜力，并为 ARIA 的不良影响提供了新的见解。这些发现产生了 6 项建议。
