Ayton Scott, Barton David, Brew Bruce, Brodtmann Amy, Clarnette Roger, Desmond Patricia, Devos David, Ellis Kathryn A, Fazlollahi Amir, Fradette Caroline, Goh Anita M Y, Kalinowski Pawel, Kyndt Christopher, Lai Rosalyn, Lim Yen Ying, Maruff Paul, O'Brien Terence J, Rowe Christopher, Salvado Olivier, Schofield Peter W, Spino Michael, Tricta Fernando, Wagen Aaron, Williams Robert, Woodward Michael, Bush Ashley I
The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Australia.
Florey Department of Neuroscience and Mental Health, The University of Melbourne, Parkville, Australia.
JAMA Neurol. 2025 Jan 1;82(1):11-18. doi: 10.1001/jamaneurol.2024.3733.
Interventions that substantially slow neurodegeneration are needed to address the growing burden of Alzheimer disease (AD) to societies worldwide. Elevated brain iron observed in AD has been associated with accelerated cognitive decline and may be a tractable drug target.
To investigate whether the brain-permeable iron chelator deferiprone slows cognitive decline in people with AD.
DESIGN, SETTING, AND PARTICIPANTS: This phase 2, double-masked, placebo-controlled randomized clinical trial of 12-month duration was conducted at 9 sites in Australia between August 2, 2018, and April 1, 2023. Patients older than 54 years with amyloid-confirmed mild cognitive impairment or early AD (a Mini-Mental State Examination score of 20 or higher) were screened. Randomization was 2:1 and masked to participants and all study staff.
Deferiprone 15 mg/kg twice a day or placebo administered orally for 12 months.
The primary outcome was a composite cognitive measure assessed at baseline, 6 months, and 12 months using a neuropsychological test battery (NTB) of memory, executive function, and attention tasks. Secondary outcomes included change in brain iron burden measured by quantitative susceptibility mapping (QSM) magnetic resonance imaging (target engagement), brain volume changes (secondary efficacy measure), and adverse events (safety analysis).
Of 167 patients screened for eligibility, 81 were included, with 53 randomly assigned to the deferiprone group (mean [SD] age, 73.0 [8.0] years; 29 male [54.7%]) and 28 to the placebo group (mean [SD] age, 71.6 [7.2] years; 17 male [60.7%]); 54 participants completed the study (7 [25.0%] withdrew from the placebo group and 20 [37.7%] from the deferiprone group). In an intention-to-treat analysis, participants in the deferiprone group showed accelerated cognitive decline on the NTB primary outcome (β for interaction = -0.50; 95% CI, -0.80 to -0.20) compared with placebo (change in NTB composite z score for deferiprone, -0.80 [95% CI, -0.98 to -0.62]; for placebo, -0.30 [95% CI, -0.54 to -0.06]). Secondary analysis revealed that this result was driven by worsening performance on executive function tests. The QSM confirmed that deferiprone decreased iron in the hippocampus compared with placebo (change in hippocampal QSM for deferiprone, -0.36 ppb [95% CI, -0.76 to 0.04 ppb]; for placebo, 0.32 ppb [95% CI, -0.12 to 0.75 ppb]; β for interaction = -0.68 [95% CI, -1.27 to -0.09]). Longitudinal hippocampal volume loss was not affected by deferiprone, but exploratory analysis of other brain regions revealed increased volume loss with deferiprone in frontal areas. The frequency of the adverse effect of neutropenia (4 participants [7.5%] in the deferiprone group) was higher than in similar studies (1.6%-4.4%).
These trial findings show that deferiprone 15 mg/kg twice a day decreased hippocampal QSM and accelerated cognitive decline in patients with amyloid-confirmed early AD, suggesting that lowering iron with deferiprone is detrimental to patients with AD.
ClinicalTrials.gov Identifier: NCT03234686.
为应对全球范围内阿尔茨海默病（AD）给社会带来的日益沉重负担，需要采取能大幅减缓神经退行性变的干预措施。AD患者大脑中铁含量升高与认知能力加速下降有关，可能是一个可处理的药物靶点。
研究可透过血脑屏障的铁螯合剂去铁酮是否能减缓AD患者的认知能力下降。
设计、地点和参与者：这项为期12个月的2期双盲、安慰剂对照随机临床试验于2018年8月2日至2023年4月1日在澳大利亚的9个地点进行。对年龄超过54岁、经淀粉样蛋白确诊为轻度认知障碍或早期AD（简易精神状态检查表评分20分或更高）的患者进行了筛查。随机分组比例为2:1，参与者和所有研究人员均不知情。
去铁酮15毫克/千克，每日两次，或安慰剂口服给药12个月。
主要结局是使用记忆、执行功能和注意力任务的神经心理测试组合（NTB）在基线、6个月和12个月时评估的综合认知指标。次要结局包括通过定量磁化率成像（QSM）磁共振成像测量的脑铁负担变化（靶点参与度）、脑容量变化（次要疗效指标）和不良事件（安全性分析）。
在167名筛查合格的患者中，81名被纳入研究，其中53名被随机分配到去铁酮组（平均[标准差]年龄，73.0[8.0]岁；29名男性[54.7%]），28名被分配到安慰剂组（平均[标准差]年龄，71.6[7.2]岁；17名男性[60.7%]）；54名参与者完成了研究（7名[25.0%]退出安慰剂组，20名[37.7%]退出去铁酮组）。在意向性分析中，与安慰剂相比，去铁酮组参与者在NTB主要结局上的认知能力下降加速（交互作用β=-0.50；95%置信区间，-0.80至-0.20）（去铁酮组NTB综合z评分变化为-0.80[95%置信区间，-0.98至-0.62]；安慰剂组为-0.30[95%置信区间，-0.54至-0.06]）。二次分析显示，这一结果是由执行功能测试中的表现恶化所致。QSM证实，与安慰剂相比，去铁酮降低了海马体中的铁含量（去铁酮组海马体QSM变化为-0.36 ppb[95%置信区间，-0.76至0.04 ppb]；安慰剂组为0.32 ppb[95%置信区间，-0.12至0.75 ppb]；交互作用β=-0.68[95%置信区间，-1.27至-。09]）。纵向海马体体积损失不受去铁酮影响，但对其他脑区的探索性分析显示，额叶区域去铁酮组的体积损失增加。中性粒细胞减少症不良反应的发生率（去铁酮组4名参与者[7.5%]）高于类似研究（1.6%-4.4%）。
这些试验结果表明，每日两次服用15毫克/千克去铁酮可降低淀粉样蛋白确诊的早期AD患者的海马体QSM并加速认知能力下降，这表明用去铁酮降低铁含量对AD患者有害。
ClinicalTrials.gov标识符：NCT03234686。
