ImportanceInterventions 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.ObjectiveTo investigate whether the brain-permeable iron chelator deferiprone slows cognitive decline in people with AD.Design, Setting, and ParticipantsThis 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.InterventionsDeferiprone 15 mg/kg twice a day or placebo administered orally for 12 months.Main Outcomes and MeasuresThe 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).ResultsOf 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%).ConclusionsThese 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.Trial RegistrationClinicalTrials.gov Identifier: NCT03234686

中文翻译：

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阿尔茨海默病中的去铁酮


重要性需要大幅减缓神经退行性变的干预措施，以解决阿尔茨海默病 （AD） 给全球社会带来的日益增长的负担。在 AD 中观察到的脑铁升高与认知能力加速下降有关，可能是一个容易处理的药物靶点。目的探讨脑渗透性铁螯合剂去铁酮是否能减缓 AD.Design、 环境和参与者的认知能力下降这项为期 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。筛选了 54 岁以上经淀粉样蛋白证实的轻度认知障碍或早期 AD （简易精神状态检查评分为 20 分或更高） 的患者。随机化为 2：1，对参与者和所有研究人员设盲。干预措施去铁酮 15 mg/kg 每天两次或安慰剂口服给药 12 个月。主要结局和测量主要结局是在基线、 6 个月和 12 个月时使用记忆、执行功能和注意力任务的神经心理学测试电池 （NTB） 评估的综合认知测量。次要结局包括通过定量磁化率映射 （QSM） 、磁共振成像 （目标参与） 测量的脑铁负荷变化、脑容量变化 （次要疗效测量） 和不良事件 （安全性分析）。结果在筛选合格的 167 例患者中，纳入 81 例，其中 53 例随机分配到去铁酮组（平均 [SD] 年龄，73.0 [8.0] 岁;29 例男性 [54.7%]），28 例分配到安慰剂组（平均 [SD] 年龄，71.6 [7.2] 岁;17 例男性 [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）。 在意向性治疗分析中，与安慰剂相比，去铁酮组的参与者在 NTB 主要结局（交互作用的 β = -0.50;95% CI，-0.80 至 -0.20）上表现出加速的认知能力下降（去铁酮的 NTB 复合 z 评分变化，-0.80 [95% CI，-0.98 至 -0.62];安慰剂组，-0.30 [95% CI，-0.54 至 -0.06]）。二次分析显示，这一结果是由执行功能测试表现恶化驱动的。QSM 证实，与安慰剂相比，去铁酮降低了海马体中的铁含量（去铁酮的海马 QSM 变化，-0.36 ppb [95% CI，-0.76 至 0.04 ppb];安慰剂为 0.32 ppb [95% CI，-0.12 至 0.75 ppb];交互作用β = -0.68 [95% CI，-1.27 至 -0.09]）。纵向海马体积损失不受去铁酮的影响，但对其他脑区域的探索性分析显示，去铁酮在额叶区域增加体积损失。中性粒细胞减少症不良反应的频率 （去铁酮组有 4 名参与者 [7.5%]）高于类似研究 （1.6%-4.4%）。结论这些试验结果表明，去铁酮 15 mg/kg 每天两次可降低淀粉样蛋白证实的早期 AD 患者的海马 QSM 并加速认知能力下降，表明使用去铁酮降低铁对 AD 患者有害。试验注册临床试验。gov 标识符： NCT03234686