Safety and efficacy of apitegromab in nonambulatory type 2 or type 3 spinal muscular atrophy (SAPPHIRE): a phase 3, double-blind, randomised, placebo-controlled trial

阿匹格罗马布治疗非行走型 2 型或 3 型脊髓性肌萎缩症的安全性和有效性（蓝宝石研究）：一项 3 期、双盲、随机、安慰剂对照试验

Approved spinal muscular atrophy therapies greatly improve clinical outcomes; however, substantial motor function deficits persist. Apitegromab, a fully human monoclonal antibody, selectively inhibits myostatin activation, improving muscle function. We aimed to assess the safety and efficacy of apitegromab in patients with nonambulatory type 2 or type 3 spinal muscular atrophy receiving nusinersen or risdiplam. Participants in the apitegromab treatment groups (combined 20 mg/kg and 10 mg/kg dose) achieved statistically significant improvements in motor function compared with placebo; however, the least squares mean difference was not significant between apitegromab 20 mg/kg and placebo. Overall, SAPPHIRE results build on findings from the phase 2 TOPAZ trial, showing improved motor function with a generally well tolerated safety profile, supporting the use of muscle-targeting therapy for spinal muscular atrophy.

已获批的脊髓性肌萎缩症疗法能显著改善临床结局；然而，严重的运动功能缺陷仍然存在。阿匹格罗单抗是一种全人源单克隆抗体，可选择性抑制肌生长抑制素激活，从而改善肌肉功能。我们旨在评估阿匹格罗单抗在接受诺西那生钠或利司扑兰治疗的非行走型2型或3型脊髓性肌萎缩症患者中的安全性和有效性。与安慰剂组相比，阿匹格罗单抗治疗组（20 mg/kg和10 mg/kg剂量合并）患者的运动功能有统计学意义的改善；然而，阿匹格罗单抗20 mg/kg组与安慰剂组的最小二乘均值差异无统计学意义。总体而言，蓝宝石（SAPPHIRE）试验结果是在2期黄玉（TOPAZ）试验结果的基础上得出的，显示其在改善运动功能的同时，安全性总体良好，支持将靶向肌肉的疗法用于脊髓性肌萎缩症的治疗。

REF: Crawford TO, Servais L, Mercuri E, et al. Safety and efficacy of apitegromab in nonambulatory type 2 or type 3 spinal muscular atrophy (SAPPHIRE): a phase 3, double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2025;24(9):727-739. doi:10.1016/S1474-4422(25)00225-X PMID: 40818473

Blood phosphorylated tau for the diagnosis of Alzheimer's disease: a systematic review and meta-analysis

血液磷酸化tau蛋白用于阿尔茨海默病的诊断：系统评价与荟萃分析

Plasma phosphorylated tau (p-tau) biomarkers show promise to transform the clinical management of Alzheimer's disease by providing more accessible and cost-effective diagnostic tools. p-tau biomarkers have emerged as leading contenders for clinical implementation; however, there have been no comprehensive meta-analyses of their diagnostic performance. We aimed to evaluate the diagnostic performance of plasma p-tau biomarkers and individual p-tau assays to identify biologically defined Alzheimer's disease. Plasma p-tau217 is a highly sensitive and specific biomarker for Alzheimer's disease pathology, despite the high risk of bias of many studies. Prospective clinical implementation studies in real-world settings are needed to characterise the effect of plasma p-tau217 on Alzheimer's disease diagnosis and clinical management.

血浆磷酸化tau（p-tau）生物标志物有望通过提供更易获取且更具成本效益的诊断工具，改变阿尔茨海默病的临床管理方式。p-tau生物标志物已成为临床应用的有力竞争者；然而，目前尚未有对其诊断性能的全面荟萃分析。我们旨在评估血浆p-tau生物标志物及单个p-tau检测方法对识别生物学定义的阿尔茨海默病的诊断性能。尽管许多研究存在较高的偏倚风险，但血浆p-tau217仍是诊断阿尔茨海默病病理特征的高灵敏度和高特异性生物标志物。需要在现实世界环境中开展前瞻性临床应用研究，以明确血浆p-tau217对阿尔茨海默病诊断和临床管理的影响。

REF: Therriault J, Brum WS, Trudel L, et al. Blood phosphorylated tau for the diagnosis of Alzheimer's disease: a systematic review and meta-analysis. Lancet Neurol. 2025;24(9):740-752. doi:10.1016/S1474-4422(25)00227-3 PMID: 40818474

Down syndrome and Alzheimer's disease: insights into biomarkers, clinical symptoms, and pathology

唐氏综合征与阿尔茨海默病：生物标志物、临床症状和病理学研究见解

Individuals with Down syndrome have a genetically determined form of Alzheimer's disease, due to an additional copy of the APP gene. Nearly all individuals with Down syndrome develop Alzheimer's disease pathology by age 40 years, and approximately 70% are diagnosed with dementia by around age 54 years, with an overall lifetime risk of 95%. Moreover, Alzheimer's disease is the leading cause of death in adults with Down syndrome older than 35 years. The intersection of Down syndrome and Alzheimer's disease has garnered substantial attention in the past 10 years as research indicates that the trajectory of clinical symptoms and biomarker changes in adults with Down syndrome closely resembles that seen in late-onset Alzheimer's disease and autosomal-dominant Alzheimer's disease (ADAD). The predictive nature of dementia onset in genetically determined populations allows precise staging of disease in individuals along the Alzheimer's disease continuum. The high prevalence of Alzheimer's disease pathology combined with the few age-related comorbidities in these cohorts, makes them ideal for understanding the biological mechanisms related to late-onset Alzheimer's disease. The more rapid disease progression seen in people with Down syndrome-related Alzheimer's disease compared with people with ADAD or late-onset Alzheimer's disease provides important insights and supports the rationale for new clinical trials. WHERE NEXT?: The Alzheimer's Clinical Trials Consortium-Down Syndrome is ushering in a new era of therapies for individuals with Down syndrome. Three ongoing clinical trials, in close collaboration with industry partners, specifically designed for this population, are focused on testing disease-modifying treatments. These innovative efforts mark a considerable stride in bringing groundbreaking therapies to a group that has long been excluded from clinical trials in Alzheimer's disease.

唐氏综合征患者由于额外复制了淀粉样前体蛋白（APP）基因，会患上一种由基因决定的阿尔茨海默病。几乎所有唐氏综合征患者到40岁时都会出现阿尔茨海默病的病理特征，约70%的患者在54岁左右会被诊断为痴呆，终生患病风险总体为95%。此外，阿尔茨海默病是35岁以上唐氏综合征成年人的主要死因。在过去10年里，唐氏综合征与阿尔茨海默病的关联受到了广泛关注，因为研究表明，唐氏综合征成年人的临床症状发展轨迹和生物标志物变化与晚发性阿尔茨海默病和常染色体显性遗传阿尔茨海默病（ADAD）极为相似。在由基因决定的人群中，痴呆发病具有可预测性，这使得我们能够对处于阿尔茨海默病病程中的个体进行精准的疾病分期。这些人群中阿尔茨海默病病理特征的高患病率，加上与年龄相关的合并症较少，使他们成为研究晚发性阿尔茨海默病生物学机制的理想对象。与ADAD患者或晚发性阿尔茨海默病患者相比，唐氏综合征相关阿尔茨海默病患者的疾病进展更为迅速，这为我们提供了重要的见解，并为开展新的临床试验提供了依据。未来方向：阿尔茨海默病临床试验联盟 - 唐氏综合征项目正在为唐氏综合征患者开启治疗的新纪元。目前有三项正在进行的临床试验与行业合作伙伴密切合作，专门针对这一人群设计，旨在测试能够改变疾病进程的治疗方法。这些创新举措标志着在为长期被排除在阿尔茨海默病临床试验之外的群体带来突破性疗法方面迈出了重要一步。

REF: Rafii MS, Schlachetzki Z, Barroeta I, Head E, Fortea J, Ances BM. Down syndrome and Alzheimer's disease: insights into biomarkers, clinical symptoms, and pathology. Lancet Neurol. 2025;24(9):753-762. doi:10.1016/S1474-4422(25)00237-6 PMID: 40818475

The relevance of primary cilia in neurological disorders

原发性纤毛在神经系统疾病中的相关性

Primary cilia are ubiquitous organelles, which play essential roles in sensing and transducing cellular signals and in mediating key developmental pathways. Pathogenic variants in genes encoding for ciliary proteins give rise to a spectrum of disorders termed primary ciliopathies. The archetypal neurodevelopmental ciliopathy is Joubert syndrome. However, in the past decade, primary cilia have been implicated in several other neurological disorders, including neurodevelopmental disorders, malformations of cortical development, neurodegenerative disorders, and psychiatric disorders. Therapeutic approaches for cilia-related disorders are still scarce. Strategies based on gene therapy and antisense oligonucleotides show promising results, especially for the treatment of retinal ciliopathies, and are currently moving towards clinical translation. Other approaches based on drug repurposing or the use of small molecules, despite positive results in a variety of cellular and animal models, are still in the experimental stage.

初级纤毛是普遍存在的细胞器，在感知和转导细胞信号以及介导关键发育通路中发挥着重要作用。编码纤毛蛋白的基因发生致病性变异会引发一系列被称为原发性纤毛疾病的病症。典型的神经发育性纤毛疾病是朱伯特综合征。然而，在过去十年中，初级纤毛与其他几种神经系统疾病有关，包括神经发育障碍、皮质发育畸形、神经退行性疾病和精神疾病。针对纤毛相关疾病的治疗方法仍然匮乏。基于基因治疗和反义寡核苷酸的策略显示出了有希望的结果，特别是在治疗视网膜纤毛疾病方面，目前正朝着临床应用推进。其他基于药物再利用或使用小分子的方法，尽管在各种细胞和动物模型中取得了积极成果，但仍处于实验阶段。

REF: Serpieri V, D'Abrusco F, Valente EM. The relevance of primary cilia in neurological disorders. Lancet Neurol. 2025;24(9):763-775. doi:10.1016/S1474-4422(25)00226-1 PMID: 40706604

Advances in the classification and management of idiopathic inflammatory myopathies

特发性炎症性肌病分类与治疗的进展

Idiopathic inflammatory myopathies are a group of immune-mediated disorders characterised by multisystem involvement and a chronic disease course in two-thirds of adult patients. Autoantibodies can aid in the identification of disease subtypes and their associated severe complications, such as cancer or interstitial lung disease. Patients with idiopathic inflammatory myopathies need to be managed in a multidisciplinary setting. Treatment with intravenous immunoglobulins is efficacious in patients with refractory dermatomyositis, and can result in improvements in disease activity in the skin and muscle. Numerous randomised controlled trials are underway testing potential therapeutic agents that hold promise for the treatment of idiopathic inflammatory myopathies. Other advances include the identification of pathophysiological mechanisms. Induction of interferons in patients with dermatomyositis leads to the upregulation of interferon-stimulated genes in blood, skin, and muscle tissue. The interferon-induced transcripts could yield diagnostic biomarkers and biomarkers for monitoring disease activity. The identification of these potential biomarkers has also propelled the development of therapies targeting the interferon pathway-either upstream by using monoclonal autoantibodies or by blocking downstream signalling pathways via JAK inhibitors. A promising strategy for patients with refractory disease is targeting B cells with CD19-targeting chimeric antigen receptor T-cell therapy. Treatments targeting T cell lymphocytes and specific T-cell subsets are also under investigation.

特发性炎性肌病是一组由免疫介导的疾病，三分之二的成年患者具有多系统受累和慢性病程的特点。自身抗体有助于识别疾病亚型及其相关的严重并发症，如癌症或间质性肺病。特发性炎性肌病患者需要在多学科环境中进行管理。静脉注射免疫球蛋白治疗对难治性皮肌炎患者有效，可改善皮肤和肌肉的疾病活动度。目前有大量随机对照试验正在测试有望用于治疗特发性炎性肌病的潜在治疗药物。其他进展还包括对病理生理机制的认识。皮肌炎患者体内干扰素的诱导会导致血液、皮肤和肌肉组织中干扰素刺激基因的上调。干扰素诱导的转录物可产生诊断生物标志物和用于监测疾病活动度的生物标志物。对这些潜在生物标志物的识别也推动了靶向干扰素通路的疗法的发展——要么通过使用单克隆自身抗体作用于上游，要么通过JAK抑制剂阻断下游信号通路。对于难治性疾病患者，一种有前景的策略是采用靶向CD19的嵌合抗原受体T细胞疗法靶向B细胞。靶向T淋巴细胞和特定T细胞亚群的治疗方法也在研究中。

REF: Raaphorst J, van der Kooi AJ, Mecoli CA, et al. Advances in the classification and management of idiopathic inflammatory myopathies. Lancet Neurol. 2025;24(9):776-788. doi:10.1016/S1474-4422(25)00233-9 PMID: 40818476

Posterior reversible encephalopathy syndrome: evolving insights in diagnosis, management, and outcomes

可逆性后部脑病综合征：诊断、治疗和预后的新见解

Posterior reversible encephalopathy syndrome (PRES) is a clinicoradiological syndrome characterised by acute or subacute neurological symptoms-including encephalopathy, seizures, headache, and visual disturbances. Recent advances in neuroimaging, biomarker research, and the increasing use of cytotoxic agents and novel immunotherapies, such as tyrosine kinase inhibitors and anti-CD19 chimeric antigen receptor T-cell therapies, have expanded the spectrum of PRES presentations and associated risk factors. PRES is thought to result from endothelial dysfunction and blood-brain barrier disruption. Emerging research into inflammatory cytokines and biomarkers, such as IL-6, IL-10, and VEGF, offers promising avenues for improved diagnosis and prognosis. Treatment is focused on removing precipitating factors and controlling blood pressure, but evidence from randomised trials is absent. Although prognosis is generally favourable, severe and recurrent PRES can occur, and complications such as epilepsy and stroke can follow. More robust observational studies with large sample sizes, prospective designs, and with more systemic imaging approaches are required to refine diagnostic criteria, clarify pathophysiological mechanisms, and identify optimal management strategies to improve outcomes in this complex and evolving syndrome.

可逆性后部脑病综合征（PRES）是一种临床影像学综合征，其特征为急性或亚急性神经系统症状，包括脑病、癫痫发作、头痛和视觉障碍。神经影像学、生物标志物研究的最新进展，以及细胞毒性药物和新型免疫疗法（如酪氨酸激酶抑制剂和抗CD19嵌合抗原受体T细胞疗法）的日益广泛应用，拓宽了PRES的临床表现谱和相关危险因素。PRES被认为是由内皮功能障碍和血脑屏障破坏所致。对炎症细胞因子和生物标志物（如IL - 6、IL - 10和VEGF）的新兴研究为改善诊断和预后提供了有前景的途径。治疗重点在于消除诱发因素和控制血压，但缺乏随机试验的证据。尽管总体预后良好，但仍可能出现严重和复发性PRES，且可能继发癫痫和中风等并发症。需要开展样本量大、采用前瞻性设计且有更系统成像方法的更可靠的观察性研究，以完善诊断标准、阐明病理生理机制，并确定优化管理策略，从而改善这种复杂且不断演变的综合征的预后。

REF: Fugate JE, Hawkes MA, Rabinstein AA. Posterior reversible encephalopathy syndrome: evolving insights in diagnosis, management, and outcomes. Lancet Neurol. 2025;24(9):789-800. doi:10.1016/S1474-4422(25)00232-7 PMID: 40818477