Safety and efficacy of intra-erythrocyte dexamethasone sodium phosphate in children with ataxia telangiectasia (ATTeST): a multicentre, randomised, double-blind, placebo-controlled phase 3 trial

红细胞内地塞米松磷酸钠治疗共济失调性毛细血管扩张症患儿的安全性和有效性 (ATTeST): 一项多中心、随机、双盲、安慰剂对照的3期试验

Ataxia telangiectasia is a multisystem disorder with progressive neurodegeneration. Corticosteroids can improve neurological functioning in patients with the disorder but adrenal suppression and symptom recurrence on treatment discontinuation has limited their use, prompting the development of novel steroid delivery systems. The aim of the ATTeST study was to evaluate the efficacy and safety of intra-erythrocyte delivery of dexamethasone sodium phosphate compared with placebo in children with ataxia telangiectasia. Although there were no safety concerns, the primary efficacy endpoint was not met, possibly related to delays in treatment reducing the number of participants who received treatment as outlined in the protocol, and potentially different treatment effects according to age. Studies of intra-erythrocyte delivery of dexamethasone sodium phosphate will continue in participants aged 6-9 years, on the basis of findings from subgroup analyses from this trial.

共济失调毛细血管扩张症是一种进行性神经变性的多系统疾病。皮质类固醇可以改善患有该疾病的患者的神经功能，但是肾上腺抑制和治疗中止后的症状复发限制了它们的使用，从而促进了新型类固醇递送系统的发展。ATTeST研究的目的是评估地塞米松磷酸钠与安慰剂相比在共济失调毛细血管扩张症儿童中红细胞内递送的有效性和安全性。尽管没有安全性问题，但未达到主要疗效终点，这可能与治疗延迟减少了接受方案中概述的治疗的参与者人数有关，并且可能因年龄而异。根据本试验亚组分析的结果，将继续在6-9岁的参与者中进行地塞米松磷酸钠的红细胞内递送研究。

REF: Zielen S, Crawford T, Benatti L, et al. Safety and efficacy of intra-erythrocyte dexamethasone sodium phosphate in children with ataxia telangiectasia (ATTeST): a multicentre, randomised, double-blind, placebo-controlled phase 3 trial. Lancet Neurol. 2024;23(9):871-882. doi:10.1016/S1474-4422(24)00220-5 PMID: 39152028

Endovascular thrombectomy for acute ischaemic stroke with established large infarct (TENSION): 12-month outcomes of a multicentre, open-label, randomised trial

血管内血栓切除术治疗大面积梗死的急性缺血性卒中 (TENSION): 一项多中心、开放标签、随机试验的12个月结果

Long-term data showing the benefits of endovascular thrombectomy for stroke with large infarct are scarce. The TENSION trial showed the safety and efficacy of endovascular thrombectomy in patients with ischaemic stroke and large infarct at 90 days. We aimed to investigate the safety and efficacy at 12 months of endovascular thrombectomy in patients who were enrolled in the TENSION trial. In patients with acute ischaemic stroke from large vessel occlusion with established large infarct, compared with medical treatment only, endovascular thrombectomy was associated at 12 months after stroke with better functional outcome, quality of life, and overall survival. These findings suggest that the benefits of endovascular thrombectomy in patients with an ischaemic stroke and a large infarct are sustained in the long term and support the use of endovascular thrombectomy in these patients.

长期数据显示血管内血栓切除术对大面积梗死卒中的益处很少。TENSION试验显示了在90天缺血性卒中和大面积梗死患者中血管内血栓切除术的安全性和有效性。我们的目的是研究TENSION试验中患者在12个月时血管内取栓的安全性和有效性。与单纯药物治疗相比，因大血管闭塞形成的急性缺血性卒中患者在卒中后12个月血管内取栓与更好的功能结局、生活质量和总生存率相关。这些发现表明，血管内血栓切除术对缺血性卒中和大面积梗死患者的益处可长期维持，并支持在这些患者中使用血管内血栓切除术。

REF: Thomalla G, Fiehler J, Subtil F, et al. Endovascular thrombectomy for acute ischaemic stroke with established large infarct (TENSION): 12-month outcomes of a multicentre, open-label, randomised trial. Lancet Neurol. 2024;23(9):883-892. doi:10.1016/S1474-4422(24)00278-3 PMID: 39074480

Collateral-based selection for endovascular treatment of acute ischaemic stroke in the late window (MR CLEAN-LATE): 2-year follow-up of a phase 3, multicentre, open-label, randomised controlled trial in the Netherlands

晚期窗口期急性缺血性卒中血管内治疗的基于抵押品的选择 (MR CLEAN-late): 荷兰一项3期、多中心、开放标签、随机对照试验的2年随访

The MR CLEAN-LATE trial provided evidence for the safety and efficacy of endovascular treatment for acute ischaemic stroke within the late window (after 6-24 h) in patients who were preselected based on the presence of collateral flow on CT angiography. We aimed to evaluate clinical outcomes 2 years after randomisation. Our results show that the effectiveness of late-window (after 6-24 h) endovascular treatment in improving clinical outcomes is sustained for up to 2 years in a population preselected based on the presence of collateral flow on CT angiography. This finding might be important for prompting further evaluations of cost-effectiveness, health-care policy development, and clinical decision making.

MR CLEAN-LATE试验为根据CT血管造影上侧支血流的存在而预选的患者在晚期窗口期内 (6-24小时后) 血管内治疗急性缺血性卒中的安全性和有效性提供了证据。我们旨在评估随机分组后2年的临床结果。我们的结果表明，在根据CT血管造影中侧支血流的存在而预选的人群中，晚期窗口期 (6-24小时后) 血管内治疗在改善临床结局方面的有效性持续长达2年。这一发现对于促进进一步评估成本效益，医疗保健政策制定和临床决策可能很重要。

REF: Huijberts I, Pinckaers FME, Olthuis SGH, et al. Collateral-based selection for endovascular treatment of acute ischaemic stroke in the late window (MR CLEAN-LATE): 2-year follow-up of a phase 3, multicentre, open-label, randomised controlled trial in the Netherlands. Lancet Neurol. 2024;23(9):893-900. doi:10.1016/S1474-4422(24)00228-X PMID: 38909624

Safety, tolerability, and pharmacokinetics of antisense oligonucleotide BIIB078 in adults with C9orf72-associated amyotrophic lateral sclerosis: a phase 1, randomised, double blinded, placebo-controlled, multiple ascending dose study

反义寡核苷酸BIIB078在C9orf72-associated肌萎缩性侧索硬化症患者中的安全性、耐受性和药代动力学: 1期、随机、双盲、安慰剂对照、多次递增剂量研究

Hexanucleotide repeat expansion of C9orf72 is a common genetic cause of amyotrophic lateral sclerosis (ALS). No C9orf72-targeted treatments are available. BIIB078 is an investigational antisense oligonucleotide targeting C9orf72 sense RNA. We aimed to assess the safety, tolerability, and pharmacokinetics of BIIB078 in participants with C9orf72-associated ALS. On the basis of these phase 1 study results, including secondary and exploratory findings showing no reduction in neurofilament levels and no benefit on clinical outcomes relative to the placebo cohort, BIIB078 clinical development has been discontinued. However, these results will be informative in furthering our understanding of the complex pathobiology of C9orf72-associated ALS.

C9orf72的六核苷酸重复扩增是肌萎缩性侧索硬化症 (ALS) 的常见遗传原因。没有C9orf72-targeted的治疗方法。BIIB078是一种针对C9orf72有义RNA的研究性反义寡核苷酸。我们旨在评估BIIB078在C9orf72-associated ALS参与者中的安全性，耐受性和药代动力学。基于这些1期研究结果，包括显示相对于安慰剂队列没有降低神经丝水平和对临床结果没有益处的次要和探索性发现，BIIB078临床开发已经停止。但是，这些结果将有助于我们进一步了解C9orf72-associated ALS的复杂病理生物学。

REF: van den Berg LH, Rothstein JD, Shaw PJ, et al. Safety, tolerability, and pharmacokinetics of antisense oligonucleotide BIIB078 in adults with C9orf72-associated amyotrophic lateral sclerosis: a phase 1, randomised, double blinded, placebo-controlled, multiple ascending dose study. Lancet Neurol. 2024;23(9):901-912. doi:10.1016/S1474-4422(24)00216-3 PMID: 39059407

γ-Secretase activity, clinical features, and biomarkers of autosomal dominant Alzheimer's disease: cross-sectional and longitudinal analysis of the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS)

常染色体显性遗传性阿尔茨海默病的 γ-分泌酶活性、临床特征和生物标志物: 显性遗传性阿尔茨海默病网络观察性研究 (DIAN-OBS) 的横断面和纵向分析

Genetic variants that cause autosomal dominant Alzheimer's disease are highly penetrant but vary substantially regarding age at symptom onset (AAO), rates of cognitive decline, and biomarker changes. Most pathogenic variants that cause autosomal dominant Alzheimer's disease are in presenilin 1 (PSEN1), which encodes the catalytic core of γ-secretase, an enzyme complex that is crucial in production of amyloid β. We aimed to investigate whether the heterogeneity in AAO and biomarker trajectories in carriers of PSEN1 pathogenic variants could be predicted on the basis of the effects of individual PSEN1 variants on γ-secretase activity and amyloid β production. Our findings suggest that clinical heterogeneity in people with autosomal dominant Alzheimer's disease can be at least partly explained by different effects of PSEN1 variants on γ-secretase activity and amyloid β production. They support targeting γ-secretase as a therapeutic approach and suggest that cell-based models could be used to improve prediction of symptom onset.

导致常染色体显性遗传阿尔茨海默病的遗传变异具有高度渗透性，但在症状发作年龄 (AAO)，认知衰退率和生物标志物变化方面存在很大差异。引起常染色体显性阿尔茨海默氏病的大多数致病变体存在于早老素1 (PSEN1) 中，该蛋白编码 γ-分泌酶的催化核心，γ-分泌酶是一种在淀粉样 β 产生中至关重要的酶复合物。我们旨在研究是否可以根据单个PSEN1变体对 γ-分泌酶活性和淀粉样蛋白 β 产生的影响来预测PSEN1致病变体携带者中AAO和生物标志物轨迹的异质性。我们的发现表明，常染色体显性遗传性阿尔茨海默氏病患者的临床异质性至少可以部分解释为PSEN1变体对 γ-分泌酶活性和淀粉样蛋白 β 产生的不同影响。他们支持靶向 γ-分泌酶作为治疗方法，并建议基于细胞的模型可用于改善症状发作的预测。

REF: Schultz SA, Liu L, Schultz AP, et al. γ-Secretase activity, clinical features, and biomarkers of autosomal dominant Alzheimer's disease: cross-sectional and longitudinal analysis of the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS). Lancet Neurol. 2024;23(9):913-924. doi:10.1016/S1474-4422(24)00236-9 PMID: 39074479

Sleep and sleep disorders in people with Parkinson's disease

帕金森病患者的睡眠和睡眠障碍

Sleep disorders are common in people with Parkinson's disease. These disorders, which increase in frequency throughout the course of the neurodegenerative disease and impair quality of life, include insomnia, excessive daytime sleepiness, circadian disorders, obstructive sleep apnoea, restless legs syndrome, and rapid eye movement (REM) sleep behaviour disorder. The causes of these sleep disorders are complex and multifactorial, including the degeneration of the neural structures that modulate sleep, the detrimental effect of some medications on sleep, the parkinsonian symptoms that interfere with mobility and comfort in bed, and comorbidities that disrupt sleep quality and quantity. The clinical evaluation of sleep disorders include both subjective (eg, questionnaires or diaries) and objective (eg, actigraphy or video polysomnography) assessments. The management of patients with Parkinson's disease and a sleep disorder is challenging and should be individualised. Treatment can include education aiming at changes in behaviour (ie, sleep hygiene), cognitive behavioural therapy, continuous dopaminergic stimulation at night, and specific medications. REM sleep behaviour disorder can occur several years before the onset of parkinsonism, suggesting that the implementation of trials of neuroprotective therapies should focus on people with this sleep disorder.

睡眠障碍在帕金森病患者中很常见。这些疾病在神经退行性疾病的整个过程中频率增加并损害生活质量，包括失眠，白天过度嗜睡，昼夜节律障碍，阻塞性睡眠呼吸暂停，不安腿综合征和快速眼动 (REM) 睡眠行为障碍。这些睡眠障碍的原因是复杂的和多因素的，包括调节睡眠的神经结构的退化，一些药物对睡眠的有害影响，干扰床上活动和舒适的帕金森病症状以及破坏睡眠质量和数量的合并症。睡眠障碍的临床评估包括主观评估 (如问卷调查或日记) 和客观评估 (如活动记录或视频多导睡眠图)。帕金森氏病和睡眠障碍患者的管理具有挑战性，应个性化。治疗可以包括针对行为改变 (即睡眠卫生) 的教育，认知行为疗法，夜间持续多巴胺能刺激和特定药物。REM睡眠行为障碍可能在帕金森病发作前几年发生，这表明神经保护疗法的试验应侧重于患有这种睡眠障碍的人。

REF: Iranzo A, Cochen De Cock V, Fantini ML, Pérez-Carbonell L, Trotti LM. Sleep and sleep disorders in people with Parkinson's disease. Lancet Neurol. 2024;23(9):925-937. doi:10.1016/S1474-4422(24)00170-4 PMID: 38942041

Intracranial pressure monitoring in adult patients with traumatic brain injury: challenges and innovations

成人创伤性脑损伤患者的颅内压监测: 挑战与创新

Intracranial pressure monitoring enables the detection and treatment of intracranial hypertension, a potentially lethal insult after traumatic brain injury. Despite its widespread use, robust evidence supporting intracranial pressure monitoring and treatment remains sparse. International studies have shown large variations between centres regarding the indications for intracranial pressure monitoring and treatment of intracranial hypertension. Experts have reviewed these two aspects and, by consensus, provided practical approaches for monitoring and treatment. Advances have occurred in methods for non-invasive estimation of intracranial pressure although, for now, a reliable way to non-invasively and continuously measure intracranial pressure remains aspirational. Analysis of the intracranial pressure signal can provide information on brain compliance (ie, the ability of the cranium to tolerate volume changes) and on cerebral autoregulation (ie, the ability of cerebral blood vessels to react to changes in blood pressure). The information derived from the intracranial pressure signal might allow for more individualised patient management. Machine learning and artificial intelligence approaches are being increasingly applied to intracranial pressure monitoring, but many obstacles need to be overcome before their use in clinical practice could be attempted. Robust clinical trials are needed to support indications for intracranial pressure monitoring and treatment. Progress in non-invasive assessment of intracranial pressure and in signal analysis (for targeted treatment) will also be crucial.

颅内压监测可以检测和治疗颅内高压，这是创伤性脑损伤后的潜在致命伤害。尽管广泛使用，但支持颅内压监测和治疗的有力证据仍然很少。国际研究表明，各中心在颅内压监测和颅内高压治疗的适应症方面存在很大差异。专家们审查了这两个方面，并以协商一致的方式提供了监测和治疗的实用方法。尽管目前，无创性连续测量颅内压的可靠方法仍然令人鼓舞，但在无创性估计颅内压的方法中已经取得了进展。对颅内压信号的分析可以提供有关脑顺应性 (即，颅骨耐受体积变化的能力) 和脑自动调节 (即，脑血管对血压变化做出反应的能力) 的信息。从颅内压信号导出的信息可以允许更个性化的患者管理。机器学习和人工智能方法越来越多地应用于颅内压监测，但是在尝试将其用于临床实践之前，需要克服许多障碍。需要强有力的临床试验来支持颅内压监测和治疗的适应症。颅内压的非侵入性评估和信号分析 (用于靶向治疗) 的进展也将至关重要。

REF: Zoerle T, Beqiri E, Åkerlund CAI, et al. Intracranial pressure monitoring in adult patients with traumatic brain injury: challenges and innovations. Lancet Neurol. 2024;23(9):938-950. doi:10.1016/S1474-4422(24)00235-7 PMID: 39152029