Safety and effectiveness of the Walk ‘n Watch structured, progressive exercise protocol delivered by physical therapists for inpatient stroke rehabilitation in Canada: a phase 3, multisite, pragmatic, stepped-wedge, cluster-randomised controlled trial

加拿大物理治疗师实施的“边走边观察”结构化渐进式运动方案用于住院脑卒中康复的安全性和有效性：一项3期、多中心、实用性、阶梯楔形、整群随机对照试验

Although clinical guidelines support high repetitions of walking after stroke, practice is slow to change. We undertook an implementation trial to enable entire stroke units to use the Walk 'n Watch structured, progressive exercise protocol. Our objective was to evaluate the effectiveness of the Walk 'n Watch implementation package on patient outcomes after 4 weeks in an inpatient stroke rehabilitation setting. The Walk 'n Watch protocol resulted in a clinically meaningful improvement in walking endurance in patients with subacute stroke in a real-world setting. The protocol can be readily implemented into practice with minimal additional resources. Further research is needed to identify characteristics of patients who might benefit the most from Walk 'n Watch.

尽管临床指南支持中风后进行高频率的步行训练，但实际做法的改变却很缓慢。我们开展了一项实施试验，以使整个中风治疗单元都能采用“边走边测”结构化渐进式运动方案。我们的目标是评估在住院中风康复环境中，“边走边测”实施包对患者四周后治疗效果的影响。“边走边测”方案在现实环境中使亚急性中风患者的步行耐力得到了具有临床意义的改善。该方案可以在只需极少额外资源的情况下轻松应用于实际治疗中。还需要进一步研究以确定哪些患者特征的人群可能从“边走边测”方案中获益最大。

REF: Peters S, Hung SH, Bayley MT, et al. Safety and effectiveness of the Walk 'n Watch structured, progressive exercise protocol delivered by physical therapists for inpatient stroke rehabilitation in Canada: a phase 3, multisite, pragmatic, stepped-wedge, cluster-randomised controlled trial. Lancet Neurol. 2025;24(8):643-655. doi:10.1016/S1474-4422(25)00201-7 PMID: 40683274

Safety and efficacy of fenebrutinib in relapsing multiple sclerosis (FENopta): a multicentre, double-blind, randomised, placebo-controlled, phase 2 trial and open-label extension study

芬布替尼治疗复发型多发性硬化症的安全性和有效性（FENopta）：一项多中心、双盲、随机、安慰剂对照的2期试验及开放标签扩展研究

The prospect for Bruton's tyrosine kinase (BTK) inhibition to meaningfully affect relapsing multiple sclerosis has recently been questioned due to inconsistent findings in the magnitude and sustainability of the effect of BTK inhibitors on disease activity. We assessed the safety, efficacy, and CSF drug concentrations of fenebrutinib, a highly selective, noncovalent, reversible BTK inhibitor, in patients with relapsing multiple sclerosis. Between March 1, 2022 and March 29, 2023, 109 patients with relapsing multiple sclerosis were randomly assigned treatment: 73 received fenebrutinib and 36 received placebo. 106 patients had evaluable post-baseline brain MRI scans and were assessed for efficacy in the fenebrutinib group (n=70) and placebo group (n=36). The combined number of new T1 Gd+ lesions at weeks 4, 8, and 12 were 0·077 (95% CI 0·043-0·135) in the fenebrutinib group and 0·245 (0·144-0·418) in the placebo group (69% relative reduction [95% CI 34-85]; p=0·0022). During the open-label extension, through week 48, the unadjusted annualised relapse rate was 0·04 and 95 (96%) of 99 patients were relapse-free. During the double-blind treatment phase, the most common adverse events that were more frequent in the fenebrutinib group than in the placebo group were hepatic enzyme elevations (four [6%] vs 0), headache (three [4%] vs one [3%]), and nasopharyngitis (two [3%] vs 0); no serious adverse events or deaths occurred.

由于布鲁顿酪氨酸激酶（BTK）抑制剂对疾病活动的影响程度和持续性的研究结果不一致，BTK抑制能否对复发型多发性硬化产生显著影响最近受到了质疑。我们评估了非共价可逆的高选择性BTK抑制剂非奈布替尼在复发型多发性硬化患者中的安全性、有效性以及脑脊液药物浓度。2022年3月1日至2023年3月29日期间，109例复发型多发性硬化患者被随机分配接受治疗：73例接受非奈布替尼治疗，36例接受安慰剂治疗。106例患者有可评估的基线后脑部磁共振成像（MRI）扫描结果，并在非奈布替尼组（n = 70）和安慰剂组（n = 36）中进行了有效性评估。在第4周、第8周和第12周时，非奈布替尼组新出现的T1加权增强（Gd+）病灶总数为0.077（95%置信区间[CI] 0.043 - 0.135），安慰剂组为0.245（0.144 - 0.418）（相对减少69%[95% CI 34 - 85]；p = 0.0022）。在开放标签延长期，直至第48周，未经调整的年化复发率为0.04，99例患者中有95例（96%）未复发。在双盲治疗阶段，非奈布替尼组比安慰剂组更常见的不良事件为肝酶升高（4例[6%] vs 0例）、头痛（3例[4%] vs 1例[3%]）和鼻咽炎（2例[3%] vs 0例）；未发生严重不良事件或死亡。

REF: Bar-Or A, Dufek M, Budincevic H, et al. Safety and efficacy of fenebrutinib in relapsing multiple sclerosis (FENopta): a multicentre, double-blind, randomised, placebo-controlled, phase 2 trial and open-label extension study. Lancet Neurol. 2025;24(8):656-666. doi:10.1016/S1474-4422(25)00174-7 PMID: 40683275

Acute-onset axonal neuropathy following infection in children with biallelic RCC1 variants: a case series

双等位基因RCC1变异患儿感染后急性起病的轴索性神经病：病例系列研究

The reasons why some individuals have severe neuropathy following an infection are not known. Through the agnostic screening of children with acute axonal neuropathy after an infection, we identified several families with biallelic variants in RCC1. We aimed to describe the clinical phenotype of these patients, and the molecular and cellular pathology associated with the genetic variants identified in these families. We describe an autosomal recessive, acute-onset paediatric axonal neuropathy, seemingly triggered by infection, that affects individuals with biallelic RCC1 variants. In these children, the disease can mimic Guillain-Barré syndrome. The pathological mechanisms underlying this novel axonal neuropathy might overlap with those of amyotrophic lateral sclerosis. Cellular studies indicate that RCC1 variants affect nucleocytoplasmic transport, which is crucial for healthy axonal function. Future studies should be directed at pre-symptomatic treatment by exploring ways to maintain nucleocytoplasmic transport.

目前尚不清楚为何有些人在感染后会出现严重的神经病变。通过对感染后患有急性轴索性神经病的儿童进行无偏筛选，我们发现了几个携带RCC1双等位基因变异的家族。我们旨在描述这些患者的临床表型，以及与这些家族中发现的基因变异相关的分子和细胞病理学特征。我们描述了一种常染色体隐性遗传、急性起病的儿童轴索性神经病，该病似乎由感染引发，影响携带RCC1双等位基因变异的个体。在这些儿童中，该疾病可能会与吉兰 - 巴雷综合征相混淆。这种新型轴索性神经病的病理机制可能与肌萎缩侧索硬化症的病理机制存在重叠。细胞研究表明，RCC1变异会影响核质运输，而核质运输对轴突的正常功能至关重要。未来的研究应着眼于通过探索维持核质运输的方法来进行症状前治疗。

REF: Harkness JR, McDermott JH, Marsden S, et al. Acute-onset axonal neuropathy following infection in children with biallelic RCC1 variants: a case series. Lancet Neurol. 2025;24(8):667-680. doi:10.1016/S1474-4422(25)00198-X PMID: 40683276

α-synuclein biomarker assays: bridging research and patient care

α-突触核蛋白生物标志物检测：架起研究与患者护理之间的桥梁

The discovery that α-synuclein can be detected in peripheral tissues of patients with Parkinson's disease and other synucleinopathies spurred the development of biomarker assays, including the α-synuclein seed amplification assay for CSF and immunofluorescence detection of dermal phosphorylated-α-synuclein. These tools aim to identify pathological α-synuclein changes, even at the early stages of disease, with the goal of eventually enabling differentiation of Parkinson's disease from other neurodegenerative disorders, including tauopathies. α-synuclein biomarkers add a biological component to the traditional clinical diagnosis of Parkinson's disease, with potential for development of complementary clinical and pathobiological frameworks for Parkinson's disease and related movement disorders. However, use of existing α-synuclein biomarkers is restricted to research settings due to variable sensitivity and specificity, restricted availability of neuropathological data for validation, and scarcity of longitudinal studies. Addressing these limitations is crucial for advancing clinical and biological disease definitions, which will be essential for the development of disease-modifying therapies.

在帕金森病及其他突触核蛋白病患者的外周组织中可检测到α-突触核蛋白这一发现推动了生物标志物检测方法的开发，包括针对脑脊液的α-突触核蛋白种子扩增检测法以及皮肤磷酸化α-突触核蛋白的免疫荧光检测法。这些检测手段旨在识别病理性α-突触核蛋白的变化，即便在疾病早期也能做到，最终目标是实现帕金森病与其他神经退行性疾病（包括tau蛋白病）的鉴别诊断。α-突触核蛋白生物标志物为帕金森病的传统临床诊断增添了生物学元素，有望为帕金森病及相关运动障碍疾病构建临床与病理生物学互补的框架。然而，由于现有α-突触核蛋白生物标志物的敏感性和特异性存在差异、用于验证的神经病理学数据有限以及纵向研究匮乏，其应用目前仅限于研究领域。解决这些局限性对于完善临床和生物学疾病定义至关重要，而这对于开发疾病修正疗法必不可少。

REF: Agin-Liebes J, Lodge A, Reddy H, et al. α-synuclein biomarker assays: bridging research and patient care. Lancet Neurol. 2025;24(8):681-697. doi:10.1016/S1474-4422(25)00194-2 PMID: 40683277

Focused ultrasound therapy for movement disorders

聚焦超声治疗运动障碍性疾病

Functional neurosurgery, such as deep brain stimulation, is an established therapeutic option for many patients with movement disorders. MR-guided focused ultrasound has emerged as an incisionless and minimally invasive neurofunctional treatment. This new approach is based on the delivery of high-intensity ultrasound energy to produce therapeutic thermoablation. Several randomised controlled trials have shown safety and symptomatic efficacy of focused ultrasound ablation, particularly to treat patients with essential tremor or Parkinson's disease. The use of focused ultrasound therapy is expanding to many centres worldwide, and its application for other indications-such as tremor of other origin and dystonia-has also been preliminarily investigated. MR-guided focused ultrasound has been explored in the modality of low-intensity ultrasound, which allows mechanical effects on brain tissue, primarily transient blood-brain barrier opening and neuromodulation, both of which could offer a wide array of experimental and clinical possibilities. Therefore, MR-guided focused ultrasound might have an important role in the future treatment of patients with movement disorders and neurodegenerative diseases.

功能性神经外科手术，如脑深部电刺激，是许多运动障碍患者的既定治疗选择。磁共振引导聚焦超声已成为一种无需切口且微创的神经功能治疗方法。这种新方法是基于输送高强度超声能量以产生治疗性热消融。多项随机对照试验已证实聚焦超声消融的安全性和症状改善疗效，尤其适用于治疗特发性震颤或帕金森病患者。聚焦超声治疗的应用正在全球多个医疗中心不断拓展，其在其他适应证（如其他原因引起的震颤和肌张力障碍）方面的应用也已开展了初步研究。磁共振引导聚焦超声还探索了低强度超声模式，这种模式可对脑组织产生机械效应，主要是短暂性血脑屏障开放和神经调节，这两者都可能提供广泛的实验和临床应用可能性。因此，磁共振引导聚焦超声可能在未来运动障碍和神经退行性疾病患者的治疗中发挥重要作用。

REF: Martínez-Fernández R, Paschen S, Del Álamo M, et al. Focused ultrasound therapy for movement disorders. Lancet Neurol. 2025;24(8):698-712. doi:10.1016/S1474-4422(25)00210-8 PMID: 40683278