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Longitudinal Magnetic Resonance Imaging in Asymptomatic C9orf72 Mutation Carriers Distinguishes Phenoconverters to Amyotrophic Lateral Sclerosis or Amyotrophic Lateral Sclerosis With Frontotemporal Dementia. 无症状 C9orf72 基因突变携带者的纵向磁共振成像可区分肌萎缩侧索硬化症或伴有额颞叶痴呆的肌萎缩侧索硬化症的表观转化者。
IF 8.1 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-11-02 DOI: 10.1002/ana.27116
Kevin van Veenhuijzen, Harold H G Tan, Abram D Nitert, Michael A van Es, Jan H Veldink, Leonard H van den Berg, Henk-Jan Westeneng

Objective: We prospectively studied asymptomatic C9orf72 mutation carriers, identifying those developing amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD).

Methods: We enrolled 56 asymptomatic family members (AFM) with a C9orf72 mutation (AFM C9+), 132 non-carriers (AFM C9-), and 359 population-based controls. Using 3 T magnetic resonance imaging, we measured cortical thickness, gyrification, and subcortical volumes longitudinally. Linear mixed-effects models on non-converting AFM C9+ scans (n = 107) created a reference for these measurements, establishing individual atrophy patterns. Atrophy patterns from presymptomatic phenoconverters (n = 10 scans) served as a template for group comparisons and similarity assessments. Similarity with phenoconverters was quantified using Dice similarity coefficient (DSC) for cortical and Kullback-Leibler similarity (KLS) for subcortical measures. Using longitudinal similarity assessments, we predicted when participants would reach the average similarity level of phenoconverters at their first post-onset scan.

Results: Five AFM C9+ converted to ALS or ALS-FTD. Up to 6 years before symptoms, these phenoconverters exhibited significant atrophy in frontal, temporal, parietal, and cingulate cortex, along with smaller thalamus, hippocampus, and amygdala compared to other AFM C9+. Some non-converted AFM C9+ had high DSC and KLS, approaching values of phenoconverters, whereas others, along with AFM C9- and controls, had lower values. At age 80, we predicted 27.9% (95% confidence interval, 13.2-40.1%) of AFM C9+ and no AFM C9- would reach the same DSC as phenoconverters.

Interpretation: Distinctive atrophy patterns are visible years before symptom onset on presymptomatic scans of phenoconverters. Combining baseline and follow-up similarity measures may serve as a promising imaging biomarker for identifying those at risk of ALS or ALS-FTD. ANN NEUROL 2024.

目的:我们对无症状的C9orf72基因突变携带者进行了前瞻性研究,以确定那些患肌萎缩侧索硬化症(ALS)或额颞叶痴呆症(FTD)的患者:我们招募了56名C9orf72突变无症状家庭成员(AFM)(AFM C9+)、132名非携带者(AFM C9-)和359名人群对照。我们使用 3 T 磁共振成像技术纵向测量了皮质厚度、回旋和皮质下体积。非转换 AFM C9+ 扫描(n = 107)的线性混合效应模型为这些测量结果提供了参考,从而确定了个体萎缩模式。无症状表型转换者的萎缩模式(n = 10 次扫描)可作为群体比较和相似性评估的模板。与表型转换者的相似性通过皮质的戴斯相似系数(DSC)和皮质下的库尔贝克-莱布勒相似性(KLS)进行量化。通过纵向相似性评估,我们预测了参与者在发病后第一次扫描时达到表型转换者平均相似性水平的时间:结果:5 名 AFM C9+ 患者转为 ALS 或 ALS-FTD。与其他 AFM C9+ 相比,这些表型转换者在症状出现前 6 年表现出额叶、颞叶、顶叶和扣带回皮层明显萎缩,丘脑、海马和杏仁核也较小。一些未转化的 AFM C9+ 具有较高的 DSC 和 KLS,接近表型转化者的数值,而其他 AFM C9+ 和对照组的数值则较低。我们预测,在 80 岁时,27.9%(95% 置信区间,13.2-40.1%)的 AFM C9+ 和 AFM C9- 将达到与表型转换者相同的 DSC 值:解释:在表型转换者的症状前扫描中,可看到症状发作前数年的独特萎缩模式。结合基线和随访相似性测量可作为一种有前途的成像生物标志物,用于识别 ALS 或 ALS-FTD 的高危人群。ann neurol 2024.
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引用次数: 0
Cost-Effectiveness of Endovascular Thrombectomy in Patients with Large Ischemic Stroke. 大面积缺血性脑卒中患者血管内血栓切除术的成本效益。
IF 8.1 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-31 DOI: 10.1002/ana.27119
Lan Gao, Leonid Churilov, Hannah Johns, Deep Pujara, Ameer E Hassan, Michael Abraham, Santiago Ortega-Gutierrez, Muhammad Shazam Hussain, Michael Chen, Spiros Blackburn, Clark W Sitton, Florentina M E Pinckaers, Wim H van Zwam, Georgios Tsivgoulis, Michael D Hill, James C Grotta, Scott Kasner, Marc Ribo, Bruce C Campbell, Amrou Sarraj

Objectives: Whereas highly cost-effective and cost-saving for patients with small infarcts, whether endovascular thrombectomy (EVT) remains cost-effective in patients with extensive ischemic injury is uncertain.

Methods: We conducted a model-based cost-effectiveness analysis from the United States, Australian, and Spanish societal perspectives, using a 7-state Markov model, with each state defined by the modified Rankin Scale (mRS) score. Initial probabilities at 3 months were derived from the SELECT2 trial. All other model inputs, including transition probabilities, health care and non-health care costs, and utility weights, were sourced from published literature and government websites. Our analysis included extensive sensitivity and subgroup analyses.

Results: EVT in patients with large ischemic stroke improved health outcomes and was associated with lower costs from a societal viewpoint. EVT was cost-effective with a mean between-group difference of 1.24 quality-adjusted life years (QALYs), and a cost-saving of $23,409 in the United States, $10,691 in Australia, and $30,036 in Spain, in addition to uncosted benefits in productivity for patients and carers. Subgroup analyses were directionally consistent with the overall population, notably with preserved cost-effectiveness in older patients (≥ 70 years) and those with more severe strokes (National Institutes of Health Stroke Scale [NIHSS] ≥ 20). Sensitivity analyses were largely consistent with the base-case results.

Interpretation: EVT demonstrated cost-effectiveness in patients with large core across different settings in the United States, Australia, and Spain, including older patients and those with more severe strokes. These results further support adaptation of systems of care to accommodate the expansion of thrombectomy eligibility to patients with large cores and maximize EVT benefits. ANN NEUROL 2024.

目的:虽然血管内血栓切除术(EVT)对小面积梗死患者具有很高的成本效益和节约成本的作用,但对大面积缺血性损伤患者是否仍然具有成本效益还不确定:虽然血管内血栓切除术(EVT)对小面积梗死患者具有很高的成本效益并能节约成本,但对大面积缺血性损伤患者是否仍具有成本效益尚不确定:我们从美国、澳大利亚和西班牙的社会角度出发,使用 7 状态马尔可夫模型进行了基于模型的成本效益分析,每个状态由修正的 Rankin 量表(mRS)评分定义。3 个月时的初始概率来自 SELECT2 试验。所有其他模型输入,包括过渡概率、医疗和非医疗成本以及效用权重,均来自已发表的文献和政府网站。我们的分析包括大量的敏感性分析和亚组分析:结果:对大面积缺血性脑卒中患者进行 EVT 可改善健康预后,从社会角度看成本更低。EVT具有成本效益,组间平均差异为1.24质量调整生命年(QALYs),在美国节省成本23,409美元,在澳大利亚节省成本10,691美元,在西班牙节省成本30,036美元。亚组分析的方向与总体人群一致,尤其是老年患者(≥ 70 岁)和脑卒中较严重的患者(美国国立卫生研究院脑卒中量表 [NIHSS] ≥ 20)的成本效益保持不变。敏感性分析结果与基础病例结果基本一致:EVT在美国、澳大利亚和西班牙不同环境下的大核心患者中显示出成本效益,包括年龄较大的患者和脑卒中较严重的患者。这些结果进一步支持对医疗系统进行调整,以适应将血栓切除术的适用范围扩大到大核心患者,并最大限度地提高 EVT 的效益。ann neurol 2024。
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引用次数: 0
Minimally Invasive Surgery for Spontaneous Intracerebral Hemorrhage: Meta-Analysis of High-Quality Randomized Clinical Trials. 治疗自发性脑内出血的微创手术:高质量随机临床试验的 Meta 分析。
IF 8.1 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-31 DOI: 10.1002/ana.27107
Ahmed Alkhiri, Aser F Alamri, Ahmed A Almaghrabi, Fahad Alturki, Basil A Alghamdi, Abdullah Alharbi, Hassan K Salamatullah, Mohamed Alzawahmah, Faisal Al-Otaibi, Abdulrahman Y Alturki, Dar Dowlatshahi, Andrew M Demchuk, Wendy C Ziai, Christopher P Kellner, Adel Alhazzani, Fahad S Al-Ajlan

Objectives: Spontaneous intracerebral hemorrhage (ICH) poses high mortality and morbidity rates with limited evidence-based therapeutic approaches. We aimed to evaluate the current evidence for the role of minimally invasive surgery (MIS) in the management of ICH.

Methods: This systematic review and meta-analysis followed recommended guidelines and protocols. Medline, Embase, Scopus, and the Cochrane Library were searched from inception up to April 12, 2024. The inclusion was restricted to randomized clinical trials (RCTs) of high quality, ensuring they were not deemed to have a high risk of bias in any of the Cochrane risk of bias tool (RoB2) domains. Primary outcomes were good functional outcome (modified Rankin scale, 0-3) and mortality beyond 90 days. Secondary outcomes were early mortality within 30 days and rebleeding rates. We pooled odds ratios (ORs) with corresponding 95% confidence intervals (CIs) using random-effects models.

Results: Fourteen high-quality RCTs were included. There were 3,027 patients with ICH (1,475 randomized to MIS, and 1,452 randomized to medical management or craniotomy). Of included patients, 1,899 (62.7%) were males. MIS resulted in higher odds of achieving long-term good functional outcome (OR, 1.51 [95% CI, 1.25-1.82]), lower odds of long-term mortality (OR, 0.72 [95% CI, 0.57-0.90]) and lower odds of early mortality (OR, 0.73 [95% CI, 0.56-0.95]). Rebleeding rates were similar (OR, 1.10 [95% CI, 0.55-2.19]). The treatment effect of MIS was consistent across multiple sensitivity and subgroup analyses, including individuals with deep ICH.

Interpretation: This meta-analysis provides high-quality clinical trial evidence supporting the use of MIS as a primary treatment strategy in the management of ICH. ANN NEUROL 2024.

目的:自发性脑内出血(ICH)的死亡率和发病率都很高,而循证治疗方法却很有限。我们旨在评估微创手术(MIS)在治疗 ICH 中的作用的现有证据:本系统综述和荟萃分析遵循推荐的指南和协议。对 Medline、Embase、Scopus 和 Cochrane 图书馆进行了检索,检索时间从开始到 2024 年 4 月 12 日。纳入的研究仅限于高质量的随机临床试验(RCT),确保这些试验在Cochrane偏倚风险工具(RoB2)的任何一个领域中都不存在高偏倚风险。主要结果是良好的功能预后(改良Rankin量表,0-3)和90天后的死亡率。次要结果是 30 天内的早期死亡率和再出血率。我们使用随机效应模型汇总了几率比(OR)及相应的 95% 置信区间(CI):结果:共纳入了 14 项高质量的 RCT。共有 3,027 名 ICH 患者(1,475 名随机接受 MIS 治疗,1,452 名随机接受药物治疗或开颅手术治疗)。在纳入的患者中,1,899 名(62.7%)为男性。MIS术后获得长期良好功能预后的几率更高(OR,1.51 [95% CI,1.25-1.82]),长期死亡率较低(OR,0.72 [95% CI,0.57-0.90]),早期死亡率较低(OR,0.73 [95% CI,0.56-0.95])。再出血率相似(OR,1.10 [95% CI,0.55-2.19])。在多项敏感性分析和亚组分析中,MIS的治疗效果是一致的,包括深部ICH患者:这项荟萃分析提供了高质量的临床试验证据,支持将 MIS 作为治疗 ICH 的主要治疗策略。ann neurol 2024.
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引用次数: 0
Directional Subthalamic Deep Brain Stimulation Better Improves Gait and Balance Disorders in Parkinson's Disease Patients: A Randomized Controlled Study. 定向丘脑下深部脑刺激能更好地改善帕金森病患者的步态和平衡障碍:随机对照研究
IF 8.1 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-30 DOI: 10.1002/ana.27099
Saoussen Cherif, Nicolas Tempier, Mathieu Yeche, Gizem Temiz, Julia Perrière, Marco Romanato, Déborah Ziri, Sara Fernandez-Vidal, Elodie Hainque, David Maltête, Stéphane Derrey, Eric Bardinet, Brian Lau, Carine Karachi, Marie-Laure Welter

Objective: To investigate the effects of directional subthalamic deep brain stimulation (STN-dDBS) on gait and balance disorders, including freezing of gait (FOG), in patients with advanced Parkinson's disease (PD).

Methods: We included 10 participants who underwent STN-DBS and presented severe preoperative FOG, in a randomized, double-blind, crossover study. We used segmented DBS electrodes to investigate whether directing the predicted volume of tissue activated (VTA) to overlap the central STN preferentially improved gait and balance disorders compared to directional DBS applied in the more posterior STN (sensorimotor). We also assessed non-directional (ring-mode) STN-DBS. Our primary outcome was gait and balance control measured using instrumented gait recordings. Each patient had a pre-operative structural and diffusion-weighted imaging to model individual VTAs and to examine cortico-subthalamic connectivity. We used linear mixed-effects models to contrast the effects of central STN-dDBS, posterior STN-dDBS, and ring-mode STN-DBS.

Results: Central STN-dDBS produced significantly better improvement in gait and balance control compared to posterior STN-dDBS (p = 0.027), with fewer FOG episodes (p < 0.001). Conversely, ring-mode STN-DBS resulted in worsened postural control compared to central STN-dDBS (p = 0.009). The cortico-subthalamic connectivity with the STN VTAs involved mostly primary sensorimotor, premotor, and medial frontal cortices, with a higher overall cortico-STN connectivity with ring-mode STN-DBS.

Interpretation: Central STN-dDBS represents the best option to improve gait and balance disorders in PD patients, including FOG. Our findings raise the possibility of reprogramming STN-DBS toward the central area in selected patients with disabling FOG and/or postural instability after surgery. ANN NEUROL 2024.

目的研究定向丘脑下深部脑刺激(STN-dDBS)对晚期帕金森病(PD)患者步态和平衡障碍(包括步态冻结(FOG))的影响:我们在一项随机、双盲、交叉研究中纳入了 10 名接受 STN-DBS、术前出现严重 FOG 的患者。我们使用分段式 DBS 电极,研究与应用于较后部 STN(感觉运动)的定向 DBS 相比,将预测的组织激活量(VTA)引导至与中央 STN 重叠是否更有利于改善步态和平衡障碍。我们还评估了非定向(环模式)STN-DBS。我们的主要研究结果是使用仪器步态记录测量步态和平衡控制。每位患者术前都进行了结构和弥散加权成像,以建立单个 VTA 模型,并检查皮质-丘脑连接。我们使用线性混合效应模型对比了中心 STN-dDBS、后 STN-dDBS、环模式 STN-DBS 的效果:结果:与后部 STN-dDBS 相比,中枢 STN-dDBS 在步态和平衡控制方面的改善效果明显更好(p = 0.027),且 FOG 发作次数更少(p 解释:中枢 STN-dDBS 代表了 STN-DBS,而后部 STN-dDBS 代表了 STN-DBS:中枢 STN-dDBS 是改善 PD 患者步态和平衡障碍(包括 FOG)的最佳选择。我们的研究结果提出了一种可能性,即在选定的术后出现致残性 FOG 和/或姿势不稳的患者中,将 STN-DBS 向中央区域重新编程。ann neurol 2024.
{"title":"Directional Subthalamic Deep Brain Stimulation Better Improves Gait and Balance Disorders in Parkinson's Disease Patients: A Randomized Controlled Study.","authors":"Saoussen Cherif, Nicolas Tempier, Mathieu Yeche, Gizem Temiz, Julia Perrière, Marco Romanato, Déborah Ziri, Sara Fernandez-Vidal, Elodie Hainque, David Maltête, Stéphane Derrey, Eric Bardinet, Brian Lau, Carine Karachi, Marie-Laure Welter","doi":"10.1002/ana.27099","DOIUrl":"https://doi.org/10.1002/ana.27099","url":null,"abstract":"<p><strong>Objective: </strong>To investigate the effects of directional subthalamic deep brain stimulation (STN-dDBS) on gait and balance disorders, including freezing of gait (FOG), in patients with advanced Parkinson's disease (PD).</p><p><strong>Methods: </strong>We included 10 participants who underwent STN-DBS and presented severe preoperative FOG, in a randomized, double-blind, crossover study. We used segmented DBS electrodes to investigate whether directing the predicted volume of tissue activated (VTA) to overlap the central STN preferentially improved gait and balance disorders compared to directional DBS applied in the more posterior STN (sensorimotor). We also assessed non-directional (ring-mode) STN-DBS. Our primary outcome was gait and balance control measured using instrumented gait recordings. Each patient had a pre-operative structural and diffusion-weighted imaging to model individual VTAs and to examine cortico-subthalamic connectivity. We used linear mixed-effects models to contrast the effects of central STN-dDBS, posterior STN-dDBS, and ring-mode STN-DBS.</p><p><strong>Results: </strong>Central STN-dDBS produced significantly better improvement in gait and balance control compared to posterior STN-dDBS (p = 0.027), with fewer FOG episodes (p < 0.001). Conversely, ring-mode STN-DBS resulted in worsened postural control compared to central STN-dDBS (p = 0.009). The cortico-subthalamic connectivity with the STN VTAs involved mostly primary sensorimotor, premotor, and medial frontal cortices, with a higher overall cortico-STN connectivity with ring-mode STN-DBS.</p><p><strong>Interpretation: </strong>Central STN-dDBS represents the best option to improve gait and balance disorders in PD patients, including FOG. Our findings raise the possibility of reprogramming STN-DBS toward the central area in selected patients with disabling FOG and/or postural instability after surgery. ANN NEUROL 2024.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142542309","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Association of Seizure Control with Mortality, Cognition, and Function in People With Dementia. 癫痫发作控制与痴呆症患者的死亡率、认知和功能的关系
IF 8.1 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-30 DOI: 10.1002/ana.27125
Ifrah Zawar, Mark Quigg, Soutik Ghosal, Vineet Punia, Yamile Calle-Lopez, Carol Manning, Jaideep Kapur

Objectives: The effects of seizure control on outcomes in persons with dementia (PWD) remain unclear. Our study aimed to investigate the impact of seizure control on mortality, function, cognition, and mood among PWD.

Methods: This longitudinal, multicenter study is based on 39 Alzheimer's disease centers (ADCs) in the United States from September 2005 to December 2021. PWD were grouped by seizure status into recurrent (seizures in the past year), remote (prior seizures but none in the past year), and no seizures (controls). The primary outcome was all-cause mortality among seizure groups. We used Weibull survival analysis to assess the mortality risks by seizure status after adjusting for age, sex, education, race, ethnicity, hypertension, diabetes, hyperlipidemia, degree of cognitive impairment, dominant Alzheimer's disease (AD) mutation, brain trauma, stroke, Parkinson's disease, alcohol abuse, and depression. Cognition (Clinical Dementia Rating), function (physical dependence and nursing home residence), day-to-day activities (Functional Assessment Scores), and mood (Geriatric Depression Scale) were compared among seizure groups after adjusting for dementia duration and age.

Results: Among 26,501 participants, 374 (1.4%) had recurrent seizures and 510 (1.9%) had remote seizures. In multivariable survival analysis, recurrent seizures were associated with a higher mortality risk than remote and no seizures (adjusted hazard ratio [aHR], 95% confidence interval [95% CI]; recurrent aHR = 1.79, 95% CI = 1.51 to 2.12; remote aHR = 1.17, 95% CI = 0.98 to 1.38). Median time-to-death for recurrent, remote, and no seizures was 2.4, 4.0, and 4.7 years, respectively. People with recurrent seizures had worse cognition, day-to-day function, and physical dependence than those with remote seizures and controls.

Interpretation: PWD with poorly controlled recurrent seizures have worse mortality, functional, and cognitive outcomes than PWD with remote and no seizures. These findings underscore the need for timely identification and management of ongoing seizures in PWD. ANN NEUROL 2024.

目的:控制癫痫发作对痴呆症患者(PWD)预后的影响仍不明确。我们的研究旨在调查癫痫发作控制对痴呆患者死亡率、功能、认知和情绪的影响:这项纵向多中心研究基于 2005 年 9 月至 2021 年 12 月期间美国的 39 个阿尔茨海默病中心(ADC)。根据癫痫发作状况将患者分为复发性(过去一年内有癫痫发作)、远期(曾有癫痫发作但过去一年内没有)和无癫痫发作(对照组)。主要结果是各癫痫发作组的全因死亡率。在对年龄、性别、教育程度、种族、民族、高血压、糖尿病、高脂血症、认知障碍程度、阿尔茨海默病 (AD) 显性突变、脑外伤、中风、帕金森病、酗酒和抑郁等因素进行调整后,我们使用 Weibull 生存分析评估了不同癫痫发作状态下的死亡率风险。在对痴呆持续时间和年龄进行调整后,比较了不同发作组的认知(临床痴呆评级)、功能(身体依赖性和疗养院居住)、日常活动(功能评估评分)和情绪(老年抑郁量表):在 26,501 名参与者中,374 人(1.4%)有复发性癫痫发作,510 人(1.9%)有远期癫痫发作。在多变量生存分析中,复发性癫痫发作与较高的死亡风险相关(调整后危险比 [aHR],95% 置信区间 [95%CI];复发性 aHR = 1.79,95% CI = 1.51 至 2.12;复发性 aHR = 1.17,95% CI = 0.98 至 1.38)。复发性、偏远地区和无发作患者的中位死亡时间分别为2.4年、4.0年和4.7年。复发性癫痫发作患者的认知能力、日常功能和身体依赖性均比远期癫痫发作患者和对照组患者差:解释:复发性癫痫发作控制不佳的残疾人的死亡率、功能和认知能力均比远期和无癫痫发作的残疾人差。这些发现强调了及时发现和控制残疾人癫痫持续发作的必要性。ann neurol 2024.
{"title":"Association of Seizure Control with Mortality, Cognition, and Function in People With Dementia.","authors":"Ifrah Zawar, Mark Quigg, Soutik Ghosal, Vineet Punia, Yamile Calle-Lopez, Carol Manning, Jaideep Kapur","doi":"10.1002/ana.27125","DOIUrl":"https://doi.org/10.1002/ana.27125","url":null,"abstract":"<p><strong>Objectives: </strong>The effects of seizure control on outcomes in persons with dementia (PWD) remain unclear. Our study aimed to investigate the impact of seizure control on mortality, function, cognition, and mood among PWD.</p><p><strong>Methods: </strong>This longitudinal, multicenter study is based on 39 Alzheimer's disease centers (ADCs) in the United States from September 2005 to December 2021. PWD were grouped by seizure status into recurrent (seizures in the past year), remote (prior seizures but none in the past year), and no seizures (controls). The primary outcome was all-cause mortality among seizure groups. We used Weibull survival analysis to assess the mortality risks by seizure status after adjusting for age, sex, education, race, ethnicity, hypertension, diabetes, hyperlipidemia, degree of cognitive impairment, dominant Alzheimer's disease (AD) mutation, brain trauma, stroke, Parkinson's disease, alcohol abuse, and depression. Cognition (Clinical Dementia Rating), function (physical dependence and nursing home residence), day-to-day activities (Functional Assessment Scores), and mood (Geriatric Depression Scale) were compared among seizure groups after adjusting for dementia duration and age.</p><p><strong>Results: </strong>Among 26,501 participants, 374 (1.4%) had recurrent seizures and 510 (1.9%) had remote seizures. In multivariable survival analysis, recurrent seizures were associated with a higher mortality risk than remote and no seizures (adjusted hazard ratio [aHR], 95% confidence interval [95% CI]; recurrent aHR = 1.79, 95% CI = 1.51 to 2.12; remote aHR = 1.17, 95% CI = 0.98 to 1.38). Median time-to-death for recurrent, remote, and no seizures was 2.4, 4.0, and 4.7 years, respectively. People with recurrent seizures had worse cognition, day-to-day function, and physical dependence than those with remote seizures and controls.</p><p><strong>Interpretation: </strong>PWD with poorly controlled recurrent seizures have worse mortality, functional, and cognitive outcomes than PWD with remote and no seizures. These findings underscore the need for timely identification and management of ongoing seizures in PWD. ANN NEUROL 2024.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142542307","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Transmantle Vein Persistence in Adulthood. 成年后的跨静脉持续存在。
IF 8.1 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-28 DOI: 10.1002/ana.27122
Marialuisa Zedde, Rosario Pascarella
{"title":"Transmantle Vein Persistence in Adulthood.","authors":"Marialuisa Zedde, Rosario Pascarella","doi":"10.1002/ana.27122","DOIUrl":"https://doi.org/10.1002/ana.27122","url":null,"abstract":"","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142520471","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A Novel Mouse Model for Cerebral Inflammatory Demyelination in X-Linked Adrenoleukodystrophy: Insights into Pathogenesis and Potential Therapeutic Targets. X-遗传性肾上腺白质营养不良症脑部炎症性脱髓鞘的新型小鼠模型:对发病机制和潜在治疗靶点的洞察。
IF 8.1 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-28 DOI: 10.1002/ana.27117
Ezzat Hashemi, Isha N Srivastava, Alejandro Aguirre, Ezra T Yoseph, Esha Kaushal, Avni Awani, Jae K Ryu, Katerina Akassoglou, Shahrzad Talebian, Pauline Chu, Laura Pisani, Patricia Musolino, Lawrence Steinman, Kristian Doyle, William H Robinson, Orr Sharpe, Romain Cayrol, Paul J Orchard, Troy Lund, Hannes Vogel, Max Lenail, May H Han, Joshua L Bonkowsky, Keith P Van Haren

Objective: X-linked adrenoleukodystrophy (ALD) is caused by mutations in ABCD1, a peroxisomal gene. More than half of males with an ABCD1 mutation develop inflammatory cerebral demyelination (cALD), but underlying mechanisms remain unknown and therapies are limited. We sought to develop and characterize a mouse model of cALD to facilitate study of disease mechanisms and therapy development.

Methods: We used immunoassays and immunohistochemistry to assess novel (interleukin 18 [IL-18]) and established molecular markers in cerebrospinal fluid (CSF) and postmortem brain tissue from cALD patients. We generated a cALD phenotype in Abcd1-knockout mice using a 2-hit method that combines cuprizone and experimental autoimmune encephalomyelitis models. We then used magnetic resonance imaging (MRI) and immunohistochemistry to assess the fidelity of cALD molecular markers in the mice.

Results: Human and mouse cALD lesions shared histologic features of myelin phagocytosis, myelin loss, abundant microglial activation, T and B-cell infiltration, and astrogliosis. Compared to wild-type controls, Abcd1-knockout mice displayed more cerebral demyelination, blood-brain barrier disruption, and perivascular immune cell infiltration. This enhanced inflammatory response was associated with higher levels of fibrin deposition, oxidative stress, demyelination, and axonal injury. IL-18 immunoreactivity co-localized with perivascular monocytes/macrophages in both human and mouse brain tissue. In cALD patients, CSF IL-18 levels correlated with MRI lesion severity.

Interpretation: Our results suggest loss of Abcd1 function in mice predisposes to more severe blood-brain barrier disruption, cerebral inflammation driven by the infiltration of peripheral immune cells, demyelination, and axonal damage, replicating human cALD features. This novel mouse model could shed light on cALD mechanisms and accelerate cALD therapy development. ANN NEUROL 2024.

目的:X连锁肾上腺白质营养不良症(ALD)是由过氧化物酶体基因ABCD1突变引起的。半数以上的ABCD1基因突变雄性患者会患上炎性脑脱髓鞘症(cALD),但其潜在机制仍不清楚,治疗方法也很有限。我们试图建立一个 cALD 小鼠模型并描述其特征,以促进对疾病机制和疗法开发的研究:我们使用免疫测定和免疫组织化学方法评估了 cALD 患者脑脊液(CSF)和死后脑组织中的新分子标记物(白细胞介素 18 [IL-18])和已有分子标记物。我们采用一种结合了铜绿素和实验性自身免疫性脑脊髓炎模型的双击法,在 Abcd1 基因敲除小鼠中产生了 cALD 表型。然后,我们使用磁共振成像(MRI)和免疫组化技术评估了小鼠体内cALD分子标记的保真度:结果:人类和小鼠的cALD病变具有共同的组织学特征:髓鞘吞噬、髓鞘缺失、大量小胶质细胞活化、T细胞和B细胞浸润以及星形胶质细胞增多。与野生型对照组相比,Abcd1 基因敲除小鼠表现出更多的脑脱髓鞘、血脑屏障破坏和血管周围免疫细胞浸润。这种炎症反应的增强与更高水平的纤维蛋白沉积、氧化应激、脱髓鞘和轴突损伤有关。在人和小鼠脑组织中,IL-18免疫反应与血管周围单核细胞/巨噬细胞共定位。在cALD患者中,CSF IL-18水平与MRI病变严重程度相关:我们的研究结果表明,小鼠Abcd1功能缺失易导致更严重的血脑屏障破坏、外周免疫细胞浸润导致的脑部炎症、脱髓鞘和轴突损伤,这与人类cALD的特征如出一辙。这种新型小鼠模型可以揭示cALD的发病机制,并加速cALD疗法的开发。ann neurol 2024.
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引用次数: 0
Association Between Early-Life and Premorbid Measurements of Body Composition and Risk of Motor Neuron Disease: A Prospective Cohort Study in the UK Biobank. 生命早期和病前身体成分测量值与运动神经元疾病风险之间的关系:英国生物库前瞻性队列研究》。
IF 8.1 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-25 DOI: 10.1002/ana.27109
Emily E Joyce, Shishi Xu, Caroline Ingre, Rosa Luisa Potenza, Christina Seitz, Huazhen Yang, Yu Zeng, Huan Song, Fang Fang

Objective: The objective of this study was to investigate the association between developmental and premorbid body composition measurements and the risk of motor neuron disease (MND).

Methods: We performed a cohort study in the UK Biobank to assess the association of developmental body metrics and premorbid body composition measures (using 28 measurements and 7 patterns of body composition) with the risk of MND. Among participants with longitudinal measures, we compared the changes in body composition over time between individuals who later developed MND and those who remained free of MND.

Results: Among the 412,691 individuals included in this study, 549 people received an MND diagnosis during the follow-up visit. Higher birth weight was associated with an increased risk of MND among individuals born over 4 kg (hazard ratio [HR] per kg increase = 2.21, 95% confidence interval [CI] = 1.38-3.55), and taller adult height was associated with an increased risk of MND (HR per 5 cm increase = 1.10, 95% CI = 1.03-1.17). We observed that measures of elevated fat mass were associated with a lower risk of MND more than 5 years before diagnosis. A higher "leg-dominant fat distribution" pattern was associated with an increased risk whereas higher "muscle strength" was associated with a reduced risk of MND 5 years before diagnosis. Longitudinal analyses indicated a faster decline in measures of fat mass and muscle strength, as well as a shift in fat distribution from arm to leg dominant, among individuals who later developed MND, compared with others.

Interpretation: Body composition at early and middle age may be indicative of the risk of MND development. ANN NEUROL 2024.

研究目的本研究旨在调查发育期和病前身体成分测量与运动神经元疾病(MND)风险之间的关系:我们在英国生物库中进行了一项队列研究,以评估发育期身体指标和病前身体成分测量(采用 28 种测量方法和 7 种身体成分模式)与 MND 风险之间的关系。在进行了纵向测量的参与者中,我们比较了后来患上MND的人和没有患上MND的人的身体成分随时间的变化:在这项研究的 412,691 名参与者中,有 549 人在随访期间确诊为 MND。出生时体重超过4千克的人患MND的风险较高(每增加1千克的危险比[HR]=2.21,95%置信区间[CI]=1.38-3.55),成人身高较高的人患MND的风险较高(每增加5厘米的危险比[HR]=1.10,95%置信区间[CI]=1.03-1.17)。我们观察到,脂肪量升高与确诊前5年以上罹患MND的风险降低有关。较高的 "腿部脂肪分布 "模式与风险增加有关,而较高的 "肌肉力量 "则与确诊前5年MND风险降低有关。纵向分析表明,与其他人相比,后来患上MND的人的脂肪量和肌肉力量下降得更快,脂肪分布也从以手臂为主转向以腿部为主:解释:早年和中年的身体成分可能预示着MND的发病风险。ann neurol 2024.
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引用次数: 0
Polygenic Landscape of Cryptogenic New-Onset Refractory Status Epilepticus: A Comprehensive Whole-Genome Sequencing Study 隐源性新发难治性癫痫状态的多基因景观:全基因组测序综合研究
IF 8.1 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-23 DOI: 10.1002/ana.27100
Yoonhyuk Jang, Sung Eun Hong, Soo Hyun Ahn, Su Yee Mon, Ji Hye You, Kon Chu, Sang Kun Lee, Murim Choi, Soon-Tae Lee

Cryptogenic new-onset refractory status epilepticus (cNORSE) is a devastating condition with unclear pathogenesis. Here, we analyzed the genetic underprints of 31 cNORSE patients from an autoimmune encephalitis observational cohort through whole-genome sequencing. Compared to their controls, cNORSE patients exhibited elevated polygenic risk scores (PRS) for traits associated with autoimmune diseases. The individual PRS against these diseases were correlated with specific clinical phenotypes of cNORSE. The variants were enriched in genes expressed in the central nervous system and lymphocytes. These results suggest a shared genetic framework between cNORSE and other autoimmune/autoinflammatory diseases, and its involvement in the disease pathogenesis. ANN NEUROL 2024;96:1201–1208

隐源性新发难治性癫痫(cNORSE)是一种发病机制不明的破坏性疾病。在这里,我们通过全基因组测序分析了来自自身免疫性脑炎观察队列的 31 名 cNORSE 患者的遗传特征。与对照组相比,cNORSE 患者在与自身免疫性疾病相关的特征方面表现出较高的多基因风险评分(PRS)。针对这些疾病的个体PRS与cNORSE的特定临床表型相关。变异富集在中枢神经系统和淋巴细胞中表达的基因中。这些结果表明,cNORSE 与其他自身免疫/自身炎症性疾病之间存在着共同的遗传框架,并与疾病的发病机制有关。ann neurol 2024.
{"title":"Polygenic Landscape of Cryptogenic New-Onset Refractory Status Epilepticus: A Comprehensive Whole-Genome Sequencing Study","authors":"Yoonhyuk Jang,&nbsp;Sung Eun Hong,&nbsp;Soo Hyun Ahn,&nbsp;Su Yee Mon,&nbsp;Ji Hye You,&nbsp;Kon Chu,&nbsp;Sang Kun Lee,&nbsp;Murim Choi,&nbsp;Soon-Tae Lee","doi":"10.1002/ana.27100","DOIUrl":"10.1002/ana.27100","url":null,"abstract":"<p>Cryptogenic new-onset refractory status epilepticus (cNORSE) is a devastating condition with unclear pathogenesis. Here, we analyzed the genetic underprints of 31 cNORSE patients from an autoimmune encephalitis observational cohort through whole-genome sequencing. Compared to their controls, cNORSE patients exhibited elevated polygenic risk scores (PRS) for traits associated with autoimmune diseases. The individual PRS against these diseases were correlated with specific clinical phenotypes of cNORSE. The variants were enriched in genes expressed in the central nervous system and lymphocytes. These results suggest a shared genetic framework between cNORSE and other autoimmune/autoinflammatory diseases, and its involvement in the disease pathogenesis. ANN NEUROL 2024;96:1201–1208</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"96 6","pages":"1201-1208"},"PeriodicalIF":8.1,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142491411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Recessive Variants in PIGG Cause a Motor Neuropathy with Variable Conduction Block, Childhood Tremor, and Febrile Seizures: Expanding the Phenotype. PIGG 的隐性变异会导致具有可变传导阻滞、儿童震颤和热性惊厥的运动神经病:扩展表型。
IF 8.1 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-23 DOI: 10.1002/ana.27113
Christopher J Record, Antoinette O'Connor, Nienke E Verbeek, Wouter van Rheenen, Eleni Zamba Papanicolaou, Stojan Peric, Peter C Ligthart, Mariola Skorupinska, Ellen van Binsbergen, Philippe M Campeau, Vukan Ivanovic, Brian Hennigan, John C McHugh, Julian C Blake, Yoshiko Murakami, Matilde Laura, Sinéad M Murphy, Mary M Reilly

Biallelic variants in phosphatidylinositol glycan anchor biosynthesis, class G (PIGG) cause hypotonia, intellectual disability, seizures, and cerebellar features. We present 8 patients from 6 families with a childhood-onset motor neuropathy and neurophysiology demonstrating variable motor conduction block and temporal dispersion. All individuals had a childhood onset tremor, 5 of 8 had cerebellar involvement, and 6 of 8 had childhood febrile seizures. All individuals have biallelic PIGG variants, including the previously reported pathogenic variant Trp505*, plus 6 novel variants. Null enzyme activity is demonstrated via PIGO/PIGG double knockout system for Val339Gly and Gly19Glu, and residual activity for Trp505* due to read-through. Emm negative blood group status was confirmed in 1 family. PIGG should be considered in unsolved motor neuropathy. ANN NEUROL 2024.

磷脂酰肌醇聚糖锚生物合成 G 类(PIGG)的双拷贝变体会导致肌张力低下、智力障碍、癫痫发作和小脑特征。我们介绍了来自 6 个家庭的 8 位患者,他们都患有儿童期发病的运动神经病变,神经生理学表现为不同的运动传导阻滞和颞叶弥散。所有患者均在儿童期发病,8 人中有 5 人有小脑受累,8 人中有 6 人在儿童期有发热性癫痫发作。所有患者都有双叶 PIGG 变异,包括之前报道的致病变异 Trp505*,以及 6 个新型变异。通过PIGO/PIGG双基因敲除系统,Val339Gly和Gly19Glu的酶活性被证明为无效,Trp505*的残余活性则是由于通读所致。1 个家庭的 Emm 阴性血型得到确认。未解决的运动神经病变应考虑 PIGG。ann neurol 2024.
{"title":"Recessive Variants in PIGG Cause a Motor Neuropathy with Variable Conduction Block, Childhood Tremor, and Febrile Seizures: Expanding the Phenotype.","authors":"Christopher J Record, Antoinette O'Connor, Nienke E Verbeek, Wouter van Rheenen, Eleni Zamba Papanicolaou, Stojan Peric, Peter C Ligthart, Mariola Skorupinska, Ellen van Binsbergen, Philippe M Campeau, Vukan Ivanovic, Brian Hennigan, John C McHugh, Julian C Blake, Yoshiko Murakami, Matilde Laura, Sinéad M Murphy, Mary M Reilly","doi":"10.1002/ana.27113","DOIUrl":"https://doi.org/10.1002/ana.27113","url":null,"abstract":"<p><p>Biallelic variants in phosphatidylinositol glycan anchor biosynthesis, class G (PIGG) cause hypotonia, intellectual disability, seizures, and cerebellar features. We present 8 patients from 6 families with a childhood-onset motor neuropathy and neurophysiology demonstrating variable motor conduction block and temporal dispersion. All individuals had a childhood onset tremor, 5 of 8 had cerebellar involvement, and 6 of 8 had childhood febrile seizures. All individuals have biallelic PIGG variants, including the previously reported pathogenic variant Trp505*, plus 6 novel variants. Null enzyme activity is demonstrated via PIGO/PIGG double knockout system for Val339Gly and Gly19Glu, and residual activity for Trp505* due to read-through. Emm negative blood group status was confirmed in 1 family. PIGG should be considered in unsolved motor neuropathy. ANN NEUROL 2024.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142491412","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
期刊
Annals of Neurology
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