首页 > 最新文献

Annals of Neurology最新文献

英文 中文
Comparison of Perfusion Imaging Definitions of the No-Reflow Phenomenon after Thrombectomy—What Is the Best Perfusion Imaging Definition? 血栓切除术后无回流现象的灌注成像定义比较--什么是最佳灌注成像定义?
IF 8.1 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-09-03 DOI: 10.1002/ana.27073
Chloe A. Mutimer MD, Adnan Mujanovic MD, Johannes Kaesmacher MD, Leonid Churilov PhD, Timothy J. Kleinig PhD, Mark W. Parsons PhD, Peter J. Mitchell MMed, Bruce C.V. Campbell PhD, Felix Ng PhD

The no-reflow phenomenon is a potential contributor to poor outcome despite successful thrombectomy. There are multiple proposed imaging-based definitions of no-reflow leading to wide variations in reported prevalence. We investigated the agreement between existing imaging definitions and compared the characteristics and outcomes of patients identified as having no-reflow.

Methods

We performed an external validation of 4 existing published definitions of no-reflow in thrombectomy patients with extended Thrombolysis in Cerebral Infarction scale 2c to 3 (eTICI2c-3) angiographic reperfusion who underwent 24-hour perfusion imaging from 2 international randomized controlled trials (EXTEND-IA TNK part-1 and 2) and a multicenter prospective observational study. Receiver-operating-characteristic and Bayesian-information-criterion (BIC) analyses were performed with the outcome variable being dependent-or-dead at 90-days (modified Rankin Score [mRS] ≥3).

Results

Of 131 patients analyzed, the prevalence of no-reflow significantly varied between definitions (0.8–22.1%; p < 0.001). There was poor agreement between definitions (kappa 5/6 comparisons <0.212). Among patients with no-reflow according to at least 1 definition, there were significant differences between definitions in the intralesional interside differences in cerebral blood flow (CBF) (p = 0.006), cerebral blood volume (CBV) (p < 0.001), and mean-transit-time (MTT) (p = 0.005). No-reflow defined by 3 definitions was associated with mRS ≥3 at 90 days. The definition of >15% CBV or CBF asymmetry was the only definition that improved model fit on BIC analysis (ΔBIC = −8.105) and demonstrated an association between no-reflow and clinical outcome among patients with eTICI3 reperfusion.

Conclusions

Existing imaging definitions of no-reflow varied significantly in prevalence and post-treatment perfusion imaging profile, potentially explaining the variable prevalence of no-reflow reported in literature. The definition of >15% CBV or CBF asymmetry best discriminated for functional outcome at 90 days, including patients with eTICI3 reperfusion. ANN NEUROL 2024;96:1104–1114

尽管血栓切除术很成功,但无回流现象是导致不良预后的一个潜在因素。目前有多种基于影像学的无回流定义,导致报告的发生率差异很大。我们研究了现有影像学定义之间的一致性,并比较了被确定为无回流患者的特征和预后:方法:我们从两项国际随机对照试验(EXTEND-IA TNK part-1和2)和一项多中心前瞻性观察研究中,对脑梗塞溶栓治疗量表 2c 至 3(eTICI2c-3)血管再灌注患者中接受 24 小时灌注成像的无回流的 4 种现有已发表定义进行了外部验证。结果显示:在131名接受24小时灌注成像的患者中,90天后死亡(修改后的Rankin评分[mRS]≥3)为结果变量:结果:在分析的 131 例患者中,不同定义的无回流发生率存在显著差异(0.8%-22.1%;p 15%),CBV 或 CBF 不对称是唯一能改善 BIC 分析模型拟合度的定义(ΔBIC = -8.105),并且在 eTICI3 再灌注患者中,无回流与临床预后之间存在关联:结论:现有的无回流成像定义在发生率和治疗后灌注成像情况方面存在显著差异,这可能是文献报道的无回流发生率不一的原因。包括 eTICI3 再灌注患者在内,CBV 或 CBF 不对称 >15% 的定义对 90 天后的功能预后最具鉴别作用。ann neurol 2024.
{"title":"Comparison of Perfusion Imaging Definitions of the No-Reflow Phenomenon after Thrombectomy—What Is the Best Perfusion Imaging Definition?","authors":"Chloe A. Mutimer MD,&nbsp;Adnan Mujanovic MD,&nbsp;Johannes Kaesmacher MD,&nbsp;Leonid Churilov PhD,&nbsp;Timothy J. Kleinig PhD,&nbsp;Mark W. Parsons PhD,&nbsp;Peter J. Mitchell MMed,&nbsp;Bruce C.V. Campbell PhD,&nbsp;Felix Ng PhD","doi":"10.1002/ana.27073","DOIUrl":"10.1002/ana.27073","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <p>The no-reflow phenomenon is a potential contributor to poor outcome despite successful thrombectomy. There are multiple proposed imaging-based definitions of no-reflow leading to wide variations in reported prevalence. We investigated the agreement between existing imaging definitions and compared the characteristics and outcomes of patients identified as having no-reflow.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We performed an external validation of 4 existing published definitions of no-reflow in thrombectomy patients with extended Thrombolysis in Cerebral Infarction scale 2c to 3 (eTICI2c-3) angiographic reperfusion who underwent 24-hour perfusion imaging from 2 international randomized controlled trials (EXTEND-IA TNK part-1 and 2) and a multicenter prospective observational study. Receiver-operating-characteristic and Bayesian-information-criterion (BIC) analyses were performed with the outcome variable being dependent-or-dead at 90-days (modified Rankin Score [mRS] ≥3).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Of 131 patients analyzed, the prevalence of no-reflow significantly varied between definitions (0.8–22.1%; <i>p</i> &lt; 0.001). There was poor agreement between definitions (kappa 5/6 comparisons &lt;0.212). Among patients with no-reflow according to at least 1 definition, there were significant differences between definitions in the intralesional interside differences in cerebral blood flow (CBF) (<i>p</i> = 0.006), cerebral blood volume (CBV) (<i>p</i> &lt; 0.001), and mean-transit-time (MTT) (<i>p</i> = 0.005). No-reflow defined by 3 definitions was associated with mRS ≥3 at 90 days. The definition of &gt;15% CBV or CBF asymmetry was the only definition that improved model fit on BIC analysis (ΔBIC = −8.105) and demonstrated an association between no-reflow and clinical outcome among patients with eTICI3 reperfusion.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Existing imaging definitions of no-reflow varied significantly in prevalence and post-treatment perfusion imaging profile, potentially explaining the variable prevalence of no-reflow reported in literature. The definition of &gt;15% CBV or CBF asymmetry best discriminated for functional outcome at 90 days, including patients with eTICI3 reperfusion. ANN NEUROL 2024;96:1104–1114</p>\u0000 </section>\u0000 </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"96 6","pages":"1104-1114"},"PeriodicalIF":8.1,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.27073","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142118506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
RAN Translation of C9orf72-Related Dipeptide Repeat Proteins in Zebrafish Recapitulates Hallmarks of Amyotrophic Lateral Sclerosis and Identifies Hypothermia as a Therapeutic Strategy 斑马鱼中与 C9orf72 相关的二肽重复蛋白的 RAN 翻译再现了肌萎缩侧索硬化症的特征,并确定了低温疗法作为一种治疗策略。
IF 8.1 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-08-31 DOI: 10.1002/ana.27068
David J. Burrows PhD, Alexander McGown PhD, Olfat Abduljabbar PhD, Lydia M. Castelli PhD, Pamela J. Shaw MBBS, MD, Guillaume M. Hautbergue PhD, Tennore M. Ramesh DVM, PhD

Objective

Hexanucleotide repeat expansions in the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). A large body of evidence implicates dipeptide repeats (DPRs) proteins as one of the main drivers of neuronal injury in cell and animal models.

Methods

A pure repeat-associated non-AUG (RAN) translation zebrafish model of C9orf72-ALS/FTD was generated. Embryonic and adult transgenic zebrafish lysates were investigated for the presence of RAN-translated DPR species and adult-onset motor deficits. Using C9orf72 cell models as well as embryonic C9orf72-ALS/FTD zebrafish, hypothermic-therapeutic temperature management (TTM) was explored as a potential therapeutic option for C9orf72-ALS/FTD.

Results

Here, we describe a pure RAN translation zebrafish model of C9orf72-ALS/FTD that exhibits significant RAN-translated DPR pathology and progressive motor decline. We further demonstrate that hypothermic-TTM results in a profound reduction in DPR species in C9orf72-ALS/FTD cell models as well as embryonic C9orf72-ALS/FTD zebrafish.

Interpretation

The transgenic model detailed in this paper provides a medium throughput in vivo research tool to further investigate the role of RAN-translation in C9orf72-ALS/FTD and further understand the mechanisms that underpin neuroprotective strategies. Hypothermic-TTM presents a viable therapeutic avenue to explore in the context of C9orf72-ALS/FTD. ANN NEUROL 2024;96:1058–1069

目的:C9orf72基因的六核苷酸重复扩增是肌萎缩侧索硬化症(ALS)和额颞叶痴呆症(FTD)最常见的遗传病因。大量证据表明,二肽重复(DPRs)蛋白是细胞和动物模型中神经元损伤的主要驱动因素之一:方法:建立了一个纯重复相关非 AUG(RAN)翻译的 C9orf72-ALS/FTD 斑马鱼模型。对胚胎和成年转基因斑马鱼裂解物进行了调查,以确定是否存在 RAN 翻译的 DPR 物种和成年发病的运动障碍。利用 C9orf72 细胞模型以及胚胎 C9orf72-ALS/FTD 斑马鱼,探索了低体温治疗温度管理 (TTM) 作为 C9orf72-ALS/FTD 的潜在治疗方案:在这里,我们描述了一种纯 RAN 翻译的 C9orf72-ALS/FTD 斑马鱼模型,该模型表现出明显的 RAN 翻译 DPR 病理学和进行性运动衰退。我们进一步证明,在 C9orf72-ALS/FTD 细胞模型以及 C9orf72-ALS/FTD 胚胎斑马鱼中,低温-TTM 可导致 DPR 种类的显著减少:本文详述的转基因模型为进一步研究RAN-翻译在C9orf72-ALS/FTD中的作用以及进一步了解神经保护策略的机制提供了一种中等通量的体内研究工具。低温-TTM为探索C9orf72-ALS/FTD提供了一条可行的治疗途径。ann neurol 2024.
{"title":"RAN Translation of C9orf72-Related Dipeptide Repeat Proteins in Zebrafish Recapitulates Hallmarks of Amyotrophic Lateral Sclerosis and Identifies Hypothermia as a Therapeutic Strategy","authors":"David J. Burrows PhD,&nbsp;Alexander McGown PhD,&nbsp;Olfat Abduljabbar PhD,&nbsp;Lydia M. Castelli PhD,&nbsp;Pamela J. Shaw MBBS, MD,&nbsp;Guillaume M. Hautbergue PhD,&nbsp;Tennore M. Ramesh DVM, PhD","doi":"10.1002/ana.27068","DOIUrl":"10.1002/ana.27068","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Hexanucleotide repeat expansions in the <i>C9orf72</i> gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). A large body of evidence implicates dipeptide repeats (DPRs) proteins as one of the main drivers of neuronal injury in cell and animal models.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A pure repeat-associated non-AUG (RAN) translation zebrafish model of C9orf72-ALS/FTD was generated. Embryonic and adult transgenic zebrafish lysates were investigated for the presence of RAN-translated DPR species and adult-onset motor deficits. Using C9orf72 cell models as well as embryonic C9orf72-ALS/FTD zebrafish, hypothermic-therapeutic temperature management (TTM) was explored as a potential therapeutic option for C9orf72-ALS/FTD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Here, we describe a pure RAN translation zebrafish model of C9orf72-ALS/FTD that exhibits significant RAN-translated DPR pathology and progressive motor decline. We further demonstrate that hypothermic-TTM results in a profound reduction in DPR species in C9orf72-ALS/FTD cell models as well as embryonic C9orf72-ALS/FTD zebrafish.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>The transgenic model detailed in this paper provides a medium throughput in vivo research tool to further investigate the role of RAN-translation in C9orf72-ALS/FTD and further understand the mechanisms that underpin neuroprotective strategies. Hypothermic-TTM presents a viable therapeutic avenue to explore in the context of C9orf72-ALS/FTD. ANN NEUROL 2024;96:1058–1069</p>\u0000 </section>\u0000 </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"96 6","pages":"1058-1069"},"PeriodicalIF":8.1,"publicationDate":"2024-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.27068","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142102525","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Fetal Intraparenchymal Hemorrhage Imaging Patterns, Etiology, and Outcomes: A Single Center Cohort Study 胎儿脑实质内出血成像模式、病因和结果:单中心队列研究
IF 8.1 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-08-31 DOI: 10.1002/ana.27072
Rachel Vassar MD, Elizabeth George MBBS, Andrew Mogga BS, Yi Li MD, Mary E. Norton MD, Orit Glenn MD, Dawn Gano MD, MAS

Objective

This study examines associations among fetal brain magnetic resonance imaging (MRI) injury patterns, etiologies, and outcomes in fetal intraparenchymal hemorrhage (IPH).

Methods

This is a retrospective, single-center cohort study of IPH diagnosed on fetal MRI (1996–2022). IPH and associated abnormalities were categorized by 2 pediatric neuroradiologists; electronic medical records were reviewed by 2 pediatric neurologists to classify etiology and outcomes including cerebral palsy, epilepsy, developmental delay, and death.

Results

Forty-four fetuses with IPH were identified (34 singleton and 10 twin gestations) with MRI at median 24 weeks gestation (interquartile range [IQR] = 22–28 weeks). IPH was commonly supratentorial (84%) and focal (50%) or focal with diffuse injury (43%) and was often associated with germinal matrix hemorrhage (GMH; 75%) and/or intraventricular hemorrhage (IVH; 52%). An etiology was identified in 75%, including twin-twin transfusion syndrome (TTTS, n = 10), COL4A1/2 variants (n = 8), or other fetal/maternal conditions (n = 15). COL4A1/2 variants were associated with focal IPH and the presence of hemorrhagic porencephaly, and intrauterine transfusion was associated with infratentorial hemorrhage. Twenty-two fetuses were liveborn, and 18 pregnancies were terminated. Among those with follow-up ≥ 12 months (median = 7 years), 12 of 13 had cerebral palsy, 6 of 13 had developmental delay, and 5 of 13 had epilepsy.

Interpretation

An etiology for fetal IPH with or without GMH-IVH is identified in most cases in our cohort and is commonly TTTS, COL4A1/2 variants, or other maternal/fetal comorbidities. Pattern of fetal IPH on MRI is associated with etiology. Cerebral palsy and neurodevelopmental impairment were common in liveborn infants. Genetic studies should be considered in cases of fetal IPH without an otherwise apparent cause. ANN NEUROL 2024;96:1137–1147

目的:本研究探讨胎儿脑磁共振成像(MRI)损伤模式、病因和胎儿脑实质内出血(IPH)预后之间的关联:本研究探讨了胎儿脑实质内出血(IPH)的胎儿脑磁共振成像(MRI)损伤模式、病因和结局之间的关联:这是一项回顾性单中心队列研究,研究对象为经胎儿磁共振成像诊断的 IPH(1996-2022 年)。两名儿科神经放射科医生对IPH及相关异常进行了分类;两名儿科神经科医生对电子病历进行了审查,以对病因和结果(包括脑瘫、癫痫、发育迟缓和死亡)进行分类:44名患有IPH的胎儿(34名单胎,10名双胎)在妊娠中位24周(四分位间距[IQR] = 22-28周)时接受磁共振成像检查。IPH常见于脑室上(84%)、局灶性(50%)或局灶性伴弥漫性损伤(43%),通常伴有胚芽基质出血(GMH;75%)和/或脑室内出血(IVH;52%)。75%的病例找到了病因,包括双胎输血综合征(TTTS,n = 10)、COL4A1/2变异(n = 8)或其他胎儿/母体疾病(n = 15)。COL4A1/2变异与局灶性IPH和出血性脑室畸形有关,宫内输血与脑室下出血有关。22名胎儿为活产,18名胎儿终止妊娠。在随访时间≥12个月(中位数=7年)的胎儿中,13个中有12个患有脑瘫,13个中有6个发育迟缓,13个中有5个患有癫痫:在我们的队列中,大多数病例的胎儿IPH伴有或不伴有GMH-IVH,其病因通常是TTTS、COL4A1/2变异或其他母体/胎儿合并症。核磁共振成像上胎儿 IPH 的形态与病因有关。活产婴儿中常见脑瘫和神经发育障碍。对于无明显病因的胎儿 IPH 病例,应考虑进行遗传学研究。ann neurol 2024.
{"title":"Fetal Intraparenchymal Hemorrhage Imaging Patterns, Etiology, and Outcomes: A Single Center Cohort Study","authors":"Rachel Vassar MD,&nbsp;Elizabeth George MBBS,&nbsp;Andrew Mogga BS,&nbsp;Yi Li MD,&nbsp;Mary E. Norton MD,&nbsp;Orit Glenn MD,&nbsp;Dawn Gano MD, MAS","doi":"10.1002/ana.27072","DOIUrl":"10.1002/ana.27072","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>This study examines associations among fetal brain magnetic resonance imaging (MRI) injury patterns, etiologies, and outcomes in fetal intraparenchymal hemorrhage (IPH).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This is a retrospective, single-center cohort study of IPH diagnosed on fetal MRI (1996–2022). IPH and associated abnormalities were categorized by 2 pediatric neuroradiologists; electronic medical records were reviewed by 2 pediatric neurologists to classify etiology and outcomes including cerebral palsy, epilepsy, developmental delay, and death.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Forty-four fetuses with IPH were identified (34 singleton and 10 twin gestations) with MRI at median 24 weeks gestation (interquartile range [IQR] = 22–28 weeks). IPH was commonly supratentorial (84%) and focal (50%) or focal with diffuse injury (43%) and was often associated with germinal matrix hemorrhage (GMH; 75%) and/or intraventricular hemorrhage (IVH; 52%). An etiology was identified in 75%, including twin-twin transfusion syndrome (TTTS, n = 10), COL4A1/2 variants (n = 8), or other fetal/maternal conditions (n = 15). COL4A1/2 variants were associated with focal IPH and the presence of hemorrhagic porencephaly, and intrauterine transfusion was associated with infratentorial hemorrhage. Twenty-two fetuses were liveborn, and 18 pregnancies were terminated. Among those with follow-up ≥ 12 months (median = 7 years), 12 of 13 had cerebral palsy, 6 of 13 had developmental delay, and 5 of 13 had epilepsy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>An etiology for fetal IPH with or without GMH-IVH is identified in most cases in our cohort and is commonly TTTS, COL4A1/2 variants, or other maternal/fetal comorbidities. Pattern of fetal IPH on MRI is associated with etiology. Cerebral palsy and neurodevelopmental impairment were common in liveborn infants. Genetic studies should be considered in cases of fetal IPH without an otherwise apparent cause. ANN NEUROL 2024;96:1137–1147</p>\u0000 </section>\u0000 </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"96 6","pages":"1137-1147"},"PeriodicalIF":8.1,"publicationDate":"2024-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.27072","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142102524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Correction to “Mutations in CLCN6 as a Novel Genetic Cause of Neuronal Ceroid Lipofuscinosis in Patients and a Murine Model” 更正 "CLCN6 基因突变是患者和小鼠模型中神经元类色素沉着病的新遗传病因"。
IF 8.1 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-08-29 DOI: 10.1002/ana.27076

He, H, Cao, X, He, F, et al. Mutations in CLCN6 as a novel genetic cause of neuronal ceroid lipofuscinosis in patients and a murine model. Ann Neurol 2024; 96: 608624. https://doi.org/10.1002/ana.27002

In the above article, the title was incorrectly published as “Mutations in CLCN6 as a Novel Genetic Cause of Neuronal Ceroid Lipofuscinosis in a Murine Model.”

The correct title is “Mutations in CLCN6 as a Novel Genetic Cause of Neuronal Ceroid Lipofuscinosis in Patients and a Murine Model.” The online version of this article has been corrected accordingly.

We apologize for this error.

He, H, Cao, X, He, F, et al.CLCN6基因突变是患者和小鼠模型神经细胞类脂膜炎的新型遗传病因Ann Neurol 2024; 96: 608-624. https://doi.org/10.1002/ana.27002 在上述文章中,标题被错误地发布为 "Mutations in CLCN6 as a Novel Genetic Cause of Neuronal Ceroid Lipofuscinosis in a Murine Model"。正确的标题是 "Mutations in CLCN6 as a Novel Genetic Cause of Neuronal Ceroid Lipofuscinosis in Patients and a Murine Model"。本文的在线版本已作相应更正。我们对此错误深表歉意。
{"title":"Correction to “Mutations in CLCN6 as a Novel Genetic Cause of Neuronal Ceroid Lipofuscinosis in Patients and a Murine Model”","authors":"","doi":"10.1002/ana.27076","DOIUrl":"10.1002/ana.27076","url":null,"abstract":"<p>\u0000 <span>He, H</span>, <span>Cao, X</span>, <span>He, F</span>, et al. <span>Mutations in <i>CLCN6</i> as a novel genetic cause of neuronal ceroid lipofuscinosis in patients and a murine model</span>. <i>Ann Neurol</i> <span>2024</span>; <span>96</span>: <span>608</span>–<span>624</span>. https://doi.org/10.1002/ana.27002\u0000 </p><p>In the above article, the title was incorrectly published as “Mutations in <i>CLCN6</i> as a Novel Genetic Cause of Neuronal Ceroid Lipofuscinosis in a Murine Model.”</p><p>The correct title is “Mutations in <i>CLCN6</i> as a Novel Genetic Cause of Neuronal Ceroid Lipofuscinosis in Patients and a Murine Model.” The online version of this article has been corrected accordingly.</p><p>We apologize for this error.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"96 4","pages":"822"},"PeriodicalIF":8.1,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.27076","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142102523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Single-Nucleus RNA Sequencing Unravels Early Mechanisms of Human Becker Muscular Dystrophy 单核 RNA 测序揭示人类贝克尔肌营养不良症的早期机制
IF 8.1 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-08-27 DOI: 10.1002/ana.27070
Zhihao Xie PhD, Chang Liu MD, Chengyue Sun MD, PhD, Yilin Liu MD, PhD, Jieru Peng MD, Lingchao Meng MD, Jianwen Deng PhD, Zhaoxia Wang MD, PhD, Chunxia Yang PhD, Yun Yuan MD, PhD, Zhiying Xie MD, PhD

Objective

The transcriptional heterogeneity at a single-nucleus level in human Becker muscular dystrophy (BMD) dystrophic muscle has not been explored. Here, we aimed to understand the transcriptional heterogeneity associated with myonuclei, as well as other mononucleated cell types that underly BMD pathogenesis by performing single-nucleus RNA sequencing.

Methods

We profiled single-nucleus transcriptional profiles of skeletal muscle samples from 7 BMD patients and 3 normal controls.

Results

A total of 17,216 nuclei (12,879 from BMD patients and 4,337 from controls) were classified into 13 known cell types, including 9 myogenic lineages and 4 non-myogenic lineages, and 1 unclassified nuclear type according to their cell identities. Among them, type IIx myonuclei were the first to degenerate in response to dystrophin reduction. Differential expression analysis revealed that the fibro-adipogenic progenitors (FAPs) population had the largest transcriptional changes among all cell types. Sub-clustering analysis identified a significantly compositional increase in the activated FAPs (aFAPs) subpopulation in BMD muscles. Pseudotime analysis, regulon inference, and deconvolution analysis of bulk RNA-sequencing data derived from 29 BMD patients revealed that the aFAPs subpopulation, a distinctive and previously unrecognized mononuclear subtype, was profibrogenic and expanded in BMD patients. Muscle quantitative real-time polymerase chain reaction and immunofluorescence analysis confirmed that the mRNA and protein levels of the aFAPs markers including LUM, DCN, and COL1A1 in BMD patients were significantly higher than those in controls, respectively.

Interpretation

Our results provide insights into the transcriptional diversity of human BMD muscle at a single-nucleus resolution and new potential targets for anti-fibrosis therapies in BMD. ANN NEUROL 2024;96:1070–1085

目的:人类贝克尔肌营养不良症(BMD)萎缩性肌肉中单核水平的转录异质性尚未得到探索。在此,我们旨在通过进行单核 RNA 测序,了解与肌核以及其他单核细胞类型相关的转录异质性,这些转录异质性是贝克尔肌营养不良症发病机制的基础:我们对 7 名 BMD 患者和 3 名正常对照者的骨骼肌样本进行了单核转录谱分析:共有 17,216 个细胞核(12,879 个来自 BMD 患者,4,337 个来自对照组)根据细胞身份被分为 13 种已知细胞类型,包括 9 种成肌系和 4 种非成肌系,以及 1 种未分类的核类型。其中,IIx型肌核在肌营养不良蛋白减少时最先退化。差异表达分析表明,在所有细胞类型中,纤维脂肪生成祖细胞(FAPs)群体的转录变化最大。子聚类分析发现,在 BMD 肌肉中,活化的 FAPs(aFAPs)亚群的组成明显增加。对来自 29 名 BMD 患者的大量 RNA 序列数据进行的伪时间分析、调节子推断和解卷积分析表明,aFAPs 亚群是一种独特的、以前未被发现的单核亚型,在 BMD 患者中具有异源性和扩增性。肌肉定量实时聚合酶链反应和免疫荧光分析证实,BMD 患者体内 aFAPs 标志物(包括 LUM、DCN 和 COL1A1)的 mRNA 和蛋白水平分别显著高于对照组:我们的研究结果提供了单核分辨率下人类 BMD 肌肉转录多样性的见解,以及 BMD 抗纤维化疗法的潜在新靶点。ann neurol 2024.
{"title":"Single-Nucleus RNA Sequencing Unravels Early Mechanisms of Human Becker Muscular Dystrophy","authors":"Zhihao Xie PhD,&nbsp;Chang Liu MD,&nbsp;Chengyue Sun MD, PhD,&nbsp;Yilin Liu MD, PhD,&nbsp;Jieru Peng MD,&nbsp;Lingchao Meng MD,&nbsp;Jianwen Deng PhD,&nbsp;Zhaoxia Wang MD, PhD,&nbsp;Chunxia Yang PhD,&nbsp;Yun Yuan MD, PhD,&nbsp;Zhiying Xie MD, PhD","doi":"10.1002/ana.27070","DOIUrl":"10.1002/ana.27070","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>The transcriptional heterogeneity at a single-nucleus level in human Becker muscular dystrophy (BMD) dystrophic muscle has not been explored. Here, we aimed to understand the transcriptional heterogeneity associated with myonuclei, as well as other mononucleated cell types that underly BMD pathogenesis by performing single-nucleus RNA sequencing.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We profiled single-nucleus transcriptional profiles of skeletal muscle samples from 7 BMD patients and 3 normal controls.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A total of 17,216 nuclei (12,879 from BMD patients and 4,337 from controls) were classified into 13 known cell types, including 9 myogenic lineages and 4 non-myogenic lineages, and 1 unclassified nuclear type according to their cell identities. Among them, type IIx myonuclei were the first to degenerate in response to dystrophin reduction. Differential expression analysis revealed that the fibro-adipogenic progenitors (FAPs) population had the largest transcriptional changes among all cell types. Sub-clustering analysis identified a significantly compositional increase in the activated FAPs (aFAPs) subpopulation in BMD muscles. Pseudotime analysis, regulon inference, and deconvolution analysis of bulk RNA-sequencing data derived from 29 BMD patients revealed that the aFAPs subpopulation, a distinctive and previously unrecognized mononuclear subtype, was profibrogenic and expanded in BMD patients. Muscle quantitative real-time polymerase chain reaction and immunofluorescence analysis confirmed that the mRNA and protein levels of the aFAPs markers including <i>LUM</i>, <i>DCN</i>, and <i>COL1A1</i> in BMD patients were significantly higher than those in controls, respectively.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>Our results provide insights into the transcriptional diversity of human BMD muscle at a single-nucleus resolution and new potential targets for anti-fibrosis therapies in BMD. ANN NEUROL 2024;96:1070–1085</p>\u0000 </section>\u0000 </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"96 6","pages":"1070-1085"},"PeriodicalIF":8.1,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142078526","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
Reply to “Letter to the Editor: Assessing the Efficacy and Limitations of Rescue Thrombectomy in Acute Ischemic Stroke” 回复 "致编辑的信:评估急性缺血性脑卒中抢救性血栓切除术的疗效和局限性"。
IF 8.1 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-08-27 DOI: 10.1002/ana.27064
Aaron Rodriguez-Calienes MD, Fazeel M. Siddiqui MD, Milagros Galecio-Castillo MD, Mahmoud H. Mohammaden MD, Jaydevsinh N. Dolia MD, Jonathan A. Grossberg MD, Aqueel Pabaney MD, Ameer E. Hassan MD, Wondwossen G. Tekle MD, Hamzah Saei MD, Samantha Miller MD, Shahram Majidi MD, Johanna T. Fifi MD, Gabrielle Valestin MD, James E. Siegler MD, Mary Penckofer MD, Linda Zhang MD, Sunil A. Sheth MD, Sergio Salazar-Marioni MD, Ananya Iyyangar MD, Thanh N. Nguyen MD, Mohamad Abdalkader MD, Italo Linfante MD, Guilherme Dabus MD, Brijesh P. Mehta MD, Joy Sessa MD, Mouhammad A. Jumma MD, Rebecca M. Sugg MD, Guillermo Linares MD, Raul G. Nogueira MD, David S. Liebeskind MD, Diogo C. Haussen MD, Santiago Ortega-Gutierrez MD, MSc
{"title":"Reply to “Letter to the Editor: Assessing the Efficacy and Limitations of Rescue Thrombectomy in Acute Ischemic Stroke”","authors":"Aaron Rodriguez-Calienes MD,&nbsp;Fazeel M. Siddiqui MD,&nbsp;Milagros Galecio-Castillo MD,&nbsp;Mahmoud H. Mohammaden MD,&nbsp;Jaydevsinh N. Dolia MD,&nbsp;Jonathan A. Grossberg MD,&nbsp;Aqueel Pabaney MD,&nbsp;Ameer E. Hassan MD,&nbsp;Wondwossen G. Tekle MD,&nbsp;Hamzah Saei MD,&nbsp;Samantha Miller MD,&nbsp;Shahram Majidi MD,&nbsp;Johanna T. Fifi MD,&nbsp;Gabrielle Valestin MD,&nbsp;James E. Siegler MD,&nbsp;Mary Penckofer MD,&nbsp;Linda Zhang MD,&nbsp;Sunil A. Sheth MD,&nbsp;Sergio Salazar-Marioni MD,&nbsp;Ananya Iyyangar MD,&nbsp;Thanh N. Nguyen MD,&nbsp;Mohamad Abdalkader MD,&nbsp;Italo Linfante MD,&nbsp;Guilherme Dabus MD,&nbsp;Brijesh P. Mehta MD,&nbsp;Joy Sessa MD,&nbsp;Mouhammad A. Jumma MD,&nbsp;Rebecca M. Sugg MD,&nbsp;Guillermo Linares MD,&nbsp;Raul G. Nogueira MD,&nbsp;David S. Liebeskind MD,&nbsp;Diogo C. Haussen MD,&nbsp;Santiago Ortega-Gutierrez MD, MSc","doi":"10.1002/ana.27064","DOIUrl":"10.1002/ana.27064","url":null,"abstract":"","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"96 4","pages":"820-821"},"PeriodicalIF":8.1,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142078597","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
Mapping Functional Connectivity Signatures of Pharmacoresistant Focal Cortical Dysplasia-Related Epilepsy. 绘制耐药性局灶性皮质发育不良相关癫痫的功能连接特征。
IF 8.1 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-08-27 DOI: 10.1002/ana.27069
Hua Xie, Venkata Sita Priyanka Illapani, L Gilbert Vezina, Taha Gholipour, Chima Oluigbo, William D Gaillard, Nathan T Cohen

Objective: To determine common network alterations in focal cortical dysplasia pharmacoresistant epilepsy (FCD-PRE) using functional connectivity analysis of resting-state functional magnetic resonance imaging (rsfMRI).

Methods: This is a retrospective imaging cohort from Children's National Hospital (Washington, DC, USA) from January, 2011 to January, 2022. Patients with 3-T MRI-confirmed FCD-PRE underwent rsfMRI as part of routine clinical care. Patients were included if they were age 5-22 years at the time of the scan, and had a minimum of 18 months of follow-up. Healthy, typically-developing controls were included from Children's National Hospital (n = 16) and matched from Human Connectome Project-Development public dataset (n = 100).

Results: A total of 42 FCD-PRE patients (20 M:22 F, aged 14.2 ± 4.1 years) and 116 healthy controls (56 M:60 F, aged 13.7 ± 3.3 years) with rsfMRI were included. Seed-based functional connectivity maps were generated for each FCD, and each seed was used to generate a patient-specific z-scored connectivity map on 116 controls. FCD-PRE patients had mutual altered connectivity in regions of dorsal attention, default mode, and control networks. Functional connectivity was diminished within the FCD dominant functional network, as well as in homotopic regions. Cluster specific connectivity patterns varied by pathological subtype. Higher FCD connectivity to the limbic network was associated with increased odds of Engel I outcome.

Interpretation: This study demonstrates diminished functional connectivity patterns in FCD-PRE, which may represent a neuromarker for the disease, independent of FCD location, involving the dorsal attention, default mode, and control functional networks. Higher connectivity to the limbic network is associated with a seizure-free outcome. Future multicenter, prospective studies are needed to allow for much earlier detection of signatures of treatment-resistant epilepsy. ANN NEUROL 2024.

目的利用静息态功能磁共振成像(rsfMRI)的功能连接分析,确定局灶性皮质发育不良耐药癫痫(FCD-PRE)的常见网络改变:这是2011年1月至2022年1月期间美国华盛顿特区儿童国立医院(Children's National Hospital)的回顾性成像队列。经 3-T 磁共振成像证实为 FCD-PRE 的患者接受了 rsfMRI 作为常规临床治疗的一部分。扫描时患者年龄为 5-22 岁,随访时间至少为 18 个月。健康、发育正常的对照组来自国立儿童医院(n = 16),匹配组来自人类连接组计划-发育公共数据集(n = 100):共纳入了42名FCD-PRE患者(20名男性:22名女性,年龄为14.2 ± 4.1岁)和116名健康对照组(56名男性:60名女性,年龄为13.7 ± 3.3岁)的rsfMRI。每个 FCD 都生成了基于种子的功能连接图,每个种子用于生成 116 个对照组的特定患者 z 评分连接图。FCD-PRE患者在背侧注意、默认模式和控制网络区域的连接性相互改变。功能性连通性在 FCD 优势功能网络内以及同位区域内都有所减弱。不同病理亚型的簇特异性连接模式各不相同。FCD与边缘网络较高的连通性与恩格尔I型结果的几率增加有关:这项研究表明,FCD-PRE的功能连接模式减弱,这可能代表了该疾病的神经标记物,与FCD位置无关,涉及背侧注意、默认模式和控制功能网络。边缘网络的连接性越高,无癫痫发作的结果就越好。未来需要开展多中心、前瞻性研究,以便更早地发现耐药癫痫的特征。ann neurol 2024。
{"title":"Mapping Functional Connectivity Signatures of Pharmacoresistant Focal Cortical Dysplasia-Related Epilepsy.","authors":"Hua Xie, Venkata Sita Priyanka Illapani, L Gilbert Vezina, Taha Gholipour, Chima Oluigbo, William D Gaillard, Nathan T Cohen","doi":"10.1002/ana.27069","DOIUrl":"https://doi.org/10.1002/ana.27069","url":null,"abstract":"<p><strong>Objective: </strong>To determine common network alterations in focal cortical dysplasia pharmacoresistant epilepsy (FCD-PRE) using functional connectivity analysis of resting-state functional magnetic resonance imaging (rsfMRI).</p><p><strong>Methods: </strong>This is a retrospective imaging cohort from Children's National Hospital (Washington, DC, USA) from January, 2011 to January, 2022. Patients with 3-T MRI-confirmed FCD-PRE underwent rsfMRI as part of routine clinical care. Patients were included if they were age 5-22 years at the time of the scan, and had a minimum of 18 months of follow-up. Healthy, typically-developing controls were included from Children's National Hospital (n = 16) and matched from Human Connectome Project-Development public dataset (n = 100).</p><p><strong>Results: </strong>A total of 42 FCD-PRE patients (20 M:22 F, aged 14.2 ± 4.1 years) and 116 healthy controls (56 M:60 F, aged 13.7 ± 3.3 years) with rsfMRI were included. Seed-based functional connectivity maps were generated for each FCD, and each seed was used to generate a patient-specific z-scored connectivity map on 116 controls. FCD-PRE patients had mutual altered connectivity in regions of dorsal attention, default mode, and control networks. Functional connectivity was diminished within the FCD dominant functional network, as well as in homotopic regions. Cluster specific connectivity patterns varied by pathological subtype. Higher FCD connectivity to the limbic network was associated with increased odds of Engel I outcome.</p><p><strong>Interpretation: </strong>This study demonstrates diminished functional connectivity patterns in FCD-PRE, which may represent a neuromarker for the disease, independent of FCD location, involving the dorsal attention, default mode, and control functional networks. Higher connectivity to the limbic network is associated with a seizure-free outcome. Future multicenter, prospective studies are needed to allow for much earlier detection of signatures of treatment-resistant epilepsy. ANN NEUROL 2024.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142078596","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
Miyazaki Syndrome as a Complication of Shunt Drainage 作为分流引流并发症的宫崎综合征。
IF 8.1 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-08-27 DOI: 10.1002/ana.27067
Rick H. G. J. van Lanen MD, MSc, Jasper van Aalst MD, PhD, Mariël P. Ter Laak-Poort MD, PhD
<p>A 41-year-old female was referred to the neurosurgery outpatient clinic with progressive bipyramidal syndrome. Medical history included premature birth and prior intraventricular hemorrhage with hydrocephalus. Ventricular-peritoneal (VP) shunting was performed in the management of hydrocephalus. However, complications related to over-drainage, along with hyperostosis of the skull and craniosynostosis, caused scaphocephaly.</p><p>Over the course of several months, she experienced progressive difficulties walking and developed right-sided weakness. Neurological examination revealed right-sided hemiparesis, hyperreflexia, and bilateral Babinski's sign. Imaging of the brain and cervical spine (Fig 1) showed scaphocephaly with slit-like ventricles and myelopathy extending from the C1 to C3 levels, along with the presence of spinal epidural venous engorgement. In the absence of a diagnosis, she was placed under long-term follow-up care by her neurologist. Follow-up magnetic resonance imaging (MRI) of the cervical spine revealed progressive myelopathy, before the diagnosis of Miyazaki syndrome was made. She underwent VP-shunt revision, with implantation of a Miethke proGAV 2.0 0-20/20 (programmable valve pressure setting 8). Outpatient clinic follow-up at 6 months showed stabilization of the bipyramidal symptoms. Follow-up MRI showed improvement of the epidural venous engorgement.</p><p>Miyazaki syndrome arises as a complication of cerebrospinal fluid (CSF) hypotension caused by excessive drainage through VP-shunting. Although CSF hypotension is often associated with well-known symptoms, like orthostatic headache and cranial nerve palsies, the development of epidural venous engorgement leading to spinal cord compression is a less common but critical manifestation.</p><p>The syndrome is characterized by cervical myelopathy or radiculopathy due to cervical epidural venous congestion, results from complex pathophysiological mechanisms.<span><sup>1, 2</sup></span> These include changes in CSF pressure, consistent with the Monro-Kellie doctrine, and dysfunction in the Starling resistor, leading to the enlargement and dilation of the spinal epidural venous plexus.<span><sup>1</sup></span> Venous congestion can lead to spinal cord or nerve roots compression or circulation hampering,<span><sup>1</sup></span> causing neurological symptoms, whereas presenting a unique diagnostic challenge. One of the striking features of Miyazaki syndrome is that it can manifest without the typical symptom of orthostatic headache, which is commonly associated with CSF hypotension. Instead, patients with Miyazaki syndrome may develop myelopathy symptoms slowly over time, making it challenging to diagnose, potentially leading to misdiagnosis.<span><sup>3</sup></span> This underlines the importance of considering Miyazaki syndrome in the differential diagnosis of patients with VP-shunts who present with myelopathy but do not experience headaches. Timely recognition is crucial and
一名 41 岁的女性因进行性双锥体综合征转诊至神经外科门诊。病史包括早产和脑室内出血并伴有脑积水。在治疗脑积水的过程中进行了脑室-腹膜(VP)分流术。然而,与过度引流有关的并发症以及颅骨骨质增生和颅骨发育不良导致了头颅骨畸形。几个月后,她逐渐出现行走困难,右侧肢体无力。神经系统检查发现她右侧偏瘫、反射亢进和双侧巴宾斯基征。脑部和颈椎的影像学检查(图 1)显示,颅骨后凸,脑室呈狭缝状,脊髓病变从 C1 水平延伸至 C3 水平,并伴有脊髓硬膜外静脉充血。在没有确诊的情况下,神经科医生对她进行了长期随访。随访的颈椎磁共振成像(MRI)显示,在确诊宫崎综合征之前,她的脊髓病变呈进行性发展。她接受了 VP 分流改造手术,植入了 Miethke proGAV 2.0 0-20/20(可编程阀门压力设置为 8)。6 个月的门诊随访显示双锥体症状趋于稳定。宫崎综合征是脑脊液(CSF)低血压的一种并发症,由 VP 分流引流过多引起。虽然 CSF 低血压常伴有众所周知的症状,如正位性头痛和颅神经麻痹,但硬膜外静脉充血导致脊髓压迫是一种不太常见但却非常重要的表现、1 静脉充血可导致脊髓或神经根受压或血液循环障碍,1 引起神经系统症状,同时也是一种独特的诊断难题。宫崎综合征的一个显著特点是,它可以没有典型的正压性头痛症状,而正压性头痛通常与脑脊液低血压有关。相反,宫崎综合征患者的脊髓病症状可能会随着时间的推移而缓慢发展,这就给诊断带来了挑战,有可能导致误诊。3 这就强调了在对出现脊髓病但不伴有头痛的 VP 分流患者进行鉴别诊断时考虑宫崎综合征的重要性。及时识别至关重要,需要进行影像学诊断,尤其是脑部和脊柱磁共振成像,重点检查静脉血流,以确诊宫崎综合征。即使没有其他典型的低血压图像,颈静脉丛肿胀也可能是该综合征的一个关键指标。可能的干预措施包括调整瓣膜系统的开放压力,必要时插入可编程瓣膜,或完全关闭/移除分流管。1-3 总之,本病例强调了了解宫崎综合征的临床重要性,这是一种罕见但可能导致衰弱的脑脊液通过 VP 分流管过度引流的并发症,并强调了早期诊断和适当治疗对改善患者预后的重要意义、J.vA.和M.P.TL-P参与了研究的构思和设计;R.H.G.J.vL.参与了文本的起草和图表的绘制;R.H.G.J.vL.和M.P.TL-P参与了数据的获取和分析。
{"title":"Miyazaki Syndrome as a Complication of Shunt Drainage","authors":"Rick H. G. J. van Lanen MD, MSc,&nbsp;Jasper van Aalst MD, PhD,&nbsp;Mariël P. Ter Laak-Poort MD, PhD","doi":"10.1002/ana.27067","DOIUrl":"10.1002/ana.27067","url":null,"abstract":"&lt;p&gt;A 41-year-old female was referred to the neurosurgery outpatient clinic with progressive bipyramidal syndrome. Medical history included premature birth and prior intraventricular hemorrhage with hydrocephalus. Ventricular-peritoneal (VP) shunting was performed in the management of hydrocephalus. However, complications related to over-drainage, along with hyperostosis of the skull and craniosynostosis, caused scaphocephaly.&lt;/p&gt;&lt;p&gt;Over the course of several months, she experienced progressive difficulties walking and developed right-sided weakness. Neurological examination revealed right-sided hemiparesis, hyperreflexia, and bilateral Babinski's sign. Imaging of the brain and cervical spine (Fig 1) showed scaphocephaly with slit-like ventricles and myelopathy extending from the C1 to C3 levels, along with the presence of spinal epidural venous engorgement. In the absence of a diagnosis, she was placed under long-term follow-up care by her neurologist. Follow-up magnetic resonance imaging (MRI) of the cervical spine revealed progressive myelopathy, before the diagnosis of Miyazaki syndrome was made. She underwent VP-shunt revision, with implantation of a Miethke proGAV 2.0 0-20/20 (programmable valve pressure setting 8). Outpatient clinic follow-up at 6 months showed stabilization of the bipyramidal symptoms. Follow-up MRI showed improvement of the epidural venous engorgement.&lt;/p&gt;&lt;p&gt;Miyazaki syndrome arises as a complication of cerebrospinal fluid (CSF) hypotension caused by excessive drainage through VP-shunting. Although CSF hypotension is often associated with well-known symptoms, like orthostatic headache and cranial nerve palsies, the development of epidural venous engorgement leading to spinal cord compression is a less common but critical manifestation.&lt;/p&gt;&lt;p&gt;The syndrome is characterized by cervical myelopathy or radiculopathy due to cervical epidural venous congestion, results from complex pathophysiological mechanisms.&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt; These include changes in CSF pressure, consistent with the Monro-Kellie doctrine, and dysfunction in the Starling resistor, leading to the enlargement and dilation of the spinal epidural venous plexus.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Venous congestion can lead to spinal cord or nerve roots compression or circulation hampering,&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; causing neurological symptoms, whereas presenting a unique diagnostic challenge. One of the striking features of Miyazaki syndrome is that it can manifest without the typical symptom of orthostatic headache, which is commonly associated with CSF hypotension. Instead, patients with Miyazaki syndrome may develop myelopathy symptoms slowly over time, making it challenging to diagnose, potentially leading to misdiagnosis.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; This underlines the importance of considering Miyazaki syndrome in the differential diagnosis of patients with VP-shunts who present with myelopathy but do not experience headaches. Timely recognition is crucial and","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"96 6","pages":"1230-1231"},"PeriodicalIF":8.1,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.27067","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142071516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Population-Based Evidence for the Use of Serum Neurofilaments as Individual Diagnostic and Prognostic Biomarkers in Amyotrophic Lateral Sclerosis 将血清神经丝作为肌萎缩侧索硬化症个体诊断和预后生物标记物的人群证据
IF 8.1 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-08-23 DOI: 10.1002/ana.27054
Simon Witzel MD, André Huss PhD, Gabriele Nagel MD, Angela Rosenbohm MD, Dietrich Rothenbacher MD, Raphael S. Peter PhD, Hansjörg Bäzner MD, Axel Börtlein MD, Silke Dempewolf MD, Martin Schabet MD, Martin Hecht MD, Andreas Kohler MD, Christian Opherk MD, Andrea Naegele MD, Norbert Sommer MD, Alfred Lindner MD, Christoforos Alexudis, Franziska Bachhuber PhD, Steffen Halbgebauer PhD, David Brenner MD, Wolfgang Ruf MD, Ulrike Weiland MD, Benjamin Mayer PhD, Joachim Schuster PhD, Johannes Dorst MD, Hayrettin Tumani MD, Albert C. Ludolph MD, and the ALS Registry Swabia Study Group

Objective

Neurofilament light chains (NfL) and phosphorylated neurofilament heavy chains (pNfH), established as diagnostic and prognostic biomarkers in hospital-based amyotrophic lateral sclerosis (ALS) cohorts, are now surrogate markers in clinical trials. This study extends their evaluation to a population level, with the aim of advancing their full establishment and assessing the transferability of biomarker findings from controlled cohorts to real-world ALS populations.

Methods

We measured serum NfL and pNfH levels in all ALS patients (n = 790) and general population controls (n = 570) with available baseline samples participating in the epidemiological ALS Registry Swabia, providing platform-specific (ELLA™) reference data and Z-scores for controls, as well as reference data, disease-specific Z-scores and longitudinal data in ALS. We evaluated the diagnostic and prognostic utility of neurofilaments and quantified the impact of ALS-related factors and non-ALS confounders.

Results

Neurofilaments showed high diagnostic and prognostic utility at the population level, with NfL superior to pNfH. The novel concept of a population-based ALS Z-score significantly improved the prognostic utility compared to absolute raw values. Both biomarkers increased more strongly with age in controls than in ALS, and age adjustment improved diagnostic accuracy. Our data show that disease progression rates, ALS phenotype, body mass index (BMI), and renal function need to be considered when interpreting neurofilament levels; longitudinal neurofilament levels were generally stable in individual patients, especially when adjusted for age and baseline levels.

Interpretation

Population-based assessment enhances the utility of particularly serum NfL as a diagnostic and prognostic biomarker in ALS and improves the translation of findings from controlled cohorts to real-world populations. ANN NEUROL 2024;96:1040–1057

目的:神经丝蛋白轻链(NfL)和磷酸化神经丝蛋白重链(pNfH神经丝蛋白轻链(NfL)和磷酸化神经丝蛋白重链(pNfH)在以医院为基础的肌萎缩性脊髓侧索硬化症(ALS)队列中被确立为诊断和预后生物标志物,现已成为临床试验中的替代标志物。本研究将对它们的评估扩展到人群水平,目的是推进它们的全面建立,并评估生物标志物研究结果从对照队列到实际 ALS 人群的可转移性:我们测量了参与斯瓦比亚 ALS 流行病学登记的所有 ALS 患者(n = 790)和普通人群对照组(n = 570)的血清 NfL 和 pNfH 水平,为对照组提供了平台特异性(ELLA™)参考数据和 Z 值,以及 ALS 的参考数据、疾病特异性 Z 值和纵向数据。我们评估了神经丝的诊断和预后效用,并量化了ALS相关因素和非ALS混杂因素的影响:结果:神经丝在人群水平上显示出很高的诊断和预后效用,NfL优于pNfH。与绝对原始值相比,基于人群的 ALS Z 评分这一新理念大大提高了预后效用。在对照组中,这两种生物标志物随年龄的增长而增加的程度比在 ALS 中更强,年龄调整提高了诊断的准确性。我们的数据显示,在解释神经丝蛋白水平时,需要考虑疾病进展率、ALS 表型、体重指数(BMI)和肾功能;纵向神经丝蛋白水平在个体患者中通常是稳定的,尤其是在根据年龄和基线水平进行调整后:基于人群的评估提高了血清神经丝蛋白作为 ALS 诊断和预后生物标志物的实用性,并改善了从对照队列到实际人群的研究结果转化。ann neurol 2024.
{"title":"Population-Based Evidence for the Use of Serum Neurofilaments as Individual Diagnostic and Prognostic Biomarkers in Amyotrophic Lateral Sclerosis","authors":"Simon Witzel MD,&nbsp;André Huss PhD,&nbsp;Gabriele Nagel MD,&nbsp;Angela Rosenbohm MD,&nbsp;Dietrich Rothenbacher MD,&nbsp;Raphael S. Peter PhD,&nbsp;Hansjörg Bäzner MD,&nbsp;Axel Börtlein MD,&nbsp;Silke Dempewolf MD,&nbsp;Martin Schabet MD,&nbsp;Martin Hecht MD,&nbsp;Andreas Kohler MD,&nbsp;Christian Opherk MD,&nbsp;Andrea Naegele MD,&nbsp;Norbert Sommer MD,&nbsp;Alfred Lindner MD,&nbsp;Christoforos Alexudis,&nbsp;Franziska Bachhuber PhD,&nbsp;Steffen Halbgebauer PhD,&nbsp;David Brenner MD,&nbsp;Wolfgang Ruf MD,&nbsp;Ulrike Weiland MD,&nbsp;Benjamin Mayer PhD,&nbsp;Joachim Schuster PhD,&nbsp;Johannes Dorst MD,&nbsp;Hayrettin Tumani MD,&nbsp;Albert C. Ludolph MD,&nbsp;and the ALS Registry Swabia Study Group","doi":"10.1002/ana.27054","DOIUrl":"10.1002/ana.27054","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Neurofilament light chains (NfL) and phosphorylated neurofilament heavy chains (pNfH), established as diagnostic and prognostic biomarkers in hospital-based amyotrophic lateral sclerosis (ALS) cohorts, are now surrogate markers in clinical trials. This study extends their evaluation to a population level, with the aim of advancing their full establishment and assessing the transferability of biomarker findings from controlled cohorts to real-world ALS populations.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We measured serum NfL and pNfH levels in all ALS patients (n = 790) and general population controls (n = 570) with available baseline samples participating in the epidemiological ALS Registry Swabia, providing platform-specific (ELLA™) reference data and Z-scores for controls, as well as reference data, disease-specific Z-scores and longitudinal data in ALS. We evaluated the diagnostic and prognostic utility of neurofilaments and quantified the impact of ALS-related factors and non-ALS confounders.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Neurofilaments showed high diagnostic and prognostic utility at the population level, with NfL superior to pNfH. The novel concept of a population-based ALS Z-score significantly improved the prognostic utility compared to absolute raw values. Both biomarkers increased more strongly with age in controls than in ALS, and age adjustment improved diagnostic accuracy. Our data show that disease progression rates, ALS phenotype, body mass index (BMI), and renal function need to be considered when interpreting neurofilament levels; longitudinal neurofilament levels were generally stable in individual patients, especially when adjusted for age and baseline levels.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>Population-based assessment enhances the utility of particularly serum NfL as a diagnostic and prognostic biomarker in ALS and improves the translation of findings from controlled cohorts to real-world populations. ANN NEUROL 2024;96:1040–1057</p>\u0000 </section>\u0000 </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"96 6","pages":"1040-1057"},"PeriodicalIF":8.1,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.27054","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142034629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Electro-Clinical Features and Functional Connectivity Analysis in SYN1-Related Epilepsy. SYN1相关癫痫的电临床特征和功能连接性分析
IF 8.1 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-08-23 DOI: 10.1002/ana.27063
Vincent Moya Quiros, Ahmed Adham, Philippe Convers, Gaetan Lesca, François Mauguiere, Hugo Soulier, Alexis Arzimanoglou, Allan Bayat, Hilde Braakman, Jean-Philippe Camdessanche, Philippe Casenave, Laurence Chaton, Yves Chaix, Maxime Chochoi, Christel Depienne, Vincent Desportes, Jessie De Ridder, Vera Dinkelacker, Elena Gardella, Gerhard J Kluger, Julien Jung, Martine Lemesle Martin, Maria Margherita Mancardi, Markus Mueller, Anne-Lise Poulat, Konrad Platzer, Agathe Roubertie, Marijn F Stokman, Anneke T Vulto-van Silfhout, Gert Wiegand, Laure Mazzola

Objective: There is currently scarce data on the electroclinical characteristics of epilepsy associated with synapsin 1 (SYN1) pathogenic variations. We examined clinical and electro-encephalographic (EEG) features in patients with epilepsy and SYN1 variants, with the aim of identifying a distinctive electroclinical pattern.

Methods: In this retrospective multicenter study, we collected and reviewed demographic, genetic, and epilepsy data of 19 male patients with SYN1 variants. Specifically, we analyzed interictal EEG data for all patients, and electro-clinical data from 10 epileptic seizures in 5 patients, using prolonged video-EEG monitoring recordings. Inter-ictal EEG functional connectivity parameters and frequency spectrum of the 10 patients over 12 years of age, were computed and compared with those of 56 age- and sex-matched controls.

Results: The main electroclinical features of epilepsy in patients with SYN1 were (1) EEG background and organization mainly normal; (2) interictal abnormalities are often rare or not visible on EEG; (3) more than 60% of patients had reflex seizures (cutaneous contact with water and defecation being the main triggers) isolated or associated with spontaneous seizures; (4) electro-clinical semiology of seizures was mainly temporal or temporo-insulo/perisylvian with a notable autonomic component; and (5) ictal EEG showed a characteristic rhythmic theta/delta activity predominating in temporo-perisylvian regions at the beginning of most seizures. Comparing patients with SYN1 to healthy subjects, we observed a shift to lower frequency bands in power spectrum of interictal EEG and an increased connectivity in both temporal regions.

Interpretation: A distinct epilepsy syndrome emerges in patients with SYN1, with a rather characteristic clinical and EEG pattern suggesting predominant temporo-insular involvement. ANN NEUROL 2024.

目的:目前,有关与突触素1(SYN1)致病变异相关的癫痫的电临床特征的数据很少。我们研究了癫痫和 SYN1 变异患者的临床和脑电图(EEG)特征,旨在确定一种独特的临床电模式:在这项回顾性多中心研究中,我们收集并审查了19名SYN1变异体男性患者的人口统计学、遗传学和癫痫数据。具体来说,我们分析了所有患者的发作间期脑电图数据,并利用长时间视频脑电图监测记录分析了 5 名患者 10 次癫痫发作的电临床数据。计算了10名12岁以上患者发作间期脑电图功能连接参数和频谱,并与56名年龄和性别匹配的对照组进行了比较:SYN1患者癫痫的主要电临床特征是:(1)脑电图背景和组织主要正常;(2)发作间期异常通常很少见或在脑电图上不明显;(3)60%以上的患者有反射性发作(皮肤接触水和排便是主要诱因),与自发性发作隔离或伴有反射性发作;(4) 癫痫发作的电-临床特征主要是颞叶或颞内/外周,并伴有明显的自主神经成分;以及 (5) 发作期脑电图显示,在大多数癫痫发作开始时,颞外周区域会出现特有的节律性θ/δ活动。将 SYN1 患者与健康受试者进行比较,我们观察到发作间期脑电图的功率谱向低频带转移,两个颞区的连接性增强:SYN1患者会出现一种独特的癫痫综合征,其临床和脑电图模式颇具特征性,表明主要受累于颞岛部。ann neurol 2024.
{"title":"Electro-Clinical Features and Functional Connectivity Analysis in SYN1-Related Epilepsy.","authors":"Vincent Moya Quiros, Ahmed Adham, Philippe Convers, Gaetan Lesca, François Mauguiere, Hugo Soulier, Alexis Arzimanoglou, Allan Bayat, Hilde Braakman, Jean-Philippe Camdessanche, Philippe Casenave, Laurence Chaton, Yves Chaix, Maxime Chochoi, Christel Depienne, Vincent Desportes, Jessie De Ridder, Vera Dinkelacker, Elena Gardella, Gerhard J Kluger, Julien Jung, Martine Lemesle Martin, Maria Margherita Mancardi, Markus Mueller, Anne-Lise Poulat, Konrad Platzer, Agathe Roubertie, Marijn F Stokman, Anneke T Vulto-van Silfhout, Gert Wiegand, Laure Mazzola","doi":"10.1002/ana.27063","DOIUrl":"https://doi.org/10.1002/ana.27063","url":null,"abstract":"<p><strong>Objective: </strong>There is currently scarce data on the electroclinical characteristics of epilepsy associated with synapsin 1 (SYN1) pathogenic variations. We examined clinical and electro-encephalographic (EEG) features in patients with epilepsy and SYN1 variants, with the aim of identifying a distinctive electroclinical pattern.</p><p><strong>Methods: </strong>In this retrospective multicenter study, we collected and reviewed demographic, genetic, and epilepsy data of 19 male patients with SYN1 variants. Specifically, we analyzed interictal EEG data for all patients, and electro-clinical data from 10 epileptic seizures in 5 patients, using prolonged video-EEG monitoring recordings. Inter-ictal EEG functional connectivity parameters and frequency spectrum of the 10 patients over 12 years of age, were computed and compared with those of 56 age- and sex-matched controls.</p><p><strong>Results: </strong>The main electroclinical features of epilepsy in patients with SYN1 were (1) EEG background and organization mainly normal; (2) interictal abnormalities are often rare or not visible on EEG; (3) more than 60% of patients had reflex seizures (cutaneous contact with water and defecation being the main triggers) isolated or associated with spontaneous seizures; (4) electro-clinical semiology of seizures was mainly temporal or temporo-insulo/perisylvian with a notable autonomic component; and (5) ictal EEG showed a characteristic rhythmic theta/delta activity predominating in temporo-perisylvian regions at the beginning of most seizures. Comparing patients with SYN1 to healthy subjects, we observed a shift to lower frequency bands in power spectrum of interictal EEG and an increased connectivity in both temporal regions.</p><p><strong>Interpretation: </strong>A distinct epilepsy syndrome emerges in patients with SYN1, with a rather characteristic clinical and EEG pattern suggesting predominant temporo-insular involvement. ANN NEUROL 2024.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142034628","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
全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1