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Structural Variants at the LMNB1 Locus: Deciphering Pathomechanisms in Autosomal Dominant Adult-Onset Demyelinating Leukodystrophy LMNB1 基因座的结构变异:解密常染色体显性遗传性成人发病脱髓鞘白营养不良症的病理机制。
IF 8.1 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-07-30 DOI: 10.1002/ana.27038
Paola Dimartino PhD, Mariia Zadorozhna PhD, Verónica Yumiceba MSc, Anna Basile MSc, Ilaria Cani MD, Uirá Souto Melo PhD, Jana Henck MSc, Marjolein Breur BSc, Caterina Tonon MD PhD, Raffaele Lodi MD, Alfredo Brusco PhD, Tommaso Pippucci PhD, Foteini-Dionysia Koufi MSc, Elisa Boschetti PhD, Giulia Ramazzotti PhD, Lucia Manzoli MD, Stefano Ratti MD, PhD, Filippo Pinto E Vairo MD, PhD, Martin B. Delatycki MD, PhD, Giovanna Vaula MD, Pietro Cortelli MD, PhD, Marianna Bugiani MD, PhD, Malte Spielmann MD, Elisa Giorgio PhD

Objective

We aimed to elucidate the pathogenic mechanisms underlying autosomal dominant adult-onset demyelinating leukodystrophy (ADLD), and to understand the genotype/phenotype correlation of structural variants (SVs) in the LMNB1 locus.

Background

Since the discovery of 3D genome architectures and topologically associating domains (TADs), new pathomechanisms have been postulated for SVs, regardless of gene dosage changes. ADLD is a rare genetic disease associated with duplications (classical ADLD) or noncoding deletions (atypical ADLD) in the LMNB1 locus.

Methods

High-throughput chromosome conformation capture, RNA sequencing, histopathological analyses of postmortem brain tissues, and clinical and neuroradiological investigations were performed.

Results

We collected data from >20 families worldwide carrying SVs in the LMNB1 locus and reported strong clinical variability, even among patients carrying duplications of the entire LMNB1 gene, ranging from classical and atypical ADLD to asymptomatic carriers. We showed that patients with classic ADLD always carried intra-TAD duplications, resulting in a simple gene dose gain. Atypical ADLD was caused by LMNB1 forebrain-specific misexpression due to inter-TAD deletions or duplications. The inter-TAD duplication, which extends centromerically and crosses the 2 TAD boundaries, did not cause ADLD. Our results provide evidence that astrocytes are key players in ADLD pathology.

Interpretation

Our study sheds light on the 3D genome and TAD structural changes associated with SVs in the LMNB1 locus, and shows that a duplication encompassing LMNB1 is not sufficient per se to diagnose ADLD, thereby strongly affecting genetic counseling. Our study supports breaking TADs as an emerging pathogenic mechanism that should be considered when studying brain diseases. ANN NEUROL 2024;96:855–870

研究目的我们旨在阐明常染色体显性成人型脱髓鞘性白质营养不良症(ALD)的致病机制,并了解LMNB1基因座结构变异(SVs)的基因型/表型相关性:背景:自从发现三维基因组结构和拓扑关联域(TADs)以来,人们对SVs提出了新的病理机制,而不管基因剂量的变化如何。ADLD是一种罕见的遗传病,与LMNB1基因座的重复(典型ADLD)或非编码缺失(非典型ADLD)有关。方法:进行高通量染色体构象捕获、RNA测序、死后脑组织的组织病理学分析以及临床和神经放射学调查:我们收集了全球超过20个携带LMNB1基因位点SV的家族的数据,结果显示,即使是携带整个LMNB1基因重复序列的患者,其临床变异性也很强,从典型和非典型ALD到无症状携带者,不一而足。我们的研究表明,典型 ADLD 患者总是携带 TAD 内重复基因,导致简单的基因剂量增加。非典型 ADLD 是由于 TAD 间的缺失或重复导致 LMNB1 前脑特异性表达错误。TAD间的重复在中心向延伸并跨越了2个TAD的边界,但不会导致ALD。我们的研究结果提供了证据,证明星形胶质细胞是ADLD病理学中的关键角色:我们的研究揭示了与 LMNB1 基因座 SV 相关的三维基因组和 TAD 结构变化,并表明包含 LMNB1 的重复本身不足以诊断 ADLD,从而对遗传咨询产生了重大影响。我们的研究支持将TADs断裂作为一种新兴的致病机制,在研究脑部疾病时应加以考虑。ann neurol 2024.
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引用次数: 0
SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability SRPK3对人类和斑马鱼的认知和眼部发育至关重要,可解释X-连锁智力障碍。
IF 8.1 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-07-29 DOI: 10.1002/ana.27037
Arkaprava Roychaudhury MS, Yu-Ri Lee PhD, Tae-Ik Choi PhD, Mervyn G. Thomas MD, PhD, Tahir N. Khan PhD, Hammad Yousaf MS, Cindy Skinner BSN, RN, Gail Maconachie PhD, Moira Crosier HNC, Holli Horak MD, Cris S. Constantinescu MD, PhD, FRCP, Tae-Yoon Kim PhD, Kang-Han Lee PhD, Jae-Jun Kyung MS, Tao Wang PhD, Bonsu Ku PhD, Bernard N. Chodirker MD, Michael F. Hammer PhD, Irene Gottlob MD, PhD, William H. J. Norton PhD, Robert Gerlai PhD, Hyung-Goo Kim PhD, Claudio Graziano MD, Tommaso Pippucci PhD, Emanuela Iovino PhD, Francesca Montanari MD, Giulia Severi MD, Camilo Toro MD, Cornelius F. Boerkoel MD, PhD, Hyo Sun Cha BS, Cheol Yong Choi PhD, Sungjin Kim PhD, Je-Hyun Yoon PhD, Kelly Gilmore MS, Neeta L. Vora MD, Erica E. Davis PhD, Albert E. Chudley MD, Charles E. Schwartz MD, PhD, Cheol-Hee Kim PhD

Objective

Intellectual disability is often the outcome of neurodevelopmental disorders and is characterized by significant impairments in intellectual and adaptive functioning. X-linked intellectual disability (XLID) is a subset of these disorders caused by genetic defects on the X chromosome, affecting about 2 out of 1,000 males. In syndromic form, it leads to a broad range of cognitive, behavioral, ocular, and physical disabilities.

Methods

Employing exome or genome sequencing, here we identified 4 missense variants (c.475C > G; p.H159D, c.1373C > A; p.T458N, and c.1585G > A; p.E529K, c.953C > T; p.S318L) and a putative truncating variant (c.1413_1414del; p.Y471*) in the SRPK3 gene in 9 XLID patients from 5 unrelated families. To validate SRPK3 as a novel XLID gene, we established a knockout (KO) model of the SRPK3 orthologue in zebrafish.

Results

The 8 patients ascertained postnatally shared common clinical features including intellectual disability, agenesis of the corpus callosum, abnormal eye movement, and ataxia. A ninth case, ascertained prenatally, had a complex structural brain phenotype. Together, these data indicate a pathological role of SRPK3 in neurodevelopmental disorders. In post-fertilization day 5 larvae (free swimming stage), KO zebrafish exhibited severe deficits in eye movement and swim bladder inflation, mimicking uncontrolled ocular movement and physical clumsiness observed in human patients. In adult KO zebrafish, cerebellar agenesis and behavioral abnormalities were observed, recapitulating human phenotypes of cerebellar atrophy and intellectual disability.

Interpretation

Overall, these results suggest a crucial role of SRPK3 in the pathogenesis of syndromic X-linked intellectual disability and provide new insights into brain development, cognitive and ocular dysfunction in both humans and zebrafish. ANN NEUROL 2024;96:914–931

目的:智力障碍通常是神经发育障碍的结果,其特点是智力和适应功能严重受损。X连锁智力障碍(XLID)是这些疾病的一个子集,由X染色体上的遗传缺陷引起,每1000名男性中约有2人患病。在综合征形式下,它会导致一系列认知、行为、眼部和身体残疾:方法:通过外显子组或基因组测序,我们在来自5个非亲缘关系家族的9名XLID患者中发现了SRPK3基因中的4个错义变异(c.475C > G; p.H159D、c.1373C > A; p.T458N、c.1585G > A; p.E529K、c.953C > T; p.S318L)和一个假定截断变异(c.1413_1414del; p.Y471*)。为了验证SRPK3是一个新的XLID基因,我们在斑马鱼中建立了一个SRPK3同源基因的基因敲除(KO)模型:结果:8 名产后确诊的患者具有共同的临床特征,包括智力障碍、胼胝体发育不全、眼球运动异常和共济失调。第 9 个病例是在产前发现的,具有复杂的大脑结构表型。这些数据共同表明,SRPK3 在神经发育障碍中起着病理作用。在受精后第5天的幼体(自由泳阶段)中,KO斑马鱼在眼球运动和鳔充气方面表现出严重的缺陷,模仿了人类患者不受控制的眼球运动和身体笨拙的表现。在成年 KO 斑马鱼中,观察到小脑发育不全和行为异常,再现了小脑萎缩和智力残疾的人类表型:总之,这些结果表明SRPK3在综合征X连锁智障的发病机制中起着关键作用,并为人类和斑马鱼的大脑发育、认知和眼部功能障碍提供了新的见解。ann neurol 2024.
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引用次数: 0
Correlations of Socioeconomic and Clinical Determinants with United States County-Level Stroke Prevalence 社会经济和临床决定因素与美国县级中风患病率的相关性。
IF 8.1 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-07-26 DOI: 10.1002/ana.27039
Eric L. Stulberg MD, MPH, Lynda Lisabeth PhD, Andrea L. C. Schneider MD, PhD, Lesli Skolarus MD, MS, Kiarri N. Kershaw PhD, Alexander R. Zheutlin MD, MS, Benjamin R. E. Harris MD, Daniel Sarpong PhD, Ka-Ho Wong MBA, Kevin N. Sheth MD, Adam de Havenon MD, MS

Socioeconomic status (SES) is a multi-faceted theoretical construct associated with stroke risk and outcomes. Knowing which SES measures best correlate with population stroke metrics would improve its accounting in observational research and inform interventions. Using the Centers for Disease Control and Prevention's (CDC) Population Level Analysis and Community Estimates (PLACES) and other publicly available databases, we conducted an ecological study comparing correlations of different United States county-level SES, health care access and clinical risk factor measures with age-adjusted stroke prevalence. The prevalence of adults living below 150% of the federal poverty level most strongly correlated with stroke prevalence compared to other SES and non-SES measures (correlation coefficient = 0.908, R2 = 0.825; adjusted partial correlation coefficient: 0.589, R2 = 0.347). ANN NEUROL 2024;96:739–744

社会经济地位(SES)是一个与中风风险和预后相关的多层面理论概念。了解哪些 SES 指标与人群卒中指标最相关,将有助于改进观察研究中的统计工作,并为干预措施提供依据。利用美国疾病控制和预防中心(CDC)的人口水平分析和社区估计(PLACES)及其他公开数据库,我们进行了一项生态学研究,比较了美国不同县级 SES、医疗保健获取途径和临床风险因素测量与年龄调整后中风患病率的相关性。与其他 SES 和非 SES 指标相比,生活在联邦贫困线 150% 以下的成年人患病率与中风患病率的相关性最强(相关系数 = 0.908,R2 = 0.825;调整后的部分相关系数:0.589,R2 = 0.347)。ann neurol 2024.
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引用次数: 0
Diagnostic MRI Score to Differentiate Susac Syndrome from Primary Angiitis of the Central Nervous System and Multiple Sclerosis 区分苏萨克综合征与中枢神经系统原发性血管炎和多发性硬化症的磁共振成像诊断评分。
IF 8.1 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-07-26 DOI: 10.1002/ana.27043
Mariano Marrodan MD, Ismael L. Calandri MD, Diana I. Bocancea MSc, Maria C. Ysrraelit MD, Enrique Gomez Figueroa MD, Montserrat Massó Páez MD, José D.J. Flores MD, Juan I. Rojas MD, Ethel Ciampi MD, Pablo Ioli MD, Gisela Zanga MD, Carolina Ardohain MD, Maria E. Fracaro MD, Mariela Amaya MD, Verónica Tkachuk MD, Victoria C. Fernandez MD, Gustavo José MD, Emanuel Silva MD, Geraldine Luetic MD, Edgar Carnero Contentti MD, Eduardo Köhler MD, Fatima Pagani Cassara MD, Dolores Moran MD, Carla Seimandi MD, Juan P. Paviolo MD, Brenda D'elio MD, Gustavo Da Prat MD, Emilia Gatto MD, Edgardo Cristiano MD, Virginia Pujol Lereis MD, Sebastian F. Ameriso MD, Marcela P. Fiol MD, Jorge Correale MD

Objective

Susac syndrome (SuS), multiple sclerosis (MS), and primary angiitis of the central nervous system (PACNS) present diagnostic challenges due to overlapping clinical features. We aimed to enhance diagnostic precision by developing the SPAMS (SuS, PACNS, MS) score, a practical radiological tool.

Methods

This multicenter study included 99 patients (43 SuS, 37 MS, 19 PACNS) from South American countries. Relevant MRI features were identified through an elastic-net model determined key variables.

Results

The SPAMS score assigned 2 points for snowball lesions, 1 point for spokes-like lesions, or if there are more than 4 lesions in the corpus callosum, corpus callosum involvement, or cerebellar involvement. It subtracted 1 point if gadolinium-enhancing lesions or 4 points if Dawson's fingers are present. Bootstrapping validated the optimal cutoff at 2 points, exhibiting a diagnostic performance of area under the curve = 0.931, sensitivity = 88%, specificity = 89%, positive predictive value = 88%, negative predictive value = 89%, and accuracy = 88%.

Interpretation

When specific MRI findings coexisted, the SPAMS score differentiated SuS from MS and PACNS. Access to MRI and standard protocol sequences makes it a valuable tool for timely diagnosis and treatment, potentially preventing disability progression and severe clinical outcomes. ANN NEUROL 2024;96:846–854

目的:苏萨克综合征(SuS)、多发性硬化症(MS)和中枢神经系统原发性血管炎(PACNS)的临床特征相互重叠,给诊断带来了挑战。我们的目标是通过开发 SPAMS(SuS、PACNS、MS)评分这一实用的放射学工具来提高诊断的精确性:这项多中心研究包括来自南美国家的 99 名患者(43 名 SuS、37 名 MS、19 名 PACNS)。通过弹性网模型确定关键变量,从而确定相关的磁共振成像特征:SPAMS评分为雪球状病变得2分,辐条状病变得1分,或胼胝体中有4个以上病变、胼胝体受累或小脑受累得1分。如果出现钆增强病变,则减去 1 分;如果出现道森指,则减去 4 分。Bootstrapping 验证了最佳分界点为 2 点,其诊断性能为曲线下面积 = 0.931、灵敏度 = 88%、特异性 = 89%、阳性预测值 = 88%、阴性预测值 = 89%、准确性 = 88%:当特定的 MRI 检查结果同时存在时,SPAMS 评分可将 SuS 与 MS 和 PACNS 区分开来。核磁共振成像和标准方案序列使其成为及时诊断和治疗的重要工具,有可能防止残疾进展和严重的临床后果。ann neurol 2024.
{"title":"Diagnostic MRI Score to Differentiate Susac Syndrome from Primary Angiitis of the Central Nervous System and Multiple Sclerosis","authors":"Mariano Marrodan MD,&nbsp;Ismael L. Calandri MD,&nbsp;Diana I. Bocancea MSc,&nbsp;Maria C. Ysrraelit MD,&nbsp;Enrique Gomez Figueroa MD,&nbsp;Montserrat Massó Páez MD,&nbsp;José D.J. Flores MD,&nbsp;Juan I. Rojas MD,&nbsp;Ethel Ciampi MD,&nbsp;Pablo Ioli MD,&nbsp;Gisela Zanga MD,&nbsp;Carolina Ardohain MD,&nbsp;Maria E. Fracaro MD,&nbsp;Mariela Amaya MD,&nbsp;Verónica Tkachuk MD,&nbsp;Victoria C. Fernandez MD,&nbsp;Gustavo José MD,&nbsp;Emanuel Silva MD,&nbsp;Geraldine Luetic MD,&nbsp;Edgar Carnero Contentti MD,&nbsp;Eduardo Köhler MD,&nbsp;Fatima Pagani Cassara MD,&nbsp;Dolores Moran MD,&nbsp;Carla Seimandi MD,&nbsp;Juan P. Paviolo MD,&nbsp;Brenda D'elio MD,&nbsp;Gustavo Da Prat MD,&nbsp;Emilia Gatto MD,&nbsp;Edgardo Cristiano MD,&nbsp;Virginia Pujol Lereis MD,&nbsp;Sebastian F. Ameriso MD,&nbsp;Marcela P. Fiol MD,&nbsp;Jorge Correale MD","doi":"10.1002/ana.27043","DOIUrl":"10.1002/ana.27043","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Susac syndrome (SuS), multiple sclerosis (MS), and primary angiitis of the central nervous system (PACNS) present diagnostic challenges due to overlapping clinical features. We aimed to enhance diagnostic precision by developing the SPAMS (SuS, PACNS, MS) score, a practical radiological tool.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This multicenter study included 99 patients (43 SuS, 37 MS, 19 PACNS) from South American countries. Relevant MRI features were identified through an elastic-net model determined key variables.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The SPAMS score assigned 2 points for snowball lesions, 1 point for spokes-like lesions, or if there are more than 4 lesions in the corpus callosum, corpus callosum involvement, or cerebellar involvement. It subtracted 1 point if gadolinium-enhancing lesions or 4 points if Dawson's fingers are present. Bootstrapping validated the optimal cutoff at 2 points, exhibiting a diagnostic performance of area under the curve = 0.931, sensitivity = 88%, specificity = 89%, positive predictive value = 88%, negative predictive value = 89%, and accuracy = 88%.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>When specific MRI findings coexisted, the SPAMS score differentiated SuS from MS and PACNS. Access to MRI and standard protocol sequences makes it a valuable tool for timely diagnosis and treatment, potentially preventing disability progression and severe clinical outcomes. ANN NEUROL 2024;96:846–854</p>\u0000 </section>\u0000 </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141755912","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
Smouldering-Associated Worsening in Multiple Sclerosis: An International Consensus Statement on Definition, Biology, Clinical Implications, and Future Directions 多发性硬化症的烟熏相关恶化:关于定义、生物学、临床意义和未来方向的国际共识声明》。
IF 8.1 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-07-25 DOI: 10.1002/ana.27034
Antonio Scalfari MD, PhD, Anthony Traboulsee MD, Jiwon Oh MD, PhD, Laura Airas MD, PhD, Stefan Bittner MD, Massimiliano Calabrese MD, PhD, Jose Manuel Garcia Dominguez MD, PhD, Cristina Granziera MD, PhD, Benjamin Greenberg MD, MHS, Kerstin Hellwig MD, Zsolt Illes MD, PhD, Jan Lycke MD, PhD, Veronica Popescu MD, Francesca Bagnato MD, PhD, Gavin Giovannoni MBBCh, PhD

Despite therapeutic suppression of relapses, multiple sclerosis (MS) patients often experience subtle deterioration, which extends beyond the definition of “progression independent of relapsing activity.” We propose the concept of smouldering-associated-worsening (SAW), encompassing physical and cognitive symptoms, resulting from smouldering pathological processes, which remain unmet therapeutic targets. We provide a consensus-based framework of possible pathological substrates and manifestations of smouldering MS, and we discuss clinical, radiological, and serum/cerebrospinal fluid biomarkers for potentially monitoring SAW. Finally, we share considerations for optimizing disease surveillance and implications for clinical trials to promote the integration of smouldering MS into routine practice and future research efforts. ANN NEUROL 2024;96:826–845

尽管治疗抑制了复发,但多发性硬化症(MS)患者的病情往往会出现微妙的恶化,这种恶化超出了 "独立于复发活动的进展 "的定义。我们提出了 "烟熏病相关恶化"(SAW)的概念,它包括由烟熏病病理过程引起的身体和认知症状,而这些病理过程仍未成为治疗目标。我们为烟雾病多发性硬化症可能的病理基础和表现提供了一个基于共识的框架,并讨论了可能监测烟雾病多发性硬化症的临床、放射学和血清/脑脊液生物标记物。最后,我们分享了优化疾病监测的注意事项和对临床试验的影响,以促进将烟雾型多发性硬化症纳入常规实践和未来的研究工作中。ann neurol 2024.
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引用次数: 0
Anticoagulation Use and Endovascular Thrombectomy in Patients with Large Core Stroke: A Secondary Analysis of the SELECT2 Trial 大面积核心卒中患者的抗凝治疗和血管内血栓切除术:SELECT2 试验的二次分析。
IF 8.1 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-07-22 DOI: 10.1002/ana.27021
Deep K. Pujara MBBS, M. Shazam Hussain MD, Michael G. Abraham MD, Santiago Ortega-Gutierrez MD, Michael Chen MD, Scott E. Kasner MD, Leonid Churilov PhD, Clark W. Sitton MD, Spiros Blackburn MD, Sophia Sundararajan MD, Yin C. Hu MD, Nabeel A. Herial MD, Ronald F. Budzik MD, William J. Hicks MD, Juan F. Arenillas MD, PhD, Jenny P. Tsai MD, Osman Kozak MD, Dennis J. Cordato PhD, Nathan W. Manning MBBS, Ricardo A. Hanel MD, Amin N. Aghaebrahim MD, Teddy Y. Wu PhD, Pere Cardona Portela MD, Natalia Pérez de la Ossa MD, PhD, Joanna D. Schaafsma MD, Jordi Blasco MD, PhD, Navdeep Sangha MD, Steven Warach MD, Chirag D. Gandhi MD, Fawaz Al-Mufti MD, Timothy J. Kleinig PhD, Faisal Al-Shaibi MD, Kelsey R. Duncan MD, Faris Shaker MBChB, Hannah Johns PhD, Wei Xiong MD, Michael DeGeorgia MD, Amanda Opaskar MD, Jeffrey Sunshine MD, Abhishek Ray MD, Pascal Jabbour MD, Nicholas Bambakidis MD, Cathy Sila MD, Thanh N. Nguyen MD, James C. Grotta MD, Ameer E. Hassan DO, Marc Ribo MD, Michael D. Hill MD, Bruce C. Campbell PhD, Amrou Sarraj MD, For SELECT2 Investigators

Endovascular thrombectomy (EVT) safety and efficacy in patients with large core infarcts receiving oral anticoagulants (OAC) are unknown. In the SELECT2 trial (NCT03876457), 29 of 180 (16%; vitamin K antagonists 15, direct OACs 14) EVT, and 18 of 172 (10%; vitamin K antagonists 3, direct OACs 15) medical management (MM) patients reported OAC use at baseline. EVT was not associated with better clinical outcomes in the OAC group (EVT 6 [4–6] vs MM 5 [4–6], adjusted generalized odds ratio 0.89 [0.53–1.50]), but demonstrated significantly better outcomes in patients without OAC (EVT 4 [3–6] vs MM 5 [4–6], adjusted generalized odds ratio 1.87 [1.45–2.40], p = 0.02). The OAC group had higher comorbidities, including atrial fibrillation (70% vs 17%), congestive heart failure (28% vs 10%), and hypertension (87% vs 72%), suggesting increased frailty. However, the results were consistent after adjustment for these comorbidities, and was similar regardless of the type of OACs used. Whereas any hemorrhage rates were higher in the OAC group receiving EVT (86% in OAC vs 70% in no OAC), no parenchymal hemorrhage or symptomatic intracranial hemorrhage were observed with OAC use in both the EVT and MM arms. Although we did not find evidence that the effect was due to excess hemorrhage or confounded by underlying cardiac disease or older age, OAC use alone should not exclude patients from receiving EVT. Baseline comorbidities and ischemic injury extent should be considered while making individualized treatment decisions. ANN NEUROL 2024;96:887–894

接受口服抗凝剂(OAC)治疗的大面积核心梗死患者接受血管内血栓切除术(EVT)的安全性和有效性尚不清楚。在 SELECT2 试验(NCT03876457)中,180 例 EVT 患者中有 29 例(16%;维生素 K 拮抗剂 15 例,直接 OAC 14 例)和 172 例药物治疗 (MM) 患者中有 18 例(10%;维生素 K 拮抗剂 3 例,直接 OAC 15 例)报告基线时使用了 OAC。在 OAC 组中,EVT 与更好的临床疗效无关(EVT 6 [4-6] vs MM 5 [4-6],调整后的广义赔率为 0.89 [0.53-1.50]),但在未使用 OAC 的患者中,EVT 的疗效显著更好(EVT 4 [3-6] vs MM 5 [4-6],调整后的广义赔率为 1.87 [1.45-2.40],P = 0.02)。OAC 组合并症较多,包括心房颤动(70% vs 17%)、充血性心力衰竭(28% vs 10%)和高血压(87% vs 72%),这表明虚弱程度增加。然而,在对这些合并症进行调整后,结果是一致的,而且无论使用哪种 OACs,结果都相似。虽然接受EVT治疗的OAC组出血率更高(OAC组为86%,无OAC组为70%),但在EVT组和MM组使用OAC时均未观察到实质出血或症状性颅内出血。虽然我们没有发现证据表明这种效应是由于出血过多或受到潜在心脏病或年龄偏大的影响,但不能仅凭使用 OAC 就将患者排除在 EVT 之外。在做出个体化治疗决定时,应考虑基线合并症和缺血性损伤程度。ann neurol 2024.
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引用次数: 0
Recurrent Posterior Circulation Infarction Caused by Vertebral Artery Dissection Secondary to Atlas Hypoplasia 继发于寰椎发育不良的椎动脉夹层引起的复发性后循环梗死。
IF 8.1 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-07-20 DOI: 10.1002/ana.27036
Ying Yu MD, Zhikai Hou MD, Jiabao Yang MD, Ning Ma MD
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引用次数: 0
Low-Dose Interleukin-2 Reverses Traumatic Brain Injury-Induced Cognitive Deficit and Pain in a Murine Model 低剂量白细胞介素-2可逆转创伤性脑损伤引起的认知缺陷和疼痛
IF 8.1 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-07-20 DOI: 10.1002/ana.26998
Katherine Czerpaniak BS, Leandro Flores do Nascimento PhD, Tingting Guo PhD, Jintao Zhang MD, PhD, Xuemei Liu MS, Mojdeh Sarzaeim MD, Zachary D. Fine BS, Yu-Qing Cao PhD

Objective

Despite the high prevalence, mild traumatic brain injury (mTBI)-induced chronic headache and cognitive deficits are poorly understood and lack effective treatments. Low-dose interleukin-2 (LD-IL-2) treatment soon after mTBI or overexpressing IL-2 in brain astrocytes prior to injury protects mice from developing post-traumatic headache (PTH)-related behaviors and cognitive decline. The present study addresses a clinically relevant knowledge gap: whether LD-IL-2 treatment long after the initial injury is still effective for chronic PTH and cognitive deficits.

Methods

mTBI was induced by a noninvasive closed-head weight drop method. LD-IL-2 was administered 4–6 weeks post-mTBI to assess its effects on chronic PTH-related facial mechanical hypersensitivity as well as mTBI-induced impairment in novel object recognition and object location tests. Endogenous regulatory T (Treg) cells were depleted to investigate the mechanism of action of LD-IL-2.

Results

Delayed LD-IL-2 treatment abolished chronic PTH-related behaviors. It also completely reversed mTBI-induced cognitive impairment in both male and female mice. Treg cell depletion not only prolonged PTH-related behaviors but also abolished the effects of LD-IL-2. Interestingly, LD-IL-2 treatment significantly increased the number of Treg cells in dura but not in brain tissues.

Interpretation

These results suggest that the beneficial effects of LD-IL-2 treatment are mediated through the expansion of meningeal Treg cells. Collectively, our study identifies Treg as a cellular target and LD-IL-2 as a promising therapy for both chronic PTH and mTBI-induced cognitive impairment for both males and females, with a wide therapeutic time window and the potential of reducing polypharmacy in mTBI treatment. ANN NEUROL 2024;96:508–525

目的:轻度创伤性脑损伤(mTBI)引起的慢性头痛和认知障碍尽管发病率很高,但人们对其了解甚少,也缺乏有效的治疗方法。轻微创伤性脑损伤后不久进行低剂量白细胞介素-2(LD-IL-2)治疗或在受伤前在脑星形胶质细胞中过表达 IL-2 可保护小鼠免于出现创伤后头痛(PTH)相关行为和认知能力下降。本研究填补了临床相关知识的空白:在初次损伤后很长时间,LD-IL-2 治疗是否仍能有效治疗慢性 PTH 和认知障碍。方法:通过无创闭头负重法诱导mTBI,在mTBI后4-6周给药LD-IL-2,以评估其对慢性PTH相关面部机械过敏以及mTBI诱导的新物体识别和物体定位测试障碍的影响。为了研究LD-IL-2的作用机制,对内源性调节性T(Treg)细胞进行了清除:结果:延迟LD-IL-2治疗可消除慢性PTH相关行为。结果:延迟LD-IL-2治疗可消除慢性PTH相关行为,还可完全逆转mTBI诱导的雌雄小鼠认知障碍。Treg细胞耗竭不仅延长了PTH相关行为,而且还取消了LD-IL-2的作用。有趣的是,LD-IL-2治疗能显著增加硬脑膜中Treg细胞的数量,但不能增加脑组织中Treg细胞的数量:这些结果表明,LD-IL-2 治疗的有益效应是通过脑膜 Treg 细胞的扩增介导的。总之,我们的研究发现,Treg是一种细胞靶点,LD-IL-2是一种治疗慢性PTH和mTBI诱发的认知障碍的有前途的疗法,无论对男性还是女性,都具有广泛的治疗时间窗和减少mTBI治疗中多药并用的潜力。ann neurol 2024.
{"title":"Low-Dose Interleukin-2 Reverses Traumatic Brain Injury-Induced Cognitive Deficit and Pain in a Murine Model","authors":"Katherine Czerpaniak BS,&nbsp;Leandro Flores do Nascimento PhD,&nbsp;Tingting Guo PhD,&nbsp;Jintao Zhang MD, PhD,&nbsp;Xuemei Liu MS,&nbsp;Mojdeh Sarzaeim MD,&nbsp;Zachary D. Fine BS,&nbsp;Yu-Qing Cao PhD","doi":"10.1002/ana.26998","DOIUrl":"10.1002/ana.26998","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Despite the high prevalence, mild traumatic brain injury (mTBI)-induced chronic headache and cognitive deficits are poorly understood and lack effective treatments. Low-dose interleukin-2 (LD-IL-2) treatment soon after mTBI or overexpressing IL-2 in brain astrocytes prior to injury protects mice from developing post-traumatic headache (PTH)-related behaviors and cognitive decline. The present study addresses a clinically relevant knowledge gap: whether LD-IL-2 treatment long after the initial injury is still effective for chronic PTH and cognitive deficits.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>mTBI was induced by a noninvasive closed-head weight drop method. LD-IL-2 was administered 4–6 weeks post-mTBI to assess its effects on chronic PTH-related facial mechanical hypersensitivity as well as mTBI-induced impairment in novel object recognition and object location tests. Endogenous regulatory T (Treg) cells were depleted to investigate the mechanism of action of LD-IL-2.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Delayed LD-IL-2 treatment abolished chronic PTH-related behaviors. It also completely reversed mTBI-induced cognitive impairment in both male and female mice. Treg cell depletion not only prolonged PTH-related behaviors but also abolished the effects of LD-IL-2. Interestingly, LD-IL-2 treatment significantly increased the number of Treg cells in dura but not in brain tissues.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>These results suggest that the beneficial effects of LD-IL-2 treatment are mediated through the expansion of meningeal Treg cells. Collectively, our study identifies Treg as a cellular target and LD-IL-2 as a promising therapy for both chronic PTH and mTBI-induced cognitive impairment for both males and females, with a wide therapeutic time window and the potential of reducing polypharmacy in mTBI treatment. ANN NEUROL 2024;96:508–525</p>\u0000 </section>\u0000 </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141730833","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
Cerebrospinal Fluid Cytokine and Chemokine Profiles in Central Nervous System Sarcoidosis: Diagnostic and Immunopathologic Insights 中枢神经系统肉样瘤病的脑脊液细胞因子和趋化因子谱:诊断和免疫病理学的启示。
IF 8.1 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-07-19 DOI: 10.1002/ana.27024
Georgios Mangioris MD, Sean J. Pittock MD, Binxia Yang PhD, James P. Fryer MS, William S. Harmsen MS, Divyanshu Dubey MBBS, Eoin P. Flanagan MB, BCh, Sebastian A. Lopez-Chiriboga MD, Andrew McKeon MB, BCh, John R. Mills PhD, Ivana Vodopivec MD, PhD, W. Oliver Tobin MB, BCh, BAO, PhD, Michel Toledano MD, Allen J. Aksamit MD, Anastasia Zekeridou MD, PhD

Objective

To evaluate the cerebrospinal fluid (CSF) cytokine/chemokine profile of central nervous system (CNS) neurosarcoidosis (NS), and its utility in differential diagnosis, treatment, and prognostication.

Methods

In this case–control study, we validated 17 cytokines/chemokines (interleukin [IL]-1-beta, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p70, IL-13, IL-17A, BAFF, IL-8/CXCL8, CXCL9, CXCL10, CXCL13, GM-CSF, interferon-gamma, and tumor necrosis factor [TNF]-alpha) in a multiplexed automated immunoassay system (ELLA; Bio-Techne, Minneapolis, MN, USA), and assessed them in CSF and serum of symptomatic patients with probable or definite CNS NS (01/2011–02/2023) with gadolinium enhancement and/or CSF pleocytosis. Patients with multiple sclerosis, primary CNS lymphoma, aquaporin-4 immunoglobulin G positivity, non-inflammatory disorders, and healthy individuals were used as controls.

Results

A total of 32 NS patients (59% women; median age, 59 years [19–81]) were included; concurrent sera were available in 12. CSF controls consisted of 26 multiple sclerosis, 8 primary CNS lymphoma, 84 aquaporin-4 immunoglobulin G positive, and 34 patients with non-inflammatory disorders. Gadolinium enhancement was present in 31 of 32 NS patients, and CSF pleocytosis in 27 of 32 (84%). CSF IL-2, IL-6, IL-10, IL-13, BAFF, IL-8/CXCL8, CXCL9, CXCL10, CXCL13, GM-CSF, interferon-gamma, and TNF-alpha levels were significantly higher in NS patients compared with non-inflammatory controls (p ≤ 0.02); elevations were more common in CSF than serum. Concurrent elevation of IL-6, CXCL9, CXCL10, GM-CSF, interferon-gamma, and TNF-alpha was present in 18 of 32 NS patients, but only in 1 control. Elevated IL-6, IL-10, IL-13, CXCL9, CXL10, GM-CSF, and TNF-alpha associated with measures of disease activity.

Interpretation

NS CSF cytokine/chemokine profiles suggest T cell (mainly T helper cell type 1), macrophage, and B-cell involvement. These signatures aid in NS diagnosis, indicate disease activity, and suggest therapeutic avenues. ANN NEUROL 2024;96:704–714

目的评估中枢神经系统(CNS)神经肉芽肿病(NS)的脑脊液(CSF)细胞因子/趋化因子谱,及其在鉴别诊断、治疗和预后中的作用:在这项病例对照研究中,我们在多重自动免疫分析系统(ELLA.Bio-Techne,明尼苏达州)中验证了 17 种细胞因子/趋化因子(白细胞介素 [IL]-1-beta、IL-2、IL-4、IL-5、IL-6、IL-10、IL-12p70、IL-13、IL-17A、BAFF、IL-8/CXCL8、CXCL9、CXCL10、CXCL13、GM-CSF、γ 干扰素和肿瘤坏死因子 [TNF]- α);Bio-Techne,Minneapolis,MN,USA),并对可能或确定患有中枢神经系统疾病(01/2011-02/2023)、伴有钆增强和/或脑脊液多细胞的有症状患者的脑脊液和血清进行评估。多发性硬化症、原发性中枢神经系统淋巴瘤、水光素-4免疫球蛋白G阳性、非炎症性疾病患者和健康人作为对照:共纳入 32 名 NS 患者(59% 为女性;中位年龄为 59 岁 [19-81]),其中 12 人有同期血清。CSF 对照组包括 26 名多发性硬化症患者、8 名原发性中枢神经系统淋巴瘤患者、84 名水肿素-4 免疫球蛋白 G 阳性患者和 34 名非炎症性疾病患者。32 名 NS 患者中有 31 人出现钆增强,32 人中有 27 人(84%)出现 CSF 多形性。与非炎症性对照组相比,NS 患者的 CSF IL-2、IL-6、IL-10、IL-13、BAFF、IL-8/CXCL8、CXCL9、CXCL10、CXCL13、GM-CSF、γ 干扰素和 TNF-α 水平显著升高(P ≤ 0.02);CSF 水平升高比血清水平升高更为常见。32 例 NS 患者中有 18 例同时出现 IL-6、CXCL9、CXCL10、GM-CSF、γ 干扰素和 TNF-α 升高,但只有 1 例对照组出现这种情况。IL-6、IL-10、IL-13、CXCL9、CXL10、GM-CSF和TNF-α的升高与疾病活动相关:NS CSF细胞因子/趋化因子图谱提示T细胞(主要是T辅助细胞1型)、巨噬细胞和B细胞受累。这些特征有助于 NS 诊断、显示疾病活动性并提示治疗途径。ann neurol 2024.
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引用次数: 0
Medical School Regulatory Compliance Burdens for the Physician-Scientist 医学院对医生-科学家的法规遵从负担。
IF 8.1 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-07-18 DOI: 10.1002/ana.27020
S. Thomas Carmichael MD, PhD

Medical school research faculty is increasingly required to complete more comprehensive and time consuming compliance steps for regulatory oversight. These relate to animal studies, information technology, biosafety, and human resources. For physician-scientists, the additional role in clinical care adds to these research areas with regulatory compliance in patient care and ever-growing web trainings. The sum of all these compliance regimes is a considerable time and cost burden, diminished research performance, and disengagement of faculty from colleagues, collaborations, and institutions. Many research and clinical compliance processes were put in place, often using legacy systems, in well-meaning attempts to address straightforward regulations in humane animal care, safe use of biological agents, and medical care delivery. However, their accumulation and negative impact on faculty performance demand time, energy, and resources that impact academic productivity. There are solutions to a relentlessly increasing regulatory load for research faculty, which involve vertical integration, convergence, and performance assessment in medical school and health system compliance regimes. ANN NEUROL 2024;96:417–422

医学院研究人员越来越多地被要求完成更全面、更耗时的合规步骤,以接受监管。这些步骤涉及动物研究、信息技术、生物安全和人力资源。对于医生科学家来说,除了这些研究领域外,他们还需要在临床护理中扮演额外的角色,遵守病人护理方面的法规,并接受不断增加的网络培训。所有这些合规制度的总和是相当大的时间和成本负担,降低了研究绩效,并使教师脱离同事、合作和机构。许多研究和临床合规流程都是在善意的尝试下建立起来的,通常使用的是传统系统,以应对人道动物护理、生物制剂的安全使用和医疗服务方面的直接规定。然而,这些问题的累积和对教师绩效的负面影响需要时间、精力和资源,从而影响了学术生产力。要解决科研人员不断增加的法规负担,有一些解决方案,其中涉及医学院和卫生系统合规制度的纵向整合、趋同和绩效评估。ann neurol 2024.
{"title":"Medical School Regulatory Compliance Burdens for the Physician-Scientist","authors":"S. Thomas Carmichael MD, PhD","doi":"10.1002/ana.27020","DOIUrl":"10.1002/ana.27020","url":null,"abstract":"<p>Medical school research faculty is increasingly required to complete more comprehensive and time consuming compliance steps for regulatory oversight. These relate to animal studies, information technology, biosafety, and human resources. For physician-scientists, the additional role in clinical care adds to these research areas with regulatory compliance in patient care and ever-growing web trainings. The sum of all these compliance regimes is a considerable time and cost burden, diminished research performance, and disengagement of faculty from colleagues, collaborations, and institutions. Many research and clinical compliance processes were put in place, often using legacy systems, in well-meaning attempts to address straightforward regulations in humane animal care, safe use of biological agents, and medical care delivery. However, their accumulation and negative impact on faculty performance demand time, energy, and resources that impact academic productivity. There are solutions to a relentlessly increasing regulatory load for research faculty, which involve vertical integration, convergence, and performance assessment in medical school and health system compliance regimes. ANN NEUROL 2024;96:417–422</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141632078","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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