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Correction to Impact of paramagnetic rim lesions on disability and race in multiple sclerosis: mediation analysis. 更正为《顺磁性边缘病变对多发性硬化症患者残疾和种族的影响:中介分析》。
IF 4.4 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-11-01 Epub Date: 2024-10-07 DOI: 10.1002/acn3.52223
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引用次数: 0
Heart meets brain: A 25-year-old with a constellation of neurologic symptoms and heart failure. 心脑交汇:一名患有神经系统症状和心力衰竭的 25 岁患者。
IF 4.4 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-11-01 Epub Date: 2024-10-23 DOI: 10.1002/acn3.52196
Noellie Rivera Torres, Rohini Samudralwar, Joseph Berger
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引用次数: 0
Progressive myoclonic ataxia as an initial symptom of typical type I sialidosis with NEU1 mutation. 进行性肌阵挛性共济失调是典型的 I 型神经鞘磷脂病(NEU1 基因突变)的最初症状。
IF 4.4 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-11-01 Epub Date: 2024-10-31 DOI: 10.1002/acn3.52212
Jingjing Lin, Yun-Lu Li, Bo-Li Chen, Hui-Zhen Su, Yi-Heng Zeng, Rui-Huang Zeng, Yu-Duo Zhang, Ru-Kai Chen, Nai-Qing Cai, Yi-Kun Chen, Ru-Ying Yuan, Jun-Yi Jiang, Xiang-Ping Yao, Ning Wang, Wan-Jin Chen, Kang Yang

Objective: Expand genetic screening for atypical Type I sialidosis (ST-1) could address its underdiagnosed in both progressive myoclonic ataxia (PMA) and ataxia patients. To evaluate the potential founder effect of mutation in the population.

Methods: We enrolled 231 patients with PMA or ataxia from the First Affiliated Hospital of Fujian Medical University. Through Whole Exome Sequencing and Sanger sequencing, we identified the causative gene in patients. Haplotype analysis was employed to explore a potential founder effect of the NEU1 c.544A>G mutation.

Results: A total of 31 patients from 23 unrelated families were genetically diagnosed with ST-1. A significant 80.6% of these patients were homozygous for the c.544A>G mutation. We discovered six different NEU1 variants, including two novel mutations: c.951_968del and c.517T>G. The mean age of onset was 18.0 ± 7.1 years. The clinical spectrum of ST-1 featured ataxia and myoclonus as the most common initial symptoms. Over 40% suffered from controlled generalized tonic-clonic seizures. Mobility and independence varied greatly across the cohort. Cherry-red spots were rare, occurring in just 9.5% (2/21) of patients. Brain MRIs were typically unremarkable, except for two patients with unusual findings. EEGs showed diffuse paroxysmal activity in 17 patients. The c.544A>G mutation in NEU1 is a founder variant in Fujian, with a unique haplotype prevalent in East Asians.

Interpretation: ST-1 should be suspected in patients with PMA or ataxia in Southeast China, even without macular cherry-red spots and seizures, and the premier test could be a variant screening of the founder variant NEU1 c.544A>G.

目的:扩大非典型Ⅰ型硅铝酸盐症(ST-1)的基因筛查可解决进行性肌阵挛性共济失调(PMA)和共济失调患者诊断不足的问题。评估突变在人群中的潜在奠基效应:方法:我们从福建医科大学附属第一医院招募了231名进行性肌阵挛性共济失调(PMA)或共济失调患者。通过全外显子组测序和 Sanger 测序,我们确定了患者的致病基因。采用单倍型分析探讨了NEU1 c.544A>G突变的潜在奠基效应:结果:共有来自 23 个无血缘关系家庭的 31 名患者被基因诊断为 ST-1。其中80.6%的患者为c.544A>G突变的同源基因。我们发现了六种不同的 NEU1 变异,包括两种新型突变:c.951_968del 和 c.517T>G。ST-1的临床表现以共济失调和肌阵挛为最常见的首发症状。40%以上的患者会出现控制性全身强直-阵挛发作。患者的活动能力和独立性差异很大。樱桃红色斑很少见,仅占患者总数的9.5%(2/21)。除两名患者有异常发现外,脑部核磁共振成像通常无异常。17 名患者的脑电图显示有弥漫性阵发性活动。NEU1的c.544A>G突变是福建的创始变异,其独特的单倍型在东亚人中很普遍:在中国东南地区,即使没有黄斑樱桃红色斑点和癫痫发作,PMA 或共济失调患者也应怀疑 ST-1,而首要的检测方法可能是对 NEU1 c.544A>G 的创始变异进行变异筛查。
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引用次数: 0
Association of multiple trace metals in scalp hair with glioma risk: the mediating role of inflammation. 头皮毛发中多种微量金属与胶质瘤风险的关系:炎症的中介作用。
IF 4.4 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-11-01 Epub Date: 2024-09-21 DOI: 10.1002/acn3.52210
Lingjun Yan, Honghai You, Huiying Wang, Chenyu Ding, Baochang He, Jing Wang, Wenhua Fang, Yuanxiang Lin, Dezhi Kang, Fa Chen

Objective: To explore the relationship between 35 trace metals in scalp hair and the glioma risk as well as the potential mediating roles of 27 plasma inflammatory cytokines.

Methods: A case-control study involving 228 participants was performed in southeastern China. Trace metals in scalp hair were analyzed using inductively coupled plasma mass spectrometry, and multiplex cytokines were detected based on Luminex® technology. The least absolute shrinkage and selection operator (LASSO) regression in combination with four machine learning methods were used to select trace metals associated with gliomas. The joint exposure effect of trace metals was estimated using the generalized weighted quantile sum (gWQS) regression and quantile-based g-computation (qgcomp) algorithms.

Results: Both LASSO regression and random forest algorithms identified five trace metals (gadolinium [Gd], lithium [Li], thulium [Tm], thorium [Th], and molybdenum [Mo]) associated with gliomas. After adjustments for potential confounders, Gd (odds ratio [OR] = 2.84, 95% confidence interval [CI]: 1.89-4.43) and Li (OR = 1.77, 95% CI: 1.04-3.02) concentrations were positively associated with glioma risk, while Tm (OR = 0.36, 95% CI: 0.17-0.73) and Th (OR = 0.45, 95% CI: 0.28-0.71) exhibited inverse associations. Both gWQS and qgcomp algorithms showed Gd contributed most to the mixture effect. Moreover, there was a significant interaction between Gd and Tm or Th on glioma risk (p < 0.05). Notably, granulocyte-macrophage colony-stimulating factor (GM-CSF) mediated the association between Gd exposure and glioma risk by 25.75%.

Interpretation: These findings suggest potential associations of certain trace metals, especially for Gd, with glioma risk, and may provide new insights into the mechanisms underlying from an inflammatory response perspective.

目的探讨头皮毛发中35种微量金属与胶质瘤风险之间的关系,以及27种血浆炎症细胞因子的潜在中介作用:方法: 在中国东南部进行了一项病例对照研究,共有228人参与。采用电感耦合等离子体质谱法分析了头皮毛发中的痕量金属,并基于 Luminex® 技术检测了多重细胞因子。采用最小绝对收缩和选择算子(LASSO)回归法结合四种机器学习方法,筛选出与胶质瘤相关的痕量金属。使用广义加权量化和(gWQS)回归和基于量化的g计算(qgcomp)算法估算了痕量金属的联合暴露效应:结果:LASSO回归和随机森林算法均确定了与胶质瘤相关的五种痕量金属(钆[Gd]、锂[Li]、铥[Tm]、钍[Th]和钼[Mo])。在对潜在混杂因素进行调整后,钆(比值比 [OR] = 2.84,95% 置信区间 [CI]:1.89-4.43)和锂(比值比 [OR] = 1.77,95% 置信区间 [CI]:1.04-3.02)浓度与胶质瘤风险呈正相关,而铥(比值比 [OR] = 0.36,95% 置信区间 [CI]:0.17-0.73)和钍(比值比 [OR] = 0.45,95% 置信区间 [CI]:0.28-0.71)浓度与胶质瘤风险呈反相关。gWQS 和 qgcomp 算法都显示,钆对混合物效应的影响最大。此外,Gd 与 Tm 或 Th 之间对胶质瘤风险有明显的交互作用(p 解释:这些研究结果表明,某些痕量金属,尤其是钆,可能与胶质瘤风险有关,并可能从炎症反应的角度为了解其潜在机制提供新的视角。
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引用次数: 0
Plasma exchange with albumin replacement for Alzheimer's disease treatment induced changes in serum and cerebrospinal fluid inflammatory mediator levels. 用白蛋白替代血浆交换治疗阿尔茨海默病会引起血清和脑脊液炎症介质水平的变化。
IF 4.4 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-30 DOI: 10.1002/acn3.52235
Ricardo Gonzalo, Carla Minguet, Ana María Ortiz, María Isabel Bravo, Oscar L López, Mercè Boada, Agustín Ruiz, Montserrat Costa

Objective: There is extensive literature indicating that inflammatory pathways are affected in Alzheimer's disease (AD). We examined whether plasma exchange with albumin replacement (PE-Alb) can impact the inflammatory status of AD patients and alter the relationship between inflammatory mediators and cognitive measures.

Methods: Serum and cerebrospinal fluid (CSF) samples from 142 AD patients participating in the AMBAR trial (14-month schedule of PE-Alb treatment vs. placebo [sham PE-Alb]) were analyzed for changes from baseline for 19 inflammatory mediators (6 inflammatory cytokines, 9 chemokines, and 4 vascular injury indicators) at representative time points across the AMBAR study (lasting effects) as well as in pre- versus post-PE-Alb procedure (acute effects). Association between mediator changes and clinical outcomes reported in the AMBAR study (cognitive, functional, behavioral function, and global change tests) was assessed.

Results: PE-Alb significantly reduced IFN-γ, eotaxin, MIP-1α and ICAM-1 levels in serum, and eotaxin-3 and MIP-1β levels in CSF, at various time points during treatment (p < 0.05; false discovery rate-corrected). Vascular injury indicators were the mediators mostly affected by post- versus pre-PE-Alb level reduction. Increased serum MIP-1α levels were associated with worsening in ADAS-Cog, CDR-sb, and ADCS-CGIC scores in the placebo group, but not in the PE-Alb-treated group.

Interpretation: Peripheral intervention could affect AD by reducing inflammatory mediators in both peripheral and central compartments. Changes in MIP-1α due to PE-Alb were associated with changes in clinical outcomes.

目的:大量文献表明,阿尔茨海默病(AD)的炎症通路受到影响。我们研究了血浆置换白蛋白(PE-Alb)是否会影响阿尔茨海默病患者的炎症状态,并改变炎症介质与认知指标之间的关系:分析了142名参与AMBAR试验(14个月的PE-Alb治疗计划与安慰剂[假PE-Alb]对比)的AD患者的血清和脑脊液(CSF)样本,以了解19种炎症介质(6种炎症细胞因子、9种趋化因子和4种血管损伤指标)在AMBAR研究的代表性时间点(持久效应)以及PE-Alb治疗前与治疗后(急性效应)的基线变化。评估了介导因子变化与 AMBAR 研究中报告的临床结果(认知、功能、行为功能和整体变化测试)之间的关联:结果:在治疗过程中的不同时间点,PE-Alb 能明显降低血清中 IFN-γ、共济失调素、MIP-1α 和 ICAM-1 的水平,以及脑脊液中共济失调素-3 和 MIP-1β 的水平(p 解释:PE-Alb 能明显降低血清中 IFN-γ、共济失调素、MIP-1α 和 ICAM-1 的水平:外周干预可通过减少外周和中枢分区的炎症介质来影响 AD。PE-Alb引起的MIP-1α的变化与临床结果的变化有关。
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引用次数: 0
Identification of fibrinogen as a plasma protein binding partner for lecanemab biosimilar IgG. 确定纤维蛋白原是莱卡奈单抗生物类似物 IgG 的血浆蛋白结合伙伴。
IF 4.4 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-30 DOI: 10.1002/acn3.52227
Jean-Pierre Bellier, Andrea M Román Viera, Caitlyn Christiano, Juliana A U Anzai, Stephanie Moreno, Emily C Campbell, Lucas Godwin, Amy Li, Alan Y Chen, Sarah M Alam, Adriana Saba, Han Bin Yoo, Hyun-Sik Yang, Jasmeer P Chhatwal, Dennis J Selkoe, Lei Liu

Objective: Recombinant monoclonal therapeutic antibodies like lecanemab, which target amyloid beta in Alzheimer's disease, offer a promising approach for modifying the disease progression. Due to its relatively short half-life, lecanemab administered as a bi-monthly infusion (typically 10 mg/kg) has a relatively brief half-life. Interaction with abundant plasma proteins binder in the bloodstream can affect pharmacokinetics of drugs, including their half-life. In this study, we investigated potential plasma protein binding (PPB) interaction to lecanemab using lecanemab biosimilar.

Methods: Lecanemab biosimilar used in this study was based on publicly available sequences. ELISA and western blotting were used to assess lecanemab biosimilar immunoreactivity in the fractions of human plasma obtained through size exclusion chromatography. The binding of lecanemab biosimilar to candidate plasma binders was confirmed by western blotting, ELISA, and surface plasmon resonance analysis.

Results: Using a combination of equilibrium dialysis, ELISA, and western blotting in human plasma, we first describe the presence of likely PPB partners to lecanemab biosimilar and then identify fibrinogen as one of them. Utilizing surface plasmon resonance, we confirmed that lecanemab biosimilar does bind to fibrinogen, although with lower affinity than to monomeric amyloid beta.

Interpretation: In the context of lecanemab therapy, these results imply that fibrinogen levels could impact the levels of free antibodies in the bloodstream and that fibrinogen might serve as a reservoir for lecanemab. More broadly, these results indicate that PPB may be an important consideration when clinically utilizing therapeutic antibodies in neurodegenerative disease.

目的:重组单克隆治疗抗体(如莱卡内单抗)以阿尔茨海默病中的β淀粉样蛋白为靶点,为改变疾病进展提供了一种前景广阔的方法。由于莱卡奈单抗的半衰期相对较短,因此每两个月输注一次(通常为 10 毫克/千克),其半衰期也相对较短。与血液中丰富的血浆蛋白粘合剂相互作用会影响药物的药代动力学,包括其半衰期。在这项研究中,我们使用莱卡奈单抗生物仿制药研究了莱卡奈单抗与血浆蛋白结合(PPB)的潜在相互作用:方法:本研究中使用的来卡尼单抗生物仿制药是基于可公开获得的序列。使用酶联免疫吸附试验(ELISA)和免疫印迹法(Western Blotting)评估通过尺寸排阻色谱法获得的人体血浆馏分中莱卡尼单抗生物类似物的免疫活性。Western 印迹、ELISA 和表面等离子体共振分析证实了 Lecanemab 生物类似药与候选血浆结合剂的结合:利用平衡透析、酶联免疫吸附试验(ELISA)和Western印迹分析法,我们首先描述了莱卡奈单抗生物类似物可能存在的PPB伙伴,然后确定纤维蛋白原是其中之一。利用表面等离子体共振,我们证实了莱卡奈单抗生物类似物确实与纤维蛋白原结合,尽管其亲和力低于与单体淀粉样蛋白β的结合力:在莱卡奈单抗治疗中,这些结果意味着纤维蛋白原水平会影响血液中游离抗体的水平,纤维蛋白原可能成为莱卡奈单抗的储库。更广泛地说,这些结果表明,在临床上利用治疗性抗体治疗神经退行性疾病时,PPB可能是一个重要的考虑因素。
{"title":"Identification of fibrinogen as a plasma protein binding partner for lecanemab biosimilar IgG.","authors":"Jean-Pierre Bellier, Andrea M Román Viera, Caitlyn Christiano, Juliana A U Anzai, Stephanie Moreno, Emily C Campbell, Lucas Godwin, Amy Li, Alan Y Chen, Sarah M Alam, Adriana Saba, Han Bin Yoo, Hyun-Sik Yang, Jasmeer P Chhatwal, Dennis J Selkoe, Lei Liu","doi":"10.1002/acn3.52227","DOIUrl":"10.1002/acn3.52227","url":null,"abstract":"<p><strong>Objective: </strong>Recombinant monoclonal therapeutic antibodies like lecanemab, which target amyloid beta in Alzheimer's disease, offer a promising approach for modifying the disease progression. Due to its relatively short half-life, lecanemab administered as a bi-monthly infusion (typically 10 mg/kg) has a relatively brief half-life. Interaction with abundant plasma proteins binder in the bloodstream can affect pharmacokinetics of drugs, including their half-life. In this study, we investigated potential plasma protein binding (PPB) interaction to lecanemab using lecanemab biosimilar.</p><p><strong>Methods: </strong>Lecanemab biosimilar used in this study was based on publicly available sequences. ELISA and western blotting were used to assess lecanemab biosimilar immunoreactivity in the fractions of human plasma obtained through size exclusion chromatography. The binding of lecanemab biosimilar to candidate plasma binders was confirmed by western blotting, ELISA, and surface plasmon resonance analysis.</p><p><strong>Results: </strong>Using a combination of equilibrium dialysis, ELISA, and western blotting in human plasma, we first describe the presence of likely PPB partners to lecanemab biosimilar and then identify fibrinogen as one of them. Utilizing surface plasmon resonance, we confirmed that lecanemab biosimilar does bind to fibrinogen, although with lower affinity than to monomeric amyloid beta.</p><p><strong>Interpretation: </strong>In the context of lecanemab therapy, these results imply that fibrinogen levels could impact the levels of free antibodies in the bloodstream and that fibrinogen might serve as a reservoir for lecanemab. More broadly, these results indicate that PPB may be an important consideration when clinically utilizing therapeutic antibodies in neurodegenerative disease.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142542304","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Rethinking antisense oligonucleotide therapeutics for amyotrophic lateral sclerosis. 反思肌萎缩侧索硬化症的反义寡核苷酸疗法。
IF 4.4 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-29 DOI: 10.1002/acn3.52234
Daisuke Ito, Kensuke Okada

Antisense oligonucleotides, which are used to silence target genes, are gaining attention as a novel drug discovery modality for proteinopathies. However, while clinical trials for neurodegenerative diseases like amyotrophic lateral sclerosis have been conducted in recent years, the results have not always been favorable. The results from a Phase III trial of the antisense oligonucleotide, that is, tofersen, which targets SOD1 mRNA, showed decreased levels of cerebrospinal fluid SOD1 and plasma neurofilament light chain but no improvements in primary clinical endpoint. Moreover, case reports pertaining to patients with amyotrophic lateral sclerosis carrying FUS and C9orf72 mutations who received antisense oligonucleotide-based treatments have demonstrated a notable reduction in the targeted protein (thus providing the proof of mechanism) but with no discernible clinical benefits. There are several possible reasons why antisense oligonucleotides knockdown fails to achieve proof of concept, which need to be addressed: on-target adverse effects resulting from the loss of function of target gene and irreversible neuronal death cascade due to toxic protein accumulation, among other factors. This review provides an overview of the current status and discusses the prospects of antisense oligonucleotides treatment for amyotrophic lateral sclerosis.

反义寡核苷酸可用于抑制靶基因,作为一种治疗蛋白质病的新型药物发现方式,它正受到越来越多的关注。然而,虽然近年来针对肌萎缩侧索硬化症等神经退行性疾病开展了临床试验,但结果并不总是令人满意。针对 SOD1 mRNA 的反义寡核苷酸(即托福森)的 III 期试验结果显示,脑脊液 SOD1 和血浆神经丝轻链的水平有所下降,但主要临床终点没有改善。此外,有关携带 FUS 和 C9orf72 突变的肌萎缩侧索硬化症患者接受反义寡核苷酸治疗的病例报告显示,靶蛋白明显减少(从而提供了机制证明),但没有明显的临床疗效。反义寡核苷酸敲除未能实现概念验证可能有几个原因,需要加以解决:靶基因功能缺失导致的靶向不良反应、毒性蛋白积累导致的不可逆神经元死亡级联等。本综述概述了反义寡核苷酸治疗肌萎缩侧索硬化症的现状并探讨了其前景。
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引用次数: 0
Safety and efficacy of intravenous thrombolytic therapy in the extended window up to 24 hours: A systematic review and meta-analysis. 静脉溶栓疗法在延长至 24 小时窗口期的安全性和有效性:系统回顾和荟萃分析。
IF 4.4 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-29 DOI: 10.1002/acn3.52239
Omar M Al-Janabi, Seyed Behnam Jazayeri, Michelle A Toruno, Yamama M Mahmood, Sherief Ghozy, Shadi Yaghi, Alejandro A Rabinstein, David F Kallmes

Objective: About 25% of patients with acute ischemic stroke (AIS) present within the intravenous thrombolytic (IVT) therapeutic window of <4.5 h. This study is to elucidate the safety and efficacy of IVT in the extended therapeutic window (ETW) in patients with AIS.

Methods: Using PRISMA guidelines, a systematic review was conducted using PubMed, Embase, and Scopus. A rigorous risk of bias assessment was conducted using the RoB2 tool. Rates of excellent and good functional outcome (mRS 0-1 and mRS 0-2) at 90 days, symptomatic intracranial hemorrhage (sICH), and mortality at 90 days were pooled using generalized linear mixed model and compared with controls. Meta-analyses were conducted employing random-effect models with risk ratio (RR) and 95% confidence intervals (CIs). Subgroup analysis was performed to assess the effect of imaging modalities used for patient selection.

Results: Eight randomized controlled trials (n = 2221, 59% male) were included. At 90 days IVT showed higher rates of functional recovery: mRS 0-1: RR 1.21 95% CI 1.1-1.34, p < 0.001, and mRS 0-2: RR 1.11 95% CI 1.03-1.18, p = 0.004. Rate of mortality at 90 day was not different between groups: RR 1.17 95% CI 0.93-1.48, p = 0.17. However, the rate of sICH was higher among IVT group: RR 2.93 95% CI 1.53-5.6, p = 0.001. Subgroup analysis showed higher mRS 0-1 among patients who were selected based on perfusion imaging (p < 0.05).

Interpretation: The use of IVT in AIS in ETW is beneficial especially with the use of perfusion imaging for patients' selection.

目的约 25% 的急性缺血性卒中(AIS)患者出现在静脉溶栓(IVT)治疗窗内:根据 PRISMA 指南,使用 PubMed、Embase 和 Scopus 进行了系统性回顾。使用 RoB2 工具进行了严格的偏倚风险评估。采用广义线性混合模型对 90 天时的优秀和良好功能预后率(mRS 0-1 和 mRS 0-2)、症状性颅内出血(sICH)和 90 天时的死亡率进行了汇总,并与对照组进行了比较。采用随机效应模型和风险比(RR)及95%置信区间(CI)进行元分析。进行了分组分析,以评估用于选择患者的成像模式的影响:共纳入八项随机对照试验(n = 2221,59% 为男性)。90天后,IVT显示出更高的功能恢复率:mRS 0-1:RR 1.21 95% CI 1.1-1.34,P 解释:对 ETW 中的 AIS 使用 IVT 是有益的,尤其是在使用灌注成像对患者进行选择时。
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引用次数: 0
FDG-PET patterns associate with survival in patients with prion disease. FDG-PET 模式与朊病毒病患者的存活率有关。
IF 4.4 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-29 DOI: 10.1002/acn3.52230
Nick Corriveau-Lecavalier, Yoav D Piura, Brian S Appleby, Dror Shir, Leland R Barnard, Venkatsampath Gogineni, David T Jones, Gregory S Day

Objective: Prion disease classically presents with rapidly progressive dementia, leading to death within months of diagnosis. Advances in diagnostic testing have improved recognition of patients with atypical presentations and protracted disease courses, raising key questions surrounding the relationship between patterns of neurodegeneration and survival. We assessed the contribution of fluorodeoxyglucose (FDG-PET) imaging for this purpose.

Methods: FDG-PET were performed in 40 clinic patients with prion disease. FDG-PET images were projected onto latent factors generated in an external dataset to yield patient-specific eigenvalues. Eigenvalues were input into a clustering algorithm to generate data-driven clusters, which were compared by survival time.

Results: Median age at FDG-PET was 65.3 years (range 23-85). Median time from FDG-PET to death was 3.7 months (range 0.3-19.0). Four data-driven clusters were generated, termed "Neocortical" (n = 7), "Transitional" (n = 12), "Temporo-parietal" (n = 13), and "Deep nuclei" (n = 6). Deep nuclei and transitional clusters had a shorter survival time than the neocortical cluster. Subsequent analyses suggested that this difference was driven by greater hypometabolism of deep nuclei relative to neocortical areas. FDG-PET-patterns were not associated with demographic (age and sex) or clinical (CSF total-tau, 14-3-3) variables.

Interpretation: Greater hypometabolism within deep nuclei relative to neocortical areas associated with more rapid decline in patients with prion disease and vice versa. FDG-PET informs large-scale network physiology and may inform the relationship between spreading pathology and survival in patients with prion disease. Future studies should consider whether FDG-PET may enrich multimodal prion disease prognostication models.

目的:朊病毒病通常表现为快速进展性痴呆,导致患者在确诊后数月内死亡。诊断检测技术的进步提高了对非典型表现和长期病程患者的识别能力,从而提出了围绕神经变性模式与存活率之间关系的关键问题。为此,我们评估了氟脱氧葡萄糖(FDG-PET)成像的作用:方法:我们对 40 名临床朊病毒病患者进行了 FDG-PET。将 FDG-PET 图像投射到外部数据集中生成的潜在因子上,以产生患者特异性特征值。将特征值输入聚类算法,生成数据驱动的聚类,并通过生存时间对这些聚类进行比较:进行 FDG-PET 时的中位年龄为 65.3 岁(23-85 岁不等)。从 FDG-PET 到死亡的中位时间为 3.7 个月(范围 0.3-19.0)。根据数据生成了四个群组,分别称为 "新皮质"(n = 7)、"过渡"(n = 12)、"颞顶叶"(n = 13)和 "深核"(n = 6)。深部核团和过渡核团的存活时间短于新皮层核团。随后的分析表明,这种差异是由于深部核团相对于新皮层区域代谢更低造成的。FDG-PET模式与人口统计学(年龄和性别)或临床(CSF总tau、14-3-3)变量无关:解释:相对于新皮质区域,深部核团内的代谢更低,这与朊病毒病患者更快的衰退有关,反之亦然。FDG-PET为大规模网络生理学提供了信息,并可能为朊病毒病患者扩散病理和生存之间的关系提供信息。未来的研究应考虑FDG-PET是否能丰富多模式朊病毒病预后模型。
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引用次数: 0
Altered exosomal miRNA profiles in patients with paraneoplastic cerebellar degeneration. 副肿瘤性小脑变性患者的外泌体miRNA谱发生变化。
IF 4.4 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-29 DOI: 10.1002/acn3.52232
Eirik Tveit Solheim, Liv Cecilie Vestrheim Thomsen, Line Bjørge, Shamundeeswari Anandan, Elise Peter, Virginie Desestret, Cecilie Totland, Christian A Vedeler

Objective: Patients with ovarian cancer (OC) may develop anti-Yo-associated paraneoplastic cerebellar degeneration (PCD)-a cerebellar ataxia associated with tumor-induced autoimmunity against CDR2 and CDR2L proteins. Dysregulation of circulating exosomal microRNAs (miRNAs) occur in OC. Here, we investigated whether PCD is associated with changes in the exosomal miRNA profiles of OC patients.

Methods: Serum exosomes were isolated from patients with OC (n = 15), patients with OC and anti-Yo-associated PCD (n = 14) and healthy controls (HC, n = 15). Small RNA sequencing was used to identify differentially expressed miRNAs. Receiver operating characteristic curves were used to evaluate biomarker sensitivity and specificity, and miRNA target prediction analysis was employed to elucidate gene targets.

Results: OC patients with PCD exhibited a distinct exosomal miRNA expression profile. We detected 103 differentially expressed exosomal miRNAs in PCD patients compared to OC patients without PCD and 139 differentially expressed exosomal miRNAs compared to controls. Particularly miR-486-5p, miR-4732-5p, miR-98-5p and miR-21-5p exhibited notable sensitivity and specificity for discriminating PCD patients from both OC patients without PCD and healthy controls. miRNA target prediction showed that several of the differentially expressed miRNAs in PCD patients targeted the CDR2 and CDR2L genes.

Interpretation: Our results demonstrate that OC patients with anti-Yo-associated PCD exhibit a distinct exosomal miRNA profile compared to OC patients without PCD. Several of the differentially expressed exosomal miRNAs in PCD patients showed diagnostic potential and may hold relevance for understanding the pathogenesis of PCD.

目的:卵巢癌(OC)患者可能会出现抗-Yo相关的副肿瘤性小脑变性(PCD)--一种与肿瘤诱导的针对CDR2和CDR2L蛋白的自身免疫相关的小脑共济失调。OC中会出现循环外泌体微RNA(miRNA)失调。在此,我们研究了PCD是否与OC患者外泌体miRNA谱的变化有关:方法:从OC患者(n = 15)、OC和抗-Yo相关PCD患者(n = 14)以及健康对照组(HC,n = 15)分离血清外泌体。利用小 RNA 测序鉴定差异表达的 miRNA。利用接收者操作特征曲线评估生物标志物的敏感性和特异性,并采用miRNA靶标预测分析来阐明基因靶标:结果:患有PCD的OC患者表现出独特的外泌体miRNA表达谱。与未患 PCD 的 OC 患者相比,我们在 PCD 患者体内检测到 103 个表达不同的外泌体 miRNA;与对照组相比,我们检测到 139 个表达不同的外泌体 miRNA。特别是 miR-486-5p、miR-4732-5p、miR-98-5p 和 miR-21-5p 在区分 PCD 患者与非 PCD OC 患者和健康对照组方面表现出显著的敏感性和特异性:我们的研究结果表明,与不伴有PCD的OC患者相比,伴有抗-Yo相关PCD的OC患者表现出独特的外泌体miRNA谱。PCD患者体内表达不同的几种外泌体miRNA具有诊断潜力,可能与了解PCD的发病机制有关。
{"title":"Altered exosomal miRNA profiles in patients with paraneoplastic cerebellar degeneration.","authors":"Eirik Tveit Solheim, Liv Cecilie Vestrheim Thomsen, Line Bjørge, Shamundeeswari Anandan, Elise Peter, Virginie Desestret, Cecilie Totland, Christian A Vedeler","doi":"10.1002/acn3.52232","DOIUrl":"https://doi.org/10.1002/acn3.52232","url":null,"abstract":"<p><strong>Objective: </strong>Patients with ovarian cancer (OC) may develop anti-Yo-associated paraneoplastic cerebellar degeneration (PCD)-a cerebellar ataxia associated with tumor-induced autoimmunity against CDR2 and CDR2L proteins. Dysregulation of circulating exosomal microRNAs (miRNAs) occur in OC. Here, we investigated whether PCD is associated with changes in the exosomal miRNA profiles of OC patients.</p><p><strong>Methods: </strong>Serum exosomes were isolated from patients with OC (n = 15), patients with OC and anti-Yo-associated PCD (n = 14) and healthy controls (HC, n = 15). Small RNA sequencing was used to identify differentially expressed miRNAs. Receiver operating characteristic curves were used to evaluate biomarker sensitivity and specificity, and miRNA target prediction analysis was employed to elucidate gene targets.</p><p><strong>Results: </strong>OC patients with PCD exhibited a distinct exosomal miRNA expression profile. We detected 103 differentially expressed exosomal miRNAs in PCD patients compared to OC patients without PCD and 139 differentially expressed exosomal miRNAs compared to controls. Particularly miR-486-5p, miR-4732-5p, miR-98-5p and miR-21-5p exhibited notable sensitivity and specificity for discriminating PCD patients from both OC patients without PCD and healthy controls. miRNA target prediction showed that several of the differentially expressed miRNAs in PCD patients targeted the CDR2 and CDR2L genes.</p><p><strong>Interpretation: </strong>Our results demonstrate that OC patients with anti-Yo-associated PCD exhibit a distinct exosomal miRNA profile compared to OC patients without PCD. Several of the differentially expressed exosomal miRNAs in PCD patients showed diagnostic potential and may hold relevance for understanding the pathogenesis of PCD.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142542303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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Annals of Clinical and Translational Neurology
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