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Subclinical imaging activity in multiple sclerosis patients during war-related psychological stress. 多发性硬化症患者在战争相关心理压力下的亚临床影像活动。
IF 4.4 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-11-06 DOI: 10.1002/acn3.52241
Omri Zveik, Tal Friedman-Korn, Ariel Rechtman, Tal Ganz, Garrick Hoichman, Lyne Shweiki, Dana Ekstein, Adi Vaknin-Dembinsky

Objectives: Psychological stress has been suggested as a contributory factor in the onset and progression of multiple sclerosis (MS). The 7 October 2023 terrorist attacks in Israel caused significant psychological stress, providing a unique context to study its impact on MS activity. This study aims to assess the impact of war-related psychological stress on MS activity using magnetic resonance imaging (MRI) scans and clinical follow-up.

Methods: This observational retrospective case-control study includes 93 patients with MS (pwMS) who had routine annual MRI scans from three periods (7 October 2021 to 7 January 2022; 7 October 2022 to 7 January 2023; and 7 October 2023 to 7 January 2024). Data were collected from medical records and MRI scans at Hadassah Medical Center. MRI scans were classified as active if new or enlarging T2 lesions and/or enhancing T1 lesions were present.

Results: MRI activity significantly increased among pwMS during the first 3 months of the war compared to the corresponding period in the preceding year (11/93 vs. 23/93, P = 0.0139), with an OR of 4.0 (95% confidence interval: 1.29-16.442). pwMS with an EDSS score ≥4 showed a significant increase in MRI activity (P = 0.045), whereas no significant increase was observed in patients with an EDSS score ≤3.5 (P = 0.23). Additionally, MRI activity increased later during the war compared to the previous year (P < 0.0001).

Interpretation: This study provides evidence of increased MRI-detected disease activity in pwMS during periods of war-related psychological stress. Our findings highlight the importance of considering psychological stress in MS management. Healthcare providers should be aware of the potential for increased disease activity in pwMS during extreme stress and may consider more frequent monitoring, including MRI scans, or treatment adjustments during such periods.

目的:心理压力被认为是多发性硬化症(MS)发病和进展的一个促成因素。2023 年 10 月 7 日在以色列发生的恐怖袭击造成了巨大的心理压力,为研究其对多发性硬化症活动的影响提供了独特的背景。本研究旨在利用磁共振成像(MRI)扫描和临床随访评估与战争有关的心理压力对多发性硬化症活动的影响:这项观察性回顾性病例对照研究包括 93 名多发性硬化症患者(pwMS),他们在三个时期(2021 年 10 月 7 日至 2022 年 1 月 7 日;2022 年 10 月 7 日至 2023 年 1 月 7 日;2023 年 10 月 7 日至 2024 年 1 月 7 日)每年进行常规磁共振成像扫描。数据来自哈大沙医疗中心的医疗记录和核磁共振扫描。如果出现新的或增大的 T2 病变和/或增强的 T1 病变,则 MRI 扫描被归类为活动:EDSS评分≥4分的pwMS患者的MRI活动明显增加(P = 0.045),而EDSS评分≤3.5分的患者的MRI活动没有明显增加(P = 0.23)。此外,与前一年相比,核磁共振成像活动在战争后期有所增加(P 解释:本研究提供的证据表明,在与战争有关的心理压力期间,pwMS 的 MRI 检测到的疾病活动增加。我们的研究结果强调了在多发性硬化症管理中考虑心理压力的重要性。医疗服务提供者应意识到,在极端应激期间,pwMS 的疾病活动可能会增加,因此可考虑在此期间进行更频繁的监测(包括 MRI 扫描)或调整治疗方法。
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引用次数: 0
Infantile Krabbe disease (0-12 months), progression, and recommended endpoints for clinical trials. 婴幼儿克拉伯病(0-12 个月)、病情发展和临床试验的推荐终点。
IF 4.4 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-11-05 DOI: 10.1002/acn3.52114
Melissa R Greco, Mabel A Lopez, Maria L Beltran-Quintero, Ecenur Tuc Bengur, Michele D Poe, Maria L Escolar

Objective: Krabbe disease is due to deficiency of galactocerebrosidase, resulting in progressive neurodegeneration due to demyelination. The purpose of this study is to document disease progression in the newly classified infantile-onset (0-12 months). We evaluated the outcomes of hematopoietic stem cell transplantation (HSCT) and described meaningful clinical endpoints.

Methods: Patients with infantile Krabbe disease were prospectively evaluated between 2000 and 2022. All patients underwent comprehensive and standardized protocols. Descriptive statistics and Kaplan-Meier survival curves were used for analysis.

Results: One hundred and thirty-seven children with infantile Krabbe disease were included (68 males and 69 females). Of the 137, 96 were not treated and 41 underwent hematopoietic stem cell transplantation. Twenty-three were asymptomatic and 18 symptomatic. Initial symptoms included irritability, developmental delay or loss of milestones, feeding difficulties, spasticity, and reflux with an average survival of 2.2. Abnormalities in nerve conduction studies, auditory brainstem responses, and brain MRIs were evident in both groups of patients. Age at transplantation and signs and symptoms determined functional outcomes. Symptomatic and asymptomatic transplanted patients showed an increase in galactocerebrosidase and a decrease in psychosine, but did not reach the normal range. The median survival for transplanted symptomatic patients was 5 years while asymptomatic was extended to 15.5 years.

Interpretation: Infantile Krabbe disease with onset before 12 months is rapidly progressive. Irreversible brain damage occurs unless timely HSCT is performed. HSCT does not prevent the progression of peripheral nerve disease. This study can be used to monitor patients and evaluate the effects of future therapies.

目的:克拉伯病是由于缺乏半乳糖脑苷脂酶,导致脱髓鞘引起的进行性神经变性。本研究的目的是记录新分类的婴儿型发病者(0-12 个月)的疾病进展情况。我们评估了造血干细胞移植(HSCT)的结果,并描述了有意义的临床终点:2000年至2022年期间,我们对婴幼儿克拉伯病患者进行了前瞻性评估。所有患者都接受了全面的标准化方案治疗。分析采用了描述性统计和卡普兰-梅耶生存曲线:结果:共纳入137名患有婴儿克拉伯病的儿童(68名男性和69名女性)。在137名患儿中,96名未接受治疗,41名接受了造血干细胞移植。23名无症状,18名有症状。最初的症状包括易怒、发育迟缓或丧失里程碑、喂养困难、痉挛和反流,平均存活时间为2.2天。两组患者的神经传导研究、听觉脑干反应和脑部核磁共振成像均明显异常。移植时的年龄以及体征和症状决定了功能性结果。有症状和无症状的移植患者半乳糖脑苷脂酶升高,精神氨酸降低,但未达到正常范围。无症状移植患者的中位生存期为5年,而无症状患者的中位生存期延长至15.5年:解读:12 个月前发病的婴儿克拉伯病进展迅速。除非及时进行造血干细胞移植,否则会造成不可逆的脑损伤。造血干细胞移植并不能阻止周围神经疾病的进展。这项研究可用于监测患者病情和评估未来疗法的效果。
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引用次数: 0
Medial intracranial carotid artery calcifications and hematoma expansion in deep intracerebral hemorrhage. 颅内颈内动脉钙化和深部脑出血血肿扩大。
IF 4.4 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-11-04 DOI: 10.1002/acn3.52240
Federico Mazzacane, Stefan Moraru, Beatrice Del Bello, Federica Ferrari, Erica Ferro, Alessandra Persico, Jawed Nawabi, Alessandro Padovani, Anna Cavallini, Andrea Morotti

Background: Medial intracranial carotid artery calcifications (ICAC) are associated with impaired vascular physiology, increased arterial stiffness and pulse pressure. Their presence might therefore be associated with increased risk of intracerebral hemorrhage (ICH) expansion, according to the avalanche model. We explored the association between ICAC presence and pattern and hematoma expansion (HE).

Methods: Retrospective analysis of a monocentric, prospectively collected cohort of ICH patients admitted between June 2017 and October 2023. ICAC pattern was determined by Kockelkoren's rating scale on admission CT; medial ICAC were defined with a >6 points cutoff. A follow-up CT scan was performed within 72 h. HE was analyzed as a dichotomous (≥6 mL and/or ≥33%) and as a categorical (none/mild/moderate/severe) variable, and its predictors were explored with logistic and ordinal regression respectively, accounting for baseline volume, onset-to-CT time, and anticoagulation. All the analyses were stratified by ICH location (supratentorial deep vs lobar ICH).

Results: A total of 201 patients were included (median age 78, 42% females, 59% deep ICH). Medial ICAC were significantly more common in deep ICH with HE compared with non-expanders (72% vs 49%, p = 0.03), whereas there was no association between ICAC and HE in lobar ICH (53% vs 52%, p = 0.85). This association between medial ICAC and HE in deep ICH remained significant in logistic (aOR 3.11, 95% CI [1.19-9.06], p = 0.03) and ordinal regression (acOR 2.42, 95% CI [1.19-4.99], p = 0.01).

Interpretation: Ipsilateral medial ICAC are associated with higher odds of HE in deep ICH. Our findings are best interpreted as hypothesis generating, requiring prospective validation and further research to characterize the underlying biological mechanisms.

背景:颅内颈动脉内侧钙化(ICAC)与血管生理功能受损、动脉僵化和脉压升高有关。因此,根据雪崩模型,钙化的存在可能与脑内出血(ICH)扩大的风险增加有关。我们探讨了 ICAC 的存在和模式与血肿扩大(HE)之间的关联:对 2017 年 6 月至 2023 年 10 月间收治的 ICH 患者进行单中心前瞻性队列回顾性分析。ICAC模式由入院CT上的Kockelkoren评分表确定;内侧ICAC的定义以大于6分为分界线。HE 作为二分变量(≥6 mL 和/或≥33%)和分类变量(无/轻度/中度/重度)进行分析,其预测因素分别采用逻辑回归和序数回归进行探讨,并考虑基线体积、发病至 CT 时间和抗凝情况。所有分析均按 ICH 位置(幕上深部 ICH 与脑叶 ICH)进行分层:共纳入 201 名患者(中位年龄 78 岁,42% 为女性,59% 为深部 ICH)。在伴有 HE 的深部 ICH 中,内侧 ICAC 明显多于非扩张者(72% vs 49%,p = 0.03),而在大叶 ICH 中,ICAC 与 HE 之间没有关联(53% vs 52%,p = 0.85)。在逻辑回归(aOR 3.11,95% CI [1.19-9.06],p = 0.03)和序数回归(acOR 2.42,95% CI [1.19-4.99],p = 0.01)中,深部 ICH 中内侧 ICAC 与 HE 之间的关系仍然显著:同侧内侧 ICAC 与深部 ICH 发生 HE 的较高几率相关。我们的发现最好被解释为假设的产生,需要前瞻性验证和进一步研究以确定其潜在的生物学机制。
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引用次数: 0
Distinct neuroinflammatory patterns between cerebral microbleeds and microinfarcts in cerebral amyloid angiopathy. 脑淀粉样变性血管病中脑微出血和微梗塞之间不同的神经炎症模式
IF 4.4 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-11-04 DOI: 10.1002/acn3.52226
Laurent Puy, Romain Barus, Marco Pasi, Maud Pétrault, Vincent Deramecourt, Charlotte Cordonnier, Vincent Bérézowski

In this neuropathological study, we investigated neuroinflammation surrounding recent and old cerebral microbleeds (CMBs) and cerebral microinfarcts (CMIs) in 18 cases of cerebral amyloid angiopathy (CAA). We used several serial stainings and immunolabellings to identify microvascular lesions, define their recent or old stage, and characterize neuroinflammatory response (scavenging activity and astrogliosis). We found that both CMBs and CMIs induce a neuroinflammatory response, which was more pronounced in old lesion than recent. Astrogliosis and scavenging activity were differentially prominent according to the ischemic/hemorrhagic nature of the lesion. Our findings provide insights into the pathophysiology of microvascular injuries in CAA.

在这项神经病理学研究中,我们调查了18例脑淀粉样血管病(CAA)患者的近期和陈旧性脑微小出血(CMBs)和脑微梗塞(CMIs)周围的神经炎症。我们使用了多种序列染色和免疫标记来识别微血管病变,确定其近期或远期阶段,并描述神经炎症反应(清除活性和星形胶质细胞增生)的特征。我们发现,CMBs 和 CMIs 都会诱发神经炎症反应,而且老病变比新病变更明显。星形胶质细胞增多和清除活性因病变的缺血/出血性质而异。我们的研究结果为了解 CAA 中微血管损伤的病理生理学提供了见解。
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引用次数: 0
Motor phenotypes associated with genetic neurodevelopmental disorders. 与遗传性神经发育障碍有关的运动表型。
IF 4.4 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-11-02 DOI: 10.1002/acn3.52231
Alexandra Santana Almansa, LeeAnne Green Snyder, Wendy K Chung, Jennifer M Bain, Siddharth Srivastava

Objective: There is a growing number of monogenic disorders implicated in neurodevelopmental disorders (NDDs), including autism spectrum disorder and intellectual disability. Motor impairment is frequently seen in these disorders, although not clearly defined. We aimed to characterize the motor phenotype of genetic NDDs.

Methods: We analyzed data from Simons Searchlight, collecting information on patients with genetic NDDs. Data analyzed included Vineland Adaptive Behavior Scales Second Edition (Vineland-II) motor standard scores, motor milestones and tone abnormalities.

Results: In total, 959 patients with 57 genetic disorders were included. Disorders associated with Vineland-II motor standard score <56 included GRIN2B-related disorder (mean standard score = 53.5), HNRNPH2-related disorder (mean standard score = 55.8) and SCN2A-related disorder (mean standard score = 49.9). The only genetic condition with a mean age of sitting unsupported ≥18 months was GRIN1-related disorder (mean age = 26.3 months). Genetic conditions with a mean age of walking independently ≥36 months included CTNNB1-related disorder (mean age = 37.4 months) and HNRNPH2-related disorder (mean age = 41.9 months). Tone abnormalities included hypotonia in 83% (577/696), hypertonia in 16% (112/696), a diagnosis of cerebral palsy (CP) in 10% (73/696) and a diagnosis specifically of spastic CP in 3% (23/696).

Interpretation: Patients with genetic NDDs have a spectrum of motor impairment, which warrant further characterization.

目的:越来越多的单基因疾病与神经发育障碍(NDD)有关,包括自闭症谱系障碍和智力障碍。这些疾病中经常出现运动障碍,但并没有明确的定义。我们旨在描述遗传性 NDDs 的运动表型特征:我们分析了西蒙斯探照灯的数据,收集了遗传性 NDDs 患者的信息。分析的数据包括维尼兰适应行为量表第二版(Vineland-II)运动标准分、运动里程碑和音调异常:结果:共纳入了 959 名患有 57 种遗传疾病的患者。与维尼兰-II 运动标准分数相关的疾病 解释:遗传性 NDD 患者的运动障碍范围广泛,需要进一步鉴定。
{"title":"Motor phenotypes associated with genetic neurodevelopmental disorders.","authors":"Alexandra Santana Almansa, LeeAnne Green Snyder, Wendy K Chung, Jennifer M Bain, Siddharth Srivastava","doi":"10.1002/acn3.52231","DOIUrl":"https://doi.org/10.1002/acn3.52231","url":null,"abstract":"<p><strong>Objective: </strong>There is a growing number of monogenic disorders implicated in neurodevelopmental disorders (NDDs), including autism spectrum disorder and intellectual disability. Motor impairment is frequently seen in these disorders, although not clearly defined. We aimed to characterize the motor phenotype of genetic NDDs.</p><p><strong>Methods: </strong>We analyzed data from Simons Searchlight, collecting information on patients with genetic NDDs. Data analyzed included Vineland Adaptive Behavior Scales Second Edition (Vineland-II) motor standard scores, motor milestones and tone abnormalities.</p><p><strong>Results: </strong>In total, 959 patients with 57 genetic disorders were included. Disorders associated with Vineland-II motor standard score <56 included GRIN2B-related disorder (mean standard score = 53.5), HNRNPH2-related disorder (mean standard score = 55.8) and SCN2A-related disorder (mean standard score = 49.9). The only genetic condition with a mean age of sitting unsupported ≥18 months was GRIN1-related disorder (mean age = 26.3 months). Genetic conditions with a mean age of walking independently ≥36 months included CTNNB1-related disorder (mean age = 37.4 months) and HNRNPH2-related disorder (mean age = 41.9 months). Tone abnormalities included hypotonia in 83% (577/696), hypertonia in 16% (112/696), a diagnosis of cerebral palsy (CP) in 10% (73/696) and a diagnosis specifically of spastic CP in 3% (23/696).</p><p><strong>Interpretation: </strong>Patients with genetic NDDs have a spectrum of motor impairment, which warrant further characterization.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142563589","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
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 : 2024-10-31 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
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。
{"title":"Plasma exchange with albumin replacement for Alzheimer's disease treatment induced changes in serum and cerebrospinal fluid inflammatory mediator levels.","authors":"Ricardo Gonzalo, Carla Minguet, Ana María Ortiz, María Isabel Bravo, Oscar L López, Mercè Boada, Agustín Ruiz, Montserrat Costa","doi":"10.1002/acn3.52235","DOIUrl":"https://doi.org/10.1002/acn3.52235","url":null,"abstract":"<p><strong>Objective: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Interpretation: </strong>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.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142542305","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
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。
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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
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Annals of Clinical and Translational Neurology
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