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Prediction of Cognitive Heterogeneity in Parkinson's Disease: A 4-Year Longitudinal Study Using Clinical, Neuroimaging, Biological and Electrophysiological Biomarkers 帕金森病认知异质性的预测:使用临床、神经影像学、生物学和电生理学生物标记物的四年纵向研究。
IF 8.1 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-08-05 DOI: 10.1002/ana.27035
Arnau Puig-Davi MSc, Saul Martinez-Horta PhD, Laura Pérez-Carasol MSc, Andrea Horta-Barba PhD, Iñigo Ruiz-Barrio MD, Ignacio Aracil-Bolaños MD, PhD, Rocío Pérez-González PhD, Elisa Rivas-Asensio BSc, Frederic Sampedro MD, PhD, Antonia Campolongo BSc, Javier Pagonabarraga MD, PhD, Jaime Kulisevsky MD, PhD

Objective

Cognitive impairment in Parkinson's disease (PD) can show a very heterogeneous trajectory among patients. Here, we explored the mechanisms involved in the expression and prediction of different cognitive phenotypes over 4 years.

Methods

In 2 independent cohorts (total n = 475), we performed a cluster analysis to identify trajectories of cognitive progression. Baseline and longitudinal level II neuropsychological assessments were conducted, and baseline structural magnetic resonance imaging, resting electroencephalogram and neurofilament light chain plasma quantification were carried out. Linear mixed-effects models were used to study longitudinal changes. Risk of mild cognitive impairment and dementia were estimated using multivariable hazard regression. Spectral power density from the electroencephalogram at baseline and source localization were computed.

Results

Two cognitive trajectories were identified. Cluster 1 presented stability (PD-Stable) over time, whereas cluster 2 showed progressive cognitive decline (PD-Progressors). The PD-Progressors group showed an increased risk for evolving to PD mild cognitive impairment (HR 2.09; 95% CI 1.11–3.95) and a marked risk for dementia (HR 4.87; 95% CI 1.34–17.76), associated with progressive worsening in posterior-cortical-dependent cognitive processes. Both clusters showed equivalent clinical and sociodemographic characteristics, structural magnetic resonance imaging, and neurofilament light chain levels at baseline. Conversely, the PD-Progressors group showed a fronto-temporo-occipital and parietal slow-wave power density increase, that was in turn related to worsening at 2 and 4 years of follow-up in different cognitive measures.

Interpretation

In the absence of differences in baseline cognitive function and typical markers of neurodegeneration, the further development of an aggressive cognitive decline in PD is associated with increased slow-wave power density and with a different profile of worsening in several posterior-cortical-dependent tasks. ANN NEUROL 2024;96:981–993

目的:帕金森病(Parkinson's disease,PD)患者的认知功能障碍可表现出非常不一致的轨迹。在此,我们探讨了4年内不同认知表型的表达和预测机制:在两个独立的队列(总人数为 475 人)中,我们进行了聚类分析,以确定认知进展的轨迹。我们进行了基线和纵向二级神经心理学评估,并进行了基线结构磁共振成像、静息脑电图和神经丝轻链血浆定量分析。线性混合效应模型用于研究纵向变化。采用多变量危险回归法估算轻度认知障碍和痴呆症的风险。计算了基线脑电图的频谱功率密度和信号源定位:结果:发现了两种认知轨迹。第 1 组随着时间的推移呈现出稳定性(PD-Sable),而第 2 组则表现出认知能力的逐步下降(PD-Progressors)。帕金森病进展者组显示出演变为帕金森病轻度认知障碍的风险增加(HR 2.09;95% CI 1.11-3.95),痴呆风险明显增加(HR 4.87;95% CI 1.34-17.76),这与后皮质依赖性认知过程的逐渐恶化有关。这两个群组的临床和社会人口学特征、结构磁共振成像和神经丝轻链水平在基线时相当。相反,帕金森病进展者组显示出额颞枕和顶叶慢波功率密度增加,而这又与随访2年和4年后不同认知测量的恶化有关:在基线认知功能和典型神经退行性变标志物没有差异的情况下,帕金森病患者认知功能的进一步恶化与慢波功率密度的增加以及几项依赖后皮质的任务的恶化情况不同有关。ann neurol 2024.
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引用次数: 0
An Approach to Successful Development of Clinician–Scientists in Neurology: The NINDS R25 Experience 成功培养神经病学临床科学家的方法:NINDS R25 的经验。
IF 8.1 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-08-05 DOI: 10.1002/ana.27050
S. Andrew Josephson MD, Michael S. Tennekoon PhD, S. Thomas Carmichael MD, PhD, Sydney S. Cash MD, PhD, John A. Detre MD, Argye E. Hillis MD, MA, Page B. Pennell MD, Scott L. Pomeroy MD, PhD, George B. Richerson MD, PhD, Lauren H. Sansing MD, MS, Stephen J. Korn PhD

Objective

Training clinician–scientists is a primary objective of many academic neurology departments, as these individuals are uniquely positioned to perform insightful clinical or laboratory-based research informed both by clinical knowledge and their own experiences caring for patients. Despite its importance, training clinician–scientists has perhaps never been so challenging. The National Institute of Neurologic Disorders and Stroke (NINDS) R25 program was designed in an attempt to support these individuals, decrease the time needed to obtain National Institutes of Health K awards, and to help educate a cohort of trainees preparing for a career in academic neurology. We endeavored to describe the structure and features of the program while examining its outcomes.

Methods

R25 outcome data from 2009 to 2024 were reviewed. Statistical comparisons were made using 2-sided Mann–Whitney U testing.

Results

A total of 67% of adult neurologists who received an R25 had a successful application for a National Institutes of Health K award compared with 45% of adult neurologists who had not received R25 support (p < 0.0001). Among child neurologists, 73% who applied went on to receive K funding after R25 support, compared with 45% who had not been part of the R25 program (p < 0.001). The average time between completion of residency and obtaining a K award for R25 participants was decreased by 26 months among those with an MD/PhD degree, and 32 months for those with an MD degree compared with non-R25 individuals.

Interpretation

The R25 program has been successful in achieving its training goals, but stands as only one component of support for aspiring clinician–scientists. Investments and commitments made by academic neurology departments are key to supporting this success. ANN NEUROL 2024;96:625–632

目的:培训临床科学家是许多神经病学学术部门的首要目标,因为这些人具有得天独厚的优势,能够根据临床知识和自身护理病人的经验,开展有见地的临床或实验室研究。尽管非常重要,但培养临床科学家或许从未如此具有挑战性。美国国立神经疾病与中风研究所(NINDS)R25 计划的设计初衷就是为这些人提供支持,缩短他们获得美国国立卫生研究院 K 奖项所需的时间,并帮助教育一批准备投身神经病学学术研究的受训人员。我们努力描述该计划的结构和特点,同时研究其成果:我们回顾了 2009 年至 2024 年的 R25 成果数据。采用双侧曼-惠特尼 U 检验法进行统计比较:结果:在获得 R25 支持的成年神经学家中,共有 67% 的人成功申请到了美国国立卫生研究院的 K 奖,而在未获得 R25 支持的成年神经学家中,只有 45% 的人成功申请到了 K 奖(P 解释:R25 计划在神经科学领域取得了成功:R25 计划成功地实现了其培训目标,但它只是为有抱负的临床科学家提供支持的一个组成部分。神经病学学术部门的投资和承诺是支持这一成功的关键。ann neurol 2024.
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引用次数: 0
Multiparametric Characterization of Focal Cortical Dysplasia Using 3D MR Fingerprinting 利用三维磁共振指纹技术对局灶性皮质发育不良进行多参数特征描述
IF 8.1 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-08-03 DOI: 10.1002/ana.27049
Ting-Yu Su, Joon Yul Choi, Siyuan Hu, Xiaofeng Wang, Ingmar Blümcke, Katherine Chiprean, Balu Krishnan, Zheng Ding, Ken Sakaie, Hiroatsu Murakami, Andreas V Alexopoulos, Imad Najm, Stephen E Jones, Dan Ma, Zhong Irene Wang

Objective

To develop a multiparametric machine-learning (ML) framework using high-resolution 3 dimensional (3D) magnetic resonance (MR) fingerprinting (MRF) data for quantitative characterization of focal cortical dysplasia (FCD).

Materials

We included 119 subjects, 33 patients with focal epilepsy and histopathologically confirmed FCD, 60 age- and gender-matched healthy controls (HCs), and 26 disease controls (DCs). Subjects underwent whole-brain 3 Tesla MRF acquisition, the reconstruction of which generated T1 and T2 relaxometry maps. A 3D region of interest was manually created for each lesion, and z-score normalization using HC data was performed. We conducted 2D classification with ensemble models using MRF T1 and T2 mean and standard deviation from gray matter and white matter for FCD versus controls. Subtype classification additionally incorporated entropy and uniformity of MRF metrics, as well as morphometric features from the morphometric analysis program (MAP). We translated 2D results to individual probabilities using the percentage of slices above an adaptive threshold. These probabilities and clinical variables were input into a support vector machine for individual-level classification. Fivefold cross-validation was performed and performance metrics were reported using receiver-operating-characteristic-curve analyses.

Results

FCD versus HC classification yielded mean sensitivity, specificity, and accuracy of 0.945, 0.980, and 0.962, respectively; FCD versus DC classification achieved 0.918, 0.965, and 0.939. In comparison, visual review of the clinical magnetic resonance imaging (MRI) detected 48% (16/33) of the lesions by official radiology report. In the subgroup where both clinical MRI and MAP were negative, the MRF-ML models correctly distinguished FCD patients from HCs and DCs in 98.3% of cross-validation trials. Type II versus non-type-II classification exhibited mean sensitivity, specificity, and accuracy of 0.835, 0.823, and 0.83, respectively; type IIa versus IIb classification showed 0.85, 0.9, and 0.87. In comparison, the transmantle sign was present in 58% (7/12) of the IIb cases.

Interpretation

The MRF-ML framework presented in this study demonstrated strong efficacy in noninvasively classifying FCD from normal cortex and distinguishing FCD subtypes. ANN NEUROL 2024;96:944–957

研究目的利用高分辨率三维(3D)磁共振(MR)指纹(MRF)数据开发一种多参数机器学习(ML)框架,用于定量表征局灶性皮质发育不良(FCD):我们纳入了 119 名受试者,其中包括 33 名局灶性癫痫且组织病理学证实为 FCD 的患者、60 名年龄和性别匹配的健康对照组 (HC) 以及 26 名疾病对照组 (DC)。受试者接受了全脑 3 特斯拉 MRF 采集,重建后生成了 T1 和 T2 弛豫测量图。我们为每个病灶手动创建了一个三维感兴趣区,并使用 HC 数据进行了 z 值归一化。我们使用 MRF T1 和 T2 平均值以及灰质和白质的标准偏差对 FCD 和对照组进行了二维分类。亚型分类还纳入了 MRF 指标的熵和均匀性,以及形态分析程序 (MAP) 的形态特征。我们使用高于自适应阈值的切片百分比将二维结果转化为个体概率。这些概率和临床变量被输入支持向量机进行个体级分类。我们进行了五倍交叉验证,并通过接受者操作特征曲线分析报告了性能指标:结果:FCD 与 HC 分类的平均灵敏度、特异度和准确度分别为 0.945、0.980 和 0.962;FCD 与 DC 分类的平均灵敏度、特异度和准确度分别为 0.918、0.965 和 0.939。相比之下,对临床磁共振成像(MRI)的目视检查通过官方放射学报告发现了 48% (16/33)的病变。在临床 MRI 和 MAP 均为阴性的亚组中,在磁共振成像阴性组和 MAP 阴性组的交叉验证试验中,MRF-ML 模型有 98.3% 正确区分了 FCD 患者与 HC 和 DC。II 型与非 II 型分类的平均灵敏度、特异度和准确度分别为 0.835、0.823 和 0.83;IIa 型与 IIb 型分类的平均灵敏度、特异度和准确度分别为 0.85、0.9 和 0.87。相比之下,58%(7/12)的 IIb 型病例存在横纹征:本研究提出的 MRF-ML 框架在无创将 FCD 从正常皮质中分类并区分 FCD 亚型方面显示出强大的功效。ann neurol 2024.
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引用次数: 0
Multimodal, Longitudinal Profiling of SCA1 Identifies Predictors of Disease Severity and Progression 对 SCA1 进行多模态、纵向剖析,发现疾病严重程度和进展的预测因素。
IF 8.1 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-08-03 DOI: 10.1002/ana.27032
Teije H. van Prooije MD, Kirsten C.J. Kapteijns, Jack J.A. van Asten, Joanna IntHout, Marcel M. Verbeek PhD, Tom W.J. Scheenen PhD, Bart P. van de Warrenburg MD, PhD

Objectives

Spinocerebellar ataxia type 1 (SCA1) is a rare autosomal dominant neurodegenerative disease. Objective surrogate markers sensitive to detect changes in disease severity are needed to reduce sample sizes in interventional trials and identification of predictors of faster disease progression would facilitate patient selection, enrichment, or stratification in such trials.

Methods

We performed a prospective 1-year longitudinal, multimodal study in 34 ataxic SCA1 individuals and 21 healthy controls. We collected clinical, patient-reported outcomes, biochemical and magnetic resonance (MR) biomarkers at baseline and after 1 year. We determined 1-year progression and evaluated the potential predictive value of several baseline markers on 1-year disease progression.

Results

At baseline, multiple structural and spectroscopic MR markers in pons and cerebellum differentiated SCA1 from healthy controls and correlated with disease severity. Plasma and cerebrospinal fluid (CSF) neurofilament light (NfL) chain and CSF glial fibrillary acidic protein (GFAP) were elevated in SCA1. In longitudinal analysis, total brainstem and pontine volume change, inventory of non-ataxia signs (INAS) count, and SCA functional index (SCAFI) showed larger responsiveness compared to the Scale for Assessment and Rating of Ataxia (SARA).

Longer disease duration, longer non-expanded CAG repeat length, and higher disease burden were associated with faster SARA increase after 1-year in the SCA1 group. Similarly, lower baseline brainstem, pontine, and cerebellar volumes, as well as lower levels of N-acetylaspartate and glutamate in the cerebellar white matter, were also associated with faster SARA increase.

Interpretation

Our results guide the selection of the most sensitive measures of disease progression in SCA1 and have identified features associated with accelerated progression that could inform the design of clinical trials. ANN NEUROL 2024;96:774–787

目的:脊髓小脑共济失调 1 型(SCA1)是一种罕见的常染色体显性神经退行性疾病。需要能检测疾病严重程度变化的客观替代标记物来减少干预性试验的样本量,而确定疾病进展更快的预测因子将有助于在此类试验中对患者进行选择、富集或分层:我们对 34 名共济失调型 SCA1 患者和 21 名健康对照者进行了为期 1 年的前瞻性多模态纵向研究。我们收集了基线和一年后的临床、患者报告结果、生化和磁共振(MR)生物标志物。我们确定了1年的病情进展,并评估了几个基线标志物对1年病情进展的潜在预测价值:基线时,脑桥和小脑中的多种结构和光谱磁共振标记物将 SCA1 与健康对照组区分开来,并与疾病严重程度相关。SCA1患者血浆和脑脊液(CSF)中神经丝轻链(NfL)和脑脊液胶质纤维酸性蛋白(GFAP)升高。在纵向分析中,与共济失调评估和评级量表(SARA)相比,脑干和桥脑总体积变化、非共济失调体征(INAS)计数和SCA功能指数(SCAFI)显示出更大的反应性。在SCA1组中,病程越长、非扩展CAG重复长度越长、疾病负担越重,1年后SARA的上升速度越快。同样,较低的基线脑干、桥脑和小脑体积以及小脑白质中较低的N-乙酰天冬氨酸和谷氨酸水平也与SARA的快速增长有关:我们的研究结果为选择最灵敏的SCA1疾病进展测量指标提供了指导,并发现了与疾病进展加速相关的特征,这些特征可为临床试验的设计提供参考。ann neurol 2024.
{"title":"Multimodal, Longitudinal Profiling of SCA1 Identifies Predictors of Disease Severity and Progression","authors":"Teije H. van Prooije MD,&nbsp;Kirsten C.J. Kapteijns,&nbsp;Jack J.A. van Asten,&nbsp;Joanna IntHout,&nbsp;Marcel M. Verbeek PhD,&nbsp;Tom W.J. Scheenen PhD,&nbsp;Bart P. van de Warrenburg MD, PhD","doi":"10.1002/ana.27032","DOIUrl":"10.1002/ana.27032","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Spinocerebellar ataxia type 1 (SCA1) is a rare autosomal dominant neurodegenerative disease. Objective surrogate markers sensitive to detect changes in disease severity are needed to reduce sample sizes in interventional trials and identification of predictors of faster disease progression would facilitate patient selection, enrichment, or stratification in such trials.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We performed a prospective 1-year longitudinal, multimodal study in 34 ataxic SCA1 individuals and 21 healthy controls. We collected clinical, patient-reported outcomes, biochemical and magnetic resonance (MR) biomarkers at baseline and after 1 year. We determined 1-year progression and evaluated the potential predictive value of several baseline markers on 1-year disease progression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>At baseline, multiple structural and spectroscopic MR markers in pons and cerebellum differentiated SCA1 from healthy controls and correlated with disease severity. Plasma and cerebrospinal fluid (CSF) neurofilament light (NfL) chain and CSF glial fibrillary acidic protein (GFAP) were elevated in SCA1. In longitudinal analysis, total brainstem and pontine volume change, inventory of non-ataxia signs (INAS) count, and SCA functional index (SCAFI) showed larger responsiveness compared to the Scale for Assessment and Rating of Ataxia (SARA).</p>\u0000 \u0000 <p>Longer disease duration, longer non-expanded CAG repeat length, and higher disease burden were associated with faster SARA increase after 1-year in the SCA1 group. Similarly, lower baseline brainstem, pontine, and cerebellar volumes, as well as lower levels of N-acetylaspartate and glutamate in the cerebellar white matter, were also associated with faster SARA increase.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>Our results guide the selection of the most sensitive measures of disease progression in SCA1 and have identified features associated with accelerated progression that could inform the design of clinical trials. ANN NEUROL 2024;96:774–787</p>\u0000 </section>\u0000 </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.27032","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141877988","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
Evaluation of Glymphatic System Development in Neonatal Brain via Diffusion Analysis along the Perivascular Space Index 通过沿血管周围空间指数的弥散分析评估新生儿脑内淋巴系统的发育情况
IF 8.1 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-08-03 DOI: 10.1002/ana.27047
Shiwei Lin MS, Meifen Guo MS, Qunjun Liang PhD, Xiaoshan Lin MS, Shengli Chen MS, Ying Li MS, Peiqi Chen MS, Yingwei Qiu MD, PhD

Objective

Glymphatic system is a recently discovered macroscopic waste clearance system associated with numerous neurological diseases. However, little is known about glymphatic system development in neonates. We sought to evaluate diffusion along the perivascular space (ALPS) index, a proxy for glymphatic system function, in neonates and investigate its potential associations with maturation, sex, and preterm birth.

Methods

Diffusion magnetic resonance imaging (MRI) data in 418 neonates, including 92 preterm neonates (57 males) and 326 term neonates (175 males), from the Developing Human Connectome Project were used for evaluating ALPS index. Linear regression modeling was performed to assess group differences in the ALPS index according to preterm birth and sex. Pearson's and partial correlation analysis were performed to assess the association between the ALPS index and gestational age (GA) as well as postmenstrual age (PMA) at MRI. Moderation analysis was performed to assess the moderation effect of preterm birth on the relationship between the ALPS index and PMA.

Results

Compared to term neonates, preterm neonates exhibited lower ALPS indices (p < 0.001). The ALPS index positively correlated with PMA (p = 0.004) and GA (p < 0.001). Preterm birth (p = 0.013) had a significant moderation effect on the relationship between the ALPS index and PMA. Sex had no significant direct effect (p = 0.639) or moderation effect (p = 0.333) on ALPS index.

Interpretation

Glymphatic system development is a dynamic process in neonates, which can be moderated by preterm birth, the ALPS index could serve as a sensitive biomarker for monitoring this process. ANN NEUROL 2024;96:970–980

目的:淋巴系统是最近发现的一种与多种神经系统疾病相关的宏观废物清除系统。然而,人们对新生儿的淋巴系统发育知之甚少。我们试图评估新生儿沿血管周围空间的弥散(ALPS)指数,该指数可代表淋巴系统的功能,并研究其与成熟度、性别和早产的潜在关联:方法:利用发展中人类连接组项目(Developing Human Connectome Project)中 418 名新生儿的弥散磁共振成像(MRI)数据评估 ALPS 指数,其中包括 92 名早产新生儿(57 名男性)和 326 名足月新生儿(175 名男性)。通过线性回归模型来评估早产儿和性别在ALPS指数上的组间差异。为评估ALPS指数与妊娠年龄(GA)和核磁共振成像时的月经后年龄(PMA)之间的关系,进行了皮尔逊分析和偏相关分析。为了评估早产对ALPS指数和PMA之间关系的调节作用,还进行了调节分析:结果:与足月新生儿相比,早产新生儿的ALPS指数较低(p 解释:早产新生儿的ALPS指数低于足月新生儿:早产儿可以作为监测这一过程的敏感生物标志物。ann neurol 2024.
{"title":"Evaluation of Glymphatic System Development in Neonatal Brain via Diffusion Analysis along the Perivascular Space Index","authors":"Shiwei Lin MS,&nbsp;Meifen Guo MS,&nbsp;Qunjun Liang PhD,&nbsp;Xiaoshan Lin MS,&nbsp;Shengli Chen MS,&nbsp;Ying Li MS,&nbsp;Peiqi Chen MS,&nbsp;Yingwei Qiu MD, PhD","doi":"10.1002/ana.27047","DOIUrl":"10.1002/ana.27047","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Glymphatic system is a recently discovered macroscopic waste clearance system associated with numerous neurological diseases. However, little is known about glymphatic system development in neonates. We sought to evaluate diffusion along the perivascular space (ALPS) index, a proxy for glymphatic system function, in neonates and investigate its potential associations with maturation, sex, and preterm birth.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Diffusion magnetic resonance imaging (MRI) data in 418 neonates, including 92 preterm neonates (57 males) and 326 term neonates (175 males), from the Developing Human Connectome Project were used for evaluating ALPS index. Linear regression modeling was performed to assess group differences in the ALPS index according to preterm birth and sex. Pearson's and partial correlation analysis were performed to assess the association between the ALPS index and gestational age (GA) as well as postmenstrual age (PMA) at MRI. Moderation analysis was performed to assess the moderation effect of preterm birth on the relationship between the ALPS index and PMA.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Compared to term neonates, preterm neonates exhibited lower ALPS indices (<i>p</i> &lt; 0.001). The ALPS index positively correlated with PMA (<i>p</i> = 0.004) and GA (<i>p</i> &lt; 0.001). Preterm birth (<i>p</i> = 0.013) had a significant moderation effect on the relationship between the ALPS index and PMA. Sex had no significant direct effect (<i>p</i> = 0.639) or moderation effect (<i>p</i> = 0.333) on ALPS index.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>Glymphatic system development is a dynamic process in neonates, which can be moderated by preterm birth, the ALPS index could serve as a sensitive biomarker for monitoring this process. ANN NEUROL 2024;96:970–980</p>\u0000 </section>\u0000 </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141877986","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
Solving the Etiology of Developmental and Epileptic Encephalopathy with Spike–Wave Activation in Sleep (D/EE-SWAS) 用睡眠中的尖峰波激活解开发育性和癫痫性脑病的病因(D/EE-SWAS)。
IF 8.1 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-08-02 DOI: 10.1002/ana.27041
Sindhu Viswanathan MBChB, Karen L. Oliver PhD, Brigid M. Regan BSc(Hons), Amy L. Schneider MGenCouns, Candace T. Myers PhD, Michele G. Mehaffey MS, Amy J. LaCroix BS, Jayne Antony MD, PhD, Richard Webster MBBS, MSc, Michael Cardamone PhD, MBBS, Gopinath M. Subramanian MBBS, MD, Annie T.G. Chiu MBBS, Eugenia Roza PhD, MD, Raluca I. Teleanu PhD, MD, Stephen Malone MBBS, PhD, Richard J. Leventer MBBS, PhD, Deepak Gill MBBS, Samuel F. Berkovic MD, FRS, Michael S. Hildebrand PhD, Beatrice S. Goad BS, Katherine B. Howell PhD, MBBS (Hon), BMedSc, Joseph D. Symonds PhD, Andreas Brunklaus MD, Lynette G. Sadleir MBChB, MD, Sameer M. Zuberi MBChB, MD, Heather C. Mefford MD, PhD, Ingrid E. Scheffer MBBS, PhD, FRS

Objective

To understand the etiological landscape and phenotypic differences between 2 developmental and epileptic encephalopathy (DEE) syndromes: DEE with spike–wave activation in sleep (DEE-SWAS) and epileptic encephalopathy with spike–wave activation in sleep (EE-SWAS).

Methods

All patients fulfilled International League Against Epilepsy (ILAE) DEE-SWAS or EE-SWAS criteria with a Core cohort (n = 91) drawn from our Epilepsy Genetics research program, together with 10 etiologically solved patients referred by collaborators in the Expanded cohort (n = 101). Detailed phenotyping and analysis of molecular genetic results were performed. We compared the phenotypic features of individuals with DEE-SWAS and EE-SWAS. Brain-specific gene co-expression analysis was performed for D/EE-SWAS genes.

Results

We identified the etiology in 42/91 (46%) patients in our Core cohort, including 29/44 (66%) with DEE-SWAS and 13/47 (28%) with EE-SWAS. A genetic etiology was identified in 31/91 (34%). D/EE-SWAS genes were highly co-expressed in brain, highlighting the importance of channelopathies and transcriptional regulators. Structural etiologies were found in 12/91 (13%) individuals. We identified 10 novel D/EE-SWAS genes with a range of functions: ATP1A2, CACNA1A, FOXP1, GRIN1, KCNMA1, KCNQ3, PPFIA3, PUF60, SETD1B, and ZBTB18, and 2 novel copy number variants, 17p11.2 duplication and 5q22 deletion. Although developmental regression patterns were similar in both syndromes, DEE-SWAS was associated with a longer duration of epilepsy and poorer intellectual outcome than EE-SWAS.

Interpretation

DEE-SWAS and EE-SWAS have highly heterogeneous genetic and structural etiologies. Phenotypic analysis highlights valuable clinical differences between DEE-SWAS and EE-SWAS which inform clinical care and prognostic counseling. Our etiological findings pave the way for the development of precision therapies. ANN NEUROL 2024;96:932–943

目的了解两种发育性癫痫性脑病(DEE)综合征的病因和表型差异:方法:所有患者均符合国际抗癫痫联盟(ILAE)的DEE-SWAS或EE-SWAS标准,其中核心队列(n = 91)来自我们的癫痫遗传学研究项目,另外还有10名由合作者转介的病因学解明患者,属于扩展队列(n = 101)。我们进行了详细的表型分析和分子遗传结果分析。我们比较了 DEE-SWAS 和 EE-SWAS 患者的表型特征。对D/EE-SWAS基因进行了脑特异性基因共表达分析:我们确定了核心队列中 42/91 例(46%)患者的病因,其中包括 29/44 例(66%)DEE-SWAS 患者和 13/47 例(28%)EE-SWAS 患者。31/91(34%)的患者确定了遗传病因。D/EE-SWAS基因在大脑中高度共表达,突出了通道病变和转录调节因子的重要性。有12/91人(13%)发现了结构性病因。我们发现了 10 个具有不同功能的新型 D/EE-SWAS 基因:ATP1A2、CACNA1A、FOXP1、GRIN1、KCNMA1、KCNQ3、PPFIA3、PUF60、SETD1B 和 ZBTB18,以及 2 个新的拷贝数变异:17p11.2 重复和 5q22 缺失。虽然这两种综合征的发育退行模式相似,但与EE-SWAS相比,DEE-SWAS与更长的癫痫持续时间和更差的智力结果相关:DEE-SWAS和EE-SWAS具有高度异质性的遗传和结构病因。表型分析强调了DEE-SWAS和EE-SWAS之间有价值的临床差异,为临床治疗和预后咨询提供了依据。我们的病因学发现为开发精准疗法铺平了道路。ann neurol 2024.
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引用次数: 0
Intramedullary Spinal Cord Abscess Caused by Acupuncture 针灸引起的脊髓髓内脓肿
IF 8.1 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-08-02 DOI: 10.1002/ana.27044
Jun Liu, Si Zhang, Hua Guo
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引用次数: 0
Multiple Acyl-Coenzyme A Dehydrogenase Deficiency Is Associated with Sertraline Use – Is There an Acquired Form? 多酰辅酶 A 脱氢酶缺乏症与舍曲林的使用有关--是否存在后天获得的形式?
IF 8.1 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-08-02 DOI: 10.1002/ana.27030
Sofie Sunebo MD, Hanna Appelqvist PhD, Bo Häggqvist PhD, Olof Danielsson MD, PhD

Objective

Multiple acyl-coenzyme A dehydrogenase deficiency (MADD) is a disorder of fatty acid oxidation and considered an inborn error of metabolism. In recent years, we have diagnosed an increasing number of patients where, despite extensive investigation, no disease-causing mutations have been found. We therefore investigated a cohort of consecutive patients, with the objective to detect possible non-genetic causes.

Methods

We searched the patient records and the registry of muscle biopsies, for patients with MADD, diagnosed within the past 10 years. The patient records were reviewed regarding symptoms, clinical findings, comorbidities, drugs, diagnostic investigations, and response to treatment. In addition, complementary investigations of muscle tissue were performed.

Results

We identified 9 patients diagnosed with late-onset MADD. All presented with muscle weakness and elevated levels of creatine kinase. A lipid storage myopathy was evident in the muscle biopsies, as was elevated acylcarnitines in blood. Despite thorough genetic investigations, a probable genetic cause was found in only 2 patients. Remarkably, all 7 patients without disease-causing mutations were treated with sertraline. In some cases, a deterioration of symptoms closely followed dose increase, and discontinuation resulted in an improved acylcarnitine profile. All 9 patients responded to riboflavin treatment with normalization of creatine kinase and muscle biopsy findings, and in 8 patients the clinical symptoms clearly improved.

Interpretation

Our findings strongly suggest that sertraline may induce an acquired form of MADD in some patients. Importantly, riboflavin treatment seems to be similarly effective as in genetic MADD, but discontinuation of sertraline is reasonably warranted. ANN NEUROL 2024;96:802–811

目的:多酰基辅酶 A 脱氢酶缺乏症(MADD)是一种脂肪酸氧化障碍,被认为是一种先天性代谢错误。近年来,我们诊断出越来越多的患者,尽管进行了广泛的调查,但仍未发现致病突变。因此,我们对一组连续患者进行了调查,目的是发现可能的非遗传原因:我们搜索了过去 10 年内确诊的 MADD 患者的病历和肌肉活检登记。我们查阅了患者的病历,包括症状、临床表现、合并症、药物、诊断检查和治疗反应。此外,还对肌肉组织进行了辅助检查:结果:我们发现了 9 名被诊断为晚发性 MADD 的患者。所有患者均表现为肌无力和肌酸激酶水平升高。在肌肉活检中发现了明显的脂质贮积性肌病,血液中的酰基肉碱也有所升高。尽管进行了全面的遗传学调查,但只有两名患者找到了可能的遗传原因。值得注意的是,所有 7 名没有致病基因突变的患者都接受了舍曲林治疗。在某些病例中,剂量增加后症状会随之恶化,停药后酰基肉碱状况会得到改善。所有 9 名患者对核黄素治疗均有反应,肌酸激酶和肌肉活检结果均恢复正常,其中 8 名患者的临床症状明显改善:我们的研究结果有力地表明,舍曲林可能会诱发某些患者的获得性MADD。重要的是,核黄素治疗似乎与遗传性 MADD 相似有效,但停用舍曲林是合理的。ann neurol 2024.
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引用次数: 0
Discordant Sign Identified by Angiogram in Intracranial Dissection 通过血管造影识别颅内分裂的不和谐体征
IF 8.1 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-07-31 DOI: 10.1002/ana.27042
Jiabao Yang MD, Zhikai Hou MD, Jianjun Tan MD, Ning Ma MD
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引用次数: 0
Genomic Analysis Identifies Risk Factors in Restless Legs Syndrome 基因组分析确定不安腿综合征的风险因素
IF 8.1 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-07-30 DOI: 10.1002/ana.27040
Fulya Akçimen, Ruth Chia, Sara Saez-Atienzar, Paola Ruffo, Memoona Rasheed, Jay P. Ross, Calwing Liao, Anindita Ray, Patrick A. Dion, Sonja W. Scholz, Guy A. Rouleau, Bryan J. Traynor

Objective

Restless legs syndrome (RLS) is a neurological condition that causes uncomfortable sensations in the legs and an irresistible urge to move them, typically during periods of rest. The genetic basis and pathophysiology of RLS are incompletely understood. We sought to identify additional novel genetic risk factors associated with RLS susceptibility.

Methods

We performed a whole-genome sequencing and genome-wide association meta-analysis of RLS cases (n = 9,851) and controls (n = 38,957) in 3 population-based biobanks (All of Us, Canadian Longitudinal Study on Aging, and CARTaGENE).

Results

Genome-wide association analysis identified 9 independent risk loci, of which 8 had been previously reported, and 1 was a novel risk locus (LMX1B, rs35196838, OR 1.14, 95% CI 1.09–1.19, p value = 2.2 × 10−9). Furthermore, a transcriptome-wide association study also identified GLO1 and a previously unreported gene, ELFN1. A genetic correlation analysis revealed significant common variant overlaps between RLS and neuroticism (rg = 0.40, se = 0.08, p value = 5.4 × 10−7), depression (rg = 0.35, se = 0.06, p value = 2.17 × 10−8), and intelligence (rg = −0.20, se = 0.06, p value = 4.0 × 10−4).

Interpretation

Our study expands the understanding of the genetic architecture of RLS, and highlights the contributions of common variants to this prevalent neurological disorder. ANN NEUROL 2024;96:994–1005

目的:不宁腿综合征(RLS)是一种神经系统疾病,会引起腿部不舒服的感觉和无法抗拒的移动腿部的冲动,通常在休息时发生。人们对 RLS 的遗传基础和病理生理学尚不完全清楚。我们试图找出更多与 RLS 易感性相关的新型遗传风险因素:我们对 3 个基于人群的生物库(All of Us、Canadian Longitudinal Study on Aging 和 CARTaGENE)中的 RLS 病例(n = 9,851 例)和对照(n = 38,957 例)进行了全基因组测序和全基因组关联荟萃分析:结果:全基因组关联分析确定了 9 个独立的风险位点,其中 8 个以前已有报道,1 个是新的风险位点(LMX1B,rs35196838,OR 1.14,95% CI 1.09-1.19,p 值 = 2.2 × 10-9)。此外,一项全转录组关联研究还发现了 GLO1 和一个以前未报道过的基因 ELFN1。遗传相关性分析显示,RLS 与神经质(rg = 0.40,se = 0.08,p 值 = 5.4 × 10-7)、抑郁(rg = 0.35,se = 0.06,p 值 = 2.17 × 10-8)和智力(rg = -0.20,se = 0.06,p 值 = 4.0 × 10-4)之间存在显著的共同变异重叠:我们的研究拓展了对 RLS 遗传结构的理解,并强调了常见变异对这一流行性神经系统疾病的贡献。ann neurol 2024.
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引用次数: 0
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Annals of Neurology
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