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Exploring synaptic pathways in traumatic brain injury: a cross-phenotype genomics approach. 探索创伤性脑损伤的突触通路:跨表型基因组学方法。
IF 4.2 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-09-12 DOI: 10.1089/neu.2024.0153
Savvina Prapiadou,Ernst Mayerhofer,Marios K Georgakis,Mart Kals,Farid Radmanesh,Saef Izzy,Sylvia Richardson,David O Okonkwo,Ava M Puccio,Nancy Temkin,Aarno Palotie,Samuli Ripatti,Ramon Diaz-Arrastia,Murray B Stein,Geoffrey T Manley,David Menon,Jonathan Rosand,Livia Parodi,Christopher D Anderson
Traumatic brain injury (TBI), a global leading cause of mortality and disability, lacks effective treatments to enhance recovery. Synaptic remodeling has been postulated as one mechanism that influences outcomes after TBI. We sought to investigate whether common mechanisms affecting synapse maintenance are shared between TBI and other neuropsychiatric conditions using pathway enrichment tools and genome-wide genotype data, with the goal of highlighting novel treatment targets. We leveraged an integrative approach, combining data from Genome-Wide Association Studies (GWAS) with pathway and gene-set enrichment analyses. Literature review-based and Reactome database-driven approaches were combined to identify synapse-related pathways of interest in TBI outcome, and to assess for shared associations with conditions in which synapse-related pathobiological mechanisms have been implicated, including Alzheimer's disease (AD), schizophrenia (SCZ), major depressive disorder (MDD), post-traumatic stress disorder (PTSD), attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Gene and pathway-level enrichment analyses were conducted using MAGMA and its extensions, e- and H-MAGMA, followed by Mendelian Randomization (MR) to investigate potential causal associations. Of the 98 pathways tested, 32 were significantly enriched in the included conditions. In TBI outcome, we identified significant enrichment in five pathways: "Serotonin clearance from the synaptic cleft" (p-value = 0.0001), "Presynaptic nicotinic acetylcholine receptors" (p-value = 0.0003), "Postsynaptic nicotinic acetylcholine receptors" (p-value = 0.0003), "Highly sodium permeable postsynaptic acetylcholine nicotinic receptors" (p-value = 0.0001), and "Acetylcholine binding and downstream events" pathways (p-value = 0.0003). These associations highlight potential involvement of the cholinergic and serotonergic systems in post-TBI recovery. Three of those pathways were shared between TBI and schizophrenia, suggesting possible pathophysiologic commonalities. In this study we utilize comparative and integrative genomic approaches across brain conditions that share synaptic mechanisms to explore the pathophysiology of TBI outcome. Our results implicate associations between TBI outcome and synaptic pathways as well as pathobiologic overlap with other neuropsychiatric diseases.
创伤性脑损伤(TBI)是导致死亡和残疾的全球主要原因,但目前缺乏有效的治疗方法来促进康复。突触重塑被认为是影响创伤性脑损伤后疗效的机制之一。我们试图利用通路富集工具和全基因组基因型数据研究影响突触维持的共同机制是否在创伤性脑损伤和其他神经精神疾病之间存在共性,目的是突出新的治疗目标。我们采用了一种综合方法,将全基因组关联研究(GWAS)数据与通路和基因组富集分析相结合。我们将基于文献综述的方法与 Reactome 数据库驱动的方法相结合,以确定创伤性脑损伤结果中与突触相关的相关通路,并评估与突触相关病理生物学机制有牵连的疾病的共同关联,这些疾病包括阿尔茨海默病 (AD)、精神分裂症 (SCZ)、重度抑郁症 (MDD)、创伤后应激障碍 (PTSD)、注意缺陷多动障碍 (ADHD) 和自闭症谱系障碍 (ASD)。我们使用 MAGMA 及其扩展工具 e-MAGMA 和 H-MAGMA 进行了基因和通路水平的富集分析,然后使用孟德尔随机化(MR)研究了潜在的因果关系。在所测试的 98 个通路中,有 32 个通路在所纳入的条件中显著富集。在创伤性脑损伤结果中,我们发现有五条通路出现了明显的富集:"突触前烟碱乙酰胆碱受体"(p-value = 0.0003)、"突触后烟碱乙酰胆碱受体"(p-value = 0.0003)、"高钠渗透性突触后乙酰胆碱烟碱受体"(p-value = 0.0001)和 "乙酰胆碱结合和下游事件 "途径(p-value = 0.0003)。这些关联凸显了胆碱能和血清素能系统在创伤后恢复中的潜在参与。其中三条通路在创伤后应激障碍和精神分裂症之间具有共通性,这表明两者可能存在病理生理学上的共性。在这项研究中,我们利用比较和整合基因组学方法,在具有相同突触机制的脑部疾病中探索创伤后脑损伤结果的病理生理学。我们的研究结果表明了创伤性脑损伤结果与突触通路之间的关联,以及与其他神经精神疾病的病理生物学重叠。
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引用次数: 0
Association between admission systolic blood pressure and outcomes in patients with isolated traumatic brain injury: A cross-national multicentre cohort study. 孤立性创伤性脑损伤患者的入院收缩压与预后之间的关系:一项跨国多中心队列研究。
IF 4.2 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-09-12 DOI: 10.1089/neu.2023.0392
Jie-Ming Chen,Yu-Chia Su,Chiao-Yin Cheng,Chih-Jung Chang,Li-Min Hsu,Sang Do Shin,Sabariah Faizah Jamaluddin,T V Ramakrishnan,Hideharu Tanaka,Pairoj Khruekarnchana,Do Ngoc Son,Wen-Chu Chiang,Jen-Tang Sun
BACKGROUNDThe optimal prehospital blood pressure in patients following traumatic brain injury (TBI) remains controversial. We aimed to assess the association between the systolic blood pressure (SBP) at emergency department triage and patient outcomes following isolated moderate-to-severe TBI.METHODSWe conducted a cross-national multicentre retrospective cohort study using the Pan-Asia Trauma Outcomes Study database from January 1, 2016, to November 30, 2018. The enrollees were adult patients with isolated moderate-to-severe TBI defined by the International Classification of Diseases code, a Glasgow Coma Scale (GCS) < 13 at triage, and a non-head Abbreviated Injury Scale ≤ 3. The studied variables were SBPs at triage categorised into different ranges. The primary outcome was 30-day mortality and the secondary outcome was poor functional status at hospital discharge defined by the modified Rankin Scale ≥ 4. Multivariable logistic regression were applied to adjust for confounders including country, sex, age, mechanism of injury, prehospital vascular access, respiratory rate, GCS, oxygen saturation, intubation, Injury Severity Score, head surgery, intensive care unit admission, and length of hospital stay. Subgroup analyses were performed on different severity of TBI.RESULTSA total of 785 patients (median age, 42 years; male patients 77.5%; mean SBP at triage, 136.3 ± 33.1 mmHg) were included in the primary analysis. The lowest 30-day mortality rate existed in patients with SBP of 100-119 mmHg. Taking it as baseline, the adjusted odds ratios (aORs) and 95% confidence intervals (CIs) of SBP < 100 mmHg, 120-139 mmHg, 140-159 mmHg, and ≥ 160mmHg were 7.05 (2.51-19.78), 3.14 (1.14-8.65), 2.91 (1.04-8.17), and 3.28 (1.14-9.42). As for the secondary outcome, the aORs and 95% CIs were 1.36 (0.68-2.68) of < 100 mmHg, 0.99 (0.57-1.70) of 120-139 mmHg, 1.23 (0.67-2.25) of 140-159 mmHg, and 1.52 (0.78-2.95) of ≥ 160 mmHg. Subgroup analyses revealed trends of the best outcomes in both moderate and severe TBI patients with SBP 100-119 mmHg, while statistical significance appeared only in patients with severe TBI.CONCLUSIONSSBP of 110-119 mmHg at triage is associated with the lowest 30-day mortality in patients following isolated moderate-to-severe TBI, and possibly related to a better functional outcome.
背景创伤性脑损伤(TBI)患者的最佳院前血压仍存在争议。我们的目的是评估急诊科分诊时的收缩压(SBP)与孤立性中重度 TBI 患者预后之间的关联。方法我们利用泛亚创伤预后研究数据库开展了一项跨国多中心回顾性队列研究,研究时间为 2016 年 1 月 1 日至 2018 年 11 月 30 日。研究对象为根据国际疾病分类代码定义的孤立性中重度创伤性脑损伤成年患者,分诊时格拉斯哥昏迷量表(GCS)<13,非头部简略损伤量表≤3。研究变量是分诊时的 SBP,分为不同的范围。主要结果是 30 天死亡率,次要结果是出院时功能状况不佳,定义为改良兰金量表≥ 4。多变量逻辑回归用于调整混杂因素,包括国家、性别、年龄、受伤机制、院前血管通路、呼吸频率、GCS、血氧饱和度、插管、受伤严重程度评分、头部手术、入住重症监护室和住院时间。结果共有 785 名患者(中位年龄 42 岁;男性患者占 77.5%;分诊时平均 SBP 为 136.3 ± 33.1 mmHg)被纳入主要分析。SBP 为 100-119 mmHg 的患者 30 天死亡率最低。以其为基线,SBP < 100 mmHg、120-139 mmHg、140-159 mmHg 和 ≥ 160 mmHg 的调整后几率比(aOR)和 95% 置信区间(CI)分别为 7.05(2.51-19.78)、3.14(1.14-8.65)、2.91(1.04-8.17)和 3.28(1.14-9.42)。至于次要结果,小于 100 mmHg 的 aOR 和 95% CI 分别为 1.36(0.68-2.68),120-139 mmHg 的 aOR 和 95% CI 分别为 0.99(0.57-1.70),140-159 mmHg 的 aOR 和 95% CI 分别为 1.23(0.67-2.25),≥ 160 mmHg 的 aOR 和 95% CI 分别为 1.52(0.78-2.95)。亚组分析显示,SBP 为 100-119 mmHg 的中度和重度 TBI 患者的预后均呈最佳趋势,而仅重度 TBI 患者的预后具有统计学意义。
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引用次数: 0
Normative Neuroimaging Library: Designing a Comprehensive and Demographically Diverse Dataset of Healthy Controls to Support Traumatic Brain Injury Diagnostic and Therapeutic Development. 规范神经影像库:设计一个全面的、人口统计学上多样化的健康对照数据集,以支持创伤性脑损伤诊断和治疗的发展。
IF 3.9 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-09-05 DOI: 10.1089/neu.2024.0128
Allyson T Gage, James R Stone, Elisabeth A Wilde, Stephen R McCauley, Robert C Welsh, John P Mugler, Nick Tustison, Brian Avants, Christopher T Whitlow, Lee Lancashire, Seema D Bhatt, Magali Haas
<p><p>The past decade has seen impressive advances in neuroimaging, moving from qualitative to quantitative outputs. Available techniques now allow for the inference of microscopic changes occurring in white and gray matter, along with alterations in physiology and function. These existing and emerging techniques hold the potential of providing unprecedented capabilities in achieving a diagnosis and predicting outcomes for traumatic brain injury (TBI) and a variety of other neurological diseases. To see this promise move from the research lab into clinical care, an understanding is needed of what normal data look like for all age ranges, sex, and other demographic and socioeconomic categories. Clinicians can only use the results of imaging scans to support their decision-making if they know how the results for their patient compare with a normative standard. This potential for utilizing magnetic resonance imaging (MRI) in TBI diagnosis motivated the American College of Radiology and Cohen Veterans Bioscience to create a reference database of healthy individuals with neuroimaging, demographic data, and characterization of psychological functioning and neurocognitive data that will serve as a normative resource for clinicians and researchers for development of diagnostics and therapeutics for TBI and other brain disorders. The goal of this article is to introduce the large, well-curated Normative Neuroimaging Library (NNL) to the research community. NNL consists of data collected from ∼1900 healthy participants. The highlights of NNL are (1) data are collected across a diverse population, including civilians, veterans, and active-duty service members with an age range (18-64 years) not well represented in existing datasets; (2) comprehensive structural and functional neuroimaging acquisition with state-of-the-art sequences (including structural, diffusion, and functional MRI; raw scanner data are preserved, allowing higher quality data to be derived in the future; standardized imaging acquisition protocols across sites reflect sequences and parameters often recommended for use with various neurological and psychiatric conditions, including TBI, post-traumatic stress disorder, stroke, neurodegenerative disorders, and neoplastic disease); and (3) the collection of comprehensive demographic details, medical history, and a broad structured clinical assessment, including cognition and psychological scales, relevant to multiple neurological conditions with functional sequelae. Thus, NNL provides a demographically diverse population of healthy individuals who can serve as a comparison group for brain injury study and clinical samples, providing a strong foundation for precision medicine. Use cases include the creation of imaging-derived phenotypes (IDPs), derivation of reference ranges of imaging measures, and use of IDPs as training samples for artificial intelligence-based biomarker development and for normative modeling to help identify injury-induced
过去十年间,神经成像技术取得了令人瞩目的进步,从定性输出发展到定量输出。现有的技术现在可以推断白质和灰质中发生的微观变化,以及生理和功能的改变。这些现有的和新兴的技术有可能为创伤性脑损伤(TBI)和其他各种神经系统疾病的诊断和预后提供前所未有的能力。要将这一前景从研究实验室转化为临床治疗,就需要了解所有年龄段、性别以及其他人口和社会经济类别的正常数据是什么样的。临床医生只有知道病人的扫描结果与正常标准的比较情况,才能利用成像扫描结果支持他们的决策。在 TBI 诊断中利用磁共振成像 (MRI) 的这一潜力促使美国放射学会和 Cohen Veterans Bioscience 建立了一个包含神经成像、人口统计学数据、心理功能特征和神经认知数据的健康人参考数据库,作为临床医生和研究人员开发 TBI 和其他脑部疾病诊断和治疗方法的标准资源。本文旨在向研究界介绍经过精心整理的大型规范神经影像库(NNL)。NNL 由从 1900 名健康参与者收集的数据组成。NNL 的亮点在于:(1) 收集的数据来自不同的人群,包括平民、退伍军人和现役军人,其年龄范围(18-64 岁)在现有数据集中没有得到很好的体现;(2) 采用最先进的序列(包括结构、弥散和功能 MRI)采集全面的结构和功能神经影像;保留原始扫描仪数据,以便将来获得更高质量的数据;(3) 收集全面的人口统计学细节、病史和广泛的结构化临床评估,包括认知和心理量表,这些都与具有功能性后遗症的多种神经系统疾病相关。因此,NNL 提供了一个人口统计学上多样化的健康人群,可作为脑损伤研究和临床样本的对比组,为精准医疗奠定了坚实的基础。用例包括创建成像衍生表型(IDP)、推导成像测量的参考范围,以及将 IDP 用作基于人工智能的生物标记开发的训练样本和常模,以帮助识别损伤引起的异常变化,从而进行精准诊断和靶向治疗开发。NNL 发布后,将支持在临床医生决策支持工具中使用先进的成像技术,验证成像生物标记物,调查大脑行为异常,从而推动精准医疗领域的发展。
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引用次数: 0
Association Between Impulsivity, Self-Harm, Suicidal Ideation, and Suicide Attempts in Patients with Traumatic Brain Injury. 脑外伤患者的冲动、自残、自杀意念和自杀企图之间的关系。
IF 3.9 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-09-05 DOI: 10.1089/neu.2024.0167
Liliana Ladner, Tyler Shick, Srijan Adhikari, Eric Marvin, Justin Weppner, Anita Kablinger
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引用次数: 0
Incidence and Prevalence of Concussion in Denmark from 1999 to 2018: A Nationwide Cohort Study. 1999-2018 年丹麦脑震荡发病率和流行率:全国队列研究》。
IF 3.9 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-09-05 DOI: 10.1089/neu.2024.0217
Peter Preben Eggertsen, Pia Cordsen, Jens Lauritsen, Søren Paaske Johnsen, Jørgen Feldbæk Nielsen

Concussion is a common diagnosis in emergency rooms, yet contemporary incidence and prevalence estimates are sparse and rely on self-reported data. A nationwide cohort study was conducted to provide up-to-date information, covering the entire Danish population from 1999 to 2018. Hospital contacts with a concussion diagnosis, including emergency room visits, hospital admissions, and outpatient contacts, were retrieved from the Danish National Patient Registry (DNPR), and incidence rates were age-standardized and stratified. The 20-year prevalence was defined as the percentage of Danes alive in 2018 who had experienced a concussion since 1999. The diagnostic codes used were the ICD-10 code S06.0 and a local Danish code for 'observation for concussion' (DZ033D). Additional data on activities related to concussion injuries were obtained from the Accident Analysis Group at Odense University Hospital through DNPR. Findings from the study showed that during the period 1999-2018, the total age-standardized concussion incidence rate increased by 10% to 308 per 100,000 person-years (95% confidence interval [CI]: 304-313). Notable time trends included (1) a reduced sex difference from 40% to 6% (95% CI: 3%-9%), (2) a doubled incidence rate in children aged 0-1 and in seniors aged over 80, (3) an increased utilization of head imaging across all age groups, except children, (4) a decline in the proportion of traffic-related concussions, and (5) a prevalence of concussion of 4.9% (95% CI: 4.89%-4.93%) in 2018. The increasing incidence of concussions among the elderly is concerning in light of an aging population and warrants further investigation, as evidence-based preventive interventions for falls exist. In addition, the increased utilization of head imaging across all age groups except children calls for attention toward avoidance of unnecessary radiation exposure. Despite a drop in traffic-related cases, concussions remain highly prevalent. In conclusion, these findings indicate that concussions are an important public health concern, necessitating ongoing surveillance, research, and targeted resource allocation to address concussion management and prevention effectively.

脑震荡是急诊室的常见诊断,但当代的发病率和流行率估计却很少,而且依赖于自我报告的数据。为了提供最新信息,我们开展了一项全国范围的队列研究,涵盖了1999年至2018年期间的所有丹麦人口。研究人员从丹麦国家患者登记处(DNPR)检索到了诊断为脑震荡的医院接触者,包括急诊就诊、入院和门诊接触者,并对发病率进行了年龄标准化和分层。20年发病率定义为自1999年以来经历过脑震荡的2018年在世丹麦人的百分比。使用的诊断代码为ICD-10代码S06.0和丹麦当地的 "脑震荡观察 "代码(DZ033D)。有关脑震荡伤害活动的其他数据是通过 DNPR 从欧登塞大学医院事故分析小组获得的。研究结果表明,在 1999-2018 年期间,年龄标准化脑震荡总发病率增加了 10%,达到每 10 万人年 308 例(95% 置信区间 (CI):304-313)。值得注意的时间趋势包括:1)性别差异从 40% 降至 6%(95% 置信区间:3%-9%);2)0-1 岁儿童和 80 岁以上老年人的发病率翻了一番;3)除儿童外,所有年龄组的头部成像利用率均有所上升;4)交通相关脑震荡的比例有所下降;5)2018 年脑震荡患病率为 4.9%(95% 置信区间:4.89% - 4.93%)。鉴于人口老龄化,老年人脑震荡发病率的增加令人担忧,值得进一步调查,因为已有针对跌倒的循证预防干预措施。此外,除儿童外,所有年龄组的头部成像使用率均有所上升,这需要注意避免不必要的辐射暴露。尽管与交通有关的病例有所减少,但脑震荡的发病率仍然很高。总之,这些研究结果表明,脑震荡是一个重要的公共卫生问题,有必要进行持续监测、研究和有针对性的资源分配,以有效解决脑震荡管理和预防问题。
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引用次数: 0
Volumetric Assessment of Traumatic Intracranial Hematomas: Is ABC/2 Reliable? 外伤性颅内血肿的体积评估:ABC/2 是否可靠?
IF 3.9 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-09-04 DOI: 10.1089/neu.2024.0248
Alexander Fletcher-Sandersjöö, Anders Lewén, Anders Hånell, David W Nelson, Marc Maegele, Mikael Svensson, Bo-Michael Bellander, Per Enblad, Eric Peter Thelin, Teodor Svedung Wettervik

Accurate measurement of traumatic intracranial hematoma volume is important for assessing disease progression and prognosis, as well as for serving as an important end-point in clinical trials aimed at preventing hematoma expansion. While the ABC/2 formula has traditionally been used for volume estimation in spontaneous intracerebral hemorrhage, its adaptation to traumatic hematomas lacks validation. This study aimed to compare the accuracy of ABC/2 with computer-assisted volumetric analysis (CAVA) in estimating the volumes of traumatic intracranial hematomas. We performed a dual-center observational study that included adult patients with moderate-to-severe traumatic brain injury. Volumes of intracerebral, subdural (SDHs), and epidural hematomas from admission computed tomography scans were measured using ABC/2 and CAVA, and compared using the Wilcoxon signed-rank test, Spearman's rank correlation, Lin's concordance correlation coefficient (CCC), and Bland-Altman plots. Prognostic significance for outcomes was evaluated through logistic and linear regression models. In total, 1,179 patients with 1,543 hematomas were included. Despite a high correlation (Spearman coefficients between 0.95 and 0.98) and excellent concordance (Lin's CCC from 0.89 to 0.96) between ABC/2 and CAVA, ABC/2 overestimated hematoma volumes compared with CAVA, in some instances exceeding 50 ml. Bland-Altman analysis highlighted wide limits of agreement, especially in SDH. While both methods demonstrated comparable accuracy in predicting outcomes, CAVA was slightly better at predicting craniotomies and midline shift. We conclude that while ABC/2 provides a generally reliable volumetric assessment suitable for descriptive purposes and as baseline variables in studies, CAVA should be the gold standard in clinical situations and studies requiring more precise volume estimations, such as those using hematoma expansion as an outcome.

准确测量外伤性颅内血肿体积对于评估疾病进展和预后非常重要,同时也是旨在防止血肿扩大的临床试验的重要终点。传统上,ABC/2 公式一直用于自发性脑内出血的血肿体积估算,但其对创伤性血肿的适应性还缺乏验证。本研究旨在比较 ABC/2 公式与计算机辅助容积分析(CAVA)在估计外伤性颅内血肿体积方面的准确性。我们进行了一项双中心观察研究,研究对象包括中重度脑外伤成年患者。我们使用 ABC/2 和 CAVA 测量了入院 CT 扫描中的脑内血肿 (ICH)、硬膜下血肿 (SDH) 和硬膜外血肿 (EDH) 的体积,并使用 Wilcoxon 符号秩检验、Spearman 等级相关性、Lin 一致性相关系数 (CCC) 和 Bland-Altman 图进行了比较。通过逻辑和线性回归模型评估了预后的重要性。共纳入了 1,179 名患者,1,543 个血肿。尽管ABC/2和CAVA之间具有很高的相关性(Spearman系数介于0.95和0.98之间)和很好的一致性(Lin's CCC介于0.89和0.96之间),但与CAVA相比,ABC/2高估了血肿体积,在某些情况下超过了50毫升。Bland-Altman分析强调了两者之间的差异,尤其是在SDH方面。虽然两种方法预测结果的准确性相当,但 CAVA 在预测开颅手术和中线移位方面略胜一筹。我们的结论是,虽然 ABC/2 提供的容积评估基本可靠,适合用于描述性目的和作为研究中的基线变量,但在需要更精确容积估计的临床情况和研究中,如将血肿扩大作为结果的研究中,CAVA 应成为金标准。
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引用次数: 0
Tempol, a Superoxide Dismutase Mimetic, Inhibits Wallerian Degeneration Following Spinal Cord Injury by Preventing Glutathione Depletion and Aldose Reductase Activation. Tempol是一种超氧化物歧化酶模拟物,可通过防止谷胱甘肽耗竭和醛糖还原酶激活来抑制脊髓损伤后的沃勒氏变性。
IF 3.9 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-09-01 Epub Date: 2024-08-21 DOI: 10.1089/neu.2024.0137
Richard J Zeman, Abraham M Brown, Xialing Wen, Nengtai Ouyang, Joseph D Etlinger

Spinal cord contusion injury results in Wallerian degeneration of spinal cord axonal tracts, which are necessary for locomotor function. Axonal swelling and loss of axonal density at the contusion site, characteristic of Wallerian degeneration, commence within hours of injury. Tempol, a superoxide dismutase mimetic, was previously shown to reduce the loss of spinal cord white matter and improve locomotor function in an experimental model of spinal cord contusion, suggesting that tempol treatment might inhibit Wallerian degeneration of spinal cord axons. Here, we report that tempol partially inhibits Wallerian degeneration, resulting in improved locomotor recovery. We previously reported that Wallerian degeneration is reduced by inhibitors of aldose reductase (AR), which converts glucose to sorbitol in the polyol pathway. We observed that tempol inhibited sorbitol production in the injured spinal cord to the same extent as the AR inhibitor, sorbinil. Tempol also prevented post-contusion upregulation of AR (AKR1B10) protein expression within degenerating axons, as previously observed for AR inhibitors. Additionally, we hypothesized that tempol inhibits axonal degeneration by preventing loss of the glutathione pool due to polyol pathway activity. Consistent with our hypothesis, tempol treatment resulted in greater glutathione content in the injured spinal cord, which was correlated with increased expression and activity of gamma glutamyl cysteine ligase (γGCL; EC 6.3.2.2), the rate-limiting enzyme for glutathione synthesis. Administration of the γGCL inhibitor buthionine sulfoximine abolished all observed effects of tempol administration. Together, these results support a pathological role for polyol pathway activation in glutathione depletion, resulting in Wallerian degeneration after spinal cord injury (SCI). Interestingly, methylprednisolone, oxandrolone, and clenbuterol, which are known to spare axonal tracts after SCI, were equally effective in inhibiting polyol pathway activation. These results suggest that prevention of AR activation is a common target of many disparate post-SCI interventions.

脊髓挫伤会导致脊髓轴突束发生沃勒氏变性,而脊髓轴突束是运动功能所必需的。轴突肿胀和轴突密度的丧失是沃勒氏变性的特征,在受伤后数小时内就会开始。在脊髓挫伤的实验模型中,超氧化物歧化酶模拟物 Tempol 可减少脊髓白质的损失并改善运动功能,这表明 tempol 治疗可抑制脊髓轴突的 Wallerian 退化。在此,我们报告了 tempol 可部分抑制 Wallerian 退化,从而改善运动功能的恢复。醛糖还原酶(AR)在多元醇途径中将葡萄糖转化为山梨醇。我们观察到,与 AR 抑制剂山梨醇(sorbinil)一样,替普醇也能抑制损伤脊髓中山梨醇的产生。与之前观察到的 AR 抑制剂一样,Tempol 也阻止了退化轴突内 AR(AKR1B10)蛋白表达的灌注后上调。此外,我们还假设,替普莫尔通过防止谷胱甘肽池因多元醇通路活动而流失,从而抑制轴突变性。与我们的假设相一致的是,tempol 治疗会增加损伤脊髓中的谷胱甘肽含量,这与谷胱甘肽合成的限速酶 γ-谷氨酰半胱氨酸连接酶(γGCL;EC 6.3.2.2)的表达和活性增加有关。服用γGCL抑制剂丁硫磺酰亚胺可消除所有观察到的服用 tempol 的影响。总之,这些结果支持多元醇途径激活在谷胱甘肽耗竭中的病理作用,从而导致脊髓损伤后的沃勒氏变性。有趣的是,已知甲基强的松龙、奥昔洛龙和克伦特罗能在脊髓损伤后保留轴突束,但它们在抑制多元醇通路激活方面同样有效。这些结果表明,防止 AR 激活是许多不同的脊髓损伤后干预措施的共同目标。
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引用次数: 0
Spinal Cord Transcutaneous Stimulation in Cervical Spinal Cord Injury: A Review Examining Upper Extremity Neuromotor Control, Recovery Mechanisms, and Future Directions. 脊髓经皮刺激治疗颈脊髓损伤:上肢神经运动控制、恢复机制和未来方向综述。
IF 3.9 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-09-01 Epub Date: 2024-07-12 DOI: 10.1089/neu.2023.0438
Goutam Singh, Pawan Sharma, Gail Forrest, Susan Harkema, Andrea Behrman, Yury Gerasimenko

Cervical spinal cord injury (SCI) results in significant sensorimotor impairments below the injury level, notably in the upper extremities (UEs), impacting daily activities and quality of life. Regaining UE function remains the top priority for individuals post-cervical SCI. Recent advances in understanding adaptive plasticity within the sensorimotor system have led to the development of novel non-invasive neurostimulation strategies, such as spinal cord transcutaneous stimulation (scTS), to facilitate UE motor recovery after SCI. This comprehensive review investigates the neuromotor control of UE, the typical recovery trajectories following SCI, and the therapeutic potential of scTS to enhance UE motor function in individuals with cervical SCI. Although limited in number with smaller sample sizes, the included research articles consistently suggest that scTS, when combined with task-specific training, improves voluntary control of arm and hand function and sensation. Further, the reported improvements translate to the recovery of various UE functional tasks and positively impact the quality of life in individuals with cervical SCI. Several methodological limitations, including stimulation site selection and parameters, training strategies, and sensitive outcome measures, require further advancements to allow successful translation of scTS from research to clinical settings. This review also summarizes the current literature and proposes future directions to support establishing approaches for scTS as a viable neuro-rehabilitative tool.

颈椎脊髓损伤(SCI)会导致受伤部位以下的感觉运动明显受损,尤其是上肢(UE),从而影响日常活动和生活质量。恢复上肢功能仍然是颈椎损伤后患者的首要任务。最近,人们对感觉运动系统内适应性可塑性的了解取得了进展,从而开发出了新型非侵入性神经刺激策略,如脊髓经皮刺激(scTS),以促进 SCI 后上肢运动功能的恢复。本综述研究了 UE 的神经运动控制、SCI 后的典型恢复轨迹以及 scTS 在增强颈椎 SCI 患者 UE 运动功能方面的治疗潜力。尽管样本数量有限且规模较小,但收录的研究文章一致表明,scTS 与特定任务训练相结合,可改善手臂和手部功能和感觉的自主控制。此外,所报道的改善还体现在各种上肢功能任务的恢复上,并对颈椎 SCI 患者的生活质量产生积极影响。一些方法学上的局限性,包括刺激部位的选择和参数、训练策略和敏感的结果测量,需要进一步的改进才能使 scTS 成功地从研究转化为临床应用。本综述还总结了当前的文献,并提出了未来的发展方向,以支持将 scTS 确立为一种可行的神经康复工具。
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引用次数: 0
Diffusion Weighted Magnetic Resonance Imaging of Spinal Cord Injuries After Instrumented Fusion Stabilization. 器械融合稳定术后脊髓损伤的弥散加权核磁共振成像。
IF 3.9 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-09-01 Epub Date: 2024-04-10 DOI: 10.1089/neu.2023.0591
Kevin M Koch, Andrew S Nencka, Shekar Kurpad, Matthew D Budde

Diffusion-weighted magnetic resonance imaging (DW-MRI) is a promising technique for assessing spinal cord injury (SCI) that has historically been challenged by the presence of metallic stabilization hardware. This study leverages recent advances in metal-artifact resistant multi-spectral DW-MRI to enable diffusion quantification throughout the spinal cord even after fusion stabilization. Twelve participants with cervical spinal cord injuries treated with fusion stabilization and 49 asymptomatic able-bodied control participants underwent multi-spectral DW-MRI evaluation. Apparent diffusion coefficient (ADC) values were calculated in axial cord sections. Statistical modeling assessed ADC differences across cohorts and within distinct cord regions of the SCI participants (at, above, or below injured level). Computed models accounted for subject demographics and injury characteristics. ADC was found to be elevated at injured levels compared with non-injured levels (z = 3.2, p = 0.001), with ADC at injured levels decreasing over time since injury (z = -9.2, p < 0.001). Below the injury level, ADC was reduced relative to controls (z = -4.4, p < 0.001), with greater reductions after more severe injuries that correlated with lower extremity motor scores (z = 2.56, p = 0.012). No statistically significant differences in ADC above the level of injury were identified. By enabling diffusion analysis near fusion hardware, the multi-spectral DW-MRI technique allowed intuitive quantification of cord diffusion changes after SCI both at and away from injured levels. This demonstrates the approach's potential for assessing post-surgical spinal cord integrity throughout stabilized regions.

弥散加权磁共振成像(DW-MRI)是一种很有前景的脊髓损伤评估技术,但一直以来都受到金属稳定硬件的挑战。本研究利用抗金属赝象多光谱 DW-MRI 的最新进展,即使在融合稳定后也能对整个脊髓进行弥散量化。12 名接受过融合稳定治疗的颈椎脊髓损伤患者和 49 名无症状对照组患者接受了多谱段 DW-MRI 评估。计算了轴向脊髓切片的表观扩散系数(ADC)值。统计建模评估了 SCI 受试者不同组群和不同脊髓区域(损伤水平、损伤水平以上或以下)的 ADC 差异。计算模型考虑了受试者的人口统计学特征和损伤特征。结果发现,与未受伤水平相比,受伤水平的 ADC 升高(z=3.2,p = 0.001),受伤水平的 ADC 随受伤时间的推移而降低(z=-9.2,p = 0.001)。
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引用次数: 0
Rosalind Franklin Society Proudly Announces the 2023 Award Recipient for Journal of Neurotrauma. 罗莎琳德-富兰克林学会自豪地宣布《神经创伤杂志》2023 年获奖者。
IF 4.2 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-09-01 DOI: 10.1089/neu.2024.65326.rfs2023
Vanessa Raymont
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引用次数: 0
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Journal of neurotrauma
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