CNS Neuroscience & Therapeutics最新文献_第9页

BETMB: A Dual-Target Compound for Synergistic Suppression of Neuronal Hyperexcitability in Refractory Epilepsy via Concurrent Modulation of Nav Channels and GABAA Receptors 通过同时调节Nav通道和GABAA受体协同抑制难治性癫痫神经元高兴奋性的双靶点化合物。

IF 5 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics

Pub Date : 2026-01-23 DOI: 10.1002/cns.70766

Di Zhang, Kai Li, Yingying Zhang, Yao Nie, Yue Li, Rui Li, Xin Wang, Shengjun Mao

Aims

This study aims to evaluate 5-(but-1-en-1-yl)-1,2,3-trimethoxybenzene (BETMB) as a novel dual-target anti-seizure agent for refractory epilepsy and elucidate the synergistic neuroelectrophysiological mechanism between Na_V channels and GABA_A receptors.

Methods

Whole-cell patch-clamp recordings characterized BETMB's dual-target activity. Antiseizure efficacy was assessed in maximal electroshock (MES), pentylenetetrazole (PTZ), and kainic acid (KA) models. Cognitive function in chronic KA mice was evaluated using the Morris water maze (MWM). Histopathological, immunohistochemical, and Western blot analyses explored neuroprotection. Synergy between Na_V and GABA_AR modulation was systematically investigated using both an in vitro Mg²⁺-free model of neuronal hyperexcitability and an in silico model of cortical spreading depolarization (CSD).

Results

BETMB acted as a GABA_AR positive allosteric modulator (EC₅₀ = 93.2 μM) and a state-dependent Na_V blocker (K_I = 1.9 μM). It significantly suppressed seizures across models, improved cognition in chronic epilepsy, and modulated downstream expression of GABRA1, NR2B, and BDNF-pAKT-CREB signaling. Synergistic Na_V and GABA_AR modulation completely abolished ictal-like discharges in Mg²⁺-free cellular models and prevented CSD initiation in computational simulations.

Conclusion

BETMB is a promising dual-target therapy for refractory epilepsy, supported by the first electrophysiological evidence that dual modulation of GABA_AR and Na_V synergistically suppresses neuronal hyperexcitability. Beyond epilepsy, this finding may also extend to CSD-related conditions such as stroke, traumatic brain injury, and migraine.

目的：本研究旨在评价5-（丁-1-烯-1-基）-1,2,3-三甲氧基苯（BETMB）作为一种新型双靶点抗难治性癫痫药物的作用，并阐明NaV通道与GABAA受体之间的协同神经电生理机制。方法：全细胞膜片钳记录表征BETMB的双靶点活性。在最大电击（MES）、戊四唑（PTZ）和kainic酸（KA）模型中评估抗癫痫效果。采用Morris水迷宫（MWM）评价慢性KA小鼠的认知功能。组织病理学、免疫组织化学和Western blot分析探讨了神经保护作用。通过体外无Mg2+神经元高兴奋性模型和皮质扩张性去极化（CSD）模型，系统地研究了NaV和GABAAR调节之间的协同作用。结果：BETMB具有GABAAR阳性变构调节剂（EC50 = 93.2 μM）和状态依赖性NaV阻滞剂（KI = 1.9 μM）的作用。它显著抑制了所有模型的癫痫发作，改善了慢性癫痫的认知，并调节了GABRA1、NR2B和BDNF-pAKT-CREB信号的下游表达。协同NaV和GABAAR调制完全消除了无Mg2+细胞模型中的初始样放电，并在计算模拟中阻止了CSD的启动。结论：BETMB是治疗难治性癫痫的一种很有前景的双靶点疗法，首次得到GABAAR和NaV双调节协同抑制神经元高兴奋性的电生理证据支持。除了癫痫，这一发现也可能延伸到与脑脊病相关的疾病，如中风、创伤性脑损伤和偏头痛。

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引用次数: 0

Intermittent Fasting Alleviates Anesthesia/Surgery-Induced Delirium-Like Behavior in Aged Mice by Remodeling Gut Microbiota 间歇性禁食通过重塑肠道微生物群减轻老年小鼠麻醉/手术诱导的谵妄样行为。

IF 5 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics

Pub Date : 2026-01-22 DOI: 10.1002/cns.70748

Peiying Huang, Longlu Cao, Tianyu Cao, Xueji Wang, Sichen Cui, Sufang Jiang, Huan Chen, Lichao Di, Sha Li, Lining Huang

Background

Postoperative delirium (POD) is a serious complication in elderly patients, associated with prolonged recovery and adverse outcomes. Recent evidence links POD to mitochondrial dysfunction. While intermittent fasting (IF) has been shown to enhance mitochondrial function and exert neuroprotective effects, potentially through gut microbiota modulation, its ability to prevent POD and the underlying mechanisms remain unclear.

Methods

We examined the effects of preoperative IF on delirium-like behavior in aged mice following anesthesia/surgery. Assessments included neurobehavioral tests, gut microbiota composition, fecal shortchain fatty acids (SCFAs), hippocampal synaptic and mitochondrial ultrastructure via transmission electron microscopy, mitochondrial function, and related molecular markers. To establish causality, fecal microbiota transplantation and SCFA supplementation experiments were conducted.

Results

Preoperative IF significantly attenuated anesthesia/surgery-induced delirium-like behaviors. Mechanistically, IF reshaped the gut microbiota and preserved SCFA levels, which collectively maintained hippocampal mitochondrial homeostasis. Both fecal microbiota transplantation and SCFA supplementation replicated the protective effects of IF, confirming the causal role of gut microbiota and its metabolites.

Conclusion

These findings demonstrate that preoperative intermittent fasting mitigates delirium-like behavior by modulating the gut microbiota–SCFA–mitochondrial axis, highlighting its potential as a non-pharmacological strategy to enhance neurocognitive resilience and prevent POD in elderly surgical patients.

背景：术后谵妄（POD）是老年患者的严重并发症，与恢复时间长和不良后果相关。最近的证据表明POD与线粒体功能障碍有关。虽然间歇性禁食（IF）已被证明可以增强线粒体功能并发挥神经保护作用，可能通过调节肠道微生物群，但其预防POD的能力及其潜在机制尚不清楚。方法：我们检查了术前IF对麻醉/手术后老年小鼠谵妄样行为的影响。评估包括神经行为测试、肠道微生物群组成、粪便短链脂肪酸（SCFAs）、海马突触和线粒体超微结构（透射电镜）、线粒体功能和相关分子标记。为了建立因果关系，进行了粪便微生物群移植和SCFA补充实验。结果：术前IF明显减轻麻醉/手术引起的谵妄样行为。从机制上讲，IF重塑了肠道微生物群并保持了SCFA水平，这共同维持了海马线粒体的稳态。粪便微生物群移植和SCFA补充都复制了IF的保护作用，证实了肠道微生物群及其代谢物的因果作用。结论：这些研究结果表明，术前间歇性禁食通过调节肠道微生物群- scfa -线粒体轴来减轻谵妄样行为，突出了其作为增强老年外科患者神经认知弹性和预防POD的非药物策略的潜力。

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引用次数: 0

Mimics and Diagnostic Pitfalls of Anti-Adenylate Kinase 5 Limbic Encephalitis 抗腺苷酸激酶5边缘脑炎的模拟物和诊断缺陷。

IF 5 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics

Pub Date : 2026-01-22 DOI: 10.1002/cns.70757

Jierui Wang, Tong Yi, Guoyu Wang, Minjin Wang, Dong Zhou, Jinmei Li

Background

The clinical understanding of limbic encephalitis associated with antibodies against adenylate kinase 5 (AK5) remains limited. Misinterpretation of antibody test results may lead to diagnostic errors and inappropriate management. We aim to assess the frequency of anti-AK5 encephalitis overdiagnosis and identify common diagnostic pitfalls.

Methods

Cases of confirmed and mimicking anti-AK5 limbic encephalitis from January 2021 to July 2024 using established criteria for autoimmune encephalitis (AE) were reviewed. AK5 mimics were defined as patients initially suspected of AE with a positive AK5 autoantibody result, but who ultimately received an alternative final diagnosis.

Results

A total of 21 patients were included (57.1% female; median age 34 years; range 14–82). Only 3 patients (14%) were diagnosed with definite anti-AK5 limbic encephalitis, while 18 patients (86%) were classified as AK5 mimics. Serum autoantibodies were predominantly of the IgG3 subclass, with titers ranging from 1:10 to 1:100. The mimics included primary psychiatric disorders (22%), central nervous system (CNS) infections (22%), other inflammatory disorders (28%), epilepsy (16%), neurodegenerative diseases (6%) and metabolic encephalopathy (6%). The most frequent confounding factor in misdiagnosis was the presence of prominent psychiatric and behavioral symptoms, seen in 50% (9 of 18) of AK5 mimics. The second most common confounder was the presence of low serum antibody titers or isolated serum positivity without corresponding cerebrospinal fluid (CSF) findings (< 1:100), observed in 94% (17 of 18) of mimics.

Conclusion

Mimics of anti-AK5 encephalitis are common and that misdiagnosis is often driven by non-specific symptoms and clinically irrelevant antibody results.

背景：临床对与腺苷酸激酶5 （AK5）抗体相关的边缘脑炎的认识仍然有限。对抗体检测结果的误解可能导致诊断错误和不适当的处理。我们的目的是评估抗ak5脑炎过度诊断的频率，并确定常见的诊断陷阱。方法：回顾性分析2021年1月至2024年7月根据自身免疫性脑炎（AE）既定标准确诊和模拟抗ak5边缘脑炎的病例。AK5模拟被定义为最初怀疑为AE的患者，其自身抗体结果为AK5阳性，但最终接受了替代的最终诊断。结果：共纳入21例患者，其中女性占57.1%，中位年龄34岁，范围14 ~ 82岁。只有3例（14%）被诊断为明确的抗AK5边缘脑炎，而18例（86%）被归类为AK5模拟物。血清自身抗体主要为IgG3亚类，滴度为1:10 ~ 1:100。模拟包括原发性精神疾病（22%）、中枢神经系统（CNS）感染（22%）、其他炎症性疾病（28%）、癫痫（16%）、神经退行性疾病（6%）和代谢性脑病（6%）。误诊中最常见的混淆因素是存在显著的精神和行为症状，在50%（18例中的9例）的AK5模拟患者中可见。第二个最常见的混杂因素是血清抗体滴度低或分离血清阳性，但没有相应的脑脊液（CSF）结果(结论：抗ak5脑炎的模拟物很常见，误诊往往是由非特异性症状和临床无关的抗体结果驱动的。

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引用次数: 0

PACAP Alleviates Paclitaxel-Induced Peripheral Neuropathy by Targeting Oxidative Stress and Mitochondrial Damage via the PGC-1α Pathway PACAP通过PGC-1α途径靶向氧化应激和线粒体损伤，减轻紫杉醇诱导的周围神经病变。

IF 5 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics

Pub Date : 2026-01-22 DOI: 10.1002/cns.70745

Ruyue Mo, Chuanming Wang, Haibei Hu, Shuqi Shi, Di Cao, Zhenhui Luo, Hua Yang, Mingzhu Zhai, Wuping Sun

Background

Paclitaxel-induced peripheral neuropathy (PIPN) is a severe and dose-limiting side effect. This study investigated the therapeutic potential of Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) and its underlying mechanism.

Methods

A murine PIPN model was established. Behavioral tests assessed neuropathic pain. Molecular and cellular analyzes, including western blot, ELISA, and transmission electron microscopy, evaluated oxidative stress, mitochondrial function, and key protein expression in dorsal root ganglia (DRG) and SH-SY5Y cells. The PGC-1α inhibitor SR-18292 was used for mechanistic validation.

Results

High-dose PACAP (100 μg/kg) significantly alleviated PTX-induced mechanical allodynia and thermal/cold hyperalgesia. It reduced oxidative stress (lowered ROS/MDA, increased SOD) and restored mitochondrial function (improved membrane potential, ATP, and ultrastructure) in DRG neurons. PACAP upregulated PGC-1α and HO-1 expression, and its protective effects were abolished by PGC-1α inhibition. Crucially, PACAP did not interfere with PTX's antitumor efficacy.

Conclusion

PACAP alleviates PIPN by activating the PGC-1α pathway to improve mitochondrial function and counteract oxidative stress, presenting a promising adjunct therapy that does not compromise chemotherapy.

背景：紫杉醇诱导的周围神经病变（PIPN）是一种严重且剂量有限的副作用。本研究探讨垂体腺苷酸环化酶激活多肽（PACAP）的治疗潜力及其潜在机制。方法：建立小鼠PIPN模型。行为测试评估神经性疼痛。分子和细胞分析，包括western blot、ELISA和透射电镜，评估了背根神经节（DRG）和SH-SY5Y细胞的氧化应激、线粒体功能和关键蛋白表达。PGC-1α抑制剂SR-18292用于机制验证。结果：大剂量PACAP （100 μg/kg）可显著减轻ptx所致的机械异常痛和热/冷痛觉过敏。它能降低DRG神经元的氧化应激（降低ROS/MDA，升高SOD），恢复线粒体功能（改善膜电位、ATP和超微结构）。PACAP上调PGC-1α和HO-1的表达，其保护作用因PGC-1α抑制而消失。关键是，PACAP不干扰PTX的抗肿瘤疗效。结论：PACAP通过激活PGC-1α通路，改善线粒体功能，对抗氧化应激，缓解PIPN，是一种很有前景的不影响化疗的辅助治疗方法。

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引用次数: 0

Pharmacovigilance Insights Into Immune Checkpoint Inhibitor-Induced Risk of Paraneoplastic Syndrome: A Large-Scale Real World Study 免疫检查点抑制剂诱导副肿瘤综合征风险的药物警戒：一项大规模的真实世界研究。

IF 5 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics

Pub Date : 2026-01-21 DOI: 10.1002/cns.70747

Bufu Tang, Xin Song, Yiting Sun, Juncheng Wan, Wenlu Hu, Yifei Ma, Yihang Lin, Jian Zhang, Yiou Wang, Hongyang Feng, Peng Luo, Dandan Guo, Xudong Qu

Background

Immune checkpoint inhibitor (ICI)-associated paraneoplastic syndromes (PS) represent a rare but potentially life-threatening adverse event. Despite the widespread use of ICIs in cancer treatment, the clinical characteristics and risk profiles of PS across different treatment regimens remain incompletely characterized.

Methods

We analyzed FAERS data (Jan 2011–Jun 2024) to identify PS cases potentially related to ICI use. Reporting odds ratios (RORs) were calculated to evaluate safety signals. Clinical features, time-to-onset, and outcomes were analyzed across different ICI regimens.

Results

Among 162,493 ICI-associated adverse event reports, 179 PS cases were identified. Disproportionate reporting of PS was observed with PD-1 inhibitors (ROR 21.77, 95% CI 16.36–28.97), PD-L1 inhibitors (ROR 23.33, 95% CI 14.13–38.41), nivolumab plus ipilimumab (ROR 24.21, 95% CI 18.07–32.42), and durvalumab plus tremelimumab (ROR 24.55, 95% CI 18.73–32.79). PS onset showed a bimodal distribution, with a median time to onset of 6 days, where 42.31% occurring within 30 days and 23.08% after 360 days of treatment initiation. Combination therapy, particularly durvalumab plus tremelimumab, was associated with higher rates of severe outcomes (27.8%). In patients with PS related to ICI therapy, those with lung malignancies are the most commonly represented group.

Conclusions

This analysis reveals distinct temporal patterns and safety signals of ICI-associated PS, with higher reporting rates and severity in combination therapy. These findings provide important insights for clinical monitoring strategies and highlight the need for increased vigilance during specific risk windows, particularly in patients receiving combination therapy.

背景：免疫检查点抑制剂（ICI）相关副肿瘤综合征（PS）是一种罕见但可能危及生命的不良事件。尽管ICIs在癌症治疗中广泛使用，但不同治疗方案中PS的临床特征和风险概况仍然不完全确定。方法：我们分析FAERS数据（2011年1月- 2024年6月），以确定可能与ICI使用相关的PS病例。计算报告优势比（RORs）来评估安全信号。分析不同ICI方案的临床特征、发病时间和结果。结果：在162493例ci相关不良事件报告中，鉴定出179例PS病例。PD-1抑制剂（ROR 21.77, 95% CI 16.36-28.97）、PD-L1抑制剂（ROR 23.33, 95% CI 14.13-38.41）、尼沃单抗+伊匹单抗（ROR 24.21, 95% CI 18.07-32.42）和杜伐单抗+ tremelimumab （ROR 24.55, 95% CI 18.73-32.79）中观察到不成比例的PS报告。PS发病呈双峰分布，中位发病时间为6天，其中42.31%发生在30天内，23.08%发生在开始治疗360天后。联合治疗，特别是durvalumab + tremelimumab，与更高的严重结局发生率相关（27.8%）。在与ICI治疗相关的PS患者中，肺恶性肿瘤患者是最常见的代表群体。结论：该分析揭示了ici相关PS的不同时间模式和安全信号，联合治疗的报告率和严重程度更高。这些发现为临床监测策略提供了重要的见解，并强调了在特定风险窗口期间提高警惕的必要性，特别是在接受联合治疗的患者中。

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引用次数: 0

Disodium Cromoglycate Attenuates the Depressive-Like Behaviors in Mice by Inhibiting Neuroinflammation 甘糖酸二钠通过抑制神经炎症减轻小鼠抑郁样行为。

IF 5 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics

Pub Date : 2026-01-20 DOI: 10.1002/cns.70721

Yun Xiao, Kaifan Liu, Zengqiang Yuan, Yajin Liao

Aims

Emerging evidence indicates that mast cells (MCs) may play a crucial role in the pathogenesis of major depression disorder (MDD). This study aimed to investigate whether the mast cell membrane stabilizer Disodium cromoglycate (DSCG) could ameliorate depressive-like behaviors by attenuating mast cell-mediated neuroinflammation.

Methods

Lipopolysaccharide (LPS)-induced and chronic restraint stress (CRS)-induced mouse models were induced in C57BL/6 mice to evaluate the therapeutic effect of the DSCG. Depressive-like behaviors were assessed using the sucrose preference test (SPT), tail suspension test (TST), and forced swimming test (FST). Histopathological and molecular changes were examined through immunofluorescence, western blot, RT-qPCR, and ELISA.

Results

Firstly, our results indicated that the number of MCs was increased in the brain from LPS-induced depression model mice. Secondly, both CRS and LPS-induced depressive-like behaviors were significantly ameliorated by DSCG. Moreover, treatment with DSCG could down-regulate the expression of MCs-associated genes in the brain of depression model mice. Mechanically, our results displayed that the use of DSCG significantly suppressed the activation of glial cells and the expression of pro-inflammatory factors.

Conclusion

Our study demonstrates that MCs infiltration and activation contribute to neuroinflammation in LPS-induced depressive mice. DSCG exerts its antidepressant effects primarily by modulating MCs-mediated neuroinflammation. These results highlight DSCG as a promising therapeutic candidate for the treatment of inflammation-associated depression.

目的：新的证据表明肥大细胞（MCs）可能在重度抑郁症（MDD）的发病机制中起关键作用。本研究旨在探讨肥大细胞膜稳定剂丙糖酸二钠（DSCG）是否能通过减轻肥大细胞介导的神经炎症来改善抑郁样行为。方法：采用脂多糖（LPS）诱导和慢性抑制应激（CRS）诱导的小鼠模型，观察C57BL/6小鼠DSCG的治疗效果。采用蔗糖偏好测试（SPT）、悬尾测试（TST）和强迫游泳测试（FST）评估抑郁样行为。通过免疫荧光、western blot、RT-qPCR和ELISA检测组织病理学和分子变化。结果：首先，我们的研究结果表明lps诱导的抑郁模型小鼠脑内MCs数量增加。其次，DSCG对CRS和lps诱导的抑郁样行为均有显著改善。此外，DSCG治疗可下调抑郁症模型小鼠大脑mcs相关基因的表达。机械地，我们的结果显示，使用DSCG显著抑制胶质细胞的激活和促炎因子的表达。结论：lps诱导抑郁小鼠的神经炎症与MCs的浸润和活化有关。DSCG主要通过调节mcs介导的神经炎症发挥其抗抑郁作用。这些结果突出了DSCG作为治疗炎症相关性抑郁症的有希望的治疗候选药物。

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引用次数: 0

OCTA-Derived Retinal Biomarkers and Infarct Topography Improve Etiologic Classification of Recent Single Subcortical Infarction: A Nomogram Model octa衍生的视网膜生物标志物和梗死地形改善了近期单一皮质下梗死的病因分类：一种Nomogram模型。

IF 5 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics

Pub Date : 2026-01-19 DOI: 10.1002/cns.70752

Shuai Jiang, William Robert Kwapong, Yuying Yan, Tang Yang, Le Cao, Chen Ye, Junfeng Liu, Bo Wu

Background

Recent single subcortical infarction (RSSI) in lenticulostriate artery territories exhibits etiological heterogeneity. Misclassification risks persist due to overlapping neuroimaging features between cerebral small-vessel disease-related lacunar infarction (CSVD-related LI) and branch atheromatous disease (BAD). We developed a nomogram that integrates retinal optical coherence tomography angiography (OCTA) metrics with infarct topography to improve etiological classification.

Methods

Patients with RSSI were prospectively enrolled between December 2021 and December 2023. LASSO regression identified predictors for a logistic regression–based nomogram. Performance was evaluated via concordance index (C-index), calibration curves, and decision-curve analysis.

Results

A total of 127 RSSI patients (86 CSVD-related LI, 41 BAD) were included. Three variables—superficial vascular complex density, number of lesion slices, and proximal lesion location—were retained in the final model. The nomogram achieved a C-index of 0.84 (95% CI, 0.80–0.89) versus 0.68 for conventional imaging, with superior net benefit across clinical thresholds (AUC 0.84 vs. 0.68, p < 0.001).

Conclusion

The novel nomogram combining OCTA-derived retinal biomarkers with infarct topography improves differentiation of BAD from CSVD-related LI in RSSI patients and may facilitate etiology-driven clinical decision-making. External validation is needed for clinical implementation.

背景：最近发生在透镜状纹状动脉区域的单一皮质下梗死（RSSI）具有病因异质性。由于脑小血管疾病相关腔隙性梗死（csvd相关LI）和分支动脉粥样硬化疾病（BAD）之间的神经影像学特征重叠，错误分类的风险仍然存在。我们开发了一种将视网膜光学相干断层扫描血管造影（OCTA）指标与梗死地形相结合的图，以改善病因分类。方法：前瞻性纳入2021年12月至2023年12月期间的RSSI患者。LASSO回归确定了基于逻辑回归的nomogram预测因子。通过一致性指数（C-index）、校准曲线和决策曲线分析来评估绩效。结果：共纳入127例RSSI患者（csvd相关LI 86例，BAD 41例）。在最终模型中保留了三个变量——浅表血管复合体密度、病变切片数和病变近端位置。该nomogram C-index为0.84 (95% CI, 0.80-0.89)，而传统影像学的C-index为0.68，在临床阈值上具有更优的净收益（AUC为0.84比0.68,p）。结论：新型nomogram结合octa衍生的视网膜生物标志物和梗死地形可以改善RSSI患者BAD与csvd相关LI的分化，并可能促进病因驱动的临床决策。临床实施需要外部验证。

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引用次数: 0

Structural Connectivity Disruption and Structural–Functional Decoupling in Working Memory Networks Across Pre-Dialysis and Maintenance Hemodialysis End-Stage Renal Disease Patients 透析前和维持性血液透析终末期肾病患者工作记忆网络的结构连接中断和结构-功能解耦

IF 5 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics

Pub Date : 2026-01-19 DOI: 10.1002/cns.70761

Xiaoling Xu, Shaohui Ma, Siyao Liu, Zhaoyao Luo, Qiange Zhu, Huijie Yuan, Xinyi Zhu, Wen Gu, Peng Li, Jianjun Zhang, Ming Zhang, Junya Mu

Aims

End-stage renal disease (ESRD) is associated with working memory (WM) impairment. We assessed how structural connectivity (SC), functional connectivity (FC), and structural–functional coupling (SFC) differ between pre-dialysis ESRD (ESRDp), maintenance hemodialysis ESRD (ESRDm), and healthy controls (HCs), and how these changes relate to serum markers and WM performance.

Methods

29 ESRDp, 29 ESRDm, and 46 HCs completed 0-, 1-, and 2-back tasks, diffusion MRI, and fMRI. WM nodes were defined by overlaying a meta-analytic map with the Harvard–Oxford atlas. SC, FC, and regional SFC were computed among WM-related regions. Group differences, correlations with serum markers, and mediation models were examined.

Results

ESRDp showed markedly lower n-back accuracy, longer reaction time (RT), reduced frontoparietal SC, and widespread SFC reductions compared with ESRDm and HCs, whereas ESRDm exhibited near-normal WM performance and partially restored SC/SFC. Elevated urea and lower sodium in ESRDp were associated with weaker SC and altered SFC, which related to poorer accuracy and slower RT; SC and SFC significantly mediated these associations.

Conclusion

ESRDp is characterized by disruption and decoupling of WM networks, while ESRDm is associated with partial network normalization. WM-related SC and SFC combined with serum markers may help identify cognitive vulnerability in ESRD.

Trial Registration

ClinicalTrials.gov identifier: NCT03961724

目的：终末期肾病（ESRD）与工作记忆（WM）损伤相关。我们评估了透析前ESRD （ESRDp）、维护性血液透析ESRD （ESRDm）和健康对照（hc）之间的结构连通性（SC）、功能连通性（FC）和结构-功能耦合（SFC）的差异，以及这些变化与血清标志物和WM表现的关系。方法：29例ESRDp、29例ESRDm和46例hc分别完成0、1、2回任务、扩散MRI和功能MRI。WM节点是通过在哈佛-牛津地图集上叠加元分析地图来定义的。计算wm相关区域的SC、FC和区域SFC。检验了组间差异、与血清标志物的相关性和中介模型。结果：与ESRDm和hc相比，ESRDp表现出明显较低的n-back准确性，较长的反应时间（RT），减少的额顶SC和广泛的SFC减少，而ESRDm表现出接近正常的WM表现和部分恢复的SC/SFC。ESRDp中尿素升高和钠降低与较弱的SC和改变的SFC相关，这与较差的准确性和较慢的RT有关；SC和SFC显著介导了这些关联。结论：ESRDp以WM网络的中断和解耦为特征，而ESRDm与部分网络规范化有关。wm相关的SC和SFC结合血清标志物可能有助于识别ESRD的认知易感性。试验注册：ClinicalTrials.gov标识符：NCT03961724。

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引用次数: 0

Altered Brain Function and Network Topology in Patients With Acromegaly: Resting-State fMRI Study of Networks Related to Cognitive and Emotional Processing 肢端肥大症患者脑功能和网络拓扑改变：认知和情绪处理相关网络的静息状态fMRI研究。

IF 5 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics

Pub Date : 2026-01-19 DOI: 10.1002/cns.70755

Zerui Wu, Xuejie Yu, Yingyue Zhang, Jinming Yang, Qilin Zhang, Shun Yao, Xuefei Shou, Xiang Zhou, Yongfei Wang, Hao Li, Liguo Jia, Yifei Yu, Weiwei Wang, Zengyi Ma, Wenqiang He

Context

Neurodegenerative diseases are particularly prevalent among patients with acromegaly, but their functional alterations remain poorly understood.

Objective

To explore the neurobiological mechanisms of excess growth hormone (GH) on brain functional activity and connectivity in acromegaly.

Methods

Neuropsychological assessments and resting-state functional magnetic resonance imaging (fMRI) were conducted on 27 patients with acromegaly and 25 healthy controls. The amplitude of low-frequency fluctuations (ALFF), fractional ALFF (fALFF), and regional homogeneity (ReHo) were compared between groups via voxel-based analyses, while graph theory was used to assess brain network topology. T-tests and multikernel support vector machine (MK-SVM) were used to identify discriminative connectome features for classification.

Results

Patients with acromegaly exhibited lower Montreal Cognitive Assessment scores, increased ALFF in the default mode network regions, and decreased fALFF in the frontal–parietal control network areas. ReHo was elevated in the visual network but reduced in the frontal–parietal network. Disruptions were observed in key hub nodes within the default mode and visual networks. The MK-SVM achieved 85.11% accuracy and 80.00% sensitivity in classifying patients.

Conclusions

Patients with acromegaly exhibited altered brain function and network disruptions. These results offer novel insights into the mechanisms of excess GH in the brain.

背景：神经退行性疾病在肢端肥大症患者中尤为普遍，但其功能改变仍知之甚少。目的：探讨过量生长激素（GH）对肢端肥大症脑功能活动和连通性影响的神经生物学机制。方法：对27例肢端肥大症患者和25例健康对照者进行神经心理评估和静息状态功能磁共振成像（fMRI）检查。通过体素分析比较各组之间的低频波动幅度（ALFF）、分数ALFF （fALFF）和区域均匀性（ReHo），同时使用图论评估脑网络拓扑结构。使用t检验和多核支持向量机（MK-SVM）识别判别性连接组特征进行分类。结果：肢端肥大症患者蒙特利尔认知评估得分较低，默认模式网络区域ALFF升高，额顶叶控制网络区域ALFF降低。ReHo在视觉网络中升高，而在额-顶叶网络中降低。在默认模式和视觉网络的关键枢纽节点中观察到中断。MK-SVM对患者的分类准确率为85.11%，灵敏度为80.00%。结论：肢端肥大症患者表现出脑功能改变和网络中断。这些结果为大脑中过量生长激素的机制提供了新的见解。

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引用次数: 0

Tregs Promote Astrocyte-Neuron Lactate Shuttle via Inhibiting STING Pathway to Improve Neurological Recovery After Ischemic Stroke Tregs通过抑制STING通路促进星形胶质细胞-神经元乳酸穿梭，促进缺血性脑卒中后神经恢复。

IF 5 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics

Pub Date : 2026-01-19 DOI: 10.1002/cns.70753

Yao Meng, Xiaoyan Li, Yonghong Bi, Pengyu Duan, Zhehao Jin, Lan Luo, Weiyu Feng, Hangbing Li, Xiangcheng Zhao, Kun Zuo, Jiali Chen, Longfei Li, Yuling Xing, Miao Yu, Muyan Cui, Yang Yu, Bing Zhang

Background

Excessive immune response following ischemic stroke is closely associated with poor clinical prognosis. Although regulatory T cell (Treg) is recognized as pivotal immunomodulator, its potential mechanisms in post-stroke neurological recovery and immunotherapy remain unclear.

Methods

Neurological recovery and neuronal remodeling were investigated by behavior tests, HE staining, Nissl staining, and LFB staining. Monocarboxylate transporter (MCT) was detected to evaluate the role of astrocyte-neuron lactate shuttle (ANLS) in Tregs-mediated neuroprotection by immunofluorescence and western blot, lactate assay, ATP assay, and cell viability assay experiments. The expression of stimulator of interferon gene (STING) and phosphorylation of downstream factors were examined by western blot.

Results

Tregs significantly attenuated neuronal injury, upregulated the expression of synaptic plasticity-related proteins, promoted myelin reconstruction, and improved spatial cognition, memory function, and motor coordination. Mechanistically, Tregs enhanced MCT-mediated lactate transfer to neurons, providing energy supply for neuronal remodeling, whereas the MCT inhibitor 4-CIN reversed Tregs-mediated neuroprotection. In addition, Tregs suppressed the activation of the STING pathway, and activation of STING by DMXAA abolished the Tregs-induced potentiation of ANLS.

Conclusions

This study clarifies a novel mechanism by which Tregs promote ANLS and provide energy supply for neuronal remodeling by inhibiting the STING pathway, thereby improving the long-term neurological recovery after stroke.

背景：缺血性脑卒中后过度的免疫反应与临床预后不良密切相关。尽管调节性T细胞（Treg）被认为是关键的免疫调节剂，但其在脑卒中后神经恢复和免疫治疗中的潜在机制尚不清楚。方法：采用行为学实验、HE染色、Nissl染色、LFB染色观察大鼠神经功能恢复及神经元重构情况。采用免疫荧光、western blot、乳酸测定、ATP测定、细胞活力测定等方法检测单羧酸转运蛋白（MCT），评价星形胶质细胞-神经元乳酸穿梭（ANLS）在tregs介导的神经保护中的作用。western blot检测干扰素刺激因子（STING）表达及下游因子磷酸化水平。结果：Tregs显著减轻神经元损伤，上调突触可塑性相关蛋白表达，促进髓磷脂重建，改善空间认知、记忆功能和运动协调能力。从机制上讲，Tregs增强了MCT介导的乳酸向神经元的转移，为神经元重塑提供能量供应，而MCT抑制剂4-CIN逆转了Tregs介导的神经保护。此外，Tregs抑制了STING通路的激活，DMXAA激活STING可消除Tregs诱导的ANLS增强。结论：本研究阐明了Tregs通过抑制STING通路促进ANLS并为神经元重构提供能量供应，从而改善脑卒中后神经系统长期恢复的新机制。

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引用次数: 0