Renfeng Zhang, Su Pan, Zhenwei Tian, Haorui Du, Jintao Wang, Xiaoyu Yang, Zhiping Qi
Background
The primary cilium (PC) is a pivotal organelle for neuronal signaling and development, while tau tubulin kinase 2 (TTBK2) is a key initiator of ciliogenesis. However, the role of TTBK2 in spinal neurons during spinal cord injury (SCI) and subsequent neural repair remains unclear.
Methods
We manipulated TTBK2 expression in spinal neurons using adenovirus-mediated overexpression and knockdown in vitro. Transcriptomic profiling (RNA-sequencing) and RT-qPCR were employed to explore the potential regulatory pathways at the molecular level. In vivo, Ttbk2fl/fl-Rosa-CreERT2+/− conditional knockout mice were subjected to a spinal cord hemisection model. Behavioral assays, immunofluorescence, and biotinylated dextran amine (BDA) tracing were conducted to assess neuronal survival, axonal regeneration, and circuit reorganization.
Results
Here, we demonstrated that intact activity of TTBK2 in PC promoted neural survival, axonal regeneration, and neural circuit remodeling. However, loss of TTBK2 impaired PC function and hindered recovery after SCI.
Conclusions
These findings extend the role of PCs beyond neurodevelopment, demonstrating that the TTBK2–PC functions as an endogenous repair mechanism after SCI. Targeting this pathway may provide novel therapeutic strategies for enhancing neural regeneration.
{"title":"TTBK2-Driven Ciliogenesis Is Required for Intrinsic Neuronal Regeneration After Spinal Cord Injury","authors":"Renfeng Zhang, Su Pan, Zhenwei Tian, Haorui Du, Jintao Wang, Xiaoyu Yang, Zhiping Qi","doi":"10.1002/cns.70763","DOIUrl":"10.1002/cns.70763","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The primary cilium (PC) is a pivotal organelle for neuronal signaling and development, while tau tubulin kinase 2 (TTBK2) is a key initiator of ciliogenesis. However, the role of TTBK2 in spinal neurons during spinal cord injury (SCI) and subsequent neural repair remains unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We manipulated TTBK2 expression in spinal neurons using adenovirus-mediated overexpression and knockdown in vitro. Transcriptomic profiling (RNA-sequencing) and RT-qPCR were employed to explore the potential regulatory pathways at the molecular level. In vivo, <i>Ttbk2</i><sup>fl/fl</sup>-Rosa-CreERT2<sup>+/−</sup> conditional knockout mice were subjected to a spinal cord hemisection model. Behavioral assays, immunofluorescence, and biotinylated dextran amine (BDA) tracing were conducted to assess neuronal survival, axonal regeneration, and circuit reorganization.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Here, we demonstrated that intact activity of TTBK2 in PC promoted neural survival, axonal regeneration, and neural circuit remodeling. However, loss of TTBK2 impaired PC function and hindered recovery after SCI.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>These findings extend the role of PCs beyond neurodevelopment, demonstrating that the TTBK2–PC functions as an endogenous repair mechanism after SCI. Targeting this pathway may provide novel therapeutic strategies for enhancing neural regeneration.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 1","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12831131/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146040037","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}
Intraventricular hemorrhage (IVH) has a high mortality and disability rate and poses significant clinical challenges, which often leads to hydrocephalus and neurological dysfunction. Emerging evidence implicates dysfunction of the glymphatic-meningeal lymphatic-deep cervical lymphatic system in the pathogenesis of post-IVH hydrocephalus. Therapeutic hypothermia (TH) holds promise for mitigating these sequelae. This study investigates the potential of TH to ameliorate IVH-induced hydrocephalus and neurological dysfunction, while elucidating its underlying mechanisms.
Methods
Rat models of IVH are established by intraventricular injection of autologous blood. TH, deep cervical lymph nodes (dCLNs) ligation, and intraperitoneal injection of AMPK inhibitor are used to intervene.
Results
In rat models of IVH, TH alleviates neurological dysfunction and attenuates hydrocephalus and pathology damage. TH protects physiological function and maintains normal structure of the glymphatic system. TH improves function and structure of the meningeal lymphatic system and promotes drainage of the deep cervical lymphatic system. TH upregulates RTN3, facilitates phosphorylation of AMPK, and suppresses ERS. All the above effects are reversed by ligation of dCLNs and AMPK inhibitor.
Conclusion
TH alleviates hydrocephalus and neurological dysfunction post IVH by enhancing drainage of the glymphatic-meningeal lymphatic-deep cervical lymphatic system. The RTN3/AMPK/ERS pathway may be the proposed mechanism mediating this effect. TH is expected to become a novel therapeutic strategy for IVH.
{"title":"Therapeutic Hypothermia Alleviates Hydrocephalus and Neurological Dysfunction Post Intraventricular Hemorrhage by Enhancing Drainage of Glymphatic-Meningeal Lymphatic-Deep Cervical Lymphatic System","authors":"Yijian Yang, Qian Ouyang, Yaxin Sun, Aijun Liang, Junqiang Wang, Kaiyue Wang, Yexin Yuan, Zhikun Liu, Jun Huang, Zhiping Zhang, Libin Wang, Yang Yuan, Cheng Wang, Zhangjie Su, Qinghua Zhang, Liyang Zhang, Gelei Xiao","doi":"10.1002/cns.70740","DOIUrl":"10.1002/cns.70740","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>Intraventricular hemorrhage (IVH) has a high mortality and disability rate and poses significant clinical challenges, which often leads to hydrocephalus and neurological dysfunction. Emerging evidence implicates dysfunction of the glymphatic-meningeal lymphatic-deep cervical lymphatic system in the pathogenesis of post-IVH hydrocephalus. Therapeutic hypothermia (TH) holds promise for mitigating these sequelae. This study investigates the potential of TH to ameliorate IVH-induced hydrocephalus and neurological dysfunction, while elucidating its underlying mechanisms.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Rat models of IVH are established by intraventricular injection of autologous blood. TH, deep cervical lymph nodes (dCLNs) ligation, and intraperitoneal injection of AMPK inhibitor are used to intervene.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In rat models of IVH, TH alleviates neurological dysfunction and attenuates hydrocephalus and pathology damage. TH protects physiological function and maintains normal structure of the glymphatic system. TH improves function and structure of the meningeal lymphatic system and promotes drainage of the deep cervical lymphatic system. TH upregulates RTN3, facilitates phosphorylation of AMPK, and suppresses ERS. All the above effects are reversed by ligation of dCLNs and AMPK inhibitor.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>TH alleviates hydrocephalus and neurological dysfunction post IVH by enhancing drainage of the glymphatic-meningeal lymphatic-deep cervical lymphatic system. The RTN3/AMPK/ERS pathway may be the proposed mechanism mediating this effect. TH is expected to become a novel therapeutic strategy for IVH.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 1","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12831171/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146040060","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}
Shuangjie Qian, Jialong Hou, Xi Xiong, Qi Duan, Tao Jiang, Yi Zheng, Weiwei Quan, Jiaxue Xu, Keke Chen, Jingjing Qian, Hongchang Gao, Chenglong Xie
Background
Parkinson's disease with motor complications (PD-MC) lacks effective diagnostic and therapeutic strategies. The perturbations of the gut microbiota and plasma metabolites are closely associated with the etiopathogenesis of PD. However, whether fecal microbiome dysbiosis and changed plasma metabolites are involved in PD progression, particularly in the development of PD-MC, is still unclear.
Methods
In this study, we performed an extensive multiomics analysis involving 108 PD patients for 16S rRNA gut microbiome profiling and 246 PD patients for plasma nontargeted metabolomics. Our findings revealed distinct gut microbiota and plasma metabolites associated with PD-MC. Utilizing these discriminative features, we developed a multivariate diagnostic model for PD-MC. The relationships between differential metabolites and microorganisms were evaluated using Spearman correlation analysis. Functional interpretation of the key metabolites was conducted through enrichment and pathway analysis, employing the KEGG and SMPDB databases.
Results
PD-MC patients had distinct gut microbial signatures as compared with PD without motor complications (PD-NMC) individuals and were increased in fecal Lactobacillus, Limosilactobacillus, Bifidobacterium, and Ligilactobacillus genera along with depleted Agathobacter. Moreover, metabolomic analysis revealed the differences in plasma 3-deoxysappanchalcone (3-DSC), 1,3-Dimethyluracil (1,3-DTl), Leucine, and N-Acetylisoleucine (N-AIL), Dodec-6-enoic acid (D-6-E), N-butyl Oleate (N-BO), and 4-hydroxyundecanoic acid (4-HUA) in PD-MC compared to PD-NMC. Spearman correlation analysis showed that the fecal microbiota aberrations in PD-MC patients were linked to plasma metabolic changes, indicating the association between key microbial populations and metabolomic profiles in PD-MC.
Conclusions
This study underscores the value of employing integrated multiomics profiling of the fecal microbiome and plasma metabolome to enhance the mechanistic understanding of PD-MC and to identify potential diagnostic biomarkers.
{"title":"Exploring the Fecal Microbiome Dysbiosis and Its Plasma Metabolome Determinants in Advanced Parkinson's Disease With Motor Complications","authors":"Shuangjie Qian, Jialong Hou, Xi Xiong, Qi Duan, Tao Jiang, Yi Zheng, Weiwei Quan, Jiaxue Xu, Keke Chen, Jingjing Qian, Hongchang Gao, Chenglong Xie","doi":"10.1002/cns.70750","DOIUrl":"10.1002/cns.70750","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Parkinson's disease with motor complications (PD-MC) lacks effective diagnostic and therapeutic strategies. The perturbations of the gut microbiota and plasma metabolites are closely associated with the etiopathogenesis of PD. However, whether fecal microbiome dysbiosis and changed plasma metabolites are involved in PD progression, particularly in the development of PD-MC, is still unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this study, we performed an extensive multiomics analysis involving 108 PD patients for 16S rRNA gut microbiome profiling and 246 PD patients for plasma nontargeted metabolomics. Our findings revealed distinct gut microbiota and plasma metabolites associated with PD-MC. Utilizing these discriminative features, we developed a multivariate diagnostic model for PD-MC. The relationships between differential metabolites and microorganisms were evaluated using Spearman correlation analysis. Functional interpretation of the key metabolites was conducted through enrichment and pathway analysis, employing the KEGG and SMPDB databases.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>PD-MC patients had distinct gut microbial signatures as compared with PD without motor complications (PD-NMC) individuals and were increased in fecal Lactobacillus, Limosilactobacillus, Bifidobacterium, and Ligilactobacillus genera along with depleted Agathobacter. Moreover, metabolomic analysis revealed the differences in plasma 3-deoxysappanchalcone (3-DSC), 1,3-Dimethyluracil (1,3-DTl), Leucine, and N-Acetylisoleucine (N-AIL), Dodec-6-enoic acid (D-6-E), N-butyl Oleate (N-BO), and 4-hydroxyundecanoic acid (4-HUA) in PD-MC compared to PD-NMC. Spearman correlation analysis showed that the fecal microbiota aberrations in PD-MC patients were linked to plasma metabolic changes, indicating the association between key microbial populations and metabolomic profiles in PD-MC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This study underscores the value of employing integrated multiomics profiling of the fecal microbiome and plasma metabolome to enhance the mechanistic understanding of PD-MC and to identify potential diagnostic biomarkers.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 1","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12828341/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146027929","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}
Zhong-Yun Chen, Min Chu, Yi-Hao Wang, Rui Liu, Jing Zhang, Ai-ling Yue, Hua Lu, Qian-qian He, Jia-hui Hou, Yu-fei Chen, Hong Ye, Li-Yong Wu
Background
Plasma markers of neuronal injury in Creutzfeldt–Jakob disease (CJD) are established, but peripheral biomarkers reflecting glial activation, synaptic dysfunction, and vascular impairment remain less explored. We systematically assessed these markers in symptomatic CJD and asymptomatic PRNP mutation carriers to improve diagnosis and identify early pathophysiology.
Methods
This prospective cohort study recruited CJD, frontotemporal dementia (FTD), healthy controls (HCs), and preclinical familial CJD pedigrees. Sixteen plasma proteins representing neuronal injury, glial activation, synaptic function, and vascular/BBB integrity were measured. Analyses included group differences, discriminative performance, clinical/imaging correlations, and longitudinal trajectories.
Results
We enrolled 130 CJD patients, 145 FTD, 70 HCs, 16 asymptomatic PRNP carriers (4–6 years follow-up, 4 converters), and 16 non-carrier family controls. In symptomatic CJD, plasma NfL, t-tau, and GFAP were strongly elevated, each showing excellent discriminative performance (AUCs > 0.93 vs. HCs and > 0.82 vs. FTD). We also observed alterations in vascular/BBB markers, with VCAM-1 levels elevated and significantly associated with both clinical decline and DWI hyperintensity. In asymptomatic carriers, biomarker levels remained largely normal and stable preclinically. Notably, two G114V carriers showed mild pre-symptomatic elevations in NfL and GFAP, and one exhibited a slight VCAM-1 increase before clinical onset; all changes exceeded the 90th percentile of control values. E200K and T188K carriers showed no pre-onset changes.
Conclusions
Plasma biomarkers in CJD may reflect multisystem involvement, with neuronal markers showing strong discriminative potential and vascular proteins indicating possible BBB dysfunction. In asymptomatic carriers, minor changes may occur only near onset in those with relatively slow-progressing mutations.
背景：克雅氏病（Creutzfeldt-Jakob disease， CJD）神经元损伤的血浆标志物已经建立，但反映神经胶质激活、突触功能障碍和血管损伤的外周生物标志物仍然很少被探索。我们在有症状的CJD和无症状的PRNP突变携带者中系统地评估了这些标记物，以提高诊断和识别早期病理生理。方法：这项前瞻性队列研究招募了克雅氏病、额颞叶痴呆（FTD）、健康对照（hc）和临床前家族性克雅氏病谱系。测量了代表神经元损伤、神经胶质活化、突触功能和血管/血脑屏障完整性的16种血浆蛋白。分析包括组间差异、鉴别表现、临床/影像学相关性和纵向轨迹。结果：我们招募了130名CJD患者，145名FTD患者，70名hc患者，16名无症状PRNP携带者（随访4-6年，4名转化者）和16名非携带者家族对照。在有症状的CJD中，血浆NfL、t-tau和GFAP均显著升高，分别表现出优异的鉴别性能（auc为> 0.93 vs. hc, > 0.82 vs. FTD）。我们还观察到血管/血脑屏障标志物的改变，VCAM-1水平升高，与临床衰退和DWI高强度显著相关。在无症状携带者中，生物标志物水平在临床前基本保持正常和稳定。值得注意的是，两名G114V携带者在症状前表现出轻微的NfL和GFAP升高，一名在临床发病前表现出轻微的VCAM-1升高；所有变化均超过控制值的第90个百分位数。E200K和T188K携带者未见发病前变化。结论：血浆生物标志物可能反映了克雅氏病的多系统参与，神经元标志物具有很强的鉴别潜力，血管蛋白表明可能存在血脑屏障功能障碍。在无症状携带者中，轻微的变化可能只发生在那些进展相对缓慢的突变的发病附近。
{"title":"Peripheral Signatures of Multidimensional Pathology in Symptomatic and Asymptomatic Creutzfeldt–Jakob Disease","authors":"Zhong-Yun Chen, Min Chu, Yi-Hao Wang, Rui Liu, Jing Zhang, Ai-ling Yue, Hua Lu, Qian-qian He, Jia-hui Hou, Yu-fei Chen, Hong Ye, Li-Yong Wu","doi":"10.1002/cns.70765","DOIUrl":"10.1002/cns.70765","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Plasma markers of neuronal injury in Creutzfeldt–Jakob disease (CJD) are established, but peripheral biomarkers reflecting glial activation, synaptic dysfunction, and vascular impairment remain less explored. We systematically assessed these markers in symptomatic CJD and asymptomatic PRNP mutation carriers to improve diagnosis and identify early pathophysiology.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This prospective cohort study recruited CJD, frontotemporal dementia (FTD), healthy controls (HCs), and preclinical familial CJD pedigrees. Sixteen plasma proteins representing neuronal injury, glial activation, synaptic function, and vascular/BBB integrity were measured. Analyses included group differences, discriminative performance, clinical/imaging correlations, and longitudinal trajectories.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We enrolled 130 CJD patients, 145 FTD, 70 HCs, 16 asymptomatic <i>PRNP</i> carriers (4–6 years follow-up, 4 converters), and 16 non-carrier family controls. In symptomatic CJD, plasma NfL, t-tau, and GFAP were strongly elevated, each showing excellent discriminative performance (AUCs > 0.93 vs. HCs and > 0.82 vs. FTD). We also observed alterations in vascular/BBB markers, with VCAM-1 levels elevated and significantly associated with both clinical decline and DWI hyperintensity. In asymptomatic carriers, biomarker levels remained largely normal and stable preclinically. Notably, two G114V carriers showed mild pre-symptomatic elevations in NfL and GFAP, and one exhibited a slight VCAM-1 increase before clinical onset; all changes exceeded the 90th percentile of control values. E200K and T188K carriers showed no pre-onset changes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Plasma biomarkers in CJD may reflect multisystem involvement, with neuronal markers showing strong discriminative potential and vascular proteins indicating possible BBB dysfunction. In asymptomatic carriers, minor changes may occur only near onset in those with relatively slow-progressing mutations.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 1","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12828275/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146027966","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}
Peripheral neuropathy (PN) is a common consequence of peripheral nervous system (PNS) disorders, yet its effective treatment remains a significant clinical challenge. Pyroptosis, an inflammatory form of programmed cell death (PCD) triggered by gasdermin A–E (GSDMA-E), contributes to the pathogenesis of PN and represents a promising therapeutic target. While reviews of pyroptosis in other diseases are extensive, comprehensive reviews focusing on PN are lacking.
Method
We systematically searched PubMed, Scopus, Web of Science, and Google Scholar (1986–2025). Only original studies investigating pyroptosis in PN were included.
Results
This review first consolidates established evidence, highlighting a context-dependent dual role of pyroptosis in PN. Its detrimental effects in chronic pain involve canonical (caspase-1/GSDMD) or noncanonical pathways (e.g., caspase-4/5/11/GSDMD, caspase-3/GSDME, caspase-8/GSDMC), often initiated by inflammasomes (e.g., NOD-like receptor family pyrin domain containing 3 [NLRP3]). Conversely, its beneficial, tumoricidal role is leveraged in neuroblastoma. Preclinically, diverse inhibitors—including NLRP3 inhibitors (e.g., MCC950), caspase-1 inhibitors (e.g., VX-765), and P2X7R antagonists (e.g., Brilliant Blue G)—alleviate pain and promote nerve repair, while pyroptosis inducers (e.g., axitinib) combat chemoresistant tumors. We then identify critical knowledge gaps and emerging frontiers. The roles of most gasdermins (GSDMA, GSDMB, GSDMC) in PN are unknown. We explore the emerging concept of PANoptosis (crosstalk among pyroptosis, apoptosis, and necroptosis) as a novel conceptual framework for PNS pathologies, where shared molecular hubs may amplify neuroinflammation. Furthermore, despite promising strategies like combination therapy and drug repurposing, a significant translational gap exists, with no current clinical trials specifically targeting pyroptosis for PN.
Conclusion and Perspective
Targeting pyroptosis is a novel therapeutic avenue for PN. This review synthesizes current mechanistic understanding, evaluates preclinical therapeutic strategies, and delineates crucial future directions, including elucidating gasdermin diversity, validating PANoptosis, and bridging the translational divide, thereby accelerating their application for patients suffering from PN.
背景：周围神经病变（PN）是周围神经系统（PNS）疾病的常见后果，但其有效治疗仍然是一个重大的临床挑战。焦亡是一种由气皮蛋白a - e （GSDMA-E）引发的程序性细胞死亡（PCD）的炎症形式，有助于PN的发病机制，是一个有希望的治疗靶点。虽然对其他疾病的焦亡的综述很广泛，但缺乏对PN的全面综述。方法：系统检索PubMed、Scopus、Web of Science和谷歌Scholar（1986-2025）。仅纳入了研究PN焦亡的原始研究。结果：这篇综述首先巩固了已有的证据，强调了焦亡在PN中依赖于环境的双重作用。它在慢性疼痛中的有害作用涉及典型（caspase-1/GSDMD）或非典型途径（如caspase-4/5/11/GSDMD、caspase-3/GSDME、caspase-8/GSDMC），通常由炎症小体（如nod样受体家族pyrin结构域3 [NLRP3]）启动。相反，其有益的杀瘤作用在神经母细胞瘤中发挥作用。临床前，多种抑制剂——包括NLRP3抑制剂（如MCC950）、caspase-1抑制剂（如VX-765）和P2X7R拮抗剂（如Brilliant Blue G）——可以缓解疼痛并促进神经修复，而焦死诱导剂（如阿西替尼）可以对抗化疗耐药肿瘤。然后，我们确定关键的知识差距和新兴的前沿。大多数gasdermins （GSDMA， GSDMB， GSDMC）在PN中的作用尚不清楚。我们将PANoptosis（焦亡、凋亡和坏死之间的串扰）这一新兴概念作为PNS病理的新概念框架进行探讨，其中共享的分子中心可能会放大神经炎症。此外，尽管联合治疗和药物再利用等有希望的策略，但存在显著的翻译差距，目前没有专门针对焦亡治疗PN的临床试验。结论与展望：靶向性焦亡是治疗PN的新途径。这篇综述综合了目前的机制理解，评估了临床前治疗策略，并描绘了关键的未来方向，包括阐明gasdermin多样性，验证PANoptosis，弥合翻译鸿沟，从而加速它们在PN患者中的应用。
{"title":"Pyroptosis in Peripheral Neuropathy: From Molecular Mechanisms to Therapeutic Targeting","authors":"Jinhuan Wei, Mingyue Liuyuan, Zhixin Ye, Xueying Wang, Xueli Zhou, Yifan Shan, Cheng He, Chunting Zhu, Chicheng Zhou, Jingyin Bao, Yonghui Zhang, Gang Chen","doi":"10.1002/cns.70760","DOIUrl":"10.1002/cns.70760","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Peripheral neuropathy (PN) is a common consequence of peripheral nervous system (PNS) disorders, yet its effective treatment remains a significant clinical challenge. Pyroptosis, an inflammatory form of programmed cell death (PCD) triggered by gasdermin A–E (GSDMA-E), contributes to the pathogenesis of PN and represents a promising therapeutic target. While reviews of pyroptosis in other diseases are extensive, comprehensive reviews focusing on PN are lacking.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Method</h3>\u0000 \u0000 <p>We systematically searched PubMed, Scopus, Web of Science, and Google Scholar (1986–2025). Only original studies investigating pyroptosis in PN were included.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>This review first consolidates established evidence, highlighting a context-dependent dual role of pyroptosis in PN. Its detrimental effects in chronic pain involve canonical (caspase-1/GSDMD) or noncanonical pathways (e.g., caspase-4/5/11/GSDMD, caspase-3/GSDME, caspase-8/GSDMC), often initiated by inflammasomes (e.g., NOD-like receptor family pyrin domain containing 3 [NLRP3]). Conversely, its beneficial, tumoricidal role is leveraged in neuroblastoma. Preclinically, diverse inhibitors—including NLRP3 inhibitors (e.g., MCC950), caspase-1 inhibitors (e.g., VX-765), and P2X7R antagonists (e.g., Brilliant Blue G)—alleviate pain and promote nerve repair, while pyroptosis inducers (e.g., axitinib) combat chemoresistant tumors. We then identify critical knowledge gaps and emerging frontiers. The roles of most gasdermins (GSDMA, GSDMB, GSDMC) in PN are unknown. We explore the emerging concept of PANoptosis (crosstalk among pyroptosis, apoptosis, and necroptosis) as a novel conceptual framework for PNS pathologies, where shared molecular hubs may amplify neuroinflammation. Furthermore, despite promising strategies like combination therapy and drug repurposing, a significant translational gap exists, with no current clinical trials specifically targeting pyroptosis for PN.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Perspective</h3>\u0000 \u0000 <p>Targeting pyroptosis is a novel therapeutic avenue for PN. This review synthesizes current mechanistic understanding, evaluates preclinical therapeutic strategies, and delineates crucial future directions, including elucidating gasdermin diversity, validating PANoptosis, and bridging the translational divide, thereby accelerating their application for patients suffering from PN.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 1","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12828674/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146027910","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}
Supratentorial focal lesions following ischemic stroke can lead to crossed cerebellar diaschisis (CCD). However, it remains unclear how CCD affects the functional connectivity between the cerebellum and the rest of the brain in ischemic stroke patients.
Methods
This case–control study involved resting-state fMRI data from 65 patients with basal ganglia ischemic stroke (Stroke) and 72 healthy controls (HC). Cerebral, cerebellar, and cerebrocerebellar inter-module functional connectivity in both 7-module and 17-module conditions were calculated and compared between the Stroke and HC groups. Spearman correlation analyses were further conducted to examine the relationships between connectivity alterations and both stroke severity and lesion size in Stroke patients.
Results
The Stroke patients exhibited disrupted inter-module functional connectivity, characterized by increased intra-hemispheric and decreased inter-hemispheric connectivity between cerebral modules, increased inter-module connectivity in the cerebellum, and reduced connectivity between ipsilesional cerebral modules and cerebellar modules while increasing connectivity between contralesional cerebral modules and cerebellar modules. Moreover, these connectivity changes, particularly disruptions in the cerebellar connectome, may be associated with lesion size and stroke severity in Stroke patients.
Conclusions
These findings highlight the importance of cerebellar connectome disruptions in ischemic stroke, which may provide valuable insights into the disease's underlying brain mechanisms.
{"title":"The Cerebellar Connectome Disruptions in Ischemic Stroke","authors":"Xiuqin Wang, Tongyue Li, Jinhui Wang, Yanhui Fu, Zhenqiang Ma, Xiaoyan Wu, Yiying Wang, Yufeng Zang, Yulin Song, Yating Lv","doi":"10.1002/cns.70759","DOIUrl":"10.1002/cns.70759","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Supratentorial focal lesions following ischemic stroke can lead to crossed cerebellar diaschisis (CCD). However, it remains unclear how CCD affects the functional connectivity between the cerebellum and the rest of the brain in ischemic stroke patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This case–control study involved resting-state fMRI data from 65 patients with basal ganglia ischemic stroke (Stroke) and 72 healthy controls (HC). Cerebral, cerebellar, and cerebrocerebellar inter-module functional connectivity in both 7-module and 17-module conditions were calculated and compared between the Stroke and HC groups. Spearman correlation analyses were further conducted to examine the relationships between connectivity alterations and both stroke severity and lesion size in Stroke patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The Stroke patients exhibited disrupted inter-module functional connectivity, characterized by increased intra-hemispheric and decreased inter-hemispheric connectivity between cerebral modules, increased inter-module connectivity in the cerebellum, and reduced connectivity between ipsilesional cerebral modules and cerebellar modules while increasing connectivity between contralesional cerebral modules and cerebellar modules. Moreover, these connectivity changes, particularly disruptions in the cerebellar connectome, may be associated with lesion size and stroke severity in Stroke patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>These findings highlight the importance of cerebellar connectome disruptions in ischemic stroke, which may provide valuable insights into the disease's underlying brain mechanisms.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 1","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12828662/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146027952","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}
This study aimed to systematically map the functional organization of the cingulate gyrus using cortical electrical stimulation (CES) guided by the Brainnetome Atlas.
Methods
We retrospectively analyzed CES data from 234 patients with drug-resistant epilepsy who underwent stereoelectroencephalography (SEEG) implantation in the cingulate cortex. A total of 1141 stimulation sites across seven cingulate subregions (A23d, A24rv, A32p, A23v, A24cd, A23c, A32sg) were examined. Responses were categorized into somatosensory, motor, autonomic, vestibular, visual, emotional, memory, and pain-related phenomena.
Results
Key findings included: (1) Somatosensory responses (n = 99) were widely distributed, with motor responses localized to middle-posterior subregions (A23c/A24rv/A24cd); (2) Autonomic (n = 58) and emotional (n = 15) responses showed broad distribution, with ventral MCC (A24rv) as an affective hub; (3) Pain responses (n = 30) involved both anterior (affective) and posterior (spatial) subregions; (4) Memory deficits (n = 8) specifically localized to posterior cingulate (A23d); (5) Visual (n = 13) and vestibular (n = 51) responses clustered in posterior and middle-posterior regions, respectively.
Conclusion
This study provides a systematic functional mapping of the cingulate gyrus using the Brainnetome Atlas, demonstrating its integrated role in diverse neurological functions. The findings advance understanding of cingulate pathophysiology and have implications for surgical planning in epilepsy.
{"title":"Function of the Human Cingulate Cortex: A Brainnetome Atlas-Based Study via Cortical Electrical Stimulation in Patients With Epilepsy","authors":"Qinqin Deng, Mengyang Wang, Guanpeng Chen, Xiongfei Wang, Zhaofen Yan, Huajun Yang, Yujiao Yang, Minghui Wang, Mengyi Guo, Zhonghua Xiong, Nan Guan, Jian Zhou, Yuguang Guan, Guoming Luan, Tianfu Li, Jing Wang","doi":"10.1002/cns.70768","DOIUrl":"10.1002/cns.70768","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>This study aimed to systematically map the functional organization of the cingulate gyrus using cortical electrical stimulation (CES) guided by the Brainnetome Atlas.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We retrospectively analyzed CES data from 234 patients with drug-resistant epilepsy who underwent stereoelectroencephalography (SEEG) implantation in the cingulate cortex. A total of 1141 stimulation sites across seven cingulate subregions (A23d, A24rv, A32p, A23v, A24cd, A23c, A32sg) were examined. Responses were categorized into somatosensory, motor, autonomic, vestibular, visual, emotional, memory, and pain-related phenomena.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Key findings included: (1) Somatosensory responses (<i>n</i> = 99) were widely distributed, with motor responses localized to middle-posterior subregions (A23c/A24rv/A24cd); (2) Autonomic (<i>n</i> = 58) and emotional (<i>n</i> = 15) responses showed broad distribution, with ventral MCC (A24rv) as an affective hub; (3) Pain responses (<i>n</i> = 30) involved both anterior (affective) and posterior (spatial) subregions; (4) Memory deficits (<i>n</i> = 8) specifically localized to posterior cingulate (A23d); (5) Visual (<i>n</i> = 13) and vestibular (<i>n</i> = 51) responses clustered in posterior and middle-posterior regions, respectively.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This study provides a systematic functional mapping of the cingulate gyrus using the Brainnetome Atlas, demonstrating its integrated role in diverse neurological functions. The findings advance understanding of cingulate pathophysiology and have implications for surgical planning in epilepsy.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 1","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12828339/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146027936","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}
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 NaV channels and GABAA 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 NaV and GABAAR 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 GABAAR positive allosteric modulator (EC50 = 93.2 μM) and a state-dependent NaV blocker (KI = 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 NaV and GABAAR 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 GABAAR and NaV synergistically suppresses neuronal hyperexcitability. Beyond epilepsy, this finding may also extend to CSD-related conditions such as stroke, traumatic brain injury, and migraine.
{"title":"BETMB: A Dual-Target Compound for Synergistic Suppression of Neuronal Hyperexcitability in Refractory Epilepsy via Concurrent Modulation of Nav Channels and GABAA Receptors","authors":"Di Zhang, Kai Li, Yingying Zhang, Yao Nie, Yue Li, Rui Li, Xin Wang, Shengjun Mao","doi":"10.1002/cns.70766","DOIUrl":"10.1002/cns.70766","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>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<sub>V</sub> channels and GABA<sub>A</sub> receptors.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>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<sub>V</sub> and GABA<sub>A</sub>R modulation was systematically investigated using both an in vitro Mg<sup>2+</sup>-free model of neuronal hyperexcitability and an <i>in silico</i> model of cortical spreading depolarization (CSD).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>BETMB acted as a GABA<sub>A</sub>R positive allosteric modulator (EC<sub>50</sub> = 93.2 μM) and a state-dependent Na<sub>V</sub> blocker (K<sub>I</sub> = 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<sub>V</sub> and GABA<sub>A</sub>R modulation completely abolished ictal-like discharges in Mg<sup>2+</sup>-free cellular models and prevented CSD initiation in computational simulations.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>BETMB is a promising dual-target therapy for refractory epilepsy, supported by the first electrophysiological evidence that dual modulation of GABA<sub>A</sub>R and Na<sub>V</sub> synergistically suppresses neuronal hyperexcitability. Beyond epilepsy, this finding may also extend to CSD-related conditions such as stroke, traumatic brain injury, and migraine.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 1","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12828663/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146027957","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}
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.
{"title":"Intermittent Fasting Alleviates Anesthesia/Surgery-Induced Delirium-Like Behavior in Aged Mice by Remodeling Gut Microbiota","authors":"Peiying Huang, Longlu Cao, Tianyu Cao, Xueji Wang, Sichen Cui, Sufang Jiang, Huan Chen, Lichao Di, Sha Li, Lining Huang","doi":"10.1002/cns.70748","DOIUrl":"10.1002/cns.70748","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>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.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>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.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>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.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>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.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 1","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12825212/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146016692","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}
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.
{"title":"Mimics and Diagnostic Pitfalls of Anti-Adenylate Kinase 5 Limbic Encephalitis","authors":"Jierui Wang, Tong Yi, Guoyu Wang, Minjin Wang, Dong Zhou, Jinmei Li","doi":"10.1002/cns.70757","DOIUrl":"10.1002/cns.70757","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>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.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>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.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>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.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Mimics of anti-AK5 encephalitis are common and that misdiagnosis is often driven by non-specific symptoms and clinically irrelevant antibody results.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 1","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12825450/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146016627","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}
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