Ying Chen, Akhilesh K. Bajpai, Nan Li, Jiahui Xiang, Angelina Wang, Qingqing Gu, Junpu Ruan, Ran Zhang, Gang Chen, Lu Lu
Aims
Chronic pain is an impeding condition that affects day-to-day life and poses a substantial economic burden, surpassing many other health conditions. This study employs a cross-species integrated approach to uncover novel pain mediators/regulators.
Methods
We used weighted gene coexpression network analysis to identify pain-enriched gene module. Functional analysis and protein-protein interaction (PPI) network analysis of the module genes were conducted. RNA sequencing compared pain model and control mice. PheWAS was performed to link genes to pain-related GWAS traits. Finally, candidates were prioritized based on node degree, differential expression, GWAS associations, and phenotype correlations.
Results
A gene module significantly over-enriched with the pain reference set was identified (referred to as “pain module”). Analysis revealed 141 pain module genes interacting with 46 pain reference genes in the PPI network, which included 88 differentially expressed genes. PheWAS analysis linked 53 of these genes to pain-related GWAS traits. Expression correlation analysis identified Vdac1, Add2, Syt2, and Syt4 as significantly correlated with pain phenotypes across eight brain regions. NCAM1, VAMP2, SYT2, ADD2, and KCND3 were identified as top pain response/regulator genes.
Conclusion
The identified genes and molecular mechanisms may enhance understanding of pain pathways and contribute to better drug target identification.
{"title":"Discovery of Novel Pain Regulators Through Integration of Cross-Species High-Throughput Data","authors":"Ying Chen, Akhilesh K. Bajpai, Nan Li, Jiahui Xiang, Angelina Wang, Qingqing Gu, Junpu Ruan, Ran Zhang, Gang Chen, Lu Lu","doi":"10.1111/cns.70255","DOIUrl":"https://doi.org/10.1111/cns.70255","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>Chronic pain is an impeding condition that affects day-to-day life and poses a substantial economic burden, surpassing many other health conditions. This study employs a cross-species integrated approach to uncover novel pain mediators/regulators.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We used weighted gene coexpression network analysis to identify pain-enriched gene module. Functional analysis and protein-protein interaction (PPI) network analysis of the module genes were conducted. RNA sequencing compared pain model and control mice. PheWAS was performed to link genes to pain-related GWAS traits. Finally, candidates were prioritized based on node degree, differential expression, GWAS associations, and phenotype correlations.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A gene module significantly over-enriched with the pain reference set was identified (referred to as “pain module”). Analysis revealed 141 pain module genes interacting with 46 pain reference genes in the PPI network, which included 88 differentially expressed genes. PheWAS analysis linked 53 of these genes to pain-related GWAS traits. Expression correlation analysis identified Vdac1, Add2, Syt2, and Syt4 as significantly correlated with pain phenotypes across eight brain regions. NCAM1, VAMP2, SYT2, ADD2, and KCND3 were identified as top pain response/regulator genes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The identified genes and molecular mechanisms may enhance understanding of pain pathways and contribute to better drug target identification.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 2","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70255","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143380373","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}
Yuheng Zhang, Bingying Du, Miaozhan Zou, Bo Peng, Yanxia Rao
Neuronal ceroid lipofuscinosis (NCL) is a group of neurodegenerative lysosomal storage disorders characterized by excessive accumulation of lysosomal lipofuscin. Thirteen subtypes of NCL have been identified, each associated with distinct genes encoding various transmembrane proteins, secretory proteins, or lysosomal enzymes. Clinically, NCL manifests in infants through vision impairment, motor and cognitive dysfunctions, epilepsy, and premature death. The pathological complexity of NCL has hindered the development of effective clinical protocols. Current treatment modalities, including enzyme replacement therapy, pharmacological approaches, gene therapy, and stem cell therapy, have demonstrated limited efficacy. However, emerging evidence suggests a significant relationship between NCL and microglial cells, highlighting the potential of novel microglial cell replacement therapies. This review comprehensively examines the pathogenic genes associated with various NCL subtypes, elucidating their roles, clinical presentations, and corresponding mouse models. Especially, we thoroughly discuss the advances in the clinical study of potential therapeutics, which crucially calls for early diagnosis and treatment more than ever.
{"title":"Neuronal Ceroid Lipofuscinosis—Concepts, Classification, and Avenues for Therapy","authors":"Yuheng Zhang, Bingying Du, Miaozhan Zou, Bo Peng, Yanxia Rao","doi":"10.1111/cns.70261","DOIUrl":"https://doi.org/10.1111/cns.70261","url":null,"abstract":"<p>Neuronal ceroid lipofuscinosis (NCL) is a group of neurodegenerative lysosomal storage disorders characterized by excessive accumulation of lysosomal lipofuscin. Thirteen subtypes of NCL have been identified, each associated with distinct genes encoding various transmembrane proteins, secretory proteins, or lysosomal enzymes. Clinically, NCL manifests in infants through vision impairment, motor and cognitive dysfunctions, epilepsy, and premature death. The pathological complexity of NCL has hindered the development of effective clinical protocols. Current treatment modalities, including enzyme replacement therapy, pharmacological approaches, gene therapy, and stem cell therapy, have demonstrated limited efficacy. However, emerging evidence suggests a significant relationship between NCL and microglial cells, highlighting the potential of novel microglial cell replacement therapies. This review comprehensively examines the pathogenic genes associated with various NCL subtypes, elucidating their roles, clinical presentations, and corresponding mouse models. Especially, we thoroughly discuss the advances in the clinical study of potential therapeutics, which crucially calls for early diagnosis and treatment more than ever.</p>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 2","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70261","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143379899","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}
Shuang Zou, Yiwei Gong, Mengqi Yan, Zhijian Yuan, Minjuan Sun, Shuo Zhang, Yuanzhi Yang, Xiongfeng Guo, Lan Huang, Fan Fei, Yi Wang, Zhong Chen, Cenglin Xu
Aims
The limited efficacy and very restricted antiseizure range of current deep brain stimulation (DBS) targets highlight the need to find an optimal target for managing various seizure types. Here, we aimed to investigate the efficacy of DBS on the ventromedial hypothalamus (VMH) in the different types of experimental epileptic seizures.
Methods
The efficacy of DBS was examined in various epileptic seizure models, and the potential mechanisms were investigated by using in vivo calcium signal recording and optogenetics.
Results
The c-fos expression was significantly increased in the glutamatergic neurons of VMH (VMHglu) following seizures. Then, 1-Hz low-frequency stimulation (LFS) at the VMH successfully attenuated the seizure severities across models of epilepsy, including the maximal electroshock, the pentylenetetrazol, the absence seizure, the cortical or hippocampal kainic acid–induced acute seizure, and the hippocampal-kindling models. The in vivo calcium imaging recordings revealed that LFS could inhibit the activities of the VMHglu. Optogenetic inhibition of VMHglu mirrored LFS's antiseizure impact. Further anterograde viral tracing confirmed the extensive distributed projections of VMHglu, which may compose the circuitry basis of the broad-spectral efficacy of LFS.
Conclusion
These findings demonstrate that VMH-LFS is a broad-spectrum treatment approach for different seizure types by decreasing VMHglu activity.
{"title":"Low-Frequency Stimulation at the Ventromedial Hypothalamus Exhibits Broad-Spectrum Efficacy Across Models of Epilepsy","authors":"Shuang Zou, Yiwei Gong, Mengqi Yan, Zhijian Yuan, Minjuan Sun, Shuo Zhang, Yuanzhi Yang, Xiongfeng Guo, Lan Huang, Fan Fei, Yi Wang, Zhong Chen, Cenglin Xu","doi":"10.1111/cns.70265","DOIUrl":"https://doi.org/10.1111/cns.70265","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>The limited efficacy and very restricted antiseizure range of current deep brain stimulation (DBS) targets highlight the need to find an optimal target for managing various seizure types. Here, we aimed to investigate the efficacy of DBS on the ventromedial hypothalamus (VMH) in the different types of experimental epileptic seizures.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The efficacy of DBS was examined in various epileptic seizure models, and the potential mechanisms were investigated by using in vivo calcium signal recording and optogenetics.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The <i>c-fos</i> expression was significantly increased in the glutamatergic neurons of VMH (VMH<sup>glu</sup>) following seizures. Then, 1-Hz low-frequency stimulation (LFS) at the VMH successfully attenuated the seizure severities across models of epilepsy, including the maximal electroshock, the pentylenetetrazol, the absence seizure, the cortical or hippocampal kainic acid–induced acute seizure, and the hippocampal-kindling models. The in vivo calcium imaging recordings revealed that LFS could inhibit the activities of the VMH<sup>glu</sup>. Optogenetic inhibition of VMH<sup>glu</sup> mirrored LFS's antiseizure impact. Further anterograde viral tracing confirmed the extensive distributed projections of VMH<sup>glu</sup>, which may compose the circuitry basis of the broad-spectral efficacy of LFS.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These findings demonstrate that VMH-LFS is a broad-spectrum treatment approach for different seizure types by decreasing VMH<sup>glu</sup> activity.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 2","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70265","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143379901","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}
Xiangqian Huang, Jiahao Song, Xiaoming Zhang, Mengqi Wang, Yuchuan Ding, Xunming Ji, Da Zhou, Ran Meng
<div> <section> <h3> Background</h3> <p>Antiplatelet drugs are a cornerstone in managing atherosclerotic vascular disease (ASVD). However, their interactions with other medications present significant challenges to treatment efficacy and safety. Patients with ASVD often require multiple treatment regimens due to complex comorbidities, which increases the risk of drug–drug interactions (DDIs). These interactions can lead to drug resistance, reduced therapeutic outcomes, or adverse effects. A thorough understanding of DDIs is crucial for optimizing patient care.</p> </section> <section> <h3> Aims</h3> <p>This review aims to explore the clinical significance. mechanisms, and implications of DDIs in antiplatelet therapy Additionally, it seeks to identify future research directions to advance personalized treatment strategies and improve therapeutic outcomes.</p> </section> <section> <h3> Materials and Methods</h3> <p>A systematic literature review was conducted using key databases, focusing on clinical studies, mechanistic research, and guidelines related to antiplatelet therapy and DDIs. Findings were analyzed to identify common interaction patterns, associated risks, and management strategies.</p> </section> <section> <h3> Results</h3> <p>The review identifies common DDIs involving antiplatelet drugs, particularly with anticoagulants, nonsteroidal anti-inflammatory drugs, and proton pump inhibitors. These interactions primarily occur through pharmacokinetic mechanisms, such as alterations in drug metabolism via cytochrome P450 enzymes, and pharmacodynamic mechanisms, including synergistic or antagonistic effects on platelet inhibition. Clinically, DDIs can increase bleeding risk, reduce antiplatelet efficacy, and contribute to adverse cardiovascular outcomes. Strategies to mitigate these risks include individualized drug selection, dose adjustments, genetic testing, and therapeutic drug monitoring.</p> </section> <section> <h3> Discussion</h3> <p>Effective management of DDIs in antiplatelet therapy is essential to improve clinical outcomes. A patient-specific approach, considering comorbidities, genetic predispositions, and concurrent medications, is crucial. The review categorizes DDIs based on clinical settings and underscores the need for further research on predictive biomarkers, pharmacogenomics, and advanced monitoring techniques.</p> </section> <section> <h3> Conclusion</h3
{"title":"Understanding Drug Interactions in Antiplatelet Therapy for Atherosclerotic Vascular Disease: A Systematic Review","authors":"Xiangqian Huang, Jiahao Song, Xiaoming Zhang, Mengqi Wang, Yuchuan Ding, Xunming Ji, Da Zhou, Ran Meng","doi":"10.1111/cns.70258","DOIUrl":"https://doi.org/10.1111/cns.70258","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Antiplatelet drugs are a cornerstone in managing atherosclerotic vascular disease (ASVD). However, their interactions with other medications present significant challenges to treatment efficacy and safety. Patients with ASVD often require multiple treatment regimens due to complex comorbidities, which increases the risk of drug–drug interactions (DDIs). These interactions can lead to drug resistance, reduced therapeutic outcomes, or adverse effects. A thorough understanding of DDIs is crucial for optimizing patient care.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>This review aims to explore the clinical significance. mechanisms, and implications of DDIs in antiplatelet therapy Additionally, it seeks to identify future research directions to advance personalized treatment strategies and improve therapeutic outcomes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Materials and Methods</h3>\u0000 \u0000 <p>A systematic literature review was conducted using key databases, focusing on clinical studies, mechanistic research, and guidelines related to antiplatelet therapy and DDIs. Findings were analyzed to identify common interaction patterns, associated risks, and management strategies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The review identifies common DDIs involving antiplatelet drugs, particularly with anticoagulants, nonsteroidal anti-inflammatory drugs, and proton pump inhibitors. These interactions primarily occur through pharmacokinetic mechanisms, such as alterations in drug metabolism via cytochrome P450 enzymes, and pharmacodynamic mechanisms, including synergistic or antagonistic effects on platelet inhibition. Clinically, DDIs can increase bleeding risk, reduce antiplatelet efficacy, and contribute to adverse cardiovascular outcomes. Strategies to mitigate these risks include individualized drug selection, dose adjustments, genetic testing, and therapeutic drug monitoring.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Discussion</h3>\u0000 \u0000 <p>Effective management of DDIs in antiplatelet therapy is essential to improve clinical outcomes. A patient-specific approach, considering comorbidities, genetic predispositions, and concurrent medications, is crucial. The review categorizes DDIs based on clinical settings and underscores the need for further research on predictive biomarkers, pharmacogenomics, and advanced monitoring techniques.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 2","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70258","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143380372","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}
Zixuan Guo, Shu Xiao, Shilin Sun, Ting Su, Xinyue Tang, Guanmao Chen, Pan Chen, Ruoyi Chen, Chao Chen, Jiaying Gong, Zibin Yang, Li Huang, Yanbin Jia, Ying Wang
Background
The pattern of abnormal resting-state brain function has been documented in schizophrenia (SCZ). However, as of yet, it remains unclear whether this pattern is of genetic predisposition or related to the illness itself.
Methods
A systematical meta-analysis was performed to identify resting-state functional differences in probands and their high-risk first-degree relatives of schizophrenia (FDRs-SCZ) using Seed-based d Mapping software. Subsequently, spatial associations between postmortem gene expression and neurotransmitters distribution data and neural activity alterations were conducted to uncover neural mechanisms underlaying FDRs-SCZ and SCZ from a multidimensional perspective.
Results
A total of 13 studies comprising 503 FDRs-SCZ and 605 healthy controls (HCs) and 129 studies comprising 6506 patients with SCZ and 6982 HCs were included. Compared to HCs, FDRs-SCZ displayed increased spontaneous functional activity in the bilateral anterior cingulate cortex/medial prefrontal cortex (ACC/mPFC); patients with SCZ showed decreased spontaneous functional activity in the bilateral ACC/mPFC, bilateral postcentral gyrus, and right middle temporal gyrus as well as increased spontaneous functional activity in the bilateral striatum. The altered functional activity in FDRs-SCZ and SCZ shared similar spatial associations with genes enriched in potassium ion transmembrane transport, channel activity, and complex. The FDRs-SCZ and SCZ-related brain functional patterns were additionally associated with dopaminergic, serotonergic, and cholinergic neurotransmitter distribution.
Conclusions
SCZ-related resting-state functional, neuroimaging transcriptomes, and neurotransmitters abnormalities may exist in high-risk unaffected FDRs-SCZ, rather than just in overt SCZ. The study extended the evidence that altered brain function, along with their spatial correlations to genetics and neurotransmitter systems, may associate with genetic vulnerability for SCZ.
{"title":"Neural Activity Alterations and Their Association With Neurotransmitter and Genetic Profiles in Schizophrenia: Evidence From Clinical Patients and Unaffected Relatives","authors":"Zixuan Guo, Shu Xiao, Shilin Sun, Ting Su, Xinyue Tang, Guanmao Chen, Pan Chen, Ruoyi Chen, Chao Chen, Jiaying Gong, Zibin Yang, Li Huang, Yanbin Jia, Ying Wang","doi":"10.1111/cns.70218","DOIUrl":"https://doi.org/10.1111/cns.70218","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The pattern of abnormal resting-state brain function has been documented in schizophrenia (SCZ). However, as of yet, it remains unclear whether this pattern is of genetic predisposition or related to the illness itself.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A systematical meta-analysis was performed to identify resting-state functional differences in probands and their high-risk first-degree relatives of schizophrenia (FDRs-SCZ) using Seed-based d Mapping software. Subsequently, spatial associations between postmortem gene expression and neurotransmitters distribution data and neural activity alterations were conducted to uncover neural mechanisms underlaying FDRs-SCZ and SCZ from a multidimensional perspective.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A total of 13 studies comprising 503 FDRs-SCZ and 605 healthy controls (HCs) and 129 studies comprising 6506 patients with SCZ and 6982 HCs were included. Compared to HCs, FDRs-SCZ displayed increased spontaneous functional activity in the bilateral anterior cingulate cortex/medial prefrontal cortex (ACC/mPFC); patients with SCZ showed decreased spontaneous functional activity in the bilateral ACC/mPFC, bilateral postcentral gyrus, and right middle temporal gyrus as well as increased spontaneous functional activity in the bilateral striatum. The altered functional activity in FDRs-SCZ and SCZ shared similar spatial associations with genes enriched in potassium ion transmembrane transport, channel activity, and complex. The FDRs-SCZ and SCZ-related brain functional patterns were additionally associated with dopaminergic, serotonergic, and cholinergic neurotransmitter distribution.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>SCZ-related resting-state functional, neuroimaging transcriptomes, and neurotransmitters abnormalities may exist in high-risk unaffected FDRs-SCZ, rather than just in overt SCZ. The study extended the evidence that altered brain function, along with their spatial correlations to genetics and neurotransmitter systems, may associate with genetic vulnerability for SCZ.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 2","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70218","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143380411","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}
Lei Chen, Zuyao Yang, Shuming Ji, Tingting Song, Hua Li, Yusha Tang, Yucheng Chen, Yajiao Li
Aims
Simple congenital heart diseases (CHD) are associated with various central nervous system diseases, including epilepsy. This study aimed to compare the risk of epilepsy in patients with different types of simple CHD.
Methods
In this prospective cohort study, from January 2008 to June 2022, patients with atrial septal defect (ASD), patent foramen ovale (PFO), ventricular septal defect (VSD), and patent ductus arteriosus (PDA) were recruited at the Registration Center of CHD in West China Hospital. Follow-up was conducted yearly until the diagnosis of epilepsy, loss to follow-up, or end of study. The outcomes included a comparison of epilepsy incidence according to different simple CHD types and a risk assessment of developing epilepsy. Multivariable Poisson regression was performed to adjusted factors of demographics and disease history.
Results
Of 10,914 patients who met the inclusion criteria, 108 were diagnosed with epilepsy at an average follow-up of 2.19 years. Epilepsy incidence in patients with PFO, VSD, PDA, and ASD was 8.58/1000, 4.85/1000, 3.98/1000, and 2.63/1000 person-years, respectively. Compared with ASD patients (reference group), the risk ratios (95% confidence intervals) in patients with PFO, VSD, and PDA were 3.28 (2.00–5.43), 1.47 (0.79–2.68), and 1.46 (0.70–2.82), respectively. Subgroup analyses determined that patients with simple CHD who underwent CHD surgery demonstrated a lower risk of epilepsy than those who did not.
Conclusion
Among the major types of simple CHD, PFO was associated with a significantly higher risk of epilepsy, while the risk was reduced in those who underwent PFO closure procedures.
{"title":"Comparing the Risk of Epilepsy in Patients With Simple Congenital Heart Diseases: A Prospective Cohort Study","authors":"Lei Chen, Zuyao Yang, Shuming Ji, Tingting Song, Hua Li, Yusha Tang, Yucheng Chen, Yajiao Li","doi":"10.1111/cns.70230","DOIUrl":"https://doi.org/10.1111/cns.70230","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>Simple congenital heart diseases (CHD) are associated with various central nervous system diseases, including epilepsy. This study aimed to compare the risk of epilepsy in patients with different types of simple CHD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this prospective cohort study, from January 2008 to June 2022, patients with atrial septal defect (ASD), patent foramen ovale (PFO), ventricular septal defect (VSD), and patent ductus arteriosus (PDA) were recruited at the Registration Center of CHD in West China Hospital. Follow-up was conducted yearly until the diagnosis of epilepsy, loss to follow-up, or end of study. The outcomes included a comparison of epilepsy incidence according to different simple CHD types and a risk assessment of developing epilepsy. Multivariable Poisson regression was performed to adjusted factors of demographics and disease history.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Of 10,914 patients who met the inclusion criteria, 108 were diagnosed with epilepsy at an average follow-up of 2.19 years. Epilepsy incidence in patients with PFO, VSD, PDA, and ASD was 8.58/1000, 4.85/1000, 3.98/1000, and 2.63/1000 person-years, respectively. Compared with ASD patients (reference group), the risk ratios (95% confidence intervals) in patients with PFO, VSD, and PDA were 3.28 (2.00–5.43), 1.47 (0.79–2.68), and 1.46 (0.70–2.82), respectively. Subgroup analyses determined that patients with simple CHD who underwent CHD surgery demonstrated a lower risk of epilepsy than those who did not.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Among the major types of simple CHD, PFO was associated with a significantly higher risk of epilepsy, while the risk was reduced in those who underwent PFO closure procedures.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 2","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70230","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143362770","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}
Minkyung Kang, Ava Nasrollahi, Feng Cheng, Yao Yao
Background
Pericytes, a type of mural cells, exert important functions in the CNS. One major challenge in pericyte research is the lack of pericyte-specific and subpopulation-specific markers.
Methods
To address this knowledge gap, we first generated a novel transgenic mouse line in which vascular smooth muscle cells (vSMCs) are permanently labeled with tdTomato. Next, we isolated PDGFRβ+tdTomato− pericytes and PDGFRβ+tdTomato+ vSMCs from the brains of these mice and subsequently performed RNAseq analysis to identify pericyte-enriched genes.
Results
Using this approach, we successfully identified 40 pericyte-enriched genes and 158 vSMC-enriched genes, which are involved in different biological processes and molecular functions. Using ISH/IHC analysis, we found that Pla1a and Cox4i2 were predominantly enriched in subpopulations of brain pericytes, although they also marked some non-vascular parenchymal cells.
Conclusions
These findings suggest that Pla1a and Cox4i2 preferably label subpopulations of pericytes in the brain compared to vSMCs, and thus, they may be useful in distinguishing these populations.
{"title":"Screening and Identification of Brain Pericyte-Selective Markers","authors":"Minkyung Kang, Ava Nasrollahi, Feng Cheng, Yao Yao","doi":"10.1111/cns.70247","DOIUrl":"https://doi.org/10.1111/cns.70247","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Pericytes, a type of mural cells, exert important functions in the CNS. One major challenge in pericyte research is the lack of pericyte-specific and subpopulation-specific markers.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>To address this knowledge gap, we first generated a novel transgenic mouse line in which vascular smooth muscle cells (vSMCs) are permanently labeled with tdTomato. Next, we isolated PDGFRβ<sup>+</sup>tdTomato<sup>−</sup> pericytes and PDGFRβ<sup>+</sup>tdTomato<sup>+</sup> vSMCs from the brains of these mice and subsequently performed RNAseq analysis to identify pericyte-enriched genes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Using this approach, we successfully identified 40 pericyte-enriched genes and 158 vSMC-enriched genes, which are involved in different biological processes and molecular functions. Using ISH/IHC analysis, we found that <i>Pla1a</i> and <i>Cox4i2</i> were predominantly enriched in subpopulations of brain pericytes, although they also marked some non-vascular parenchymal cells.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>These findings suggest that <i>Pla1a</i> and <i>Cox4i2</i> preferably label subpopulations of pericytes in the brain compared to vSMCs, and thus, they may be useful in distinguishing these populations.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 2","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70247","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143248877","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}
Alzheimer's disease (AD) is a common neurodegenerative disorder with a substantial genetic component. Despite advances in elucidating the genetic underpinnings of AD, much of its heritability remains unexplained. Discovering novel genetic variants and understanding their pathogenic roles are crucial challenges in AD research.
Objective
This study aimed to identify pathogenic genes and elucidate their role in familial early-onset AD (EOAD).
Methods
Blood samples from an EOAD pedigree and Sorbin and SH3 Domain-Containing Protein 2 (SORBS2) T189M transgenic mice were analyzed. Cognitive function was assessed via the Morris water maze (MWM). Protein expression was evaluated by western blotting, while amyloid-β (Aβ) levels were quantified via immunohistochemistry and enzyme-linked immunosorbent assay. Inflammatory markers were measured using immunofluorescence and quantitative reverse transcription polymerase chain reaction (PCR). Neuronal morphology, including dendritic and spine alterations, was examined using Golgi staining.
Results
We identified a novel SORBS2 variant (c. 566C>T, p. T189M) in a Han Chinese family, segregating with AD in a Mendelian fashion. SORBS2 T189M transgenic mice exhibited cognitive deficits, cortical Aβ accumulation, and an increased Aβ42/Aβ40 ratio. Additionally, elevated levels of interleukin (IL)-1β, IL-6, tumor necrosis factor α (TNF-α), and ionized calcium-binding adaptor molecule 1 (Iba1)-positive microglia, along with neuronal loss, were observed in the brains of T189M mice.
Conclusion
Our study suggest that the SORBS2 T189M variant is a novel candidate causal mutation associated with familial AD in a Chinese pedigree, contributing to AD pathogenesis by promoting neuroinflammation and neuronal injury. Notably, this study is the first to establish a link between SORBS2 mutations and AD.
{"title":"A Novel Missense Variant in SORBS2 Is Causative With Familial Alzheimer's Disease","authors":"Qi Wang, Shiyuan Wang, Shuman Cao, Qigeng Wang, Yiping Wei, Ying Li, Yan Wang, Yan Li, Wei Qin, Meina Quan, Jianping Jia","doi":"10.1111/cns.70256","DOIUrl":"https://doi.org/10.1111/cns.70256","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Alzheimer's disease (AD) is a common neurodegenerative disorder with a substantial genetic component. Despite advances in elucidating the genetic underpinnings of AD, much of its heritability remains unexplained. Discovering novel genetic variants and understanding their pathogenic roles are crucial challenges in AD research.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>This study aimed to identify pathogenic genes and elucidate their role in familial early-onset AD (EOAD).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Blood samples from an EOAD pedigree and Sorbin and SH3 Domain-Containing Protein 2 (<i>SORBS2</i>) T189M transgenic mice were analyzed. Cognitive function was assessed via the Morris water maze (MWM). Protein expression was evaluated by western blotting, while amyloid-β (Aβ) levels were quantified via immunohistochemistry and enzyme-linked immunosorbent assay. Inflammatory markers were measured using immunofluorescence and quantitative reverse transcription polymerase chain reaction (PCR). Neuronal morphology, including dendritic and spine alterations, was examined using Golgi staining.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We identified a novel <i>SORBS2</i> variant (c. 566C>T, p. T189M) in a Han Chinese family, segregating with AD in a Mendelian fashion. <i>SORBS2</i> T189M transgenic mice exhibited cognitive deficits, cortical Aβ accumulation, and an increased Aβ42/Aβ40 ratio. Additionally, elevated levels of interleukin (IL)-1β, IL-6, tumor necrosis factor α (TNF-α), and ionized calcium-binding adaptor molecule 1 (Iba1)-positive microglia, along with neuronal loss, were observed in the brains of T189M mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our study suggest that the <i>SORBS2</i> T189M variant is a novel candidate causal mutation associated with familial AD in a Chinese pedigree, contributing to AD pathogenesis by promoting neuroinflammation and neuronal injury. Notably, this study is the first to establish a link between <i>SORBS2</i> mutations and AD.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 2","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70256","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143248594","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}
Caloric restriction is a health-promoting lifestyle that has been reported to protect both white and gray matter in cases of ischemic stroke. This study will explore the underlying mechanism of restricted feeding (RF) and provide a theoretical basis for precise clinical treatment of stroke.
Methods
In this study, we pretreated C57BL/6J mice with 70% RF for a continuous 28-day period prior to 60 min of transient focal cerebral ischemia (tFCI). Histological staining, diffusion tensor imaging (DTI), and behavioral assessments were used to assess RF's neuroprotection following tFCI. Immunofluorescence staining, quantitative real-time PCR, and flow cytometry were conducted to evaluate brain inflammation post-tFCI. Western blot, immunofluorescence staining, tracers, and electric microscopy were used to assess the blood–brain barrier (BBB) integrity. Peripheral neutrophils were cleared by administrating an anti-Ly6G antibody.
Results
Initially, DTI, NeuN staining, and a batch of behavioral tests verified that RF significantly mitigated both gray/white matter injury and neurological deficits in the short- and long-term following tFCI. RF mice showed more anti-inflammatory microglia in their brains, along with reduced inflammatory cytokines, and chemokines. Interestingly, RF significantly reduced the neutrophils and macrophage infiltration. Subsequently, we observed that RF mice exhibited better BBB integrity following tFCI, with reduced neutrophil infiltration and matrix metalloprotein-9 release. Furthermore, the clearance of neutrophils with anti-Ly6G antibody in ad libitum feeding mice (LF-Ly6G) elicited comparable neuroprotective effects to those observed in RF, including improvements in neurological deficits, reductions in infarct volume, and mitigation of BBB damage.
Conclusions
In summary, our findings suggest that RF maintains the BBB integrity following ischemic stroke at least partially by reducing neutrophil infiltration, thereby alleviating both neurological and histological impairments.
{"title":"Caloric Restriction Preserves BBB Integrity After Transient Focal Cerebral Ischemia Through Reducing Neutrophil Infiltration","authors":"Chenran Wang, Leilei Mao, Miao He, Jia Zhang, Yichen Huang, Yue Zhang, Jing Xu, Shaoqiang Huang, Yanqin Gao","doi":"10.1111/cns.70257","DOIUrl":"https://doi.org/10.1111/cns.70257","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>Caloric restriction is a health-promoting lifestyle that has been reported to protect both white and gray matter in cases of ischemic stroke. This study will explore the underlying mechanism of restricted feeding (RF) and provide a theoretical basis for precise clinical treatment of stroke.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this study, we pretreated C57BL/6J mice with 70% RF for a continuous 28-day period prior to 60 min of transient focal cerebral ischemia (tFCI). Histological staining, diffusion tensor imaging (DTI), and behavioral assessments were used to assess RF's neuroprotection following tFCI. Immunofluorescence staining, quantitative real-time PCR, and flow cytometry were conducted to evaluate brain inflammation post-tFCI. Western blot, immunofluorescence staining, tracers, and electric microscopy were used to assess the blood–brain barrier (BBB) integrity. Peripheral neutrophils were cleared by administrating an anti-Ly6G antibody.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Initially, DTI, NeuN staining, and a batch of behavioral tests verified that RF significantly mitigated both gray/white matter injury and neurological deficits in the short- and long-term following tFCI. RF mice showed more anti-inflammatory microglia in their brains, along with reduced inflammatory cytokines, and chemokines. Interestingly, RF significantly reduced the neutrophils and macrophage infiltration. Subsequently, we observed that RF mice exhibited better BBB integrity following tFCI, with reduced neutrophil infiltration and matrix metalloprotein-9 release. Furthermore, the clearance of neutrophils with anti-Ly6G antibody in ad libitum feeding mice (LF-Ly6G) elicited comparable neuroprotective effects to those observed in RF, including improvements in neurological deficits, reductions in infarct volume, and mitigation of BBB damage.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>In summary, our findings suggest that RF maintains the BBB integrity following ischemic stroke at least partially by reducing neutrophil infiltration, thereby alleviating both neurological and histological impairments.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 2","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70257","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143362810","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}
Vascular dementia (VaD) includes a group of brain disorders that are characterized by cerebrovascular pathology.Neuroinflammation, disruption of the blood–brain barrier (BBB) permeability, white matter lesions, and neuronal loss are all significant pathological manifestations of VaD and play a key role in disease progression. Necroptosis, also known asprogrammed necrosis, is a mode of programmed cell death distinct from apoptosis and is closely associated with ischemic injury and neurodegenerative diseases. Recent studies have shown that necroptosis in VaD exacerbates BBB destruction, activates neuroinflammation, promotes neuronal loss, and severely affects VaD prognosis.
Results and Conclusions
In this review, we outline the significant roles of necroptosis and its molecular mechanisms in the pathological process of VaD, with a particular focus on the role of necroptosis in modulating neuroinflammation and exacerbating the disruption of BBB permeability in VaD, and elaborate on the molecular regulatory mechanisms and the centrally involved cells of necroptosis mediated by tumor necrosis factor-α in neuroinflammation in VaD. We also analyze the possibility and specific strategy that targeting necroptosis would help inhibit neuroinflammation and BBB destruction in VaD. With a focus on necroptosis, this study delved into its impact on the pathological changes and prognosis of VaD to provide new treatment ideas.
{"title":"Advances in the Study of Necroptosis in Vascular Dementia: Focus on Blood–Brain Barrier and Neuroinflammation","authors":"Yuemin Qiu, Lin Cheng, Yinyi Xiong, Ziying Liu, Chunxiao Shen, Liangliang Wang, Yujia Lu, Shufei Wei, Lushun Zhang, Seung Bum Yang, Xiaorong Zhang","doi":"10.1111/cns.70224","DOIUrl":"https://doi.org/10.1111/cns.70224","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Vascular dementia (VaD) includes a group of brain disorders that are characterized by cerebrovascular pathology.Neuroinflammation, disruption of the blood–brain barrier (BBB) permeability, white matter lesions, and neuronal loss are all significant pathological manifestations of VaD and play a key role in disease progression. Necroptosis, also known asprogrammed necrosis, is a mode of programmed cell death distinct from apoptosis and is closely associated with ischemic injury and neurodegenerative diseases. Recent studies have shown that necroptosis in VaD exacerbates BBB destruction, activates neuroinflammation, promotes neuronal loss, and severely affects VaD prognosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results and Conclusions</h3>\u0000 \u0000 <p>In this review, we outline the significant roles of necroptosis and its molecular mechanisms in the pathological process of VaD, with a particular focus on the role of necroptosis in modulating neuroinflammation and exacerbating the disruption of BBB permeability in VaD, and elaborate on the molecular regulatory mechanisms and the centrally involved cells of necroptosis mediated by tumor necrosis factor-α in neuroinflammation in VaD. We also analyze the possibility and specific strategy that targeting necroptosis would help inhibit neuroinflammation and BBB destruction in VaD. With a focus on necroptosis, this study delved into its impact on the pathological changes and prognosis of VaD to provide new treatment ideas.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 2","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70224","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143362812","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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