Shamseddin Ahmadi, Shiler Khaledi, Kimia Ahmadi, Kambiz Hassanzadeh
Main Problems
The accumulation of amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs) composed of Tau protein is two characteristic brain pathologies in Alzheimer's disease (AD). However, the Aβ hypothesis has recently faced challenges due to the limited clinical efficacy of anti-Aβ antibodies, such as aducanumab and lecanemab.
Methods
This comprehensive review highlights recent advances and debates regarding the pathophysiology of Aβ peptides and plaques in AD, as well as their use as biomarkers and drug targets.
Results
Aβ aggregation is primarily driven by an imbalance between its generation from amyloid precursor protein (APP) and its clearance from the brain, processes influenced by various risk factors. The toxicity of amyloid plaques is affected by the accumulation of different Aβ species with varying lengths and post-translational modifications of Aβ. Additionally, pathways including neuroinflammation, blood–brain barrier deterioration, autophagy and mitochondrial dysfunction, lipid raft changes, and oxidative stress have pivotal roles in AD. Therefore, a clear map of Aβ's upstream regulators and downstream effectors is crucial for developing effective diagnostics and treatments for AD.
Conclusions
Incorporating new research findings and ongoing debates surrounding the Aβ cascade hypothesis is crucial for improving early diagnosis and for guiding the development of effective treatments for AD.
{"title":"Amyloid Beta in Alzheimer's Disease: Mechanisms, Biomarker Potential, and Therapeutic Targets","authors":"Shamseddin Ahmadi, Shiler Khaledi, Kimia Ahmadi, Kambiz Hassanzadeh","doi":"10.1002/cns.70688","DOIUrl":"10.1002/cns.70688","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Main Problems</h3>\u0000 \u0000 <p>The accumulation of amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs) composed of Tau protein is two characteristic brain pathologies in Alzheimer's disease (AD). However, the Aβ hypothesis has recently faced challenges due to the limited clinical efficacy of anti-Aβ antibodies, such as aducanumab and lecanemab.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This comprehensive review highlights recent advances and debates regarding the pathophysiology of Aβ peptides and plaques in AD, as well as their use as biomarkers and drug targets.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Aβ aggregation is primarily driven by an imbalance between its generation from amyloid precursor protein (APP) and its clearance from the brain, processes influenced by various risk factors. The toxicity of amyloid plaques is affected by the accumulation of different Aβ species with varying lengths and post-translational modifications of Aβ. Additionally, pathways including neuroinflammation, blood–brain barrier deterioration, autophagy and mitochondrial dysfunction, lipid raft changes, and oxidative stress have pivotal roles in AD. Therefore, a clear map of Aβ's upstream regulators and downstream effectors is crucial for developing effective diagnostics and treatments for AD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Incorporating new research findings and ongoing debates surrounding the Aβ cascade hypothesis is crucial for improving early diagnosis and for guiding the development of effective treatments for AD.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 12","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12686972/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145706874","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}
Meiling Shang, Gezhi Yan, Wanghuan Dun, Fude Liu, Ling Ma, Lu Quan, Fernando Pico, Shiliang Jiang, Xiaotong Chi, Bingbing Guo, Huiping Liu, Zepeng Tian, Peizhang Yan, Xuan Niu, Jingmei Xie, Jianfeng Han, Ming Zhang
Aims
To investigate the characteristics of hypoperfusion and structural impairment in patients with transient ischemic attack (TIA) or minor stroke (MS) with intracranial atherosclerotic stenosis (ICAS) and evaluate its impact on cognitive decline.
Methods
Cognitive function in 47 patients and 33 health controls (HC) was assessed using the Montreal Cognitive Assessment (MoCA) tool. Arterial spin labeling with two distinct postlabeling delays and 3D T1 imaging was conducted to assess cerebral blood flow (CBF), morphometric features, and asymmetry index (AI).
Results
Compared with HC, both the left and right involved patients showed reduced scores for total MoCA score. Comparisons of CBF with HC revealed that significant ischemic areas in patients were primarily localized to the perfusion territory of the middle cerebral artery in the affected hemisphere (p < 0.05, family-wise error [FWE] corrected). Despite morphometry abnormality being locally confined, AI exhibits more widespread alterations across a wider range of brain regions (both p < 0.05, FWE corrected). Both hypoperfusion and structural impairment were significantly associated with reduced MoCA score in left-involved patients, whereas only hypoperfusion showed a significant association in those with right-hemisphere involvement (p < 0.05, FWE corrected). Furthermore, the effect of ischemia on cognition was mediated by structural impairment and compensatory CBF simultaneously.
Conclusion
These findings highlight that hypoperfusion and structural impairment are already concerning and jointly associated with cognitive impairment in MS/TIA patients with ICAS, emphasizing the need for early detection and intervention.
{"title":"Perfusion and Structural Impairment in Minor Stroke and Transient Ischemic Attack With Intracranial Atherosclerotic Stenosis: Associations With Cognitive Decline","authors":"Meiling Shang, Gezhi Yan, Wanghuan Dun, Fude Liu, Ling Ma, Lu Quan, Fernando Pico, Shiliang Jiang, Xiaotong Chi, Bingbing Guo, Huiping Liu, Zepeng Tian, Peizhang Yan, Xuan Niu, Jingmei Xie, Jianfeng Han, Ming Zhang","doi":"10.1002/cns.70693","DOIUrl":"10.1002/cns.70693","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>To investigate the characteristics of hypoperfusion and structural impairment in patients with transient ischemic attack (TIA) or minor stroke (MS) with intracranial atherosclerotic stenosis (ICAS) and evaluate its impact on cognitive decline.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Cognitive function in 47 patients and 33 health controls (HC) was assessed using the Montreal Cognitive Assessment (MoCA) tool. Arterial spin labeling with two distinct postlabeling delays and 3D T1 imaging was conducted to assess cerebral blood flow (CBF), morphometric features, and asymmetry index (AI).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Compared with HC, both the left and right involved patients showed reduced scores for total MoCA score. Comparisons of CBF with HC revealed that significant ischemic areas in patients were primarily localized to the perfusion territory of the middle cerebral artery in the affected hemisphere (<i>p</i> < 0.05, family-wise error [FWE] corrected). Despite morphometry abnormality being locally confined, AI exhibits more widespread alterations across a wider range of brain regions (both <i>p</i> < 0.05, FWE corrected). Both hypoperfusion and structural impairment were significantly associated with reduced MoCA score in left-involved patients, whereas only hypoperfusion showed a significant association in those with right-hemisphere involvement (<i>p</i> < 0.05, FWE corrected). Furthermore, the effect of ischemia on cognition was mediated by structural impairment and compensatory CBF simultaneously.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These findings highlight that hypoperfusion and structural impairment are already concerning and jointly associated with cognitive impairment in MS/TIA patients with ICAS, emphasizing the need for early detection and intervention.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 12","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12690161/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145712754","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}
<div> <section> <h3> Background and Aim</h3> <p>Glioma is a highly aggressive malignancy of the central nervous system with a poor prognosis. The nucleoside-binding oligomerization domain-containing protein 1 (NOD1)/receptor-interacting protein 2 (RIP2) pathway is involved in various inflammatory responses and is closely associated with microglial polarization. Microglial M2 polarization alters the glioma microenvironment, promoting tumor growth. This study aimed to investigate the role of the NOD1/RIP2 pathway in glioma progression.</p> </section> <section> <h3> Methods</h3> <p>We explored the mechanism of NOD1/RIP2 in glioma progression through bioinformatics analysis, clinical sample evaluation, and in vivo and in vitro experiments. Bioinformatics analysis was conducted to assess NOD1 expression in glioma tissues. Multiparameter MRI and histologic analyses were performed on human tissues, and the correlation between the relative apparent diffusion coefficient (rADC) and NOD1 expression was analyzed. C6 and U251 glioma cells were treated with ML130, a NOD1 inhibitor, and assessed using 5-ethynyl-2′-deoxyuridine (EdU), plate cloning, Transwell, and wound healing assays. Key molecules of the NOD1/RIP2 pathway were examined through immunofluorescence and Western blotting. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect Arg1 and CD206 expression in BV2 mouse microglia cultured with C6-derived conditioned medium (CM). The changes in glioma cell biologic behavior were assessed using C6/BV2-derived CM through EdU, wound healing, and Transwell assays. Finally, the role and mechanism of NOD1 in glioma growth were evaluated using a rat glioma model.</p> </section> <section> <h3> Results</h3> <p>Bioinformatics analysis showed that NOD1 was highly expressed in glioma tissues and strongly correlated with glioma grade. Human brain glioma samples exhibited increased expression of NOD1, RIP2, Iba1, interleukin-1β, and CD206, with higher expression in high-grade gliomas compared to low-grade gliomas. The NOD1 expression was negatively correlated with rADC values. Treatment with ML130 inhibited glioma cell proliferation, migration, and invasion while reducing NOD1 and RIP2 expression. The expression levels of Arg1 and CD206 in BV2 cells cultured with C6-derived CM decreased in both ML130 and GSK-583 groups, while the expression levels increased in the ie-DAP group. Compared with the control group, the expressions of Arg1 and CD206 in microglia in the GSK-583 + ML130 and GSK-583 + ie-DAP groups were inhibited, and the inhibitory effect in the GSK-583 + ML130 group was more significant. Furthermore, after culturing with C6/BV2 derived C
{"title":"NOD1/RIP2 Pathway Promotes Glioma Progression Through Microglial M2 Polarization","authors":"Yuxue Luan, Miao Yu, Haimo Zhang, Xiaozu Zhang, Peilun Xiao, Fenghua Zhou, Tianyu Zhao, Xiaoli Wang, Xizhen Wang","doi":"10.1111/cns.70674","DOIUrl":"10.1111/cns.70674","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Aim</h3>\u0000 \u0000 <p>Glioma is a highly aggressive malignancy of the central nervous system with a poor prognosis. The nucleoside-binding oligomerization domain-containing protein 1 (NOD1)/receptor-interacting protein 2 (RIP2) pathway is involved in various inflammatory responses and is closely associated with microglial polarization. Microglial M2 polarization alters the glioma microenvironment, promoting tumor growth. This study aimed to investigate the role of the NOD1/RIP2 pathway in glioma progression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We explored the mechanism of NOD1/RIP2 in glioma progression through bioinformatics analysis, clinical sample evaluation, and in vivo and in vitro experiments. Bioinformatics analysis was conducted to assess NOD1 expression in glioma tissues. Multiparameter MRI and histologic analyses were performed on human tissues, and the correlation between the relative apparent diffusion coefficient (rADC) and NOD1 expression was analyzed. C6 and U251 glioma cells were treated with ML130, a NOD1 inhibitor, and assessed using 5-ethynyl-2′-deoxyuridine (EdU), plate cloning, Transwell, and wound healing assays. Key molecules of the NOD1/RIP2 pathway were examined through immunofluorescence and Western blotting. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect Arg1 and CD206 expression in BV2 mouse microglia cultured with C6-derived conditioned medium (CM). The changes in glioma cell biologic behavior were assessed using C6/BV2-derived CM through EdU, wound healing, and Transwell assays. Finally, the role and mechanism of NOD1 in glioma growth were evaluated using a rat glioma model.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Bioinformatics analysis showed that NOD1 was highly expressed in glioma tissues and strongly correlated with glioma grade. Human brain glioma samples exhibited increased expression of NOD1, RIP2, Iba1, interleukin-1β, and CD206, with higher expression in high-grade gliomas compared to low-grade gliomas. The NOD1 expression was negatively correlated with rADC values. Treatment with ML130 inhibited glioma cell proliferation, migration, and invasion while reducing NOD1 and RIP2 expression. The expression levels of Arg1 and CD206 in BV2 cells cultured with C6-derived CM decreased in both ML130 and GSK-583 groups, while the expression levels increased in the ie-DAP group. Compared with the control group, the expressions of Arg1 and CD206 in microglia in the GSK-583 + ML130 and GSK-583 + ie-DAP groups were inhibited, and the inhibitory effect in the GSK-583 + ML130 group was more significant. Furthermore, after culturing with C6/BV2 derived C","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 12","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12686968/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145706816","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}
Ischemic stroke remains a major cause of global disability and mortality, with blood–brain barrier (BBB) dysfunction being a pivotal event in its pathology. Major facilitator superfamily domain-containing 2a (Mfsd2a), a key lipid transporter at the BBB, has emerged as a promising yet underexplored therapeutic target.
Objective
This review proposes a unifying framework that positions Mfsd2a as a central indicator of ischemic stroke pathophysiology and a potential target for treatment. Although direct clinical evidence remains in its early stages, this review synthesizes foundational knowledge from diverse fields.
Methods
We revisit the established biological functions of Mfsd2a, including its role in inhibiting caveolae-mediated transcytosis and transporting omega-3 fatty acids, and detail its core mechanisms in maintaining BBB integrity. This review also correlates these functions with their significant downregulation following ischemic stroke. We then critically evaluate the limited but compelling preclinical evidence from models in which Mfsd2a has been directly targeted and explore innovative therapeutic strategies. Finally, we explicitly address the current limitations, including the scarcity of direct intervention studies, and outline a translational roadmap for future research.
Results
By integrating this dispersed evidence chain, this review aims to solidify the theoretical foundation for Mfsd2a-targeted therapies and accelerate their clinical development.
Conclusion
Targeting Mfsd2a shows a promising therapeutic strategy to protect the BBB and improve neurological outcomes after ischemic stroke.
{"title":"Mfsd2a-Targeted Therapy for Ischemic Stroke: Mechanisms, Evidence, and Future Prospects","authors":"Zhidong He, Jing Sun","doi":"10.1002/cns.70684","DOIUrl":"10.1002/cns.70684","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Ischemic stroke remains a major cause of global disability and mortality, with blood–brain barrier (BBB) dysfunction being a pivotal event in its pathology. Major facilitator superfamily domain-containing 2a (Mfsd2a), a key lipid transporter at the BBB, has emerged as a promising yet underexplored therapeutic target.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>This review proposes a unifying framework that positions Mfsd2a as a central indicator of ischemic stroke pathophysiology and a potential target for treatment. Although direct clinical evidence remains in its early stages, this review synthesizes foundational knowledge from diverse fields.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We revisit the established biological functions of Mfsd2a, including its role in inhibiting caveolae-mediated transcytosis and transporting omega-3 fatty acids, and detail its core mechanisms in maintaining BBB integrity. This review also correlates these functions with their significant downregulation following ischemic stroke. We then critically evaluate the limited but compelling preclinical evidence from models in which Mfsd2a has been directly targeted and explore innovative therapeutic strategies. Finally, we explicitly address the current limitations, including the scarcity of direct intervention studies, and outline a translational roadmap for future research.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>By integrating this dispersed evidence chain, this review aims to solidify the theoretical foundation for Mfsd2a-targeted therapies and accelerate their clinical development.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Targeting Mfsd2a shows a promising therapeutic strategy to protect the BBB and improve neurological outcomes after ischemic stroke.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 12","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12683601/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145699465","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}
Systemic therapeutic options for meningiomas remain limited. Emerging evidence indicates meningiomas harbor an immunosuppressive microenvironment and programmed cell death ligand 1 (PD-L1) expression is significantly upregulated in both tumor cells and tumor-infiltrating immune cells. Here we conducted a single-arm, single-center, open-label, phase 2 clinical trial (NCT 04728568) evaluating the programmed cell death receptor-1 (PD-1) inhibitor sintilimab in patients with recurrent/progressive meningiomas following standard surgery and/or radiotherapy.
Methods
Forty patients (9 grade 1, 18 grade 2, and 13 grade 3) received intravenous sintilimab (200 mg every 3 weeks). According to Response Assessment in Neuro-Oncology for meningioma (RANO-meningioma) criteria, the 6-month progression-free survival rate (PFS-6) was used as the primary endpoint. Secondary endpoints included the 12-month progression-free survival rate (PFS-12), PFS, overall survival (OS), and safety. Peripheral lymphocyte subpopulations, tumor-infiltrating lymphocyte (TIL) densities, and tumor mutational burden (TMB) were evaluated as immunocorrelated biomarkers.
Results
Patients with grade 1 exhibited a PFS-6 of 67.0%, a PFS-12 of 56.0%, and the median PFS was 14 months (95% CI: 0, 31.5). Grade 2/3 patients showed a PFS-6 of 42.0%, a PFS-12 of 19.0%, and the median PFS was 5.0 months (95% CI: 3.46, 6.54). The median OS was 27.0 months (95% CI: 17.26, 36.73) in grade 2/3 patients. The best outcome among all patients was stable disease (SD). Sintilimab was well tolerated without severe adverse events. A patient with a high TMB (13.14 muts/Mb) had a pseudoprogression with sintilimab and maintained stable disease among subsequent treatments. Among 3 patients with matched pre-/post-treatment tumor samples, 2 showed increased PD-1+ T cell expression after sintilimab.
Conclusion
Sintilimab failed to improve PFS-6 in both grade 1 and grade 2/3 recurrent/progressive meningiomas in this single-arm, single-center, and small-sample trial. When evaluating PD-1 inhibitor treatment for recurrent/progressive meningioma patients, who generally have a longer expected survival and high TMB, the use of the Immunotherapy Response Assessment in Neuro-Oncology (iRANO) criteria may be more appropriate to avoid overlooking potential clinical benefits.
{"title":"Phase 2 Trial of PD-1 Inhibitor Sintilimab in Recurrent/Progressive Meningioma","authors":"Yali Wang, Can Wang, Shuo Yin, Chunna Yu, Xiaojie Li, Xun Kang, Shoubo Yang, Wenting Xie, Yi Lin, Zhen Wu, Wenbin Li, Feng Chen","doi":"10.1111/cns.70659","DOIUrl":"10.1111/cns.70659","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Systemic therapeutic options for meningiomas remain limited. Emerging evidence indicates meningiomas harbor an immunosuppressive microenvironment and programmed cell death ligand 1 (PD-L1) expression is significantly upregulated in both tumor cells and tumor-infiltrating immune cells. Here we conducted a single-arm, single-center, open-label, phase 2 clinical trial (NCT 04728568) evaluating the programmed cell death receptor-1 (PD-1) inhibitor sintilimab in patients with recurrent/progressive meningiomas following standard surgery and/or radiotherapy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Forty patients (9 grade 1, 18 grade 2, and 13 grade 3) received intravenous sintilimab (200 mg every 3 weeks). According to Response Assessment in Neuro-Oncology for meningioma (RANO-meningioma) criteria, the 6-month progression-free survival rate (PFS-6) was used as the primary endpoint. Secondary endpoints included the 12-month progression-free survival rate (PFS-12), PFS, overall survival (OS), and safety. Peripheral lymphocyte subpopulations, tumor-infiltrating lymphocyte (TIL) densities, and tumor mutational burden (TMB) were evaluated as immunocorrelated biomarkers.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Patients with grade 1 exhibited a PFS-6 of 67.0%, a PFS-12 of 56.0%, and the median PFS was 14 months (95% CI: 0, 31.5). Grade 2/3 patients showed a PFS-6 of 42.0%, a PFS-12 of 19.0%, and the median PFS was 5.0 months (95% CI: 3.46, 6.54). The median OS was 27.0 months (95% CI: 17.26, 36.73) in grade 2/3 patients. The best outcome among all patients was stable disease (SD). Sintilimab was well tolerated without severe adverse events. A patient with a high TMB (13.14 muts/Mb) had a pseudoprogression with sintilimab and maintained stable disease among subsequent treatments. Among 3 patients with matched pre-/post-treatment tumor samples, 2 showed increased PD-1+ T cell expression after sintilimab.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Sintilimab failed to improve PFS-6 in both grade 1 and grade 2/3 recurrent/progressive meningiomas in this single-arm, single-center, and small-sample trial. When evaluating PD-1 inhibitor treatment for recurrent/progressive meningioma patients, who generally have a longer expected survival and high TMB, the use of the Immunotherapy Response Assessment in Neuro-Oncology (iRANO) criteria may be more appropriate to avoid overlooking potential clinical benefits.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 12","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12683679/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145699503","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}
Nan Wang, Xiaoke Chai, Jiuxiang Song, Yifang He, Qiheng He, Tan Zhang, Dongsheng Liu, Jingqi Li, Tianqing Cao, Sipeng Zhu, Yitong Jia, Juanning Si, Wenbin Ma, Yi Yang, Jizong Zhao
Objective
The current application of single-modality electroencephalography (EEG) or functional near-infrared spectroscopy (fNIRS) to assess consciousness levels in patients with disorders of consciousness (DoC) has garnered significant attention. However, the diagnostic accuracy of unimodal approaches remains suboptimal. Therefore, this study aims to apply the multimodal fusion technology of EEG and fNIRS to the clinical diagnosis of DoC patients.
Methods
Eleven patients with DoC (six with a minimally conscious state [MCS] and five with a vegetative state [VS]) were enrolled. The motor intention-based brain-computer interface (MI-BCI) paradigm was adopted. EEG and fNIRS were recorded simultaneously. The synchronous states of EEG and fNIRS were analyzed, including time-frequency analysis, event-related desynchronization (ERD), and changes in oxy-hemoglobin (HbO)/de-oxygenated (HbR)/total hemoglobin (HbT) content. A multimodal method combining EEG and fNIRS was used to classify DoC patients.
Results
The machine-learning results of the MI-BCI model showed that the EEG-fNIRS multimodal approach was superior to single-modality techniques in the diagnosis of healthy controls (HC), MCS, and VS. The multimodal model achieved a mean AUC of 0.69 ± 0.10, significantly outperforming both unimodal EEG (0.43 ± 0.19; p < 0.01) and standalone fNIRS (0.63 ± 0.10; p < 0.05). The EEG_ERD index of left-handed MI-BCI significantly differentiated the MCS and VS groups. Meanwhile, for the classification tasks of HC, MCS, and VS, the importance ranking of the indicators was as follows: fNIRS_ACC, EEG_ACC, fNIRS_slope, fNIRS_centroid, EEG_ERD, fNIRS_integral, and fNIRS_mean.
Conclusion
The integration of multimodal MI-BCI paradigms demonstrates clinical potential in evaluating consciousness levels, while the synergistic combination of neurophysiological and hemodynamic biomarkers provides a robust framework for enhancing the precision of bedside diagnostic protocols.
{"title":"Motor Intention Quantization for Patients With Disorders of Consciousness by Multimodal BCI Combining Electroencephalography and Functional Near-Infrared Spectroscopy","authors":"Nan Wang, Xiaoke Chai, Jiuxiang Song, Yifang He, Qiheng He, Tan Zhang, Dongsheng Liu, Jingqi Li, Tianqing Cao, Sipeng Zhu, Yitong Jia, Juanning Si, Wenbin Ma, Yi Yang, Jizong Zhao","doi":"10.1002/cns.70679","DOIUrl":"10.1002/cns.70679","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>The current application of single-modality electroencephalography (EEG) or functional near-infrared spectroscopy (fNIRS) to assess consciousness levels in patients with disorders of consciousness (DoC) has garnered significant attention. However, the diagnostic accuracy of unimodal approaches remains suboptimal. Therefore, this study aims to apply the multimodal fusion technology of EEG and fNIRS to the clinical diagnosis of DoC patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Eleven patients with DoC (six with a minimally conscious state [MCS] and five with a vegetative state [VS]) were enrolled. The motor intention-based brain-computer interface (MI-BCI) paradigm was adopted. EEG and fNIRS were recorded simultaneously. The synchronous states of EEG and fNIRS were analyzed, including time-frequency analysis, event-related desynchronization (ERD), and changes in oxy-hemoglobin (HbO)/de-oxygenated (HbR)/total hemoglobin (HbT) content. A multimodal method combining EEG and fNIRS was used to classify DoC patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The machine-learning results of the MI-BCI model showed that the EEG-fNIRS multimodal approach was superior to single-modality techniques in the diagnosis of healthy controls (HC), MCS, and VS. The multimodal model achieved a mean AUC of 0.69 ± 0.10, significantly outperforming both unimodal EEG (0.43 ± 0.19; <i>p</i> < 0.01) and standalone fNIRS (0.63 ± 0.10; <i>p</i> < 0.05). The EEG_ERD index of left-handed MI-BCI significantly differentiated the MCS and VS groups. Meanwhile, for the classification tasks of HC, MCS, and VS, the importance ranking of the indicators was as follows: fNIRS_ACC, EEG_ACC, fNIRS_slope, fNIRS_centroid, EEG_ERD, fNIRS_integral, and fNIRS_mean.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The integration of multimodal MI-BCI paradigms demonstrates clinical potential in evaluating consciousness levels, while the synergistic combination of neurophysiological and hemodynamic biomarkers provides a robust framework for enhancing the precision of bedside diagnostic protocols.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Trial Registration</h3>\u0000 \u0000 <p>Clinical Trial Registry: ChiCTR2400085830</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 12","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cns.70679","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145686703","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}
Drug-resistant epilepsy (DRE) affects nearly one-third of patients and remains a major unmet clinical need, despite advances in anti-seizure medications (ASMs). Carbogen, a low-concentration carbon dioxide (CO2) and oxygen (O2) gas mixture, has reemerged as a physiology-based therapy owing to renewed insights into pH-sensitive seizure mechanisms.
Methods
This review summarizes preclinical and clinical evidence on carbogen inhalation for seizure control. Mechanistic data on pH-dependent ion channels, GABAergic inhibition, and adenosine signaling were condensed, and clinical outcomes across seizure types and inhalation protocols were compared for safety and efficacy.
Results
Carbogen induces short-term respiratory acidosis, lowering brain extracellular pH to activate acid-sensitive ion channels (e.g., ASIC1a and NaV1.2), enhance GABAergic inhibition, and boost adenosine signaling. These effects are rapid, reversible, and distinct from conventional ASMs. Preclinical studies show strong seizure suppression, especially under hyperventilation-induced alkalosis. Clinically, brief low-dose inhalation (5% CO2 for ≤ 3 min) is effective and well tolerated in focal and absence seizures, whereas earlier high-concentration protocols caused adverse effects. Efficacy varies by seizure type: benefits in nonconvulsive status epilepticus (NCSE) are limited, and the CARDIF trial found no advantage for pediatric febrile seizures. Ongoing work, such as the CRESCENT trial, is exploring carbogen as an adjunct therapy for pediatric convulsive status epilepticus (CSE).
Conclusions
Evidence supports carbogen's therapeutic promise and highlights the need for precise patient selection, controlled delivery, and comprehensive safety testing. Future research should develop biomarker-guided, closed-loop systems and test synergy with established ASMs to advance carbogen as a mechanism-based therapy within precision epilepsy care.
{"title":"Carbogen Inhalation Therapy for Epileptic Seizures: Mechanisms, Evidence, and Future Directions","authors":"Li Wang, Yue Liu, Wenwen Ding, Meng Yang, Qing Liu, Fuqiang Xu","doi":"10.1002/cns.70686","DOIUrl":"10.1002/cns.70686","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Drug-resistant epilepsy (DRE) affects nearly one-third of patients and remains a major unmet clinical need, despite advances in anti-seizure medications (ASMs). Carbogen, a low-concentration carbon dioxide (CO<sub>2</sub>) and oxygen (O<sub>2</sub>) gas mixture, has reemerged as a physiology-based therapy owing to renewed insights into pH-sensitive seizure mechanisms.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This review summarizes preclinical and clinical evidence on carbogen inhalation for seizure control. Mechanistic data on pH-dependent ion channels, GABAergic inhibition, and adenosine signaling were condensed, and clinical outcomes across seizure types and inhalation protocols were compared for safety and efficacy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Carbogen induces short-term respiratory acidosis, lowering brain extracellular pH to activate acid-sensitive ion channels (e.g., ASIC1a and NaV1.2), enhance GABAergic inhibition, and boost adenosine signaling. These effects are rapid, reversible, and distinct from conventional ASMs. Preclinical studies show strong seizure suppression, especially under hyperventilation-induced alkalosis. Clinically, brief low-dose inhalation (5% CO<sub>2</sub> for ≤ 3 min) is effective and well tolerated in focal and absence seizures, whereas earlier high-concentration protocols caused adverse effects. Efficacy varies by seizure type: benefits in nonconvulsive status epilepticus (NCSE) are limited, and the CARDIF trial found no advantage for pediatric febrile seizures. Ongoing work, such as the CRESCENT trial, is exploring carbogen as an adjunct therapy for pediatric convulsive status epilepticus (CSE).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Evidence supports carbogen's therapeutic promise and highlights the need for precise patient selection, controlled delivery, and comprehensive safety testing. Future research should develop biomarker-guided, closed-loop systems and test synergy with established ASMs to advance carbogen as a mechanism-based therapy within precision epilepsy care.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 12","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12676256/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145666567","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}
Post-stroke depression represents a prevalent neuropsychiatric complication following intracerebral hemorrhage (ICH), yet its underlying mechanisms remain less understood compared to ischemic stroke.
Methods
This translational investigation employed a multi-omics approach, combining bioinformatics analysis of depression-related (GSE214921) and ICH-related (GSE18193) datasets from the GEO database with experimental validation. Using a collagenase-induced striatal ICH murine model, we evaluated the effects of intranasal administration of osteopontin (OPN, encoded by SPP1) through neurobehavioral tests, histopathological evaluation, and molecular biology techniques.
Results
Integrated bioinformatics analysis identified the SPP1 signaling pathway as a potential key regulator in post-ICH depression pathogenesis. In vivo, OPN treatment produced sustained neurobehavioral improvements at 28 days post-ICH, significantly ameliorating neurological deficits, mitigating anxiety-depressive behaviors, and enhancing spatial learning-memory performance. Histopathological evaluation revealed OPN's multifaceted neuroprotective effects, including attenuated hippocampal neuroinflammation, preserved Nissl body integrity, and restored dendritic arborization complexity. Mechanistically, OPN exerted its therapeutic effects through activation of the Nrf2/BDNF signaling axis, as pharmacological inhibition of Nrf2 with ML385 completely abrogated both neuroprotection and BDNF upregulation.
Conclusion
Our study is the first to demonstrate the critical role of SPP1 signaling in post-ICH depression through modulation of the Nrf2/BDNF pathway, providing novel therapeutic targets for clinical management of this debilitating neuropsychiatric sequela.
{"title":"SPP1/OPN Alleviates Post-Intracerebral Hemorrhage Depression and Cognitive Impairment via Nrf2/BDNF Signaling Activation in Mice","authors":"Pengpeng Li, Yangyang Gao, Shiqing Du, Zhengqian Mu, Zhenxing Tao, Xuqi Zhang, Xudong Zhao","doi":"10.1002/cns.70680","DOIUrl":"10.1002/cns.70680","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Post-stroke depression represents a prevalent neuropsychiatric complication following intracerebral hemorrhage (ICH), yet its underlying mechanisms remain less understood compared to ischemic stroke.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This translational investigation employed a multi-omics approach, combining bioinformatics analysis of depression-related (GSE214921) and ICH-related (GSE18193) datasets from the GEO database with experimental validation. Using a collagenase-induced striatal ICH murine model, we evaluated the effects of intranasal administration of osteopontin (OPN, encoded by SPP1) through neurobehavioral tests, histopathological evaluation, and molecular biology techniques.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Integrated bioinformatics analysis identified the SPP1 signaling pathway as a potential key regulator in post-ICH depression pathogenesis. In vivo, OPN treatment produced sustained neurobehavioral improvements at 28 days post-ICH, significantly ameliorating neurological deficits, mitigating anxiety-depressive behaviors, and enhancing spatial learning-memory performance. Histopathological evaluation revealed OPN's multifaceted neuroprotective effects, including attenuated hippocampal neuroinflammation, preserved Nissl body integrity, and restored dendritic arborization complexity. Mechanistically, OPN exerted its therapeutic effects through activation of the Nrf2/BDNF signaling axis, as pharmacological inhibition of Nrf2 with ML385 completely abrogated both neuroprotection and BDNF upregulation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our study is the first to demonstrate the critical role of SPP1 signaling in post-ICH depression through modulation of the Nrf2/BDNF pathway, providing novel therapeutic targets for clinical management of this debilitating neuropsychiatric sequela.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 12","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cns.70680","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145675877","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}
Xinwei Li, Guomei Xu, Guohong Geng, Wei Wang, Jun Hu, Zhangyong Li, Shuyu Li
Aim
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by significant heterogeneity in clinical symptoms and underlying neurobiology. This study aimed to identify distinct ASD biotypes and uncover their neurobiological underpinnings using a novel graph-based subtyping approach.
Methods
Resting-state fMRI and clinical data from 443 males with ASD (17.22 ± 8.63 years) were analyzed. We proposed a population graph-based dual autoencoder for subtyping (PG-DAS), a deep clustering framework that integrates imaging data and nonimaging data to extract deep features for biotype identification. Statistical analyses were conducted to compare clinical scores and functional connectivity patterns between biotypes. Correlation analyses examined the associations between intra- and internetwork connectivity and clinical symptoms. Predictive modeling using support vector regression assessed the ability of network connectivity to predict clinical scores.
Results
Two distinct ASD biotypes were identified. ASD1 exhibited significantly lower clinical scores and reduced network integration, characterized by weaker intra- and internetwork connectivity, particularly in core networks such as the cingulo-opercular network, linked to communication symptom scores. In contrast, ASD2 exhibited greater network segregation, with internetwork connectivity in sensorimotor-related networks correlating with total symptom scores. Predictive modeling further revealed biotype-specific brain-behavior associations, with ASD1 and ASD2 showing positive correlations with social and communication scores, respectively.
Conclusion
This study underscores the critical role of biotype-specific brain network patterns in understanding ASD heterogeneity. The proposed PG-DAS framework proved effective in ASD subtyping and holds promise for broader applications in exploring other neuroheterogeneous disorders.
{"title":"Subtyping Autism Spectrum Disorder With a Population Graph-Based Dual Autoencoder: Revealing Two Distinct Biotypes","authors":"Xinwei Li, Guomei Xu, Guohong Geng, Wei Wang, Jun Hu, Zhangyong Li, Shuyu Li","doi":"10.1002/cns.70675","DOIUrl":"10.1002/cns.70675","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by significant heterogeneity in clinical symptoms and underlying neurobiology. This study aimed to identify distinct ASD biotypes and uncover their neurobiological underpinnings using a novel graph-based subtyping approach.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Resting-state fMRI and clinical data from 443 males with ASD (17.22 ± 8.63 years) were analyzed. We proposed a population graph-based dual autoencoder for subtyping (PG-DAS), a deep clustering framework that integrates imaging data and nonimaging data to extract deep features for biotype identification. Statistical analyses were conducted to compare clinical scores and functional connectivity patterns between biotypes. Correlation analyses examined the associations between intra- and internetwork connectivity and clinical symptoms. Predictive modeling using support vector regression assessed the ability of network connectivity to predict clinical scores.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Two distinct ASD biotypes were identified. ASD1 exhibited significantly lower clinical scores and reduced network integration, characterized by weaker intra- and internetwork connectivity, particularly in core networks such as the cingulo-opercular network, linked to communication symptom scores. In contrast, ASD2 exhibited greater network segregation, with internetwork connectivity in sensorimotor-related networks correlating with total symptom scores. Predictive modeling further revealed biotype-specific brain-behavior associations, with ASD1 and ASD2 showing positive correlations with social and communication scores, respectively.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This study underscores the critical role of biotype-specific brain network patterns in understanding ASD heterogeneity. The proposed PG-DAS framework proved effective in ASD subtyping and holds promise for broader applications in exploring other neuroheterogeneous disorders.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 12","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12675305/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145666509","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}
Zilu Shen, Xuesong Shan, Shenglan Zhang, Dan Huang, Haijun Hu, Yonglin Liang, Hong Zhu, Lieliang Zhang, Yayu Chen
Aims
Parkinson's disease (PD) is a complex neurodegenerative disorder lacking disease-modifying therapies. This study aimed to systematically investigate the therapeutic potential and underlying mechanisms of Alpinetin in PD.
Methods
An integrated approach combining network pharmacology and molecular docking was employed to predict the core targets and pathways of Alpinetin in PD. These computational predictions were subsequently validated through in vivo animal experiments.
Results
Network pharmacology analysis predicted that Alpinetin exerts its effects by modulating mitophagy and dopaminergic synaptic pathways. Molecular docking revealed strong binding affinities between Alpinetin and key targets, including HIF1A, SQSTM1, and SRC. Guided by these findings, animal experiments confirmed the neuroprotective effects of Alpinetin, aligning with the predicted mechanisms.
Conclusion
Our findings demonstrate that Alpinetin has significant therapeutic potential for PD, likely mediated through the regulation of mitophagy and dopaminergic synapses. This study elucidates the molecular targets and mechanisms of Alpinetin, providing a solid foundation for its further investigation as an anti-PD agent.
{"title":"Alpinetin Targets Mitophagy Pathways to Mitigate Parkinson's Disease Progression","authors":"Zilu Shen, Xuesong Shan, Shenglan Zhang, Dan Huang, Haijun Hu, Yonglin Liang, Hong Zhu, Lieliang Zhang, Yayu Chen","doi":"10.1002/cns.70676","DOIUrl":"10.1002/cns.70676","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>Parkinson's disease (PD) is a complex neurodegenerative disorder lacking disease-modifying therapies. This study aimed to systematically investigate the therapeutic potential and underlying mechanisms of Alpinetin in PD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>An integrated approach combining network pharmacology and molecular docking was employed to predict the core targets and pathways of Alpinetin in PD. These computational predictions were subsequently validated through in vivo animal experiments.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Network pharmacology analysis predicted that Alpinetin exerts its effects by modulating mitophagy and dopaminergic synaptic pathways. Molecular docking revealed strong binding affinities between Alpinetin and key targets, including HIF1A, SQSTM1, and SRC. Guided by these findings, animal experiments confirmed the neuroprotective effects of Alpinetin, aligning with the predicted mechanisms.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our findings demonstrate that Alpinetin has significant therapeutic potential for PD, likely mediated through the regulation of mitophagy and dopaminergic synapses. This study elucidates the molecular targets and mechanisms of Alpinetin, providing a solid foundation for its further investigation as an anti-PD agent.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 12","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12672210/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145659993","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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