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Activation of cerebral Ras-related C3 botulinum toxin substrate(Rac) 1 promotes post-ischemic stroke functional recovery in aged mice

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Neural Regeneration Research 2024年第4期19卷 881-886页

作者： Fan Bu Jia-Wei Min Md Abdur Razzaque Ahmad El Hamamy Anthony Patrizz Li Qi Akihiko Urayama Jun Li department of neurology University of Texas Health Science Center department of neurology&Psychology The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine

Brain functional impairment after stroke is common;however,the molecular mechanisms of post-stroke recovery remain unclear.It is well-recognized that age is the most important independent predictor of poor outcomes after stroke as older patients show poorer functional outcomes following stroke.Mounting evidence suggests that axonal regeneration and angiogenesis,the major forms of brain plasticity responsible for post-stroke recovery,diminished with advanced age.Previous studies suggest that Ras-related C3 botulinum toxin substrate(Rac)1 enhances stroke recovery as activation of Rac1 improved behavior recovery in a young mice stroke model.Here,we investigated the role of Rac1 signaling in long-term functional recovery and brain plasticity in an aged(male,18 to 22 months old C57BL/6J)brain after ischemic stroke.We found that as mice aged,Rac1 expression declined in the brain.Delayed overexpression of Rac1,using lentivirus encoding Rac1 injected day 1 after ischemic stroke,promoted cognitive(assessed using novel object recognition test)and sensorimotor(assessed using adhesive removal tests)recovery on days 14–28.This was accompanied by the increase of neurite and proliferative endothelial cells in the periinfarct zone assessed by immunostaining.In a reverse approach,pharmacological inhibition of Rac1 by intraperitoneal injection of Rac1 inhibitor NSC23766 for 14 successive days after ischemic stroke worsened the outcome with the reduction of neurite and proliferative endothelial cells.Furthermore,Rac1 inhibition reduced the activation of p21-activated kinase 1,the protein level of brain-derived neurotrophic factor,and increased the protein level of glial fibrillary acidic protein in the ischemic brain on day 28 after stroke.Our work provided insight into the mechanisms behind the diminished plasticity after cerebral ischemia in aged brains and identified Rac1 as a potential therapeutic target for improving functional recovery in the older adults after stroke.

关键词： aging angiogenesis brain-derived neurotrophic factor(BDNF) cerebral ischemia cognitive recovery neurite Pak1 Rac1 sensorimotor recovery

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Rationale and design of Tenecteplase Reperfusion Therapy in Acute Ischaemic Cerebrovascular Events III (TRACE III): a randomised, phase III, open- label, controlled trial

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Stroke & Vascular neurology 2024年第1期9卷 82-89页

作者： Yunyun Xiong Bruce C V Campbell Marc Fisher Lee H Schwamm Mark Parsons Hao Li Yuesong Pan Xia Meng Xingquan Zhao Yongjun Wang neurology Beijing Tiantan HospitalBeijingChina China National Clinical Research center for Neurological Diseases BeijingChina department of medicine and neurology The University of MelbourneMelbourneVictoriaAustralia neurology Beth Israel Deaconess Medical CenterBostonMassachusettsUSA department of neurology and Comprehensive Stroke center Massachusetts General HospitalBostonMassachusettsUSA department of neurology University of New South Wales South Western Sydney Clinical SchoolLiverpoolNew South WalesAustralia

Background and purpose Recombinant human TNK tissue-type plasminogen activator(rhTNK-tPA)was not inferior to alteplase for ischaemic stroke within 4.5hours.Our study aimed to investigate the efficacy and safety of rhTNK-tPA in patients who had an ischaemic stroke due to large vessel occlusion(LVO)of anterior circulation beyond 4.5hours.Methods and design Tenecteplase Reperfusion Therapy in Acute Ischaemic Cerebrovascular Events-III(TRACE III)is a multicentre,prospective,randomised,open-label,blind endpoint,controlled clinical trial.Patients who had an ischaemic stroke due to anterior circulation LVO(internal carotid artery,middle cerebral artery M1 and M2 segments)within 4.5–24hours from last known well(including wake-up stroke and no witness stroke)and with salvageable tissue(ischaemic core volume6s at 24 hours and NIHSS score change from baseline at 7days.Safety outcomes are symptomatic intracerebral haemorrhage within 36 hours and mortality at 90 days.Discussion TRACE III will provide evidence for the efficacy and safety of rhTNK-tPA in patients who had an ischaemic strokes due to anterior circulation LVO beyond 4.5hours.Trial registration number NCT05141305.

关键词： Therapy random Rational

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Mortality from cerebrovascular diseases in China:Exploration of recent and future trends

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Chinese Medical Journal 2024年第5期137卷 588-595页

作者： Bin Lv Ge Song Feng Jing Mingyu Li Hua Zhou Wanjun Li Jiacai Lin Shengyuan Yu Jun Wang Xiangyu Cao Chenglin Tian department of neurology The First Medical CenterChinese PLA General HospitalBeijing 100853China department of neurology the 305 Hospital of Chinese PLABeijing 100017China department of Internal medicine Gucheng County Hospital of Traditional Chinese MedicineHengshuiHebei 253800China department of neurology Tangshan Hospital of Traditional Chinese MedicineTangshanHebei 063000China department of neurology Hainan Hospital of Chinese PLA General HospitalSanyaHainan 572013China

Background:Cerebrovascular disease(CVD)ranks among the foremost factors responsible for mortality on a global scale.The mortality patterns of CVDs and temporal trends in China need to be well-illustrated and updated.Methods:We collected mortality data on patients with CVD from Chinese center for Disease Control and Prevention’s Disease Surveillance Points(CDC-DSP)system.The mortality of CVD in 2020 was described by age,sex,residence,and region.The temporal trend from 2013 to 2019 was evaluated using joinpoint regression,and estimated rates of decline were extrapolated until 2030 using time series models.Results:In 2019,the age-standardized mortality in China(ASMRC)per 100,000 individuals was 113.2.The ASMRC for males(137.7/10^(5))and rural areas(123.0/10^(5))were both higher when stratified by gender and urban/rural residence.The central region had the highest mortality(126.5/10^(5)),the western region had a slightly lower mortality(123.5/10^(5)),and the eastern region had the lowest mortality(97.3/10^(5)).The age-specific mortality showed an accelerated upward trend from aged 55-59 years,with maximum mortality observed in individuals over 85 years of age.The age-standardized mortality of CVD decreased by 2.43%(95%confidence interval,1.02-3.81%)annually from 2013 to 2019.Notably,the age-specific mortality of CVD increased from 2013 to 2019 for the age group of over 85 years.In 2020,both the absolute number of CVD cases and the crude mortality of CVD have increased compared to their values in 2019.The estimated total deaths due to CVD were estimated to reach 2.3 million in 2025 and 2.4 million in 2030.Conclusion:The heightened focus on the burden of CVD among males,rural areas,the central and western of China,and individuals aged 75 years and above has emerged as a pivotal determinant in further decreasing mortalities,consequently presenting novel challenges to strategies for disease prevention and control.

关键词： Cerebrovascular diseases Mortality Epidemiology Global Burden of Disease China COVID-19 pandemic

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Is medical management useful in Moyamoya disease?

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World Journal of Clinical Cases 2024年第3期12卷 466-473页

作者： Sombat Muengtaweepongsa Vatcharasorn Panpattanakul center of Excellence in Stroke Division of NeurologyDepartment of MedicineFaculty of MedicineThammasat UniversityRangsit CampusKlonglaung 12120Pathum ThaniThailand Division of neurology Department of Internal MedicineSchool of MedicineUniversity of PhayaoPhayao 56000Thailand

Moyamoya disease(MMD),characterized by progressive internal carotid artery stenosis and collateral vessel formation,prompts cerebral perfusion complications and is stratified into idiopathic and Moyamoya syndrome subtypes.A multifa-ceted approach toward MMD management addresses cerebral infarctions through revascularization surgery and adjunctive medical therapy,while also navigating risks such as intracranial hemorrhage and cerebral infarction resulting from arte-rial stenosis and fragile collateral vessels.Addressing antithrombotic management reveals a potential role for treatments like antiplatelet agents and anticoagulants,despite the ambiguous contribution of thrombosis to MMD-related infarctions and the critical balance between preventing ischemic events and averting hemo-rrhagic complications.Transcranial doppler has proven useful in thromboembolic detection,despite persisting challenges concerning the efficacy and safety of an-tithrombotic treatments.Furthermore,antihypertensive interventions aim to ma-nage blood pressure meticulously,especially during intracerebral hemorrhage,with recommendations and protocols varying based on the patient’s hypertension status.Additionally,lipid-lowering therapeutic strategies,particularly employing statins,are appraised for their possible beneficial role in MMD management,even as comprehensive data from disease-specific clinical trials remains ***-prehensive guidelines and protocols to navigate the multifaceted therapeutic ave-nues for MMD,while maintaining a delicate balance between efficacy and safety,warrant further meticulous research and development.This protocol manuscript seeks to elucidate the various aspects and challenges imbued in managing and navigating through the complex landscape of MMD treatment.

关键词： Moyamoya disease Cerebral infarction Antithrombotic management Transcranial doppler Revascularization Intracerebral hemorrhage Antihypertensive intervention Lipid-lowering therapies

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Use of donepezil for neurocognitive recovery after brain injury in adult and pediatric populations:a scoping review

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Neural Regeneration Research 2024年第8期19卷 1686-1695页

作者： Avery L.Miller Nathan K.Evanson J.Michael Taylor University of Cincinnati College of medicine CincinnatiOHUSA department of Pediatrics University of CincinnatiCincinnatiOHUSA department of neurology and Rehabilitation medicine University of CincinnatiCincinnatiOHUSA Division of Pediatric Rehabilitation medicine Cincinnati Children’s Hospital Medical CenterCincinnatiOHUSA Division of neurology Cincinnati Children’s Hospital Medical CenterCincinnatiOHUSA

There are few pharmacologic options for the treatment of cognitive deficits associated with traumatic brain injury in pediatric patients.Acetylcholinesterase inhibitors such as donepezil have been evaluated in adult patients after traumatic brain injury,but relatively less is known about the effect in pediatric populations.The goal of this review is to identify knowledge gaps in the efficacy and safety of acetylcholinesterase inhibito rs as a potential a djuvant treatment fo r neurocognitive decline in pediatric patients with traumatic brain injury.Investigators queried PubMed to identify literature published from database inception thro ugh June 2023 desc ribing the use of donepezil in young adult traumatic brain injury and pediatric patients with predefined conditions.Based on preselected search criteria,340 unique papers we re selected for title and abstra ct screening.Thirty-two reco rds were reviewed in full after eliminating preclinical studies and pape rs outside the scope of the project.In adult traumatic brain injury,we review results from 14 papers detailing 227 subjects where evidence suggests donepezil is well tole rated and shows both objective and patient-reported efficacy for reducing cognitive impairment.In children,3 pape rs report on 5 children recovering from traumatic brain injury,showing limited efficacy.An additional 15 pediatric studies conducted in populations at risk for cognitive dysfunction provide a broader look at safety and efficacy in 210 patients in the pediatric age group.Given its promise for efficacy in adults with traumatic brain injury and tole rability in pediatric patients,we believe further study of donepezil for children and adolescents with traumatic brain injury is warranted.

关键词： acetylcholinesterase inhibitor adult cognition donepezil pediatrics traumatic brain injury

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Circulating proteomic biomarkers for diagnosing sporadic amyotrophic lateral sclerosis:a cross-sectional study

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Neural Regeneration Research 2024年第8期19卷 1842-1848页

作者： Lu He Qinming Zhou Chaoyang Xiu Yaping Shao Dingding Shen Huanyu Meng Weidong Le Sheng Chen department of neurology and Institute of neurology Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina department of neurology Hospital of Chengdu University of Traditional Chinese MedicineChengduSichuan ProvinceChina center for Translational Research on Neurological Diseases the First Affiliated HospitalDalian Medical UniversityDalianLiaoning ProvinceChina Co-innovation center of Neuroregeneration Nantong UniversityNantongJiangsu ProvinceChina Institute of neurology Sichuan Academy of Medical Sciences-Sichuan Provincial HospitalChengduSichuan ProvinceChina department of neurology Xinrui HospitalWuxiJiangsu ProvinceChina

Biomarke rs are required for the early detection,prognosis prediction,and monitoring of amyotrophic lateral sclerosis,a progressive disease.Proteomics is an unbiased and quantitative method that can be used to detect neurochemical signatures to aid in the identification of candidate biomarke rs.In this study,we used a label-free quantitative proteomics approach to screen for substantially differentially regulated proteins in ten patients with sporadic amyotrophic lateral scle rosis compared with five healthy controls.Su bstantial upregulation of serum proteins related to multiple functional clusters was observed in patients with spo radic amyotrophic lateral sclerosis.Potential biomarke rs were selected based on functionality and expression specificity.To validate the proteomics profiles,blood samples from an additional cohort comprising 100 patients with sporadic amyotrophic lateral sclerosis and 100 healthy controls were subjected to enzyme-linked immunosorbent assay.Eight substantially upregulated serum proteins in patients with spora dic amyotrophic lateral sclerosis were selected,of which the cathelicidin-related antimicrobial peptide demonstrated the best discriminative ability between patients with sporadic amyotrophic lateral sclerosis and healthy controls(area under the curve[AUC]=0.713,P<0.0001).To further enhance diagnostic accuracy,a multi-protein combined discriminant algorithm was developed incorporating five proteins(hemoglobin beta,cathelicidin-related antimicrobial peptide,talin-1,zyxin,and translationally-controlled tumor protein).The algo rithm achieved an AUC of 0.811 and a P-value of<0.0001,resulting in 79%sensitivity and 71%specificity for the diagnosis of sporadic amyotrophic lateral scle rosis.Subsequently,the ability of candidate biomarkers to discriminate between early-stage amyotrophic lateral sclerosis patients and controls,as well as patients with different disease severities,was examined.A two-protein panel comprising talin-1 and translationally-controlled tumor protein effectively d

关键词： amyotrophic lateral sclerosis cathelicidin-related antimicrobial peptide hemoglobin label-free quantitative proteomics multi-protein combined diagnostic panel serum biomarkers talin-1 translationally-controlled tumor protein zyxin

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Strain-dependent alpha-synuclein spreading in Parkinson's disease and multiple system atrophy

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Neural Regeneration Research 2024年第12期19卷 2581-2582页

作者： Shuyu Zhang Paul Lingor department of neurology School of MedicineUniversity Hospital rechts der IsarTechnical University of MunichMunichGermany department of neurology University Medical Center GöttingenGöttingenGermany center for Biostructural Imaging of Neurodegeneration University Medical Center GöttingenGöttingenGermany

Parkinson's disease(PD) and atypical Parkinsonian syndromes,such as multiple system atrophy(MSA) and Dementia with Lewy bodies,are neurodegenerative movement disorders characterized by the accumulation of alphasynuclein(a-syn) aggregates.These a-syn aggregates propagate throughout the brain in a prion-like manner,where pathological a-syn recruits endogenous a-syn to form insoluble aggregates.Oligomeric forms representing intermediates on the way to insoluble aggregates result in the most pronounced neurotoxic effects.

关键词： atrophy endogenous atypical

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Ketogenic diet therapy in children with epilepsy caused by SLC2A1 mutations:a single-center single-arm retrospective study

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World Journal of Pediatrics 2024年第5期20卷 517-524页

作者： Ying-Yan Wang Yun-Qing Zhou Li-Juan Luo Cui-Jin Wang Nan Shen Hao Li Ji-Wen Wang department of neurology Shanghai Children’s Medical CenterSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina department of Infectious Diseases Shanghai Children’s Medical CenterSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina Clinical Research Ward Clinical Research CenterShanghai Children’s Medical CenterSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina

Background This retrospective study assessed the efficacy and safety of ketogenic diet therapies in children with epilepsy caused by SLC2A1 genetic mutations and glucose transporter type 1 deficiency syndrome.Methods Pediatric patients with epilepsy symptoms admitted to our medical center between January 2017 and October 2021 were included if they presented with an SLC2A1 genetic mutation on whole-exome sequencing.We analyzed the patients’convulsions and treatment with antiepileptic drugs.The patients were followed up at different time periods after ketogenic diet therapies.Results Six patients with SLC2A1 mutations were included in this study.The patients had seizures of different types and frequencies,and they took antiepileptic drugs to relieve their symptoms.They were then treated with a ketogenic diet for at least four months.We analyzed epilepsy control rates at 1,2,3,6,and 12 months after ketogenic diet treatment.All patients were seizure-free within a month of receiving the diet therapy.All patients were followed up for six months,three were followed up for 12 months after the treatment,and there was no recurrence of epilepsy during this period.After antiepileptic drug withdrawal,none of the patients experienced seizure relapse when receiving ketogenic diet treatment alone.No severe adverse events occurred during the therapy.Conclusions Ketogenic diet therapy is very effective and safe for the treatment of epilepsy caused by SLC2A1 mutations.Therefore,patients with glucose transporter type 1 deficiency syndrome caused by SLC2A1 mutations should begin ketogenic diet treatment as soon as possible.

关键词： Epilepsy Glucose transporter type 1 Ketogenic diet SLC2A1

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Alterations in nasal microbiota of patients with amyotrophic lateral sclerosis

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Chinese Medical Journal 2024年第2期137卷 162-171页

作者： Kaixiong Liu Qifu Guo Ying Ding Li Luo Jianchai Huang Qijie Zhang department of Respiratory and Critical Care medicine The First Affiliated HospitalFujian Medical UniversityFuzhouFujian 350005China Department of Respiratory and Critical Care MedicineNational Regional Medical CenterBinhai Campus of The First Affiliated HospitalFujian Medical UniversityFuzhouFujian 350212China department of neurology Fujian Institute of NeurologyThe First Affiliated HospitalFujian Medical UniversityFuzhouFujian 350005China Department of NeurologyNational Regional Medical CenterBinhai Campus of The First Affiliated HospitalFujian Medical UniversityFuzhouFujian 350212China

Background:Links between alterations in gut microbiota composition and amyotrophic lateral sclerosis(ALS)have previously been reported.This study aimed to examine the microbiota in the nasal cavity of ALS.Methods:Sixty-six ALS patients and 40 healthy caregivers who live in close proximity with patients were enrolled.High throughput metagenomic sequencing of the 16S ribosomal deoxyribonucleic acid(rDNA)gene V3-V4 region of nasal microbiota was used to characterize the alpha and beta diversity and relative abundance of bacterial taxa,predict function,and conduct correlation analysis between specific taxa and clinical features.Results:The nasal microbiome of ALS patients showed lower alpha diversity than that of corresponding healthy family members.Genera Gaiella,Sphingomonas,Polaribacter_1,Lachnospiraceae_NK4A136_group,Klebsiella,and Alistipes were differentially enriched in ALS patients compared to controls.Nasal microbiota composition in ALS patients significantly differed from that in healthy subjects(unweighted UniFrac P=0.001),while Linear discriminant analysis Effect Size(LEfSe)analysis indicated that Bacteroidetes and Firmicutes dominated healthy nasal communities at the phylum level,whereas Actinobacteria was the predominant phylum and Thermoleophilia was the predominant class in ALS patients.Genus Faecalibacterium and Alistipes were positively correlated with ALS functional rating scale revised(ALSFRS-R;r_(s)=0.349,P=0.020 and r_(s)=0.393,P=0.008),while Prevotella-9 and Bacteroides operational taxonomic units(OTUs)were positively associated with lung function(FVC)in ALS patients(r_(s)=0.304,P=0.045,and r_(s)=0.300,P=0.048,respectively).Prevotella-1 was positively correlated with white blood cell counts(WBC,r_(s)=0.347,P=0.021),neutrophil percentage(Neu%,r_(s)=0.428,P=0.004),and neutrophil-to-lymphocyte ratio(NLR,r_(s)=0.411,P=0.006),but negatively correlated with lymphocyte percentage(Lym%,r_(s)=-0.408,P=0.006).In contrast,Streptococcus was negatively associated with Neu%(r_(s)=-0.445,P=0.003)and NLR(r_(s)

关键词： Amyotrophic lateral sclerosis Nasal microbiota Dysbiosis Inflammation

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Emerging strategies for nerve repair and regeneration in ischemic stroke:neural stem cell therapy

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Neural Regeneration Research 2024年第11期19卷 2430-2443页

作者： Siji Wang Qianyan He Yang Qu Wenjing Yin Ruoyu Zhao Xuyutian Wang Yi Yang Zhen-Ni Guo Stroke center Department of Neurologythe First Hospital of Jilin UniversityChangchunJilin ProvinceChina Neuroscience Research center Department of Neurologythe First Hospital of Jilin UniversityChangchunJilin ProvinceChina department of Breast Surgery General Surgery Centerthe First Hospital of Jilin UniversityChangchunJilin ProvinceChina

Ischemic stroke is a major cause of mortality and disability worldwide,with limited treatment options available in clinical practice.The emergence of stem cell therapy has provided new hope to the field of stroke treatment via the restoration of brain neuron function.Exogenous neural stem cells are beneficial not only in cell replacement but also through the bystander effect.Neural stem cells regulate multiple physiological responses,including nerve repair,endogenous regeneration,immune function,and blood-brain barrier permeability,through the secretion of bioactive substances,including extracellular vesicles/exosomes.However,due to the complex microenvironment of ischemic cerebrovascular events and the low survival rate of neural stem cells following transplantation,limitations in the treatment effect remain unresolved.In this paper,we provide a detailed summary of the potential mechanisms of neural stem cell therapy for the treatment of ischemic stroke,review current neural stem cell therapeutic strategies and clinical trial results,and summarize the latest advancements in neural stem cell engineering to improve the survival rate of neural stem cells.We hope that this review could help provide insight into the therapeutic potential of neural stem cells and guide future scientific endeavors on neural stem cells.

关键词： bystander effect cell replacement extracellular vesicles ischemic stroke neural stem cells neural stem cell engineering

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