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Alzheimer’s disease early diagnostic and staging biomarkers revealed by large-scale cerebrospinal fluid and serum proteomic profiling

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The Innovation 2024年第1期5卷 118-126页

作者： Qing-Qing Tao Xue Cai Yan-Yan Xue Weigang Ge Liang Yue Xiao-Yan Li Rong-Rong Lin Guo-Ping Peng Wenhao Jiang Sainan Li Kun-Mu Zheng Bin Jiang Jian-Ping Jia Tiannan Guo zhi-ying wu Department of Neurology and Research Center of Neurology in the Second Affiliated Hospital and Key Laboratory of Medical Neurobiology of Zhejiang Province Zhejiang University School of MedicineHangzhou 310009China Liangzhu Laboratory Zhejiang UniversityHangzhou 311100China Westlake Laboratory of Life Sciences and Biomedicine Key Laboratory of Structural Biology of Zhejiang ProvinceSchool of Life SciencesWestlake UniversityHangzhou 310024China Institute of Basic Medical Sciences Westlake Institute for Advanced StudyHangzho 310024China Department of Neurology First Affiliated HospitalZhejiang University School of MedicineHangzhou 310009China Department of Neurology First Affiliated HospitalSchool of MedicineXiamen UniversityXiamen 361009China Innovation Center for Neurological Disorders and Department of Neurology Xuanwu HospitalCapital Medical UniversityNational Clinical Research Center for Geriatric DiseasesBeijing 100053China MOE Frontier Science Center for Brain Science and Brain-machine Integration School of Brain Science and Brain MedicineZhejiang UniversityHangzhou 310058China CAS Center for Excellence in Brain Science and Intelligence Technology Shanghai 200031China

Amyloid-b,tau pathology,and biomarkers of neurodegeneration make up the core diagnostic biomarkers of Alzheimer disease(AD).However,these proteins represent only a fraction of the complex biological processes underlying AD,and individuals with other brain diseases in which AD pathology is a comorbidity also test positive for these diagnostic biomarkers.More ADspecific early diagnostic and disease staging biomarkers are needed.In this study,we performed tandem mass tag proteomic analysis of paired cerebrospinal fluid(CSF)and serum samples in a discovery cohort comprising 98 participants.Candidate biomarkers were validated by parallel reaction monitoring–based targeted proteomic assays in an independent multicenter cohort comprising 288 participants.We quantified 3,238 CSF and 1,702 serum proteins in the discovery cohort,identifying 171 and 860 CSF proteins and 37 and 323 serum proteins as potential early diagnostic and staging biomarkers,respectively.In the validation cohort,58 and 21 CSF proteins,as well as 12 and 18 serum proteins,were verified as early diagnostic and staging biomarkers,respectively.Separate 19-protein CSF and an 8-protein serum biomarker panels were built by machine learning to accurately classify mild cognitive impairment(MCI)due to AD from normal cognition with areas under the curve of 0.984 and 0.881,respectively.The 19-protein CSF biomarker panel also effectively discriminated patients with MCI due to AD from patients with other neurodegenerative diseases.Moreover,we identified 21 CSF and 18 serum stage-associated proteins re-flecting AD stages.Our findings provide a foundation for developing bloodbased tests for AD screening and staging in clinical practice.

关键词： cerebrospinal Alzheimer fluid

Clinical feature difference between juvenile amyotrophic lateral sclerosis with SPTLC1 and FUS mutations

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Chinese Medical Journal 2023年第2期136卷 176-183页

作者： Peishan Wang Qiao Wei Hongfu Li zhi-ying wu Department of Neurology Second Affiliated HospitalZhejiang University School of Medicineand Key Laboratory of Medical Neurobiology of Zhejiang ProvinceHangzhouZhejiang 310009China Department of Medical Genetics Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang 310009China

Background: Juvenile amyotrophic lateral sclerosis (JALS) is an uncommon form of amyotrophic lateral sclerosis whose age at onset (AAO) is defined as prior to 25 years. FUS mutations are the most common cause of JALS. SPTLC1 was recently identified as a disease-causative gene for JALS, which has rarely been reported in Asian populations. Little is known regarding the difference in clinical features between JALS patients carrying FUS and SPTLC1 mutations. This study aimed to screen mutations in JALS patients and to compare the clinical features between JALS patients with FUS and SPTLC1 mutations. Methods: Sixteen JALS patients were enrolled, including three newly recruited patients between July 2015 and August 2018 from the Second Affiliated Hospital, Zhejiang University School of Medicine. Mutations were screened by whole-exome sequencing. In addition, clinical features such as AAO, onset site and disease duration were extracted and compared between JALS patients carrying FUS and SPTLC1 mutations through a literature review. Results: A novel and de novo SPTLC1 mutation (c.58G>A, p.A20T) was identified in a sporadic patient. Among 16 JALS patients, 7/16 carried FUS mutations and 5/16 carried respective SPTLC1 , SETX , NEFH , DCTN1 , and TARDBP mutations. Compared with FUS mutation patients, those with SPTLC1 mutations had an earlier AAO (7.9 ± 4.6 years vs. 18.1 ± 3.9 years, P < 0.01), much longer disease duration (512.0 [416.7-607.3] months vs. 33.4 [21.6-45.1] months, P < 0.01), and no onset of bulbar. Conclusion: Our findings expand the genetic and phenotypic spectrum of JALS and help to better understand the genotype-phenotype correlation of JALS.

关键词： FUS Juvenile amyotrophic lateral sclerosis Phenotype SPTLC1

Latest innovations in the treatment of Wilson's disease

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iLIVER 2022年第3期1卷 181-186页

作者： Zi-Wei Zheng Yi Dong zhi-ying wu Department of Neurology and Department of Medical Genetics in Second Affiliated Hospital And Key Laboratory of Medical Neurobiology of Zhejiang ProvinceZhejiang University School of MedicineHangzhouChina

Wilson's disease(WD),also called hepatolenticular degeneration,is an autosomal recessive copper dysfunction disorder that is among the few treatable neurogenetic disorders.The main goals for controlling WD are to lower copper intake and encourage copper removal.Medical treatments and low-copper diets are available,but many problems remain.For example,the current treatments cannot fix copper metabolism and are unable to cross the blood-brain barrier.Furthermore,severe side effects have been experienced by many patients with WD.Because lifelong therapy is required for this disease,adherence to medical therapy and best practices for monitoring and personalizing therapy continue to evolve;some of these issues are being addressed in ongoing studies.Additionally,novel chelating agents,gene therapies using adeno-associated viruses,and variant-specific therapies that may improve neurological outcomes are in development.Here,we review the latest treatment innovations that may play an essential role for patients with WD in the future.

关键词： Wilson's disease Treatment Innovation ATP7B

Huntington Disease in Asia

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Chinese Medical Journal 2015年第13期128卷 1815-1819页

作者： Miao Xu zhi-ying wu Department of Neurology and Institute of Neurology Huashan Hospital Shanghai Medical College Fudan University Shanghai 200040 China Department of Neurology and Research Center of Neurology Second Affiliated Hospital Zhejiang University School of Medicine Hangzhou Zhejiang 310009 China

Objective： The objective was to review the major di fferences of Huntington disease （HD） in Asian population fiom those in the Caucasian population. Data Sources： Data cited in this review were obtained from PubMed database and China National Knowledge Infrastructure （CN KI） fiom 1994 to 2014. All the papers were written in English or Chinese languages, with the terms of Asia/Asian, H D, genotype, epidemiology, phenotype, and treatment used for the literature search. Study Selection： From the PubMed database, we included the articles and reviews which contained the HD patients＇ data from Asian countries. From the CNKI, we excluded the papers which were not original research. Due to tile language＇s restrictions, those data published in other languages were not included. Results： In total, 50 papers were cited in this review, authors of which were from tile mainland of China, .lapan, India, Thailand, Taiwan （China）, Korea, and western countries. Conclusions： The lower epidemiology in Asians can be partly explained by the less cytosine-adenine-guanine repeats, different haplotypes, and CCG polymorphisms. For the physicians, atypical clinical profiles such as the initial symptom of ataxia, movement abnormalities of Parkinsonism, dystonia, or tics need to be paid more attention to and suggest gene testing if necessary. Moreover, some pathogenesis studies may help progress some new advanced treatments. The clinicians in Asian especially in China should promote the usage of genetic testing and put more effects in rehabilitation, palliative care, and offer comfort of patients and their families. The unified HD rating scale also needs to be popularized in Asia to assist in evaluating the progression of HD.

关键词： China Genotype Huntington Disease Phenotype

Genotype-phenotype correlations of amyotrophic lateral sclerosis

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Translational Neurodegeneration 2016年第1期5卷 18-27页

作者： Hong-Fu Li zhi-ying wu Department of Neurology and Research Center of Neurology in Second Affiliated Hospital and the Collaborative Innovation Center for Brain ScienceZhejiang University School of Medicine88 Jiefang RdHangzhou 310009China

Amyotrophic lateral sclerosis(ALS)is a devastating neurodegenerative disease characterized by progressive neuronal loss and degeneration of upper motor neuron(UMN)and lower motor neuron(LMN).The clinical presentations of ALS are heterogeneous and there is no single test or procedure to establish the diagnosis of ALS.Most cases are diagnosed based on symptoms,physical signs,progression,EMG,and tests to exclude the overlapping conditions.Familial ALS represents about 5~10% of ALS cases,whereas the vast majority of patients are sporadic.To date,more than 20 causative genes have been identified in hereditary ALS.Detecting the pathogenic mutations or risk variants for each ALS individual is challenging.However,ALS patients carrying some specific mutations or variant may exhibit subtly distinct clinical features.Unraveling the respective genotype-phenotype correlation has important implications for the genetic explanations.In this review,we will delineate the clinical features of ALS,outline the major ALS-related genes,and summarize the possible genotype-phenotype correlations of ALS.

关键词： Amyotrophic lateral sclerosis Diagnosis of ALS Causative genes Genetic explanations Genotypephenotype correlations

Wilson's Disease in China

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Neuroscience Bulletin 2017年第3期33卷 323-330页

作者： Juan-Juan Xie zhi-ying wu Department of Neurology and Research Center of Neurologyin the Second Affiliated Hospital and the Collaborative Innovation Center for Brain ScienceZhejiang University School of MedicineHangzhou 310009China

Wilson＇s disease（WD） is an autosomal recessive disorder of copper metabolism. Its incidence is higher in China than in western countries. ATP7 B is the causative gene and encodes a P-type ATPase, which participates in the synthesis of holoceruloplasmin and copper excretion. Disease-causing variants of ATP7 B disrupt the normal structure or function of the enzyme and cause copper deposition in multiple organs,leading to diverse clinical manifestations. Given the variety of presentations, misdiagnosis is not rare. Genetic diagnosis plays an important role and has gradually become a routine test in China. The first Chinese spectrum of disease-causing mutations of ATP7 B has been established. As a remediable hereditary disorder, most WD patients have a good prognosis with an early diagnosis and chelation treatment. However, clinical trials are relatively few in China, and most treatments are based on the experience of experts and evidences from other countries. It is necessary to study and develop appropriate regimens specific for Chinese WD patients.

关键词： Wilson’s Disease Copper Epidemiology Pathogenesis Management

Challenges and suggestions for precise diagnosis and treatment of Wilson’s disease

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World Journal of Pediatrics 2021年第6期17卷 561-565页

作者： Yi Dong zhi-ying wu Department of Neurology Second Affiliated HospitalZhejiang University School of Medicine88 Jiefang RoadHangzhou 310009China Department of Medical Genetics Second Affiliated HospitalZhejiang University School of Medicine88 Jiefang Road.Hangzhou 310009China

Hepatolenticular degeneration,also known as Wilson's disease(WD),is an autosomal recessive disorder of copper dysfunction.The causative gene ATP7B encodes a copper transporting P-type ATPase,and the pathogenic mutations within ATP7B may lead to impaired copper excretion via the biliary tract and to massive copper accumulation in the liver,brain,kidney,bone and joints,cornea and other tissues and organs[1-3].Therefore,individuals with Wilson's disease may suffer liver damage,neuropsychiatric expressions,renal damage and osteoarthropathy.In general,the clinical manifestations of WD are complex and diverse,and early diagnosis is difficult.

关键词： diagnosis impaired organs

Amyotrophic Lateral Sclerosis： Precise Diagnosis and Individualized Treatment

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Chinese Medical Journal 2017年第19期130卷 2269-2272页

作者： Qing-Qing Tao zhi-ying wu Department of Neurology and Research Center of Neurology Second Affiliated Hospital Zhejiang University School of Medicine Hangzhou Zhejiang 310009 China

INTRODUCTION Amyotrophic lateral sclerosis （ALS） is a progressive neurodegenerative disease characterized by selective death of upper motor neurons （UMNs） and lower motor neurons （LMNs）, typically may die from respiratory failure within 2-5 years of symptorn onset）H About 10% orALS patients are familial whereas the remaining patients are sporadic. ALS is highly heterogeneous in genetic and clinical phenotype, with lack of definitive diagnostic tools, making it extremely difficult to make early diagnosis.

关键词： Amyotrophic Lateral Sclerosis Individualized Treatment Precise Diagnosis

Development of Research on Huntington Disease in China

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Neuroscience Bulletin 2017年第3期33卷 312-316页

作者： Hong-Lei Li Yan-Bin Zhang zhi-ying wu Department of Neurology The Second Affiliated HospitalZhejiang University School of MedicineHangzhou 310009China Department of Neurology and Institute of Neurology TheFirst Affiliated HospitalFujian Medical UniversityFuzhou 350005China

Huntington disease（HD） is a progressive autosomal dominantly inherited neurodegenerative disorder, characterized with the typical manifestations of involuntary movements, cognitive dysfunction, and psychiatric or behavioral disturbance. It results from an expansion in the number of CAG repeats in the first exon of the huntingtin（HTT） gene. In China, since the first case report in 1959, the knowledge of this disorder has been involving a lot, especially in the latest decade. In this review, we meta-analysis and summarize the research reports that were published by Chinese researchers since 1959, so that researchers whose native language were not Chinese can get a general idea of the research development of HD in China. Briefly, the research of HD in China can be broadly divided into three stages. Firstly,before 1993, there were scattered case reports of HD that were solely based on Clinical features and family history. Then,with the discovery of the HD gene in 1993, it became possible for the genetic confirmation of the reported cases that made the diagnosis more accurate and informative. In the last few years,Chinese researchers who were active in the HD research started to build their own database to study the clinical and genetic feature of this disorder and also collaborated a lot in this field. The progress outlined in this review indicates the beginning of an exciting new era in HD research in China.

关键词： Huntington disease China Research