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CsF Aβ1-42 level is associated with cognitive decline in early parkinson’s disease with rapid eye movement sleep behavior disorder

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Translational Neurodegeneration 2018年第1期7卷 212-220页

作者： Maowen Ba Guoping Yu Min Kong Hui Liang Ling Yu Department of Neurology the Affiliated Yantai Yuhuangding Hospital of Qingdao UniversityYantai CityShandong 264000People’s Republic of China Department of Neurology Yantaishan HospitalYantai CityShandong 264000People’s Republic of China

Background:Rapid eye movement sleep behavior disorder(RBD)is associated with cognitive decline in early parkinson’s disease(PD).However,the underlyling basis for this association remains unclear.Methods:parkinson’s Progression Marker’s Initiative(PPMI)subjects underwent baseline RBD testing with RBD sleep questionnaire(RBDsQ).serial assessments included measures of motor symptoms,non-motor symptoms(NMs),neuropsychological assessment,blood and cerebrospinal fluid(CsF)biomarkers.Up to three years follow-up data were included.We stratified early PD subjects into PD with RBD(RBDsQ score>5)and PD without RBD groups.Then,we evaluated baseline biomarkers in each group as a predictor of cognitive decline using Montreal Cognitive Assessment(MoCA)score changes over three years in regression models.Results:Four hundred twenty-three PD subjects were enrolled at baseline,and a total of 350 PD subjects had completed 3 years of study follow-up with completely serial assessments.We found that at baseline,only CsF β-amyloid 1–42(Aβ1–42)was significantly lower in PD subjects with RBD.On three years follow-up analysis,PD subjects with RBD were more likely to develop incident mild cognitive impairment(MCI)and presented greater cognitive decline in MoCA score.Lower baseline CsF Aβ1–42 predicted cognitive decline over 3 years only in PD subjects with RBD(β=−0.03,P=0.003).A significant interaction between Aβ1–42 and the 2 groups confirmed that this effect was indeed higher in PD with RBD than the other individual(β=−2.85,P=0.014).Conclusion:These findings indicate that CsF Aβ1–42 level is associated with global cognitive decline in early PD with RBD.The addition of CsF Aβ1–42 to RBD testing increase the likelihood of identifying those at high risk for cognitive decline in early PD.

关键词： parkinson’s disease Rapid eye movement sleep behavior disorder Cognitive decline β-Amyloid

Replacing what’s lost: a new era of stem cell therapy for parkinson’s disease

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Translational Neurodegeneration 2020年第1期9卷 10-19页

作者： Yong Fan Winanto shi-Yan Ng The Third Affiliated Hospital of Guangzhou Medical University Guangzhou 510150China Institute of Molecular and Cell Biology A^*STAR Research EntitiesSingapore 138673Singapore Yong Loo Lin school of Medicine(Physiology) National University of SingaporeSingapore 117456Singapore National Neuroscience Institute Singapore 308433Singapore

Background stem cells hold tremendous promise for regenerative medicine because they can be expanded infinitely,giving rise to large numbers of differentiated cells required for transplantation.stem cells can be derived from fetal sources,embryonic origins(embryonic stem cells or EsCs)or reprogrammed from adult cell types(induced pluripotent stem cells or iPsCs).One unique property of stem cells is their ability to be directed towards specific cell types of clinical interest,and can mature into functional cell types in vivo.While transplantations of fetal or EsC-derived tissues are known to illicit a host immunogenic response,autologous transplantations using cell types derived from one’s own iPsCs eliminate risks of tissue rejection and reduce the need for immunosuppressants.However,even with these benefits,cell therapy comes with significant hurdles that researchers are starting to overcome.In this review,we will discuss the various steps to ensure safety,efficacy and clinical practicality of cell replacement therapy in neurodegenerative diseases,in particular,parkinson’s disease.Main body parkinson’s disease(PD)results from a loss of dopaminergic neurons from the substantia nigra and is an ideal target for cell replacement therapy.Early trials using fetal midbrain material in the late 1980s have resulted in long term benefit for some patients,but there were multiple shortcomings including the non-standardization and quality control of the transplanted fetal material,and graft-induced dyskinesia that some patients experience as a result.On the other hand,pluripotent stem cells such as EsCs and iPsCs serve as an attractive source of cells because they can be indefinitely cultured and is an unlimited source of cells.stem cell technologies and our understanding of the developmental potential of EsCs and iPsCs have deepened in recent years and a clinical trial for iPsC-derived dopaminergic cells is currently undergoing for PD patients in Japan.In this focused review,we will first provide a historical aspect of cell

关键词： parkinson’s disease Induced pluripotent stem cells Cell therapy Regenerative medicine

Using induced pluripotent stem cells for modeling parkinson’s disease

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World Journal of stem Cells 2019年第9期11卷 634-649页

作者： Minjing Ke Cheong-Meng Chong Huanxing su state Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical Sciences University of Macao

parkinson’s disease(PD)is an age-related neurodegenerative disease caused by the progressive loss of dopaminergic(DA)neurons in the substantia nigra.As DA neurons degenerate,PD patients gradually lose their ability of movement.To date no effective therapies are available for the treatment of PD and its pathogenesis remains unknown.Experimental models that appropriately mimic the development of PD are certainly needed for gaining mechanistic insights into PD pathogenesis and identifying new therapeutic targets.Human induced pluripotent stem cells(iPsCs)could provide a promising model for fundamental research and drug screening.In this review,we summarize various iPsCs-based PD models either derived from PD patients through reprogramming technology or established by gene-editing technology,and the promising application of iPsC-based PD models for mechanistic studies and drug testing.

关键词： parkinson’s disease Dopaminergic neurons Induced pluripotent stem cells somatic cell reprogramming Aging

Efficacy and safety of rasagiline in Chinese patients with early parkinson’s disease:a randomized, double-blind,parallel,placebo-controlled,fixed-dose study

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Translational Neurodegeneration 2018年第1期7卷 352-360页

作者： Zhenxin Zhang Jian Wang shengdi Chen Chunfeng Liu Baorong Zhang Rong Peng shenggang sun Xiangru sun Gang Zhao Qiumin Qu Yansheng Li suiqiang Zhu Xiaoping Pan Ming shao Yanping Wang Peking Union Medical College Hospital BeijingChina Huashan Hospital Fudan UniversityShanghaiChina Ruijin Hospital Shanghai Jiaotong University School of MedicineShanghaiChina The second Affiliated Hospital of soochow University SuzhouChina The second Affiliated Hospital School of MedicineZhejiang UniversityZhejiangHangzhouChina West China Hospital Sichuan UniversityChengduChina Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of science and Technology WuhanChina Peking University First Hospital BeijingChina Xijing Hospital The First Affiliated Hospital of The Fourth Military Medical UniversityXi’anChina The First Affiliated Hospital of Xi’an Jiaotong University Xi’anChina Renji Hospital Shanghai Jiaotong University School of MedicineShanghaiChina Tongji Hospital of Tongji Medical College Huazhong University of Science and TechnologyWuhanChina Guangzhou First People’s Hospital School of MedicineSouth China University of TechnologyGuangzhouChina The First Affiliated Hospital of Guangzhou Medical University GuangzhouChina The second Affiliated Hospital of Guangzhou Medical University GuangzhouChina

Background:Rasagiline is a monoamine oxidase-B inhibitor used for parkinson’s disease(PD)treatment,but its effectiveness on Chinese patients is unclear.This study aimed to evaluate the efficacy and safety of rasagiline monotherapy in Chinese patients with early PD.Methods:A 26-weeks,randomized,double-blind,placebo-controlled study has been performed at 15 sites in China and enrolled outpatients(≥35 years old)with idiopathic PD without a history of using any dopaminergic drugs.Participants were randomized 1:1 to receive rasagiline 1 mg once daily or placebo.The primary endpoint was the change of the Unified parkinson’s Disease Rating scale(UPDRs)total score from baseline to 26 weeks treatment.secondary endpoints included changes in UPDRs subscale scores from part Ⅰ to Ⅲ.Health status was assessed with the PD Questionnaire(PDQ)-39 and EuroQol-Five-Dimension(EQ-5D)questionnaire.safety profile was collected until 30 weeks after randomization.Results:A total of 130 patients(n=65/group)were recruited,and 127(rasagiline,n=64;placebo,n=63)were included in the full analysis set.Baseline characteristics were comparable between the two groups.The decrease in the mean UPDRs total score was greater in the rasagiline group than in the placebo group(−3.18±0.95 vs.−0.18±0.98,P=0.025),and the mean UPDRs part I non-motor symptoms score(−0.54±0.15 vs.-0.08±0.15,P=0.003)were significantly decreased in the rasagiline group compared with placebo treated patients.An improvement trend was observed in the active treatment group for the subscales evaluation with parts Ⅱ and Ⅲ,while the difference to placebo was not statistically significant.Life quality assessed by the EQ-5D visual analog scale improved in the rasagiline group but worsened in placebo treated patients.The overall incidence of treatment-emergent adverse events(AEs)was slightly lower in the rasagiline group(41.5%)than in the placebo group(46.2%).Conclusions:Rasagiline is effective,safe,and well tolerated as monotherapy for the treatment of Chinese PD patients.

关键词： parkinson’s disease Monoamine oxidase inhibitor Rasagiline Monotherapy China

Co-transplantation of macaque autologous schwann cells and human embryonic nerve stem cells in treatment of macaque parkinson's disease

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Asian Pacific Journal of Tropical Medicine 2012年第1期5卷 7-14页

作者： Ying Xia Chengchuan Jiang Zuowei Cao Keshan shi Yang Wang Department of Neurosurgery Haikou HospitalXiangya Medical SchoolCentral South University Department of Neurosurgery Huashan HospitalFudan University Department of Neurosurgery Haikou HospitalXiangya Medical SchoolCentral South Unirersity Department of Anatomy Histology and EmbryologyShanghai Medical CenterFudan University

Objective:To investigate the therapeutic effects of co-transplantation with schwann cells（sCs） and human embryonic nerve stem cells（NsCs） on macaque parkinson’s disease（PD）.Methods: Macaque autologous sCs and human embryonic NsCs were adopled for the treatment of macaque PD.Results:six months after transplantation,positron emission computerized tomography showed that sup>18sup>F-FP-β-CIT was significantly concentrated in the injured striatum in the cotransplanted group.Immunohistoehemieal staining of transplanted area tissue showed migration of tyrosine hydroxylase positive cells from the transplant area to the surrounding area was significantly increased in the co-transplanted group.Conclusions:Co-transplantation of sCs and NsCs could effectively cure PD in macaques.sCs harvested from the autologous peripheral nerves can avoid rejection and the ethics problems,so it is expected to be applied clinically.

关键词： schwann cells Nerve stem cells parkinson’s disease Co-transplantation Macaque

Cells therapy for parkinson's disease-so close and so far away

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science China(Life sciences) 2009年第7期52卷 610-614页

作者： REN ZhenHua & ZHANG Yu Cell Therapy Center,Xuanwu Hospital,Capital Medical University and Key Laboratory of Neurodegeneration,Ministry of Education,Beijing 100053,China Cell Therapy Center Xuanwu Hospital Capital Medical University and Key Laboratory of Neurodegeneration Ministry of Education Beijing China

One of the strategies of treating parkinson's disease(PD) is the replacement of lost neurons in the substantia nigra with healthy dapamingergic cells.Potential sources for cells range from autologous grafts of dopamine secreting cells,fetal ventral mesencephalon tissue,to various stem cell types.Over the past quarter century,many experimental replacement therapies have been tried on PD animal models as well as human patients,yet none resulted in satisfactory outcomes that warrant wide applications.Recent progress in stem cell biology has shown that nuclear transfer embryonic stem cells(ntEs) or induced pluripotent stem cells(iPs) derived cells can be used to successfully treat rodent PD models,thus solving the problem of immunorejection and paving the way for future autologous transplantations for treating PD.Meanwhile,however,post mortem analysis of patients who received fetal brain cell transplantation revealed that implanted cells are prone to degeneration just like endogenous neurons in the same pathological area,indicating long-term efficacy of cell therapy of PD needs to overcome the degenerating environment in the brain.A better understanding of neurodegeneration in the midbrain appeared to be a necessary step in developing new cell therapies in parkinson's disease.It is likely that future cell replacement will focus on not only ameliorating symptoms of the disease but also trying to slow the progression of the disease by either neuroprotection or restoring the micro-environment in the midbrain.

关键词： parkinson’s disease dopamine neurons cell replacement transplantation stem cell fetal ventral mesencephalon carotid body embryonic stem cells nuclear transfer embryonic stem cells induced pluripotent stem cells

Prevalence of wearing-off and dyskinesia among the patients with parkinson’s disease on levodopa therapy: a multi-center registry survey in China's Mainland

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Translational Neurodegeneration 2014年第1期3卷 204-211页

作者： Wei Chen Qin Xiao Ming shao Tao Feng Wei-Guo Liu Xiao-Guang Luo Xiao-Chun Chen An-Mu Xie Chun-Feng Liu Zhen-Guo Liu Yi-Ming Liu Jian Wang sheng-Di Chen Department of Neurology Rui Jin Hospital affiliated to Shanghai Jiao Tong University School of MedicineRui Jin 2nd Road 197Shanghai 200025China Department of Neurology The First Affiliated Hospital of Guangzhou Medical CollegeGuangzhouChina Department of Neurology Beijing Tiantan Hospital affiliated to Capital Medical UniversityBeijingChina Department of Neurology Nanjing Brain Hospital affiliated to Nanjing Medical UniversityNanjingChina Department of Neurology The First Hospital of China Medical UniversityShenyangChina Department of Neurology Union XieHe HospitalFujian Medical UniversityFuzhouChina Department of Neurology The Affiliated Hospital of Medical College Qingdao UniversityQingdaoChina Department of Neurology The Second Affiliated Hospital of Soochow UniversitySuzhouChina Department of Neurology Xinhua Hospital affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina Department of Neurology Qilu Hospital of Shandong UniversityJinanChina Department of Neurology Huashan Hospital affiliated to Fudan UniversityShanghaiChina

Objective:Chronic levodopa(L-dopa)treatment in parkinson’s disease(PD)is often associated with the development of motor complications,but the corresponding epidemiological data is rare in Chinese PD patients.The present survey was to investigate the prevalence rate of wearing-off(WO)and dyskinesia among the patients with PD in China.Methods:From May 2012 to October 2012,a 3-step registry survey for wearing off(WO)and dyskinesia patients with PD receiving levodopa therapy was performed simultaneously at 28 movement disorders clinics in China.Results:There were 1,558 PD patients fulfilling the inclusion criteria.Among them,1,051 had at least one positive response of 9-item wearing off questionnaire(WOQ-9),724 and 160 patients were finally diagnosed with WO and dyskinesia by movement disorders specialists,respectively.The overall prevalence rates of WO and dyskinesia were 46.5%(95%CI 44.0%-48.9%)and 10.3%(95%CI 8.8%-11.8%),respectively.The mean score of WOQ-9 for those with WO was 3.8(sD=1.8),with movement slowness being the most common motor symptoms and pain/aching being the most common non-motor symptoms.Better improvement of motor symptoms(n=354,87.8%)and long-term disease control and drug selection(n=288,71.5%)were the two most frequently considered factors when movement disorders specialists adjusted therapeutic strategies for patients with WO.Conclusions:This survey provided the first multi-center epidemiological data of motor complications among PD patients on L-dopa therapy from China's Mainland.WO prevalence rate among Chinese PD patients was in line with,while dyskinesia prevalence rate was lower than previous reports from other Countries.

关键词： parkinson’s disease Wearing-off Dyskinesia Epidemiology

Oral rehabilitation of a parkinson's patient:A case report

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World Journal of Clinical Cases 2013年第1期1卷 67-70页

作者： Yashpal singh Monika saini Neha Garg Department of Prosthodontics Subharti Dental College Meerut UP 250005India

parkinson's disease is an idiopathic disorder of the central nervous system, characterized by resting tremors, muscular rigidity, slow and decreased movements. Oral rehabilitation of these patients requires special care, especially in those cases where the patient's socioeconomic status is not good and patient cannot come several times for fabrication of a complete denture. This clinical report presents a case of a parkinson's patient who was completely rehabilitated in 3 appointments using special techniques. Border molding, f inal impression and jaw relation procedures were done in one appointment by using a custom tray with detachable handles and occlusal rims.

关键词： parkinson’s disease Tich buttons Detachable handles and occlusal rims Monoplane teeth

Alpha-synuclein overexpression in the olfactory bulb initiates prodromal symptoms and pathology of parkinson’s disease

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Translational Neurodegeneration 2018年第1期7卷 244-260页

作者： Haichen Niu Lingyu shen Tongzhou Li Chao Ren sheng Ding Lei Wang Zhonghai Zhang Xiaoyu Liu Qiang Zhang Deqin Geng Xiujuan Wu Haiying Li Department of Genetics Xuzhou Medical UniversityXuzhou 221004China Department of Epidemiology and Health statistics Xuzhou Medical UniversityXuzhou 221004China Department of Neurology Affiliated Yantai Yuhuangding Hospital of Qingdao UniversityYantai 264000China College of Medicine Institute for Behavioral Medicine ResearchThe Ohio State UniversityColumbusOHUSA Department of Neurology Affiliated Hospital of Xuzhou Medical UniversityXuzhou 221004China Department of Pathology Xuzhou Medical UniversityXuzhou 221004China

Background:parkinson’s disease(PD)is a neurodegenerative disease characterized by intraneuronal Lewy Body(LB)aggregates composed of misfolded alpha-synuclein(α-syn).The spread of misfoldedα-syn follows a typical pattern:starting in the olfactory bulb(OB)and the gut,this pathology is followed by the progressive invasion of misfoldedα-syn to the posterior part of the brain.It is unknown whether the administration of human mutant alpha-synuclein(hm-α-syn,a human mutation which occurs in familial PD)into the OB of rats would trigger similarα-syn propagation and subsequently cause pathological changes in broader brain fields associated to PD and establish an animal model of prodromal PD.Methods:hm-α-syn was overexpressed in the OB of rats with an AAV injection.Then motor and non-motor symptoms of the sD rats were tested in different behavioral tasks following the AAV injection.In follow-up studies,pathological mechanisms ofα-syn spread were explored at the histological,biochemical and micro-structure levels.Results:The experimental results indicated that hm-α-syn was overexpressed in the OB 3 weeks after the AAV injection.1)overexpression of the Hm-α-syn in the OB by the AAV injection could transfer to wider adjacent fields beyond the monosynaptic scope.2)The number of tyrosine hydroxylase positive cells body and fibers was decreased in the substantia nigra(sN)12 weeks after AAV injection.This was consistent with decreased levels of the DA neurotransmitter.Importantly,behavioral dysfunctions were found that included olfactory impairment after 3 weeks,motor ability impairment and decreased muscular coordination on a rotarod 6 weeks after the AAV injection.3)The morphological level studies found that the Golgi staining revealed the number of neuronal branches and synapses in the OB,prefrontal cortex(PFC),hippocampus(Hip)and striatum caudate putamen(CPU)were decreased.4)phosphorylatedα-syn,at ser-129(pser129),was found to be increased in hm-α-syn injected animals in comparison to controls that overexpressed GFP alone,whi

关键词： Alpha-synuclein Prodromal animal model parkinson’s disease Olfactory bulb Autophagy