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转化神经变性病(英文)

转化神经变性病(英文)

Translational Neurodegeneration is an open access, peer-reviewed journal that covers research, therapeutics and education for all aspects of neurodegenerative diseases. By offering a high-visibility forum for new insights and discussions, Translational Neurodegeneration creates a novel interface between the fields of basic, translational, and clinical research. It includes Parkinson's disease and movement disorders, Alzheimer's disease and other dementias, motor neuron disease and other neurodegenerative diseases.
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  • 发文量：41
  • 被引量：2
  • H指数：0
  • 开始收录时间：2020,9(1)
  • CNKI综合因子：0.0
  • 维普期刊影响因子： 0.0
  • 万方期刊影响因子：0.0
  • 创刊时间：2012
  • 国内刊号/CN：31-2159/R74
    国际刊号/ISSN：2096-6466
  • 发行周期：季刊
    邮发代号：
  • 主管单位：
    主办单位：上海交通大学医学院附属瑞金医院;上海交通大学
转化神经变性病(英文)-联系信息
  • 主编：陈胜迪
  • 电话：021-64370045
  • 邮箱：trans_neuro@126.com
  • 地址：上海市黄浦区
  • 邮编：201802
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  • 摘要：Background:We aimed to evaluate the frequency of various types of B and T cells expressing CD21,CD32,and CD35 in multiple sclerosis(MS)clinical courses.Methods:Peripheral blood mononuclear cell from 30 MS patients(17 relapsing remitting[RRMS],six secondary progressive[SPMS],and seven primary progressive MS[PPMS])and 18 healthy subjects were analyzed.All patients were in acute attack.Healthy controls were matched for age and gender ratio.The frequencies of various subsets of B and T cells were determined using flow cytometry.Results:The frequency of CD4^(+)T cells was lower in MS patients compared to control subjects(41.14±9.45%vs.46.88±6.98%,respectively,P<0.05).The CD32^(+)fraction of CD4^(+)T cells and the CD21^(+)fraction of CD8^(+)T cells were higher in MS patients(2.85±3.72%vs.1.06±0.62%for CD32^(+)CD4^(+)T cells,2.71±1.86%vs.1.16±0.99%for CD21^(+)CD8^(+)T cells in MS patients and control subjects,respectively,P<0.05).After dividing subjects by type of MS course,higher values of these two T cell subsets were found in SPMS patients compared to control subjects(P<0.05).Further,RRMS patients had lower levels of CD32^(+)CD4^(+)T cells than SPMS patients and also they had lower levels of CD32^(+)CD8^(+)T cells than PPMS patients(P<0.05).However,neither the expression of CD35 on T cells nor the various B cell subsets were statistically different between the compared groups.Conclusions:Our findings demonstrate that T cell subsets expressing CD21 and CD32 may differ with respect to the presence or clinical forms of MS disease.By contrast,CD35^(+)T cells and different subsets of B cells are not altered in various MS clinical courses.
  • 摘要：Presenilins(PSs)are the catalytic core of γ-secretase complex.However,the mechanism of FAD-associated PS mutations in AD pathogenesis still remains elusive.Here we review the general biology and mechanism of γ-secretase and focus on the catalytic components–presenilins and their biological functions and contributions to the AD pathogenesis.The functions of presenilins are divided into γ-secretase dependent and γ-secretase independent ones.The γ-secretase dependent functions of presenilins are exemplified by the sequential cleavages in the processing of APP and Notch;the γ-secretase independent functions of presenilins include stabilizing β-catenin in Wnt signaling pathway,regulating calcium homeostasis and their interaction with synaptic transmission.
  • 摘要：α-Synucleinopathies are a subgroup of neurodegenerative diseases including dementia with Lewy bodies(DLB)and Parkinson’s disease(PD).Pathologically,these disorders can be characterized by the presence of intraneuronal aggregates composed mainly of α-synuclein(αSyn),which are called Lewy bodies and Lewy neurites.Recent report showed that more than 90% of αSyn aggregates are present in the form of very small deposits in presynaptic terminals of the affected neurons in DLB.However,the mechanisms responsible for presynaptic accumulation of abnormal αSyn remain unclear.In this article,we review recent findings on the involvement of presynaptic dysfunction in the initiation of neuronal dysfunctional changes.This review highlights that the presynaptic failure can be a potential trigger of the dying-back neuronal death in neurodegenerative diseases.
  • 摘要：Autism spectrum disorder(ASD)is a neurological disorder in which a significant number of children experience a developmental regression characterized by a loss of previously-acquired skills and abilities.Loss of neurological function in ASD,as observed in affected children who have regressed,can be explained as neurodegeneration.Although there is research evidence of neurodegeneration or progressive encephalopathy in ASD,the issue of neurodegeneration in ASD is still under debate.Evidence of neurodegeneration in the brain in ASD includes:(1)neuronal cell loss,(2)activated microglia and astrocytes,(3)proinflammatory cytokines,(4)oxidative stress,and(5)elevated 8-oxo-guanosine levels.The evidence from this review suggests that neurodegeneration underlies the loss of neurological function in children with ASD who have experienced regression and loss of previously acquired skills and abilities,and that research into treatments to address the issue of neurodegeneration in ASD are warranted.
  • 摘要：This review is to analyze the role of National Natural Science Foundation of China(NSFC)on the development of basic research of Parkinson’s disease from 1990 to 2012.Data on the total number of projects and funding of NSFC allocated to Parkinson’s disease,as well as hotspots in western countries,papers published,awards,personnel training,subject construction were collected,and the role of NSFC on other sources of funding was evaluated.Over the past 23 years,a full range of continuous funding from NSFC has led to fruitful results and a strong impetus to the progress of basic research of Parkinson’s disease.
  • 摘要：There is a substantial amount of evidence from experimental parkinsonian models to show the neuroprotective effects of monoamine oxidase-B(MAOB)inhibitors.They have been studied for their potential disease-modifying effects in Parkinson’s disease(PD)for over 20 years in various clinical trials.This review provides a summary of the clinical trials and discusses the implications of their results in the context of disease-modification in PD.Earlier clinical trials on selegiline were confounded by symptomatic effects of this drug.Later clinical trials on rasagiline using delayed-start design provide newer insights in disease-modification in PD but success in achieving the aims of this strategy remain elusive due to obstacles,some of which may be insurmountable.
  • 摘要：The accumulation and aggregation of alpha-synuclein(α-syn)in several tissue including the brain is a major pathological hallmark in Parkinson’s disease(PD).In this study,we show that α-syn can be taken up by primary human cortical neurons,astrocytes and skin-derived fibroblasts in vitro.Our findings that brain and peripheral cells exposed to α-syn can lead to impaired mitochondrial function,leading to cellular degeneration and cell death,provides additional evidence for the involvement of mitochondrial dysfunction as a mechanism of toxicity of α-syn in human cells.
  • 摘要：Increasing evidence suggests that inflammatory and immune components in brain are important in Alzheimer’s disease(AD)and anti-inflammatory and immunotherapeutic approaches may be amenable to AD treatment.It is known that complement activation occurs in the brain of patients with AD,and contributes to a local inflammatory state development which is correlated with cognitive impairment.In addition to the complement’s critical role in the innate immune system recognizing and killing,or targeting for destruction,complement proteins can also interact with cell surface receptors to promote a local inflammatory response and contributes to the protection and healing of the host.On the other hand,complement activation also causes inflammation and cell damage as an essential immune function to eliminate cell debris and potentially toxic protein aggregates.It is the balance of these seemingly competing events that influences the ultimate state of neuronal function.Our mini review will be focusing on the unique molecular interactions happening in the AD development,the functional outcomes of those interactions,as well as the contribution of each element to AD.
  • 摘要：For the last 50 years,levodopa has been the cornerstone of Parkinson’s disease management.However,a majority of patients develop motor complications a few years after therapy onset.Deep brain stimulation has been approved by the FDA as an adjunctive treatment in Parkinson disease,especially aimed at controlling these complications.However,the exact mechanism of action of deep brain stimulation,the best nucleus to target as well as the best timing for surgery are still debatable.We here provide an in-depth and critical review of the current literature on this topic.
  • 摘要：Background:Parkinson’s disease characterized by oxidative stress and mitochondrial damage in the pars compacta of substantia nigra remains a challenge to manage with an added disadvantage of side effects of L-levo dopa,the standard drug used for therapy.Thus,an alternative approach of utilizing natural components would be beneficial in the management of the disease.The present study was aimed to investigate the potential role of asiaticoside(As),a trisaccaride triterpene against1–methyl 4–phenyl 1,2,3,6 tetrahydropyridine(MPTP)-induced neurotoxicity in experimental mice.Methods:Mice were divided into 4 groups:Group I received vehicle saline,group II was treated with 20 mg/kg of body weight of MPTP(2 doses with 2 h intervals),group III received MPTP along with 50 mg/kg body weight of As for the 21 consecutive days starting from the day of MPTP intoxication.Group IV received 50 mg/kg body weight of asiaticoside for the same period serving as drug control.Animals were sacrificed at the end of experimental period and the striatum and midbrain samples were analyzed for enzyme assays,transmission electron microscopic(TEM)analysis.Immunofluorescent assay was performed to study the expression of GFAP to detect astrocyte,which are activated due to neuronal damage.Imunohistochemical studies were carried out to quantify the expression of Bax and Bcl2,the molecular signatures that would provide clues of the extent of neurodegeneration.Results:The activities of enzymes were increased on As administration when compared with those of group II animals.Expressions of Bax and Bcl2 along with GFAP did show significant variations(p<0.05)on MPTP treatment when compared to control animals and the changes were found to be reversed significantly(p<0.05)after treatment with asiaticoside.TEM analysis also showed attenuated degenerative architecture on As administration.The mice which received As alone(drug control IV)did not show significant variation from that of the control mice.Conclusion:The observations suggest that asiaticoside may be efficacious in protecting neurons from the oxidative damage caused by the insult of MPTP.
  • 摘要：Alzheimer’s disease(AD),the most common dementia,is characterized by potentially neurotoxic aggregation of Aβ peptide and tau protein,and their deposition as amyloid plaques and neurofibrillary tangles(NFTs).Tau aggregation also occurs in other common neurodegenerative diseases.Frontotemporal dementia(FTD)can be caused by tau mutations that increase the susceptibility of tau to hyperphosphorylation and aggregation,which may cause neuronal dysfunction and deposition of NFTs.17-allylamino-17-demethoxygeldanamycin(17-AAG)is a potent inhibitor of heat shock protein 90(Hsp90),a cytosolic chaperone implicated in the proper folding and functions of a repertoire of client proteins.17-AAG binds to Hsp90 and enhances degradation of Hsp90 client protein.We sought to determine whether 17-AAG can reduce Aβ and tau pathology in the brains of AD and FTD model mice expressing Aβ or P301L mutant tau,respectively.Mice were randomized to receive 25,5,or 0 mg/kg 17-AAG thrice weekly from age eight to 11 months.Analysis was performed by rotarod test on motor function,on the area occupied by plaques in hippocampus or NFTs in medulla tissue sections,and on mortality.A high dose of 17-AAG tended to decrease NFTs in male mice(p=0.08).Further studies are required to confirm the effect of 17-AAG in diseases of tau aggregation.
  • 摘要：Background:Autism spectrum disorder(ASD)is defined by standardized criteria of qualitative impairments in social interaction,qualitative impairments in communication,and restricted and stereotyped patterns of behavior,interests,and activities.A significant number of children diagnosed with ASD suffer a loss of previously-acquired skills,which is suggestive of neurodegeneration or a type of progressive encephalopathy with an etiological pathogenic basis occurring after birth.To date,the etiology of ASD remains under debate,however,many studies suggest toxicity,especially from mercury(Hg),in individuals diagnosed with an ASD.The present study evaluated concerns about the toxic effects of organic-Hg exposure from Thimerosal(49.55%Hg by weight)in childhood vaccines by conducting a two-phased(hypothesis generating/hypothesis testing)study with documented exposure to varying levels of Thimerosal from vaccinations.Methods:A hypothesis generating cohort study was undertaken to evaluate the relationship between exposure to organic-Hg from a Thimerosal-containing Diphtheria-Tetanus-acellular-Pertussis(DTaP)vaccine in comparison to a Thimerosal-free DTaP vaccine administered,from 1998 through 2000,for the risk of ASD as reported in the Vaccine Adverse Event Reporting System(VAERS)database(phase I).A hypothesis testing case–control study was undertaken to evaluate the relationship between organic-Hg exposure from Thimerosal-containing hepatitis B vaccines administered at specific intervals in the first six months of life among cases diagnosed with an ASD and controls born between 1991 through 1999 in the Vaccine Safety Datalink(VSD)database(phase II).Results:In phase I,it was observed that there was a significantly increased risk ratio for the incidence of ASD reported following the Thimerosal-containing DTaP vaccine in comparison to the Thimerosal-free DTaP vaccine.In phase II,it was observed that cases diagnosed with an ASD were significantly more likely than controls to receive increased organic-Hg from Thimerosal-containing hepatitis B vaccine administered within the first,second,and sixth month of life.Conclusions:Routine childhood vaccination is an important public health tool to reduce the morbidity and mortality associated with infectious diseases,but the present study provides new epidemiological evidence supporting an association between increasing organic-Hg exposure from Thimerosal-containing childhood vaccines and the subsequent risk of an ASD diagnosis.
  • 摘要：To quantitatively evaluate severity of behavioral and psychological symptoms of dementia(BPSD)for vascular dementia(VD).Changes of 51 patients with VD in BPSD between the first and 24th week were assessed using the Neuropsychiatric Inventory(NPI)and the behavioral pathology in Alzheimer’s disease(BEHAVE-AD)rating scale,in detrended fluctuation analysis(DFA)represented by diurnal activity(DA),evening activity(EA),and nocturnal activity(NA),and the relationships were analyzed.The subscores of activity disturbances,diurnal rhythm disturbances,and anxieties and phobias in the BEHAVE-AD score,and that of agitation,irritability,and sleep disorder in the NPI score were significantly increased compared with the first week,as was for the changes for EA in the DFA value.A linear correlation was observed between the changes of activity disturbances plus anxieties and phobias,and those of DA,and between the development of diurnal rhythm and those of EA,the vehement and autism scores and those of DA,and the difference in sleep disorder scores and those of EA,respectively.Analysis of DA,NA,and EA may reflect the fluctuational degrees of VD-BPSD,can provide a useful assessment of VD-BPSD accompanied by clinical scores for VD.
  • 摘要：Background:There is an urgent need for developing objective,effective and convenient measurements to help clinicians accurately identify bradykinesia.The purpose of this study is to evaluate the accuracy of an objective approach assessing bradykinesia in finger tapping(FT)that uses evolutionary algorithms(EAs)and explore whether it can be used to identify early stage Parkinson’s disease(PD).Methods:One hundred and seven PD,41 essential tremor(ET)patients and 49 normal controls(NC)were recruited.Participants performed a standard FT task with two electromagnetic tracking sensors attached to the thumb and index finger.Readings from the sensors were transmitted to a tablet computer and subsequently analyzed by using EAs.The output from the device(referred to as"PD-Monitor")scaled from−1 to+1(where higher scores indicate greater severity of bradykinesia).Meanwhile,the bradykinesia was rated clinically using the Movement Disorder Society-Sponsored Revision of the Unified Parkinson’s Disease Rating Scale(MDS-UPDRS)FT item.Results:With an increasing MDS-UPDRS FT score,the PD-Monitor score from the same hand side increased correspondingly.PD-Monitor score correlated well with MDS-UPDRS FT score(right side:r=0.819,P=0.000;left side:r=0.783,P=0.000).Moreover,PD-Monitor scores in 97 PD patients with MDS-UPDRS FT bradykinesia and each PD subgroup(FT bradykinesia scored from 1 to 3)were all higher than that in NC.Receiver operating characteristic(ROC)curves revealed that PD-Monitor FT scores could detect different severity of bradykinesia with high accuracy(≥89.7%)in the right dominant hand.Furthermore,PD-Monitor scores could discriminate early stage PD from NC,with area under the ROC curve greater than or equal to 0.899.Additionally,ET without bradykinesia could be differentiated from PD by PD-Monitor scores.A positive correlation of PD-Monitor scores with modified Hoehn and Yahr stage was found in the left hand sides.Conclusions:Our study demonstrated that a simple to use device employing classifiers derived from EAs could not only be used to accurately measure different severity of bradykinesia in PD,but also had the potential to differentiate early stage PD from normality.
  • 摘要：Background:Amyotrophic lateral sclerosis(ALS)is currently an incurable disease without highly effective pharmacological treatments.The peptide drug GM604(GM6 or Alirinetide)was developed as a candidate ALS therapy,which has demonstrated safety and good drug-like properties with a favorable pharmacokinetic profile.GM6 is hypothesized to bolster neuron survival through the multi-target regulation of developmental pathways,but mechanisms of action are not fully understood.Methods:This study used RNA-seq to evaluate transcriptome responses in SH-SY5Y neuroblastoma cells following GM6 treatment(6,24 and 48 h).Results:We identified 2867 protein-coding genes with expression significantly altered by GM6(FDR<0.10).Early(6 h)responses included up-regulation of Notch and hedgehog signaling components,with increased expression of developmental genes mediating neurogenesis and axon growth.Prolonged GM6 treatment(24 and 48 h)altered the expression of genes contributing to cell adhesion and the extracellular matrix.GM6 further down-regulated the expression of genes associated with mitochondria,inflammatory responses,mRNA processing and chromatin organization.GM6-increased genes were located near GC-rich motifs interacting with C2H2 zinc finger transcription factors,whereas GM6-decreased genes were located near AT-rich motifs associated with helix-turn-helix homeodomain factors.Such motifs interacted with a diverse network of transcription factors encoded by GM6-regulated genes(STAT3,HOXD11,HES7,GLI1).We identified 77 ALS-associated genes with expression significantly altered by GM6 treatment(FDR<0.10),which were known to function in neurogenesis,axon guidance and the intrinsic apoptosis pathway.Conclusions:Our findings support the hypothesis that GM6 acts through developmental-stage pathways to influence neuron survival.Gene expression responses were consistent with neurotrophic effects,ECM modulation,and activation of the Notch and hedgehog neurodevelopmental pathways.This multifaceted mechanism of action is unique among existing ALS drug candidates and may be applicable to multiple neurodegenerative diseases.
  • 摘要：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.
  • 摘要：Background:Down syndrome(DS)individuals,by the age of 40s,are at increased risk to develop Alzheimer-like dementia,with deposition in brain of senile plaques and neurofibrillary tangles.Our laboratory recently demonstrated the disturbance of PI3K/AKT/mTOR axis in DS brain,prior and after the development of Alzheimer Disease(AD).The aberrant modulation of the mTOR signalling in DS and AD age-related cognitive decline affects crucial neuronal pathways,including insulin signaling and autophagy,involved in pathology onset and progression.Within this context,the therapeutic use of mTOR-inhibitors may prevent/attenuate the neurodegenerative phenomena.By our work we aimed to rescue mTOR signalling in DS mice by a novel rapamycin intranasal administration protocol(InRapa)that maximizes brain delivery and reduce systemic side effects.Methods:Ts65Dn mice were administered with InRapa for 12 weeks,starting at 6 months of age demonstrating,at the end of the treatment by radial arms maze and novel object recognition testing,rescued cognition.Results:The analysis of mTOR signalling,after InRapa,demonstrated in Ts65Dn mice hippocampus the inhibition of mTOR(reduced to physiological levels),which led,through the rescue of autophagy and insulin signalling,to reduced APP levels,APP processing and APP metabolites production,as well as,to reduced tau hyperphosphorylation.In addition,a reduction of oxidative stress markers was also observed.Discussion:These findings demonstrate that chronic InRapa administration is able to exert a neuroprotective effect on Ts65Dn hippocampus by reducing AD pathological hallmarks and by restoring protein homeostasis,thus ultimately resulting in improved cognition.Results are discussed in term of a potential novel targeted therapeutic approach to reduce cognitive decline and AD-like neuropathology in DS individuals.
  • 摘要：Background:Parkinson’s disease(PD)is often accompanied by clinically identified depression.Providing effective pharmacotherapies that concomitantly treat both motor and psychological symptoms can pose a challenge to physicians.For this reason,alternatives to standard anti-depressant treatments,such as repetitive transcranial magnetic stimulation(rTMS),have been evaluated within the Parkinson’s population.Methods:A literature search was conducted on the PubMed database for all studies that evaluated rTMS as a treatment in patients with both depression and PD.A meta-analysis was performed on all studies that reported mean pre-and post-rTMS depression inventory scores.Widely used depression inventories included both self-report and clinician-administered measures.Effect size for individual study groups and across all studies was calculated.Results:Six of 7 studies meeting inclusion criteria reported significantly improved depression scores,large effect sizes,and significant p-values.Total weighted average effect size was calculated at 1.32 across all study groups that applied rTMS.Conclusions:Across all but one study,rTMS appears to effectively reduce depression scores among self-reported and clinician administered inventories.The total weight average effect size showed that,when considering study sample sizes and degree of findings,this form of neurostimulation can relieve PD patients of their depressive symptoms.Further,rTMS is a promising alternative to traditional anti-depressant therapies when treating refractory depression in patients with PD.
  • 摘要：Background:The differential diagnosis of Parkinson’s disease(PD)and multiple system atrophy(MSA)remains a challenge,especially in the early stage.Here,we assessed the value of transcranial sonography(TCS)to discriminate non-tremor dominant(non-TD)PD from MSA with predominant parkinsonism(MSA-P).Methods:Eighty-six MSA-P patients and 147 age and gender-matched non-TD PD patients who had appropriate temporal acoustic bone windows were included in this study.All the patients were followed up for at least 2 years to confirm the initial diagnosis.Patients with at least one substantia nigra(SN)echogenic size≥18 mm^(2) were classified as hyperechogenic,those with at least one SN echogenic size≥25 mm^(2) was defined as markedly hyperechogenic.Results:The frequency of SN hyperechogenicity in non-TD PD patients was significantly higher than that in MSA-P patients(74.1%vs.38.4%,p<0.001).SN hyperechogenicity discriminated non-TD PD from MSA-P with sensitivity of 74.1%,specificity of 61.6%,and positive predictive value of 76.8%.If marked SN hyperechogenicity was used as the cutoff value(≥25 mm^(2)),the sensitivity decreased to 46.3%,but the specificity and positive predictive value increased to 80.2 and 80.0%.Additionally,in those patients with SN hyperechogenicity,positive correlation between SN hyperechogenicity area and disease duration was found in non-TD PD rather than in MSA-P patients.In this context,among early-stage patients with disease duration≤3 years,the sensitivity,specificity and positive predictive value of SN hyperechogenicity further declined to 69.8%,52.2%,and 66.7%,respectively.Conclusions:TCS could help discriminate non-TD PD from MSA-P in a certain extent,but the limitation was also obvious with relatively low specificity,especially in the early stage.
  • 摘要：Background:Visinin-like protein-1(VILIP-1)and chitinase-3-like protein 1(CHI3L1 or YKL-40)in cerebrospinal fluid(CSF)are newly discovered markers indicating neuronal damage and microglial activation,respectively.Phosphorylated tau(p-tau)reflects the neuropathology of Alzheimer’s disease(AD)and is useful as diagnostic markers for AD.However,it is unknown whether these biomarkers have similar or complementary information in AD.Methods:We stratified 121 participants from the Alzheimer’s Disease Neuroimaging Initiative(ADNI)database into cognitively normal(CN),stable mild cognitive impairment(sMCI),progressive MCI(pMCI),and dementia due to AD.Analysis of covariance(ANOVA)and chi-square analyses,Spearman correlation,and logistic regression models were performed to test the demographic,associations between biomarkers,and diagnostic accuracies,respectively.Linear mixed-effects models were used to evaluate the effects of CSF amyloid-β(Aβ)on above biomarkers within diagnostic groups,the combination of diagnostic group and Aβstatus as predictor,and CSF biomarkers as predictors of AD features,including cognition measured by Mini–Mental State Examination(MMSE)and brain structure and white matter hyperintensity(WMH)measured by magnetic resonance imaging(MRI).Results:P-tau,VILIP-1,and YKL-40 were all predictors of AD diagnosis,but combinations of biomarkers did not improve the diagnostic accuracy(AUC 0.924 for p-tau,VILIP-1,and YKL-40)compared to p-tau(AUC 0.922).P-tau and VILIP-1 were highly correlated(r=0.639,p<0.001)and strongly associated with Aβpathology across clinical stages of AD,while YKL-40 was correlated with Aβpathology in CN and AD groups.VILIP-1 was associated with acceleration of cognitive decline,hippocampal atrophy,and expansion of ventricles in longitudinal analyses.YKL-40 was associated with hippocampal atrophy at baseline and follow-up,while p-tau was only associated with worsening WMH at baseline.Conclusions:CSF levels of p-tau,VILIP-1,and YKL-40 may have utility for discriminating between cognitively normal subjects and patients with AD.Increased levels of both VILIP-1 and YKL-40 may be associated with disease degeneration.These CSF biomarkers should be considered for future assessment in the characterization of the natural history of AD.
  • 摘要：Correction to:Transl Neurodegener https://doi.org/10.1186/s40035-018-0134-8 In the original publication of this article[1]surname of the first author is wrong.The correct name of the first author should be Dan Zheng.The original publication has been corrected.
  • 摘要：Background:Alzheimer’s disease(AD)is a fatal disease that threatens the quality of life of an aging population at a global scale.Various hypotheses on the etiology of AD have been developed over the years to guide efforts in search of therapeutic strategies.Main body:In this review,we focus on four AD hypotheses currently relevant to AD onset:the prevailing amyloid cascade hypothesis,the well-recognized tau hypothesis,the increasingly popular pathogen(viral infection)hypothesis,and the infection-related antimicrobial protection hypothesis.In briefly reviewing the main evidence supporting each hypothesis and discussing the questions that need to be addressed,we hope to gain a better understanding of the complicated multi-layered interactions in potential causal and/or risk factors in AD pathogenesis.As a defining feature of AD,the existence of amyloid deposits is likely fundamental to AD onset but is insufficient to wholly reproduce many complexities of the disorder.A similar belief is currently also applied to hyperphosphorylated tau aggregates within neurons,where tau has been postulated to drive neurodegeneration in the presence of pre-existing Aβplaques in the brain.Although infection of the central nerve system by pathogens such as viruses may increase AD risk,it is yet to be determined whether this phenomenon is applicable to all cases of sporadic AD and whether it is a primary trigger for AD onset.Lastly,the antimicrobial protection hypothesis provides insight into a potential physiological role for Aβpeptides,but how Aβ/microbial interactions affect AD pathogenesis during aging awaits further validation.Nevertheless,this hypothesis cautions potential adverse effects in Aβ-targeting therapies by hindering potential roles for Aβin anti-viral protection.Conclusion:AD is a multi-factor complex disorder,which likely requires a combinatorial therapeutic approach to successfully slow or reduce symptomatic memory decline.A better understanding of how various causal and/or risk factors affecting disease onset and progression will enhance the likelihood of conceiving effective treatment paradigms,which may involve personalized treatment strategies for individual patients at varying stages of disease progression.
  • 摘要：Background:Neuron-microglia communication plays a crucial role in the motor neurons(MNs)death in amyotrophic lateral sclerosis(ALS).Neurons can express chemokine(C-X3-C motif)ligand 1(CX3CL1),which mediates microglial activation via interacting with its sole receptor CX3CR1 in microglia.In the present study,we aimed to investigate the dynamic changes of CX3CL1/CX3CR1 axis during microglial activation and MNs loss in SOD1G93A mouse model of ALS.Methods:qPCR,western blot and immunofluorescent staining were used to examine the mRNA and protein levels and localization of CX3CL1/CX3CR1 in the anterior horn region of spinal cord in both SOD1G93A mice and their agematched wild type(WT)littermates at 40,60,90 and 120 days of age.The M1/M2 microglial activation in the spinal cord tissues of SOD1G93A mice and WT mice were evaluated by immunofluorescent staining of M1/M2 markers and further confirmed by qPCR analysis of M1/M2-related cytokines.Results:The immunofluorescent staining revealed that CX3CL1 was predominately expressed in MNs,while CX3CR1 was highly expressed in microglia in the anterior horn region of spinal cord.Compared with age-matched WT mice,CX3CL1 mRNA level was elevated at 40 days but decreased at 90 and 120 days in the anterior horn region of spinal cords in ALS mice.Consistently,CX3CR1 mRNA level was increased at 90 and 120 days.Western blot assay further confirmed the dynamic changes of CX3CL1/CX3CR1 axis in ALS mice.Additionally,the levels of M1/M2 markers of microglia and their related cytokines in the anterior horn region of spinal cord in ALS mice were increased at 90 and 120 days.Moreover,while M1-related cytokines in ALS mice were persistently increased at 120 days,the upregulated M2-related cytokines started to decline at 120 days,suggesting an altered microglial activation.Conclusions:Our data revealed the dynamic changes of CX3CL1/CX3CR1 axis and an imbalanced M1/M2 microglial activation during ALS pathological progression.These findings may help identify potential molecular targets for ALS therapy.
  • 摘要：Background:Cell replacement therapy has been envisioned as a promising treatment for neurodegenerative diseases.Due to the ethical concerns of ESCs-derived neural progenitor cells(NPCs)and tumorigenic potential of iPSCs,reprogramming of somatic cells directly into multipotent NPCs has emerged as a preferred approach for cell transplantation.Methods:Mouse astrocytes were reprogrammed into NPCs by the overexpression of transcription factors(TFs)Foxg1,Sox2,and Brn2.The generation of subtypes of neurons was directed by the force expression of cell-type specific TFs Lhx8 or Foxa2/Lmx1a.Results:Astrocyte-derived induced NPCs(AiNPCs)share high similarities,including the expression of NPC-specific genes,DNA methylation patterns,the ability to proliferate and differentiate,with the wild type NPCs.The AiNPCs are committed to the forebrain identity and predominantly differentiated into glutamatergic and GABAergic neuronal subtypes.Interestingly,additional overexpression of TFs Lhx8 and Foxa2/Lmx1a in AiNPCs promoted cholinergic and dopaminergic neuronal differentiation,respectively.Conclusions:Our studies suggest that astrocytes can be converted into AiNPCs and lineage-committed AiNPCs can acquire differentiation potential of other lineages through forced expression of specific TFs.Understanding the impact of the TF sets on the reprogramming and differentiation into specific lineages of neurons will provide valuable strategies for astrocyte-based cell therapy in neurodegenerative diseases.
  • 摘要：Background:The TANK-Binding Kinase 1(TBK1)gene has recently been identified as the third or fourth most frequent cause of frontotemporal dementia(FTD)and amyotrophic lateral sclerosis(ALS).The aim of this study was to assess the genetic contribution of TBK1 in a Chinese cohort.Methods:A total of 270 cases with ALS,FTD,or their combination were recruited into this study.All the coding exons of TBK1 and intron-exon boundaries were sequenced using Sanger sequencing.The frequency of TBK1 variants and the correlation with clinical phenotypes were analyzed.Results:A novel mutation(c.1959_1960insGT,p.E653fs)was identified in a sporadic case with semantic dementia,secondarily developing ALS.Another novel variant(c.2063_2064delTT,p.L688Rfs*14)was found in an ALS-FTD family.Totally,the TBK1 variants could only account for 0.7% of cases.Conclusions:This study enlarges the genetic and phenotypic spectrum of TBK1 mutation in a Chinese cohort.Our data indicates that TBK1 mutation is not a common cause for ALS and FTD in Chinese patients.
  • 摘要：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.
  • 摘要：Background:Cognitive impairment is one of the non-motor symptoms in Parkinson’s disease(PD).In the present study,we aim to examine the cognitive function of non-demented Parkinson’s disease patients and compare the results between male and female patients as well as control groups in search of any gender effect.Methods:Sixty PD Patients(30 males and 30 females)from the Movement Disorders Clinic at Huashan Hospital Affiliated to Fudan University were recruited to participate in the study.One hundred age and gender matched control subjects without neurological or psychiatric disorders were voluntarily recruited.The participants were administered measures of cognition in five domains including memory,language,spatial processing abilities,attention and executive function.Results:PD patients attained significantly lower scores in the visual spatial function,language and attention/executive function compared with the control group.Anti-parkinsonian treated patients performed worse in Rey-copy score,Clock Drawing Test(CDT)and Verbal Fluency-City than untreated ones.In regard to gender differences,though no general cognitive differences were found in Mini-mental State Examination(MMSE),men surpassed women on Boston naming test(BNT)while women were superior on Auditory Verbal Learning Test-long(AVLT)delayed cued recall test.Conclusions:Cognitive impairments were common in PD patients even in the absence of dementia.PD patients with anti-parkinsonian medication had worse cognitive impairment than untreated patients.Genders may have different manifestations of cognitive impairment in PD patients.
  • 摘要：Background:The cardinal features of Parkinson’s disease(PD)are bradykinesia,rigidity and rest tremor.Abnormal activity in the basal ganglia is predicted to underlie the mechanism of motor symptoms.This study aims to characterize properties of oscillatory activity in the basal ganglia and motor thalamus in patients with PD.Methods:Twenty-nine patients with PD who underwent bilateral or unilateral electrode implantation for subthalamic nucleus(STN)DBS(n=11),unilateral pallidotomy(n=9)and unilateral thalamotomy(n=9)were studied.Microelectrode recordings in the STN,globus pallidus internus(GPi)and ventral oral posterior/ventral intermediate of thalamus(Vop/Vim)were performed.Electromyography of the contralateral limbs was recorded.Single unit characteristics including interspike intervals were analyzed.Spectral and coherence analyses were assessed.Mean spontaneous firing rate(MSFR)of neurons was calculated.Analysis of variance and χ^(2) test were performed.Results:Of 76 STN neurons,39.5% were 4–6 Hz band oscillatory neurons and 28.9% were β frequency band(βFB)oscillatory neurons.The MSFR was 44.2±7.6 Hz.Of 62 GPi neurons,37.1% were 4–6 Hz band oscillatory neurons and 27.4% were βFB neurons.The MSFR was 80.9±9.6 Hz.Of 44 Vop neurons,65.9% were 4–6 Hz band oscillatory neurons and 9%were βFB neurons.The MSFR was 24.4±4.2 Hz.Of 30 Vim oscillatory neurons,70% were 4–6 Hz band oscillatory neurons and 13.3% were β FB neurons.The MSFR was 30.3±3.6 Hz.Further analysis indicated that proportion of βFB oscillatory neurons in STN and GPi was higher than that of similar neurons in the Vop and Vim(P<0.05).Conversely,the proportion of 4–6 Hz band oscillatory neurons and tremor related neurons in the Vim and Vop was higher than that of STN and GPi(P<0.05).The highest MSFR was for GPi oscillatory neurons whereas the lowest MSFR was for Vop oscillatory neurons(P<0.005).Conclusion:The alterations in neuronal activity in basal ganglia play a critical role in generation of parkinsonism.β oscillatory activity is more prominent in basal ganglia than in thalamus suggesting that the activity likely results from dopaminergic depletion.While both basal ganglia and thalamus have tremor activity,the thalamus appears to play a more important role in tremor production,and basal ganglia β oscillatory activity might be the trigger.
  • 摘要：Background:Circadian rhythms are oscillating physiological and behavioral changes governed by an internal molecular clock,and dysfunctions in circadian rhythms have been associated with ageing and various neurodegenerative diseases.However,the evidence directly connecting the neurodegeneration-associated proteins to circadian control at the molecular level remains sparse.Methods:Using meta-analysis,synchronized animals and cell lines,cells and tissues from FUS R521C knock-in rats,we examined the role of FUS in circadian gene expression regulation.Results:We found that FUS,an oscillating expressed nuclear protein implicated in the pathogenesis of amyotrophic lateral sclerosis(ALS)and frontotemporal dementia(FTD),exerted a novel feedback route to regulate circadian gene expression.Nr1d1-encoded core circadian protein REV-ERBαbound the Fus promoter and regulated the expression of Fus.Meanwhile,FUS was in the same complex as PER/CRY,and repressed the expression of E box-containing core circadian genes,such as Per2,by mediating the promoter occupancy of PSF-HDAC1.Remarkably,a common pathogenic mutant FUS(R521C)showed increased binding to PSF,and caused decreased expression of Per2.Conclusions:Therefore,we have demonstrated FUS as a modulator of circadian gene expression,and provided novel mechanistic insights into the mutual influence between circadian control and neurodegeneration-associated proteins.
  • 摘要：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,which was also found in the most of LB stained by the thioflavine S(ThS)in the SN field.5)A marker of autophagy(LC3B)was increased in serval fields,which was colacolizated with a marker of apoptosis in the SN field.Conclusions:These results demonstrate that expression of exogenous mutantα-syn in the OB induces pathological changes in the sensitive brain fields by transferring pathogenicα-syn to adjacent fields.This method may be useful for establishing an animal model of prodromal PD.

    转化神经变性病(英文)的期刊信息

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