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Neuropsychological features of progranulin-associated frontotemporal dementia: a nested case-control study
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作者 Marisa Lima Miguel Tábuas-Pereira +5 位作者 Diana Duro João Durães Daniela Vieira Inês Baldeiras Maria Rosário Almeida Isabel Santana 《Neural Regeneration Research》 SCIE CAS CSCD 2021年第5期910-915,共6页
The distinction between sporadic and genetic behavioural-variant frontotemporal dementia(bvFTD)regarding some neuropsychological(NP)features remains challenging.Specifically,progranulin(GRN)-associated bvFTD frequentl... The distinction between sporadic and genetic behavioural-variant frontotemporal dementia(bvFTD)regarding some neuropsychological(NP)features remains challenging.Specifically,progranulin(GRN)-associated bvFTD frequently presents with early episodic memory impairment and some degree of parietal dysfunction which are supporters of Alzheimer’s disease(AD)diagnosis.In this context,we aimed to characterize the NP profile of GRN-bvFTD as compared to sporadic-bvFTD and AD in patients with mild dementia(Mini-Mental State Examination score≥17 and Clinical Dementia Rating Scale score≤1.We identified 21 patients at Centro Hospitalar e Universitário de Coimbra,Portugal with GRN mutations belonging to fifteen different families.As our focus was bvFTD variants,FTD-related aphasic forms(3 patients)were excluded.The remaining 18 GRN-bvFTD were further matched with 18 sporadic-bvFTD and 18 AD patients according to disease staging,age and education.All patients completed the Mini-Mental State Examination,Montreal Cognitive Assessment(MoCA)and a comprehensive NP assessment battery.Results were converted into z-scores.Differences between groups in individual NP measures and NP domains were assessed through non-parametric tests(Kruskal-Wallis test analysis)and eta squared(ŋ2)was calculated as a measure of effect size.Group comparisons show that GRN patients have worse performances on verbal retrieval processes(P=0.039,ŋ2=0.110)and visuoconstructive abilities(P=0.039,ŋ2=0.190)than sporadic bvFTD forms.When compared to AD,GRN patients present a higher impairment in frontal(P=0.001,ŋ2=0.211)and parietal(P=0.041,ŋ2=0.129)measures and a better performance in memory tasks(P=0.020,ŋ2=0.120).Sporadic-bvFTD forms are worse than AD in frontal measures(P=0.032,ŋ2=0.200),being better in both memory(P=0.010,ŋ2=0.131)and visuospatial skills(P=0.023,ŋ2=0.231).Considering these results,we conclude that GRN-bvFTD patients present a NP profile that associates the typical patterns of FTD and AD deficits.This is particularly expressive in visuoconstructive abilities,which was the more discriminative feature between groups,followed by episodic verbal memory.This study was approved by the Institutional Ethics Committee of Centro Hospitalar e Universitário de Coimbra,Portugal(CE-029/2019)on June 24,2019. 展开更多
关键词 Alzheimer’s disease behavioral variant frontotemporal dementia cognitive profile frontotemporal dementia GENETICS memory NEUROPSYCHOLOGY progranulin visuoconstructive ability
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MicroRNA biomarkers in frontotemporal dementia and to distinguish from Alzheimer's disease and amyotrophic lateral sclerosis 被引量:1
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作者 Bridget Martinez Philip V.Peplow 《Neural Regeneration Research》 SCIE CAS CSCD 2022年第7期1412-1422,共11页
Frontotemporal lobar degeneration describes a group of progressive brain disorders that primarily are associated with atrophy of the prefrontal and anterior temporal lobes.Frontotemporal lobar degeneration is consider... Frontotemporal lobar degeneration describes a group of progressive brain disorders that primarily are associated with atrophy of the prefrontal and anterior temporal lobes.Frontotemporal lobar degeneration is considered to be equivalent to frontotemporal dementia.Frontotemporal dementia is characterized by progressive impairments in behavior,executive function,and language.There are two main clinical subtypes:behavioral-variant frontotemporal dementia and primary progressive aphasia.The early diagnosis of frontotemporal dementia is critical for developing management strategies and interventions for these patients.Without validated biomarkers,the clinical diagnosis depends on recognizing all the core or necessary neuropsychiatric features,but misdiagnosis often occurs due to overlap with a range of neurologic and psychiatric disorders.In the studies reviewed a very large number of microRNAs were found to be dysregulated but with limited overlap between individual studies.Measurement of specific miRNAs singly or in combination,or as miRNA pairs(as a ratio)in blood plasma,serum,or cerebrospinal fluid enabled frontotemporal dementia to be discriminated from healthy controls,Alzheimer’s disease,and amyotrophic lateral sclerosis.Furthermore,upregulation of miR-223-3p and downregulation of miR-15a-5p,which occurred both in blood serum and cerebrospinal fluid,distinguished behavioral-variant frontotemporal dementia from healthy controls.Downregulation of miR-132-3p in frontal and temporal cortical tissue distinguished frontotemporal lobar degeneration and frontotemporal dementia,respectively,from healthy controls.Possible strong miRNA biofluid biomarker contenders for behavioral-variant frontotemporal dementia are miR-223-3p,miR-15a-5p,miR-22-3p in blood serum and cerebrospinal fluid,and miR-124 in cerebrospinal fluid.No miRNAs were identified able to distinguish between behavioral-variant frontotemporal dementia and primary progressive aphasia subtypes.Further studies are warranted on investigating miRNA expression in biofluids and frontal/temporal cortical tissue to validate and extend these findings. 展开更多
关键词 Alzheimer’s disease amyotrophic lateral sclerosis behavioral variant biomarker blood plasma blood serum brain cerebrospinal fluid cortical tissue frontotemporal dementia frontotemporal lobar degeneration MICRORNA primary progressive aphasia
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Protein synthesis modulation as a therapeutic approach for amyotrophic lateral sclerosis and frontotemporal dementia 被引量:1
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作者 Santiago E.Charif M.Florencia Vassallu +1 位作者 Lara Salvañal Lionel M.Igaz 《Neural Regeneration Research》 SCIE CAS CSCD 2022年第7期1423-1430,共8页
Protein synthesis is essential for cells to perform life metabolic processes.Pathological alterations of protein content can lead to particular diseases.Cells have an intrinsic array of mechanisms and pathways that ar... Protein synthesis is essential for cells to perform life metabolic processes.Pathological alterations of protein content can lead to particular diseases.Cells have an intrinsic array of mechanisms and pathways that are activated when protein misfolding,accumulation,aggregation or mislocalization occur.Some of them(like the unfolded protein response)represent complex interactions between endoplasmic reticulum sensors and elongation factors that tend to increase expression of chaperone proteins and/or repress translation in order to restore protein homeostasis(also known as proteostasis).This is even more important in neurons,as they are very susceptible to harmful effects associated with protein overload and proteostatic mechanisms are less effective with age.Several neurodegenerative pathologies such as Alzheimer’s,Parkinson’s,and Huntington’s diseases,amyotrophic lateral sclerosis and frontotemporal dementia exhibit a particular molecular signature of distinct,unbalanced protein overload.In amyotrophic lateral sclerosis and frontotemporal dementia,the majority of cases present intracellular inclusions of ubiquitinated transactive response DNA-binding protein of 43 kDa(TDP-43).TDP-43 is an RNA binding protein that participates in RNA metabolism,among other functions.Dysregulation of TDP-43(e.g.aggregation and mislocalization)can dramatically affect neurons,and this has been linked to disease development.Expression of amyotrophic lateral sclerosis/frontotemporal dementia TDP-43-related mutations in cellular and animal models has been shown to recapitulate key features of the amyotrophic lateral sclerosis/frontotemporal dementia disease spectrum.These variants can be causative of degeneration onset and progression.Most neurodegenerative diseases(including amyotrophic lateral sclerosis and frontotemporal dementia)have no cure at the moment;however,modulating translation has recently emerged as an attractive approach that can be performed at several steps(i.e.regulating activation of initiation and elongation factors,inhibiting unfolded protein response activation or inducing chaperone expression and activity).This review focuses on the features of protein imbalance in neurodegenerative disorders and the relevance of developing therapeutical compounds aiming at restoring proteostasis.We strive to highlight the importance of research on drugs that,not only restore protein imbalance without compromising translational activity of cells,but are also as safe as possible for the patients. 展开更多
关键词 amyotrophic lateral sclerosis frontotemporal dementia NEURODEGENERATION neurodegenerative diseases protein imbalance protein synthesis modulation PROTEOSTASIS therapeutical compounds transactive response DNA-binding protein of 43 kDa TRANSLATION unfolded protein response
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Strategies for translating proteomics discoveries into drug discovery for dementia 被引量:1
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作者 Aditi Halder Eleanor Drummond 《Neural Regeneration Research》 SCIE CAS CSCD 2024年第1期132-139,共8页
Tauopathies,diseases characterized by neuropathological aggregates of tau including Alzheimer's disease and subtypes of fro ntotemporal dementia,make up the vast majority of dementia cases.Although there have been... Tauopathies,diseases characterized by neuropathological aggregates of tau including Alzheimer's disease and subtypes of fro ntotemporal dementia,make up the vast majority of dementia cases.Although there have been recent developments in tauopathy biomarkers and disease-modifying treatments,ongoing progress is required to ensure these are effective,economical,and accessible for the globally ageing population.As such,continued identification of new potential drug targets and biomarkers is critical."Big data"studies,such as proteomics,can generate information on thousands of possible new targets for dementia diagnostics and therapeutics,but currently remain underutilized due to the lack of a clear process by which targets are selected for future drug development.In this review,we discuss current tauopathy biomarkers and therapeutics,and highlight areas in need of improvement,particularly when addressing the needs of frail,comorbid and cognitively impaired populations.We highlight biomarkers which have been developed from proteomic data,and outline possible future directions in this field.We propose new criteria by which potential targets in proteomics studies can be objectively ranked as favorable for drug development,and demonstrate its application to our group's recent tau interactome dataset as an example. 展开更多
关键词 Alzheimer's disease biomarkers drug development drug discovery druggability frontotemporal dementia INTERACTOME PROTEOMICS tau TAUOPATHIES THERAPEUTICS
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Role of the C9ORF72 Gene in the Pathogenesis of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia 被引量:1
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作者 Zongbing Hao Rui Wang +1 位作者 Haigang Ren Guanghui Wang 《Neuroscience Bulletin》 SCIE CAS CSCD 2020年第9期1057-1070,共14页
Since the discovery of the C9ORF72 gene in2011,great advances have been achieved in its genetics and in identifying its role in disease models and pathological mechanisms;it is the most common genetic cause of amyotro... Since the discovery of the C9ORF72 gene in2011,great advances have been achieved in its genetics and in identifying its role in disease models and pathological mechanisms;it is the most common genetic cause of amyotrophic lateral sclerosis(ALS) and frontotemporal dementia(FTD).ALS patients with C9ORF72 expansion show heterogeneous symptoms.Those who are C9ORF72 expansion carriers have shorter survival after disease onset than non-C9ORF72 expansion patients.Pathological and clinical features of C9ORF72 patients have been well mimicked via several models,including induced pluripotent stem cell-derived neurons and transgenic mice that were embedded with bacterial artificial chromosome construct and that overexpressing dipeptide repeat proteins.The mechanisms implicated in C9ORF72 pathology include DNA damage,changes of RNA metabolism,alteration of phase separation,and impairment of nucleocytoplasmic transport,which may underlie C9ORF72 expansion-related ALS/FTD and provide insight into nonC9ORF72 expansion-related ALS,FTD,and other neurodegenerative diseases. 展开更多
关键词 Amyotrophic lateral sclerosis frontotemporal dementia C9ORF72 Dipeptide repeat proteins Pathological inclusions
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Cardiovascular risk factors and frontotemporal dementia: a case–control study 被引量:1
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作者 Angel Golimstok Nuria Cámpora +4 位作者 Juan I Rojas María C Fernandez Cristina Elizondo Enrique Soriano Edgardo Cristiano 《Translational Neurodegeneration》 SCIE CAS 2014年第1期98-103,共6页
Cardiovascular risk factors(CRF)were widely described as related to dementia.There are very few studies regarding this association in FTD.The objective of the study was to compare the frequency of CRF in our populatio... Cardiovascular risk factors(CRF)were widely described as related to dementia.There are very few studies regarding this association in FTD.The objective of the study was to compare the frequency of CRF in our population with FTD and controls.100 consecutive subjects with FTD diagnosis according to Lund-Manchester clinical criteria and 200 controls matched by age and sex were included between January 2003 to February 2007 at the Cognitive and Behavior Unit of Hospital Italiano de Buenos Aires.Clinical evaluation,laboratory tests,brain images(CT/MRI),neuropsychological and neuropsychiatric assessment were performed.Multiple regression analysis was performed to analyze the association in CRF between FTD patients vs.controls.The mean age in FTD was 69.7±0.9 vs.70.1±0.8 in controls(p 0.12).No difference in gender was observed between cases and controls.No differences were identified between patients and controls regarding hypertension(HTA)(65%vs.67,3%p 0.44);dyslipidemia(57%vs.54.7%p 0.74);obesity(39%vs.27.6%p 0.14)and hypothyroidism(26%vs.17.1%p 0.1).A significant difference was observed for Diabetes Mellitus(39%vs.22.6%p 0.001).In our population,Diabetes Mellitus was associated as an independent risk factor for FTD.To our knowledge this is the first report in which CRF were evaluated prospectively in FTD patients.More studies are needed to confirm this finding in larger populations. 展开更多
关键词 Cardiovascular risk factors frontotemporal dementia dementia FTD DIABETES DBT DM
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Amyotrophic lateral sclerosis with frontotemporal dementia presented with prominent psychosis 被引量:1
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作者 Cui Bo Cui Liying +2 位作者 Liu Mingsheng Ma Junfang Fang Jia 《Chinese Medical Journal》 SCIE CAS CSCD 2014年第22期3996-3998,共3页
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease mainly involving motor neurons in spinal cord,brain stem,and motor cortex of brain,characterized by variable combinations of limb weakness,muscle at... Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease mainly involving motor neurons in spinal cord,brain stem,and motor cortex of brain,characterized by variable combinations of limb weakness,muscle atrophy,and pyramidal signs.TAR DNA-binding protein 43 (TDP-43) serves as the pathological protein for both ALS and a proportion of frontotemporal dementia (FTD),where lies the foundation of a disease complex,ALS-FTD.Delusion and hallucination,core features of schizophrenia,are also regarded as common symptoms in the context of neurodegenerative dementia,including Alzheimer disease and dementia with Lewy body.Although rare in the course of FTD,these manifestations could be rather notable,causing a great challenge to differentiate FTD from schizophrenia.Emphasis of psychotic phenomenon also lies in its importance of predicting the progression to ALS-FTD and its underlying genetic mutation.Herein we report two cases of ALS-FTD presented with psychosis. 展开更多
关键词 amyotrophic lateral sclerosis frontotemporal dementia PSYCHOSIS
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Plasma glial fibrillary acidic protein and neurofilament light chain for the diagnostic and prognostic evaluation of frontotemporal dementia
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作者 Nuole Zhu Miguel Santos-Santos +18 位作者 Ignacio lllán-Gala Victor Montal Teresa Estellés Isabel Barroeta Miren Altuna Javier Arranz Laia Muñoz Olivia Belbin Isabel Sala Maria Belén Sánchez-Saudinós Andrea Subirana Laura Videla Jordi Pegueroles Rafael Blesa Jordi Clarimón Maria Carmona-Iragui Juan Fortea Alberto Lleó Daniel Alcolea 《Translational Neurodegeneration》 SCIE CAS 2021年第4期666-677,共12页
Background:Astrocytes play an essential role in neuroinflammation and are involved in the pathogenesis of neurodenegerative diseases.Studies of glial fibrillary acidic protein(GFAP),an astrocytic damage marker,may hel... Background:Astrocytes play an essential role in neuroinflammation and are involved in the pathogenesis of neurodenegerative diseases.Studies of glial fibrillary acidic protein(GFAP),an astrocytic damage marker,may help advance our understanding of different neurodegenerative diseases.In this study,we investigated the diagnostic performance of plasma GFAP(pGFAP),plasma neurofilament light chain(pNfL)and their combination for frontotemporal dementia(FTD)and Alzheimer's disease(AD)and their clinical utility in predicting disease progression.Methods:pGFAP and pNfL concentrations were measured in 72 FTD,56 AD and 83 cognitively normal(CN)participants using the Single Molecule Array technology.Of the 211 participants,199 underwent cerebrospinal(CSF)analysis and 122 had magnetic resonance imaging.We compared cross-sectional biomarker levels between groups,studied their diagnostic performance and assessed correlation between CSF biomarkers,cognitive performance and cortical thickness.The prognostic performance was investigated,analyzing cognitive decline through group comparisons by tertile.Results:Unlike pNfL,which was increased similarly in both clinical groups,pGFAP was increased in FTD but lower than in AD(all P<0.01).Combination of both plasma markers improved the diagnostic performance to discriminate FTD from AD(area under the curve[AUC]:combination 0.78;pGFAP 0.7;pNfL 0.61,all P<0.05).In FTD,pGFAP correlated with cognition,CSF and plasma NfL,and cortical thickness(all P<0.05).The higher tertile of pGFAP was associated with greater change in MMSE score and poor cognitive outcome during follow-up both in FTD(1.40 points annually,hazard ratio[HR]3.82,P<0.005)and in AD(1.20 points annually,HR 2.26,P<0.005).Conclusions:pGFAP and pNfL levels differ in FTD and AD;and their combination is useful for distinguishing between the two diseases.pGFAP could also be used to track disease severity and predict greater cognitive decline during follow-up in patients with FTD. 展开更多
关键词 Glial fibrillary acidic protein NEUROFILAMENT frontotemporal dementia Plasma biomarkers
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Randomized controlled trials in frontotemporal dementia: cognitive and behavioral outcomes
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作者 Justin B Miller Sarah J Banks +1 位作者 Gabriel C Léger Jeffrey L Cummings 《Translational Neurodegeneration》 SCIE CAS 2014年第1期89-97,共9页
Progress has been made in understanding the genetics and molecular biology of frontotemporal dementia(FTD).Targets for intervention have been identified,therapies are being developed,and clinical trials are advancing.... Progress has been made in understanding the genetics and molecular biology of frontotemporal dementia(FTD).Targets for intervention have been identified,therapies are being developed,and clinical trials are advancing.A major challenge for FTD research is that multiple underlying pathologies can be associated with heterogeneous phenotypes.The neuropsychological profiles associated with FTD spectrum disorders often include executive dysfunction,language impairments and behavioral disturbance.Behavioral variant FTD is characterized by an initial presentation of changes in personality,behavior and/or emotion,which are often difficult to objectively capture using traditional neuropsychological measures.The two principal language variants of FTD are Progressive Nonfluent Aphasia(PNFA)with predominant agrammatic/non-fluent impairments and Semantic Dementia(SD)with semantic impairments and visual agnosia.Selection of appropriate endpoints for clinical trials is critical to ensure that the measures are adequately sensitive to detect change,yet specific enough to isolate signal from noise,and acceptable to regulatory agencies.Given the anticipated potential for small effect sizes,measures must be able to identify small incremental changes over time.It is also imperative that the measures provide adequate coverage of the constructs or behaviors of interest.Selected outcome measures should be suitable for repeat administration,yet relatively robust to practice effects to ensure that observed changes reflect true signal variance and not residual effects due to repeated measurement or poor reliability.To facilitate widespread adoption as an endpoint,measures should be readily accessible.We provide several examples of potential global,composite,and individual cognitive measures,as well as behavioral measures promising for FTD trials.Development and application of appropriate trial outcomes is critically important to success in advancing new treatments for FTD patients. 展开更多
关键词 frontotemporal dementia Primary endpoints Secondary endpoints Randomized controlled trial METHODS
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A transcranial magnetic stimulation study on Alzheimer's diseae and behavioral variant frontotemporal dementia
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作者 陈蕾 《China Medical Abstracts(Internal Medicine)》 2016年第3期186-187,共2页
Objective To investigate the changes in cortical excitability and inhibitory circuits of patients with Alzheimer’s disease(AD)or behavioral variant frontotemporal dementia(bv FTD)using transcranial magnetic stimulati... Objective To investigate the changes in cortical excitability and inhibitory circuits of patients with Alzheimer’s disease(AD)or behavioral variant frontotemporal dementia(bv FTD)using transcranial magnetic stimulation(TMS).Methods Forty-four patients with AD,30 patients with bv FTD and 44 healthy controls were enrolled in the study.The epidemiological data 展开更多
关键词 FTD TMS HAMD MMSE A transcranial magnetic stimulation study on Alzheimer’s diseae and behavioral variant frontotemporal dementia ADL
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What can imaging tell us about cognitive impairment and dementia? 被引量:7
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作者 Leela Narayanan Alison Dorothy Murray 《World Journal of Radiology》 CAS 2016年第3期240-254,共15页
Dementia is a contemporary global health issue with far reaching consequences, not only for affected individuals and their families, but for national and global socio-economic conditions. The hallmark feature of demen... Dementia is a contemporary global health issue with far reaching consequences, not only for affected individuals and their families, but for national and global socio-economic conditions. The hallmark feature of dementia is that of irreversible cognitive decline, usually affecting memory, and impaired activities of daily living. Advances in healthcare worldwide have facilitated longer life spans, increasing the risks of developing cognitive decline and dementia in late life. Dementia remains a clinical diagnosis. The role of structural and molecular neuroimaging in patients with dementia is primarily supportive role rather than diagnostic, American and European guidelines recommending imaging to exclude treatable causes of dementia, such as tumor, hydrocephalus or intracranial haemorrhage, but also to distinguish between different dementia subtypes, the commonest of which is Alzheimer&#x02019;s disease. However, this depends on the availability of these imaging techniques at individual centres. Advanced magnetic resonance imaging (MRI) techniques, such as functional connectivity MRI, diffusion tensor imaging and magnetic resonance spectroscopy, and molecular imaging techniques, such as 18F fluoro-deoxy glucose positron emission tomography (PET), amyloid PET, tau PET, are currently within the realm of dementia research but are available for clinical use. Increasingly the research focus is on earlier identification of at risk preclinical individuals, for example due to family history. Intervention at the preclinical stages before irreversible brain damage occurs is currently the best hope of reducing the impact of dementia. 展开更多
关键词 dementia Alzheimer’s disease Magnetic resonance imaging Molecular imaging frontotemporal dementia Lewy body dementia Vascular dementia
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Associated mortality risk of atypical antipsychotic medication in individuals with dementia 被引量:1
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作者 Peter Phiri Tomas Engelthaler +3 位作者 Hannah Carr Gayathri Delanerolle Clive Holmes Shanaya Rathod 《World Journal of Psychiatry》 SCIE 2022年第2期298-307,共10页
BACKGROUND Antipsychotic medications such as risperidone,olanzapine and aripiprazole are used to treat psychological and behavioural symptoms among dementia patients.Current evidence indicate prescription rates for an... BACKGROUND Antipsychotic medications such as risperidone,olanzapine and aripiprazole are used to treat psychological and behavioural symptoms among dementia patients.Current evidence indicate prescription rates for antipsychotics vary and wider consensus to evaluate clinical epidemiological outcomes is limited.AIM To investigate the potential impact of atypical antipsychotics on the mortality of patients with dementia.METHODS A retrospective clinical cohort study was developed to review United Kingdom Clinical Record Interactive Search system based data between January 1,2013 to December 31,2017.A descriptive statistical method was used to analyse the data.Mini Mental State Examination(MMSE)scores were used to assess the severity and stage of disease progression.A cox proportional hazards model was developed to evaluate the relationship between survival following diagnosis and other variables.RESULTS A total of 1692 patients were identified using natural language processing of which,587 were prescribed olanzapine,quetiapine or risperidone(common group)whilst 893(control group)were not prescribed any antipsychotics.Patients prescribed olanzapine showed an increased risk of death[hazard ratio(HR)=1.32;95%confidence interval(CI):1.08-1.60;P<0.01],as did those with risperidone(HR=1.35;95%CI:1.18-1.54;P<0.001).Patients prescribed quetiapine showed no significant association(HR=1.09;95%CI:0.90-1.34;P=0.38).Factors associated with a lower risk of death were:High MMSE score at diagnosis(HR=0.72;95%CI:0.62-0.83;P<0.001),identifying as female(HR=0.73;95%CI:0.64-0.82;P<0.001),and being of a White-British ethnic group(HR=0.82;95%CI:0.72-0.94;P<0.01).CONCLUSION A significant mortality risk was identified among those prescribed olanzapine and risperidone which contradicts previous findings although the study designs used were different.Comprehensive research should be conducted to better assess clinical epidemiological outcomes associated with diagnosis and therapies to improve clinical management of these patients. 展开更多
关键词 dementia ANTIPSYCHOTICS Mortality VASCULAR Alzheimer’s disease frontotemporal dementia Lewy bodies Parkinson’s and mixed
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Dysfunction of Fronto-Subcortical Circuitry in Fronto-Temporal Dementia
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作者 S. Laurentino E. B. Sougey 《Open Journal of Psychiatry》 2020年第4期171-186,共16页
In the last years, some studies have shown that behavior disorder seems in frontotemporal dementia is related to dysfunction in the fronto-subcortical circuitry. <strong>Objectives:</strong> We did a narra... In the last years, some studies have shown that behavior disorder seems in frontotemporal dementia is related to dysfunction in the fronto-subcortical circuitry. <strong>Objectives:</strong> We did a narrative literature review concerning fronto-subcortical circuitry and frontotemporal dementia (FTD). <strong>Methods:</strong> Manuscripts related to fronto-subcortical network and frontotemporal dementia were selected for further analysis. <strong>Results:</strong> From the executions of simple motor actions to the most complex behaviors like goal-direct behavior and social cognition, the fronto-subcortical circuitry involves an intrigued network of fibers that reaches to basal ganglia nuclei. Recently, researchers have shown five parallel fronto-subcortical circuits integrating and segregating information from the frontal cortex to basal ganglia. Understanding the relationship between the fronto-subcortical circuit dysfunctions and neurodegenerative diseases requires studying the functional anatomy and neurochemical basis involved.<strong> Conclusions:</strong> In this view, it is essential to review the functional anatomy of the fronto-subcortical network, and it’s correlated with clinical aspects to pursuing a better therapeutic approach. 展开更多
关键词 frontotemporal dementia Fronto-Subcortical Circuitry Basal Ganglia NEUROTRANSMITTERS Fronto-Subcortical Syndrome
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Therapies for Tau-associated neurodegenerative disorders:targeting molecules,synapses,and cells 被引量:2
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作者 Miranda Robbins 《Neural Regeneration Research》 SCIE CAS CSCD 2023年第12期2633-2637,共5页
Advances in experimental and computational technologies continue to grow rapidly to provide novel avenues for the treatment of neurodegenerative disorders. Despite this, there remain only a handful of drugs that have ... Advances in experimental and computational technologies continue to grow rapidly to provide novel avenues for the treatment of neurodegenerative disorders. Despite this, there remain only a handful of drugs that have shown success in late-stage clinical trials for Tau-associated neurodegenerative disorders. The most commonly prescribed treatments are symptomatic treatments such as cholinesterase inhibitors and N-methyl-D-aspartate receptor blockers that were approved for use in Alzheimer's disease. As diagnostic screening can detect disorders at earlier time points, the field needs pre-symptomatic treatments that can prevent, or significantly delay the progression of these disorders(Koychev et al., 2019). These approaches may be different from late-stage treatments that may help to ameliorate symptoms and slow progression once symptoms have become more advanced should early diagnostic screening fail. This mini-review will highlight five key avenues of academic and industrial research for identifying therapeutic strategies to treat Tau-associated neurodegenerative disorders. These avenues include investigating(1) the broad class of chemicals termed “small molecules”;(2) adaptive immunity through both passive and active antibody treatments;(3) innate immunity with an emphasis on microglial modulation;(4) synaptic compartments with the view that Tau-associated neurodegenerative disorders are synaptopathies. Although this mini-review will focus on Alzheimer's disease due to its prevalence, it will also argue the need to target other tauopathies, as through understanding Alzheimer's disease as a Tau-associated neurodegenerative disorder, we may be able to generalize treatment options. For this reason, added detail linking back specifically to Tau protein as a direct therapeutic target will be added to each topic. 展开更多
关键词 Alzheimer's disease ANTIBODY frontotemporal dementia IMMUNOTHERAPY small molecules synapses TAU THERAPEUTICS
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Targeting prion-like protein spreading in neurodegenerative diseases
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作者 Zhaohui Zhang Shuke Nie Liam Chen 《Neural Regeneration Research》 SCIE CAS CSCD 2018年第11期1875-1878,共4页
The infectious template-mediated protein conversion is a unique mechanism for the onset of rare and fatal neurodegenerative disorders known as transmissible spongiform encephalopathies, or prion diseases, which affect... The infectious template-mediated protein conversion is a unique mechanism for the onset of rare and fatal neurodegenerative disorders known as transmissible spongiform encephalopathies, or prion diseases, which affect humans and other animal species. However, emerging studies are now demonstrating prion-like mechanisms of self-propagation of protein misfolding in a number of common, non-infectious neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. It has been proposed that distinct and unrelated proteins(beta-amyloid, tau, α-synuclein, TAR DNA-binding protein 43 and huntingtin, etc.) associated with common neurodegenerative disorders can seed conversion and spread via cellto-cell transfer, sustaining the transmission of neurotoxic agents along a stereotypic route, sharing features at the heart of the intrinsic nature of prions. Here we review the most recent development on both the molecular mechanisms underlying the pathogenesis of prion-like neurodegenerative diseases as well as innovative methods and strategies for potential therapeutic applications. 展开更多
关键词 prion-like SYNUCLEIN tau TAR DNA-binding protein 43 BETA-AMYLOID Parkinson's disease frontotemporal dementia amyotrophic lateral sclerosis Alzheimer's disease NEURODEGENERATION
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The parallel tetrameric DNA G-quadruplex formed by the two-repeat C9orf72 GGGGCC sequence in solution Dedicated to Professor Chaohui Ye on the occasion of his 80th birthday
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作者 Changdong Liu Bo Zhou +5 位作者 Naining Xu Chun Po Fung Bing Yan Monica Ching Suen Zeguo Huang Guang Zhu 《Magnetic Resonance Letters》 2022年第4期196-204,共9页
The abnormal expansion of G-rich hexanucleotide repeat,GGGGCC(G4C2),in chromosome 9 open reading frame 72(C9orf72)is known to be the prevailing genetic cause of two fatal degenerative neurological diseases,amyotrophi... The abnormal expansion of G-rich hexanucleotide repeat,GGGGCC(G4C2),in chromosome 9 open reading frame 72(C9orf72)is known to be the prevailing genetic cause of two fatal degenerative neurological diseases,amyotrophic lateral sclerosis(ALS)and frontotemporal dementia(FTD).It is well known that the DNA G4C2 repeat expansion with different lengths can form G-quadruplexes which affect gene transcription related to ALS/FTD,therefore it is crucial to understand DNA G4C2 G-quadruplex structures.Herein,by utilizing nuclear magnetic resonance(NMR)spectroscopy,we examined DNA G-quadruplex structure adopted by two G4C2 hexanucleotide repeats with an inosine substitution at position 4,d(G4C2)2-I4.We show that d(G4C2)2-I4 folds into an eight-layer parallel tetrameric G-quadruplex containing two parallel dimeric G-quadruplexes stacking together through p-p interaction via 50-to-50 mode in solution.Each dimeric G-quadruplex unit involves two propeller loops composed of two cytosine bases.This result is consistent with the observation in the crystal structure of d(G4C2)2.Our work not only sheds light on the structural diversity of G-quadruplexes adopted by d(G4C2)n but also provides a structural basis for drug design in treatment of ALS and FTD. 展开更多
关键词 Hexanucleotide repeat G4C2 expansion G-QUADRUPLEX Amyotrophic lateral sclerosis(ALS) frontotemporal dementia(FTD) Nuclear magnetic resonance(NMR)
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The 5’-Untranslated Region of the C9orf72 mRNA Exhibits a Phylogenetic Alignment to the Cis-Aconitase Iron-Responsive Element;Novel Therapies for Amytrophic Lateral Sclerosis
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作者 Monica A. Lu Susruthi Rajanala +4 位作者 Sohan V. Mikkilineni Catherine M. Cahill Robert Brown James D. Berry Jack T. Rogers 《Neuroscience & Medicine》 2016年第1期15-26,共12页
The hexanucleotide repeat mutation in the intron-1 of the chromosome 9 open reading frame (C9orf72) is a frequent cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Altered RNA folding pla... The hexanucleotide repeat mutation in the intron-1 of the chromosome 9 open reading frame (C9orf72) is a frequent cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Altered RNA folding plays a role in ALS pathogenesis in two ways: non-ATG translation of the repeat can lead to aggregates of the known C9orf72 specific dipeptide polymer, whereas the repeat also can form neurotoxic RNA inclusions that dose-responsively kill motor neurons. We report the presence of a homology in the 5’untranslated region (UTR) of the messenger RNA encoding C9orf72 with the iron responsive elements (IRE) that control expression of iron-associated transcripts and predict that this RNA structure may iron-dependently regulate C9orf72 translation. We previously report altered serum ferritin levels track with severity of ALS in patients. Here, we conduct bioinformatics analyses to determine the secondary structure of the 5’UTR in C9orf72 mRNA and find it aligned with IREs in the human mitochondrial cis-aconitase and L and H-ferritin transcripts. Comparison of the role of RNA repeats in Friedriech’s ataxia and fragile X mental retardation suggests the utility of RNA based therapies for treatment of ALS. Antisense oligonucleotides (ASO) have been reported to therapeutically target these GGGGCC repeats. At the same time, because the function of C9orf72 is unknown, knockdown strategies carry some risk of inducing or compounding haploinsufficiency. We propose, for consideration, an approach that may enhance its therapeutic dynamic range by increasing the 5’UTR driven translation of C9orf72 protein to compensate for any potential ALS-specific or ASO-induced haploinsufficieny. 展开更多
关键词 Amyotrophic Lateral Sclerosis (ALS) Iron-Responsive Element (IRE) C9orf72 mRNA Mitochondrial Aconitase (mACO) frontotemporal dementia (FTD) Amyloid Precursor Protein (APP) HIV Trans-Activation Response Element (TAR) Antisense Oligonucleotides (ASO) Iron-Regulatory Proteins-1 and -2 (IRP1 and IRP2)
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ALS-linked C9orf72 dipeptide repeats inhibit starvation-induced autophagy through modulating BCL2–BECN1 interaction
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作者 Shiqiang Xu Qilian Ma +9 位作者 Junwen Shen Ningning Li Shan Sun Nana Wang Yang Chen Chunsheng Dong Kin Yip Tam Jochen H.M.Prehn Hongfeng Wang Zheng Ying 《Acta Pharmaceutica Sinica B》 SCIE CAS CSCD 2024年第5期2026-2038,共13页
Growing evidences indicate that dysfunction of autophagy contributes to the disease pathogenesis of amyotrophic lateral sclerosis(ALS)and frontotemporal dementia(FTD),two neurodegenerative disorders.The GGGGCC·GG... Growing evidences indicate that dysfunction of autophagy contributes to the disease pathogenesis of amyotrophic lateral sclerosis(ALS)and frontotemporal dementia(FTD),two neurodegenerative disorders.The GGGGCC·GGCCCC repeat RNA expansion in chromosome 9 open reading frame 72(C9orf72)is the most genetic cause of both ALS and FTD.According to the previous studies,GGGGCC·GGCCCC repeat undergoes the unconventional repeat-associated non-ATG translation,which produces dipeptide repeat(DPR)proteins.Although there is a growing understanding that C9orf72 DPRs have a strong ability to harm neurons and induce C9orf72-linked ALS/FTD,whether these DPRs can affect autophagy remains unclear.In the present study,we find that poly-GR and poly-PR,two arginine-containing DPRs which display the most cytotoxic properties according to the previous studies,strongly inhibit starvation-induced autophagy.Moreover,our data indicate that arginine-rich DPRs enhance the interaction between BCL2 and BECN1/Beclin 1 by inhibiting BCL2 phosphorylation,therefore they can impair autophagic clearance of neurodegenerative disease-associated protein aggregates under starvation condition in cells.Importantly,our study not only highlights the role of C9orf72 DPR in autophagy dysfunction,but also provides novel insight that pharmacological intervention of autophagy using SW063058,a small molecule compound that can disrupt the interaction between BECN1 and BCL2,may reduce C9orf72 DPR-induced neurotoxicity. 展开更多
关键词 Amyotrophic lateral sclerosis frontotemporal dementia C9orf72 AUTOPHAGY BCL2 BECN1/Beclin 1 Dipeptide repeat Neurodegeneration
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Disease modification and Neuroprotection in neurodegenerative disorders 被引量:5
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作者 Jeffrey Cummings 《Translational Neurodegeneration》 SCIE CAS 2017年第1期232-238,共7页
Background:Disease modifying therapies(DMTs)are urgently needed for neurodegenerative diseases(NDD)such as Alzheimer’s disease(AD)and many other disorders characterized by protein aggregation and neurodegeneration.De... Background:Disease modifying therapies(DMTs)are urgently needed for neurodegenerative diseases(NDD)such as Alzheimer’s disease(AD)and many other disorders characterized by protein aggregation and neurodegeneration.Despite advances in understanding the neurobiology of NDD,there are no approved DMTs.Discussion:Defining disease-modification is critical to drug-development programs.A DMT is an intervention that produces an enduring change in the trajectory of clinical decline of an NDD by impacting the disease processes leading to nerve cell death.A DMT is neuroprotective,and neuroprotection will result in disease modification.Disease modification can be demonstrated in clinical trials by a drug-placebo difference in clinical outcomes supported by a drug-placebo difference on biomarkers reflective of the fundamental pathophysiology of the NDD.Alternatively,disease modification can be supported by findings on a staggered start or delayed withdrawal clinical trial design.Collecting multiple biomarkers is necessary to support a comprehensive view of disease modification.Conclusion:Disease modification is established by demonstrating an enduring change in the clinical trajectory of an NDD based on intervention in the fundamental pathophysiology of the disease leading to nerve cell death.Supporting data are collected in clinical trials.Effectively defining a DMT will assist in NDD drug development programs. 展开更多
关键词 Alzheimer’s disease frontotemporal dementia Progressive supranuclear palsy Corticobasal degeneration Amyotropic lateral sclerosis Multiple system atrophy Disease modification Disease modifying therapy
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Altered levels of CSF proteins in patients with FTD, presymptomatic mutation carriers and non-carriers 被引量:1
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作者 Julia Remnestål Linn Oijerstedt +9 位作者 Abbe Ullgren Jennie Olofsson Sofia Bergström Kim Kultima Martin Ingelsson Lena Kilander Mathias Uhlén Anna Månberg Caroline Graff Peter Nilsson 《Translational Neurodegeneration》 SCIE CAS 2020年第2期309-321,共13页
Background The clinical presentations of frontotemporal dementia(FTD)are diverse and overlap with other neurological disorders.There are,as of today,no biomarkers in clinical practice for diagnosing the disorders.Here... Background The clinical presentations of frontotemporal dementia(FTD)are diverse and overlap with other neurological disorders.There are,as of today,no biomarkers in clinical practice for diagnosing the disorders.Here,we aimed to find protein markers in cerebrospinal fluid(CSF)from patients with FTD,presymptomatic mutation carriers and non-carriers.Methods Antibody suspension bead arrays were used to analyse 328 proteins in CSF from patients with behavioural variant FTD(bvFTD,n=16)and progressive primary aphasia(PPA,n=13),as well as presymptomatic mutation carriers(PMC,n=16)and non-carriers(NC,n=8).A total of 492 antibodies were used to measure protein levels by direct labelling of the CSF samples.The findings were further examined in an independent cohort including 13 FTD patients,79 patients with Alzheimer’s disease and 18 healthy controls.Results We found significantly altered protein levels in CSF from FTD patients compared to unaffected individuals(PMC and NC)for 26 proteins.The analysis show patterns of separation between unaffected individuals and FTD patients,especially for those with a clinical diagnosis of bvFTD.The most statistically significant differences in protein levels were found for VGF,TN-R,NPTXR,TMEM132D,PDYN and NF-M.Patients with FTD were found to have higher levels of TN-R and NF-M,and lower levels of VGF,NPTXR,TMEM132D and PDYN,compared to unaffected individuals.The main findings were reproduced in the independent cohort.Conclusion In this pilot study,we show a separation of FTD patients from unaffected individuals based on protein levels in CSF.Further investigation is required to explore the CSF profiles in larger cohorts,but the results presented here has the potential to enable future clinical utilization of these potential biomarkers within FTD. 展开更多
关键词 frontotemporal dementia Cerebrospinal fluid Biomarkers Proteomics Antibody suspension bead array
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