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
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
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
Background Dementia is a chronic brain disorder classified by four distinct diseases that impact cognition and mental degeneration. Each subgroup exhibits similar brain deficiencies and mutations. This review will foc...Background Dementia is a chronic brain disorder classified by four distinct diseases that impact cognition and mental degeneration. Each subgroup exhibits similar brain deficiencies and mutations. This review will focus on four dementia subgroups: Alzheimer's disease, vascular dementia, frontotemporal dementia and dementia Lewy body. Aim The aim of this systematic review is to create a concise overview of unique similarities within dementia used to locate and identify new biomarker methods in diagnosing dementia. Methods 123 300 articles published after 2010 were identified from PubMed, JSTOR, WorldCat Online Computer Library and PALNI (Private Academic Library Network of Indiana) using the following search items (in title or abstract):'Neurodegenerative Diseases' OR 'Biomarkers' OR 'Alzheimer's Disease' OR 'Frontal Temporal Lobe Dementia' OR 'Vascular Dementia, OR 'Dementia Lewy Body' OR 'Cerebral Spinal Fluid' OR 'Mental Cognitive Impairment'. 47 studies were included in the qualitative synthesis. Results Evidence suggested neuroimaging with amyloid positron emission tomography (PET) scanning and newly found PET tracers to be more effective in diagnosing Alzheimer's and amnesiac mental cognitive impairment than carbon-11 Pittsburgh compound-B radioisotope tracer. Newly created methods to make PET scans more accurate and practical in clinical settings signify a major shift in diagnosing dementia and neurodegenerative diseases. Conclusion Vast improvements in neuroimaging techniques have led to newly discovered biomarkers and diagnostics. Neuroimaging with amyloid PET scanning surpasses what had been considered the dominant method of neuroimaging and MRI. Newly created methods to make PET scans more accurate and practical in clinical settings signify a major shift in diagnosing dementia pathology. Continued research and studies must be conducted to improve current findings and streamline methods to further subcategorise neurodegenerative disorders and diagnosis.展开更多
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
Alzheimer’s disease (AD) and associated dementia patient numbers continue to increase globally with associated economic costs to healthcare systems. Of note is the increase in numbers in lower and middle-income count...Alzheimer’s disease (AD) and associated dementia patient numbers continue to increase globally with associated economic costs to healthcare systems. Of note is the increase in numbers in lower and middle-income countries (LMICs) including Sub-Saharan African (SSA) countries, which already face challenges with their health budgets from communicable and non-communicable diseases. Ghana, an SSA country, faces the problem of healthcare budgetary difficulties and the additional impact of AD as a consequence of increasing population strata of old aged persons (OAPs) due to the demographic transition effect. This article uses examples of known patients’ illness courses to give a perspective on the lived experience of patients with dementia (PWD) in Ghana, living amongst a populace with a culture of stigmatization of PWD, and a relatively fragile public mental health system (PMHS) for those with mental illness, including AD. The lived experience of AD patients is characterised by stigmatisation, discrimination, non-inclusiveness, diminished dignity and human rights abuses in the face of their mental disability, and eventually death. This article is an advocacy article giving voice to the voiceless and all persons suffering from AD and other dementias in Ghana, whilst pleading for a call to action from healthcare professionals and responsible state agencies.展开更多
BACKGROUND Numerous observational studies have documented a correlation between inflammatory bowel disease(IBD)and an increased risk of dementia.However,the causality of their associations remains elusive.AIM To asses...BACKGROUND Numerous observational studies have documented a correlation between inflammatory bowel disease(IBD)and an increased risk of dementia.However,the causality of their associations remains elusive.AIM To assess the causal relationship between IBD and the occurrence of all-cause dementia using the two-sample Mendelian randomization(MR)method.METHODS Genetic variants extracted from the large genome-wide association study(GWAS)for IBD(the International IBD Genetics Consortium,n=34652)were used to identify the causal link between IBD and dementia(FinnGen,n=306102).The results of the study were validated via another IBD GWAS(United Kingdom Biobank,n=463372).Moreover,MR egger intercept,MR pleiotropy residual sum and outlier,and Cochran's Q test were employed to evaluate pleiotropy and heterogeneity.Finally,multiple MR methods were performed to estimate the effects of genetically predicted IBD on dementia,with the inverse variance weighted approach adopted as the primary analysis.RESULTS The results of the pleiotropy and heterogeneity tests revealed an absence of significant pleiotropic effects or heterogeneity across all genetic variants in outcome GWAS.No evidence of a causal effect between IBD and the risk of dementia was identified in the inverse variance weighted[odds ratio(OR)=0.980,95%CI:0.942-1.020,P value=0.325],weighted median(OR=0.964,95%CI:0.914-1.017,P value=0.180),and MR-Egger(OR=0.963,95%CI:0.867-1.070,P value=0.492)approaches.Consistent results were observed in validation analyses.Reverse MR analysis also showed no effect of dementia on the development of IBD.Furthermore,MR analysis suggested that IBD and its subtypes did not causally affect allcause dementia and its four subtypes,including dementia in Alzheimer's disease,vascular dementia,dementia in other diseases classified elsewhere,and unspecified dementia.CONCLUSION Taken together,our MR study signaled that IBD and its subentities were not genetically associated with all-cause dementia or its subtypes.Further large prospective studies are warranted to elucidate the impact of intestinal inflammation on the development of dementia.展开更多
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
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
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
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
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
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 atro...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
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...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.展开更多
Type 2 diabetes mellitus patients have a markedly higher risk of developing dementia.While multiple factors contribute to this predisposition,one of these involves the increased secretion of amylin,or islet amyloid po...Type 2 diabetes mellitus patients have a markedly higher risk of developing dementia.While multiple factors contribute to this predisposition,one of these involves the increased secretion of amylin,or islet amyloid polypeptide,that accompanies the pathophysiology of type 2 diabetes mellitus.Islet amyloid polypeptide accumulation has undoubtedly been implicated in various forms of dementia,including Alzheimer’s disease and vascular dementia,but the exact mechanisms underlying islet amyloid polypeptide’s causative role in dementia are unclear.In this review,we have summarized the literature supporting the various mechanisms by which islet amyloid polypeptide accumulation may cause neuronal damage,ultimately leading to the clinical symptoms of dementia.We discuss the evidence for islet amyloid polypeptide deposition in the brain,islet amyloid polypeptide interaction with other amyloids implicated in neurodegeneration,neuroinflammation caused by islet amyloid polypeptide deposition,vascular damage induced by islet amyloid polypeptide accumulation,and islet amyloid polypeptide-induced cytotoxicity.There are very few therapies approved for the treatment of dementia,and of these,clinical responses have been controversial at best.Therefore,investigating new,targetable pathways is vital for identifying novel therapeutic strategies for treating dementia.As such,we conclude this review by discussing islet amyloid polypeptide accumulation as a potential therapeutic target not only in treating type 2 diabetes mellitus but as a future target in treating or even preventing dementia associated with type 2 diabetes mellitus.展开更多
Dementia is a disorder with high societal impact and severe consequences for its patients who suffer from a progressive cognitive decline that leads to increased morbidity,mortality,and disabilities.Since there is a c...Dementia is a disorder with high societal impact and severe consequences for its patients who suffer from a progressive cognitive decline that leads to increased morbidity,mortality,and disabilities.Since there is a consensus that dementia is a multifactorial disorder,which portrays changes in the brain of the affected individual as early as 15 years before its onset,prediction models that aim at its early detection and risk identification should consider these characteristics.This study aims at presenting a novel method for ten years prediction of dementia using on multifactorial data,which comprised 75 variables.There are two automated diagnostic systems developed that use genetic algorithms for feature selection,while artificial neural network and deep neural network are used for dementia classification.The proposed model based on genetic algorithm and deep neural network had achieved the best accuracy of 93.36%,sensitivity of 93.15%,specificity of 91.59%,MCC of 0.4788,and performed superior to other 11 machine learning techniques which were presented in the past for dementia prediction.The identified best predictors were:age,past smoking habit,history of infarct,depression,hip fracture,single leg standing test with right leg,score in the physical component summary and history of TIA/RIND.The identification of risk factors is imperative in the dementia research as an effort to prevent or delay its onset.展开更多
Background:Whether or not there is targeted pharmacotherapy for dementia,an active and healthy lifestyle that includes physical activity(PA)may be a better option than medication for preventing dementia.We examined th...Background:Whether or not there is targeted pharmacotherapy for dementia,an active and healthy lifestyle that includes physical activity(PA)may be a better option than medication for preventing dementia.We examined the association between leisure-time sedentary behavior(SB)and the risk of dementia incidence and mortality.We further quantified the effect on dementia risk of replacing sedentary time with an equal amount of time spent on different physical activities.Methods:In the UK Biobank,484,169 participants(mean age=56.5 years;45.2%men)free of dementia were followed from baseline(2006-2010)through July 30,2021.A standard questionnaire measured individual leisure-time SB(watching TV,computer use,and driving)and PA(walking for pleasure,light and heavy do-it-yourself activity,strenuous sports,and other exercise)frequency and duration in the 4 weeks prior to evaluation.Apolipoprotein E(APOE)genotype data were available for a subset of 397,519(82.1%)individuals.A Cox proportional hazard model and an isotemporal substitution model were used in this study.Results:During a median 12.4 years of follow-up,6904 all-cause dementia cases and 2115 deaths from dementia were recorded.In comparison to participants with leisure-time SB<5 h/day,the hazard ratio((HR),95%confidence interval(95%CI))of dementia incidence was 1.07(1.02-1.13)for 5-8 h/day and 1.25(1.13-1.38)for>8 h/day,and the HR of dementia mortality was 1.35(1.12-1.61)for>8 h/day.A 1 standard deviation increment of sedentary time(2.33 h/day)was strongly associated with a higher incidence of dementia and mortality(HR=1.06,95%CI:1.03-1.08 and HR=1.07,95%CI:1.03-1.12,respectively).The association between sedentary time and the risk of developing dementia was more profound in subjects<60 years than in those>60 years(HR=1.26,95%CI:1.00-1.58 vs.HR=1.21,95%CI:1.08-1.35 in>8 h/day,p for interaction=0.013).Replacing 30 min/day of leisure sedentary time with an equal time spent in total PA was associated with a6%decreased risk and 9%decreased mortality from dementia,with exercise(e.g.,swimming,cycling,aerobics,bowling)showing the strongest benefit(HR=0.82,95%CI:0.78-0.86 and HR=0.79,95%CI:0.72-0.86).Compared with APOEε4 noncarriers,APOEε4 carriers are more likely to see a decrease in Alzheimer’s disease incidence and mortality when PA is substituted for SB.Conclusion:Leisure-time SB was positively associated with the risk of dementia incidence and mortality.Replacing sedentary time with equal time spent doing PA may be associated with a significant reduction in dementia incidence and mortality risk.展开更多
Background: Previous studies have shown that Hand Care Treatment, a form of passive horticultural therapy, is effective in preventing dementia and MCI and reducing the rate of progression. Due to the Covid-19 pandemic...Background: Previous studies have shown that Hand Care Treatment, a form of passive horticultural therapy, is effective in preventing dementia and MCI and reducing the rate of progression. Due to the Covid-19 pandemic, various activity restrictions were implemented in Japan from March 2020, and the number of elderly people without care and rehabilitation will the number of elderly people without care and rehabilitation has been increasing. Purpose: Progression of cognitive, physical, and mental disability was examined for long-term horticultural therapy study subjects by level of care required. Methods: One subject who had been diagnosed with dementia and was residing in an elderly care facility and consented to a long-term study was selected. In addition to assessments using various evaluation forms, data recorded from time to time, including changes in care plans, were analyzed using text mining methods. Results: This subject tended to progress slowly from 1 to 2 care needs, but progressed from 3 to 5 care needs over a 2-year period. The results of the assessment chart test showed that cognitive impairment and IADL decreased with each increase in the level of care required, but DBD remained the same at the time of admission, even at 5 years of care required. A comparison of HCT and aroma intervention with and without aroma intervention during the nursing care level 1 showed that the improvement in physical, mental, and cognitive function was expected to be higher at the time of intervention. Text-mining inspections have revealed that during the period of nursing care level 1 - 5, active horticultural therapy techniques, and passive horticultural therapy techniques such as HCT and brain rejuvenation aromatherapy were found to betweenness centrality with each other. Conclusion: From the results of mean score of DBD, although the nursing care level has progressed from 1 to a maximum of 5, it can be concluded that the burden of care has not become heavier. There was no tendency for the progression of cognitive impairment in this subject to be faster than in the general AD population, despite the influences of Covid-19. The results indicated that caregiving techniques and active and passive horticultural therapy techniques in Japanese welfare facilities for the elderly are expected to be effective in preventing the progression of cognitive impairment.展开更多
The topological connectivity information derived from the brain functional network can bring new insights for diagnosing and analyzing dementia disorders.The brain functional network is suitable to bridge the correlat...The topological connectivity information derived from the brain functional network can bring new insights for diagnosing and analyzing dementia disorders.The brain functional network is suitable to bridge the correlation between abnormal connectivities and dementia disorders.However,it is challenging to access considerable amounts of brain functional network data,which hinders the widespread application of data-driven models in dementia diagnosis.In this study,a novel distribution-regularized adversarial graph auto-Encoder(DAGAE)with transformer is proposed to generate new fake brain functional networks to augment the brain functional network dataset,improving the dementia diagnosis accuracy of data-driven models.Specifically,the label distribution is estimated to regularize the latent space learned by the graph encoder,which canmake the learning process stable and the learned representation robust.Also,the transformer generator is devised to map the node representations into node-to-node connections by exploring the long-term dependence of highly-correlated distant brain regions.The typical topological properties and discriminative features can be preserved entirely.Furthermore,the generated brain functional networks improve the prediction performance using different classifiers,which can be applied to analyze other cognitive diseases.Attempts on the Alzheimer’s Disease Neuroimaging Initiative(ADNI)dataset demonstrate that the proposed model can generate good brain functional networks.The classification results show adding generated data can achieve the best accuracy value of 85.33%,sensitivity value of 84.00%,specificity value of 86.67%.The proposed model also achieves superior performance compared with other related augmentedmodels.Overall,the proposedmodel effectively improves cognitive disease diagnosis by generating diverse brain functional networks.展开更多
BACKGROUND Dementia is a prevalent condition in type 2 diabetes mellitus(T2DM)patients.While Chinese herbal medicine(CHM)is often employed as complementary therapy for glycemic control,its effect in controlling likeli...BACKGROUND Dementia is a prevalent condition in type 2 diabetes mellitus(T2DM)patients.While Chinese herbal medicine(CHM)is often employed as complementary therapy for glycemic control,its effect in controlling likelihood of dementia has not yet been fully elucidated.AIM To compare the risk of dementia between T2DM patients with and without CHM treatment.METHODS We undertook a nested case-control study and obtained data on patients 20-70 years of age who received medical care for T2DM between 2001 and 2010 from the National Health Insurance Research database in Taiwan.Cases,defined as those with dementia that occurred at least one year after the diagnosis of T2DM,were randomly matched to controls without dementia from the study cohort at a 1:1 ratio.We applied conditional logistic regression to explore the associations between CHM treatment and dementia.RESULTS A total of 11699 dementia cases were matched to 11699 non-dementia controls.We found that adding CHM to conventional care was related to a lower risk of dementia[adjusted odds ratio(OR)=0.51],and high-intensity CHM treatment was associated with an adjusted OR of 0.22.CONCLUSION This study shows that the cumulative CHM exposure was inversely associated with dementia risk in an exposureresponse manner,implying that CHM treatment may be embraced as a disease management approach for diabetic patients to prevent dementia.展开更多
基金ML was supported by Portuguese Foundation for Science and Technology(FCT),No.SFRH/BD/144001/2019.
文摘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.
基金supported by research grants to LMI from University of Buenos Aires(UBACyT)the Agencia Nacional de Promoción Científica y Tecnológica(ANPCyT)under grants PICT 2015-0975 and PICT 2017-2140。
文摘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.
文摘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.
基金the Municipal Human Resources Development Program for Outstanding Leaders in Medical Discipline in Shanghai (2017BR054)Shanghai Jiao Tong University School of Medicine Collaborative Innovation Project (TM201728)+1 种基金Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support (20172029)the National Natural Science Foundation of China (81571298).
文摘Background Dementia is a chronic brain disorder classified by four distinct diseases that impact cognition and mental degeneration. Each subgroup exhibits similar brain deficiencies and mutations. This review will focus on four dementia subgroups: Alzheimer's disease, vascular dementia, frontotemporal dementia and dementia Lewy body. Aim The aim of this systematic review is to create a concise overview of unique similarities within dementia used to locate and identify new biomarker methods in diagnosing dementia. Methods 123 300 articles published after 2010 were identified from PubMed, JSTOR, WorldCat Online Computer Library and PALNI (Private Academic Library Network of Indiana) using the following search items (in title or abstract):'Neurodegenerative Diseases' OR 'Biomarkers' OR 'Alzheimer's Disease' OR 'Frontal Temporal Lobe Dementia' OR 'Vascular Dementia, OR 'Dementia Lewy Body' OR 'Cerebral Spinal Fluid' OR 'Mental Cognitive Impairment'. 47 studies were included in the qualitative synthesis. Results Evidence suggested neuroimaging with amyloid positron emission tomography (PET) scanning and newly found PET tracers to be more effective in diagnosing Alzheimer's and amnesiac mental cognitive impairment than carbon-11 Pittsburgh compound-B radioisotope tracer. Newly created methods to make PET scans more accurate and practical in clinical settings signify a major shift in diagnosing dementia and neurodegenerative diseases. Conclusion Vast improvements in neuroimaging techniques have led to newly discovered biomarkers and diagnostics. Neuroimaging with amyloid PET scanning surpasses what had been considered the dominant method of neuroimaging and MRI. Newly created methods to make PET scans more accurate and practical in clinical settings signify a major shift in diagnosing dementia pathology. Continued research and studies must be conducted to improve current findings and streamline methods to further subcategorise neurodegenerative disorders and diagnosis.
基金supported by funding from the Bluesand Foundation,Alzheimer's Association(AARG-21-852072 and Bias Frangione Early Career Achievement Award)to EDan Australian Government Research Training Program scholarship and the University of Sydney's Brain and Mind Centre fellowship to AH。
文摘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.
文摘Alzheimer’s disease (AD) and associated dementia patient numbers continue to increase globally with associated economic costs to healthcare systems. Of note is the increase in numbers in lower and middle-income countries (LMICs) including Sub-Saharan African (SSA) countries, which already face challenges with their health budgets from communicable and non-communicable diseases. Ghana, an SSA country, faces the problem of healthcare budgetary difficulties and the additional impact of AD as a consequence of increasing population strata of old aged persons (OAPs) due to the demographic transition effect. This article uses examples of known patients’ illness courses to give a perspective on the lived experience of patients with dementia (PWD) in Ghana, living amongst a populace with a culture of stigmatization of PWD, and a relatively fragile public mental health system (PMHS) for those with mental illness, including AD. The lived experience of AD patients is characterised by stigmatisation, discrimination, non-inclusiveness, diminished dignity and human rights abuses in the face of their mental disability, and eventually death. This article is an advocacy article giving voice to the voiceless and all persons suffering from AD and other dementias in Ghana, whilst pleading for a call to action from healthcare professionals and responsible state agencies.
文摘BACKGROUND Numerous observational studies have documented a correlation between inflammatory bowel disease(IBD)and an increased risk of dementia.However,the causality of their associations remains elusive.AIM To assess the causal relationship between IBD and the occurrence of all-cause dementia using the two-sample Mendelian randomization(MR)method.METHODS Genetic variants extracted from the large genome-wide association study(GWAS)for IBD(the International IBD Genetics Consortium,n=34652)were used to identify the causal link between IBD and dementia(FinnGen,n=306102).The results of the study were validated via another IBD GWAS(United Kingdom Biobank,n=463372).Moreover,MR egger intercept,MR pleiotropy residual sum and outlier,and Cochran's Q test were employed to evaluate pleiotropy and heterogeneity.Finally,multiple MR methods were performed to estimate the effects of genetically predicted IBD on dementia,with the inverse variance weighted approach adopted as the primary analysis.RESULTS The results of the pleiotropy and heterogeneity tests revealed an absence of significant pleiotropic effects or heterogeneity across all genetic variants in outcome GWAS.No evidence of a causal effect between IBD and the risk of dementia was identified in the inverse variance weighted[odds ratio(OR)=0.980,95%CI:0.942-1.020,P value=0.325],weighted median(OR=0.964,95%CI:0.914-1.017,P value=0.180),and MR-Egger(OR=0.963,95%CI:0.867-1.070,P value=0.492)approaches.Consistent results were observed in validation analyses.Reverse MR analysis also showed no effect of dementia on the development of IBD.Furthermore,MR analysis suggested that IBD and its subtypes did not causally affect allcause dementia and its four subtypes,including dementia in Alzheimer's disease,vascular dementia,dementia in other diseases classified elsewhere,and unspecified dementia.CONCLUSION Taken together,our MR study signaled that IBD and its subentities were not genetically associated with all-cause dementia or its subtypes.Further large prospective studies are warranted to elucidate the impact of intestinal inflammation on the development of dementia.
文摘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.
基金supported by the National Natural Science Foundation of China (31871023 and 31970966)the National Key Scientific R&D Program of China (2016YFC1306000)a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions。
文摘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.
基金supported by the Fondo de Investigaciones Sanitario(FIS)Institute de Salud Carlos III(P114/01126,P117/01019 and PI20/01473 to JF,PI13/01532 and PI16/01825 to RB,PI18/00335 to MCI,PI18/00435 and INT19/00016 to DA,PI17/01896 and AC19/00103to AL)+4 种基金the CIBERNED program(Program 1,Alzheimer Disease to AL)jointly funded by Fondo Europeo de Desarrollo Regional,Unión Europea,"Una manera de hacer Europa"supported by Generalitat de Catalunya(2017-SGR-547,SLT006/17/125 to DA,SLT006/17/119 to JF,SLT002/16/408 to AL)"MaratóTV3"foundation grants 20141210 to JF,044412 to RB and 20142610 to ALsupported by a grant from the Fundacio Bancaria La Caixa to RB(DABNI project).
文摘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.
文摘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.
文摘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
文摘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.
基金This study was supported by the National Natural Science Foundation of China(No.81471295 and No.81671075 to Lu Shen,No.81701134 to Bin Jiao)the National Key Plan for Scientific Research and Development of China(No.2016YFC1306000 to Beisha Tang)the Xiangya Hospital Youth Scientific Research Fund(No.2016Q01 to Bin Jiao).
文摘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.
基金supported by The Mike Hogg FundBaylor College of Medicine Medical Scientist Training Program,NICHD R01HD099252(to RJP)and R01HD098131(to RJP)the NHLBI T32 HL092332(to ASB)。
文摘Type 2 diabetes mellitus patients have a markedly higher risk of developing dementia.While multiple factors contribute to this predisposition,one of these involves the increased secretion of amylin,or islet amyloid polypeptide,that accompanies the pathophysiology of type 2 diabetes mellitus.Islet amyloid polypeptide accumulation has undoubtedly been implicated in various forms of dementia,including Alzheimer’s disease and vascular dementia,but the exact mechanisms underlying islet amyloid polypeptide’s causative role in dementia are unclear.In this review,we have summarized the literature supporting the various mechanisms by which islet amyloid polypeptide accumulation may cause neuronal damage,ultimately leading to the clinical symptoms of dementia.We discuss the evidence for islet amyloid polypeptide deposition in the brain,islet amyloid polypeptide interaction with other amyloids implicated in neurodegeneration,neuroinflammation caused by islet amyloid polypeptide deposition,vascular damage induced by islet amyloid polypeptide accumulation,and islet amyloid polypeptide-induced cytotoxicity.There are very few therapies approved for the treatment of dementia,and of these,clinical responses have been controversial at best.Therefore,investigating new,targetable pathways is vital for identifying novel therapeutic strategies for treating dementia.As such,we conclude this review by discussing islet amyloid polypeptide accumulation as a potential therapeutic target not only in treating type 2 diabetes mellitus but as a future target in treating or even preventing dementia associated with type 2 diabetes mellitus.
文摘Dementia is a disorder with high societal impact and severe consequences for its patients who suffer from a progressive cognitive decline that leads to increased morbidity,mortality,and disabilities.Since there is a consensus that dementia is a multifactorial disorder,which portrays changes in the brain of the affected individual as early as 15 years before its onset,prediction models that aim at its early detection and risk identification should consider these characteristics.This study aims at presenting a novel method for ten years prediction of dementia using on multifactorial data,which comprised 75 variables.There are two automated diagnostic systems developed that use genetic algorithms for feature selection,while artificial neural network and deep neural network are used for dementia classification.The proposed model based on genetic algorithm and deep neural network had achieved the best accuracy of 93.36%,sensitivity of 93.15%,specificity of 91.59%,MCC of 0.4788,and performed superior to other 11 machine learning techniques which were presented in the past for dementia prediction.The identified best predictors were:age,past smoking habit,history of infarct,depression,hip fracture,single leg standing test with right leg,score in the physical component summary and history of TIA/RIND.The identification of risk factors is imperative in the dementia research as an effort to prevent or delay its onset.
基金supported by Shanghai Municipal Human Resources and Social Security Bureau(2020074)Clinical Research Plan of SHDC(SHDC2020CR4006)+2 种基金Shanghai Ninth People’s Hospital(YBKA201909)Innovative research team of high-level local universities in Shanghai(SHSMU-ZDCX20212501)Shanghai Municipal Health Commission(2022XD017)。
文摘Background:Whether or not there is targeted pharmacotherapy for dementia,an active and healthy lifestyle that includes physical activity(PA)may be a better option than medication for preventing dementia.We examined the association between leisure-time sedentary behavior(SB)and the risk of dementia incidence and mortality.We further quantified the effect on dementia risk of replacing sedentary time with an equal amount of time spent on different physical activities.Methods:In the UK Biobank,484,169 participants(mean age=56.5 years;45.2%men)free of dementia were followed from baseline(2006-2010)through July 30,2021.A standard questionnaire measured individual leisure-time SB(watching TV,computer use,and driving)and PA(walking for pleasure,light and heavy do-it-yourself activity,strenuous sports,and other exercise)frequency and duration in the 4 weeks prior to evaluation.Apolipoprotein E(APOE)genotype data were available for a subset of 397,519(82.1%)individuals.A Cox proportional hazard model and an isotemporal substitution model were used in this study.Results:During a median 12.4 years of follow-up,6904 all-cause dementia cases and 2115 deaths from dementia were recorded.In comparison to participants with leisure-time SB<5 h/day,the hazard ratio((HR),95%confidence interval(95%CI))of dementia incidence was 1.07(1.02-1.13)for 5-8 h/day and 1.25(1.13-1.38)for>8 h/day,and the HR of dementia mortality was 1.35(1.12-1.61)for>8 h/day.A 1 standard deviation increment of sedentary time(2.33 h/day)was strongly associated with a higher incidence of dementia and mortality(HR=1.06,95%CI:1.03-1.08 and HR=1.07,95%CI:1.03-1.12,respectively).The association between sedentary time and the risk of developing dementia was more profound in subjects<60 years than in those>60 years(HR=1.26,95%CI:1.00-1.58 vs.HR=1.21,95%CI:1.08-1.35 in>8 h/day,p for interaction=0.013).Replacing 30 min/day of leisure sedentary time with an equal time spent in total PA was associated with a6%decreased risk and 9%decreased mortality from dementia,with exercise(e.g.,swimming,cycling,aerobics,bowling)showing the strongest benefit(HR=0.82,95%CI:0.78-0.86 and HR=0.79,95%CI:0.72-0.86).Compared with APOEε4 noncarriers,APOEε4 carriers are more likely to see a decrease in Alzheimer’s disease incidence and mortality when PA is substituted for SB.Conclusion:Leisure-time SB was positively associated with the risk of dementia incidence and mortality.Replacing sedentary time with equal time spent doing PA may be associated with a significant reduction in dementia incidence and mortality risk.
文摘Background: Previous studies have shown that Hand Care Treatment, a form of passive horticultural therapy, is effective in preventing dementia and MCI and reducing the rate of progression. Due to the Covid-19 pandemic, various activity restrictions were implemented in Japan from March 2020, and the number of elderly people without care and rehabilitation will the number of elderly people without care and rehabilitation has been increasing. Purpose: Progression of cognitive, physical, and mental disability was examined for long-term horticultural therapy study subjects by level of care required. Methods: One subject who had been diagnosed with dementia and was residing in an elderly care facility and consented to a long-term study was selected. In addition to assessments using various evaluation forms, data recorded from time to time, including changes in care plans, were analyzed using text mining methods. Results: This subject tended to progress slowly from 1 to 2 care needs, but progressed from 3 to 5 care needs over a 2-year period. The results of the assessment chart test showed that cognitive impairment and IADL decreased with each increase in the level of care required, but DBD remained the same at the time of admission, even at 5 years of care required. A comparison of HCT and aroma intervention with and without aroma intervention during the nursing care level 1 showed that the improvement in physical, mental, and cognitive function was expected to be higher at the time of intervention. Text-mining inspections have revealed that during the period of nursing care level 1 - 5, active horticultural therapy techniques, and passive horticultural therapy techniques such as HCT and brain rejuvenation aromatherapy were found to betweenness centrality with each other. Conclusion: From the results of mean score of DBD, although the nursing care level has progressed from 1 to a maximum of 5, it can be concluded that the burden of care has not become heavier. There was no tendency for the progression of cognitive impairment in this subject to be faster than in the general AD population, despite the influences of Covid-19. The results indicated that caregiving techniques and active and passive horticultural therapy techniques in Japanese welfare facilities for the elderly are expected to be effective in preventing the progression of cognitive impairment.
基金This paper is partially supported by the British Heart Foundation Accelerator Award,UK(AA\18\3\34220)Royal Society International Exchanges Cost Share Award,UK(RP202G0230)+9 种基金Hope Foundation for Cancer Research,UK(RM60G0680)Medical Research Council Confidence in Concept Award,UK(MC_PC_17171)Sino-UK Industrial Fund,UK(RP202G0289)Global Challenges Research Fund(GCRF),UK(P202PF11)LIAS Pioneering Partnerships Award,UK(P202ED10)Data Science Enhancement Fund,UK(P202RE237)Fight for Sight,UK(24NN201)Sino-UK Education Fund,UK(OP202006)Biotechnology and Biological Sciences Research Council,UK(RM32G0178B8)LIAS Seed Corn,UK(P202RE969).
文摘The topological connectivity information derived from the brain functional network can bring new insights for diagnosing and analyzing dementia disorders.The brain functional network is suitable to bridge the correlation between abnormal connectivities and dementia disorders.However,it is challenging to access considerable amounts of brain functional network data,which hinders the widespread application of data-driven models in dementia diagnosis.In this study,a novel distribution-regularized adversarial graph auto-Encoder(DAGAE)with transformer is proposed to generate new fake brain functional networks to augment the brain functional network dataset,improving the dementia diagnosis accuracy of data-driven models.Specifically,the label distribution is estimated to regularize the latent space learned by the graph encoder,which canmake the learning process stable and the learned representation robust.Also,the transformer generator is devised to map the node representations into node-to-node connections by exploring the long-term dependence of highly-correlated distant brain regions.The typical topological properties and discriminative features can be preserved entirely.Furthermore,the generated brain functional networks improve the prediction performance using different classifiers,which can be applied to analyze other cognitive diseases.Attempts on the Alzheimer’s Disease Neuroimaging Initiative(ADNI)dataset demonstrate that the proposed model can generate good brain functional networks.The classification results show adding generated data can achieve the best accuracy value of 85.33%,sensitivity value of 84.00%,specificity value of 86.67%.The proposed model also achieves superior performance compared with other related augmentedmodels.Overall,the proposedmodel effectively improves cognitive disease diagnosis by generating diverse brain functional networks.
文摘BACKGROUND Dementia is a prevalent condition in type 2 diabetes mellitus(T2DM)patients.While Chinese herbal medicine(CHM)is often employed as complementary therapy for glycemic control,its effect in controlling likelihood of dementia has not yet been fully elucidated.AIM To compare the risk of dementia between T2DM patients with and without CHM treatment.METHODS We undertook a nested case-control study and obtained data on patients 20-70 years of age who received medical care for T2DM between 2001 and 2010 from the National Health Insurance Research database in Taiwan.Cases,defined as those with dementia that occurred at least one year after the diagnosis of T2DM,were randomly matched to controls without dementia from the study cohort at a 1:1 ratio.We applied conditional logistic regression to explore the associations between CHM treatment and dementia.RESULTS A total of 11699 dementia cases were matched to 11699 non-dementia controls.We found that adding CHM to conventional care was related to a lower risk of dementia[adjusted odds ratio(OR)=0.51],and high-intensity CHM treatment was associated with an adjusted OR of 0.22.CONCLUSION This study shows that the cumulative CHM exposure was inversely associated with dementia risk in an exposureresponse manner,implying that CHM treatment may be embraced as a disease management approach for diabetic patients to prevent dementia.
