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1.
Neurology ; 96(11): e1501-e1511, 2021 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-33504642

RESUMO

OBJECTIVE: To determine whether severe perivascular space (PVS) dilation is associated with longitudinal cognitive decline and incident dementia over 4 and 8 years, respectively, we analyzed data from a prospective cohort study. METHODS: A total of 414 community-dwelling older adults aged 72-92 years were assessed at baseline and biennially for up to 8 years, with cognitive assessments, consensus dementia diagnoses, and 3T MRI. The numbers of PVS in 2 representative slices in the basal ganglia (BG) and centrum semiovale (CSO) were counted and severe PVS pathology defined as the top quartile. The effects of severe PVS pathology in either region or both regions and those with severe BG PVS and severe CSO PVS were examined. White matter hyperintensity volume, cerebral microbleed number, and lacune number were calculated. RESULTS: Participants with severe PVS pathology in both regions or in the CSO alone had greater decline in global cognition over 4 years, even after adjustment for the presence of other small vessel disease neuroimaging markers. The presence of severe PVS pathology in both regions was an independent predictor of dementia across 8 years (odds ratio 2.91, 95% confidence interval 1.43-5.95, p = 0.003). The presence of severe PVS pathology in all groups examined was associated with greater dementia risk at either year 4 or 6. CONCLUSIONS: Severe PVS pathology is a marker for increased risk of cognitive decline and dementia, independent of other small vessel disease markers. The differential cognitive associations for BG and CSO PVS may represent differences in their underlying pathology.


Assuntos
Disfunção Cognitiva/patologia , Demência/patologia , Sistema Glinfático/patologia , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Humanos , Estudos Longitudinais , Masculino
2.
BMC Med ; 18(1): 407, 2020 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-33342434

RESUMO

BACKGROUND: The objectives of this study are to determine the effects of regularly scheduled administration of paracetamol (acetaminophen) on quality of life (QoL), discomfort, pain and neuropsychiatric symptoms of persons with dementia living in long-term care facilities (LTCFs). METHODS: A multicentre randomised double-blind placebo-controlled crossover trial for 13 weeks (January 2018 to June 2019) in 17 LTCFs across the west of the Netherlands. Inclusion criteria were age ≥ 65 years, (advanced) dementia and a moderate to low QoL, independent of the presence of pain (QUALIDEM ≤ 70). Exclusion criteria were the use of regular pain treatment, allergies to the study medication, severe liver disease, use of > 4 units of alcohol/day, weight < 50 kg and/or concomitant use of flucloxacillin. Participants received study medication (paracetamol/placebo) in two periods of 6 weeks each (1 week in between as a wash-out period). Randomisation decided in which order participants received paracetamol and placebo. Primary outcomes included QoL (QUALIDEM) and discomfort (DS-DAT), secondary outcomes included pain (MOBID-2) and neuropsychiatric symptoms (NPI-NH). RESULTS: Ninety-five LTCF residents (mean age 83.9 years [SD 7.6], 57.9% females) were included. Repeated linear mixed models showed no difference in mean differences of QUALIDEM (paracetamol +1.3 [95% CI -1.0-3.5], placebo +1.5 [95% CI -0.7-3.8]), DS-DAT (paracetamol -0.1 [95% CI -1.4-1.2], placebo 0.6 [95 CI -0.7-1.8]), MOBID-2 (paracetamol 0.0 [95% CI -0.5-0.5], placebo -0.2 [95% CI -0.7-0.3]) and NPI-NH (paracetamol +1.5 [95% CI -2.3-5.4], placebo -2.1 [95% CI -6.0-1.7]) in favour of either paracetamol or placebo. CONCLUSIONS: Compared to placebo, paracetamol showed no positive effect on QoL, discomfort, pain and neuropsychiatric symptoms in persons with advanced dementia with low QoL. It is important to find out more specifically which individual persons with advanced dementia could benefit from pain treatment with paracetamol, and for clinicians to acknowledge that a good assessment, monitoring and multidomain approach is vital for improving QoL in this vulnerable group. TRIAL REGISTRATION: Netherlands Trial Register NTR6766 . Trial registration date: 20 October 2017.


Assuntos
Acetaminofen/uso terapêutico , Demência/tratamento farmacológico , Dor/tratamento farmacológico , Conforto do Paciente , Qualidade de Vida , Acetaminofen/administração & dosagem , Acetaminofen/farmacologia , Idoso , Idoso de 80 Anos ou mais , Estudos Cross-Over , Demência/patologia , Demência/psicologia , Progressão da Doença , Método Duplo-Cego , Feminino , Avaliação Geriátrica , Humanos , Assistência de Longa Duração/métodos , Masculino , Países Baixos , Casas de Saúde , Dor/epidemiologia , Dor/psicologia , Manejo da Dor/métodos , Conforto do Paciente/normas , Placebos , Qualidade de Vida/psicologia , Resultado do Tratamento
3.
Phys Rev Lett ; 125(12): 128102, 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-33016724

RESUMO

Neurodegenerative diseases, such as Alzheimer's or Parkinson's disease, show characteristic degradation of structural brain networks. This degradation eventually leads to changes in the network dynamics and degradation of cognitive functions. Here, we model the progression in terms of coupled physical processes: The accumulation of toxic proteins, given by a nonlinear reaction-diffusion transport process, yields an evolving brain connectome characterized by weighted edges on which a neuronal-mass model evolves. The progression of the brain functions can be tested by simulating the resting-state activity on the evolving brain network. We show that while the evolution of edge weights plays a minor role in the overall progression of the disease, dynamic biomarkers predict a transition over a period of 10 years associated with strong cognitive decline.


Assuntos
Demência/patologia , Modelos Neurológicos , Doenças Neurodegenerativas/patologia , Animais , Relógios Biológicos , Encéfalo/patologia , Encéfalo/fisiopatologia , Morte Celular/fisiologia , Disfunção Cognitiva/patologia , Disfunção Cognitiva/fisiopatologia , Conectoma/métodos , Demência/fisiopatologia , Humanos , Camundongos , Doenças Neurodegenerativas/fisiopatologia , Neurônios/patologia
4.
Proc Natl Acad Sci U S A ; 117(26): 15230-15241, 2020 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-32513711

RESUMO

Mutations in UBQLN2 cause amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and other neurodegenerations. However, the mechanism by which the UBQLN2 mutations cause disease remains unclear. Alterations in proteins involved in autophagy are prominent in neuronal tissue of human ALS UBQLN2 patients and in a transgenic P497S UBQLN2 mouse model of ALS/FTD, suggesting a pathogenic link. Here, we show UBQLN2 functions in autophagy and that ALS/FTD mutant proteins compromise this function. Inactivation of UBQLN2 expression in HeLa cells reduced autophagic flux and autophagosome acidification. The defect in acidification was rescued by reexpression of wild type (WT) UBQLN2 but not by any of the five different UBQLN2 ALS/FTD mutants tested. Proteomic analysis and immunoblot studies revealed P497S mutant mice and UBQLN2 knockout HeLa and NSC34 cells have reduced expression of ATP6v1g1, a critical subunit of the vacuolar ATPase (V-ATPase) pump. Knockout of UBQLN2 expression in HeLa cells decreased turnover of ATP6v1g1, while overexpression of WT UBQLN2 increased biogenesis of ATP6v1g1 compared with P497S mutant UBQLN2 protein. In vitro interaction studies showed that ATP6v1g1 binds more strongly to WT UBQLN2 than to ALS/FTD mutant UBQLN2 proteins. Intriguingly, overexpression of ATP6v1g1 in UBQLN2 knockout HeLa cells increased autophagosome acidification, suggesting a therapeutic approach to overcome the acidification defect. Taken together, our findings suggest that UBQLN2 mutations drive pathogenesis through a dominant-negative loss-of-function mechanism in autophagy and that UBQLN2 functions as an important regulator of the expression and stability of ATP6v1g1. These findings may have important implications for devising therapies to treat UBQLN2-linked ALS/FTD.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Esclerose Amiotrófica Lateral/genética , Autofagossomos/fisiologia , Proteínas Relacionadas à Autofagia/metabolismo , Autofagia/genética , Demência/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Esclerose Amiotrófica Lateral/metabolismo , Esclerose Amiotrófica Lateral/patologia , Animais , Proteínas Relacionadas à Autofagia/genética , Biomarcadores/metabolismo , Linhagem Celular , Demência/metabolismo , Demência/patologia , Predisposição Genética para Doença , Humanos , Concentração de Íons de Hidrogênio , Glicoproteínas de Membrana Associadas ao Lisossomo/genética , Glicoproteínas de Membrana Associadas ao Lisossomo/metabolismo , Camundongos , Camundongos Transgênicos , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Mutação , Ligação Proteica , Proteína Sequestossoma-1/genética , Proteína Sequestossoma-1/metabolismo , Regulação para Cima , ATPases Vacuolares Próton-Translocadoras/genética , ATPases Vacuolares Próton-Translocadoras/metabolismo
5.
Neurobiol Aging ; 92: 135-140, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32417749

RESUMO

To assess volume loss and flortaucipir uptake in patients with semantic dementia (SD) over time. Eight SD patients (3 female) underwent clinical evaluations, flortaucipir positron emission tomography, and brain magnetic resonance imaging at 2 visits. Voxel-level comparisons of magnetic resonance imaging gray and white matter volume loss and flortaucipir positron emission tomography uptake were performed in SPM12, comparing SD patients to controls at each visit. T-tests on difference images and paired t-tests of flortaucipir uptake were also performed. At the voxel level, SD patients showed asymmetric, bilateral gray volume loss in the temporal lobes, which, via visual inspection, extended posteriorly at follow-up. White matter loss and flortaucipir uptake were noted in SD patients in the left temporal lobe only, which appeared to extend posteriorly, without involvement of the right hemisphere at follow-up. Longitudinal analyses did not support significant changes in flortaucipir uptake between visits. The biological mechanisms of flortaucipir signal in suspected underlying TAR-DNA binding protein 43 pathology are unknown. A 1-year interval is not sufficient time to demonstrate significant longitudinal flortaucipir uptake changes in SD.


Assuntos
Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Carbolinas , Demência/diagnóstico por imagem , Demência/patologia , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Idoso , Proteínas de Ligação a DNA , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Proteinopatias TDP-43
6.
PLoS One ; 15(5): e0233650, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32453771

RESUMO

OBJECTIVES: Evaluate the independent and interactive effects of dementia and racial/ethnic minority status on functional outcomes during a home health (HH) admission among Medicare beneficiaries. METHODS: Secondary analysis of data from the Outcome and Assessment Information Set [OASIS] and billing records in a non-profit HH agency in New York. Participants were adults ≥ 65 years old who received HH in CY 2017 with OASIS records at HH admission and HH discharge. Dementia was identified by diagnosis (ICD-10 codes) and cognitive impairment (OASIS: M1700, M1710, M1740). We used OASIS records to assess race/ethnicity (M0140) and functional status (M1800-M1870 on activities of daily living [ADL]). Functional outcome was measured as change in the composite ADL score from HH admission to HH discharge, where a negative score means improvement and a positive score means decline. RESULTS: The sample included 4,783 patients, among whom 93.9% improved in ADLs at HH discharge. In multivariable linear regression that adjusted for HH service use and covariates (R2 = 0.23), being African American (ß = 0.21, 95% confidence interval [CI]: 0.06, 0.35, p = 0.005) and having dementia (ß = 0.51, 95% CI: 0.41, 0.62, p<0.001) were independently related to less ADL improvement at HH discharge, with significant interaction related to further decrease in ADL improvement. Relative to white patients without dementia, African American patients with dementia (ß = 1.08, 95% CI: 0.81, 1.35, p<0.001), Hispanics with dementia (ß = 0.92, 95% CI: 0.38, 1.47, p = 0.001) and Asian Americans with dementia (ß = 1.47, 95% CI: 0.81, 2.13, p<0.001) showed the least ADL improvement at HH discharge. CONCLUSION: Racial/ethnic minority status and dementia were associated with less ADL improvement in HH with independent and interactive effects. Policies should ensure that these patients have equitable access to appropriate, adequate community-based services to meet their needs in ADLs and disease management for improved outcomes.


Assuntos
Disfunção Cognitiva/epidemiologia , Demência/epidemiologia , Grupos Minoritários , Atividades Cotidianas , Afro-Americanos , Idoso , Idoso de 80 Anos ou mais , Americanos Asiáticos , Disfunção Cognitiva/fisiopatologia , Demência/patologia , Demência/prevenção & controle , Grupo com Ancestrais do Continente Europeu , Feminino , Hispano-Americanos , Humanos , Masculino , Medicare , Estados Unidos/epidemiologia
7.
Adv Exp Med Biol ; 1233: 177-194, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32274757

RESUMO

Tauopathies are a heterogeneous group of neurodegenerative dementias involving perturbations in the levels, phosphorylation or mutations of the neuronal microtubule-binding protein Tau. Tauopathies are characterized by accumulation of hyperphosphorylated Tau leading to formation of a range of aggregates including macromolecular ensembles such as Paired Helical filaments and Neurofibrilary Tangles whose morphology characterizes and differentiates these disease states. Why nonphysiological Tau proteins elude the surveillance normal proteostatic mechanisms and eventually form these macromolecular assemblies is a central mostly unresolved question of cardinal importance for diagnoses and potential therapeutic interventions. We discuss the response of the Ubiquitin-Proteasome system, autophagy and the Endoplasmic Reticulum-Unfolded Protein response in Tauopathy models and patients, revealing interactions of components of these systems with Tau, but also of the effects of pathological Tau on these systems which eventually lead to Tau aggregation and accumulation. These interactions point to potential disease biomarkers and future potential therapeutic targets.


Assuntos
Proteostase , Tauopatias/metabolismo , Tauopatias/patologia , Demência/genética , Demência/metabolismo , Demência/patologia , Humanos , Emaranhados Neurofibrilares/genética , Emaranhados Neurofibrilares/metabolismo , Emaranhados Neurofibrilares/patologia , Fosforilação , Complexo de Endopeptidases do Proteassoma/metabolismo , Tauopatias/genética , Ubiquitina/metabolismo , Proteínas tau/química , Proteínas tau/genética , Proteínas tau/metabolismo
8.
PLoS One ; 15(4): e0231848, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32310969

RESUMO

OBJECTIVES: Much is known about the demands of caregiving for persons with dementia (PWD) and its effects on family caregivers, however sex and gender aspects have received less attention. We synthesized the evidence on sex and gender distinctions in: (1) the caregiving burden and (2) the impact of caregiving on the physical and mental health of family caregivers of PWD. DESIGN: Systematic review. DATA SOURCES: Medline, Embase, PsycINFO and Cumulative Index to Nursing and Allied Health Literature between January 2007 and October 2019 were searched. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Included studies met the following criteria: (1) examine experiences and/or impacts of caregiving among family caregivers of individuals with any form of dementia; (2) report sex and/or gender distribution of study population and/or report results stratified by sex and/or gender, and (3) include both male and female family caregivers. DATA EXTRACTION AND SYNTHESIS: Two independent reviewers extracted the data and assessed risk of bias using the Critical Appraisal Skills Program checklist and National Institutes of Health Quality Assessment Tool for Observational Cohort and Cross-sectional Studies. Data were synthesized using a narrative synthesis approach. RESULTS: A total of 22 studies were included. Caregiving burden was measured using various methods. A majority of studies reported higher burden among females. All studies that did not report a sex and gender difference in caregiving burden accounted for confounders. Findings on sex and gender differences on physical and mental health conditions were inconsistent with most studies failing to account for confounders in their analyses. CONCLUSIONS: Current evidence on sex and gender differences in caregiving burden, mental and physical health is limited. Findings suggest presence of sex and gender differences in caregiving burden. Given the variety of mental and physical health constructs that were examined, further research is required to substantiate the evidence. PROPSERO Registration Number: CRD 42018070032.


Assuntos
Cuidadores/psicologia , Demência/patologia , Bases de Dados Factuais , Humanos , Saúde Mental , Qualidade de Vida , Autoimagem , Fatores Sexuais , Estresse Psicológico
9.
Neurobiol Aging ; 91: 36-44, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32311609

RESUMO

The hippocampus is one of the first regions to demonstrate atrophy during the prodromal stage of Alzheimer's disease. Volumetric analysis of its individual subfields could provide biomarkers with higher sensitivity than whole hippocampal volume during an earlier disease stage. We quantified the hippocampal subfields volume in a large cohort comprising healthy participants (aged 40-59) with dementia family history (FH) and controls (without FH), examined at 2 time points across 2 years. Subfield volumes were quantified using both a T1-weighted and a high-resolution T2 hippocampal magnetic resonance imaging acquisition with Freesurfer. The participants were stratified based on dementia FH, APOE genotype, and CAIDE (Cardiovascular Risk Factors, Aging and Dementia) risk score. Whole hippocampal volume did not differ between the groups. The volume of the molecular layer was lower in participants with an APOE ε4 genotype, but there were no differences between subjects with and without dementia FH or with an increasing CAIDE score. The molecular layer may be the first hippocampal region to demonstrate volumetric alterations in subjects at risk of dementia.


Assuntos
Envelhecimento/patologia , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/patologia , Demência/diagnóstico , Demência/patologia , Hipocampo/patologia , Adulto , Doença de Alzheimer/genética , Apolipoproteínas E/genética , Atrofia , Demência/genética , Imagem de Difusão por Ressonância Magnética , Escolaridade , Feminino , Genótipo , Hipocampo/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão , Risco
10.
Fortschr Neurol Psychiatr ; 88(4): 266-284, 2020 Apr.
Artigo em Alemão | MEDLINE | ID: mdl-32325519

RESUMO

According to the German S3 guideline dementia every patient with a dementia disorder should have a MRI. The goal is not only to uncover treatable conditions but also to detect region-specific atrophy pattern which are characteristic of primary dementia disorders such as Alzheimer's disease, fronto-temporal lobar degeneration and others. Diagnostic accuracy can be improved by Voxel- and Region-based volumetric analysis of the individual brain compared to age-matched controls.


Assuntos
Demência/diagnóstico por imagem , Doença de Alzheimer/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Demência/patologia , Demência/terapia , Degeneração Lobar Frontotemporal/diagnóstico por imagem , Alemanha , Humanos , Imagem por Ressonância Magnética , Guias de Prática Clínica como Assunto
11.
J Neurol Neurosurg Psychiatry ; 91(6): 586-592, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32332103

RESUMO

OBJECTIVE: To determine whether subjects with chronic traumatic encephalopathy (CTE) and dementia have distinct clinical features compared to subjects with pathologically confirmed Alzheimer's disease (AD). METHODS: Among 339 subjects assessed for CTE in the National Alzheimer's Coordinating Center dataset, 6 subjects with CTE and 25 subjects with AD neuropathologic change matched for age (±5 years) and sex were identified. All subjects had a clinical diagnosis of dementia. Neurological examination, neuropsychological testing and emotional/behavioural data were compared between CTE and AD subjects at the time of dementia diagnosis and last clinical visit near death. RESULTS: A history of traumatic brain injury with loss of consciousness (LOC) was reported in one CTE and one AD subject; information about injuries without LOC or multiple injuries was unavailable. CTE and AD subjects did not differ significantly at the time of diagnosis or last visit on the Unified Parkinson's Disease Rating Scale-Motor Exam, global measures of cognitive functioning (Mini-Mental State Exam and Clinical Dementia Rating Scale), emotional/behaviour symptoms as assessed with the Neuropsychiatric Inventory questionnaire or across neuropsychological measures. All CTE participants had co-occurring neuropathologic processes, including AD and most had TAR DNA-binding protein 43 (TDP-43) neuropathology. CONCLUSIONS: CTE pathology was rare in a large multicentre national dataset, and when present, was accompanied by AD and TDP-43 pathologies. CTE was not associated with a different clinical presentation from AD or with greater cognitive impairment or neurobehavioral symptoms. These findings suggest that CTE may not have a distinct clinical profile when other neuropathologic processes are coexistent with CTE pathology.


Assuntos
Encefalopatia Traumática Crônica/psicologia , Cognição/fisiologia , Demência/psicologia , Memória/fisiologia , Idoso , Idoso de 80 Anos ou mais , Encéfalo/patologia , Encefalopatia Traumática Crônica/diagnóstico , Encefalopatia Traumática Crônica/patologia , Demência/diagnóstico , Demência/patologia , Avaliação da Deficiência , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Índice de Gravidade de Doença
12.
Orv Hetil ; 161(18): 727-737, 2020 05 01.
Artigo em Húngaro | MEDLINE | ID: mdl-32338488

RESUMO

Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are two major neurodegenerative diseases sharing common clinical, pathophysiological and morphologic features. The pathological hallmark of both diseases is the presence of Lewy-bodies (LB). The main constituent of these inclusions is the pathologically aggregated α-synuclein protein. In DLB, LBs are predominantly located in the cortex, whereas in PDD, the subcortical regions are predominantly affected. Furthermore, in DLB, coexisting Alzheimer's disease (AD), pathology with ß-amyloid plaques and neurofibrillary tangles are more common. It is still debated whether DLB and PDD are two distinct entities or different phenotypes of the same disease. Clinical diagnosis is based on the temporal sequence of motor and cognitive symptoms. Dementia often precedes parkinsonism in DLB, while in PDD, cognitive decline generally appears after the onset of motor symptoms. Also, fluctuation of cognitive functions and neuroleptic sensitivity is more severe in DLB than PDD. The recent advancements of imaging techniques revealed that cortical damage, cholinergic deficit and concomitant AD pathology are more severe in DLB compared to PDD. The analysis of cerebrospinal fluid biomarkers shows higher oligomeric α-synuclein burden in PDD. Levodopa is less effective in DLB than in PDD and may increase the risk of psychosis. In this review, we comprehensively analyse the pathological, radiological and clinical features of DLB and PDD, highlighting the overlaps and differences. Orv Hetil. 2020; 161(18): 727-737.


Assuntos
Demência/patologia , Doença por Corpos de Lewy/patologia , Doença de Parkinson/patologia , Humanos
14.
Isr Med Assoc J ; 22(3): 178-184, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32147984

RESUMO

BACKGROUND: The authors reviewed the two most common current uses of brain 18F-labeled fluoro-2-deoxyglucose positron emission tomography (FDG-PET) at a large academic medical center. For epilepsy patients considering surgical management, FDG-PET can help localize epileptogenic lesions, discriminate between multiple or discordant EEG or MRI findings, and predict prognosis for post-surgical seizure control. In elderly patients with cognitive impairment, FDG-PET often demonstrates lobar-specific patterns of hypometabolism that suggest particular underlying neurodegenerative pathologies, such as Alzheimer's disease. FDG-PET of the brain can be a key diagnostic modality and contribute to improved patient care.


Assuntos
Encéfalo/diagnóstico por imagem , Demência/diagnóstico por imagem , Epilepsia/diagnóstico por imagem , Fluordesoxiglucose F18 , Tomografia por Emissão de Pósitrons/métodos , Encéfalo/patologia , Demência/patologia , Epilepsia/patologia , Humanos
15.
Sci Rep ; 10(1): 2924, 2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-32076055

RESUMO

Alzheimer disease (AD) is a chronic neurodegenerative disease with a multitude of contributing genetic factors, many of which are related to inflammation. The apolipoprotein E (APOE) ε4 allele is the most common genetic risk factor for AD and is related to a pro-inflammatory state. To test the hypothesis that microglia and AD-implicated cytokines were differentially associated with AD pathology based on the presence of APOE ε4, we examined the dorsolateral frontal cortex from deceased participants within a community-based aging cohort (n = 154). Cellular density of Iba1, a marker of microglia, was positively associated with tau pathology only in APOE ε4 positive participants (p = 0.001). The cytokines IL-10, IL-13, IL-4, and IL-1α were negatively associated with tau pathology, independent of Aß1-42 levels, only in APOE ε4 negative participants. Overall, the association of mostly anti-inflammatory cytokines with less tau pathology suggests a protective effect in APOE ε4 negative participants. These associations are largely absent in the presence of APOE ε4 where tau pathology was significantly associated with increased microglial cell density. Taken together, these results suggest that APOE ε4 mediates an altered inflammatory response and increased tau pathology independent of Aß1-42 pathology.


Assuntos
Apolipoproteína E4/genética , Encéfalo/patologia , Inflamação/genética , Inflamação/patologia , Idoso de 80 Anos ou mais , Alelos , Peptídeos beta-Amiloides/metabolismo , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Biomarcadores/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Contagem de Células , Estudos de Coortes , Citocinas/metabolismo , Demência/patologia , Feminino , Genótipo , Humanos , Masculino , Proteínas dos Microfilamentos/metabolismo , Microglia/metabolismo , Microglia/patologia , Modelos Biológicos , Proteínas tau/metabolismo
16.
Brain ; 143(2): 635-649, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-32040564

RESUMO

Age being the main risk factor for Alzheimer's disease, it is particularly challenging to disentangle structural changes related to normal brain ageing from those specific to Alzheimer's disease. Most studies aiming to make this distinction focused on older adults only and on a priori anatomical regions. Drawing on a large, multi-cohort dataset ranging from young adults (n = 468; age range 18-35 years), to older adults with intact cognition (n = 431; age range 55-90 years) and with Alzheimer's disease (n = 50 with late mild cognitive impairment and 71 with Alzheimer's dementia, age range 56-88 years), we investigated grey matter organization and volume differences in ageing and Alzheimer's disease. Using independent component analysis on all participants' structural MRI, we first derived morphometric networks and extracted grey matter volume in each network. We also derived a measure of whole-brain grey matter pattern organization by correlating grey matter volume in all networks across all participants from the same cohort. We used logistic regressions and receiver operating characteristic analyses to evaluate how well grey matter volume in each network and whole-brain pattern could discriminate between ageing and Alzheimer's disease. Because increased heterogeneity is often reported as one of the main features characterizing brain ageing, we also evaluated interindividual heterogeneity within morphometric networks and across the whole-brain organization in ageing and Alzheimer's disease. Finally, to investigate the clinical validity of the different grey matter features, we evaluated whether grey matter volume or whole-brain pattern was related to clinical progression in cognitively normal older adults. Ageing and Alzheimer's disease contributed additive effects on grey matter volume in nearly all networks, except frontal lobe networks, where differences in grey matter were more specific to ageing. While no networks specifically discriminated Alzheimer's disease from ageing, heterogeneity in grey matter volumes across morphometric networks and in the whole-brain grey matter pattern characterized individuals with cognitive impairments. Preservation of the whole-brain grey matter pattern was also related to lower risk of developing cognitive impairment, more so than grey matter volume. These results suggest both ageing and Alzheimer's disease involve widespread atrophy, but that the clinical expression of Alzheimer's disease is uniquely associated with disruption of morphometric organization.


Assuntos
Envelhecimento , Doença de Alzheimer/patologia , Encéfalo/patologia , Disfunção Cognitiva/patologia , Demência/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/patologia , Disfunção Cognitiva/metabolismo , Demência/complicações , Progressão da Doença , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
18.
J Clin Neurosci ; 72: 482-484, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31937505

RESUMO

Autosomal dominant amyloid precursor protein (APP) mutations in familial Alzheimer's disease accelerate the amyloid beta (Aß) pathology. Here we describe Japanese siblings with a new N-terminal mutation (a heterogeneous c.674T>C, p.Val225Ala) of the APP gene, developing a progressive dementia at 57 years and Aß and tau pathologies in cerebrospinal fluid studies. However, the brother and sister showed different clinical and neuroimaging features, suggesting different Aß pathologies for each sibling.


Assuntos
Precursor de Proteína beta-Amiloide/genética , Demência/genética , Demência/patologia , Mutação , Doença de Alzheimer , Peptídeos beta-Amiloides/metabolismo , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Neuroimagem , Irmãos , Proteínas tau/metabolismo
19.
PLoS One ; 15(1): e0227471, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31978127

RESUMO

BACKGROUND: Delirium is a common and serious acute neuropsychiatric syndrome which is often missed in routine clinical care. Inattention is the core cognitive feature. Diagnostic test accuracy (including cut-points) of a smartphone Delirium App (DelApp) for assessing attention deficits was assessed in older hospital inpatients. METHODS: This was a case-control study of hospitalised patients aged ≥65 years with delirium (with or without pre-existing cognitive impairment), who were compared to patients with dementia without delirium, and patients without cognitive impairment. Reference standard delirium assessment, which included a neuropsychological test battery, was based on Diagnostic and Statistical Manual of Mental Disorders-5 criteria. A separate blinded assessor administered the DelApp arousal assessment (score 0-4) and attention task (0-6) yielding an overall score of 0 to 10 (lower scores indicate poorer performance). Analyses included receiver operating characteristic curves and sensitivity and specificity. Optimal cut-points for delirium detection were determined using Youden's index. RESULTS: A total of 187 patients were recruited, mean age 83.8 (range 67-98) years, 152 (81%) women; n = 61 with delirium; n = 61 with dementia without delirium; and n = 65 without cognitive impairment. Patients with delirium performed poorly on the DelApp (median score = 4/10; inter-quartile range 3.0, 5.5) compared to patients with dementia (9.0; 5.5, 10.0) and those without cognitive impairment (10.0; 10.0, 10.0). Area under the curve for detecting delirium was 0.89 (95% Confidence Interval 0.84, 0.94). At an optimal cut-point of ≤8, sensitivity was 91.7% (84.7%, 98.7%) and specificity 74.2% (66.5%, 81.9%) for discriminating delirium from the other groups. Specificity was 68.3% (56.6%, 80.1%) for discriminating delirium from dementia (cut-point ≤6). CONCLUSION: Patients with delirium (with or without pre-existing cognitive impairment) perform poorly on the DelApp compared to patients with dementia and those without cognitive impairment. A cut-point of ≤8/10 is suggested as having optimal sensitivity and specificity. The DelApp is a promising tool for assessment of attention deficits associated with delirium in older hospitalised adults, many of whom have prior cognitive impairment, and should be further validated in representative patient cohorts.


Assuntos
Delírio/diagnóstico , Aplicativos Móveis , Testes Neuropsicológicos , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Estudos de Casos e Controles , Disfunção Cognitiva/complicações , Disfunção Cognitiva/patologia , Delírio/complicações , Demência/complicações , Demência/patologia , Feminino , Hospitalização , Humanos , Masculino , Curva ROC , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Smartphone
20.
J Neuropathol Exp Neurol ; 79(2): 144-162, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31851313

RESUMO

The neuropathology associated with cognitive decline in military personnel exposed to traumatic brain injury (TBI) and chronic stress is incompletely understood. Few studies have examined clinicopathologic correlations between phosphorylated-tau neurofibrillary tangles, ß-amyloid neuritic plaques, neuroinflammation, or white matter (WM) lesions, and neuropsychiatric disorders in veterans. We describe clinicopathologic findings in 4 military veterans with early-onset dementia (EOD) who had varying histories of blunt- and blast-TBI, cognitive decline, behavioral abnormalities, post-traumatic stress disorder, suicidal ideation, and suicide. We found that pathologic lesions in these military-EOD cases could not be categorized as classic Alzheimer's disease (AD), chronic traumatic encephalopathy, traumatic axonal injury, or other well-characterized clinicopathologic entities. Rather, we observed a mixture of polypathology with unusual patterns compared with pathologies found in AD or other dementias. Also, ultrahigh resolution ex vivo MRI in 2 of these 4 brains revealed unusual patterns of periventricular WM injury. These findings suggest that military-EOD cases are associated with atypical combinations of brain lesions and distribution rarely seen in nonmilitary populations. Future prospective studies that acquire neuropsychiatric data before and after deployments, as well as genetic and environmental exposure data, are needed to further elucidate clinicopathologic correlations in military-EOD.


Assuntos
Encéfalo/patologia , Demência/patologia , Idade de Início , Idoso , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/patologia , Demência/complicações , Humanos , Glicoproteínas de Membrana , Pessoa de Meia-Idade , Placa Amiloide/complicações , Placa Amiloide/patologia , Receptores de Interleucina-1 , Veteranos
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