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INTRODUCTION: Subjective cognitive decline (SCD) in amyloid-positive (Aß+) individuals was proposed as a clinical indicator of Stage 2 in the Alzheimer's disease (AD) continuum, but this requires further validation across cultures, measures, and recruitment strategies. METHODS: Eight hundred twenty-one participants from SILCODE and DELCODE cohorts, including normal controls (NC) and individuals with SCD recruited from the community or from memory clinics, underwent neuropsychological assessments over up to 6 years. Amyloid positivity was derived from positron emission tomography or plasma biomarkers. Global cognitive change was analyzed using linear mixed-effects models. RESULTS: In the combined and stratified cohorts, Aß+ participants with SCD showed steeper cognitive decline or diminished practice effects compared with NC or Aß- participants with SCD. These findings were confirmed using different operationalizations of SCD and amyloid positivity, and across different SCD recruitment settings. DISCUSSION: Aß+ individuals with SCD in German and Chinese populations showed greater global cognitive decline and could be targeted for interventional trials. HIGHLIGHTS: SCD in amyloid-positive (Aß+) participants predicts a steeper cognitive decline. This finding does not rely on specific SCD or amyloid operationalization. This finding is not specific to SCD patients recruited from memory clinics. This finding is valid in both German and Chinese populations. Aß+ older adults with SCD could be a target population for interventional trials.
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AIMS: Focal cortical dysplasia (FCD) is a major cause of drug-resistant paediatric epilepsy and is amenable to successful neurosurgical resection. FCD ILAE Type IIb is the most common FCD subtype, and brain somatic mutations affecting the mTOR pathway play a major pathogenic role. The aim of this study was to comprehensively describe the genotype-phenotype association of 20 patients with histopathologically confirmed FCDIIb using next generation sequencing (NGS) of paired blood-brain samples. METHODS: Clinical and neuropathological data were retrospectively reviewed from the hospital archive. The NGS panel included 11 mTOR-pathway-related genes with maximum coverage of 2000×. The detected variants were validated by digital droplet PCR. RESULTS: Pathogenic MTOR variants were identified in 10 patients (50%). Further comparison with MTOR-wildtype FCDIIb suggested a profound genotype-phenotype association characterised by (1) a non-temporal lobe lesion on MRI, (2) a larger lesion volume occupying grey and white matter (3.032 ± 1.859 cm3 vs 1.110 ± 0.856 cm3 , p = 0.014), (3) more balloon cells (50.20 ± 14.40 BC/mm2 vs 31.64 ± 30.56 BC/mm2 , p = 0.099) and dysmorphic neurons (48.72 ± 19.47DN/mm2 vs 15.28 ± 13.95DN/mm2 , p = 0.000) and (4) a positive correlation between VAF and the lesion volume (r = 0.802, p = 0.017). CONCLUSIONS: Our study identified frequent MTOR mutations in the cell-rich FCDIIb phenotype, clinically characterised by a non-temporal location and large lesion volume. Comprehensive genotype-phenotype associations will help us further explore and define the broad spectrum of FCD lesions to make more targeted therapies available in the realm of epileptology.
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Epilepsia , Displasia Cortical Focal , Malformações do Desenvolvimento Cortical , Humanos , Mosaicismo , Estudos Retrospectivos , Malformações do Desenvolvimento Cortical/genética , Epilepsia/patologia , Serina-Treonina Quinases TOR/metabolismoRESUMO
BACKGROUND: Abnormal activation of immune system is an important pathogenesis of Parkinson's disease, but the relationship between peripheral inflammation, central microglia activation and dopaminergic degeneration remains unclear. OBJECTIVES: To evaluate the brain regional microglia activation and its relationship with clinical severity, dopaminergic presynaptic function, and peripheral inflammatory biomarkers related to adaptive immunity. METHODS: In this case-control study, we recruited 23 healthy participants and 24 participants with early-stage Parkinson's disease. 18F-PBR06 PET/MR for microglia activation, 18F-FP-DTBZ for dopaminergic denervation, total account of T cells and subpopulations of T helper (Th1/Th2/Th17) cells, and the levels of serum inflammatory cytokines were assessed. Sanger sequencing was used to exclude the mix-affinity binders of 18F-PBR06-PET. RESULTS: Compared to healthy controls, patients with Parkinson's disease had an increased 18F-PBR06-PET standardized uptake value ratio (SUVR) in the putamen, particularly in the ipsilateral side of the motor onset. 18F-PBR06-PET SUVR was positively associated with 18F-FP-DTBZ-PET SUVR in the brainstem and not associated with disease severity measured by Hoehn and Yahr stage, MDS-UPDRS III scores. Patients with Parkinson's disease had elevated frequencies of Th1 cells and serum levels of IL10 and IL17A as compared to healthy controls. No significant association between peripheral inflammation markers and microglia activation in the brain of PD was observed. CONCLUSION: Parkinson's disease is associated with early putaminal microglial activation and peripheral phenotypic Th1 bias. Peripheral adaptive immunity might be involved in microglia activation in the process of neurodegeneration in PD indirectly, which may be a potential biomarker for the early detection and the target for immunomodulating therapy.
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Doença de Parkinson , Imunidade Adaptativa , Encéfalo/patologia , Estudos de Casos e Controles , Dopamina , Humanos , Inflamação , Microglia/patologia , Doença de Parkinson/patologia , Tomografia por Emissão de PósitronsRESUMO
BACKGROUND: Hypomethylation of intron 1 of the α-synuclein (SNCA) gene has been extensively reported in the blood of patients with α-synucleinopathies. Idiopathic rapid eye movement sleep behavior disorder represents a prodromal stage of α-synucleinopathies. Methylation of α-synuclein intron 1 in idiopathic rapid eye movement sleep behavior disorder patients is largely unexplored. The objective of the current study was to assess blood α-synuclein intron 1 methylation in patients and to explore it as a potential biomarker to predict phenoconversion and monitor disease progression. METHODS: Seventy-eight polysomnography-confirmed patients and 74 healthy controls were enrolled. After an average of 3.75 years of follow up, 16 patients converted to neurodegenerative diseases (converters), whereas 59 did not (nonconverters). Blood DNA was obtained at baseline from all participants, as well as at the follow-up visit for 27 patients. DNA methylation levels were determined using bisulfite pyrosequencing methods and were compared between patients and healthy controls, converters and nonconverters, and baseline and follow-up visits. RESULTS: Hypomethylation at cytosine-phosphate-guanine 10, 11, 12, 13, and 17 was found in patients compared with healthy controls. Hypomethylation at cytosine-phosphate-guanine 17 was associated with an increased risk of clinical phenoconversion, which was further enhanced with the presence of subtle motor abnormalities. In addition, it appeared that later reduction in methylation levels at cytosine-phosphate-guanine 14, 15, and 16 was associated with disease progression. CONCLUSIONS: Peripheral blood α-synuclein intron 1 was hypomethylated in idiopathic rapid eye movement sleep behavior disorder patients. α-Synuclein methylation levels may be useful biomarkers to screen patients, predict phenoconversion, and monitor disease progression. © 2020 International Parkinson and Movement Disorder Society.
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Transtorno do Comportamento do Sono REM , Sinucleinopatias , Metilação de DNA/genética , Humanos , Sintomas Prodrômicos , Transtorno do Comportamento do Sono REM/genética , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismoRESUMO
We investigated the relationship between urinary Alzheimer-associated neuronal thread protein (AD7c-NTP) levels and apolipoprotein epsilon 4 (ApoE É4) alleles, as well as other factors that cause cognitive decline, in the cognitively normal population. We recruited 329 cognitively normal right-handed Han Chinese subjects who completed ApoE gene testing and urinary AD7c-NTP testing. There was no significant difference in urinary AD7c-NTP levels between the normal control and subjective cognitive decline groups. Urinary AD7c-NTP levels were significantly higher in subjects with ApoE É3/4 and 4/4 [0.6074 (0.6541) ng/mL] than in subjects without ApoE É4 [0.4368 (0.3392) ng/mL and 0.5287 (0.3656) ng/mL], and urinary AD7c-NTP levels positively correlated with ApoE genotype grade (r = 0.165, p = 0.003). There were significant differences in urinary AD7c-NTP levels between subjects with and without a history of coronary heart disease or diabetes. Urinary AD7c-NTP levels were not related to years of education, nature of work, family history of dementia, a history of hypertension, stroke, anemia, or thyroid dysfunction. Urinary AD7c-NTP levels were positively correlated with ApoE grade in the cognitively normal population. The relationship between risk factors of cognitive decline and urinary AD7c-NTP levels provides a new way for us to understand AD and urinary AD7c-NTP.
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Alelos , Apolipoproteína E4/genética , Cognição/fisiologia , Proteínas do Tecido Nervoso/urina , Idoso , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Testes NeuropsicológicosRESUMO
Introduction: Mitochondrial DNA polymerase gamma (pol γ) encoded by POLG plays an indispensable role in the process of mitochondrial DNA replication and repair. The mutation of POLG can result in mitochondrial dysfunction leading to a broad spectrum of disease.Methods: We report a 29-year-old Chinese female presented with levodopa-responsive parkinsonism, external ophthalmoplegia and optic atrophy. We conducted clinical, molecular iconographic, histological and genetic analyses on this patient.Results: Sequencing of the POLG gene revealed compound heterozygote mutations of a novel c.2693T > C (p.I898T) mutation in exon17 and c.2993C > T (p.S998L) in exon19. The mutation c.2693T > C (p.I898T) has never been reported. Also our patient's cardinal symptoms are rare and different from other cases which have been reported.Conclusion: This finding of ours has broadened the spectrum of phenotype caused by the mutation of POLG.
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DNA Polimerase gama/genética , Oftalmoplegia Externa Progressiva Crônica/genética , Atrofia Óptica/genética , Transtornos Parkinsonianos/genética , Adulto , Idade de Início , Feminino , Humanos , Mutação de Sentido Incorreto , Atrofia Óptica/patologia , FenótipoRESUMO
It has been recently reported that mutations in SLC20A2 gene are a major cause of primary familial brain calcifications, a rare neurodegenerative disorder characterized by symmetrical and bilateral intracranial calcification. We conducted a pedigree study by performing next Generation Sequencing in a Chinese family with three generations. Three members in this family developed Parkinsonism in their sixth decade, also, the proband presented with schizophrenia for 40 years. Next Generation Sequencing identified a novel nonsense heterozygous substitution c.1158C > A (p.Thr 386*) of SLC20A2 gene, introducing a stop codon in exon 10. The mutation was present in symptomatic and asymptomatic individuals with intracranial calcification, but absent in the individual without calcification, suggesting the mutation segregates with brain calcification. mRNA expression was decreased by 35% in the proband. We are the first to demonstrate a novel c.1158C > A mutation of SLC20A2 gene in a Chinese family with primary familial brain calcifications.
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Encefalopatias/genética , Calcinose/genética , Saúde da Família , Mutação/genética , Proteínas Cotransportadoras de Sódio-Fosfato Tipo III/genética , Adulto , Idoso , Povo Asiático , Encefalopatias/complicações , Encefalopatias/diagnóstico por imagem , Calcinose/complicações , Calcinose/diagnóstico por imagem , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Tomografia Computadorizada por Raios XRESUMO
The Cardiovascular and Cognitive Health Study (CCHS-Beijing) is a population-based study of cardiovascular disease (CVD) and cognitive impairment in adults aged 55 and older in Beijing. The main aims of the study are to investigate the prevalence rates of CVD, asymptomatic atherosclerosis, and cognitive impairment, as well as validate the risk factors related to the onset and development of CVD, Alzheimer's disease (AD) and mild cognitive impairment (MCI). The study was designed to detect the traditional and new risk factors in this age group. Participants were recruited randomly from residential regions in the greater Beijing municipality area based on the average levels of development in Beijing, China in 2012 (based on socioeconomic, demographic, and geographical characteristics). Thorough physical and laboratory examination were performed at baseline (also the cross-sectional survey) to identify the risk factors such as hypertension, dyslipidemia, diabetes, as well as newly defined risk factors like elevated homocysteine, high sensitivity C-reactive protein, and urine micro-albumin. Subclinical disease of the cerebral vasculature included atherosclerosis of carotid arteries, intracranial arteries, and retinal vessels. Subclinical cardiac diseases included left ventricular enlargement, arrhythmias, chamber hypertrophy and myocardial ischemia. Blood pressure was documented using the ankle-arm method. In addition, neuropsychological assessments were performed for all subjects aged 65 and above. Baseline evaluation began during the period August 2013 to December 2014. Follow-up examination will occur in 5 years. The initial and recurrent CVD, AD and MCI events will be verified and validated during the follow-up period.
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Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/epidemiologia , Projetos de Pesquisa Epidemiológica , Nível de Saúde , Idoso , Pequim/epidemiologia , Doenças Cardiovasculares/metabolismo , Transtornos Cognitivos/metabolismo , Estudos de Coortes , Estudos Transversais , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Distribuição AleatóriaRESUMO
2,2,2-Trichloroethanol (TCOH) is responsible for the pharmacological actions of chloral hydrate (CH), and is a major metabolite of trichloroethylene. Human exposure to TCOH is known to be increasing. Recently, it was reported that TCOH causes a significant phase delay of Per2 expression in mouse liver when injected daily over the course of several days. However, it is not clear whether TCOH directly modulates the molecular clock. In the present study we used a cell-based assay system to test this possibility. We found that the daily oscillation period of Bmal1 was lengthened to 3 h following treatment with 1.5 mM TCOH, and increased to 5 h with 3 mM TCOH treatment. However, low concentrations of TCOH had no noticeable effects. The effect of TCOH on Per2 oscillation was marginal. Interestingly, serum from rats anesthetized with CH also modulated Bmal1 period, suggesting that exposure to anesthesia should be taken into consideration for circadian rhythm studies. In summary, our study reveals a direct regulation of TCOH on molecular clock.
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Fatores de Transcrição ARNTL/genética , Ritmo Circadiano/efeitos dos fármacos , Ritmo Circadiano/genética , Etilenocloroidrina/análogos & derivados , Animais , Proteínas CLOCK/genética , Linhagem Celular , Hidrato de Cloral/farmacologia , Hidrato de Cloral/toxicidade , Etilenocloroidrina/farmacologia , Etilenocloroidrina/toxicidade , Humanos , Hipnóticos e Sedativos/farmacologia , Hipnóticos e Sedativos/toxicidade , Medições Luminescentes , Masculino , Camundongos , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/genética , Proteínas Circadianas Period/genética , Ratos , Ratos Endogâmicos F344RESUMO
Neural progenitor cells (NPCs) derived from mouse embryonic stem (mES) cells can lead to tumors after transplantation. The cellular source of such tumors remains under debate. We investigated the tumor formation resulting from mES cell-derived NPCs in a rat stroke model and in nude mice. After 2 hr of ischemia and 48 hr of reperfusion, the NPCs were transplanted into the ischemic core of the xenogeneic rats. Four weeks after transplantation, the grafted cells were found to be viable at the border of the necrosis and had differentiated into neurons. Transplanted rats did not exhibit any behavioral improvement, because tumor formed in 90% of the animals. Immunosuppression facilitated tumor formation. Tumors were observed in 40% of normal rats after NPC transplantation when cyclosporin A was administered. Meanwhile, no tumor formation was observed without cyclosporin A. Ischemic damage also facilitated tumor formation, because NPCs gave rise to tumors in 90% of ischemic rats, a percentage significantly higher than that in intact rats, which was 40%. The SSEA-1-positive cells isolated from stage 4 are not exactly undifferentiated ES cells. They exhibited a marker gene transcription profile different from that of ES cells and did not form tumors in transplanted nude mice. The undifferentiated ES cells remaining after differentiation did not contribute to tumors either. First, the tumor formation rate resulting from undifferentiated ES cells in the brains of normal rats is 0%, significantly lower than that of NPCs. Second, transplanted NPCs that led to 100% tumors in nude mice contained approximately 1.5 × 10(3) Oct-4-positive cells; however, even 5 × 10(5) undifferentiated ES cells formed neoplasm only in 40% nude mice.
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Isquemia Encefálica/patologia , Neoplasias Encefálicas/patologia , Células-Tronco Embrionárias/transplante , Terapia de Imunossupressão , Antígenos CD15/metabolismo , Células-Tronco Neurais/transplante , Animais , Isquemia Encefálica/metabolismo , Neoplasias Encefálicas/metabolismo , Contagem de Células , Diferenciação Celular , Células-Tronco Embrionárias/metabolismo , Células-Tronco Embrionárias/patologia , Masculino , Camundongos , Camundongos Nus , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/patologia , Ratos , Ratos Wistar , Transplante de Células-Tronco/métodosRESUMO
Background: Gait disturbance is a vital characteristic of motor manifestation in α- synucleinopathies, especially Parkinson's disease. Subtle gait alterations are present in isolated rapid eye movement sleep behavior disorder (iRBD) patients before phenoconversion; it is yet unclear, if gait analysis may predict phenoconversion. Objective: To investigate subtle gait alterations and explore whether gait analysis using wearable sensors is associated with phenoconversion of iRBD to α-synucleinopathies. Methods: Thirty-one polysomnography-confirmed iRBD patients and 33 healthy controls (HCs) were enrolled at baseline. All participants walked for a minute while wearing 6 inertial sensors on bilateral wrists, ankles, and the trunk (sternal and lumbar region). Three conditions were tested: (i) normal walking, (ii) fast walking, and (iii) dual-task walking. Results: Decreased arm range of motion and increased gait variation (stride length, stride time and stride velocity) discriminate converters from HCs at baseline. After an average of 5.40 years of follow-up, 10 patients converted to neurodegenerative diseases (converters). Cox regression analysis showed higher value of stride length asymmetry under normal walking condition to be associated with an early conversion of iRBD to α- synucleinopathies (adjusted HR 4.468, 95% CI 1.088- 18.349, pâ=â0.038). Conclusions: Stride length asymmetry is associated with progression to α- synucleinopathies in patients with iRBD. Gait analysis with wearable sensors may be useful for screening, monitoring, and risk stratification for disease-modifying therapy trials in patients with iRBD.
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Análise da Marcha , Polissonografia , Transtorno do Comportamento do Sono REM , Dispositivos Eletrônicos Vestíveis , Humanos , Transtorno do Comportamento do Sono REM/fisiopatologia , Transtorno do Comportamento do Sono REM/diagnóstico , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Análise da Marcha/instrumentação , Sinucleinopatias/fisiopatologia , Sinucleinopatias/diagnóstico , Progressão da Doença , Doença de Parkinson/fisiopatologia , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico , Transtornos Neurológicos da Marcha/fisiopatologia , Transtornos Neurológicos da Marcha/etiologia , Transtornos Neurológicos da Marcha/diagnósticoRESUMO
BACKGROUND: Cognitive impairment is common in patients with Parkinson's disease (PD) and occurs through multiple mechanisms, including Alzheimer's disease (AD) pathology and the involvement of α-synucleinopathies. We aimed to investigate the pathological biomarkers of both PD and AD in plasma and neuronal extracellular vesicles (EVs) and their association with different types of cognitive impairment in PD patients. METHODS: A total of 122 patients with PD and 30 healthy controls were included in this cross-sectional cohort study between March 2021 and July 2023. Non-dementia PD patients were divided into amnestic and non-amnestic groups according to the memory domain of a neuropsychological assessment. Plasma and neuronal EV biomarkers, including α-synuclein (α-syn), beta-amyloid (Aß), total tau (T-tau), phosphorylated tau181 (p-tau181), and glial fibrillary acidic protein (GFAP), were measured using a single-molecule array and a chemiluminescence immunoassay, respectively. RESULTS: Neuronal EV but not plasma α-syn levels, were significantly increased in PD as compared to healthy controls, and they were positively associated with UPDRS part III scores and the severity of cognitive impairment. A lower plasma Aß42 level and higher neuronal EV T-tau level were found in the amnestic PD group compared to the non-amnestic PD group. CONCLUSIONS: The results of the current study demonstrate that neuronal EV α-syn levels can be a sensitive biomarker for assisting in the diagnosis and disease severity prediction of PD. Both AD and PD pathologies are important factors in cognitive impairment associated with PD, and AD pathologies are more involved in amnestic memory deficit in PD.
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BACKGROUND: Growing evidence shows that the expression of brain-derived neurotrophic factor (BDNF) is altered in the peripheral blood of participants with Alzheimer's disease (AD). It is unclear, however, whether altered BDNF expression is also observed in the early stages of AD. METHODS: In the present study, 138 normal controls (NC), 57 participants with subjective cognitive decline (SCD), and 37 participants with amnestic mild cognitive impairment (aMCI) and AD were included. Plasma BDNF protein levels were assessed using a commercial multiplex Luminex-based kit. Patient samples were also probed for the presence of BDNF gene variant rs6265. RESULTS: Pairwise comparisons between the groups showed that there was not a significant difference in BDNF levels when comparing SCD with NC and when comparing SCD with aMCI/AD, but BDNF levels in aMCI/AD samples were increased when compared with NC samples. For models differentiating clinical groups, discriminant analysis was performed by including education, APOE genotype, and BDNF levels in the model. This approach distinguishes participants with SCD (AUC = 0.630) and aMCI/AD (AUC = 0.665) from NC. CONCLUSION: Our results suggest that expression of BDNF in plasma is altered at the clinical stage of AD.
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Doença de Alzheimer , Disfunção Cognitiva , Humanos , Fator Neurotrófico Derivado do Encéfalo/genética , Estudos Transversais , Doença de Alzheimer/genética , Disfunção Cognitiva/genética , GenótipoRESUMO
Background: Alzheimer's disease (AD) is the most common form of dementia in older adults. There is accumulating evidence that inflammatory processes play a critical role in AD pathogenesis. In this study, we investigated whether inflammatory factors in plasma and astrocyte-derived exosomes (ADEs) from plasma are differentially expressed in the early stages of AD and their potential role in pathological processes in the AD continuum. Method: We included 39 normal controls (NCs), 43 participants with subjective cognitive decline (SCD), and 43 participants with amnestic mild cognitive impairment (aMCI)/AD. IL-6, IL-8, and MCP-1 in plasma and ADEs from plasma were evaluated using a commercial multiplex Luminex-based kit. Results: Pairwise comparisons between the groups showed no significant differences in plasma levels of IL-6, IL-8, or MCP-1. However, ADEs in the SCD group showed an increase in MCP-1 levels compared to the NC group. To differentiate the preclinical group, discriminant analysis was performed using sex, age, years of education, and genotype. This revealed a difference between the SCD and NC groups (area under the curve: 0.664). A Spearman correlation analysis of MCP-1 in plasma and ADEs showed no or weak correlation in the SCD (R = 0.150, p = 0.350) and aMCI/AD (R = 0.310, p = 0.041) groups, while a positive correlation in the NC group (R = 0.360, p = 0.026). Conclusion: Plasma IL-6, IL-8, and MCP-1 levels were not significantly different. However, the concentration of MCP-1 in ADEs is slightly altered during the preclinical phase of AD, which could be a potential role of the central neuron system (CNS) immune response in the AD continuum. Clinical trial registration: www.ClinicalTrials.gov, identifier: NCT03370744.
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BACKGROUND: Several studies have examined NCAPH2 methylation in amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD), but little is known of NCAPH2 methylation in subjective cognitive decline (SCD). OBJECTIVE: To examine whether methylation of peripheral NCAPH2 are differentially changed at various phases of AD, and whether it could serve as a diagnostic biomarker for SCD. METHODS: A total of 40 AD patients, 52 aMCI patients, 148 SCD patients, and 193 cognitively normal controls (NCs) were recruited in the current case-control study. Besides, 54 cognitively normal individuals have received amyloid positron emission tomography (amyloid PET) scans. Using bisulfite pyrosequencing method, we measured blood DNA methylation in the NCAPH2 gene promoter. RESULTS: The main outcomes were: 1) For SCD, there was no significant difference between SCD and NC regarding NCAPH2 methylation; 2) For aMCI, NCAPH2 methylation at CpG2 were significantly lower in aMCI compared with NC and SCD in the entire population and male subgroup; 3) For AD, NCAPH2 methylation at CpG1 were significantly lower in AD compared with NC among females; 4) A relationship with apolipoprotein E (APOE) É4 status was shown. Receiver operating characteristic (ROC) analysis by combining NCAPH2 methylation, age, education, and APOEÉ4 status could distinguish between patients with aMCI (area under the curve (AUC): 0.742) and AD (AUC: 0.873) from NCs. CONCLUSION: NCAPH2 methylation levels were altered at the aMCI and AD stage and may be convenient and cost-effective biomarkers of AD and aMCI.
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Doença de Alzheimer , Disfunção Cognitiva , Feminino , Humanos , Masculino , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Estudos de Casos e Controles , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/genética , Estudos Transversais , Metilação de DNA/genéticaRESUMO
Emerging evidence indicates that circRNA can regulate various diseases. However, the mechanisms of circRNA in these diseases have not been fully understood. Therefore, detecting potential circRNA-disease associations has far-reaching significance for pathological development and treatment of these diseases. In recent years, deep learning models are used in association analysis of circRNA-disease, but a lack of circRNA-disease association data limits further improvement. Therefore, there is an urgent need to mine more semantic information from data. In this paper, we propose a novel method called Semantic Association Analysis by Embedding and Deep learning (SAAED), which consists of two parts, a neural network embedding model called Entity Relation Network (ERN) and a Pseudo-Siamese network (PSN) for analysis. ERN can fuse multiple sources of data and express the information with low-dimensional embedding vectors. PSN can extract the feature between circRNA and disease for the association analysis. CircRNA-disease, circRNA-miRNA, disease-gene, disease-miRNA, disease-lncRNA, and disease-drug association information are used in this paper. More association data can be introduced for analysis without restriction. Based on the CircR2Disease benchmark dataset for evaluation, a fivefold cross-validation experiment showed an AUC of 98.92%, an accuracy of 95.39%, and a sensitivity of 93.06%. Compared with other state-of-the-art models, SAAED achieves the best overall performance. SAAED can expand the expression of the biological related information and is an efficient method for predicting potential circRNA-disease association.
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Introduction: Fatigue is one of the most common and disabling symptoms of Parkinson's Disease (PD). The occurrence and clinical features of fatigue in patients with prodromal PD remain largely elusive. This study aimed to investigate the prevalence and clinical characteristics of fatigue in patients with idiopathic/isolated REM sleep behavior disorders (iRBD). Methods: A total of 97 polysomnography-confirmed iRBD patients were enrolled in this study. A comprehensive neurological assessment (including motor and non-motor assessment) was performed. Fatigue was assessed using the Fatigue Severity Scale (FSS). Motor and non-motor characteristics were compared between iRBD patients with and without fatigue. Logistic regression was used to identify the factors associated with fatigue. Results: The prevalence of fatigue was 35.05%. Compared to the non-fatigue patients, patients with fatigue had higher non-motor symptom scale (NMSS) score (p = 0.009), higher Hamilton Depression Rating Scale (HAMD) score (p = 0.002), and a higher prevalence of orthostatic hypotension (p = 0.021). Multivariate regression analysis showed that depression (OR 4.17, 95% CI 1.13−15.49, p = 0.033) and orthostatic hypotension (OR 2.80, 95% CI 1.09−7.18, p = 0.032) were significantly associated with fatigue in iRBD patients. Additionally, both NMSS (rs = 0.310, p = 0.002) and HAMD (rs = 0.385, p < 0.001) scores were mildly correlated with fatigue severity. Conclusion: Our study showed that fatigue is common in patients with iRBD. In addition, depression and orthostatic hypotension were independently associated with fatigue in iRBD patients.
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OBJECTIVE: Blood-based biomarkers for the early diagnosis of Alzheimer's disease (AD) are a 'Holy Grail' of AD research. Growing evidence shows that levels of apolipoproteins and various inflammation-related factors are altered in the peripheral blood of patients with AD. The purpose of this study was to clear and definite whether these biomarkers are differentially expressed at the early stages of AD, and could be a biomarker as an early diagnosis of the disease. DESIGN: Observation study. SETTING: This study was a part of the Sino Longitudinal Study on Cognitive Decline, an ongoing prospective cohort study (ClinicalTrials.gov identifier: NCT03370744) that centres on Xuanwu Hospital (Beijing, China) in cooperation with an alliance of 94 hospitals from 50 cities across China. PARTICIPANTS: In the present study, 416 right-handed Chinese Han subjects were recruited through standardised public advertisements from 2014 to 2019. OUTCOME MEASURES: Concentrations of plasma apolipoprotein A1, apolipoprotein CIII (ApoCIII), apolipoprotein E (ApoE), A-2-macroglobulin (A2M), complement C3 (C3) and complement factor H (FH) were determined using a commercial multiplex Luminex-based panel in normal controls (NC), subjective cognitive decline (SCD), mild cognitive impairment and AD groups. RESULTS: For individual analysis, pairwise comparisons showed that: (1) For SCD versus NC, no biomarker showed significant difference; (2) For amnestic mild cognitive impairment (aMCI) versus NC, levels of ApoCIII, ApoE, A2M, C3 and FH increased significantly; and (3) For AD versus NC, amounts of C3 increased. For models differentiating clinical groups, discriminant analysis was performed by including all protein markers, age, sex, genotype and education level in the model. This approach could distinguish between patients with aMCI (area under the curve (AUC): 0.743) and AD (AUC: 0.837) from NC. CONCLUSION: Our results suggest that concentrations of certain apolipoproteins and inflammation-related factors are altered at the early stage of AD, and could be useful biomarkers for early diagnosis. TRIAL REGISTRATION NUMBER: NCT03370744.
Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Doença de Alzheimer/psicologia , Apolipoproteínas E/genética , Biomarcadores , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/psicologia , Estudos Transversais , Humanos , Inflamação , Testes Neuropsicológicos , Estudos ProspectivosRESUMO
BACKGROUND: Plasma amyloid-ß (Aß) may facilitate identification of individuals with brain amyloidosis. Gut microbial dysbiosis in Alzheimer's disease (AD) is increasingly being recognized. However, knowledge about alterations of gut microbiota in preclinical AD, as well as whether the combination of plasma Aß and gut microbiota could identify preclinical AD, remains largely unknown. METHODS: This study recruited 34 Aß-negative cognitively normal (CN-) participants, 32 Aß-positive cognitively normal (CN+) participants, and 22 patients with cognitive impairment (CI), including 11 patients with mild cognitive impairment (MCI) and 11 AD dementia patients. All participants underwent neuropsychological assessments and fecal microbiota analysis through 16S ribosomal RNA (rRNA) Illumina Miseq sequencing technique. Meso Scale Discovery (MSD) kits were used to quantify the plasma Aß40, Aß42, and Aß42/Aß40 in CN- and CN+ participants. Using Spearman's correlation analysis, the associations of global standard uptake value rate (SUVR) with altered gut microbiota and plasma Aß markers were separately evaluated. Furthermore, the discriminative power of the combination of gut microbiota and plasma Aß markers for identifying CN+ individuals was investigated. RESULTS: Compared with the CN- group, the CN+ group showed significantly reduced plasma Aß42 (p = 0.011) and Aß42/Aß40 (p = 0.003). The relative abundance of phylum Bacteroidetes was significantly enriched, whereas phylum Firmicutes and class Deltaproteobacteria were significantly decreased in CN+ individuals in comparison with that in CN- individuals. Particularly, the relative abundance of phylum Firmicutes and its corresponding SCFA-producing bacteria exhibited a progressive decline tendency from CN- to CN+ and CI. Besides, the global brain Aß burden was negatively associated with the plasma Aß42/Aß40 (r = -0.298, p = 0.015), family Desulfovibrionaceae (r = -0.331, p = 0.007), genus Bilophila (r = -0.247, p = 0.046), and genus Faecalibacterium (r = -0.291, p = 0.018) for all CN participants. Finally, the combination of plasma Aß markers, altered gut microbiota, and cognitive performance reached a relatively good discriminative power in identifying individuals with CN+ from CN- (AUC = 0.869, 95% CI 0.782 ~ 0.955). CONCLUSIONS: This study provided the evidence that the gut microbial composition was altered in preclinical AD. The combination of plasma Aß and gut microbiota may serve as a non-invasive, cost-effective diagnostic tool for early AD screening. Targeting the gut microbiota may be a novel therapeutic strategy for AD. TRIAL REGISTRATION: This study has been registered in ClinicalTrials.gov (NCT03370744, https://www.clinicaltrials.gov ) in November 15, 2017.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides/sangue , Disfunção Cognitiva , Microbioma Gastrointestinal , Doença de Alzheimer/diagnóstico , Biomarcadores/sangue , Estudos Transversais , Humanos , Fragmentos de Peptídeos/sangueRESUMO
BACKGROUND: Blood biomarkers that can be used for preclinical Alzheimer's disease (AD) diagnosis would enable trial enrollment at a time when the disease is potentially reversible. Here, we investigated plasma neuronal-derived extracellular vesicle (nEV) cargo in patients along the Alzheimer's continuum, focusing on cognitively normal controls (NCs) with high brain ß-amyloid (Aß) loads (Aß+). METHODS: The study was based on the Sino Longitudinal Study on Cognitive Decline project. We enrolled 246 participants, including 156 NCs, 45 amnestic mild cognitive impairment (aMCI) patients, and 45 AD dementia (ADD) patients. Brain Aß loads were determined using positron emission tomography. NCs were classified into 84 Aß- NCs and 72 Aß+ NCs. Baseline plasma nEVs were isolated by immunoprecipitation with an anti-CD171 antibody. After verification, their cargos, including Aß, tau phosphorylated at threonine 181, and neurofilament light, were quantified using a single-molecule array. Concentrations of these cargos were compared among the groups, and their receiver operating characteristic (ROC) curves were constructed. A subset of participants underwent follow-up cognitive assessment and magnetic resonance imaging. The relationships of nEV cargo levels with amyloid deposition, longitudinal changes in cognition, and brain regional volume were explored using correlation analysis. Additionally, 458 subjects in the project had previously undergone plasma Aß quantification. RESULTS: Only nEV Aß was included in the subsequent analysis. We focused on Aß42 in the current study. After normalization of nEVs, the levels of Aß42 were found to increase gradually across the cognitive continuum, with the lowest in the Aß- NC group, an increase in the Aß+ NC group, a further increase in the aMCI group, and the highest in the ADD group, contributing to their diagnoses (Aß- NCs vs. Aß+ NCs, area under the ROC curve values of 0.663; vs. aMCI, 0.857; vs. ADD, 0.957). Furthermore, nEV Aß42 was significantly correlated with amyloid deposition, as well as longitudinal changes in cognition and entorhinal volume. There were no differences in plasma Aß levels among NCs, aMCI, and ADD individuals. CONCLUSIONS: Our findings suggest the potential use of plasma nEV Aß42 levels in diagnosing AD-induced cognitive impairment and Aß+ NCs. This biomarker reflects cortical amyloid deposition and predicts cognitive decline and entorhinal atrophy.