Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 3.374
Filtrar
1.
Int J Nanomedicine ; 16: 1901-1911, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33707945

RESUMO

Purpose: Developing a sensitive SERS-based method to quantitatively detect serum biomarkers (Aß1-42 and P-Tau-181) for the early diagnosis of Alzheimer's disease (AD). Methods: In this study, a novel SERS-based sandwich immunoassay, which consists of tannin-capped silver nanoparticles and magnetic graphene oxide (Fe3O4@GOs), was developed. We firstly applied this method for the detection of protein standards in buffer solution, obtaining the regression equation. Then, its potential value on real serum samples of AD was further explored. Results: The detection linear range of Aß1-42 and P-Tau-181 protein standards were observed to range from 100 pg mL-1 to 10 fg mL-1, 100 pg mL-1 to 1 fg mL-1 respectively. We finally explored clinical application of the proposed method in 63 serum samples. As a result, P-tau-181 differentiated AD from non-AD dementia patients (AUC = 0.770), with a more favored ROC than Aß1-42 (AUC = 0.383). Conclusion: The developed SERS-based immunoassay is successfully applied to the determination of Aß1-42 and P-Tau-181 in human serum specimens, which provides a promising tool for the early diagnosis of AD.


Assuntos
Doença de Alzheimer/sangue , Doença de Alzheimer/diagnóstico , Biomarcadores/sangue , Imunoensaio/métodos , Sondas Moleculares/química , Prata/química , Análise Espectral Raman/métodos , Peptídeos beta-Amiloides/sangue , Benzoatos/química , Calibragem , Feminino , Grafite/química , Humanos , Limite de Detecção , Masculino , Nanopartículas Metálicas/química , Nanopartículas Metálicas/ultraestrutura , Compostos de Sulfidrila/química , Difração de Raios X , Proteínas tau/sangue
2.
Cochrane Database Syst Rev ; 2: CD010945, 2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33566374

RESUMO

BACKGROUND: Dementia is a syndrome that comprises many differing pathologies, including Alzheimer's disease dementia (ADD), vascular dementia (VaD) and frontotemporal dementia (FTD). People may benefit from knowing the type of dementia they live with, as this could inform prognosis and may allow for tailored treatment. Beta-amyloid (1-42) (ABeta42) is a protein which decreases in both the plasma and cerebrospinal fluid (CSF) of people living with ADD, when compared to people with no dementia. However, it is not clear if changes in ABeta42 are specific to ADD or if they are also seen in other types of dementia. It is possible that ABeta42 could help differentiate ADD from other dementia subtypes. OBJECTIVES: To determine the accuracy of plasma and CSF ABeta42 for distinguishing ADD from other dementia subtypes in people who meet the criteria for a dementia syndrome. SEARCH METHODS: We searched MEDLINE, and nine other databases up to 18 February 2020. We checked reference lists of any relevant systematic reviews to identify additional studies. SELECTION CRITERIA: We considered cross-sectional studies that differentiated people with ADD from other dementia subtypes. Eligible studies required measurement of participant plasma or CSF ABeta42 levels and clinical assessment for dementia subtype. DATA COLLECTION AND ANALYSIS: Seven review authors working independently screened the titles and abstracts generated by the searches. We collected data on study characteristics and test accuracy. We used the second version of the 'Quality Assessment of Diagnostic Accuracy Studies' (QUADAS-2) tool to assess internal and external validity of results. We extracted data into 2 x 2 tables, cross-tabulating index test results (ABeta42) with the reference standard (diagnostic criteria for each dementia subtype). We performed meta-analyses using bivariate, random-effects models. We calculated pooled estimates of sensitivity, specificity, positive predictive values, positive and negative likelihood ratios, and corresponding 95% confidence intervals (CIs). In the primary analysis, we assessed accuracy of plasma or CSF ABeta42 for distinguishing ADD from other mixed dementia types (non-ADD). We then assessed accuracy of ABeta42 for differentiating ADD from specific dementia types: VaD, FTD, dementia with Lewy bodies (DLB), alcohol-related cognitive disorder (ARCD), Creutzfeldt-Jakob disease (CJD) and normal pressure hydrocephalus (NPH). To determine test-positive cases, we used the ABeta42 thresholds employed in the respective primary studies. We then performed sensitivity analyses restricted to those studies that used common thresholds for ABeta42. MAIN RESULTS: We identified 39 studies (5000 participants) that used CSF ABeta42 levels to differentiate ADD from other subtypes of dementia. No studies of plasma ABeta42 met the inclusion criteria. No studies were rated as low risk of bias across all QUADAS-2 domains. High risk of bias was found predominantly in the domains of patient selection (28 studies) and index test (25 studies). The pooled estimates for differentiating ADD from other dementia subtypes were as follows: ADD from non-ADD: sensitivity 79% (95% CI 0.73 to 0.85), specificity 60% (95% CI 0.52 to 0.67), 13 studies, 1704 participants, 880 participants with ADD; ADD from VaD: sensitivity 79% (95% CI 0.75 to 0.83), specificity 69% (95% CI 0.55 to 0.81), 11 studies, 1151 participants, 941 participants with ADD; ADD from FTD: sensitivity 85% (95% CI 0.79 to 0.89), specificity 72% (95% CI 0.55 to 0.84), 17 studies, 1948 participants, 1371 participants with ADD; ADD from DLB: sensitivity 76% (95% CI 0.69 to 0.82), specificity 67% (95% CI 0.52 to 0.79), nine studies, 1929 participants, 1521 participants with ADD. Across all dementia subtypes, sensitivity was greater than specificity, and the balance of sensitivity and specificity was dependent on the threshold used to define test positivity. AUTHORS' CONCLUSIONS: Our review indicates that measuring ABeta42 levels in CSF may help differentiate ADD from other dementia subtypes, but the test is imperfect and tends to misdiagnose those with non-ADD as having ADD. We would caution against the use of CSF ABeta42 alone for dementia classification. However, ABeta42 may have value as an adjunct to a full clinical assessment, to aid dementia diagnosis.


Assuntos
Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides/sangue , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Fragmentos de Peptídeos/sangue , Fragmentos de Peptídeos/líquido cefalorraquidiano , Alcoolismo/complicações , Doença de Alzheimer/sangue , Doença de Alzheimer/líquido cefalorraquidiano , Viés , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Disfunção Cognitiva/sangue , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/etiologia , Intervalos de Confiança , Síndrome de Creutzfeldt-Jakob/sangue , Síndrome de Creutzfeldt-Jakob/líquido cefalorraquidiano , Síndrome de Creutzfeldt-Jakob/diagnóstico , Demência Vascular/sangue , Demência Vascular/líquido cefalorraquidiano , Demência Vascular/diagnóstico , Diagnóstico Diferencial , Demência Frontotemporal/sangue , Demência Frontotemporal/líquido cefalorraquidiano , Demência Frontotemporal/diagnóstico , Humanos , Hidrocefalia de Pressão Normal/sangue , Hidrocefalia de Pressão Normal/líquido cefalorraquidiano , Hidrocefalia de Pressão Normal/diagnóstico , Doença por Corpos de Lewy/sangue , Doença por Corpos de Lewy/líquido cefalorraquidiano , Doença por Corpos de Lewy/diagnóstico , Funções Verossimilhança , Sensibilidade e Especificidade
3.
Biomed Environ Sci ; 34(1): 19-28, 2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33531104

RESUMO

Objective: In the present study, the ABCA1 was used as a label to capture specific exosomes, the level of ABCA1-labeled exosomal microRNA-135a (miR-135a) was evaluated for the diagnosis of Alzheimer's disease (AD), especially in patients with early stages of AD. Methods: This is a preliminary research focused on the levels of ABCA1 in WBCs, RBCs, HT-22 cells, and neuron cells. The diagnostic value of ABCA1-labeled exosomal miR-135a was examined using the CSF and serum of APP/PS1 double transgenic mice, and 152 patients with SCD, 131 patients with MCI, 198 patients with DAT, and 30 control subjects. Results: The level of ABCA1 exosomes harvested from HT-22 cells and neuron culture medium was significantly higher compared to that of RBCs and WBCs ( P < 0.05). The levels of ABCA1-labeled exosomal miR-135a increased in the CSF of MCI and DAT group compared to those of control group ( P < 0.05), slightly increased ( P > 0.05) in the serum of SCD patient group, and significantly increased in MCI and DAT patient groups compared to those of the control group ( P < 0.05). Conclusion: This study outlines a method to capture specific exosomes and detect them using immunological methods, which is more efficient for early diagnosis of AD.


Assuntos
Transportador 1 de Cassete de Ligação de ATP , Disfunção Cognitiva/sangue , Exossomos , MicroRNAs/sangue , Transportador 1 de Cassete de Ligação de ATP/sangue , Transportador 1 de Cassete de Ligação de ATP/líquido cefalorraquidiano , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/sangue , Doença de Alzheimer/líquido cefalorraquidiano , Animais , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Linhagem Celular , Disfunção Cognitiva/líquido cefalorraquidiano , Eritrócitos/metabolismo , Feminino , Humanos , Leucócitos/metabolismo , Masculino , Camundongos Transgênicos , Neurônios/metabolismo
4.
Am J Med Sci ; 361(2): 261-268, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33526214

RESUMO

BACKGROUND: The most vexing problem in hyponatremic conditions is to differentiate the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) from cerebral/renal salt wasting (C-RSW). Both have identical clinical parameters but diametrically opposite therapeutic goals of water- restricting water-logged patients with SIADH or administering salt and water to dehydrated patients with C-RSW. While C-RSW is considered a rare condition, the report of a high prevalence of C-RSW in the general hospital wards creates an urgency to differentiate one syndrome from the other on first encounter. We decided to identify the natriuretic factor (NF) we previously demonstrated in plasma of neurosurgical and Alzheimer diseases (AD) who had findings consistent with C-RSW. METHODS: We performed the same rat renal clearance studies to determine natriuretic activity (NA) in serum from a patient with a subarachnoid hemorrhage (SAH) and another with AD and demonstrated NA in their sera. The sera were subjected to proteomic and SWATH (Sequential Windowed Acquisition of All) analyses which identified increased levels of haptoglobin related protein (Hpr) without signal peptide (Hpr-WSP). RESULTS: Recombinant Hpr with His tag at the N terminus had no NA. Hpr-WSP had a robust NA in a dose-dependent manner when injected into rats. Serum after recovery from C-RSW in the SAH patient had no NA. CONCLUSIONS: Hpr-WSP may be the NF in C-RSW which should be developed as a biomarker to differentiate C-RSW from SIADH on first encounter, introduces a new syndrome of C-RSW in AD and can serve as a proximal diuretic to treat congestive heart failure.


Assuntos
Doença de Alzheimer/sangue , Antígenos de Neoplasias/sangue , Natriuréticos/sangue , Hemorragia Subaracnóidea/sangue , Desequilíbrio Hidroeletrolítico/sangue , Idoso , Animais , Biomarcadores/sangue , Encéfalo/metabolismo , Feminino , Haptoglobinas , Humanos , Rim/metabolismo , Masculino , Ratos , Síndrome
6.
Artigo em Inglês | MEDLINE | ID: mdl-32682282

RESUMO

Polyunsaturated fatty acids (PUFAs) are closely related to various physiological conditions. In several age-related diseases including Alzheimer's disease (AD) altered PUFAs metabolism has been reported. However, the mechanism behind PUFAs impairment and AD developpement remains unclear. In humans, PUFAs biosynthesis requires delta-5 desaturase (D5D), delta-6 desaturase (D6D) and elongase 2 activities; which are encoded by fatty acid desaturase 1 (FADS1), fatty acid desaturase 2 (FADS2), and elongation of very-long-chain fatty acids-like 2 (ELOVL2) genes, respectively. In the present work, we aim to assess whether genetic variants in FADS1, FADS2 and ELOVL2 genes influence plasma and erythrocyte PUFA composition and AD risk. A case-control study was carried out in 113 AD patients and 161 healthy controls.Rs174556, rs174617, and rs3756963 of FADS1, FADS2, and ELOVL2 genes, respectively were genotyped using PCR-RFLP. PUFA levels were quantified using Gas Chromatography. Genotype distributions of rs174556 (FADS1) and rs3756963 (ELOVL2) were different between case and control groups. The genotype TT of rs174556 and rs3756963 single nucleotide polymorphism (SNP) increases significantly the risk of AD in our population. PUFA analysis showed higher plasma and erythrocyte arachidonic acid (AA) level in patients with AD, whereas only plasma docosahexaenoic acid (DHA) was significantly decreased in AD patients. The indexes AA/Dihomo-gamma-linolenic acid (DGLA) and C24:4n-6/Adrenic acid (AdA) were both higher in the AD group. Interestingly, patients with TT genotype of rs174556 presented higher AA level and AA/DGLA index in both plasma and erythrocyte. In addition, higher AA and AA/DGLA index were observed in erythrocyte of TT genotype ofrs3756963 carrier's patients. Along with, positive correlation between AA/DGLA index, age or Gamma-linolenic acid (GLA)/ Linoleic acid (LA) index was seen in erythrocyte and /or plasma of AD patients. After adjustment for confounding factors, the genotype TT of rs174556, erythrocyte AA and AA/DGLA index were found to be predictive risk factors for AD while plasma DHA was found associated with lower AD risk. Both rs174556 and rs3756963 influence AD risk in the Tunisian population and they are likely associated with high AA level. The combination of the two variants increases further the susceptibility to AD. We suggest that FADS1 and ELOVL2 variants could likely regulate the efficiency of AA biosynthesis which could be at the origin of inflammatory derivate.


Assuntos
Doença de Alzheimer/genética , Ácido Araquidônico/sangue , Ácidos Graxos Dessaturases/genética , Elongases de Ácidos Graxos/genética , Ácidos Graxos Insaturados/sangue , Ácido 8,11,14-Eicosatrienoico/análise , Ácido 8,11,14-Eicosatrienoico/sangue , Alelos , Doença de Alzheimer/sangue , Doença de Alzheimer/fisiopatologia , Ácido Araquidônico/análise , Estudos de Casos e Controles , Cromatografia Gasosa , Ácidos Docosa-Hexaenoicos/análise , Ácidos Docosa-Hexaenoicos/sangue , Eritrócitos/metabolismo , Ácidos Graxos Insaturados/análise , Genótipo , Humanos , Ácido Linoleico/análise , Polimorfismo de Nucleotídeo Único , Análise de Regressão , Fatores de Risco , Tunísia/epidemiologia , Ácido gama-Linolênico/análise
7.
JAMA ; 324(8): 772-781, 2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32722745

RESUMO

Importance: There are limitations in current diagnostic testing approaches for Alzheimer disease (AD). Objective: To examine plasma tau phosphorylated at threonine 217 (P-tau217) as a diagnostic biomarker for AD. Design, Setting, and Participants: Three cross-sectional cohorts: an Arizona-based neuropathology cohort (cohort 1), including 34 participants with AD and 47 without AD (dates of enrollment, May 2007-January 2019); the Swedish BioFINDER-2 cohort (cohort 2), including cognitively unimpaired participants (n = 301) and clinically diagnosed patients with mild cognitive impairment (MCI) (n = 178), AD dementia (n = 121), and other neurodegenerative diseases (n = 99) (April 2017-September 2019); and a Colombian autosomal-dominant AD kindred (cohort 3), including 365 PSEN1 E280A mutation carriers and 257 mutation noncarriers (December 2013-February 2017). Exposures: Plasma P-tau217. Main Outcomes and Measures: Primary outcome was the discriminative accuracy of plasma P-tau217 for AD (clinical or neuropathological diagnosis). Secondary outcome was the association with tau pathology (determined using neuropathology or positron emission tomography [PET]). Results: Mean age was 83.5 (SD, 8.5) years in cohort 1, 69.1 (SD, 10.3) years in cohort 2, and 35.8 (SD, 10.7) years in cohort 3; 38% were women in cohort 1, 51% in cohort 2, and 57% in cohort 3. In cohort 1, antemortem plasma P-tau217 differentiated neuropathologically defined AD from non-AD (area under the curve [AUC], 0.89 [95% CI, 0.81-0.97]) with significantly higher accuracy than plasma P-tau181 and neurofilament light chain (NfL) (AUC range, 0.50-0.72; P < .05). The discriminative accuracy of plasma P-tau217 in cohort 2 for clinical AD dementia vs other neurodegenerative diseases (AUC, 0.96 [95% CI, 0.93-0.98]) was significantly higher than plasma P-tau181, plasma NfL, and MRI measures (AUC range, 0.50-0.81; P < .001) but not significantly different compared with cerebrospinal fluid (CSF) P-tau217, CSF P-tau181, and tau-PET (AUC range, 0.90-0.99; P > .15). In cohort 3, plasma P-tau217 levels were significantly greater among PSEN1 mutation carriers, compared with noncarriers, from approximately 25 years and older, which is 20 years prior to estimated onset of MCI among mutation carriers. Plasma P-tau217 levels correlated with tau tangles in participants with (Spearman ρ = 0.64; P < .001), but not without (Spearman ρ = 0.15; P = .33), ß-amyloid plaques in cohort 1. In cohort 2, plasma P-tau217 discriminated abnormal vs normal tau-PET scans (AUC, 0.93 [95% CI, 0.91-0.96]) with significantly higher accuracy than plasma P-tau181, plasma NfL, CSF P-tau181, CSF Aß42:Aß40 ratio, and MRI measures (AUC range, 0.67-0.90; P < .05), but its performance was not significantly different compared with CSF P-tau217 (AUC, 0.96; P = .22). Conclusions and Relevance: Among 1402 participants from 3 selected cohorts, plasma P-tau217 discriminated AD from other neurodegenerative diseases, with significantly higher accuracy than established plasma- and MRI-based biomarkers, and its performance was not significantly different from key CSF- or PET-based measures. Further research is needed to optimize the assay, validate the findings in unselected and diverse populations, and determine its potential role in clinical care.


Assuntos
Doença de Alzheimer/diagnóstico , Doenças Neurodegenerativas/diagnóstico , Proteínas tau/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/sangue , Peptídeos beta-Amiloides , Área Sob a Curva , Biomarcadores/sangue , Estudos Transversais , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Mutação , Doenças Neurodegenerativas/sangue , Placa Amiloide/sangue , Tomografia por Emissão de Pósitrons , Presenilina-1/genética
8.
PLoS One ; 15(6): e0234632, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32559242

RESUMO

Evidence indicate that the brain-specific protein, brevican, is proteolytically cleaved during neurodegeneration, hence positioning fragments of brevican as potential blood biomarkers of neurodegenerative diseases, such as dementia. We aimed to develop two assays capable of detecting the brevican N-terminal (N-Brev) and the ADAMTS4-generated fragment (Brev-A), cleaved at Ser401, in serum and to perform a preliminary assessment of their diagnostic potential in dementias. Monoclonal antibodies against N-Brev and Brev-A were used to develop two ELISAs detecting each epitope. A comparison of brevican fragments in serum from individuals with AD (n = 28), other dementia (OD) (n = 41), and non-dementia-related memory complaints (NDCs) (n = 48) was conducted. Anti-N-Brev and anti-Brev-A antibodies selectively recognized their targets and dilution and spike recoveries were within limits of ±20%. Intra- and inter-assay CVs were below limits of 10% and 15%, respectively. For the N-Brev biomarker, serum from patients with OD showed significantly lower levels than those with AD (p = 0.05) and NDCs (p < 0.01). The opposite pattern was evident for Brev-A: serum levels in patients with OD were significantly higher than for AD (p = 0.04) and NDCs (p = 0.01). For both N-Brev and Brev-A, levels did not differ between AD and NDCs. The ratio of N-Brev/Brev-A resulted in increased significant differences between OD and AD (p < 0.01) and between OD and NDCs (p < 0.0001). The ratio discriminated between NDCs and OD (AUC: 0.75, 95% CI: 0.65-0.85, p < 0.0001) and between OD and AD (AUC: 0.72, 95% CI: 0.59-0.85, p < 0.01). In conclusion, we developed the first assays detecting the N-terminal of brevican as well as an ADAMTS4-cleaved fragment of brevican in blood. Differential levels of N-Brev and Brev-A between AD and OD allow for these biomarkers to possibly distinguish between different forms of dementias.


Assuntos
Proteína ADAMTS4/metabolismo , Doença de Alzheimer/sangue , Brevicam/metabolismo , Sistema Nervoso Central/metabolismo , Demência/sangue , Idoso , Doença de Alzheimer/diagnóstico , Estudos de Casos e Controles , Estudos Transversais , Demência/diagnóstico , Feminino , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Especificidade de Órgãos , Peptídeos/metabolismo , Curva ROC , Reprodutibilidade dos Testes
9.
Neuron ; 106(6): 881-883, 2020 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-32553204
10.
PLoS One ; 15(6): e0234519, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32530970

RESUMO

Axonal damage leads to the release of neurofilament light chain (NFL), which enters the CSF or blood. In this work, an assay kit for plasma NFL utilizing immunomagnetic reduction (IMR) was developed. Antibodies against NFL were immobilized on magnetic nanoparticles to develop an IMR NFL kit. The preclinical properties, such as the standard curve, limit of detection (LoD), and dynamic range, were characterized. Thirty-one normal controls (NC), fifty-two patients with Parkinson's disease (PD) or PD dementia (PDD) and thirty-one patients with Alzheimer's disease (AD) were enrolled in the study evaluating the plasma NFL assay using an IMR kit. T-tests and receiver operating characteristic (ROC) curve analysis were performed to investigate the capability for discrimination among the clinical groups according to plasma NFL levels. The LoD of the NFL assay using the IMR kit was found to be 0.18 fg/ml. The dynamic range of the NFL assay reached 1000 pg/ml. The NC group showed a plasma NFL level of 7.70 ± 4.00 pg/ml, which is significantly lower than that of the PD/PDD (15.85 ± 7.82 pg/ml, p < 0.001) and AD (19.24 ± 8.99 pg/ml, p < 0.001) groups. A significant difference in plasma NFL levels was determined between the PD and AD groups (p < 0.01). Through ROC curve analysis, the cut-off value of the plasma NFL concentration for differentiating NCs from dementia patients (AD and PD/PDD) was found to be 12.71 pg/ml, with a clinical sensitivity and specificity of 73.5% and 90.3%, respectively. The AUC was 0.868. Furthermore, the cut-off value of the plasma NFL concentration for discriminating AD from PD/PDD was found to be 18.02 pg/ml, with a clinical sensitivity and specificity of 61.3% and 65.4%, respectively. The AUC was 0.630. An ultrasensitive assay for measuring plasma NFL utilizing IMR technology was developed. Clear differences in plasma NFL concentrations were observed among NCs and PD and AD patients. These results imply that the determination of plasma NFL is promising not only for screening dementia but also for differential diagnosis.


Assuntos
Peptídeos beta-Amiloides/sangue , Biomarcadores/sangue , Proteínas de Neurofilamentos/sangue , Proteínas tau/sangue , Doença de Alzheimer/sangue , Doença de Alzheimer/patologia , Axônios/metabolismo , Axônios/patologia , Disfunção Cognitiva/sangue , Disfunção Cognitiva/genética , Disfunção Cognitiva/patologia , Feminino , Humanos , Separação Imunomagnética , Filamentos Intermediários/genética , Filamentos Intermediários/patologia , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/sangue , Doença de Parkinson/genética , Doença de Parkinson/patologia
11.
PLoS One ; 15(5): e0233289, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32469899

RESUMO

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by two aggregates, namely, amyloid-ß (Aß) plaques and neurofibrillary tangles (NFTs) of hyperphosphorylated tau protein (tau-p), which are released into the blood in a very small amount and cannot be easily detected. An increasing number of recent studies have suggested that S-glutathionylated glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is highly correlated with Aß in patients with AD and that S-glutathionylated GAPDH plays a role as a proapoptotic factor in AD. We found that S-glutathionylated GAPDH is abundant in the blood of AD patients, which is unusual because S-glutathionylated GAPDH cannot exist in the blood under normal conditions. The aim of this study was to further explore the correlation between the S-glutathionylated GAPDH levels in blood plasma and AD progression. As controls, we recruited 191 people without AD, which included 111 healthy individuals and 37 patients with depression and insomnia, in the psychosomatic clinic. Moreover, 47 patients with AD (aged 40-89 years) were recruited at the neurology clinic. The blood S-glutathionylated GAPDH levels in the AD patients were significantly (p < 0.001) higher (752.7 ± 301.7 ng/dL) than those in the controls (59.92 ± 122.4 ng/dL), irrespective of gender and age. For AD diagnosis, the criterion blood S-glutathionylated GAPDH level > 251.62 ng/dL exhibited 95.74% sensitivity and 92.67% specificity. In fact, the individuals aged 70-89 years, namely, 37 patients from the psychosomatic clinic and 42 healthy individuals, showed significant blood S-glutathionylated GAPDH levels (230.5 ± 79.3 and 8.05 ± 20.51 ng/dL, respectively). This finding might indicate neurodegenerative AD progression in psychosomatic patients and suggests that the degree of neuronal apoptosis during AD progression might be sensitively evaluated based on the level of S-glutathionylated GAPDH in blood.


Assuntos
Doença de Alzheimer/sangue , Doença de Alzheimer/patologia , Proteínas Sanguíneas/metabolismo , Glutationa/química , Gliceraldeído-3-Fosfato Desidrogenase (Fosforiladora)/sangue , Processamento de Proteína Pós-Traducional , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Progressão da Doença , Feminino , Seguimentos , Gliceraldeído-3-Fosfato Desidrogenase (Fosforiladora)/química , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico
12.
Lancet Neurol ; 19(6): 513-521, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32470423

RESUMO

BACKGROUND: Neurofilament light chain (NfL) is a promising biomarker of active axonal injury and neuronal degeneration. We aimed to characterise cross-sectional and longitudinal plasma NfL measurements and determine the age at which NfL concentrations begin to differentiate between carriers of the presenilin 1 (PSEN1) E280A (Glu280Ala) mutation and age-matched non-carriers from the Colombian autosomal dominant Alzheimer's disease kindred. METHODS: In this cross-sectional and longitudinal cohort study, members of the familial Alzheimer's disease Colombian kindred aged 8-75 years with no other neurological or health conditions were recruited from the Alzheimer's Prevention Initiative Registry at the University of Antioquia (Medellín, Colombia) between Aug 1, 1995, and Dec 15, 2018. We used a single molecule array immunoassay and log-transformed data to examine the relationship between plasma NfL concentrations and age, and establish the earliest age at which NfL concentrations begin to diverge between mutation carriers and non-carriers. FINDINGS: We enrolled a cohort of 1070 PSEN1 E280A mutation carriers and 1074 non-carriers with baseline assessments; of these participants, longitudinal measures (with a mean follow-up of 6 years) were available for 242 mutation carriers and 262 non-carriers. Plasma NfL measurements increased with age in both groups (p<0·0001), and began to differentiate carriers from non-carriers when aged 22 years (22 years before the estimated median age at mild cognitive impairment onset of 44 years), although the ability of plasma NfL to discriminate between carriers and non-carriers only reached high sensitivity close to the age of clinical onset. INTERPRETATION: Our findings further support the promise of plasma NfL as a biomarker of active neurodegeneration in the detection and tracking of Alzheimer's disease and the evaluation of disease-modifying therapies. FUNDING: National Institute on Aging, National Institute of Neurological Disorders and Stroke, Banner Alzheimer's Foundation, COLCIENCIAS, the Torsten Söderberg Foundation, the Swedish Research Council, the Swedish Alzheimer Foundation, the Swedish Brain Foundation, and the Swedish state under the ALF-agreement.


Assuntos
Doença de Alzheimer/diagnóstico , Doença de Alzheimer/genética , Proteínas de Neurofilamentos/análise , Adolescente , Adulto , Idoso , Doença de Alzheimer/sangue , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Biomarcadores/sangue , Encéfalo/metabolismo , Criança , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Filamentos Intermediários/metabolismo , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Proteínas de Neurofilamentos/sangue , Polimorfismo de Nucleotídeo Único/genética , Presenilina-1/genética , Presenilina-1/metabolismo
13.
J Neurol Neurosurg Psychiatry ; 91(5): 540-546, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32234968

RESUMO

OBJECTIVE: To examine the association between serum total homocysteine levels (tHcy) and dementia risk. METHODS: A total of 1588 Japanese adults aged ≥60 years without dementia were prospectively followed from 2002 to 2012. Cox proportional hazards models and restricted cubic splines were used to estimate the HRs of tHcy levels on the risk of dementia. RESULTS: During the follow-up, 372 subjects developed all-cause dementia; 247 had Alzheimer's disease (AD) and 98 had vascular dementia (VaD). Compared with the lowest tHcy quintile (≤6.4 µmol/L), the multivariable-adjusted HRs (95% CI) of the highest quintile (≥11.5 µmol/L) were 2.28 (1.51-3.43) for all-cause dementia, 1.96 (1.19-3.24) for AD and 2.51 (1.14-5.51) for VaD. In restricted cubic splines, the risk of all-cause dementia steadily increased between approximately 8-15 µmol/L and plateaued thereafter, with a similar non-linear shape observed for AD and VaD (all p for non-linearity ≤0.02). In stratified analyses by the most recognised genetic polymorphism affecting tHcy concentrations (methylenetetrahydrofolate reductase C677T), the positive association of tHcy with all-cause dementia persisted in both non-carriers and carriers of the risk allele, and even tended to be stronger in the former (p for heterogeneity=0.07). CONCLUSION: High serum tHcy levels are associated with an elevated risk of dementia, AD and VaD in a non-linear manner, such that an exposure-response association is present only within a relatively high range of tHcy levels. Non-genetic factors affecting serum tHcy concentrations may play important roles in tHcy-dementia associations irrespective of the genetic susceptibility for raised tHcy.


Assuntos
Demência/etiologia , Homocisteína/sangue , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/sangue , Doença de Alzheimer/etiologia , Demência/sangue , Demência/genética , Demência Vascular/sangue , Demência Vascular/etiologia , Predisposição Genética para Doença/genética , Humanos , Hiper-Homocisteinemia/sangue , Hiper-Homocisteinemia/complicações , Japão/epidemiologia , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de Risco
14.
Lancet Neurol ; 19(5): 422-433, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32333900

RESUMO

BACKGROUND: CSF and PET biomarkers of amyloid ß and tau accurately detect Alzheimer's disease pathology, but the invasiveness, high cost, and poor availability of these detection methods restrict their widespread use as clinical diagnostic tools. CSF tau phosphorylated at threonine 181 (p-tau181) is a highly specific biomarker for Alzheimer's disease pathology. We aimed to assess whether blood p-tau181 could be used as a biomarker for Alzheimer's disease and for prediction of cognitive decline and hippocampal atrophy. METHODS: We developed and validated an ultrasensitive blood immunoassay for p-tau181. Assay performance was evaluated in four clinic-based prospective cohorts. The discovery cohort comprised patients with Alzheimer's disease and age-matched controls. Two validation cohorts (TRIAD and BioFINDER-2) included cognitively unimpaired older adults (mean age 63-69 years), participants with mild cognitive impairment (MCI), Alzheimer's disease, and frontotemporal dementia. In addition, TRIAD included healthy young adults (mean age 23 years) and BioFINDER-2 included patients with other neurodegenerative disorders. The primary care cohort, which recruited participants in Montreal, Canada, comprised control participants from the community without a diagnosis of a neurological condition and patients referred from primary care physicians of the Canadian National Health Service for specialist care. Concentrations of plasma p-tau181 were compared with established CSF and PET biomarkers and longitudinal measurements using Spearman correlation, area under the curve (AUC), and linear regression analyses. FINDINGS: We studied 37 individuals in the discovery cohort, 226 in the first validation cohort (TRIAD), 763 in the second validation cohort (BioFINDER-2), and 105 in the primary care cohort (n=1131 individuals). In all cohorts, plasma p-tau181 showed gradual increases along the Alzheimer's disease continuum, from the lowest concentrations in amyloid ß-negative young adults and cognitively unimpaired older adults, through higher concentrations in the amyloid ß-positive cognitively unimpaired older adults and MCI groups, to the highest concentrations in the amyloid ß-positive MCI and Alzheimer's disease groups (p<0·001, Alzheimer's disease vs all other groups). Plasma p-tau181 distinguished Alzheimer's disease dementia from amyloid ß-negative young adults (AUC=99·40%) and cognitively unimpaired older adults (AUC=90·21-98·24% across cohorts), as well as other neurodegenerative disorders, including frontotemporal dementia (AUC=82·76-100% across cohorts), vascular dementia (AUC=92·13%), progressive supranuclear palsy or corticobasal syndrome (AUC=88·47%), and Parkinson's disease or multiple systems atrophy (AUC=81·90%). Plasma p-tau181 was associated with PET-measured cerebral tau (AUC=83·08-93·11% across cohorts) and amyloid ß (AUC=76·14-88·09% across cohorts) pathologies, and 1-year cognitive decline (p=0·0015) and hippocampal atrophy (p=0·015). In the primary care cohort, plasma p-tau181 discriminated Alzheimer's disease from young adults (AUC=100%) and cognitively unimpaired older adults (AUC=84·44%), but not from MCI (AUC=55·00%). INTERPRETATION: Blood p-tau181 can predict tau and amyloid ß pathologies, differentiate Alzheimer's disease from other neurodegenerative disorders, and identify Alzheimer's disease across the clinical continuum. Blood p-tau181 could be used as a simple, accessible, and scalable test for screening and diagnosis of Alzheimer's disease. FUNDING: Alzheimer Drug Discovery Foundation, European Research Council, Swedish Research Council, Swedish Alzheimer Foundation, Swedish Dementia Foundation, Alzheimer Society Research Program.


Assuntos
Doença de Alzheimer/diagnóstico , Disfunção Cognitiva/sangue , Proteínas tau/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/sangue , Biomarcadores/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Teóricos , Fosforilação , Estudos Prospectivos , Adulto Jovem
15.
Zhongguo Zhen Jiu ; 40(4): 375-8, 2020 Apr 12.
Artigo em Chinês | MEDLINE | ID: mdl-32275365

RESUMO

OBJECTIVE: To compare the therapeutic effect of electroacupuncture (EA) combined with donepezil hydrochloride and donepezil hydrochloride alone on improving learning-memory ability in patients with Alzheimer's disease (AD), and to explore its action mechanism. METHODS: Sixty patients of AD were randomly divided into an observation group and a control group, 30 cases in each group. The patients in the observation group were treated with EA at governor vessel (GV) combined with donepezil hydrochloride. EA was applied at Baihui (GV 20) and Fengfu (GV 16) with dilatational wave (10 Hz/50 Hz of frequency, 0.5 to 5.0 mA of intensity), and the needles were kept for 40 min, EA was given once a day; the donepezil hydrochloride tablet was taken orally, 5 mg, once a day, and after 4 weeks the dosage might be increased to 10 mg per day according to the specific situation. All the treatment was given for 8 weeks. The patients in the control group were only treated with donepezil hydrochloride with the identical procedure as the observation group. The Montreal cognitive assessment (MoCA) and Alzheimer's disease assessment scale cognitive part (ADAS-Cog) were evaluated before and after treatment; P300 (latency and amplitude of N2 and P3) was detected by EEG/ERP system brain event related potential instrument, and amyloid precursor protein (APP) and ß-amyloid protein 1-42 (Aß1-42) were detected by ELISA. RESULTS: Compared before treatment, the MoCA scores were increased after treatment in the two groups (P<0.05), and the MoCA score in the observation group was higher than that in the control group (P<0.05). Compared before treatment, the ADAS-Cog scores were decreased after treatment in the two groups (P<0.05), and the ADAS-Cog score in the observation group was lower than that in the control group (P<0.05). Compared before treatment, the latency of N2 and P3 was shortened and the amplitude was increased after treatment in the two groups (P<0.05); after treatment, the latency of N2 and P3 in the observation group was shorter than that in the control group and the amplitude was higher than that in the control group (P<0.05). Compared before treatment, the serum levels of APP and Aß1-42 were lower after treatment in the two groups (P<0.05), and the serum levels of APP and Aß1-42 in the observation group were lower than those in the control group (P<0.05). CONCLUSION: EA at Baihui (GV 20) and Fengfu (GV 6) combined with donepezil hydrochloride can effectively reduce the serum levels of APP and Aß1-42 and improve the scores of MoCA and ADAS-Cog and the levels of N2 and P3 of P300 in AD patients, which has superior effect to donepezil hydrochloride alone in improving the learning-memory of AD patients.


Assuntos
Doença de Alzheimer/terapia , Peptídeos beta-Amiloides/sangue , Precursor de Proteína beta-Amiloide/sangue , Eletroacupuntura , Aprendizagem , Memória , Fragmentos de Peptídeos/sangue , Doença de Alzheimer/sangue , Cognição , Donepezila/uso terapêutico , Humanos
16.
Ann Neurol ; 87(6): 950-961, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32281118

RESUMO

OBJECTIVE: The pathology of frontotemporal dementia, termed frontotemporal lobar degeneration (FTLD), is characterized by distinct molecular classes of aggregated proteins, the most common being TAR DNA-binding protein-43 (TDP-43), tau, and fused in sarcoma (FUS). With a few exceptions, it is currently not possible to predict the underlying pathology based on the clinical syndrome. In this study, we set out to investigate the relationship between pathological and clinical presentation at single symptom level, including neuropsychiatric features. METHODS: The presence or absence of symptoms from the current clinical guidelines, together with neuropsychiatric features, such as hallucinations and delusions, were scored and compared across pathological groups in a cohort of 150 brain donors. RESULTS: Our cohort consisted of 68.6% FTLD donors (35.3% TDP-43, 28% tau, and 5.3% FUS) and 31.3% non-FTLD donors with a clinical diagnosis of frontotemporal dementia and a different pathological substrate, such as Alzheimer's disease (23%). The presence of hyperorality points to FTLD rather than non-FTLD pathology (p < 0.001). Within the FTLD group, hallucinations in the initial years of the disease were related to TDP-43 pathology (p = 0.02), including but not limited to chromosome 9 open reading frame 72 (C9orf72) repeat expansion carriers. The presence of perseverative or compulsive behavior was more common in the TDP-B and TDP-C histotypes (p = 0.002). INTERPRETATION: Our findings indicate that neuropsychiatric features are common in FTLD and form an important indicator of underlying pathology. In order to allow better inclusion of patients in targeted molecular trials, the routine evaluation of patients with frontotemporal dementia should include the presence and nature of neuropsychiatric symptoms. ANN NEUROL 2020;87:950-961.


Assuntos
Demência Frontotemporal/patologia , Demência Frontotemporal/psicologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/sangue , Doença de Alzheimer/psicologia , Autopsia , Encéfalo/patologia , Estudos de Coortes , Proteínas de Ligação a DNA/sangue , Delusões/etiologia , Delusões/psicologia , Diagnóstico Diferencial , Feminino , Demência Frontotemporal/metabolismo , Degeneração Lobar Frontotemporal/patologia , Alucinações/etiologia , Alucinações/psicologia , Humanos , Masculino , Pessoa de Meia-Idade , Proteína FUS de Ligação a RNA/sangue
18.
J Clin Neurosci ; 75: 188-194, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32223973

RESUMO

BACKGROUND: Alzheimer's Disease (AD) is the most common form of dementia seen in advanced age. It is characterized by progressive deterioration in cognitive functions. The prevalence of Alzheimer's disease increasing day by day due to the increase in the share of the elderly population in the general population due to developing health and living conditions, is limited and early diagnosis and effective treatment possibilities are very limited. From this point of view, a specific biomarker for AD is very important. As a new oxidative stress biomarker, the levels of thiol-disulfide balance, ischemia-modified albumin and seroloplazminin were evaluated. The aim of this study was to determine the serum levels of oxidative stress biomarkers in the early stages of the disease and to compare these oxidative stress markers with patients with mild cognitive impairment as a precursor form of Alzheimer's disease and to determine whether these markers develop at an earlier stage. METHODS: 30 volunteers with early stage AD according to NINCDS-ARDRA criteria, 19 volunteers with Midl Cognitive Impairment according to PCA criteria and 30 volunteers with defined criteria were selected from the subjects aged between 55 and 88 who applied to Gazi University Health Research. Statistical analysis of the data showed that there was a significant difference between the endgroups and biomarkers for the early diagnosis of Alzheimer's disease, but this complicated matter has to be investigated in more comprehensive and detailed studie. RESULTS: In the present study, we investigated oxidative stress parameters, thiol-disulphide balance, ischemia modified abumin and seruloplasmin in parallel with the impairment in cognitive dysfunction from control group to Mild Cognitive Impairment (MCD) and AD group by using a newly-developed method. CONCLUSIONS: This is the first study in literature comparing Early Stages Alzheimer Disease (ESAD), MCD and healthy volunteer groups. Our study has revealed that these newly developed tests may be candidates as oxidative stress biomarkers in pathgenesis of AD. However it was concluded that more comprehensive and detailed studies are required to enlighten this issue.


Assuntos
Doença de Alzheimer/sangue , Disfunção Cognitiva/sangue , Estresse Oxidativo/fisiologia , Compostos de Sulfidrila/sangue , Sulfitos/sangue , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico , Biomarcadores/sangue , Calorimetria/métodos , Cognição/fisiologia , Disfunção Cognitiva/diagnóstico , Diagnóstico Precoce , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Albumina Sérica Humana
19.
Sci Rep ; 10(1): 3915, 2020 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-32127559

RESUMO

Alzheimer's disease (AD), a neurodegenerative disease, causes behavioural abnormalities such as disinhibition, impulsivity, and hyperphagia. Preclinical studies using AD model mice have investigated these phenotypes by measuring brain activity in awake, behaving mice. In this study, we monitored the behavioural alterations of impulsivity and hyperphagia in middle-aged AD model mice. As a behavioural readout, we trained the mice to accept a water-reward under thirsty conditions. To analyse brain activity, we developed a measure for licking behaviour combined with visualisation of whole brain activity using awake fMRI. In a water-reward learning task, the AD model mice showed significant hyperactivity of the dorsal raphe nucleus in thirsty conditions. In summary, we successfully visualised altered brain activity in AD model mice during reward-oriented behaviour for the first time using awake fMRI. This may help in understanding the causes of behavioural alterations in AD patients.


Assuntos
Doença de Alzheimer/fisiopatologia , Doença de Alzheimer/psicologia , Comportamento Animal , Núcleo Dorsal da Rafe/fisiopatologia , Ingestão de Líquidos , Oxigênio/sangue , Recompensa , Doença de Alzheimer/sangue , Doença de Alzheimer/diagnóstico por imagem , Animais , Imagem por Ressonância Magnética , Camundongos
20.
Nat Commun ; 11(1): 1148, 2020 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-32123170

RESUMO

Late-onset Alzheimer's disease (AD) can, in part, be considered a metabolic disease. Besides age, female sex and APOE ε4 genotype represent strong risk factors for AD that also give rise to large metabolic differences. We systematically investigated group-specific metabolic alterations by conducting stratified association analyses of 139 serum metabolites in 1,517 individuals from the AD Neuroimaging Initiative with AD biomarkers. We observed substantial sex differences in effects of 15 metabolites with partially overlapping differences for APOE ε4 status groups. Several group-specific metabolic alterations were not observed in unstratified analyses using sex and APOE ε4 as covariates. Combined stratification revealed further subgroup-specific metabolic effects limited to APOE ε4+ females. The observed metabolic alterations suggest that females experience greater impairment of mitochondrial energy production than males. Dissecting metabolic heterogeneity in AD pathogenesis can therefore enable grading the biomedical relevance for specific pathways within specific subgroups, guiding the way to personalized medicine.


Assuntos
Doença de Alzheimer/sangue , Doença de Alzheimer/genética , Apolipoproteínas E/genética , Sangue/metabolismo , Metaboloma/genética , Idoso , Doença de Alzheimer/diagnóstico por imagem , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Estudos de Coortes , Feminino , Genótipo , Humanos , Masculino , Mitocôndrias/genética , Mitocôndrias/metabolismo , Tomografia por Emissão de Pósitrons , Fatores Sexuais
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...