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1.
Biosci Biotechnol Biochem ; 84(1): 1-16, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31538538

RESUMO

Recent investigations suggest that soluble oligomeric amyloid ß (Aß) species may be involved in early onset of Alzheimer's disease (AD). Using systematic proline replacement, solid-state NMR, and ESR, we identified a toxic turn at position 22 and 23 of Aß42, the most potent neurotoxic Aß species. Through radicalization, the toxic turn can induce formation of the C-terminal hydrophobic core to obtain putative Aß42 dimers and trimers. Synthesized dimer and trimer models showed that the C-terminal hydrophobic core plays a critical role in the formation of high molecular weight oligomers with neurotoxicity. Accordingly, an anti-toxic turn antibody (24B3) that selectively recognizes a toxic dimer model of E22P-Aß42 was developed. Sandwich enzyme-linked immunosorbent assay with 24B3 and 82E1 detected a significantly higher ratio of Aß42 with a toxic turn to total Aß42 in cerebrospinal fluid of AD patients compared with controls, suggesting that 24B3 could be useful for early onset of AD diagnosis.


Assuntos
Doença de Alzheimer/diagnóstico , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Peptídeos beta-Amiloides/imunologia , Anticorpos Monoclonais/uso terapêutico , Fragmentos de Peptídeos/líquido cefalorraquidiano , Fragmentos de Peptídeos/imunologia , Doença de Alzheimer/líquido cefalorraquidiano , Peptídeos beta-Amiloides/química , Animais , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Humanos , Camundongos , Modelos Moleculares , Emaranhados Neurofibrilares/química , Fragmentos de Peptídeos/química , Placa Amiloide/química , Prolina/química , Agregados Proteicos , Agregação Patológica de Proteínas , Estrutura Terciária de Proteína
3.
Postgrad Med ; 131(7): 501-508, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31483196

RESUMO

Objectives: Aiginition Longitudinal Biomarker Investigation Of Neurodegeneration (ALBION) is a longitudinal ongoing study initiated in 2018 that takes place in the Cognitive Disorders Clinic of Aiginition Hospital of the National and Kapodistrian University of Athens. Its aim is to address several research questions concerning the preclinical and prodromal stage of Alzheimer's disease and explore potential markers for early detection, prediction, and primary prevention of dementia. Methods: We here present the design and the preliminary baseline characteristics of ALBION. The sample of our study consists of people aged over 50 who are concerned about their memory but are cognitively normal (CN) or have mild cognitive deficits. Each participant undergoes an extensive assessment including several demographic, medical, social, environmental, clinical, nutritional, neuropsychological determinants and lifestyle activities. Furthermore, we are collecting data from portable devices, neuroimaging techniques and biological samples (blood, stools, CSF). All participants are assessed annually for a period of 10 years. Results: In total, 47 participants have completed the initial evaluation up to date and are divided in two groups, CN individuals (N = 26) and MCI patients (N = 21), based on their cognitive status. The participants are, on average, 64 years old, 46.3% of the sample is male with an average of 12.73 years of education. MCI patients report more comorbidities and have a lower score in the MMSE test. Regarding APOE status, 2 participants are ε4 homozygotes and 10 ε4 heterozygotes. CSF analyses (Aß42, Τ-tau, P-tau) revealed no differences between the two groups. Conclusion: The ALBION study offers an opportunity to explore preclinical dementia and identify new and tailored markers, particularly relating to lifestyle. Further investigation of these populations may provide a wider profile of the changes taking place in the preclinical phase of dementia, leading to potentially effective therapeutic and preventive strategies.


Assuntos
Doença de Alzheimer/prevenção & controle , Disfunção Cognitiva/metabolismo , Prevenção Primária , Sintomas Prodrômicos , Idoso , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Apolipoproteínas E/genética , Biomarcadores , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/fisiopatologia , Diagnóstico Precoce , Eletroencefalografia , Feminino , Neuroimagem Funcional , Grécia , Humanos , Estudos Longitudinais , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/líquido cefalorraquidiano , Dados Preliminares , Proteínas tau/líquido cefalorraquidiano
4.
Nat Commun ; 10(1): 3442, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31371707

RESUMO

The presence of amyloid beta (Aß) plaques in the brain of some individuals with Creutzfeldt-Jakob or Gertsmann-Straussler-Scheinker diseases suggests that pathogenic prions (PrPSc) would have stimulated the production and deposition of Aß peptides. We here show in prion-infected neurons and mice that deregulation of the PDK1-TACE α-secretase pathway reduces the Amyloid Precursor Protein (APP) α-cleavage in favor of APP ß-processing, leading to Aß40/42 accumulation. Aß predominates as monomers, but is also found as trimers and tetramers. Prion-induced Aß peptides do not affect prion replication and infectivity, but display seedable properties as they can deposit in the mouse brain only when seeds of Aß trimers are co-transmitted with PrPSc. Importantly, brain Aß deposition accelerates death of prion-infected mice. Our data stress that PrPSc, through deregulation of the PDK1-TACE-APP pathway, provokes the accumulation of Aß, a prerequisite for the onset of an Aß seeds-induced Aß pathology within a prion-infectious context.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Doenças Priônicas/metabolismo , Príons/metabolismo , /metabolismo , Proteína ADAM17/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Comportamento Animal , Encéfalo/metabolismo , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Doenças Neurodegenerativas/metabolismo , Neurônios/metabolismo , Fragmentos de Peptídeos/líquido cefalorraquidiano , Placa Amiloide/metabolismo , Doenças Priônicas/líquido cefalorraquidiano , Doenças Priônicas/patologia , Células-Tronco
5.
Neurology ; 93(4): e334-e346, 2019 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-31266904

RESUMO

OBJECTIVE: To investigate the relationship between cognitive reserve (CR) and clinical progression across the Alzheimer disease (AD) spectrum. METHODS: We selected 839 ß-amyloid (Aß)-positive participants with normal cognition (NC, n = 175), mild cognitive impairment (MCI, n = 437), or AD dementia (n = 227) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). CR was quantified using standardized residuals (W scores) from a (covariate-adjusted) linear regression with global cognition (13-item Alzheimer's Disease Assessment Scale-cognitive subscale) as an independent variable of interest, and either gray matter volumes or white matter hyperintensity volume as dependent variables. These W scores, reflecting whether an individual's degree of cerebral damage is lower or higher than clinically expected, were tested as predictors of diagnostic conversion (i.e., NC to MCI/AD dementia, or MCI to AD dementia) and longitudinal changes in memory (ADNI-MEM) and executive functions (ADNI-EF). RESULTS: The median follow-up period was 24 months (interquartile range 6-42). Corrected for age, sex, APOE4 status, and baseline cerebral damage, higher gray matter volume-based W scores (i.e., greater CR) were associated with a lower diagnostic conversion risk (hazard ratio [HR] 0.22, p < 0.001) and slower decline in memory (ß = 0.48, p < 0.001) and executive function (ß = 0.67, p < 0.001). Stratified by disease stage, we found similar results for NC (diagnostic conversion: HR 0.30, p = 0.038; ADNI-MEM: ß = 0.52, p = 0.028; ADNI-EF: ß = 0.42, p = 0.077) and MCI (diagnostic conversion: HR 0.21, p < 0.001; ADNI-MEM: ß = 0.43, p = 0.003; ADNI-EF: ß = 0.59, p < 0.001), but opposite findings (i.e., more rapid decline) for AD dementia (ADNI-MEM: ß = -0.91, p = 0.002; ADNI-EF: ß = -0.77, p = 0.081). CONCLUSIONS: Among Aß-positive individuals, greater CR related to attenuated clinical progression in predementia stages of AD, but accelerated cognitive decline after the onset of dementia.


Assuntos
Doença de Alzheimer/psicologia , Disfunção Cognitiva/psicologia , Reserva Cognitiva , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Compostos de Anilina , Estudos de Casos e Controles , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/diagnóstico por imagem , Meios de Contraste , Progressão da Doença , Etilenoglicóis , Função Executiva , Feminino , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/patologia , Humanos , Masculino , Memória , Pessoa de Meia-Idade , Tamanho do Órgão , Fragmentos de Peptídeos/líquido cefalorraquidiano , Tiazóis , Substância Branca/diagnóstico por imagem , Substância Branca/patologia
6.
Braz J Psychiatry ; 41(6): 479-484, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31166546

RESUMO

OBJECTIVE: The relationship between biomarkers of amyloid-beta aggregation (Aß1-42) and/or neurodegeneration (Tau protein) in cerebrospinal fluid (CSF) and cognitive decline is still unclear. We aimed to ascertain whether CSF biomarkers correlate with cognitive performance in healthy and cognitively impaired subjects, starting from clinical diagnoses. METHODS: We tested for correlation between CSF biomarkers and Mini-Mental State Examination (MMSE) scores in 208 subjects: 54 healthy controls, 82 with mild cognitive impairment (MCI), 46 with Alzheimer's disease (AD), and 26 with other dementias (OD). RESULTS: MMSE correlated weakly with all CSF biomarkers in the overall sample (r = 0.242, p < 0.0006). Aß1-42 and MMSE correlated weakly in MCI (r = 0.247, p = 0.030), and moderately in OD (r = 0.440, p = 0.027). t-Tau showed a weak inverse correlation with MMSE in controls (r = -0.284, p = 0.043) and MCI (r = -0.241, p = 0.036), and a moderate/strong correlation in OD (r = 0.665), p = 0.0003). p-Tau correlated weakly with MMSE in AD (r = -0.343, p = 0.026) and moderately in OD (r = -0.540, p = 0.0005). The Aß1-42/p-Tau ratio had a moderate/strong correlation with MMSE in OD (r = 0.597, p = 0.001). CONCLUSION: CSF biomarkers correlated best with cognitive performance in OD. t-Tau correlated weakly with cognition in controls and patients with MCI. In AD, only p-Tau levels correlated with cognitive performance. This pattern, which has been reported previously, seems to indicate that CSF biomarkers might not be reliable as indicators of disease severity.


Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Disfunção Cognitiva/líquido cefalorraquidiano , Fragmentos de Peptídeos/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/psicologia , Análise de Variância , Biomarcadores/líquido cefalorraquidiano , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Masculino , Testes de Estado Mental e Demência , Pessoa de Meia-Idade , Valores de Referência , Estatísticas não Paramétricas
7.
J Neurol ; 266(9): 2304-2311, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31179518

RESUMO

BACKGROUND: Cerebrospinal fluid (CSF) biomarkers are increasingly used to diagnose Alzheimer's disease (AD). However, important methodological and technical remain regarding measurement variability between kit providers and users. We compared the Lumipulse fully automated assays with the manual INNOTEST assays (both from Fujirebio Europe NV, Gent, Belgium) on a clinically representative sample of patients and controls. METHODS: CSF samples of 156 patients were used to quantify Amyloïd Aß1-42 peptide (Aß1-42) and Total-Tau (T-Tau) protein by chemiluminescent enzyme-immunoassay (Lumipulse). Patients were divided into several subgroups: Alzheimer (AD = 44), mild-cognitive impairment (MCI = 23), other dementias (OD = 36), non-dementing neurological conditions (ND = 11), and controls (CTRL = 42). Clinical cut-offs were determined by comparing AD and CTRL with ROC curves for the two markers and their related ratio (T-Tau/Aß1-42). Subgroups of 58 (for phosphorylated-Tau) and 115 samples (for Aß1-42 and T-Tau) were used to evaluate the concordance of this analyzer with the INNOTEST assays. RESULTS: Lumipulse and INNOTEST assays showed good concordance for all markers, but systematic bias was observed justifying the need to redefine new clinical cut-offs. To discriminate AD from CTRL subjects, T-Tau/Aß1-42 ratio was the best biomarker, with a cut-off value of 1.12 (sensitivity 81.8% and specificity 92.9%). Similar clinical performances were observed for the Lumipulse and Innotests assays on the subsample of 115 subjects. CONCLUSIONS: Our results demonstrate that the Lumipulse Aß1-42 and T-Tau assays show good analytical and clinical performances in the context of patient evaluation referred to a memory clinic. Automated analyzers should be preferred for the measurement of CSF AD biomarkers to reduce inter- and intra-laboratory variability.


Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Técnicas Imunoenzimáticas/métodos , Medições Luminescentes/métodos , Fragmentos de Peptídeos/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Idoso , Idoso de 80 Anos ou mais , Peptídeos beta-Amiloides/análise , Biomarcadores/análise , Biomarcadores/líquido cefalorraquidiano , Feminino , Humanos , Técnicas Imunoenzimáticas/normas , Medições Luminescentes/normas , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/análise , Proteínas tau/análise
8.
J Am Soc Mass Spectrom ; 30(7): 1325-1329, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31073890

RESUMO

Immunoprecipitation (IP) combined with MALDI-TOF mass spectrometry is a powerful instrument for peptide and protein identification in biological samples. In this study, the analytical capabilities of MALDI-TOF/TOF mass spectrometry for relative quantitation of isoAsp7 in Aß(1-42) and Aß(1-16) were investigated. The possibility of quantitative determination of isoAsp7 in Aß(1-42) with the detection limit as low as 2 pmol has been demonstrated. The same approach was applied for a shorter peptide Aß(1-16) and resulted in enhanced accuracy (± 3.2%), and lower detection limit (50 fmol). Pilot experiments with artificial cerebrospinal fluid and mouse brain tissue were performed and showed that the proposed IP-MALDI-TOF/TOF approach could be applied for measuring isoAß content in biological fluids and tissues. Additionally, it was shown that 6E10 anti-amyloid antibodies might affect the accuracy of the amyloid-ß quantitation in the presence of the isomerized peptide.


Assuntos
Peptídeos beta-Amiloides/análise , Ácido Aspártico/análise , Fragmentos de Peptídeos/análise , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Animais , Ácido Aspártico/líquido cefalorraquidiano , Química Encefálica , Humanos , Isomerismo , Camundongos , Camundongos Transgênicos , Fragmentos de Peptídeos/líquido cefalorraquidiano
9.
Neurobiol Aging ; 79: 131-141, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31055223

RESUMO

Amyloid ß (Aß) and tau are key hallmark features of Alzheimer's disease (AD) neuropathology. The interplay of Aß and tau for cognitive impairment in early AD was examined with cross-sectional analysis, measured by cerebrospinal fluid biomarkers (Aß1-42, total tau [t-tau], and phosphorylated tau [p-tau181P]), and on cognitive performance by the repeatable battery for assessment of neuropsychological status (RBANS). Participants (n = 246) included cognitively normal (Aß-), mild cognitively impaired (Aß-), preclinical AD (Aß+), and prodromal AD (Aß+). Overall, cognitive scores (RBANS total scale score) had a moderate negative correlation to t-tau (n = 246; r = -0.434; p < 0.001) and p-tau181P (r = -0.389; p < 0.001). When classified by Aß status, this correlation to t-tau was applicable only in Aß+ participants (n = 139; r = -0.451, p < 0.001) but not Aß- participants (n = 107; r = 0.137, p = 0.16), with identical findings for p-tau. Both tau (p < 0.0001) and interaction of Aß1-42 with tau (p = 0.006) affected RBANS, but not Aß1-42 alone. Cognitive/memory performance correlated well with cerebrospinal fluid tau levels across early stages of AD, although the correlation is Aß dependent.


Assuntos
Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Cognição , Fragmentos de Peptídeos/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Idoso , Doença de Alzheimer/diagnóstico , Biomarcadores/líquido cefalorraquidiano , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos
10.
Neurology ; 92(23): e2699-e2705, 2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-31068481

RESUMO

OBJECTIVE: To identify potential predictors for outcome in individuals with mild cognitive impairment (MCI) who have reverted to normal cognition (NC). METHODS: We selected individuals with MCI, who reverted at follow-up to NC, with follow-up after reversion from Alzheimer's Disease Neuroimaging Initiative. Common clinical markers, Alzheimer disease (AD) biomarkers, and neurodegeneration imaging markers were used to compare MCI reverters based on subsequent clinical outcome (i.e., subsequent decline or stable reversion). For independent comparison, findings of the clinical Amsterdam Dementia Cohort are presented. RESULTS: Seventy-seven (10%) out of 757 individuals with MCI reverted to NC and 61 of these individuals had follow-up data available. After 3.2 ± 2.2 years, 16 (24%) progressed to MCI, and 3 (5%) to dementia. Those who declined were older and had a higher amyloid PET burden and higher CSF tau levels. CONCLUSION: In MCI reverters, abnormal biomarkers for AD pathology are associated with subsequent decline. AD biomarkers may aid in the prognosis of reverting MCI.


Assuntos
Encéfalo/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagem , Demência/epidemiologia , Placa Amiloide/diagnóstico por imagem , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Compostos de Anilina , Biomarcadores , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/epidemiologia , Progressão da Doença , Etilenoglicóis , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/líquido cefalorraquidiano , Tomografia por Emissão de Pósitrons , Prognóstico , Recidiva , Remissão Espontânea , Medição de Risco , Tiazóis , Proteínas tau/líquido cefalorraquidiano
11.
Neurology ; 92(23): e2717-e2726, 2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-31068482

RESUMO

OBJECTIVE: To identify CSF biomarkers that are related to decreased white matter (WM) integrity and poor cognitive performance in former professional athletes with a history of multiple concussions. METHODS: Concentrations of phosphorylated tau181, total tau (t-tau), and ß-amyloid in the CSF were measured in 3 groups: 22 former professional athletes with multiple concussions (mean ± SD age 55.9 ± 12.2 years), 5 healthy controls (age 57.4 ± 5.2 years), and 12 participants (age 60.0 ± 6.6 years) diagnosed with Alzheimer disease (AD). All participants in the former athletes group underwent diffusion tensor imaging to determine WM tract integrity and completed neuropsychological testing. We divided the former athletes group into those with normal (<300 pg/mL) and high (>300 pg/mL) CSF t-tau. RESULTS: CSF t-tau in the former athletes group was significantly higher than in the healthy control group (349.3 ± 182.6 vs 188.8 ± 39.9 pg/mL, p = 0.003) and significantly lower than in the patients with AD (349.3 ± 182.6 vs 857.0 ± 449.3 pg/mL, p = 0.007). Fractional anisotropy values across all the tracts were significantly lower in the high CSF t-tau group compared to the normal CSF t-tau group (p = 0.036). Participants in the high CSF t-tau group scored significantly lower on the Trail Making Test (TMT) Part B compared to the normal CSF t-tau group (t scores 45.6 ± 18.8 vs 62.3 ± 10.1, p = 0.017). CONCLUSION: Our findings indicate that former athletes with multiple concussions are at increased risk of elevated levels of CSF t-tau and that high CSF t-tau is associated with reduced WM integrity and worse scores on the TMT Part B.


Assuntos
Peptídeos beta-Amiloides/líquido cefalorraquidiano , Atletas , Concussão Encefálica/líquido cefalorraquidiano , Cognição , Fragmentos de Peptídeos/líquido cefalorraquidiano , Substância Branca/diagnóstico por imagem , Proteínas tau/líquido cefalorraquidiano , Adulto , Idoso , Doença de Alzheimer/líquido cefalorraquidiano , Concussão Encefálica/diagnóstico por imagem , Concussão Encefálica/psicologia , Estudos de Casos e Controles , Encefalopatia Traumática Crônica , Imagem de Tensor de Difusão , Futebol Americano/lesões , Hóquei/lesões , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Esqui/lesões , Teste de Sequência Alfanumérica
12.
Ann Surg ; 269(6): 1200-1205, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31082921

RESUMO

OBJECTIVE: To test the hypothesis that APOE ε4 status and cerebrospinal fluid (CSF) Aß42, T-tau and P-tau would independently predict the risk of postoperative delirium. BACKGROUND: Delirium following surgery is common and associated with adverse outcomes. Age and cognitive impairment are consistent risk factors for postoperative delirium. METHODS: This observational cohort study recruited 282 participants aged 65 years or older, without a diagnosis of dementia, admitted for primary elective hip or knee arthroplasty. Cognitive tests were undertaken preoperatively, blood and CSF were sampled at the time of spinal anesthesia, and participants were assessed daily postoperatively for delirium. RESULTS: Increasing age (P = 0.04), preoperative comorbidity (P = 0.03), type of surgery (P = 0.05), intravenous opioid usage (P = 0.04), and low CSF Aß42 (P < 0.01) were independent predictors of postoperative delirium. CONCLUSIONS: This study is the first to show an independent association between CSF Aß42 and delirium incidence in an elective surgical population, suggesting that postoperative delirium may indicate incipient Alzheimer disease.


Assuntos
Peptídeos beta-Amiloides/líquido cefalorraquidiano , Artroplastia de Quadril/efeitos adversos , Artroplastia do Joelho/efeitos adversos , Delírio/líquido cefalorraquidiano , Delírio/etiologia , Fragmentos de Peptídeos/líquido cefalorraquidiano , Complicações Pós-Operatórias/etiologia , Idoso , Idoso de 80 Anos ou mais , Apolipoproteína E4/metabolismo , Estudos de Coortes , Procedimentos Cirúrgicos Eletivos/efeitos adversos , Feminino , Humanos , Masculino , Complicações Pós-Operatórias/líquido cefalorraquidiano , Proteínas tau/metabolismo
13.
Nat Commun ; 10(1): 2240, 2019 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-31110178

RESUMO

The beta-site APP cleaving enzyme 1 (BACE1) is known primarily for its initial cleavage of the amyloid precursor protein (APP), which ultimately leads to the generation of Aß peptides. Here, we provide evidence that altered BACE1 levels and activity impact the degradation of Aß40 and Aß42 into a common Aß34 intermediate. Using human cerebrospinal fluid (CSF) samples from the Amsterdam Dementia Cohort, we show that Aß34 is elevated in individuals with mild cognitive impairment who later progressed to dementia. Furthermore, Aß34 levels correlate with the overall Aß clearance rates in amyloid positive individuals. Using CSF samples from the PREVENT-AD cohort (cognitively normal individuals at risk for Alzheimer's disease), we further demonstrate that the Aß34/Aß42 ratio, representing Aß degradation and cortical deposition, associates with pre-clinical markers of neurodegeneration. We propose that Aß34 represents a marker of amyloid clearance and may be helpful for the characterization of Aß turnover in clinical samples.


Assuntos
Doença de Alzheimer/patologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Disfunção Cognitiva/patologia , Fragmentos de Peptídeos/metabolismo , Idoso , Doença de Alzheimer/líquido cefalorraquidiano , Secretases da Proteína Precursora do Amiloide/genética , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Animais , Ácido Aspártico Endopeptidases/genética , Biomarcadores/líquido cefalorraquidiano , Biomarcadores/metabolismo , Encéfalo/patologia , Linhagem Celular Tumoral , Disfunção Cognitiva/líquido cefalorraquidiano , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Fragmentos de Peptídeos/líquido cefalorraquidiano , Proteólise , Ratos , Ratos Sprague-Dawley
14.
Nutrients ; 11(5)2019 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-31126170

RESUMO

As malnutrition is common in patients with Alzheimer's disease (AD), we evaluated nutritional status and body composition of patients with AD, mild cognitive impairment (MCI) and controls, and studied associations of AD biomarkers and cognitive performance with nutritional status and body composition. We included 552 participants, of which 198 patients had AD, 135 patients had MCI and 219 controls. We assessed nutritional status (mini nutritional assessment (MNA)) and body composition (body mass index (BMI), fat-free mass (FFM) and waist circumference). Linear regression analyses (adjusted for age, gender and education where appropriate) were applied to test associations of AD biomarkers and cognitive performance on five domains with nutritional parameters (dependent). Patients with MCI and AD had a lower BMI and MNA score than controls. Worse performance in all cognitive domains was associated with lower MNA score, but not with body composition. AD biomarkers were associated with MNA score, BMI and waist circumference, and associations with MNA score remained after adjustment for cognitive performance. Both AD biomarkers and cognitive performance were associated with nutritional status, associations with AD biomarkers remained after adjustment for cognition. Our data suggest that malnutrition is not only related to impaired cognition but also to AD pathology.


Assuntos
Doença de Alzheimer/psicologia , Composição Corporal , Cognição , Disfunção Cognitiva/psicologia , Desnutrição/fisiopatologia , Estado Nutricional , Idoso , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/genética , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Apolipoproteína E4/genética , Biomarcadores/líquido cefalorraquidiano , Índice de Massa Corporal , Estudos de Casos e Controles , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/genética , Disfunção Cognitiva/fisiopatologia , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos , Fragmentos de Peptídeos/líquido cefalorraquidiano , Fosforilação , Estudos Prospectivos , Fatores de Risco , Circunferência da Cintura , Proteínas tau/líquido cefalorraquidiano
15.
Clin Biochem ; 72: 7-14, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31129181

RESUMO

BACKGROUND: Alzheimer's disease (AD) biomarkers, such as cerebrospinal fluid (CSF) amyloid-ß (1-42; Aß42), can provide high diagnostic accuracy. Several immunoassays are available for Aß42 quantitation, but standardisation across assays remains an issue. We compared the Elecsys® ß-Amyloid (1-42) CSF assay with three assays and two liquid chromatography tandem mass spectrometry (LC-MS/MS) methods. METHODS: Three method comparison studies evaluated the correlation between the Elecsys® ß-Amyloid (1-42) CSF assay versus: INNOTEST® ß-AMYLOID(1-42) (860 samples) and the Roche Diagnostics-developed LC-MS/MS method (250 samples); INNO-BIA AlzBio3 and the University of Pennsylvania (UPenn)-developed LC-MS/MS method (250 samples); and ADx-EUROIMMUN Beta-Amyloid (1-42) enzyme-linked immunosorbent assay (ELISA) (49 samples). RESULTS: High correlation was demonstrated between Elecsys® ß-Amyloid (1-42) CSF and comparator assays: INNOTEST® ß-AMYLOID(1-42) (Spearman's ρ, 0.954); INNO-BIA AlzBio3 (Spearman's ρ, 0.864); ADx-EUROIMMUN Beta-Amyloid (1-42) ELISA (Pearson's r, 0.925). Elecsys® assay and LC-MS/MS measurements were highly correlated: Pearson's r, 0.949 (Roche Diagnostics-developed method) and 0.943 (UPenn-developed method). CONCLUSION: Findings from this multicentre evaluation further support use of the Elecsys® ß-Amyloid (1-42) CSF assay to aid AD diagnosis. CSF-based certified reference materials should improve agreement across assays and mass spectrometry-based methods, which is essential to establish a global uniform CSF Aß42 cut-off to detect amyloid pathology.


Assuntos
Peptídeos beta-Amiloides/líquido cefalorraquidiano , Técnicas Eletroquímicas/métodos , Imunoensaio/métodos , Fragmentos de Peptídeos/líquido cefalorraquidiano , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico , Biomarcadores/líquido cefalorraquidiano , Cromatografia Líquida/métodos , Ensaio de Imunoadsorção Enzimática/métodos , Humanos , Espectrometria de Massas em Tandem/métodos
16.
Eur J Clin Microbiol Infect Dis ; 38(8): 1443-1447, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31093802

RESUMO

Biomarkers classically studied in Alzheimer's disease have been analyzed in numerous central nervous system infections in adults, but there are scarce data on these biomarkers in children. Enteroviruses appear to be the most common cause of aseptic meningitis throughout the world. The aim of the study was to investigate neuroinflammatory properties of non-polio enteroviruses by measuring CSF concentrations of biomarkers that are involved in neuropathological pathways of neurodegenerative disorders. We measured Aß42, t-tau, and S100B concentrations in 42 children with enteroviral meningitis (EM) compared to control group without central nervous system infection. We found enteroviral meningitis (EM) to reduce CSF concentration of Aß42 (median, 1051.1 pg/mL; interquartile range (IQR), 737.6-1559.5 vs. median, 459.4 pg/mL; IQR, 312.0-662.0, p < 0.001). In contrast, CSF concentrations of t-tau and S100B were not affected by EM. There was a correlation between total neutrophil count in CSF and Aß42 (R = - 0.59, p < 0.001). Absolute number of mononuclear cells in the CSF correlated with CSF t-tau (R = 0.41, p < 0.05). Both correlations remained significant after adjustment for age, blood leukocytes, serum CRP, CSF leukocytes, and CSF protein concentration.


Assuntos
Peptídeos beta-Amiloides/líquido cefalorraquidiano , Infecções por Enterovirus/líquido cefalorraquidiano , Meningite Viral/líquido cefalorraquidiano , Fragmentos de Peptídeos/líquido cefalorraquidiano , Adolescente , Biomarcadores/líquido cefalorraquidiano , Criança , Pré-Escolar , Enterovirus , Feminino , Hospitalização , Humanos , Masculino , Polônia , Subunidade beta da Proteína Ligante de Cálcio S100/líquido cefalorraquidiano , Centros de Atenção Terciária , Proteínas tau/líquido cefalorraquidiano
17.
Neurobiol Aging ; 79: 101-109, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31029938

RESUMO

Apolipoprotein E (APOE) ε4 genotype is associated with increased cerebral amyloid beta (Aß) deposition in nondemented elderly and suggested to influence ApoE as well as ApoJ (clusterin [Clu]) and ApoA1 expression. We aimed to assess whether APOE affects early Alzheimer's disease pathophysiology via these apolipoproteins. Cerebrospinal fluid (CSF) ApoE, Clu, ApoA1, and CSF amyloid beta1-42 (Aß42) and tau levels were assessed in 403 individuals with subjective cognitive decline and mild cognitive impairment using enzyme-linked immunosorbent assay. Whether CSF apolipoprotein levels mediated APOEε4 allele frequency effects on CSF Aß42 and tau in nondemented elderly was investigated using mediation analysis, with age- and gender-adjusted linear regression analyses. CSF ApoE mediated 48% of the association between APOEε4 and CSF tau, whereas Clu and ApoA1 did not. In addition, CSF Clu partially mediated the relation between CSF ApoE and tau (12%). CSF apolipoproteins did not mediate the inverse relation between APOEε4 and CSF Aß42, despite a strong association between the latter 2 biomarkers. In summary, our findings suggest that ApoE and Clu are involved in Aß-independent pathways as part of the cascade leading to Alzheimer pathology.


Assuntos
Apolipoproteínas E/líquido cefalorraquidiano , Apolipoproteínas E/genética , Encéfalo/metabolismo , Clusterina/líquido cefalorraquidiano , Disfunção Cognitiva/líquido cefalorraquidiano , Genótipo , Proteínas tau/líquido cefalorraquidiano , Idoso , Doença de Alzheimer/etiologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Apolipoproteína A-I/líquido cefalorraquidiano , Feminino , Frequência do Gene , Humanos , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/líquido cefalorraquidiano
19.
Mol Cell Biochem ; 458(1-2): 71-78, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31004306

RESUMO

Repetitive transcranial magnetic stimulation (rTMS) is a technique protecting neurons against diverse neurodegenerative disorders by delivering magnetic stimuli into the brain through the intact scalp. In the current study, the protection effect of rTMS on Parkinson's disease (PD) and the associated mechanism driving the treatment were explored. The PD symptoms were induced using 6-OHDA in mice, and the effect of rTMS of two frequencies (1 Hz and 10 Hz) on the cognitive behaviors and neuron viability was detected. Afterwards, the level of Aß1-42 and activity of MKK7-ERK-Fos-APP axis under the administration of rTMS were recorded as well. The intracranial injection of 6-OHDA impaired the cognitive behaviors of the mice in the test of Morris water maze as well as reducing the viability and number of neurons in PD mice. After the treatment of rTMS of both frequencies, the cognitive function of mice was improved and the neuron viability and number were restored in mice brain tissues. The administration of rTMS also increased the cerebrospinal fluid (CSF) level of Aß1-42 in PD mice, which was accompanied by the suppressed levels of p-MKK7, p-ERK1/2, p-c-Fos, and APP. Moreover, the effect of rTMS on mice nerve system was all exerted in a frequency-dependent manner. In conclusion, the findings outlined in the current study affirmed the protection effect of rTMS against PD. The anti-PD function of rTMS was associated with the suppression of MKK7-ERK-Fos-APP axis, which subsequently resulted in the increased CSF Aß1-42 level and decreased brain Aß1-42 level.


Assuntos
Peptídeos beta-Amiloides/líquido cefalorraquidiano , Encéfalo , Aprendizagem em Labirinto/efeitos dos fármacos , Oxidopamina/toxicidade , Doença de Parkinson Secundária , Fragmentos de Peptídeos/líquido cefalorraquidiano , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Camundongos , Neurônios/metabolismo , Neurônios/patologia , Doença de Parkinson Secundária/metabolismo , Doença de Parkinson Secundária/patologia , Doença de Parkinson Secundária/fisiopatologia , Doença de Parkinson Secundária/terapia , Estimulação Magnética Transcraniana
20.
J Neurol ; 266(7): 1685-1692, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30963253

RESUMO

BACKGROUND: Atypical cerebrospinal fluid (CSF) patterns, involving an increase in the concentration of phosphorylated-tau (P-tau) proteins but normal amyloid-ß concentration, are not uncommon in patients with mild neurocognitive disorders and suspected Alzheimer's disease (AD). In these conditions, however, AD diagnosis may be ruled out in the absence of any amyloid deposition at positron-emission tomography (PET). This pilot cross-sectional study was aimed to determine whether this negativity of amyloid PET can be predicted by CSF profiles in such patients. METHODS: Twenty-five patients (73 [68-80] years, 10 women) with mild neurocognitive disorders, suspected AD and an increase in the CSF concentration of P-tau proteins but normal Aß42 concentration and Aß42/Aß40 ratio were prospectively included and referred to a 18F-florbetaben PET. The latter was considered as definitively negative with the conjunction of both visual (brain amyloid plaque load score) and quantified (standard uptake value ratios) criteria. Predictors of a negative PET were searched among current CSF biomarkers (Aß42, Aß40, T-tau, P-tau, Aß42/Aß40, Aß42/p-tau). RESULTS: Amyloid PET was negative in 15 patients (60%) with a CSF Aß42 concentration being the sole independent predictor of this negativity. The criterion of an Aß42 concentration in the very high range (> 843 pg/mL), observed in 60% (15/25) of the study patients, was associated with a negative amyloid PET in 93% (14/15) of cases. CONCLUSIONS: In mild neurocognitive disorders patients with suspected AD and showing an increase in CSF P-tau protein level, amyloid PETs are commonly negative, when Aß42 concentration is in the very high range. In such case, AD diagnosis based on biomarkers can be ruled out with reasonable certainty, without the need for additional CSF second-line assays or results from amyloid PET.


Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Fragmentos de Peptídeos/líquido cefalorraquidiano , Tomografia por Emissão de Pósitrons/métodos , Proteínas tau/líquido cefalorraquidiano , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Biomarcadores/líquido cefalorraquidiano , Estudos Transversais , Feminino , Humanos , Masculino , Fragmentos de Peptídeos/metabolismo , Fosforilação/fisiologia , Projetos Piloto , Estudos Prospectivos , Proteínas tau/metabolismo
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