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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.
Nervenarzt ; 90(9): 907-913, 2019 Sep.
Artigo em Alemão | MEDLINE | ID: mdl-31407045

RESUMO

In accordance with the current German dementia guidelines, the dementia biomarkers amyloid beta 42, the tau peptides total tau and phosphorylated tau 181 are recommended for cerebrospinal fluid (CSF)-based diagnostics of dementia. Several studies have clearly shown that determination of the amyloid beta 42 to amyloid beta 40 peptide ratio is superior to the interpretation of amyloid beta 42 alone and should be implemented in the clinical work-up; however, in recent years different studies have presented many other innovative CSF and blood-based biomarkers. Besides CSF-based neurochemical diagnostics of dementia promising novel protocols for the detection of amyloid beta peptides in blood have meanwhile been published, which can currently be used in clinical studies for blood-based early diagnostics of Alzheimer's dementia. Following further validation and assay optimization these blood assays should be available for routine diagnostics in the near future.


Assuntos
Doença de Alzheimer , Biomarcadores , Doença de Alzheimer/sangue , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Humanos
5.
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
6.
Expert Opin Pharmacother ; 20(17): 2095-2099, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31423903

RESUMO

Introduction: The amyloid-beta (Aß) cascade hypothesis is that reducing Aß levels in the brain will be beneficial in treating Alzheimer's disease. Aß is formed by the cleavage of amyloid precursor protein by ß-site amyloid precure protein cleaving enzyme (BACE1) and the BACE1 inhibitor verubecestat was developed to lower the brain levels of Aß. However, in the EPOCH trial of verubecestat in mild-to-moderate Alzheimer's disease, it was not beneficial and increased adverse effects.Areas covered: Prior to completing EPOCH, APECS, which trialled verubecestat in prodromal Alzheimer's disease, was commenced. Like EPOCH, APECS was terminated early. In APECS, verubecestat 40 mg worsened cognition and increased adverse effects.Expert opinion: In recruiting subjects to clinical trials in Alzheimer's disease, a clinical diagnosis involving the measurement of Aß should be undertaken for all subjects, as this may help to clarify the findings. In my opinion, the failure of verubecestat in EPOCH and APECS probably could have been avoided if a safety and potential efficacy trial (phase 2) had been completed prior to starting phase 3. It seems to me that, as we have a poor understanding of the underlying mechanisms/cause of Alzheimer's disease, this is where the research emphasis should be, not phase 3 clinical trials.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Óxidos S-Cíclicos/uso terapêutico , Tiadiazinas/uso terapêutico , Doença de Alzheimer/patologia , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Óxidos S-Cíclicos/efeitos adversos , Depressão/etiologia , Dermatite/etiologia , Humanos , Índice de Gravidade de Doença , Tiadiazinas/efeitos adversos , Falha de Tratamento
7.
Biosens Bioelectron ; 142: 111518, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31326861

RESUMO

Alzheimer's disease (AD) is a progressive neurodegenerative illness that affects the elderly population worldwide. The definite diagnosis of AD still depends on post-mortem pathological examination of amyloid plaques consisting of amyliod-ß peptides (Aß) fibrils in the brain so far. However, these fibrils are not closely linked to the development of the disease. Alternatively, soluble Aß are believed to be more reliable biomarkers for early diagnosis of AD. Here, we report a simple approach to quantitative detection of soluble Aß species using N-(6-(benzothiazol-2-yl)pyridin-3-yl)-5-(dimethylamino)naphthalene-1-sulfonamide (BPNS) as a ratiometric fluorescence Zn2+ probe. This ratiometric fluorescence assay is based on the competition of soluble Aß with BPNS for Zn2+, that is, soluble Aß species with higher chelation affinity can capture Zn2+ from BPNS‒Zn2+ adduct, thereby reactivating the ratiometric fluorescence response of BPNS. BPNS exhibited perfect linear relationship (R2 = 0.998) in accordance with the concentration of soluble Aß in the presence of Zn2+. The assay possesses strong anti-interference capacity against exogenous agent or the other proteins, thanks to the high selectivity for soluble Aß species. Importantly, this assay can quantitatively detect soluble Aß species from different types of biological fluids, such as artificial cerebrospinal fluid (ACSF), serum, and plasma in half an hour. This assay provides a low-cost, fast, sensitive, and simple approach for quantitative detection of soluble Aß species and may serve as a potential tool for early-stage AD diagnosis.


Assuntos
Peptídeos beta-Amiloides/análise , Técnicas Biossensoriais/métodos , Quelantes/química , Corantes Fluorescentes/química , Naftalenos/química , Doença de Alzheimer/sangue , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides/sangue , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Cátions Bivalentes/química , Humanos , Espectrometria de Fluorescência/métodos , Zinco/química
8.
Dement Geriatr Cogn Disord ; 47(4-6): 289-296, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31311013

RESUMO

BACKGROUND: Neuropathological studies indicate concomitant Alzheimer's disease (AD) pathology in patients with dementia with Lewy bodies (DLB). OBJECTIVES: To measure cerebrospinal fluid (CSF) levels of ß-amyloid peptide with 42 amino acids (Aß42), total tau protein (τT), and tau phosphorylated at threonine 181 (τP-181) in 38 patients fulfilling the diagnostic criteria of probable DLB according to the most recent (4th consensus) report. METHODS: Double-sandwich commercial ELISAs (Innotest; Fujirebio, Gent, Belgium) were used for measurements. RESULTS: According to the current cutoff values of our laboratory, 4 biomarker profiles were noted: abnormal levels of Aß42 only (44.7%), full AD profile (39.5%), abnormal levels of τT only (5.3%), and normal levels of all 3 biomarkers (10.5%). AD profile was associated with female sex, older age, lower education, and lower MMSE scores. CONCLUSIONS: Reduction in Αß42 in DLB may be more common (>80% of patients) than previously thought, and ∼40% may have the typical CSF AD biomarker profile. AD biochemistry in DLB may be an evolving process showing increasing frequency with disease progression.


Assuntos
Doença de Alzheimer/metabolismo , Biomarcadores/análise , Doença por Corpos de Lewy/metabolismo , Fatores Etários , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Escolaridade , Feminino , Humanos , Doença por Corpos de Lewy/psicologia , Masculino , Testes de Estado Mental e Demência , Pessoa de Meia-Idade , Prevalência , Valores de Referência , Estudos Retrospectivos , Fatores Sexuais , Proteínas tau/análise
9.
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
10.
Neurology ; 93(4): e322-e333, 2019 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-31289148

RESUMO

OBJECTIVE: To determine the time required for a preclinical Alzheimer disease population to decline in a meaningful way, use estimates of decline to update previous clinical trial design assumptions, and identify factors that modify ß-amyloid (Aß)-related decline. METHODS: In 1,120 cognitively unimpaired individuals from 3 international cohorts, we estimated the relationship between Aß status and longitudinal changes across multiple cognitive domains and assessed interactions between Aß and baseline factors. Power analyses were performed to explore sample size as a function of treatment effect. RESULTS: Cognitively unimpaired Aß+ participants approach mild cognitive impairment (MCI) levels of performance 6 years after baseline, on average. Achieving 80% power in a simulated 4-year treatment trial, assuming a 25% treatment effect, required 2,000 participants/group. Multiple factors interacted with Aß to predict cognitive decline; however, these findings were all cohort-specific. Despite design differences across the cohorts, with large sample sizes and sufficient follow-up time, the Aß+ groups declined consistently on cognitive composite measures. CONCLUSIONS: A preclinical AD population declines to the cognitive performance of an early MCI population in 6 years. Slowing this rate of decline by 40%-50% delays clinically relevant impairment by 3 years-a potentially meaningful treatment effect. However, assuming a 40%-50% drug effect highlights the difficulties in preclinical AD trial design, as a more commonly assumed treatment effect of 25% results in a required sample size of 2,000/group. Designers of preclinical AD treatment trials need to prepare for larger and longer trials than are currently being considered. Interactions with Aß status were inconsistent and not readily generalizable.


Assuntos
Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Encéfalo/diagnóstico por imagem , Disfunção Cognitiva/psicologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico por imagem , Compostos de Anilina , Doenças Assintomáticas , Benzotiazóis , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/diagnóstico por imagem , Meios de Contraste , Progressão da Doença , Etilenoglicóis , Feminino , Humanos , Masculino , Rememoração Mental , Testes de Estado Mental e Demência , Pessoa de Meia-Idade , Testes Neuropsicológicos , Tomografia por Emissão de Pósitrons , Tiazóis , Fatores de Tempo , Teste de Sequência Alfanumérica
11.
Clin Biochem ; 72: 15-23, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31194969

RESUMO

During the last two decades, neuropathological examination of the brain has evolved both technically and scientifically. The increasing use of immunohistochemistry to detect protein aggregates paralleled a better understanding of neuroanatomical progression of protein deposition. As a consequence, an international effort was achieved to standardize hyperphosphorylated-Tau (phospho-TAU), ßAmyloid (Aß), alpha syncuclein (alpha-syn), phosphorylated transactive response DNA-binding protein 43 (phospho-TDP43) and vascular pathology detection. Meanwhile harmonized staging systems emerged in order to increase inter rater reproducibility. Therefore, a refined definition of Alzheimer's disease was recommended., a clearer picture of the neuropathological lesions diversity emerged secondarily to the systematic assessment of concomitant pathology highlighting finally a low rate of pure AD pathology. This brings new challenges to laboratory medicine in the field of cerebrospinal fluid (CSF) markers of Alzheimer's disease: how to further validate total Tau, phospho-TAU, Aß40 and Aß42 and new marker level cut-offs while autopsy rates are declining?


Assuntos
Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/normas , Biomarcadores/líquido cefalorraquidiano , Biomarcadores/química , Encéfalo/patologia , Progressão da Doença , Humanos , Fosforilação , Proteínas tau/química , Proteínas tau/normas
12.
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
13.
BMC Neurol ; 19(1): 113, 2019 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-31164098

RESUMO

BACKGROUND AND AIM: Toxic oligomeric α-synuclein (αS; O-αS) has been suggested to play a central role in the pathogenesis of Lewy body diseases such as Parkinson's disease (PD). Cerebrospinal fluid (CSF) levels of αS, O-αS, total and phosphorylated tau, and amyloid ß 1-42 (Aß1-42) are thought to reflect the pathophysiology or clinical symptoms in PD. In this study, we examined correlations of the CSF levels of these proteins with the clinical symptoms, and with each other in drug-naïve patients with PD. METHODS: Twenty-seven drug-naïve patients with PD were included. Motor and cognitive functions were assessed using the Unified Parkinson's Disease Rating Scale (UPDRS), Montreal Cognitive Assessment (MoCA), and Neurobehavioral Cognitive Status Examination (COGNISTAT). CSF levels of total αS, O-αS, Aß1-42, total tau and tau phosphorylated at threonine 181 (P-tau181p) were measured. CSF levels of these proteins were compared with clinical assessments from the UPDRS, MoCA and COGNISTAT using Spearman correlation analysis. Spearman correlation coefficients among CSF protein levels were also evaluated. RESULTS: CSF levels of αS were negatively correlated with UPDRS part III (motor score) (p < 0.05) and bradykinesia (p < 0.01), and positively correlated with COGNISTAT subtest of judgement (p < 0.01) and CSF levels of Aß1-42 (p < 0.001), total tau (p < 0.001) and P-tau181p (p < 0.01). Lower CSF levels of Aß1-42, total tau and P-tau181p were significantly related to worsening of some motor and/or cognitive functions. The CSF level of O-αS showed no correlation with any motor and cognitive assessments or with CSF levels of the other proteins. CONCLUSION: CSF levels of αS are correlated with some clinical symptoms and CSF levels of other pathogenic proteins in drug-naïve PD patients. These correlations suggest a central role for interaction and aggregation of αS with Aß1-42, tau, and phosphorylated tau in the pathogenesis of PD. Although O-αS has been shown to have neurotoxic effects, CSF levels do not reflect clinical symptoms or levels of other proteins in cross-sectional assessment.


Assuntos
Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Doença de Parkinson/líquido cefalorraquidiano , alfa-Sinucleína/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Idoso , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/fisiopatologia
14.
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
15.
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
16.
Clin Chim Acta ; 495: 318-325, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31051162

RESUMO

The clinical diagnosis of Parkinson's disease (PD) and Dementia with Lewy bodies (DLB) is challenging due to highly variable clinical presentation and clinical and pathological overlap with other neurodegenerative diseases. Since cerebrospinal fluid (CSF) mirrors the pathological changes taking place in the brain, it represents a promising source of biomarkers. With respect to classical AD biomarkers, low CSF Aß42 levels have shown a robust prognostic value in terms of development of cognitive impairment in PD and DLB. In the differential diagnosis between AD and DLB, a potential role of t-tau, p-tau and Aß42/Aß38 ratio has been demonstrated. Regarding CSF α-synuclein (α-syn) species, lower levels of total α-synuclein (t-α-syn) and higher concentration of oligomeric-α-synuclein (o-α-syn) and phosphorylated α-synuclein (p-α-syn) have been observed in PD. Furthermore, the detection of "pro-aggregating" α-synuclein has enabled the discrimination of patients affected by synucleinopathies with high sensitivity and specificity. New promising biomarkers are emerging: GCase activity (reduced in PD and DLB patients vs. controls), CSF/serum albumin ratio (increased in PD and DLB), fatty-acid-binding protein (increased in AD and DLB vs. PD), visinin-like protein-1 (increased in AD vs. DLB) and monoamines (useful in differential diagnosis among PD and DLB). These encouraging results need to be confirmed by future studies.


Assuntos
Biomarcadores/líquido cefalorraquidiano , Doença por Corpos de Lewy/diagnóstico , Doença de Parkinson/diagnóstico , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Diagnóstico Diferencial , Humanos , alfa-Sinucleína/líquido cefalorraquidiano
17.
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
18.
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
19.
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
20.
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
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