Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 9 de 9
Filtrar
1.
Eur J Neurol ; 29(8): 2431-2438, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35524506

RESUMEN

BACKGROUND AND PURPOSE: Cerebrospinal fluid (CSF) real-time quaking-induced conversion (RT-QuIC) has a high degree of sensitivity and specificity for the diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) and this has led to its being included in revised European CJD Surveillance Network diagnostic criteria for sCJD. As CSF RT-QuIC becomes more widely established, it is crucial that the analytical performance of individual laboratories is consistent. The aim of this ring-trial was to ascertain the degree of concordance between European countries undertaking CSF RT-QuIC. METHODS: Ten identical CSF samples, seven from probable or neuropathologically confirmed sCJD and three from non-CJD cases, were sent to 13 laboratories from 11 countries for RT-QuIC analysis. A range of instrumentation and different recombinant prion protein substrates were used. Each laboratory analysed the CSF samples blinded to the diagnosis and reported the results as positive or negative. RESULTS: All 13 laboratories correctly identified five of the seven sCJD cases and the remaining two sCJD cases were identified by 92% of laboratories. Of the two sCJD cases that were not identified by all laboratories, one had a disease duration >26 months with a negative 14-3-3, whilst the remaining case had a 4-month disease duration and a positive 14-3-3. A single false positive CSF RT-QuIC result was observed in this study. CONCLUSIONS: This study shows that CSF RT-QuIC demonstrates an excellent concordance between centres, even when using a variety of instrumentation, recombinant prion protein substrates and CSF volumes. The adoption of CSF RT-QuIC by all CJD surveillance centres is recommended.


Asunto(s)
Síndrome de Creutzfeldt-Jakob , Priones , Síndrome de Creutzfeldt-Jakob/líquido cefalorraquídeo , Síndrome de Creutzfeldt-Jakob/diagnóstico , Humanos , Proteínas Priónicas , Priones/líquido cefalorraquídeo , Proteínas Recombinantes , Sensibilidad y Especificidad
2.
Alzheimers Dement ; 18(10): 1788-1796, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-34874603

RESUMEN

BACKGROUND: Cerebrospinal fluid (CSF) platelet-derived growth factor receptor-ß (PDGFRß) has been proposed as a biomarker of blood-brain barrier (BBB) breakdown. We studied PDGFRß levels as a biomarker for cerebral amyloid angiopathy (CAA), amnestic mild cognitive impairment (aMCI), or Alzheimer's disease (AD). METHODS: CSF PDGFRß levels were quantified by enzyme-linked immunosorbent assay in patients with CAA, patients with aMCI/AD, and in matched controls. In aMCI/AD we evaluated CSF PDGFRß both by clinical phenotype and by using the AT(N) biomarker classification system defined by CSF amyloid (A), tau (T), and neurodegeneration (N) biomarkers. RESULTS: PDGFRß levels were similar in CAA patients and controls (P = .78) and in aMCI/AD clinical phenotype and controls (P = .91). aMCI/AD patients with an AD+ biomarker profile (A+T+[N+]) had increased PDGFRß levels compared to (A-T-[N-]) controls (P = .006). CONCLUSION: Our findings indicate that PDGFRß levels are associated with an AD+ biomarker profile but are not a suitable biomarker for CAA or aMCI/AD clinical syndrome.


Asunto(s)
Enfermedad de Alzheimer , Angiopatía Amiloide Cerebral , Disfunción Cognitiva , Humanos , Enfermedad de Alzheimer/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Angiopatía Amiloide Cerebral/líquido cefalorraquídeo , Disfunción Cognitiva/líquido cefalorraquídeo , Fragmentos de Péptidos/líquido cefalorraquídeo , Receptor beta de Factor de Crecimiento Derivado de Plaquetas , Proteínas tau/líquido cefalorraquídeo
3.
J Neurosci ; 31(33): 11992-2000, 2011 Aug 17.
Artículo en Inglés | MEDLINE | ID: mdl-21849559

RESUMEN

More than 80% of Alzheimer's disease (AD) patients have some degree of cerebral amyloid angiopathy (CAA). In addition to arteries and veins, capillaries can also be affected. Capillary CAA (capCAA), rather than CAA in larger vessels, is associated with flame-like amyloid-beta (Aß) deposits that may extend beyond the vessel wall and radiate into the neuropil, a phenomenon also known as "dyshoric angiopathy." Aß deposits in AD, parenchymal as well as (cap)CAA and dyshoric angiopathy, are associated with a local inflammatory reaction, including activation of microglial cells and astrocytes that, among others, produce cytokines and reactive oxygen species. This neuroinflammatory reaction may account for at least part of the cognitive decline. In previous studies we observed that small heat shock proteins (sHsps) are associated with Aß deposits in AD. In this study the molecular chaperones Hsp20, HspB8 and HspB2B3 were found to colocalize with CAA and capCAA in AD brains. In addition, Hsp20, HspB8 and HspB2B3 colocalized with intercellular adhesion molecule 1 (ICAM-1) in capCAA-associated dyshoric angiopathy. Furthermore, we demonstrated that Hsp20, HspB8 and HspB2B3 induced production of interleukin 8, soluble ICAM-1 and monocyte chemoattractant protein 1 by human leptomeningeal smooth muscle cells and human brain astrocytes in vitro and that Hsp27 inhibited production of transforming growth factor beta 1 and CD40 ligand. Our results suggest a central role for sHsps in the neuroinflammatory reaction in AD and CAA and thus in contributing to cognitive decline.


Asunto(s)
Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Encéfalo/metabolismo , Encéfalo/patología , Angiopatía Amiloide Cerebral/metabolismo , Angiopatía Amiloide Cerebral/patología , Proteínas de Choque Térmico Pequeñas/fisiología , Mediadores de Inflamación/fisiología , Anciano , Anciano de 80 o más Años , Astrocitos/metabolismo , Astrocitos/patología , Células Cultivadas , Femenino , Proteínas del Choque Térmico HSP20/fisiología , Proteínas de Choque Térmico HSP27/fisiología , Proteínas de Choque Térmico/fisiología , Humanos , Masculino , Chaperonas Moleculares , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Proteínas Serina-Treonina Quinasas/fisiología , Proteínas Recombinantes/farmacología
4.
Proteins ; 79(10): 2956-67, 2011 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-21905118

RESUMEN

The fibrillization of α-synuclein (α-syn) is a key event in the pathogenesis of α-synucleinopathies. Mutant α-syn (A53T, A30P, or E46K), each linked to familial Parkinson's disease, has altered aggregation properties, fibril morphologies, and fibrillization kinetics. Besides α-syn, Lewy bodies also contain several associated proteins including small heat shock proteins (sHsps). Since α-syn accumulates intracellularly, molecular chaperones like sHsps may regulate α-syn folding and aggregation. Therefore, we investigated if the sHsps αB-crystallin, Hsp27, Hsp20, HspB8, and HspB2B3 bind to α-syn and affect α-syn aggregation. We demonstrate that all sHsps bind to the various α-syns, although the binding kinetics suggests a weak and transient interaction only. Despite this transient interaction, the various sHsps inhibited mature α-syn fibril formation as shown by a Thioflavin T assay and atomic force microscopy. Interestingly, HspB8 was the most potent sHsp in inhibiting mature fibril formation of both wild-type and mutant α-syn. In conclusion, sHsps may regulate α-syn aggregation and, therefore, optimization of the interaction between sHsps and α-syn may be an interesting target for therapeutic intervention in the pathogenesis of α-synucleinopathies.


Asunto(s)
Proteínas de Choque Térmico Pequeñas/metabolismo , alfa-Sinucleína/metabolismo , Proteínas de Choque Térmico HSP27/metabolismo , Proteínas de Choque Térmico/metabolismo , Humanos , Microscopía de Fuerza Atómica , Chaperonas Moleculares , Mutación , Unión Proteica , Proteínas Serina-Treonina Quinasas/metabolismo , Resonancia por Plasmón de Superficie , alfa-Sinucleína/genética
5.
Alzheimers Res Ther ; 13(1): 160, 2021 09 24.
Artículo en Inglés | MEDLINE | ID: mdl-34560885

RESUMEN

BACKGROUND: Neuroleukin (NLK) is a protein with neurotrophic properties and is present in a proportion of senile plaques and amyloid laden vessels. It has been suggested that NLK is part of a neuroprotective response to amyloid ß-induced cell death. The aim of our study was to investigate the value of cerebrospinal fluid (CSF) NLK levels as a biomarker of vascular amyloid deposition in patients with cerebral amyloid angiopathy (CAA) and in patients with amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD). METHODS: CSF NLK levels were quantified by ELISA in CAA patients (n = 25) and controls (n = 27) and in two independent samples of aMCI patients, AD patients, and controls: (1) From the Radboud University Medical Center (Nijmegen), we included n = 19 aMCI patients, n = 40 AD patients, and n = 32 controls. (2) From the Hospital of Sant Pau (Barcelona), we included n = 33 aMCI patients, n = 17 AD patients, and n = 50 controls. RESULTS: CSF NLK levels were similar in CAA patients and controls (p = 0.95). However, we found an elevated CSF concentration of NLK in aMCI (p < 0.0001) and AD patients (p < 0.0001) compared to controls in both samples sets. In addition, we found a correlation of CSF NLK with CSF YKL-40 (age-adjusted-spearman-rank-coefficient = 0.82, p < 0.0001) in aMCI/AD patients, a well-known glial marker of neuro-inflammation. CONCLUSIONS: We found that CSF NLK levels are elevated in aMCI and AD patients compared to controls, but are not increased in CAA patients. CSF NLK levels may be related to an increased neuroinflammatory state in early stages of AD, given its association with YKL-40.


Asunto(s)
Enfermedad de Alzheimer , Angiopatía Amiloide Cerebral , Enfermedad de Alzheimer/complicaciones , Péptidos beta-Amiloides , Biomarcadores , Angiopatía Amiloide Cerebral/complicaciones , Glucosa-6-Fosfato Isomerasa , Humanos , Factores de Crecimiento Nervioso , Proteínas Serina-Treonina Quinasas
6.
J Alzheimers Dis ; 55(2): 585-595, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-27662293

RESUMEN

BACKGROUND: Frontotemporal dementia (FTD) is a heterogeneous disease both at the clinical, genetic, and pathobiological level. The underlying pathological spectrum (termed FTLD, frontotemporal lobar degeneration) is in most cases defined by accumulation of either tau (FTLD-tau) or TDP-43 proteins (FTLD-TDP). Biomarkers to differentiate these subtypes are not yet available, whereas these are essential requirements to study the natural course of disease and for homogeneous inclusion of patients in clinical studies. OBJECTIVE: To study if a combination of total (t-) and phosphorylated (p-)tau, and t-TDP-43 and p-TDP-43 proteins in cerebrospinal fluid (CSF) is suitable to discriminate FTLD-tau and FTLD-TDP subtypes. METHODS: We developed immunoassays for the quantification of t-TDP-43 and p-TDP-43 proteins and used commercially available assays for the quantification of t-tau and p-tau proteins. We quantified these proteins in ventricular CSF samples from neuropathologically defined FTLD-tau and FTLD-TDP cases to study the reflection of underlying brain pathology in CSF composition, and in lumbar CSF samples from FTLD-tau and FTLD-TDP patients to study the diagnostic potential of CSF biomarkers. RESULTS: In ventricular CSF, t-TDP-43 and t-tau levels, when combined into one model, were significantly different between neuropathologically-defined FTLD-tau and FTLD-TDP cases. In a pilot study using lumbar CSF, the p-tau/t-tau ratio, but not t-TDP-43 levels, were significantly different between FTLD-TDP and FTLD-tau patients. CONCLUSION: We conclude that with current available methods, CSF tau, rather than TDP-43 proteins, may have diagnostic value in the differentiation of FTLD patients with either tau or TDP-43 pathology.


Asunto(s)
Proteínas de Unión al ADN/líquido cefalorraquídeo , Degeneración Lobar Frontotemporal/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeo , Anciano , Anciano de 80 o más Años , Biomarcadores/líquido cefalorraquídeo , Encéfalo/patología , Femenino , Degeneración Lobar Frontotemporal/clasificación , Degeneración Lobar Frontotemporal/patología , Humanos , Inmunoensayo , Masculino , Persona de Mediana Edad , Proyectos Piloto
7.
Front Neurol ; 8: 310, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28725210

RESUMEN

BACKGROUND: Before implementation in clinical practice, biomarker assays need to be thoroughly analytically validated. There is currently a strong interest in implementation of the ratio of amyloid-ß peptide 1-42 and 1-40 (Aß42/Aß40) in clinical routine. Therefore, in this study, we compared the analytical performance of six assays detecting Aß40 in cerebrospinal fluid (CSF) in six laboratories according to a recently standard operating procedure (SOP) developed for implementation of ELISA assays for clinical routine. METHODS: Aß40 assays of six vendors were validated in up to three centers per assay according to recently proposed international consensus validation protocols. The performance parameters included sensitivity, precision, dilutional linearity, recovery, and parallelism. Inter-laboratory variation was determined using a set of 20 CSF samples. In addition, test results were used to critically evaluate the SOPs that were used to validate the assays. RESULTS: Most performance parameters of the different Aß40 assays were similar between labs and within the predefined acceptance criteria. The only exceptions were the out-of-range results of recovery for the majority of experiments and of parallelism by three laboratories. Additionally, experiments to define the dilutional linearity and hook-effect were not executed correctly in part of the centers. The inter-laboratory variation showed acceptable low levels for all assays. Absolute concentrations measured by the assays varied by a factor up to 4.7 for the extremes. CONCLUSION: All validated Aß40 assays appeared to be of good technical quality and performed generally well according to predefined criteria. A novel version of the validation SOP is developed based on these findings, to further facilitate implementation of novel immunoassays in clinical practice.

8.
J Alzheimers Dis ; 52(4): 1321-33, 2016 04 16.
Artículo en Inglés | MEDLINE | ID: mdl-27104900

RESUMEN

MicroRNAs (miRNAs) regulate translational inhibition of proteins, but are also detected in body fluids, including cerebrospinal fluid (CSF), where they may serve as disease-specific biomarkers. Previously, we showed differential expression of miR-146a, miR-29a, and miR-125b in the CSF of Alzheimer's disease (AD) patients versus controls. In this study, we aim to confirm these findings by using larger, independent sample cohorts of AD patients and controls from three different centers. Furthermore, we aim to identify confounding factors that possibly arise using such a multicenter approach. The study was extended by including patients diagnosed with mild cognitive impairment due to AD, frontotemporal dementia and dementia with Lewy bodies. Previous results of decreased miR-146a levels in AD patients compared to controls were confirmed in one center. When samples from all three centers were combined, several confounding factors were identified. After controlling for these factors, we did not identify differences in miRNA levels between the different groups. However, we provide suggestions to circumvent various pitfalls when measuring miRNAs in CSF to improve future studies.


Asunto(s)
Demencia/líquido cefalorraquídeo , MicroARNs/líquido cefalorraquídeo , Anciano , Enfermedad de Alzheimer/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Estudios de Casos y Controles , Disfunción Cognitiva/líquido cefalorraquídeo , Progresión de la Enfermedad , Femenino , Demencia Frontotemporal/líquido cefalorraquídeo , Humanos , Enfermedad por Cuerpos de Lewy/líquido cefalorraquídeo , Masculino , Persona de Mediana Edad
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA