RESUMEN
BACKGROUND: Oligomeric amyloid-ß (Aß) is one of the major contributors to the pathomechanism of Alzheimer's disease (AD); Aß oligomerization in plasma can be measured using a Multimer Detection System-Oligomeric Aß (MDS-OAß) after incubation with spiked synthetic Aß. OBJECTIVE: We evaluated the clinical sensitivity and specificity of the MDS-OAß values for prediction of AD. METHODS: The MDS-OAß values measured using inBlood™ OAß test in heparin-treated plasma samples from 52 AD patients in comparison with 52 community-based subjects with normal cognition (NC). The inclusion criterion was proposed by the NINCDS-ADRDA and additionally required at least 6 months of follow-up from the initial clinical diagnosis in the course of AD. RESULTS: The MDS-OAß values were 1.43±0.30âng/ml in AD and 0.45±0.19 (pâ<â0.001) in NC, respectively. Using a cut-off value of 0.78âng/ml, the results revealed 100% sensitivity and 92.31% specificity. CONCLUSION: MDS-OAß to measure plasma Aß oligomerization is a valuable blood-based biomarker for clinical diagnosis of AD, with high sensitivity and specificity.
Asunto(s)
Enfermedad de Alzheimer/diagnóstico , Péptidos beta-Amiloides/sangre , Fragmentos de Péptidos/sangre , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/sangre , Biomarcadores/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: Soluble amyloid-ß (Aß) oligomers are the major toxic substances associated with the pathology of Alzheimer's disease (AD). The ability to measure Aß oligomer levels in the blood would provide simple and minimally invasive tools for AD diagnostics. In the present study, the recently developed Multimer Detection System (MDS) for AD, a new enzyme-linked immunosorbent assay for measuring Aß oligomers selectively, was used to detect Aß oligomers in the plasma of patients with AD and healthy control individuals. METHODS: Twenty-four patients with AD and 37 cognitively normal control individuals underwent extensive clinical evaluations as follows: blood sampling; detailed neuropsychological tests; brain magnetic resonance imaging; cerebrospinal fluid (CSF) measurement of Aß42, phosphorylated tau protein (pTau), and total tau protein (tTau); and 11C-Pittsburgh compound B (PIB) positron emission tomography. Pearson's correlation analyses between the estimations of Aß oligomer levels by MDS and other conventional AD biomarkers (CSF Aß42, pTau, and tTau, as well as PIB standardized uptake value ratio [PIB SUVR]) were conducted. ROC analyses were used to compare the diagnostic performance of each biomarker. RESULTS: The plasma levels of Aß oligomers by MDS were higher in patients with AD than in normal control individuals, and they correlated well with conventional AD biomarkers (levels of Aß oligomers by MDS vs. CSF Aß42, r = -0.443; PIB SUVR, r = 0.430; CSF pTau, r = 0.530; CSF tTau, r = 0.604). The sensitivity and specificity of detecting plasma Aß oligomers by MDS for differentiating AD from the normal controls were 78.3% and 86.5%, respectively. The AUC for plasma Aß oligomers by MDS was 0.844, which was not significantly different from the AUC of other biomarkers (p = 0.250). CONCLUSIONS: Plasma levels of Aß oligomers could be assessed using MDS, which might be a simple, noninvasive, and accessible assay for evaluating brain amyloid deposition related to AD pathology.
Asunto(s)
Enfermedad de Alzheimer/sangre , Péptidos beta-Amiloides/sangre , Fragmentos de Péptidos/sangre , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/diagnóstico por imagen , Péptidos beta-Amiloides/líquido cefalorraquídeo , Compuestos de Anilina , Benzotiazoles/farmacocinética , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Fragmentos de Péptidos/líquido cefalorraquídeo , Tomografía de Emisión de Positrones , Escalas de Valoración Psiquiátrica , República de Corea , Estudios Retrospectivos , Tiazoles , Proteínas tau/sangre , Proteínas tau/líquido cefalorraquídeoRESUMEN
BACKGROUND: A reliable blood-based assay is required to properly diagnose and monitor Alzheimer's disease (AD). Many attempts have been made to develop such a diagnostic tool by measuring amyloid-ß oligomers (AßOs) in the blood, but none have been successful in terms of method reliability. We present a multimer detection system (MDS), initially developed for the detection of prion oligomers in the blood, to detect AßOs. METHODS: To characterize Aß in the blood, plasma was spiked with synthetic amyloid-ß (Aß) and incubated over time. Then, the MDS was used to monitor the dynamic changes of AßO levels in the plasma. RESULTS: Increasing concentrations of AßOs were observed in the plasma of patients with AD but not in the plasma of normal control subjects. The plasma from patients with AD (n = 27) was differentiated from that of the age-matched normal control subjects (n = 144) with a sensitivity of 83.3% and a specificity of 90.0%. CONCLUSIONS: Synthetic Aß spiked into the blood plasma of patients with AD, but that of not elderly normal control subjects, induced dynamic changes in the formation of AßOs over time. AßOs were detected by the MDS, which is a useful blood-based assay with high sensitivity and specificity for AD diagnosis.
Asunto(s)
Enfermedad de Alzheimer/sangre , Péptidos beta-Amiloides/sangre , Multimerización de Proteína , Anciano , Biomarcadores/sangre , Análisis Químico de la Sangre/métodos , Electroforesis en Gel de Poliacrilamida , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Immunoblotting , Masculino , Persona de Mediana Edad , Sensibilidad y EspecificidadRESUMEN
Transmissible spongiform encephalopathies (TSEs) are zoonotic fatal neurodegenerative diseases in animals and humans. TSEs are commonly known as bovine spongiform encephalopathy in cattle, scrapie in sheep and goats, chronic wasting disease in cervids, and Creutzfeldt-Jakob disease in humans. The putative transmissible agents are infectious prion proteins (PrP(Sc)), which are formed by the conversion of the normal prion protein on the glycoprotein cell surface in the presence of other PrP(Sc). Reports of the transmission of TSEs through blood raised considerable concern about the safety of blood and blood products. To address this issue, many laboratories attempted to develop a sensitive and accurate blood diagnostic test to detect PrP(Sc). Previously, we reported that, compared to normal controls, the multimer detection system (MDS) was more efficient in detecting PrP(Sc) in infected hamster brain homogenate, mouse plasma spiked with purified PrP(Sc) from scrapie mouse brain, and scrapie-infected hamster plasmas. MDS differentiates prion multimers from the cellular monomer through the multimeric expression of epitopes on prion multimers, in contrast to the monomeric form. In this study, MDS detected PrP(Sc) in plasma samples from scrapie-infected sheep expressing clinical symptoms, demonstrating 100% sensitivity and specificity in these samples. Plasma samples from asymptomatic lambs at the preclinical stage (8-month-old naturally infected offspring of scrapie-infected parents expressing a highly susceptible genotype) tested positive with 50% sensitivity and 100% specificity. In the first of two coded analyses using clinical scrapie-infected sheep and normal healthy samples, MDS successfully identified all but one of the clinical samples with 92% sensitivity and 100% specificity. Similar results were obtained in the second coded analysis using preclinical samples. MDS again successfully identified all but one of the samples with 87% sensitivity and 100% specificity. The false-negative sample was subjected to a protease pretreatment. In conclusion, MDS could accurately detect scrapie in plasma samples at both preclinical and clinical stages. From these studies, we conclude that MDS could be a promising tool for the early diagnosis of TSEs from blood samples.