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Article ; Online: A RELAXATION VIEWPOINT TO COVID-19 INFECTION

Sotolongo-Costa, Oscar / Weberszpil, José / Sotolongo-Grau, Oscar

medRxiv

Abstract: An analogy relaxation model, able to describe the dynamics of Covid-19 pandemics, in terms of daily presented new cases, is obtained. The main objective here is the prediction of pandemic dynamics, as the forecast of herd immunity time, and provide ... ...

Abstract	An analogy relaxation model, able to describe the dynamics of Covid-19 pandemics, in terms of daily presented new cases, is obtained. The main objective here is the prediction of pandemic dynamics, as the forecast of herd immunity time, and provide quantitative criteria for some predictions. We propose an analogy based on the concept of fractal derivative and justify the appearance of fractal time. A Burr XII-shaped solution of a fractal-like equation was obtained. The data fitting shows that the obtained function is useful to describe the behavior of the pandemic in the studied countries. The temporal evolution of contagion over different countries and worldwide are presented and discussed. We also show that a deformed derivative model leads to the same analytical results.
Keywords	covid19
Language	English
Publishing date	2020-06-05
Publisher	Cold Spring Harbor Laboratory Press
Document type	Article ; Online
DOI	10.1101/2020.06.03.20120576
Database	COVID19

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Book ; Online: A fractal viewpoint to COVID-19 infection

Sotolongo-Costa, Oscar / Weberszpil, José / Sotolongo-Grau, Oscar

2020

Abstract: One of the central tools to control the COVID-19 pandemics is the knowledge of its spreading dynamics. Here we develop a fractal model capable of describe this dynamics, in term of daily new cases, and provide quantitative criteria for some predictions. ... ...

Abstract	One of the central tools to control the COVID-19 pandemics is the knowledge of its spreading dynamics. Here we develop a fractal model capable of describe this dynamics, in term of daily new cases, and provide quantitative criteria for some predictions. We propose a fractal dynamical model using conformed derivative and fractal time scale. A Burr-XII shaped solution of the fractal-like equation is obtained. The model is tested using data from several countries, showing that a single function is able to describe very different shapes of the outbreak. The diverse behavior of the outbreak on those countries is presented and discussed. Moreover, a criterion to determine the existence of the pandemic peak and a expression to find the time to reach herd immunity are also obtained. Comment: 16 pages, 8 figures. To be submitted for publicantion
Keywords	Physics - Physics and Society ; Physics - Biological Physics ; Quantitative Biology - Populations and Evolution ; covid19
Subject code	612
Publishing date	2020-07-14
Publishing country	us
Document type	Book ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: A fractal viewpoint to COVID-19 infection

Sotolongo-Costa, Oscar / Weberszpil, Jos'e / Sotolongo-Grau, Oscar

Abstract	One of the central tools to control the COVID-19 pandemics is the knowledge of its spreading dynamics. Here we develop a fractal model capable of describe this dynamics, in term of daily new cases, and provide quantitative criteria for some predictions. We propose a fractal dynamical model using conformed derivative and fractal time scale. A Burr-XII shaped solution of the fractal-like equation is obtained. The model is tested using data from several countries, showing that a single function is able to describe very different shapes of the outbreak. The diverse behavior of the outbreak on those countries is presented and discussed. Moreover, a criterion to determine the existence of the pandemic peak and a expression to find the time to reach herd immunity are also obtained.
Keywords	covid19
Publisher	ArXiv
Document type	Article
Database	COVID19

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Article ; Online: A Relaxation Viewpoint to Covid-19 Infection

Sotolongo-Costa, Oscar / Weberszpil, JosÃ© / Sotolongo-Grau, Oscar

Abstract	One of the central tools to control the COVID-19 pandemics is the knowledge of its spreading dynamics. Here we develop a fractal model capable of describe this dynamics, in term of daily new cases, and provide quantitative criteria for some predictions. We propose a fractal dynamical model using conformed derivative and fractal time scale. A Burr-XII shaped solution of the fractal-like equation is obtained. The model is tested using data from several countries, showing that a single function is able to describe very different shapes of the outbreak. The diverse behavior of the outbreak on those countries is presented and discussed. Moreover, a criterion to determine the existence of the pandemic peak and a expression to find the time to reach herd immunity are also obtained.
Keywords	covid19
Publisher	MedRxiv; WHO
Document type	Article ; Online
Note	WHO #Covidence: #20120576
DOI	10.1101/2020.06.03.20120576
Database	COVID19

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Article ; Online: Macular vessel density in the superficial plexus is not a proxy of cerebrovascular damage in non-demented individuals: data from the NORFACE cohort.

García-Sánchez, Ainhoa / Sotolongo-Grau, Oscar / Tartari, Juan Pablo / Sanabria, Ángela / Esteban-De Antonio, Ester / Pérez-Cordón, Alba / Alegret, Montserrat / Pytel, Vanesa / Martínez, Joan / Aguilera, Núria / de Rojas, Itziar / Cano, Amanda / García-González, Pablo / Puerta, Raquel / Olivé, Clàudia / Capdevila, Maria / García-Gutiérrez, Fernando / Vivas, Assumpta / Gómez-Chiari, Marta /

Giménez, Juan / Tejero, Miguel Ángel / Castilla-Martí, Miguel / Castilla-Martí, Luis / Tárraga, Lluís / Valero, Sergi / Ruiz, Agustín / Boada, Mercè / Marquié, Marta

Alzheimer's research & therapy

2024 Volume 16, Issue 1, Page(s) 42

Abstract: Introduction: Optical coherence tomography angiography (OCT-A) is a novel tool that allows the detection of retinal vascular changes. We investigated the association of macular vessel density (VD) in the superficial plexus assessed by OCT-A with ... ...

Abstract	Introduction: Optical coherence tomography angiography (OCT-A) is a novel tool that allows the detection of retinal vascular changes. We investigated the association of macular vessel density (VD) in the superficial plexus assessed by OCT-A with measures of cerebrovascular pathology and atrophy quantified by brain magnetic resonance imaging (MRI) in non-demented individuals. Methods: Clinical, demographical, OCT-A, and brain MRI data from non-demented research participants were included. We analyzed the association of regional macular VD with brain vascular burden using the Fazekas scale assessed in a logistic regression analysis, and the volume of white matter hyperintensities (WMH) assessed in a multiple linear regression analysis. We also explored the associations of macular VD with hippocampal volume, ventricle volume and Alzheimer disease cortical signature (ADCS) thickness assessed in multiple linear regression analyses. All analyses were adjusted for age, sex, syndromic diagnosis and cardiovascular variables. Results: The study cohort comprised 188 participants: 89 with subjective cognitive decline and 99 with mild cognitive impairment. No significant association of regional macular VD with the Fazekas categories (all, p > 0.111) and WMH volume (all, p > 0.051) were detected. VD in the nasal quadrant was associated to hippocampal volume (p = 0.007), but no other associations of macular VD with brain atrophy measures were detected (all, p > 0.05). Discussion: Retinal vascular measures were not a proxy of cerebrovascular damage in non-demented individuals, while VD in the nasal quadrant was associated with hippocampal atrophy independently of the amyloid status.
MeSH term(s)	Humans ; Fluorescein Angiography/methods ; Retinal Vessels/diagnostic imaging ; Retinal Vessels/pathology ; Atrophy/pathology ; Tomography, Optical Coherence/methods
Language	English
Publishing date	2024-02-20
Publishing country	England
Document type	Journal Article
ZDB-ID	2506521-X
ISSN	1758-9193 ; 1758-9193
ISSN (online)	1758-9193
ISSN	1758-9193
DOI	10.1186/s13195-024-01408-9
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Article ; Online: Plasma extracellular vesicles reveal early molecular differences in amyloid positive patients with early-onset mild cognitive impairment.

Cano, Amanda / Esteban-de-Antonio, Ester / Bernuz, Mireia / Puerta, Raquel / García-González, Pablo / de Rojas, Itziar / Olivé, Claudia / Pérez-Cordón, Alba / Montrreal, Laura / Núñez-Llaves, Raúl / Sotolongo-Grau, Óscar / Alarcón-Martín, Emilio / Valero, Sergi / Alegret, Montserrat / Martín, Elvira / Martino-Adami, Pamela V / Ettcheto, Miren / Camins, Antonio / Vivas, Assumpta /

Gomez-Chiari, Marta / Tejero, Miguel Ángel / Orellana, Adelina / Tárraga, Lluís / Marquié, Marta / Ramírez, Alfredo / Martí, Mercè / Pividori, María Isabel / Boada, Mercè / Ruíz, Agustín

Journal of nanobiotechnology

2023 Volume 21, Issue 1, Page(s) 54

Abstract: In the clinical course of Alzheimer's disease (AD) development, the dementia phase is commonly preceded by a prodromal AD phase, which is mainly characterized by reaching the highest levels of Aβ and p-tau-mediated neuronal injury and a mild cognitive ... ...

Abstract	In the clinical course of Alzheimer's disease (AD) development, the dementia phase is commonly preceded by a prodromal AD phase, which is mainly characterized by reaching the highest levels of Aβ and p-tau-mediated neuronal injury and a mild cognitive impairment (MCI) clinical status. Because of that, most AD cases are diagnosed when neuronal damage is already established and irreversible. Therefore, a differential diagnosis of MCI causes in these prodromal stages is one of the greatest challenges for clinicians. Blood biomarkers are emerging as desirable tools for pre-screening purposes, but the current results are still being analyzed and much more data is needed to be implemented in clinical practice. Because of that, plasma extracellular vesicles (pEVs) are gaining popularity as a new source of biomarkers for the early stages of AD development. To identify an exosome proteomics signature linked to prodromal AD, we performed a cross-sectional study in a cohort of early-onset MCI (EOMCI) patients in which 184 biomarkers were measured in pEVs, cerebrospinal fluid (CSF), and plasma samples using multiplex PEA technology of Olink
MeSH term(s)	Humans ; Amyloid beta-Peptides ; Cross-Sectional Studies ; Alzheimer Disease/metabolism ; Cognitive Dysfunction/diagnosis ; tau Proteins/cerebrospinal fluid ; Extracellular Vesicles/metabolism ; Biomarkers ; Peptide Fragments
Chemical Substances	Amyloid beta-Peptides ; tau Proteins ; Biomarkers ; Peptide Fragments
Language	English
Publishing date	2023-02-14
Publishing country	England
Document type	Journal Article
ZDB-ID	2100022-0
ISSN	1477-3155 ; 1477-3155
ISSN (online)	1477-3155
ISSN	1477-3155
DOI	10.1186/s12951-023-01793-7
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Article ; Online: Early detection of amyloid load using

Alzheimer's research & therapy

2021 Volume 13, Issue 1, Page(s) 67

Abstract: Background: A low amount and extent of Aβ deposition at early stages of Alzheimer's disease (AD) may limit the use of previously developed pathology-proven composite SUVR cutoffs. This study aims to characterize the population with earliest abnormal Aβ ... ...

Abstract	Background: A low amount and extent of Aβ deposition at early stages of Alzheimer's disease (AD) may limit the use of previously developed pathology-proven composite SUVR cutoffs. This study aims to characterize the population with earliest abnormal Aβ accumulation using Methods: The study population consisted of 686 subjects (n = 287 (cognitively normal healthy controls), n = 166 (subjects with subjective cognitive decline (SCD)), n = 129 (subjects with MCI), and n = 101 (subjects with AD dementia)). Three categories in the Aβ-deposition continuum were defined based on the developed SUVR cutoffs: Aβ-negative subjects, subjects with early Aβ deposition ("gray zone"), and subjects with established Aβ pathology. Results: SUVR using the whole cerebellum as the reference region and centiloid (CL) cutoffs for early and established amyloid pathology were 1.10 (13.5 CL) and 1.24 (35.7 CL), respectively. Cingulate cortices and precuneus, frontal, and inferior lateral temporal cortices were the regions showing the initial pathological tracer retention. Subjects in the "gray zone" or with established Aβ pathology accumulated more amyloid over time than Aβ-negative subjects. After a 4-year clinical follow-up, none of the Aβ-negative or the gray zone subjects progressed to AD dementia while 91% of the MCI subjects with established Aβ pathology progressed. Tau deposition was infrequent in those subjects without established Aβ pathology. Conclusions: This study supports the utility of using two cutoffs for amyloid PET abnormality defining a "gray zone": a lower cutoff of 13.5 CL indicating emerging Aβ pathology and a higher cutoff of 35.7 CL where amyloid burden levels correspond to established neuropathology findings. These cutoffs define a subset of subjects characterized by pre-AD dementia levels of amyloid burden that precede other biomarkers such as tau deposition or clinical symptoms and accelerated amyloid accumulation. The determination of different amyloid loads, particularly low amyloid levels, is useful in determining who will eventually progress to dementia. Quantitation of amyloid provides a sensitive measure in these low-load cases and may help to identify a group of subjects most likely to benefit from intervention. Trial registration: Data used in this manuscript belong to clinical trials registered in ClinicalTrials.gov ( NCT00928304 , NCT00750282 , NCT01138111 , NCT02854033 ) and EudraCT (2014-000798-38).
MeSH term(s)	Alzheimer Disease/diagnostic imaging ; Amyloid beta-Peptides ; Aniline Compounds ; Cognitive Dysfunction/diagnostic imaging ; Humans ; Positron-Emission Tomography ; Stilbenes
Chemical Substances	Amyloid beta-Peptides ; Aniline Compounds ; Stilbenes ; 4-(N-methylamino)-4'-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)stilbene (TLA7312TOI)
Language	English
Publishing date	2021-03-27
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2506521-X
ISSN	1758-9193 ; 1758-9193
ISSN (online)	1758-9193
ISSN	1758-9193
DOI	10.1186/s13195-021-00807-6
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Article ; Online: BIOFACE: A Prospective Study of Risk Factors, Cognition, and Biomarkers in a Cohort of Individuals with Early-Onset Mild Cognitive Impairment. Study Rationale and Research Protocols.

Journal of Alzheimer's disease : JAD

2021 Volume 83, Issue 3, Page(s) 1233–1249

Abstract: Background: Mild cognitive impairment (MCI) due to Alzheimer's disease (AD) diagnosis is based on cerebrospinal fluid (CSF) or neuroimaging biomarkers. Currently, non-invasive and inexpensive blood-based biomarkers are being investigated, such as ... ...

Abstract	Background: Mild cognitive impairment (MCI) due to Alzheimer's disease (AD) diagnosis is based on cerebrospinal fluid (CSF) or neuroimaging biomarkers. Currently, non-invasive and inexpensive blood-based biomarkers are being investigated, such as neuronal-derived plasma exosomes (NPEs). Neuroinflammation and early vascular changes have been described in AD pathogenesis and can be traced in plasma and NPEs. However, they have not been studied in early onset MCI (EOMCI). Objective: To describe the rationale, design, and baseline characteristics of the participants from the BIOFACE cohort, a two-year observational study on EOMCI conducted at Fundació ACE. The study goal is to characterize the different phenotypes from a clinical, neuropsychological, and biomarker point of view and to investigate the CSF and plasma proteomics as well as the role of NPEs as early biomarkers of AD. Methods: Participants underwent extended neurological and neuropsychological batteries, multimodal biomarkers including brain MRI, blood, saliva, CSF, anthropometric, and neuro-ophthalmological examinations. Results: Ninety-seven patients with EOMCI were recruited. 59.8%were women. Mean age at symptom onset was 57 years; mean MMSE was 28. First degree and presenile family history of dementia was present in 60.8%and 15.5%, respectively. Depressive and anxiety disorders along with vascular risk factors were the most frequent comorbidities. 29%of participants were APOE ɛ4 carriers, and 67%showed a CSF normal ATN profile. Conclusion: BIOFACE is a two-year study of clinical, cognition, and biomarkers that will shed light on the physiopathology and the potential utility of plasma and NPEs as non-invasive early diagnostic and prognostic biomarkers in people younger than 65 years.
MeSH term(s)	Biomarkers/blood ; Biomarkers/cerebrospinal fluid ; Cognition/physiology ; Cognitive Dysfunction/blood ; Cognitive Dysfunction/diagnosis ; Female ; Humans ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Neuropsychological Tests/statistics & numerical data ; Prospective Studies ; Risk Factors
Chemical Substances	Biomarkers
Language	English
Publishing date	2021-08-19
Publishing country	Netherlands
Document type	Journal Article ; Observational Study ; Research Support, Non-U.S. Gov't
ZDB-ID	1440127-7
ISSN	1875-8908 ; 1387-2877
ISSN (online)	1875-8908
ISSN	1387-2877
DOI	10.3233/JAD-210254
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Article ; Online: Automatized FACEmemory® scoring is related to Alzheimer's disease phenotype and biomarkers in early-onset mild cognitive impairment: the BIOFACE cohort.

Alegret, Montserrat / Sotolongo-Grau, Oscar / de Antonio, Ester Esteban / Pérez-Cordón, Alba / Orellana, Adelina / Espinosa, Ana / Gil, Silvia / Jiménez, Daniel / Ortega, Gemma / Sanabria, Angela / Roberto, Natalia / Hernández, Isabel / Rosende-Roca, Maitee / Tartari, Juan Pablo / Alarcon-Martin, Emilio / de Rojas, Itziar / Montrreal, Laura / Morató, Xavier / Cano, Amanda /

Rentz, Dorene M / Tárraga, Lluís / Ruiz, Agustín / Valero, Sergi / Marquié, Marta / Boada, Mercè

Alzheimer's research & therapy

2022 Volume 14, Issue 1, Page(s) 43

Abstract: Background: FACEmemory® is the first computerized, self-administered verbal episodic memory test with voice recognition. It can be conducted under minimal supervision and contains an automatic scoring system to avoid administrator errors. Moreover, it ... ...

Abstract	Background: FACEmemory® is the first computerized, self-administered verbal episodic memory test with voice recognition. It can be conducted under minimal supervision and contains an automatic scoring system to avoid administrator errors. Moreover, it is suitable for discriminating between cognitively healthy and amnestic mild cognitive impairment (MCI) individuals, and it is associated with Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers. This study aimed to determine whether FACEmemory scoring is related to performance on classical memory tests and to AD biomarkers of brain magnetic resonance imaging (MRI) and CSF in patients with early-onset MCI (EOMCI). Methods: Ninety-four patients with EOMCI from the BIOFACE study completed FACEmemory, classical memory tests (the Spanish version of the Word Free and Cued Selective Reminding Test -FCSRT-, the Word List from the Wechsler Memory Scale, third edition, and the Spanish version of the Rey-Osterrieth Complex Figure Test), and a brain MRI. Eighty-two individuals also underwent a lumbar puncture. Results: FACEmemory scoring was moderately correlated with FCSRT scoring. With regard to neuroimaging MRI results, worse execution on FACEmemory was associated with lower cortical volume in the right prefrontal and inferior parietal areas, along with the left temporal and associative occipital areas. Moreover, the total FACEmemory score correlated with CSF AD biomarkers (Aβ1-42/Aβ1-40 ratio, p181-tau, and Aβ1-42/p181-tau ratio). When performance on FACEmemory was compared among the ATN classification groups, significant differences between the AD group and normal and SNAP groups were found. Conclusions: FACEmemory is a promising tool for detecting memory deficits sensitive to early-onset AD, but it also allows the detection of memory-impaired cases due to other etiologies. Our findings suggest that FACEmemory scoring can detect the AD endophenotype and that it is also associated with AD-related changes in MRI and CSF in patients with EOMCI. The computerized FACEmemory tool might be an opportunity to facilitate early detection of MCI in younger people than 65, who have a growing interest in new technologies.
MeSH term(s)	Alzheimer Disease/diagnosis ; Amyloid beta-Peptides/cerebrospinal fluid ; Biomarkers/cerebrospinal fluid ; Cognitive Dysfunction/diagnosis ; Diagnosis, Computer-Assisted ; Humans ; Memory, Episodic ; Neuropsychological Tests ; Peptide Fragments/cerebrospinal fluid ; Phenotype ; tau Proteins/cerebrospinal fluid
Chemical Substances	Amyloid beta-Peptides ; Biomarkers ; Peptide Fragments ; tau Proteins
Language	English
Publishing date	2022-03-18
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2506521-X
ISSN	1758-9193 ; 1758-9193
ISSN (online)	1758-9193
ISSN	1758-9193
DOI	10.1186/s13195-022-00988-8
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Article ; Online: Plasma Aβ42/40 ratio alone or combined with FDG-PET can accurately predict amyloid-PET positivity: a cross-sectional analysis from the AB255 Study.

Pérez-Grijalba, Virginia / Arbizu, Javier / Romero, Judith / Prieto, Elena / Pesini, Pedro / Sarasa, Leticia / Guillen, Fernando / Monleón, Inmaculada / San-José, Itziar / Martínez-Lage, Pablo / Munuera, Josep / Hernández, Isabel / Buendía, Mar / Sotolongo-Grau, Oscar / Alegret, Montserrat / Ruiz, Agustín / Tárraga, Lluis / Boada, Mercè / Sarasa, Manuel

Alzheimer's research & therapy

2019 Volume 11, Issue 1, Page(s) 96

Abstract: Background: To facilitate population screening and clinical trials of disease-modifying therapies for Alzheimer's disease, supportive biomarker information is necessary. This study was aimed to investigate the association of plasma amyloid-beta (Aβ) ... ...

Abstract	Background: To facilitate population screening and clinical trials of disease-modifying therapies for Alzheimer's disease, supportive biomarker information is necessary. This study was aimed to investigate the association of plasma amyloid-beta (Aβ) levels with the presence of pathological accumulation of Aβ in the brain measured by amyloid-PET. Both plasma Aβ42/40 ratio alone or combined with an FDG-PET-based biomarker of neurodegeneration were assessed as potential AD biomarkers. Methods: We included 39 cognitively normal subjects and 20 patients with mild cognitive impairment from the AB255 Study who had undergone PiB-PET scans. Total Aβ40 and Aβ42 levels in plasma (TP42/40) were quantified using ABtest kits. Subjects were dichotomized as Aβ-PET positive or negative, and the ability of TP42/40 to detect Aβ-PET positivity was assessed by logistic regression and receiver operating characteristic analyses. Combination of plasma Aβ biomarkers and FDG-PET was further assessed as an improvement for brain amyloidosis detection and diagnosis classification. Results: Eighteen (30.5%) subjects were Aβ-PET positive. TP42/40 ratio alone identified Aβ-PET status with an area under the curve (AUC) of 0.881 (95% confidence interval [CI] = 0.779-0.982). Discriminating performance of TP42/40 to detect Aβ-PET-positive subjects yielded sensitivity and specificity values at Youden's cutoff of 77.8% and 87.5%, respectively, with a positive predictive value of 0.732 and negative predictive value of 0.900. All these parameters improved after adjusting the model for significant covariates. Applying TP42/40 as the first screening tool in a sequential diagnostic work-up would reduce the number of Aβ-PET scans by 64%. Combination of both FDG-PET scores and plasma Aβ biomarkers was found to be the most accurate Aβ-PET predictor, with an AUC of 0.965 (95% CI = 0.913-0.100). Conclusions: Plasma TP42/40 ratio showed a relevant and significant potential as a screening tool to identify brain Aβ positivity in preclinical and prodromal stages of Alzheimer's disease.
MeSH term(s)	Aged ; Aged, 80 and over ; Alzheimer Disease/diagnosis ; Alzheimer Disease/diagnostic imaging ; Alzheimer Disease/metabolism ; Amyloid/metabolism ; Amyloid beta-Peptides/blood ; Amyloid beta-Peptides/metabolism ; Cognitive Dysfunction/diagnosis ; Cognitive Dysfunction/diagnostic imaging ; Cognitive Dysfunction/metabolism ; Cross-Sectional Studies ; Female ; Fluorodeoxyglucose F18 ; Humans ; Longitudinal Studies ; Male ; Peptide Fragments/blood ; Peptide Fragments/metabolism ; Positron-Emission Tomography
Chemical Substances	Amyloid ; Amyloid beta-Peptides ; Peptide Fragments ; Fluorodeoxyglucose F18 (0Z5B2CJX4D)
Language	English
Publishing date	2019-12-01
Publishing country	England
Document type	Journal Article ; Multicenter Study ; Research Support, Non-U.S. Gov't
ZDB-ID	2506521-X
ISSN	1758-9193 ; 1758-9193
ISSN (online)	1758-9193
ISSN	1758-9193
DOI	10.1186/s13195-019-0549-1
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