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Article ; Online: Blood Biomarkers in Neurodegenerative Diseases: Implications for the Clinical Neurologist.

Alcolea, Daniel / Beeri, Michal Schnaider / Rojas, Julio C / Gardner, Raquel C / Lleó, Alberto

2023 Volume 101, Issue 4, Page(s) 172–180

Abstract: Blood-based biomarkers offer a major advance in the clinical evaluation of neurodegenerative diseases. Currently, research studies have reported robust assays of blood markers for the detection of amyloid and tau pathologies specific to Alzheimer disease ...

Abstract	Blood-based biomarkers offer a major advance in the clinical evaluation of neurodegenerative diseases. Currently, research studies have reported robust assays of blood markers for the detection of amyloid and tau pathologies specific to Alzheimer disease (amyloid-β peptides, and p-tau) and nonspecific blood markers of neuronal (neurofilament light, β-synuclein, and ubiquitin-C-terminal-hydrolase-L1) and glial degeneration (glial fibrillary acidic protein) that can measure key pathophysiologic processes in several neurodegenerative diseases. In the near future, these markers may be used for screening, diagnosis, or disease and treatment response monitoring. Blood-based biomarkers for neurodegenerative diseases have been rapidly implemented in research, and they have the potential to enter clinical use soon in different clinical settings. In this review, we will describe the main developments and their potential implications for the general neurologist.
MeSH term(s)	Humans ; Alzheimer Disease/diagnosis ; Neurodegenerative Diseases/diagnosis ; Neurologists ; Amyloid beta-Peptides ; Biomarkers/blood
Chemical Substances	Amyloid beta-Peptides ; Biomarkers
Language	English
Publishing date	2023-03-06
Publishing country	United States
Document type	Journal Article ; Review ; Comment
ZDB-ID	207147-2
ISSN	1526-632X ; 0028-3878
ISSN (online)	1526-632X
ISSN	0028-3878
DOI	10.1212/WNL.0000000000207193
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Article: The cognitive aftermath of COVID-19

Lleó, Alberto / Alcolea, Daniel

Brain Communications

Keywords	covid19
Publisher	WHO
Document type	Article
Note	WHO #Covidence: #437239
Database	COVID19

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Article ; Online: The cognitive aftermath of COVID-19

Lleó, Alberto / Alcolea, Daniel

Brain Communications

2020 Volume 2, Issue 2

Abstract: This scientific commentary refers to ‘The cognitive consequences of the COVID-19 epidemic: collateral damage?’, by Ritchie et al. (https://doi.org/10.1093/braincomms/fcaa069). ...

Abstract	This scientific commentary refers to ‘The cognitive consequences of the COVID-19 epidemic: collateral damage?’, by Ritchie et al. (https://doi.org/10.1093/braincomms/fcaa069).
Keywords	covid19
Language	English
Publisher	Oxford University Press (OUP)
Publishing country	uk
Document type	Article ; Online
ISSN	2632-1297
DOI	10.1093/braincomms/fcaa072
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Evaluation of cerebrospinal fluid levels of synaptic vesicle protein, VAMP-2, across the sporadic Alzheimer's disease continuum.

Goossens, Julie / Cervantes González, Alba / Dewit, Nele / Lidón, Laia / Fortea, Juan / Alcolea, Daniel / Lleó, Alberto / Belbin, Olivia / Vanmechelen, Eugeen

Alzheimer's research & therapy

2023 Volume 15, Issue 1, Page(s) 186

Abstract: Background: Synapse loss is an early event that precedes neuronal death and symptom onset and is considered the best neuropathological correlate of cognitive decline in Alzheimer's disease (AD). Vesicle-associated membrane protein 2 (VAMP-2) has emerged ...

Abstract	Background: Synapse loss is an early event that precedes neuronal death and symptom onset and is considered the best neuropathological correlate of cognitive decline in Alzheimer's disease (AD). Vesicle-associated membrane protein 2 (VAMP-2) has emerged as a promising biomarker of AD-related synapse degeneration in cerebrospinal fluid (CSF). The aim of this study was to explore the CSF profile of VAMP-2 across the AD continuum in relation to core AD biomarkers, other synaptic proteins, neurogranin (Ng) and synaptosomal-associated Protein-25 kDa (SNAP-25) and cognitive performance. Methods: We developed a digital immunoassay on the Single Molecule Array platform to quantify VAMP-2 in CSF and used existing immunoassays to quantify Ng, SNAP-25 and core CSF AD biomarkers. The clinical study included 62 cognitively unimpaired AD biomarker-negative subjects and 152 participants across the AD continuum from the SPIN cohort (Sant Pau Initiative on Neurodegeneration). Cognitive measures of episodic, semantic, executive and visuospatial domains and global cognition were included. Statistical methods included χ Results: The VAMP-2 assay had a good analytical performance (repeatability 8.9%, intermediate precision 10.3%). Assay antibodies detected native VAMP-2 protein in human brain homogenates. CSF concentrations of VAMP-2, neurogranin and SNAP-25 were lower in preclinical AD stage 1 compared to controls and higher at later AD stages compared to AD stage 1 and were associated with core AD biomarkers, particularly total tau (adj. r Conclusions: Our novel digital immunoassay accurately measures VAMP-2 changes in CSF, which reflect AD biomarkers and cognitive performance across multiple domains.
MeSH term(s)	Humans ; Alzheimer Disease/pathology ; Amyloid beta-Peptides/cerebrospinal fluid ; Biomarkers/cerebrospinal fluid ; Cognitive Dysfunction/diagnosis ; Neurogranin/cerebrospinal fluid ; Synaptic Vesicles/pathology ; tau Proteins/cerebrospinal fluid ; Vesicle-Associated Membrane Protein 2
Chemical Substances	Amyloid beta-Peptides ; Biomarkers ; Neurogranin (132654-77-4) ; tau Proteins ; Vesicle-Associated Membrane Protein 2 ; VAMP2 protein, human
Language	English
Publishing date	2023-10-28
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/s13195-023-01336-0
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Article ; Online: APOE4 homozygozity represents a distinct genetic form of Alzheimer's disease.

Fortea, Juan / Pegueroles, Jordi / Alcolea, Daniel / Belbin, Olivia / Dols-Icardo, Oriol / Vaqué-Alcázar, Lídia / Videla, Laura / Gispert, Juan Domingo / Suárez-Calvet, Marc / Johnson, Sterling C / Sperling, Reisa / Bejanin, Alexandre / Lleó, Alberto / Montal, Víctor

Nature medicine

2024

Abstract: This study aimed to evaluate the impact of APOE4 homozygosity on Alzheimer's disease (AD) by examining its clinical, pathological and biomarker changes to see whether APOE4 homozygotes constitute a distinct, genetically determined form of AD. Data from ... ...

Abstract	This study aimed to evaluate the impact of APOE4 homozygosity on Alzheimer's disease (AD) by examining its clinical, pathological and biomarker changes to see whether APOE4 homozygotes constitute a distinct, genetically determined form of AD. Data from the National Alzheimer's Coordinating Center and five large cohorts with AD biomarkers were analyzed. The analysis included 3,297 individuals for the pathological study and 10,039 for the clinical study. Findings revealed that almost all APOE4 homozygotes exhibited AD pathology and had significantly higher levels of AD biomarkers from age 55 compared to APOE3 homozygotes. By age 65, nearly all had abnormal amyloid levels in cerebrospinal fluid, and 75% had positive amyloid scans, with the prevalence of these markers increasing with age, indicating near-full penetrance of AD biology in APOE4 homozygotes. The age of symptom onset was earlier in APOE4 homozygotes at 65.1, with a narrower 95% prediction interval than APOE3 homozygotes. The predictability of symptom onset and the sequence of biomarker changes in APOE4 homozygotes mirrored those in autosomal dominant AD and Down syndrome. However, in the dementia stage, there were no differences in amyloid or tau positron emission tomography across haplotypes, despite earlier clinical and biomarker changes. The study concludes that APOE4 homozygotes represent a genetic form of AD, suggesting the need for individualized prevention strategies, clinical trials and treatments.
Language	English
Publishing date	2024-05-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	1220066-9
ISSN	1546-170X ; 1078-8956
ISSN (online)	1546-170X
ISSN	1078-8956
DOI	10.1038/s41591-024-02931-w
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Article ; Online: HDL-like-Mediated Cell Cholesterol Trafficking in the Central Nervous System and Alzheimer's Disease Pathogenesis.

Borràs, Carla / Mercer, Aina / Sirisi, Sònia / Alcolea, Daniel / Escolà-Gil, Joan Carles / Blanco-Vaca, Francisco / Tondo, Mireia

International journal of molecular sciences

2022 Volume 23, Issue 16

Abstract: The main aim of this work is to review the mechanisms via which high-density lipoprotein (HDL)-mediated cholesterol trafficking through the central nervous system (CNS) occurs in the context of Alzheimer's disease (AD). Alzheimer's disease is ... ...

Abstract	The main aim of this work is to review the mechanisms via which high-density lipoprotein (HDL)-mediated cholesterol trafficking through the central nervous system (CNS) occurs in the context of Alzheimer's disease (AD). Alzheimer's disease is characterized by the accumulation of extracellular amyloid beta (Aβ) and abnormally hyperphosphorylated intracellular tau filaments in neurons. Cholesterol metabolism has been extensively implicated in the pathogenesis of AD through biological, epidemiological, and genetic studies, with the
MeSH term(s)	Alzheimer Disease/metabolism ; Amyloid beta-Peptides/metabolism ; Apolipoproteins E/metabolism ; Brain/metabolism ; Cholesterol/metabolism ; Cholesterol, HDL/metabolism ; Humans
Chemical Substances	Amyloid beta-Peptides ; Apolipoproteins E ; Cholesterol, HDL ; Cholesterol (97C5T2UQ7J)
Language	English
Publishing date	2022-08-19
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms23169356
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Article: Thimet oligopeptidase as a potential CSF biomarker for Alzheimer's disease: A cross-platform validation study.

Hok-A-Hin, Yanaika S / Bolsewig, Katharina / Ruiters, Daimy N / Lleó, Alberto / Alcolea, Daniel / Lemstra, Afina W / van der Flier, Wiesje M / Teunissen, Charlotte E / Del Campo, Marta

Alzheimer's & dementia (Amsterdam, Netherlands)

2023 Volume 15, Issue 3, Page(s) e12456

Abstract: Introduction: Our previous antibody-based cerebrospinal fluid (CSF) proteomics study showed that Thimet oligopeptidase (THOP1), an amyloid beta (Aβ) neuropeptidase, was increased in mild cognitive impairment with amyloid pathology (MCI-Aβ+) and ... ...

Abstract	Introduction: Our previous antibody-based cerebrospinal fluid (CSF) proteomics study showed that Thimet oligopeptidase (THOP1), an amyloid beta (Aβ) neuropeptidase, was increased in mild cognitive impairment with amyloid pathology (MCI-Aβ+) and Alzheimer's disease (AD) dementia compared with controls and dementia with Lewy bodies (DLB), highlighting the potential of CSF THOP1 as an early specific biomarker for AD. We aimed to develop THOP1 immunoassays for large-scale analysis and validate our proteomics findings in two independent cohorts. Methods: We developed in-house CSF THOP1 immunoassays on automated Ella and Simoa platforms. The performance of the different assays were compared using Passing-Bablok regression analysis in a subset of CSF samples from the discovery cohort ( Results: THOP1 concentrations moderately correlated between proteomics analysis and our novel assays ( Discussion: Validation of our proteomics findings underpins the potential of CSF THOP1 as an early specific biomarker associated with AD pathology. The use of antibody-based platforms in both the discovery and validation phases facilitated the translation of proteomics findings, providing an additional workflow that may accelerate the development of biofluid-based biomarkers.
Language	English
Publishing date	2023-07-26
Publishing country	United States
Document type	Journal Article
ZDB-ID	2832898-X
ISSN	2352-8729
ISSN	2352-8729
DOI	10.1002/dad2.12456
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Article: Diagnostic performance of plasma pTau 217, pTau 181, Aβ 1-42 and Aβ 1-40 in the LUMIPULSE automated platform for the detection of Alzheimer disease.

Arranz, Javier / Zhu, Nuole / Rubio-Guerra, Sara / Rodríguez-Baz, Íñigo / Ferrer, Rosa / Carmona-Iragui, María / Barroeta, Isabel / Illán-Gala, Ignacio / Santos-Santos, Miguel / Fortea, Juan / Lleó, Alberto / Tondo, Mireia / Alcolea, Daniel

Research square

2023

Abstract: Background: Recently developed blood markers for Alzheimer's disease (AD) detection have high accuracy but usually require ultra-sensitive analytic tools not commonly available in clinical laboratories, and their performance in clinical practice is ... ...

Abstract	Background: Recently developed blood markers for Alzheimer's disease (AD) detection have high accuracy but usually require ultra-sensitive analytic tools not commonly available in clinical laboratories, and their performance in clinical practice is unknown. Methods: We analyzed plasma samples from 290 consecutive participants that underwent lumbar puncture in routine clinical practice in a specialized memory clinic (66 cognitively unimpaired, 130 participants with mild cognitive impairment, and 94 with dementia). Participants were classified as amyloid positive (A+) or negative (A-) according to CSF Aβ Results: Plasma pTau Conclusion: The evaluation of blood biomarkers on an automated platform exhibited high diagnostic accuracy for AD pathophysiology, and pTau
Language	English
Publishing date	2023-12-13
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-3725688/v1
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Effects of storage conditions on the stability of blood-based markers for the diagnosis of Alzheimer's disease.

Mansilla, Andrea / Canyelles, Marina / Ferrer, Rosa / Arranz, Javier / Rodríguez-Baz, Íñigo / Zhu, Nuole / Rubio-Guerra, Sara / El Bounasri, Shaimaa / Sánchez, Oriol / Torres, Soraya / Fortea, Juan / Lleó, Alberto / Alcolea, Daniel / Tondo, Mireia

Clinical chemistry and laboratory medicine

2023 Volume 61, Issue 9, Page(s) 1580–1589

Abstract: Objectives: Alzheimer's disease (AD) is considered the most common cause of dementia in older people. Recently, blood-based markers (BBM) Aβ1-42, Aβ1-40, and phospho Tau181 (p-Tau181) have demonstrated the potential to transform the diagnosis and ... ...

Abstract	Objectives: Alzheimer's disease (AD) is considered the most common cause of dementia in older people. Recently, blood-based markers (BBM) Aβ1-42, Aβ1-40, and phospho Tau181 (p-Tau181) have demonstrated the potential to transform the diagnosis and prognostic assessment of AD. Our aim was to investigate the effect of different storage conditions on the quantification of these BBM and to evaluate the interchangeability of plasma and serum samples. Methods: Forty-two individuals with some degree of cognitive impairment were studied. Thirty further patients were retrospectively selected. Aβ1-42, Aβ1-40, and p-Tau181 were quantified using the LUMIPULSE-G600II automated platform. To assess interchangeability between conditions, correction factors for magnitudes that showed strong correlations were calculated, followed by classification consistency studies. Results: Storing samples at 4 °C for 8-9 days was associated with a decrease in Aβ fractions but not when stored for 1-2 days. Using the ratio partially attenuated the pre-analytical effects. For p-Tau181, samples stored at 4 °C presented lower concentrations, whereas frozen samples presented higher ones. Concerning classification consistency in comparisons that revealed strong correlations (p-Tau181), the percentage of total agreement was greater than 90 % in a large number of the tested cut-offs values. Conclusions: Our findings provide relevant information for the standardization of sample collection and storage in the analysis of AD BBM in an automated platform. This knowledge is crucial to ensure their introduction into clinical settings.
MeSH term(s)	Humans ; Aged ; Alzheimer Disease/diagnosis ; tau Proteins ; Amyloid beta-Peptides ; Retrospective Studies ; Biomarkers
Chemical Substances	tau Proteins ; Amyloid beta-Peptides ; Biomarkers
Language	English
Publishing date	2023-04-24
Publishing country	Germany
Document type	Journal Article
ZDB-ID	1418007-8
ISSN	1437-4331 ; 1434-6621 ; 1437-8523
ISSN (online)	1437-4331
ISSN	1434-6621 ; 1437-8523
DOI	10.1515/cclm-2023-0245
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Article: Dense core vesicle markers in CSF and cortical tissues of patients with Alzheimer's disease.

Barranco, Neus / Plá, Virginia / Alcolea, Daniel / Sánchez-Domínguez, Irene / Fischer-Colbrie, Reiner / Ferrer, Isidro / Lleó, Alberto / Aguado, Fernando

Translational neurodegeneration

2021 Volume 10, Issue 1, Page(s) 37

Abstract: Background: New fluid biomarkers for Alzheimer's disease (AD) that reveal synaptic and neural network dysfunctions are needed for clinical practice and therapeutic trial design. Dense core vesicle (DCV) cargos are promising cerebrospinal fluid (CSF) ... ...

Abstract	Background: New fluid biomarkers for Alzheimer's disease (AD) that reveal synaptic and neural network dysfunctions are needed for clinical practice and therapeutic trial design. Dense core vesicle (DCV) cargos are promising cerebrospinal fluid (CSF) indicators of synaptic failure in AD patients. However, their value as biomarkers has not yet been determined. Methods: Immunoassays were performed to analyze the secretory proteins prohormone convertases PC1/3 and PC2, carboxypeptidase E (CPE), secretogranins SgIII and SgII, and Cystatin C in the cerebral cortex (n = 45, provided by Bellvitge University Hospital) and CSF samples (n = 66, provided by The Sant Pau Initiative on Neurodegeneration cohort) from AD patients (n = 56) and age-matched controls (n = 55). Results: In AD tissues, most DCV proteins were aberrantly accumulated in dystrophic neurites and activated astrocytes, whereas PC1/3, PC2 and CPE were also specifically accumulated in hippocampal granulovacuolar degeneration bodies. AD individuals displayed an overall decline of secretory proteins in the CSF. Interestingly, in AD patients, the CSF levels of prohormone convertases strongly correlated inversely with those of neurodegeneration markers and directly with cognitive impairment status. Conclusions: These results demonstrate marked alterations of neuronal-specific prohormone convertases in CSF and cortical tissues of AD patients. The neuronal DCV cargos are biomarker candidates for synaptic dysfunction and neurodegeneration in AD.
MeSH term(s)	Alzheimer Disease/metabolism ; Biomarkers/cerebrospinal fluid ; Cerebral Cortex/metabolism ; Cognitive Dysfunction/cerebrospinal fluid ; Dense Core Vesicles ; Humans
Chemical Substances	Biomarkers
Language	English
Publishing date	2021-09-26
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2653701-1
ISSN	2047-9158
ISSN	2047-9158
DOI	10.1186/s40035-021-00263-0
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