Cerebrospinal Fluid Mitochondrial DNA in Rapid and Slow Progressive Forms of Alzheimer’s Disease

Alzheimer’s type dementia (AD) exhibits clinical heterogeneity, as well as differences in disease progression, as a subset of patients with a clinical diagnosis of AD progresses more rapidly (rpAD) than the typical AD of slow progression (spAD). Previous findings indicate that low cerebrospinal flui...

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Autores: Podlesniy, Petar, Llorens, Franc, Puigros Serra, Margalida, Serra, Nuria, Sepúlveda-Falla, Diego, Schmidt, Christian B., Hermann, Peter, Zerr, Inga, Trullas, Ramón
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2020
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/230334
Acceso en línea:http://hdl.handle.net/10261/230334
Access Level:acceso abierto
Palabra clave:Mitochondrial DNA
Cerebrospinal fluid
Alzheimer’s disease
Biomarkers
Digital PCR
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repository_id_str
dc.title.none.fl_str_mv Cerebrospinal Fluid Mitochondrial DNA in Rapid and Slow Progressive Forms of Alzheimer’s Disease
title Cerebrospinal Fluid Mitochondrial DNA in Rapid and Slow Progressive Forms of Alzheimer’s Disease
spellingShingle Cerebrospinal Fluid Mitochondrial DNA in Rapid and Slow Progressive Forms of Alzheimer’s Disease
Podlesniy, Petar
Mitochondrial DNA
Cerebrospinal fluid
Alzheimer’s disease
Biomarkers
Digital PCR
title_short Cerebrospinal Fluid Mitochondrial DNA in Rapid and Slow Progressive Forms of Alzheimer’s Disease
title_full Cerebrospinal Fluid Mitochondrial DNA in Rapid and Slow Progressive Forms of Alzheimer’s Disease
title_fullStr Cerebrospinal Fluid Mitochondrial DNA in Rapid and Slow Progressive Forms of Alzheimer’s Disease
title_full_unstemmed Cerebrospinal Fluid Mitochondrial DNA in Rapid and Slow Progressive Forms of Alzheimer’s Disease
title_sort Cerebrospinal Fluid Mitochondrial DNA in Rapid and Slow Progressive Forms of Alzheimer’s Disease
dc.creator.none.fl_str_mv Podlesniy, Petar
Llorens, Franc
Puigros Serra, Margalida
Serra, Nuria
Sepúlveda-Falla, Diego
Schmidt, Christian B.
Hermann, Peter
Zerr, Inga
Trullas, Ramón
author Podlesniy, Petar
author_facet Podlesniy, Petar
Llorens, Franc
Puigros Serra, Margalida
Serra, Nuria
Sepúlveda-Falla, Diego
Schmidt, Christian B.
Hermann, Peter
Zerr, Inga
Trullas, Ramón
author_role author
author2 Llorens, Franc
Puigros Serra, Margalida
Serra, Nuria
Sepúlveda-Falla, Diego
Schmidt, Christian B.
Hermann, Peter
Zerr, Inga
Trullas, Ramón
author2_role author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Ciencia, Innovación y Universidades (España)
Agencia Estatal de Investigación (España)
Instituto de Salud Carlos III
Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (España)
Competence Network for Neurodegenerative Dementia (Germany)
Federal Ministry of Education and Research (Germany)
Llorens, Franc [0000-0002-9756-7497]
Schmidt, Christian [0000-0003-2210-4153]
Zerr, Inga [0000-0002-6722-2463]
Trullas, Ramón [0000-0001-7951-9881]
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Mitochondrial DNA
Cerebrospinal fluid
Alzheimer’s disease
Biomarkers
Digital PCR
topic Mitochondrial DNA
Cerebrospinal fluid
Alzheimer’s disease
Biomarkers
Digital PCR
description Alzheimer’s type dementia (AD) exhibits clinical heterogeneity, as well as differences in disease progression, as a subset of patients with a clinical diagnosis of AD progresses more rapidly (rpAD) than the typical AD of slow progression (spAD). Previous findings indicate that low cerebrospinal fluid (CSF) content of cell-free mitochondrial DNA (cf-mtDNA) precedes clinical signs of AD. We have now investigated the relationship between cf-mtDNA and other biomarkers of AD to determine whether a particular biomarker profile underlies the different rates of AD progression. We measured the content of cf-mtDNA, beta-amyloid peptide 1–42 (Aβ), total tau protein (t-tau) and phosphorylated tau (p-tau) in the CSF from a cohort of 95 subjects consisting of 49 controls with a neurologic disorder without dementia, 30 patients with a clinical diagnosis of spAD and 16 patients with rpAD. We found that 37% of controls met at least one AD biomarker criteria, while 53% and 44% of subjects with spAD and rpAD, respectively, did not fulfill the two core AD biomarker criteria: high t-tau and low Aβ in CSF. In the whole cohort, patients with spAD, but not with rpAD, showed a statistically significant 44% decrease of cf-mtDNA in CSF compared to control. When the cohort included only subjects selected by Aβ and t-tau biomarker criteria, the spAD group showed a larger decrease of cf-mtDNA (69%), whereas in the rpAD group cf-mtDNA levels remained unaltered. In the whole cohort, the CSF levels of cf-mtDNA correlated positively with Aβ and negatively with p-tau. Moreover, the ratio between cf-mtDNA and p-tau increased the sensitivity and specificity of spAD diagnosis up to 93% and 94%, respectively, in the biomarker-selected cohort. These results show that the content of cf-mtDNA in CSF correlates with the earliest pathological markers of the disease, Aβ and p-tau, but not with the marker of neuronal damage t-tau. Moreover, these findings confirm that low CSF content of cf-mtDNA is a biomarker for the early detection of AD and support the hypothesis that low cf-mtDNA, together with low Aβ and high p-tau, constitute a distinctive CSF biomarker profile that differentiates spAD from other neurological disorders.
publishDate 2020
dc.date.none.fl_str_mv 2020
2021
2021
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
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dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/230334
url http://hdl.handle.net/10261/230334
dc.language.none.fl_str_mv Inglés
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SAF2017-89791-R/AEI/10.13039/501100011033
https://doi.org/10.3390/ijms21176298
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dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
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dc.publisher.none.fl_str_mv Molecular Diversity Preservation International
publisher.none.fl_str_mv Molecular Diversity Preservation International
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
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spelling Cerebrospinal Fluid Mitochondrial DNA in Rapid and Slow Progressive Forms of Alzheimer’s DiseasePodlesniy, PetarLlorens, FrancPuigros Serra, MargalidaSerra, NuriaSepúlveda-Falla, DiegoSchmidt, Christian B.Hermann, PeterZerr, IngaTrullas, RamónMitochondrial DNACerebrospinal fluidAlzheimer’s diseaseBiomarkersDigital PCRAlzheimer’s type dementia (AD) exhibits clinical heterogeneity, as well as differences in disease progression, as a subset of patients with a clinical diagnosis of AD progresses more rapidly (rpAD) than the typical AD of slow progression (spAD). Previous findings indicate that low cerebrospinal fluid (CSF) content of cell-free mitochondrial DNA (cf-mtDNA) precedes clinical signs of AD. We have now investigated the relationship between cf-mtDNA and other biomarkers of AD to determine whether a particular biomarker profile underlies the different rates of AD progression. We measured the content of cf-mtDNA, beta-amyloid peptide 1–42 (Aβ), total tau protein (t-tau) and phosphorylated tau (p-tau) in the CSF from a cohort of 95 subjects consisting of 49 controls with a neurologic disorder without dementia, 30 patients with a clinical diagnosis of spAD and 16 patients with rpAD. We found that 37% of controls met at least one AD biomarker criteria, while 53% and 44% of subjects with spAD and rpAD, respectively, did not fulfill the two core AD biomarker criteria: high t-tau and low Aβ in CSF. In the whole cohort, patients with spAD, but not with rpAD, showed a statistically significant 44% decrease of cf-mtDNA in CSF compared to control. When the cohort included only subjects selected by Aβ and t-tau biomarker criteria, the spAD group showed a larger decrease of cf-mtDNA (69%), whereas in the rpAD group cf-mtDNA levels remained unaltered. In the whole cohort, the CSF levels of cf-mtDNA correlated positively with Aβ and negatively with p-tau. Moreover, the ratio between cf-mtDNA and p-tau increased the sensitivity and specificity of spAD diagnosis up to 93% and 94%, respectively, in the biomarker-selected cohort. These results show that the content of cf-mtDNA in CSF correlates with the earliest pathological markers of the disease, Aβ and p-tau, but not with the marker of neuronal damage t-tau. Moreover, these findings confirm that low CSF content of cf-mtDNA is a biomarker for the early detection of AD and support the hypothesis that low cf-mtDNA, together with low Aβ and high p-tau, constitute a distinctive CSF biomarker profile that differentiates spAD from other neurological disorders.This work has been funded by the Ministerio de Economia y Competitividad of Spain (Grant: SAF2017-89791-R) and by the Instituto Carlos III (Grant: PI2016/06-3) from Centro de Investigacion Biomedica en Red de Enfermedades Neurodegenerativas (CIBERNED) to R.T. and P.P.; by the Competence Network for Neurodegenerative Dementia (Kompetenznetzwerk Degenerative Demenzen, KNDD), by the Bundesministerium für Bildung und Forschung (BMBF) and by the Alzheimer-Forschungs-Initiative e.V. (AFI 12851) to I.Z., and by the Instituto Carlos III (grants CP16/00041 and PI19/00144) to F.Ll.Peer reviewedMolecular Diversity Preservation InternationalMinisterio de Ciencia, Innovación y Universidades (España)Agencia Estatal de Investigación (España)Instituto de Salud Carlos IIICentro Investigación Biomédica en Red Enfermedades Neurodegenerativas (España)Competence Network for Neurodegenerative Dementia (Germany)Federal Ministry of Education and Research (Germany)Llorens, Franc [0000-0002-9756-7497]Schmidt, Christian [0000-0003-2210-4153]Zerr, Inga [0000-0002-6722-2463]Trullas, Ramón [0000-0001-7951-9881]Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202120212020info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/230334reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/SAF2017-89791-RSAF2017-89791-R/AEI/10.13039/501100011033https://doi.org/10.3390/ijms21176298Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2303342026-05-22T06:33:51Z
score 15,81155

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