Person: Acha Santamaría, Blanca
Loading...
Email Address
person.page.identifierURI
Birth Date
Research Projects
Organizational Units
Job Title
Last Name
Acha Santamaría
First Name
Blanca
person.page.departamento
Ciencias de la Salud
person.page.instituteName
ORCID
0000-0002-6776-5644
person.page.upna
TA128310
Name
7 results
Search Results
Now showing 1 - 7 of 7
Publication Open Access Association of blood-based DNA methylation markers with late-onset alzheimer disease: a potential diagnostic approach(Lippincott Williams & Wilkins, 2023) Acha Santamaría, Blanca; Corroza, Jon; Sánchez Ruiz de Gordoa, Javier; Cabello, Carolina; Robles Solano, Maitane; Méndez López, Iván; Macías, Mónica; Zueco, Sara; Roldán, Miren; Urdánoz Casado, Amaya; Jericó Pascual, Ivonne; Erro Aguirre, María Elena; Alcolea, Daniel; Lleo, Alberto; Blanco Luquin, Idoia; Mendióroz Iriarte, Maite; Ciencias de la Salud; Osasun ZientziakBackground and Objectives: There is an urgent need to identify novel noninvasive biomarkers for Alzheimer disease (AD) diagnosis. Recent advances in blood-based measurements of phosphorylated tau (pTau) species are promising but still insufficient to address clinical needs. Epigenetics has been shown to be helpful to better understand AD pathogenesis. Epigenetic biomarkers have been successfully implemented in other medical disciplines, such as oncology. The objective of this study was to explore the diagnostic accuracy of a blood-based DNA methylation marker panel as a noninvasive tool to identify patients with late-onset Alzheimer compared with age-matched controls. Methods: A case-control study was performed. Blood DNA methylation levels at 46 cytosine-guanine sites (21 genes selected after a comprehensive literature search) were measured by bisulfite pyrosequencing in patients with “probable AD dementia” following National Institute on Aging and the Alzheimer's Association guidelines (2011) and age-matched and sex-matched controls recruited at Neurology Department-University Hospital of Navarre, Spain, selected by convenience sampling. Plasma pTau181 levels were determined by Simoa technology. Multivariable logistic regression analysis was performed to explore the optimal model to discriminate patients with AD from controls. Furthermore, we performed a stratified analysis by sex. Results: The final study cohort consisted of 80 patients with AD (age: median [interquartile range] 79 [11] years; 58.8% female) and 100 cognitively healthy controls (age 77 [10] years; 58% female). A panel including DNA methylation levels at NXN, ABCA7, and HOXA3 genes and plasma pTau181 significantly improved (area under the receiver operating characteristic curve 0.93, 95% CI 0.89–0.97) the diagnostic performance of a single pTau181-based model, adjusted for age, sex, and APOE ɛ4 genotype. The sensitivity and specificity of this panel were 83.30% and 90.00%, respectively. After sex-stratified analysis, HOXA3 DNA methylation levels showed consistent association with AD. Discussion: These results highlight the potential translational value of blood-based DNA methylation biomarkers for noninvasive diagnosis of AD. Registration Information: Research Ethics Committee of the University Hospital of Navarre (PI17/02218).Publication Embargo Identificación de biomarcadores epigenéticos de metilación del DNA en la sangre periférica de pacientes con enfermedad de Alzheimer(2024) Acha Santamaría, Blanca; Mendióroz Iriarte, Maite; Blanco Luquin, Idoia; Ciencias de la Salud; Osasun ZientziakEn esta tesis doctoral, se investiga el papel de la metilación del DNA como un potencial biomarcador diagnóstico de la EA, dada la novedad que los mecanismos epigenéticos han supuesto en la búsqueda de biomarcadores en la última década. Para su desarrollo, se plantea una aproximación de gen candidato. Tras una extensa revisión bibliográfica, se seleccionaron 21 genes candidatos, cuyos niveles de metilación del DNA se midieron mediante la técnica de pirosecuencación por bisulfito en un grupo de 80 pacientes con EA y 100 controles. El análisis estadístico identificó 11 posiciones (CpGs) de metilación diferencial entre pacientes y controles. Con estos resultados se construyó un modelo de regresión logística multivariable que incluyó las posiciones diferencialmente metiladas (Differentially Methylated Positions, DMPs) identificadas en los genes NXN, TREML2, ABCA7 y HOXA3, cuya capacidad de discriminación de pacientes con EA fue del 87%. La construcción de un modelo de regresión logística donde se combinaron las marcas de metilación del DNA y pTau181 plasmático, con una capacidad de discriminación del 93%, mejoró la capacidad diagnóstica de pTau181 plasmático (85%), considerada la herramienta diagnóstica plasmática más promotedora hasta la fecha. El sexo y el genotipo APOE son, junto con la edad, los principales factores de riesgo (FR) de la EA, por lo que se estudió su asociación con las marcas de metilación del DNA identificadas en este estudio. Se encontraron marcas de metilación del DNA diferenciales entre pacientes con EA y controles en función del sexo y del genotipo APOE. Curiosamente, los niveles de metilación de la CpG localizada en el gen HOXA3 Chr7:27153577 mostraron diferencias estadísticamente significativas entre pacientes con EA y controles en la cohorte global y en todos los grupos tras la estratificación por sexo y genotipo APOE. Además, también mostraron correlación con la variable que refleja el estado cognitivo, el MMSE, y con los niveles de pTau181 plasmático, postulándose como una herramienta prometedora en la mejora de la precisión diagnóstica de la EA como parte de un panel de biomarcadores en sangre periférica. A su vez, las DMPs localizadas en los genes IRS2, HAND2 y RHBDF2 correlacionaron con los niveles de los biomarcadores core de líquido cefalorraquídeo (LCR) en los pacientes con EA de nuestra cohorte iBEAS, sin ser validados en una cohorte externa cedida por el Hospital Sant Pau (Barcelona). Como conclusión, este trabajo muestra la existencia de marcas de metilación del DNA en la sangre como potenciales herramientas en la mejora de la capacidad diagnóstica en la EA, ntegrados en paneles de biomarcadores periféricos. Además, estos resultados apoyan la posible implicación de la metilación del DNA en la patología de la EA.Publication Open Access Gender-dependent deregulation of linear and circular RNA variants of homer1 in the entorhinal cortex of Alzheimer’s disease(MDPI, 2021) Urdánoz Casado, Amaya; Sánchez Ruiz de Gordoa, Javier; Robles Solano, Maitane; Acha Santamaría, Blanca; Roldán, Miren; Zelaya Huerta, María Victoria; Blanco Luquin, Idoia; Mendióroz Iriarte, Maite; Ciencias de la Salud; Osasun Zientziak; Gobierno de Navarra / Nafarroako GobernuaThe HOMER1 gene is involved in synaptic plasticity, learning and memory. Recent studies show that circular RNA derived from HOMER1 (circHOMER1) expression is altered in some Alzheimer’s disease (AD) brain regions. In addition, HOMER1 messenger (mRNA) levels have been associated with β-Amyloid (Aβ) deposits in brain cortical regions. Our aim was to measure the expression levels of HOMER1 circRNAs and their linear forms in the human AD entorhinal cortex. First, we showed downregulation of HOMER1B/C and HOMER1A mRNA and hsa_circ_0006916 and hsa_circ_0073127 levels in AD female cases compared to controls by RT-qPCR. A positive correlation was observed between HOMER1B/C, HOMER1A mRNA, and hsa_circ_0073128 with HOMER1B/C protein only in females. Global average area of Aβ deposits in entorhinal cortex samples was negatively correlated with HOMER1B/C, HOMER1A mRNA, and hsa_circ_0073127 in both genders. Furthermore, no differences in DNA methylation were found in two regions of HOMER1 promoter between AD cases and controls. To sum up, we demonstrate that linear and circular RNA variants of HOMER1 are downregulated in the entorhinal cortex of female patients with AD. These results add to the notion that HOMER1 and its circular forms could be playing a female-specific role in the pathogenesis of AD.Publication Open Access NXN gene epigenetic changes in an adult neurogenesis model of Alzheimer's disease(MDPI, 2022) Blanco Luquin, Idoia; Acha Santamaría, Blanca; Urdánoz Casado, Amaya; Gómez Orte, Eva; Roldán, Miren; Pérez Rodríguez, Diego R.; Cabello, Juan; Mendióroz Iriarte, Maite; Ciencias de la Salud; Osasun Zientziak; Gobierno de Navarra / Nafarroako GobernuaIn view of the proven link between adult hippocampal neurogenesis (AHN) and learning and memory impairment, we generated a straightforward adult neurogenesis in vitro model to recapitulate DNA methylation marks in the context of Alzheimer’s disease (AD). Neural progenitor cells (NPCs) were differentiated for 29 days and Aβ peptide 1–42 was added. mRNA expression of Neuronal Differentiation 1 (NEUROD1), Neural Cell Adhesion Molecule 1 (NCAM1), Tubulin Beta 3 Class III (TUBB3), RNA Binding Fox-1 Homolog 3 (RBFOX3), Calbindin 1 (CALB1), and Glial Fibrillary Acidic Protein (GFAP) was determined by RT-qPCR to characterize the culture and framed within the multistep process of AHN. Hippocampal DNA methylation marks previously identified in Contactin-Associated Protein 1 (CNTNAP1), SEPT5-GP1BB Readthrough (SEPT5-GP1BB), T-Box Transcription Factor 5 (TBX5), and Nucleoredoxin (NXN) genes were profiled by bisulfite pyrosequencing or bisulfite cloning sequencing; mRNA expression was also measured. NXN outlined a peak of DNA methylation overlapping type 3 neuroblasts. Aβ-treated NPCs showed transient decreases of mRNA expression for SEPT5-GP1BB and NXN on day 9 or 19 and an increase in DNA methylation on day 29 for NXN. NXN and SEPT5-GP1BB may reflect alterations detected in the brain of AD human patients, broadening our understanding of this disease.Publication Open Access Liquid biopsy in alzheimer's disease patients reveals epigenetic changes in the PRLHR gene(MDPI, 2023) Macías, Mónica; Acha Santamaría, Blanca; Corroza, Jon; Urdánoz Casado, Amaya; Roldán, Miren; Robles, Maitane; Sánchez Ruiz de Gordoa, Javier; Erro Aguirre, María Elena; Jericó Pascual, Ivonne; Blanco Luquin, Idoia; Mendióroz Iriarte, Maite; Ciencias de la Salud; Osasun ZientziakIn recent years, new DNA methylation variants have been reported in genes biologically relevant to Alzheimer’s disease (AD) in human brain tissue. However, this AD-specific epigenetic information remains brain-locked and unreachable during patients’ lifetimes. In a previous methylome performed in the hippocampus of 26 AD patients and 12 controls, we found higher methylation levels in AD patients in the promoter region of PRLHR, a gene involved in energy balance regulation. Our aim was to further characterize PRLHR’s role in AD and to evaluate if the liquid biopsy technique would provide life access to this brain information in a non-invasive way. First, we extended the methylation mapping of PRLHR and validated previous methylome results via bisulfite cloning sequencing. Next, we observed a positive correlation between PRLHR methylation levels and AD-related neuropathological changes and a decreased expression of PRLHR in AD hippocampus. Then, we managed to replicate the hippocampal methylation differences in plasma cfDNA from an additional cohort of 35 AD patients and 35 controls. The isolation of cfDNA from the plasma of AD patients may constitute a source of potential epigenetic biomarkers to aid AD clinical management.Publication Open Access Early epigenetic changes of Alzheimer's disease in the human hippocampus(2020) Blanco Luquin, Idoia; Acha Santamaría, Blanca; Urdánoz Casado, Amaya; Sánchez Ruiz de Gordoa, Javier; Vicuña-Urriza, Janire; Roldán, Miren; Labarga Gutiérrez, Alberto; Zelaya Huerta, María Victoria; Cabello, Carolina; Méndez López, Iván; Mendióroz Iriarte, Maite; Ciencias de la Salud; Osasun Zientziak; Sociología y Trabajo Social; Soziologia eta Gizarte Lana; Gobierno de Navarra / Nafarroako GobernuaThe discovery of new biomarkers would be very valuable to improve the detection of early Alzheimer's disease (AD). DNA methylation marks may serve as epigenetic biomarkers of early AD. Here we identified epigenetic marks that are present in the human hippocampus from the earliest stages of AD. A previous methylome dataset of the human AD hippocampus was used to select a set of eight differentially methylated positions (DMPs) since early AD stages. Next, bisulphite pyrosequencing was performed in an expanded homogeneous cohort of 18 pure controls and 35 hippocampal samples with neuropathological changes of pure AD. Correlation between DNA methylation levels in DMPs and phospho-tau protein burden assessed by immunohistochemistry in the hippocampus was also determined. We found four DMPs showing higher levels of DNA methylation at early AD stages compared to controls, involving ELOVL2, GIT1/TP53I13 and the histone gene locus at chromosome 6. DNA methylation levels assessed by bisulphite pyrosequencing correlated with phospho-tau protein burden for ELOVL2 and HIST1H3E/HIST1H3 F genes. In this discovery study, a set of four epigenetic marks of early AD stages have been identified in the human hippocampus. It would be worth studying in-depth the specific pathways related to these epigenetic marks. These early alterations in DNA methylation in the AD hippocampus could be regarded as candidate biomarkers to be explored in future translational studies.Publication Open Access Is the phenotype designation by PSP-MDS criteria stable throughout the disease course and consistent with tau distribution?(Frontiers Media, 2022) Sánchez Ruiz de Gordoa, Javier; Zelaya Huerta, María Victoria; Tellechea-Aramburo, Paula; Acha Santamaría, Blanca; Roldán, Miren; López Molina, Carlos; Coca, Valle; Galbete Jiménez, Arkaitz; Mendióroz Iriarte, Maite; Erro Aguirre, María Elena; Estadística, Informática y Matemáticas; Estatistika, Informatika eta MatematikaIntroduction: the MDS-PSP criteria have shown high sensitivity for the PSP diagnosis, but do not discriminate the phenotype diversity. Our purpose was to search for anatomopathological differences among PSP phenotypes resulting from the application of the MDS-PSP criteria comparing with the previous ones. Methods: thirty-four PSP cases from a single brain bank were retrospectively classified according to the criteria used by Respondek et al. in 2014 and the PSP-MDS criteria at 3 years (MDS-3y), 6 years (MDS-6y) and at the last clinical evaluation before death (MDS-last). Semiquantitative measurement of total, cortical and subcortical tau load was compared. For comparative analysis, PSP-Richardson syndrome and PSP postural instability were grouped (PSP-RS/PI) as well as the PSP atypical cortical phenotypes (PSP-Cx). Results: applying the Respondek's criteria, PSP phenotypes were distributed as follow: 55.9% PSP-RS/PI, 26.5% PSP-Cx, 11.8% PSP-Parkinsonism (PSP-P), and 5.9% PSP-Cerebellum. PSP-RS/PI and PSP-Cx had a higher total tau load than PSP-P; PSP-Cx showed a higher cortical tau load than PSP-RS/PI and PSP-P; and PSP-RS/PI had a higher subcortical tau load than PSP-P. Applying the MDS-3y, MDS-6y and MDS-last criteria; the PSP-RS/PI group increased (67.6, 70.6 and 70.6% respectively) whereas the PSP-Cx group decreased (8.8, and 8.8 and 11.8%). Then, only differences in total and subcortical tau burden between PSP-RS/PI and PSP-P were observed. Interpretation: after the retrospective application of the new MDS-PSP criteria, total and subcortical tau load is higher in PSP-RS/PI than in PSP-P whereas no other differences in tau load between phenotypes were found, as a consequence of the loss of phenotypic diversity.