Person: Sánchez Ruiz de Gordoa, Javier
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Sánchez Ruiz de Gordoa
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Javier
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Ciencias de la Salud
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0000-0001-6467-5830
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109233
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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 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 Twofold binary image consensus for medical imaging meta-analysis(Springer, 2018) López Molina, Carlos; Sánchez Ruiz de Gordoa, Javier; Zelaya Huerta, María Victoria; Baets, Bernard de; Estadística, Informática y Matemáticas; Estatistika, Informatika eta MatematikaIn the field of medical imaging, ground truth is often gathered from groups of experts, whose outputs are generally heterogeneous. This procedure raises questions on how to compare the results obtained by automatic algorithms to multiple ground truth items. Secondarily, it raises questions on the meaning of the divergences between experts. In this work, we focus on the case of immunohistochemistry image segmentation and analysis. We propose measures to quantify the divergence in groups of ground truth images, and we observe their behaviour. These measures are based upon fusion techniques for binary images, which is a common example of non-monotone data fusion process. Our measures can be used not only in this specific field of medical imagery, but also in any task related to meta-quality evaluation for image processing, e.g. ground truth validation or expert rating.Publication Open Access Parálisis supranuclear progresiva: correlación clínico-patológica y aproximación al papel patogénico de lamicroglía(2022) Sánchez Ruiz de Gordoa, Javier; Erro Aguirre, María Elena; Mendióroz Iriarte, Maite; Zelaya Huerta, María Victoria; Ciencias de la Salud; Osasun ZientziakLa parálisis supranuclear progresiva (PSP) es una enfermedad neurodegenerativa que se manifiesta clínicamente como un parkinsonismo atípico y su base patológica son los depósitos de proteína tau en neuronas y células gliales. Es la taupatía primaria más frecuente. El diagnóstico definitivo es neuropatológico y, en los últimos años, se ha avanzado en la definición de criterios clínicos de diagnóstico más sensibles y específicos y en la identificación de potenciales biomarcadores. La hipótesis de este trabajo es que existe una correlación entre la diferente densidad y distribución de los depósitos de proteína tau en las distintas estructuras del encéfalo y la expresión fenotípica de la PSP. A su vez, esta expresión clínica podría estar influida por la interacción de la proteína tau con otros depósitos proteicos neuronales. Además, se plantea que la activación de la microglía puede jugar un papel en la fisiopatología de la enfermedad. El objetivo general de este trabajo es analizar las características clínicopatológicas de la PSP en un estudio retrospectivo postmortem y explorar el papel de la microglía en su fisiopatología. Para ello se propone estudiar la distribución de fenotipos clínicos tras la aplicación de diferentes criterios clínicos de diagnóstico para la PSP y comparar los fenotipos resultantes en función de la carga y distribución de la proteína tau; explorar la relación del depósito de la proteína tau con los de otras proteínas mal plegadas como la alfa-sinucleína; y explorar la expresión génica de un gen candidato, TREM2 (Triggering Receptor Expressed in Myeloid cells type 2), relacionado con la inflamación y la activación microglial en la PSP y su potencial uso como biomarcador de la enfermedad. Para su desarrollo, se han elaborado 3 trabajos que constituyen una unidad temática. En el primero de ellos, se realiza un estudio descriptivo transversal de las características clinico-patológicas de la serie de 34 casos de PSP del biobanco de Navarrabiomed que fallecieron entre los años 2005 y 2017, y se compara los depósitos de la proteína tau entre los fenotipos clínicos resultantes tras la aplicación retrospectiva de diferentes criterios clínicos de diagnóstico. En el segundo trabajo, se describen los casos que presentan una coexpresión en las mismas neuronas de la proteína tau y alfa-sinucleína mediante técnicas de doble inmunohistoquímica e inmunofluorescencia. En el tercer trabajo, se realiza un estudio observacional descriptivo de casos y controles comparando la expresión del gen TREM2 en muestras de la SN de 24 casos de PSP y controles sin neuropatología, y se analiza la correlación entre la expresión del gen y los depósitos de la proterína tau.Publication Open Access Profile of TREM2-derived circRNA and mRNA variants in the entorhinal cortex of Alzheimer's disease patients(MDPI, 2022) Urdánoz Casado, Amaya; Sánchez Ruiz de Gordoa, Javier; Robles, Maitane; Roldán, Miren; Zelaya Huerta, María Victoria; Blanco Luquin, Idoia; Mendióroz Iriarte, Maite; Ciencias de la Salud; Osasun Zientziak; Gobierno de Navarra / Nafarroako GobernuaGenetic variants in TREM2, a microglia-related gene, are well-known risk factors for Alzheimer’s disease (AD). Here, we report that TREM2 originates from circular RNAs (circRNAs), a novel class of non-coding RNAs characterized by a covalent and stable closed-loop structure. First, divergent primers were designed to amplify circRNAs by RT-PCR, which were further assessed by Sanger sequencing. Then, additional primer sets were used to confirm back-splicing junctions. In addition, HMC3 cells were used to assess the microglial expression of circTREM2s. Three candidate circTREM2s were identified in control and AD human entorhinal samples. One of the circRNAs, circTREM2_1, was consistently amplified by all divergent primer sets in control and AD entorhinal cortex samples as well as in HMC3 cells. In AD cases, a moderate negative correlation (r = −0.434) was found between the global average area of Aβ deposits in the entorhinal cortex and circTREM2_1 expression level. In addition, by bioinformatics tools, a total of 16 miRNAs were predicted to join with circTREM2s. Finally, TREM2 mRNA corresponding to four isoforms was profiled by RTqPCR. TREM2 mRNA levels were found elevated in entorhinal samples of AD patients with low or intermediate ABC scores compared to controls. To sum up, a novel circRNA derived from the TREM2 gene, circTREM2_1, has been identified in the human entorhinal cortex and TREM2 mRNA expression has been detected to increase in AD compared to controls. Unraveling the molecular genetics of the TREM2 gene may help to better know the innate immune response in AD.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 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.