Person:
Gil Gregorio, Pedro

First Name

Pedro

Last Name

Gil Gregorio

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Universidad Complutense de Madrid

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Medicina

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Medicina

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Medicina

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Spatial analysis of thickness changes in ten retinal layers of Alzheimer’s disease patients based on optical coherence tomography
(Nature Publishing Group, 2019) Jañez Escalada, Luis; Jáñez García, Lucía; García Martín, Elena Salobrar; Santos Mayo, Alejandro; Hoz Montañana, María Rosa de; Yubero Pancorbo, Raquel; Gil Gregorio, Pedro; Ramirez Sebastian, Jose Manuel
The retina is an attractive source of biomarkers since it shares many features with the brain. Thickness differences in 10 retinal layers between 19 patients with mild Alzheimer’s disease (AD) and a control group of 24 volunteers were investigated. Retinal layers were automatically segmented and their thickness at each scanned point was measured, corrected for tilt and spatially normalized. When the mean thickness of entire layers was compared between patients and controls, only the outer segment layer of patients showed statistically significant thinning. However, when the layers were compared point-by point, patients showed statistically significant thinning in irregular regions of total retina and nerve fiber, ganglion cell, inner plexiform, inner nuclear and outer segment layers. Our method, based on random field theory, provides a precise delimitation of regions where total retina and each of its layers show a statistically significant thinning in AD patients. All layers, except inner nuclear and outer segments, showed thickened regions. New analytic methods have shown that thinned regions are interspersed with thickened ones in all layers, except inner nuclear and outer segments. Across different layers we found a statistically significant trend of the thinned regions to overlap and of the thickened ones to avoid overlapping.
Alzheimer’s disease: a continuum with visual involvements
(Frontiers Media, 2023-07-06) Elvira Hurtado, Lorena; López Cuenca, Inés; Hoz Montañana, María Rosa De; Salas, Mario; Sánchez-Puebla Fernández, Lidia; Matamoros, José Antonio; Fernández Albarral, José; Rojas Lozano, María Del Pilar; Alfonsín, Soraya; Delgado Losada, María Luisa; Ramírez Sebastián, Ana Isabel; Salazar Corral, Juan José; Maestu Unturbe, Fernando; Gil Gregorio, Pedro; Ramírez Sebastián, José Manuel; García Martín, Elena Salobrar
Introduction: Alzheimer’s disease (AD) is the most common form of dementia affecting the central nervous system, and alteration of several visual structures has been reported. Structural retinal changes are usually accompanied by changes in visual function in this disease. The aim of this study was to analyse the differences in visual function at different stages of the pathology (family history group (FH+), mild cognitive impairment (MCI), mild AD and moderate AD) in comparison with a control group of subjects with no cognitive decline and no family history of AD. Methods: We included 53 controls, 13 subjects with FH+, 23 patients with MCI, 25 patients with mild AD and, 21 patients with moderate AD. All were ophthalmologically healthy. Visual acuity (VA), contrast sensitivity (CS), colour perception, visual integration, and fundus examination were performed. Results: The analysis showed a statistically significant decrease in VA, CS and visual integration score between the MCI, mild AD and moderate AD groups compared to the control group. In the CS higher frequencies and in the colour perception test (total errors number), statistically significant differences were also observed in the MCI, mild AD and moderate AD groups with respect to the FH+ group and also between the control and AD groups. The FH+ group showed no statistically significant difference in visual functions compared to the control group. All the test correlated with the Mini Mental State Examination score and showed good predictive value when memory decline was present, with better values when AD was at a more advanced stage. Conclusion: Alterations in visual function appear in subjects with MCI and evolve when AD is established, being stable in the initial stages of the disease (mild AD and moderate AD). Therefore, visual psychophysical tests are a useful, simple and complementary tool to neuropsychological tests to facilitate diagnosis in the preclinical and early stages of AD.
Changes in visual function and retinal structure in the progression of Alzheimer's disease
(Public Library Science, 2019-08-15) García Martín, Elena Salobrar; Hoz Montañana, Rosa de; Ramírez Sebastián, Ana Isabel; López Cuenca, Inés; Rojas Lozano, Pilar; Vazirani Ballesteros, Ravi; Amarante Cuadrado, Carla; Yubero Pancorbo, Raquel; Gil Gregorio, Pedro; Pinazo Durán, Mª Dolores; Salazar Corral, Juan José; Ramirez Sebastian, Jose Manuel
Background: Alzheimer’s Disease (AD) can cause degeneration in the retina and optic nerve either directly, as a result of amyloid beta deposits, or secondarily, as a result of the degradation of the visual cortex. These effects raise the possibility that tracking ophthalmologic changes in the retina can be used to assess neurodegeneration in AD. This study aimed to detect retinal changes and associated functional changes in three groups of patients consisting of AD patients with mild disease, AD patients with moderate disease and healthy controls by using non-invasive psychophysical ophthalmological tests and optical coherence tomography (OCT). Methods: We included 39 patients with mild AD, 21 patients with moderate AD and 40 age-matched healthy controls. Both patients and controls were ophthalmologically healthy. Visual acuity, contrast sensitivity, colour perception, visual integration, and choroidal thicknesses were measured. In addition, OCT and OCT angiography (OCTA) were applied. Findings: Visual acuity, contrast sensitivity, colour perception, and visual integration were significantly lower in AD patients than in healthy controls. Compared to healthy controls, macular thinning in the central region was significant in the mild AD patients, while macular thickening in the central region was found in the moderate AD group. The analysis of macular layers revealed significant thinning of the retinal nerve fibre layer, the ganglion cell layer and the outer plexiform layer in AD patients relative to controls. Conversely, significant thickening was observed in the outer nuclear layer of the patients. However, mild AD was associated with significant thinning of the subfovea and the nasal and inferior sectors of the choroid. Significant superonasal and inferotemporal peripapillary thinning was observed in patients with moderate disease. Conclusions: The first changes in the mild AD patients appear in the psychophysical tests and in the central macula with a decrease in the central retinal thickness. When there was a disease progression to moderate AD, psychophysical tests remained stable with respect to the decrease in mild AD, but significant thinning in the peripapillary retina and thickening in the central retina appeared. The presence of AD is best indicated based on contrast sensitivity.
Ophthalmologic Psychophysical Tests Support OCT Findings in Mild Alzheimer's Disease
(HINDAWI PUBLISHING CORPORATION, 2015-05-20) García Martín, Elena Salobrar; Hoz Montañana, María Rosa de; Rojas López, María Blanca; Ramírez Sebastián, Ana Isabel; Salazar Corral, Juan José; Yubero Pancorbo, Raquel; Gil Gregorio, Pedro; Triviño Casado, Alberto; Ramirez Sebastian, Jose Manuel
Purpose. To analyze in mild Alzheimer's disease (MAD) patients, GDS-4 (Reisberg Scale), whether or not some psychophysical tests (PTs) support OCT macular findings in the same group of MAD patients reported previously. Methods. Twenty-three MAD patients and 28 age-matched control subjects with mean Mini Mental State Examination of 23.3 and 28.2, respectively, with no ocular disease or systemic disorders affecting vision were included. Best-corrected visual acuity (VA), contrast sensitivity (CS) (3, 6, 12, and 18 cpds), color perception (CP), and perception digital test (PDT) were tested in one eye of each patient. Results. In comparison with the controls, MAD patients presented (i) a significant decrease in VA, PDT, and CS for all spatial frequencies analyzed, especially the higher ones, and (ii) a significant increase in unspecific errors on the blue axis (P < 0.05 in all instances). In MAD patients, a wide a ROC curve was plotted in all PTs. Conclusions. In MAD, CS, VA, and the tritan axis in CP were impaired. The PTs with the greatest predictive value are the higher spatial frequencies in CS and tritan unspecific errors in CP. PT abnormalities are consistent with the structural findings reported in the same MAD patients using OCT.
Exploratory Longitudinal Study of Ocular Structural and Visual Functional Changes in Subjects at High Genetic Risk of Developing Alzheimer’s Disease
(MDPI, 2023-07-18) Barabash Bustelo, Ana; López Cuenca, Inés; Ramírez Toraño, Federico; Sánchez Puebla, Lidia; Fernández Albarral, José; García Martín, Elena Salobrar; Nebreda Pérez, Alberto; Álvarez Gutierrez, María; Elvira Hurtado, Lorena; Matamoros, José A.; García Colomo, Alejandra; Maestu Unturbe, Fernando; Ana I. Ramírez; Ramírez Sebastián, Ana Isabel; Juan J. Salazar; Salazar Corral, Juan José; Pedro Gil; Gil Gregorio, Pedro; Fernando Maestú; José M. Ramírez; Ramírez Sebastián, José Manuel; Rosa de Hoz; Hoz Montañana, María Rosa De
This study aimed to analyze the evolution of visual changes in cognitively healthy individuals at risk for Alzheimer’s disease (AD). Participants with a first-degree family history of AD (FH+) and carrying the Ε4+ allele for the ApoE gene (ApoE ε4+) underwent retinal thickness analysis using optical coherence tomography (OCT) and visual function assessments, including visual acuity (VA), contrast sensitivity (CS), color perception, perception digital tests, and visual field analysis. Structural analysis divided participants into FH+ ApoE ε4+ and FH− ApoE ε4− groups, while functional analysis further categorized them by age (40–60 years and over 60 years). Over the 27-month follow-up, the FH+ ApoE ε4+ group exhibited thickness changes in all inner retinal layers. Comparing this group to the FH− ApoE ε4− group at 27 months revealed progressing changes in the inner nuclear layer. In the FH+ ApoE ε4+ 40–60 years group, no progression of visual function changes was observed, but an increase in VA and CS was maintained at 3 and 12 cycles per degree, respectively, compared to the group without AD risk at 27 months. In conclusion, cognitively healthy individuals at risk for AD demonstrated progressive retinal structural changes over the 27-month follow-up, while functional changes remained stable.
Complexity analysis of spontaneous brain activity in alzheimer disease and mild cognitive impairment: An MEG study
(Wolters Kluwer Health, 2010-04) Fernández, Alberto; Hornero, Roberto; Gómez, Carlos; Turrero, Agustín; Gil Gregorio, Pedro; Matías Santos, Juan; Ortiz, Tomás
Nonlinear analyses have shown that Alzheimer disease (AD) patients' brain activity is characterized by a reduced complexity and connectivity. The aim of this study is to define complexity patterns of mild cognitive impairment (MCI) patients. Whole-head magnetoencephalography recordings were obtained from 18 diagnosed AD patients, 18 MCI patients, and 18 healthy controls during resting conditions. Lempel-Ziv complexity (LZC) values were calculated. MCI patients exhibited intermediary LZC scores between AD patients and controls. A combination of age and posterior LZC scores allowed ADs-MCIs discrimination with 94.4% sensitivity and specificity, whereas no LZC score allowed MCIs---controls discrimination. AD patients and controls showed a parallel tendency to diminished LZC scores as a function of age, but MCI patients did not exhibit such “normal” tendency. Accordingly, anterior LZC scores allowed MCIs-controls discrimination for subjects below 75 years. MCIs exhibited a qualitatively distinct relationship between aging and complexity reduction, with scores higher than controls in older individuals. This fact might be considered a new example of compensatory mechanism in MCI before fully established dementia.
The relationship between retinal layers and brain areas in asymptomatic first-degree relatives of sporadic forms of Alzheimer’s disease: an exploratory analysis
(BMC (Springer), 2022-06-04) López Cuenca, Inés; Marcos Dolado, Alberto; Yus Fuertes, Miguel; García Martín, Elena Salobrar; Elvira Hurtado, Lorena; Fernández Albarral, José Antonio; Salazar Corral, Juan José; Ramírez Sebastián, Ana Isabel; Sánchez Puebla, Lídia; Fuentes Ferrer, Manuel Enrique; Barabash, Ana; Ramírez Toraño, Federico; Gil Martínez, Lidia; Arrazola García, Juan Lorenzo; Gil Gregorio, Pedro; Hoz Montañana, María Rosa de; Ramirez Sebastian, Jose Manuel
Background: Two main genetic risks for sporadic Alzheimer’s disease (AD) are a family history and ɛ4 allele of apolipoprotein E. The brain and retina are part of the central nervous system and share pathophysiological mechanisms in AD. Methods: We performed a cross-sectional study with 30 participants without a family history of sporadic AD (FH−) and noncarriers of ApoE ɛ4 (ApoE ɛ4−) as a control group and 34 participants with a family history of sporadic AD (FH+) and carriers of at least one ɛ4 allele (ApoE ɛ4+). We analyzed the correlations between macular volumes of retinal layers and thickness of the peripapillary retinal nerve fiber layer (pRNFL) measured by optical coherence tomography (OCT) with the brain area parameters measured by magnetic resonance imaging (MRI) in participants at high genetic risk of developing AD (FH+ ApoE ɛ4+). Results: We observed a significant volume reduction in the FH+ ApoE ɛ4+ group compared with the control group in some macular areas of (i) macular RNFL (mRNFL), (ii) inner plexiform layer (IPL), (iii) inner nuclear layer (INL), and (iv) outer plexiform layer (OPL). Furthermore, in the FH+ ApoE ɛ4+ group, the retinal sectors that showed statistically significant volume decrease correlated with brain areas that are affected in the early stages of AD. In the same group, the peripapillary retinal nerve fiber layer (pRNFL) did not show statistically significant changes in thickness compared with the control group. However, correlations of these sectors with the brain areas involved in this disease were also found. Conclusions: In cognitively healthy participants at high genetic risk of developing sporadic forms of AD, there are significant correlations between retinal changes and brain areas closely related to AD such as the entorhinal cortex, the lingual gyrus, and the hippocampus.
MEG Delta Mapping Along the Healthy Aging-Alzheimer's Disease Continuum: Diagnostic Implications
(IOS Press, 2013) Fernández, Alberto; Turrero, Agustín; Zuluaga Arias, Pilar; Gil Gregorio, Pedro; Pozo, Francisco del; Maestú Unturbe, Fernando; Moratti, Stephan
New diagnostic criteria for Alzheimer's disease (AD) stress the role of in vivo biomarkers. Neurophysiological markers are usually not considered as such criteria, although theoretical and practical reasons would justify them. In order to assess the value of neurophysiology as an AD biomarker, whole-head magnetoencephalographic (MEG) resting state recordings were obtained from 35 AD patients, 23 mild cognitive impairment (MCI) patients, and 24 healthy controls. The AD group was further split into two groups differing in severity according to the GDS/FAST criteria. A Minimum Norm Estimation procedure was utilized to estimate the cortical origin of slow brain oscillatory activity in the delta band (2–4 Hz). Eight regions of interest (ROIs) discriminated between AD patients and controls. Delta current density (DCD) in all ROIs showed a significant negative correlation with cognitive status (p < 0.001). DCD values in posterior parietal, occipital, prerolandic, and precuneus cortices distinguished reliably between MCI patients, AD patients with different severity scores, and controls. Importantly, an increase of DCD in right parietal cortex and precuneus indexed the transition from MCI to mild dementia and from mild to more severe dementia. MEG delta mapping might be a serious candidate for a “neural degeneration” marker of AD reflecting dysfunctional synaptic transmission. More importantly, the localization of DCD values is in line with functional imaging markers of AD. However, MEG delta mapping is a totally non-invasive technique that directly measures neural activity. We propose that individuals with enhanced DCD in posterior parietal and precuneus cortices are at risk of progression to full dementia.
Exploratory Longitudinal Study of Ocular Structural and Visual Functional Changes in Subjects at High Genetic Risk of Developing Alzheimer’s Disease
(MDPI, 2023-07-18) Barabash Bustelo, Ana; López Cuenca, Inés; Sánchez-Puebla Fernández, Lidia; García Martín, Elena Salobrar; Álvarez Gutierrez, María; Elvira Hurtado, Lorena; Ramírez Toraño, Federico; Fernández Albarral, José; Matamoros, José Antonio; Nebreda Pérez, Alberto; García Colomo, Alejandra; Ramírez Sebastián, Ana Isabel; Salazar Corral, Juan José; Gil Gregorio, Pedro; Maestú Unturbe, Fernando; Ramírez Sebastián, José Manuel; Hoz Montañana, Rosa, de
This study aimed to analyze the evolution of visual changes in cognitively healthy individuals at risk for Alzheimer’s disease (AD). Participants with a first-degree family history of AD (FH+) and carrying the Ε4+ allele for the ApoE gene (ApoE ε4+) underwent retinal thickness analysis using optical coherence tomography (OCT) and visual function assessments, including visual acuity (VA), contrast sensitivity (CS), color perception, perception digital tests, and visual field analysis. Structural analysis divided participants into FH+ ApoE ε4+ and FH− ApoE ε4− groups, while functional analysis further categorized them by age (40–60 years and over 60 years). Over the 27-month follow-up, the FH+ ApoE ε4+ group exhibited thickness changes in all inner retinal layers. Comparing this group to the FH− ApoE ε4− group at 27 months revealed progressing changes in the inner nuclear layer. In the FH+ ApoE ε4+ 40–60 years group, no progression of visual function changes was observed, but an increase in VA and CS was maintained at 3 and 12 cycles per degree, respectively, compared to the group without AD risk at 27 months. In conclusion, cognitively healthy individuals at risk for AD demonstrated progressive retinal structural changes over the 27-month follow-up, while functional changes remained stable.
Roughness of retinal layers in Alzheimer’s disease
(Nature publishing group, 2021-06-03) Jáñez García, Lucía; Bachtoula, Omar; García Martín, Elena Salobrar; de Hoz Montañana, María Rosa; Ramírez Sebastián, Ana Isabel; Gil Gregorio, Pedro; Ramirez Sebastian, Jose Manuel; Jañez Escalada, Luis
There is growing evidence that thinned retinal regions are interspersed with thickened regions in all retinal layers of patients with Alzheimer’s disease (AD), causing roughness to appear on layer thickness maps. The hypothesis is that roughness of retinal layers, assessed by the fractal dimension (FD) of their thickness maps, is an early biomarker of AD. Ten retinal layers have been studied in macular volumes of optical coherence tomography from 24 healthy volunteers and 19 patients with mild AD (Mini-Mental State Examination 23.42 ± 3.11). Results show that FD of retinal layers is greater in the AD group, the differences being statistically significant (p < 0.05). Correlation of layer FD with cognitive score, visual acuity and age reach statistical significance at 7 layers. Nearly all (44 out of 45) FD correlations among layers are positive and half of them reached statistical significance (p < 0.05). Factor analysis unveiled two independent factors identified as the dysregulation of the choroidal vascular network and the retinal inflammatory process. Conclusions: surface roughness is a holistic feature of retinal layers that can be assessed by the FD of their thickness maps and it is an early biomarker of AD.