Person:
Cuesta Prieto, Pablo

First Name

Pablo

Last Name

Cuesta Prieto

URI

https://hdl.handle.net/20.500.14352/80709

Affiliation

Universidad Complutense de Madrid

Faculty / Institute

Medicina

Department

Radiología, Rehabilitación y Fisioterapia

Area

Radiología y Medicina Física

Identifiers

Full item page

Search Results

Now showing 1 - 10 of 23

Episodic memory dysfunction and hypersynchrony in brain functional networks in cognitively intact subjects and MCI: a study of 379 individuals
(Geroscience, 2022) Chino, Brenda; Cuesta Prieto, Pablo; Pacios García, Javier; De Frutos Lucas, Jaisalmer; Torres Simón, Lucía; Doval Moreno, Sandra; Marcos Dolado, Alberto; Bruña Fernández, Ricardo; Maestu Unturbe, Fernando
Delayed recall (DR) impairment is one of the most significant predictive factors in defining the progression to Alzheimer’s disease (AD). Changes in brain functional connectivity (FC) could accompany this decline in the DR performance even in a resting state condition from the preclinical stages to the diagnosis of AD itself, so the characterization of the relationship between the two phenomena has attracted increasing interest. Another aspect to contemplate is the potential moderator role of the APOE genotype in this association, considering the evidence about their implication for the disease. 379 subjects (118 mild cognitive impairment (MCI) and 261 cognitively intact (CI) individuals) underwent an extensive evaluation, including MEG recording. Applying cluster-based permutation test, we identified a cluster of differences in FC and studied which connections drove such an effect in DR. The moderation effect of APOE genotype between FC results and delayed recall was evaluated too. Higher FC in beta band in the right occipital region is associated with lower DR scores in both groups. A significant anteroposterior link emerged in the seed-based analysis with higher values in MCI. Moreover, APOE genotype appeared as a moderator between beta FC and DR performance only in the CI group. An increased beta FC in the anteroposterior brain region appears to be associated with lower memory performance in MCI. This finding could help discriminate the pattern of the progression of healthy aging to MCI and the relation between resting state and memory performance.
Hypersynchronization in mild cognitive impairment: the ‘X’ model
(Brain, 2019) Pusil Arce, Sandra Angélica; López García, María Eugenia; Cuesta Prieto, Pablo; Bruña Fernández, Ricardo; Pereda, Ernesto; Maestu Unturbe, Fernando
Hypersynchronization has been proposed as a synaptic dysfunction biomarker in the Alzheimer's disease continuum, reflecting the alteration of the excitation/inhibition balance. While animal models have verified this idea extensively, there is still no clear evidence in humans. Here we test this hypothesis, evaluating the risk of conversion from mild cognitive impairment (MCI) to Alzheimer's disease in a longitudinal study. We compared the functional resting state eyes-closed magnetoencephalographic networks of 54 patients with MCI who were followed-up every 6 months. According to their clinical outcome, they were split into: (i) the 'progressive' MCI (n = 27) group; and (ii) the 'stable' MCI group (n = 27). They did not differ in gender or educational level. For all participants, two magnetoencephalographic recordings were acquired. Functional connectivity was evaluated using the phase locking value. To extract the functional connectivity network with significant changes between both magnetoencephalographic recordings, we evaluated the functional connectivity ratio, defined as functional connectivity post-/pre-condition, in a network-based statistical model with an ANCOVA test with age as covariate. Two significant networks were found in the theta and beta bands, involving fronto-temporal and fronto-occipital connections, and showing a diminished functional connectivity ratio in the progressive MCI group. These topologies were then evaluated at each condition showing that at baseline, patients with progressive MCI showed higher synchronization than patients with stable MCI, while in the post-condition this pattern was reversed. These results may be influenced by two main factors in the post-condition: the increased synchrony in the stable MCI patients and the network failure in the progressive MCI patients. These findings may be explained as an 'X' form model where the hypersynchrony predicts conversion, leading subsequently to a network breakdown in progressive MCI. Patients with stable MCI showed an opposite phenomenon, which could indicate that they were a step beyond in the Alzheimer's disease continuum. This model would be able to predict the risk for the conversion to dementia in MCI patients.
Efficiency at rest: Magnetoencephalographic resting-state connectivity and individual differences in verbal working memory
(International Journal of Psychophysiology, 2012) Del Río Grande, David Pedro; Cuesta Prieto, Pablo; Bajo Bretón, Ricardo; Pacios García, Javier; López Sánchez, Ramón; Pozo, Francisco del; Maestu Unturbe, Fernando
Inter-individual differences in cognitive performance are based on an efficient use of task-related brain resources. However, little is known yet on how these differences might be reflected on resting-state brain networks. Here we used Magnetoencephalography resting-state recordings to assess the relationship between a behavioral measurement of verbal working memory and functional connectivity as measured through Mutual Information. We studied theta (4–8 Hz), low alpha (8–10 Hz), high alpha (10–13 Hz), low beta (13–18 Hz) and high beta (18–30 Hz) frequency bands. A higher verbal working memory capacity was associated with a lower mutual information in the low alpha band, prominently among right-anterior and left-lateral sensors. The results suggest that an efficient brain organization in the domain of verbal working memory might be related to a lower resting-state functional connectivity across large-scale brain networks possibly involving right prefrontal and left perisylvian areas.
Influence of the APOE ε4 allele and mild cognitive impairment diagnosis in the disruption of the MEG resting state functional connectivity in sources space
(Journal of Alzheimer's Disease, 2015) Cuesta Prieto, Pablo; Garcés, Pilar; Castellanos, Nazareth P; López García, María Eugenia; Aurtenetxe, Sara; Bajo, Ricardo; Pineda-Pardo, José Angel; Bruña Fernández, Ricardo; Marín, Antonio García; Delgado Losada, María Luisa; Barabash Bustelo, Ana; Ancín, Inés; Cabranes Díaz, José Antonio; Fernández Lucas, Alberto Amable; del Pozo, Francisco; Sancho Ruiz, Miguel; Marcos Dolado, Alberto; Nakamura, Akinori; Maestu Unturbe, Fernando
The apolipoprotein E (APOE) ε4 allele constitutes the major genetic risk for the development of late onset Alzheimer's disease (AD). However, its influence on the neurodegeneration that occurs in early AD remains unresolved. In this study, the resting state magnetoencephalography(MEG) recordings were obtained from 27 aged healthy controls and 36 mild cognitive impairment (MCI) patients. All participants were divided into carriers and non-carriers of the ε4 allele. We have calculated the functional connectivity (FC) in the source space along brain regions estimated using the Harvard-Oxford atlas and in the classical bands. Then, a two way ANOVA analysis (diagnosis and APOE) was performed in each frequency band. The diagnosis effect consisted of a diminished FC within the high frequency bands in the MCI patients, affecting medial temporal and parietal regions. The APOE effect produced a decreased long range FC in delta band in ε4 carriers. Finally, the interaction effect showed that the FC pattern of the right frontal-temporal region could be reflecting a compensatory/disruption process within the ε4 allele carriers. Several of these results correlated with cognitive decline and neuropsychological performance. The present study characterizes how the APOE ε4 allele and MCI status affect the brain's functional organization by analyzing the FC patterns in MEG resting state in the sources space. Therefore a combination of genetic, neuropsychological, and neurophysiological information might help to detect MCI patients at higher risk of conversion to AD and asymptomatic subjects at higher risk of developing a manifest cognitive deterioration.
The effects of white matter hyperintensities on MEG power spectra in population with mild cognitive impairment
(Frontiers in Human Neuroscience, 2023) Torres Simón, Lucía; Cuesta Prieto, Pablo; del Cerro León, Alberto; Chino, Brenda; Orozco, Lucia H.; Marsh, Elisabeth B.; Gil Gregorio, Pedro; Maestu Unturbe, Fernando
Cerebrovascular disease is responsible for up to 20% of cases of dementia worldwide, but also it is a major comorbid contributor to the progression of other neurodegenerative diseases, like Alzheimer’s disease. White matter hyperintensities (WMH) are the most prevalent imaging marker in cerebrovascular disease. The presence and progression of WMH in the brain have been associated with general cognitive impairment and the risk to develop all types of dementia. The aim of this piece of work is the assessment of brain functional differences in an MCI population based on the WMH volume. One-hundred and twenty-nine individuals with mild cognitive impairment (MCI) underwent a neuropsychological evaluation, MRI assessment (T1 and Flair), and MEG recordings (5 min of eyes closed resting state). Those participants were further classified into vascular MCI (vMCI; n = 61, mean age 75 ± 4 years, 35 females) or non-vascular MCI (nvMCI; n = 56, mean age 72 ± 5 years, 36 females) according to their WMH total volume, assessed with an automatic detection toolbox, LST (SPM12). We used a completely data-driven approach to evaluate the differences in the power spectra between the groups. Interestingly, three clusters emerged: One cluster with widespread larger theta power and two clusters located in both temporal regions with smaller beta power for vMCI compared to nvMCI. Those power signatures were also associated with cognitive performance and hippocampal volume. Early identification and classification of dementia pathogenesis is a crucially important goal for the search for more effective management approaches. These findings could help to understand and try to palliate the contribution of WMH to particular symptoms in mixed dementia progress.
Age and APOE genotype affect the relationship between objectively measured physical activity and power in the alpha band, a marker of brain disease
(Alzheimer's Research & Therapy, 2020) De Frutos Lucas, Jaisalmer; Cuesta Prieto, Pablo; Ramírez Toraño, Federico; Nebreda Pérez, Alberto; Cuadrado Soto, Esther; Peral Suárez, África; López Sanz, David; Bruña Fernández, Ricardo; Marcos-de Pedro, Silvia; Delgado Losada, María Luisa; López Sobaler, Ana María; Rodríguez Rojo, Inmaculada Concepción; Barabash Bustelo, Ana; Serrano Rodríguez, Juan Manuel; Laws, Simon M.; Marcos Dolado, Alberto; López Sánchez, Ramón; Brown, Belinda M.; Maestu Unturbe, Fernando
BACKGROUND: Electrophysiological studies show that reductions in power within the alpha band are associated with the Alzheimer’s disease (AD) continuum. Physical activity (PA) is a protective factor that has proved to reduce AD risk and pathological brain burden. Previous research has confirmed that exercise increases power in the alpha range. However, little is known regarding whether other non-modifiable risk factors for AD, such as increased age or APOE ε4 carriage, alter the association between PA and power in the alpha band. METHODS: The relationship between PA and alpha band power was examined in a sample of 113 healthy adults using magnetoencephalography. Additionally, we explored whether ε4 carriage and age modulate this association. The correlations between alpha power and gray matter volumes and cognition were also investigated. RESULTS: We detected a parieto-occipital cluster in which PA positively correlated with alpha power. The association between PA and alpha power remained following stratification of the cohort by genotype. Younger and older adults were investigated separately, and only younger adults exhibited a positive relationship between PA and alpha power. Interestingly, when four groups were created based on age (younger-older adult) and APOE (E3/E3-E3/E4), only younger E3/E3 (least predicted risk) and older E3/E4 (greatest predicted risk) had associations between greater alpha power and higher PA. Among older E3/E4, greater alpha power in these regions was associated with improved memory and preserved brain structure. CONCLUSION: PA could protect against the slowing of brain activity that characterizes the AD continuum, where it is of benefit for all individuals, especially E3/E4 older adults.
BDNF Val66Met polymorphism and gamma band disruption in resting state brain functional connectivity: A magnetoencephalography study in cognitively intact older females
(Frontiers in Neuroscience, 2018) Rodríguez Rojo, Inmaculada Concepción; Cuesta Prieto, Pablo; López García, María Eugenia; De Frutos Lucas, Jaisalmer; Bruña Fernández, Ricardo; Pereda de Pablo, Ernesto; Barabash Bustelo, Ana; Montejo, Pedro; Montenegro Peña, María Mercedes; Marcos Dolado, Alberto; López-Higes, Ramón; Fernández Lucas, Alberto Amable; Maestu Unturbe, Fernando
The pathophysiological processes undermining brain functioning decades before the onset of the clinical symptoms associated with dementia are still not well understood. Several heritability studies have reported that the Brain Derived Neurotrophic Factor (BDNF) Val66Met genetic polymorphism could contribute to the acceleration of cognitive decline in aging. This mutation may affect brain functional connectivity (FC), especially in those who are carriers of the BDNF Met allele. The aim of this work was to explore the influence of the BDNF Val66Met polymorphism in whole brain eyes-closed, resting-state magnetoencephalography (MEG) FC in a sample of 36 cognitively intact (CI) older females. All of them were ε3ε3 homozygotes for the apolipoprotein E (APOE) gene and were divided into two subgroups according to the presence of the Met allele: Val/Met group (n = 16) and Val/Val group (n = 20). They did not differ in age, years of education, Mini-Mental State Examination scores, or normalized hippocampal volumes. Our results showed reduced antero-posterior gamma band FC within the Val/Met genetic risk group, which may be caused by a GABAergic network impairment. Despite the lack of cognitive decline, these results might suggest a selective brain network vulnerability due to the carriage of the BDNF Met allele, which is linked to a potential progression to dementia. This neurophysiological signature, as tracked with MEG FC, indicates that age-related brain functioning changes could be mediated by the influence of particular genetic risk factors.
How to Build a Functional Connectomic Biomarker for Mild Cognitive Impairment From Source Reconstructed MEG Resting-State Activity: The Combination of ROI Representation and Connectivity Estimator Matters
(Frontiers in Neuroscience, 2018) López García, María Eugenia; Bruña Fernández, Ricardo; Cuesta Prieto, Pablo; Marcos Dolado, Alberto; Maestu Unturbe, Fernando
Our work aimed to demonstrate the combination of machine learning and graph theory for the designing of a connectomic biomarker for mild cognitive impairment (MCI) subjects using eyes-closed neuromagnetic recordings. The whole analysis based on source-reconstructed neuromagnetic activity. As ROI representation, we employed the principal component analysis (PCA) and centroid approaches. As representative bi-variate connectivity estimators for the estimation of intra and cross-frequency interactions, we adopted the phase locking value (PLV), the imaginary part (iPLV) and the correlation of the envelope (CorrEnv). Both intra and cross-frequency interactions (CFC) have been estimated with the three connectivity estimators within the seven frequency bands (intra-frequency) and in pairs (CFC), correspondingly. We demonstrated how different versions of functional connectivity graphs single-layer (SL-FCG) and multi-layer (ML-FCG) can give us a different view of the functional interactions across the brain areas. Finally, we applied machine learning techniques with main scope to build a reliable connectomic biomarker by analyzing both SL-FCG and ML-FCG in two different options: as a whole unit using a tensorial extraction algorithm and as single pair-wise coupling estimations. We concluded that edge-weighed feature selection strategy outperformed the tensorial treatment of SL-FCG and ML-FCG. The highest classification performance was obtained with the centroid ROI representation and edge-weighted analysis of the SL-FCG reaching the 98% for the CorrEnv in α1:α2 and 94% for the iPLV in α2. Classification performance based on the multi-layer participation coefficient, a multiplexity index reached 52% for iPLV and 52% for CorrEnv. Selected functional connections that build the multivariate connectomic biomarker in the edge-weighted scenario are located in default-mode, fronto-parietal, and cingulo-opercular network. Our analysis supports the notion of analyzing FCG simultaneously in intra and cross-frequency whole brain interactions with various connectivity estimators in beamformed recordings.
Perfiles biomagnéticos de la actividad en reposo cerebral en las fases preclínica y prodrómica de la Enfermedad de Alzheimer: influencia del alelo APOE-ε4 y de la acumulación de β-amiloide
(2015) Cuesta Prieto, Pablo; Sancho Ruiz, Miguel; Nakamura, Akinori; Maestú Unturbe, Fernando
Introducción La acumulación de beta-amiloide (Ab) es una característica principal de la Enfermedad de Alzheimer (EA) y está muy relacionada con el alelo 4 de la Apoliproteina E (APOE). Existen dos enfoques principales para el estudio de la actividad cerebral. El primero (potencia espectral), da una visión estática y caracteriza la activación cerebral en cada región. El segundo, da una perspectiva dinámica y analiza la dependencia estadística entre las señales registradas en distintas partes de cerebro mediante la conectividad funcional (FC). El uso de ambas aproximaciones se basa en que la Ab se acumula principalmente en aquellas áreas del cerebro que muestran una mayor actividad como la Red por Defecto (DMN, Default Mode Network). El objetivo principal ha sido contribuir a la comprensión del efecto que produce el alelo APOE-¿4 y la acumulación de Ab en la actividad cerebral, medida con Magnetoencefalografía (MEG) en los estados preclínicos y prodrómicos de la EA de cara a conseguir nuevos biomarcadores de la progresión de la EA. Resultados Todos los estudios fueron realizados en el espacio de fuentes generadoras. Estudio 1: APOE-Potencia. Se analizaron los registros MEG de 25 CN y 36 pacientes con DCL. Ambos grupos fueron divididos en portadores o no del alelo APOE-¿4. Los pacientes con DCL mostraron un incremento en la potencia de baja frecuencia además de un decremento en el rango de alta frecuencia. Los sujetos con APOE-¿4 tenían mayor potencia entre 4.5-6.5 Hz en los lóbulos frontales. Estudio 2: APOE-FC. Se estudió la actividad de 27 CN y 36 pacientes con DCL divididos en portadores o no del alelo APOE-¿4. Los sujetos DCL mostraron una disminución de la FC en alfa y beta en las regiones temporales mediales y parietales. Los portadores mostraron un decremento de FC en la banda delta en regiones fronto-occipitales. Por último, se halló un patrón de hipo/hipersincronización en las regiones fronto-temporales derechas. Estudio 3: Ab-Potencia. Participaron 37 CN y 27 pacientes con DCL. En base a la acumulación de Ab, se obtuvieron cuatro grupos: 25 CN-, 12 CN +, 11 DCL- y 15 DCL+. El efecto asociado al diagnóstico mostró un típico patrón de enlentecimiento de la actividad cerebral. El efecto de la acumulación de Ab consistió en un incremento en la potencia alfa en regiones fronto-mediales. Estudio 4: Ab-FC. Participaron 32CN- y 13 CN+. Los resultados fueron: 1) en delta, el precuneus (Pc) mostró una disminución de la FC a nivel intra-ROI en el grupo CN+; 2) la comunicación entre el Pc y ambos lóbulos parietales inferiores (IPL) se vio incrementada en los sujetos CN+. Discusión Análisis de Potencia Esta tesis ha añadido información sobre la influencia del genotipo APOE y la acumulación de Ab en la actividad cerebral. En particular, la presencia del alelo APOE-¿4 pareció estar relacionada con un mayor enlentecimiento de la actividad mientras que la Ab se encontró especialmente relacionada con una anteriorización de la actividad alfa. Estos efectos son clave para discernir qué cambios en la actividad espontánea se deben al envejecimiento y cuales a la EA. Análisis de FC El hallazgo de patrones de hiposincronización/hipersincronización en los sujetos con APOE-¿4 o acumulación de Ab puede explicarse de la siguiente forma: 1) en la etapa no sintomática, los sujetos APOE-¿4 o Ab+ tratarían de compensar incrementando la FC; 2) además en la etapa con DCL, la red perdería su capacidad para compensar, lo que conduciría a la interrupción de la FC normal entre regiones fronto-temporales derechas y el resto del cerebro. Estos resultados casan bien con los hechos de que la Ab se acumula fundamentalmente en la DMN y que afecta la actividad sináptica a nivel local. Este daño podría estar ocasionando la desestabilización de la actividad de la red cortical generando la ocurrencia de una diasquisis caracterizada por una aparición de circuitos de compensación.
Searching for Primary Predictors of Conversion from Mild Cognitive Impairment to Alzheimer’s Disease: A Multivariate Follow-Up Study
(Journal of Alzheimer's Disease, 2016) López García, María Eugenia; Turrero Nogués, Agustín; Cuesta Prieto, Pablo; López Sanz, David; Bruña Fernández, Ricardo; Marcos Dolado, Alberto; Gil Gregorio, Pedro; Yus, Miguel; Barabash Bustelo, Ana; Cabranes Díaz, José Antonio; Maestu Unturbe, Fernando; Fernández Lucas, Alberto Amable
Recent proposals of diagnostic criteria within the healthy aging-Alzheimer’s disease (AD) continuum stressed the role of biomarker information. More importantly, such information might be critical to predict those mild cognitive impairment (MCI) patients at a higher risk of conversion to AD. Usually, follow-up studies utilize a reduced number of potential markers although the conversion phenomenon may be deemed as multifactorial in essence. In addition, not only biological but also cognitive markers may play an important role. Considering this background, we investigated the role of cognitive reserve, cognitive performance in neuropsychological testing, hippocampal volumes, APOE genotype, and magnetoencephalography power sources to predict the conversion to AD in a sample of 33 MCI patients. MCIs were followed up during a 2-year period and divided into two subgroups according to their outcome: The “stable” MCI group (sMCI, 21 subjects) and the “progressive” MCI group (pMCI, 12 subjects). Baseline multifactorial information was submitted to a hierarchical logistic regression analysis to build a predictive model of conversion to AD. Results indicated that the combination of left hippocampal volume, occipital cortex theta power, and clock drawing copy subtest scores predicted conversion to AD with a 100% of sensitivity and 94.7% of specificity. According to these results it might be suggested that anatomical, cognitive, and neurophysiological markers may be considered as “first order” predictors of progression to AD, while APOE or cognitive reserve proxies might play a more secondary role.