SubCMap: subject and condition specific effect maps

Current methods for statistical analysis of neuroimaging data identify condition related structural alterations in the human brain by detecting group differences. They construct detailed maps showing population-wide changes due to a condition of interest. Although extremely useful, methods do not provide information on the subject-specific structural alterations and they have limited diagnostic value because group assignments for each subject are required for the analysis. In this article, we propose SubCMap, a novel method to detect subject and condition specific structural alterations. SubCMap is designed to work without the group assignment information in order to provide diagnostic value. Unlike outlier detection methods, SubCMap detections are condition-specific and can be used to study the effects of various conditions or for diagnosing diseases. The method combines techniques from classification, generalization error estimation and image restoration to the identify the condition-related alterations. Experimental evaluation is performed on synthetically generated data as well as data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Results on synthetic data demonstrate the advantages of SubCMap compared to population-wide techniques and higher detection accuracy compared to outlier detection. Analysis with the ADNI dataset show that SubCMap detections on cortical thickness data well correlate with non-imaging markers of Alzheimer's Disease (AD), the Mini Mental State Examination Score and Cerebrospinal Fluid amyloid-β levels, suggesting the proposed method well captures the inter-subject variation of AD effects

Inferring Geodesic Cerebrovascular Graphs: Image Processing, Topological Alignment and Biomarkers Extraction

A vectorial representation of the vascular network that embodies quantitative features - location, direction, scale, and bifurcations - has many potential neuro-vascular applications. Patient-specific models support computer-assisted surgical procedures in neurovascular interventions, while analyses on multiple subjects are essential for group-level studies on which clinical prediction and therapeutic inference ultimately depend. This first motivated the development of a variety of methods to segment the cerebrovascular system. Nonetheless, a number of limitations, ranging from data-driven inhomogeneities, the anatomical intra- and inter-subject variability, the lack of exhaustive ground-truth, the need for operator-dependent processing pipelines, and the highly non-linear vascular domain, still make the automatic inference of the cerebrovascular topology an open problem. In this thesis, brain vessels’ topology is inferred by focusing on their connectedness. With a novel framework, the brain vasculature is recovered from 3D angiographies by solving a connectivity-optimised anisotropic level-set over a voxel-wise tensor field representing the orientation of the underlying vasculature. Assuming vessels joining by minimal paths, a connectivity paradigm is formulated to automatically determine the vascular topology as an over-connected geodesic graph. Ultimately, deep-brain vascular structures are extracted with geodesic minimum spanning trees. The inferred topologies are then aligned with similar ones for labelling and propagating information over a non-linear vectorial domain, where the branching pattern of a set of vessels transcends a subject-specific quantized grid. Using a multi-source embedding of a vascular graph, the pairwise registration of topologies is performed with the state-of-the-art graph matching techniques employed in computer vision. Functional biomarkers are determined over the neurovascular graphs with two complementary approaches. Efficient approximations of blood flow and pressure drop account for autoregulation and compensation mechanisms in the whole network in presence of perturbations, using lumped-parameters analog-equivalents from clinical angiographies. Also, a localised NURBS-based parametrisation of bifurcations is introduced to model fluid-solid interactions by means of hemodynamic simulations using an isogeometric analysis framework, where both geometry and solution profile at the interface share the same homogeneous domain. Experimental results on synthetic and clinical angiographies validated the proposed formulations. Perspectives and future works are discussed for the group-wise alignment of cerebrovascular topologies over a population, towards defining cerebrovascular atlases, and for further topological optimisation strategies and risk prediction models for therapeutic inference. Most of the algorithms presented in this work are available as part of the open-source package VTrails

IN VIVO IMAGING OF STEM CELL MEDIATED TREATMENT IN A MOUSE MODEL OF SPINAL CORD INJURY

Introduction: The use of adult stem cells in cell-mediated therapies is an area of considerable interest within tissue regeneration research. However, important variables such as the distribution of the injected cells, cell survival, target organ localisation cell proliferation and differentiation cannot be evaluated in vivo by using classical imaging approaches. This study propose multiple labelling protocols for in vivo visualisation by MRI, nuclear imaging and BLI of adult murine neural stem cell-mediated therapy, in spinal cord injury animal models. Methods: Murine neural stem cells (mNSCs) were directly labelled with different amounts of SPIOs (0 - 100 - 200 - 400 \u3bcg Fe/ml) in the culture medium and incubated with iron labelled medium for 24, 48 or 72 h in presence of carriers such as poly-L-Lysine (PLL), polybrene (PB) and protamine sulphate (PS). PLL and PS were tested at different ratio (Fe/PLL 1:0,03, 1:0,06 and 1:0,09 and Fe/PS 1:0,025 and 1:0,05). Labelled cells were analysed for viability, iron content (Perl\u2019s Staining and spectrophotometer analysis), morphology, staminality and differentiation capability. After the labelling protocol set up, the loaded cells were injected into the tail vein of a spinal cord injury murine model and their distribution was followed by MRI for two months. Initial cell distribution was also followed by nuclear imaging after cell labelling with 111In-oxine (60 \u3bcCi/106 cells). Cells localization, distribution e viability, over time, were analysed in vivo by BLI after injection of mNCS infected with a viral vector expressing Luciferase under a PGK constitutive promoter (PLW vector). Results: the iron content/cell increased in proportion to the incubation time and to the iron concentration in the medium and in relation to different carriers (PLL, PB and PS) in labelled mNSCs. Longer incubation time (48 and 72h) and higher iron concentration (400 \u3bcg Fe/ml) resulted in marked toxicity and lower cell viability. The use of PB and PLL, as carriers, didn\u2019t produce any increase of the labelling efficiency. The incubation for 24h with 200 \u3bcg Fe/ml in presence of different amount of PS didn\u2019t influence significantly the cell viability and the proliferation rate. Furthermore, the percentage of iron-positive cells and the iron content/cell increased in proportion to the PS content in the medium even if higher amount of PS (Fe/PS 1:0.05 ratio) resulted in an aberrant morphology. For this reason, 200 \u3bcg Fe/ml incubated with Fe/PS 1:0.025 ratio for 24h, has been chosen as the best labelling condition. Labelled cells were able to form new neurospheres and maintained the nestin expression demonstrating the maintenance of self-renewal capability and stem cell features and were also able to differentiate, as confirmed by \u3b2-tubulin III and GFAP expression analysis. Nuclear imaging confirmed initial distribution to filter organs while MRI allowed to detect the presence of an iron signal due to stem cell localization into the lesion site since 7 days after injection. BLI permitted to demonstrate the viability of PLW infected mNSCs migrated at the lesion site and supported the MRI data. Conclusions: These results permitted to conclude that NSCs can be efficiently labelled with different molecules without significantly perturbing physiological stem cell features and self-renewal capability. These labelling protocols can be applied for the in vivo visualisation by MRI, nuclear imaging, and BLI of the distribution of stem cells after their transplantation into murine model of disease

Early Medial Temporal Atrophy Scale (EMTA)

186 p.[ES]La atrofia del lóbulo temporal medial puede ser medida a través del uso de escalas de atrofia visual tales como la escala de atrofia del lóbulo temporal medial (MTA). La escala MTA ha sido diseñada y validada para el estudio de pacientes con Enfermedad de Alzheimer moderada (EA). Sin embargo, la MTA no ha sido diseñada para medir los cambios de atrofia de bajo grado que ocurren en la etapa precoz y media del proceso de envejecimiento. El objetivo de este estudio fue desarrollar y validar una nueva MTA; La “Goiz” (en Euskera) GMTA o “Early” (en ingles) EMTA, una nueva escala diseñada para la valoración de la atrofia precoz del lóbulo temporal medial que tiene la capacidad de medir los cambios de atrofia de bajo grado.[EN]Medial temporal lobe atrophy can be measured through visual rating scales such us the medial temporal lobe atrophy scale (MTA). MTA has been designed and validated for the study of patients with mild to moderate Alzheimer disease (AD). However, MTA has not been designed to measure the low-grade atrophy changes that occur at the early and middle aging process. The aim of this study was develop and validate a new MTA; the early (“Goiz” in Basque language) medial temporal lobe atrophy scale (EMTA) that has the capability to measure the low-grade atrophy changes

XXIV congreso anual de la sociedad española de ingeniería biomédica (CASEIB2016)

En la presente edición, más de 150 trabajos de alto nivel científico van a ser presentados en 18 sesiones paralelas y 3 sesiones de póster, que se centrarán en áreas relevantes de la Ingeniería Biomédica. Entre las sesiones paralelas se pueden destacar la sesión plenaria Premio José María Ferrero Corral y la sesión de Competición de alumnos de Grado en Ingeniería Biomédica, con la participación de 16 alumnos de los Grados en Ingeniería Biomédica a nivel nacional. El programa científico se complementa con dos ponencias invitadas de científicos reconocidos internacionalmente, dos mesas redondas con una importante participación de sociedades científicas médicas y de profesionales de la industria de tecnología médica, y dos actos sociales que permitirán a los participantes acercarse a la historia y cultura valenciana. Por primera vez, en colaboración con FENIN, seJane Campos, R. (2017). XXIV congreso anual de la sociedad española de ingeniería biomédica (CASEIB2016). Editorial Universitat Politècnica de València. http://hdl.handle.net/10251/79277EDITORIA

Orchestration of the neural stem cell fate by NRF2 and TAZ

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de lectura: 11-10-2019Neurogenesis is a multiple step process that must be tightly regulated or otherwise results in pathological events. Therefore, a deep characterization of the molecular mechanisms that control the biology of neural stem/progenitor cells (NSPCs) will provide a better understanding of the role of neurogenic niches and new therapeutic strategies for neurodegenerative diseases and brain tumours. In this thesis we have analyzed the regulation of NSCs fate by the transcription factor Nuclear factor (erythroid-derived 2)-like 2 (NRF2), which is considered a master regulator of cellular homeostasis, and the Transcriptional co-activator with PDZ-binding motif (TAZ), a major effector of the Hippo pathway. NRF2 controls the expression of a wide battery of cytoprotective genes that have a tremendous impact on physiological responses such as inflammation, senescence or metabolism. However, its relevance in neurogenesis is just starting to be unveiled. On the other hand, TAZ is a major effector of the Hippo pathway, which plays a key role in tissue homeostasis and organ size control by regulating tissue-specific stem cells. However, the implication of TAZ in neurogenesis has not been analyzed. In this study, we have identified NRF2 as a regulator of hippocampal NSCs self-renewal and differentiation. We show that genetic manipulation of NRF2 results in the modulation of NSPCs differentiation and proliferation capacity. To assess the functional relevance of NRF2 in neurogenesis under pathological conditions, we analyzed the impact of NRF2 deficiency in neurogenesis of the subgranular zone (SGZ) of the hippocampus in a mouse model of Alzheimer´s Disease (AD). We found that NRF2 deficiency results in an accelerated loss of NSCs, loss of synaptic plasticity measured as long term potentiation (LTP) and impaired the execution of cognitive tasks. At the molecular level, we have identified NRF2 enhancer sequences, termed Antioxidant Response Elements (AREs), in the promoter region of the TAZ coding gene. Consequently, we show that genetic and pharmacological manipulation of NRF2 results in the modulation of TAZ gene expression in NSPCs. These findings open a new window to understand the molecular mechanisms underlying NRF2 function in stemness. We have also established a novel role of TAZ as repressor of neuronal differentiation, based on the transcriptional repression of SOX2 and the basic helix-loop-helix (bHLH) factors ASCL1, NEUROG2 and NEUROD1. Data mining of The Cancer Genome Atlas showed a negative correlation between TAZ and the expression of these proneurogenic factors in lower grade gliomas and glioblastomas. We found that TAZ favours glioblastoma CSCs tumorigenic capacity and that genetic modulation of TAZ in these cells inversely correlated with proneurogenic genes expression. Due to the relevance of these proneurogenic factors in the ablation of glioblastoma cancer stem cells (CSCs), this novel TAZ/proneurogenic factors axis may have important implications in the development of this type of brain tumours. The characterization of molecular mechanism governing NSPCs fate provides new insights to harness these cells for brain repair. Overall, this thesis describes a novel role of NRF2 and TAZ in the control of neural stem cell fate, suggesting a new strategy to combat brain pathology

Vitamina D en la hipertensión pulmonar

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Medicina, leída el 01-04-2022Pulmonary arterial hypertension (PAH) is a vascular chronic disorder, characterized by sustained vasoconstriction, vascular remodelling, thrombosis in situ and inflammation. Although there have been important advances in the knowledge of its pathophysiology and consequently of its pharmacological treatments, PAH remains a debilitating, limiting and rapidly progressive disease. In recent years, epidemiological, nutritional studies and animal models have reported an association between nutritional factors and PAH. Moreover, some authors suggest that nutritional intervention may be a new preventive strategy in PAH. Vitamin D (vitD) deficiency is a worldwide health problem of pandemic proportions. Preliminary studies have suggested that vitD deficiency is more prevalent in PAH patients than in general population. There are some basic and clinic evidences which suggest that hypovitaminosis D may negatively impact on disease progression. The active form of vitD, i.e.,calcitriol, exerts its functions through the vitamin D receptor (VDR), which acts as a transcription factor, regulating changes in gene expression. The discovery of VDR in many tissues and cell types that do not participate in calcium and phosphorous homeostasis, (the main functions of calcitriol), led to identify a great variety of functions mediated by VDR, and of potential relevance in the cardiovascular system, such as cell proliferation, differentiation, control of vascular tone or immunomodulation...La hipertensión arterial pulmonar (HAP) es una enfermedad vascular crónica, caracterizada por una vasoconstricción sostenida, remodelado vascular, trombosis in situ e inflamación en las arterias pulmonares (AP). A pesar de los importantes avances en el conocimiento de su fisiopatología y consecuentemente la identificación de terapias farmacológicas, la HAP continúa siendo una enfermedad debilitante, limitante y progresiva. En los últimos años, estudios epidemiológicos, nutricionales, así como modelos animales han identificado una asociación entre factores nutricionales e HAP; incluso algunos autores sugieren que la intervención nutricional podría ser una nueva estrategia preventiva en pacientes con HAP. La deficiencia de vitamina D (vitD) es un problema de salud a nivel global de proporciones pandémicas, incluso se estima que es más prevalente en pacientes con HAP que en la población en general. Existen algunas evidencias que sugieren que la deficiencia de vit Dpuede tener un impacto negativo en progresión de dicha patología. La forma activa de la vitD, denominada calcitriol ejerce sus funciones a través del receptor de vitD (VDR), que actúa como un factor de transcripción, regulando la expresión de genes diana. El descubrimiento de VDR en diversos tejidos y células, que no participan en la homeostasis del calcio y el fósforo (las principales funciones del calcitriol), permitió la identificación de una gran variedad defunciones mediadas por VDR con gran relevancia a nivel cardiovascular, como, por ejemplo, la regulación de la proliferación y diferenciación celular, control del tono vascular e inmunomodulación...Fac. de MedicinaTRUEunpu

Recent Advances in Signal Processing

The signal processing task is a very critical issue in the majority of new technological inventions and challenges in a variety of applications in both science and engineering fields. Classical signal processing techniques have largely worked with mathematical models that are linear, local, stationary, and Gaussian. They have always favored closed-form tractability over real-world accuracy. These constraints were imposed by the lack of powerful computing tools. During the last few decades, signal processing theories, developments, and applications have matured rapidly and now include tools from many areas of mathematics, computer science, physics, and engineering. This book is targeted primarily toward both students and researchers who want to be exposed to a wide variety of signal processing techniques and algorithms. It includes 27 chapters that can be categorized into five different areas depending on the application at hand. These five categories are ordered to address image processing, speech processing, communication systems, time-series analysis, and educational packages respectively. The book has the advantage of providing a collection of applications that are completely independent and self-contained; thus, the interested reader can choose any chapter and skip to another without losing continuity

Identificación y caracterización de subgrupos clínicos en el Síndrome de Fatiga Crónica/Encefalomielitis Miálgica. Propuesta de un protocolo para su estudio.

316 p.El trabajo se centra en la determinación de subgrupos clínicos en una enfermedad neurológica como el Síndrome de Fatiga Crónica/Encefalomielitis Miálgica (CIE-11: 8E49), y el establecimiento tras análisis de un protocolo para su estudio. Como objetivo general: proponer una batería de pruebas sencillas pero suficientes para identificar la enfermedad y sus subgrupos clínicos