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  • National Institutes of Health
  • US
  • Catalan; Valencian

  • image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    Authors: Mata Valldaura, Olga;

    Este trabajo trata de encontrar aquellos factores del espacio arquitectónico que influyen en su carácter, identidad, atmósfera o esencia; aquellos que son dificiles de apreciar de manera consciente, a simple vista; pero están presentes en el espacio y son los que acaban definiéndolo. Mediante un estudio del pensamiento de Peter Zumthor, comprendemos los factores esenciales para generar las atmósferas interiores de sus obras. Después de conocer el pensamiento del arquitecto se elabora un análisis de tres obras que han tenido una gran relevancia a lo largo de su trayectoria, donde se refleja la coherencia de las ideas que el arquitecto quiere transmitir al usuario a través de la atmósfera. Aquest treball tracta de buscar aquells factors de l'espai arquitectònic que influeixen en el seu caràcter, identitat, atmosfera o essència; aquells que costa d'apreciar de manera conscient, a simple vista; però estan presents en l'espai i són els que acaban difinint-lo. Mitjançant un estudi del pensament de Peter Zumthor, comprenem els factors essencials per a generar les atmosferes interiors de les seves obres. Després de conèixer el pensament de l'arquitecte s'elabora una anàlisi de tres obres que han tingut una gran rellevància al llarg de la seva trajectòria, on es reflecteix la coherència de les idees que l'arquitecte vol transmetre a l'usuari a través de l'atmosfera. This work seeks to find those factors in the architectural space that influence its character, identity, atmosphere or essence; those which are difficult to consciously appreciate, at first sight; but are present in space and are the ones that define it. Through a study of the thought of Peter Zumthor, we understand the essential factors to generate the interior atmospheres of his works. After learning the architect's thought, and the analysis of three works which have had great significance throughout his career, reflecting the consistency of the ideas that the architect wants to transmit to the user through the atmosphere.

    image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/ UPCommons. Portal de...arrow_drop_down
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    image/svg+xml Jakob Voss, based on art designer at PLoS, modified by Wikipedia users Nina and Beao Closed Access logo, derived from PLoS Open Access logo. This version with transparent background. http://commons.wikimedia.org/wiki/File:Closed_Access_logo_transparent.svg Jakob Voss, based on art designer at PLoS, modified by Wikipedia users Nina and Beao
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      image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/ UPCommons. Portal de...arrow_drop_down
      image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
      image/svg+xml Jakob Voss, based on art designer at PLoS, modified by Wikipedia users Nina and Beao Closed Access logo, derived from PLoS Open Access logo. This version with transparent background. http://commons.wikimedia.org/wiki/File:Closed_Access_logo_transparent.svg Jakob Voss, based on art designer at PLoS, modified by Wikipedia users Nina and Beao
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  • image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    Authors: Denuc Isern, Amanda;

    [cat] La present Tesi Doctoral es presenta com una agrupació de quatre publicacions que resumeixen el treball realitzat al Departament de Genètica de la Facultat de Biologia de la Universitat de Barcelona. El principal objectiu és la caracterització funcional de les regions estructurals de la isoforma muscular de l’enzim deubiquitinat USP25, inicialment definides amb eines bioinformàtiques. A més a més, es pretén fer un estudi de noves interaccions moleculars tipus proteïna-proteïna per la cerca de nous substrats o reguladors enzimàtics. La cèl·lula eucariota posseeix, entre altres, un sistema senyalitzador intracel·lular basat en una família de pèptids, el representant dels quals és la ubiquitina. Aquest sistema presenta diferents categories funcionals, entre elles, els enzims deubiquitinants, un centenar a l’espècie humana. Aquests enzims hidrolitzen l’enllaç que uneix la ubiquitina als seus precursors o substrats, mantenint així l’homeostasi d’aquest pèptid dins la cèl·lula. Una alteració de la seva funció pot portar diferents conseqüències depenent de la via metabòlica que es vegi afectada, doncs suposa una desregulació estequiomètrica dels substrats ubiquitinants respecte els no ubiquitinats. L’enzim deubiquitinant USP25 es va descriure en el grup d’investigació d’aquesta tesi durant la cerca de nous gens relacionats amb la síndrome de Down. Un cop caracteritzat funcionalment com una proteasa específica d’ubiquitina, els estudis d’expressió van mostrar l’existència de tres isoformes proteiques, una d’elles, USP25m, restringida al teixit muscular i cardíac. Tenint en compte que en el fenotip dels pacients amb síndrome de Down, entre altres trets, hi ha deficiència cardiovascular i atonia muscular, els esforços del grup es van centrar en la descripció i anàlisi d’aquesta isoforma. Els primers estudis van mostrar la seva situació citosòlica, l’expressió correlativa amb la diferenciació de cèl·lules musculars i la relació específica amb diverses proteines del sarcòmer. En el treball realitzat per la present Tesi Doctoral, s’han caracteritzat funcionalment diferents regions reguladores descrites a nivell bioinformàtic, així com també s’ha analitzat la seva implicació fisiológica a la funció d’USP25m. A més a més, mitjançant un estudi de cerca de nous interactors proteics, s’ha trobat una nova molècula que pertany a la mateixa via senyalitzadora i que es relaciona de manera específica amb USP25m, la lligasa d’ubiquititna MKRN1 (makorin 1) Mitjançant l’ús de diferents construccions amb delecions i mutacions puntuals de la proteïna que afecten a les regions d’interès, s’ha arribat a diferents conclusions, entre elles, que USP25m és monoubiquitinat i té la capacitat d’autodeubiquitinar-se. La monoubiquitinació en regula la seva activitat enzimàtica i es proposa un mecanisme de regulació basat en la conjugació alternativa de SUMO (una altra molècula de la família de la ubiquitina) i ubiquitina, en el mateix residu aminoacídic, la lisina 99 (Lys99). Els dominis d’unió a ubiquitina regulen el reconeixement de substrat i afavoreixen la monoubiquitinació. USP25m oligomeritza dins la cèl·lula i es troba present en diferents formacions proteiques d’elevat pes molecular. S’ha comprovat la relació específica amb la nova lligasa MKRN1 i es suggereixen diferents escenaris moleculars on poden trobar-se inclosos els dos pèptids. [eng] The main aim of the present PhD work, titled “Structural domains and new protein interactions of the deubiquitinating enzyme USP25”, is the functional characterisation of the structural domains of the muscle isoform of USP25, USP25m, as well as the analysis of new protein‐protein interactions. The ubiquitin‐proteasome pathway is widely known as the preferential system to get ride of old or non‐functional proteins. Recently, it has become more apparent that this is not the only function. Ubiquitin (Ub) and all ubiquitin–like (UbLs) molecules acted as regulatory tags involved in different cellular events as subcellular localization, enzyme activation, DNA repair, etc. The intricate Ub‐signalling networks require a tight regulation of both conjugation and deconjugationprocesses, which are controlled by ubiquitin ligases and deubiquitinating enzymes (DUBs), respectively. USP25 is a DUB described while looking for novel genes involved in Down syndrome phenotype. First studies showed that it encoded three alternative protein isoforms, one of them, muscle specific. This muscle isoform, USP25m, is a cytosolic protein, upregulated during myogenesis that interacts in a specific manner with different sarcomeric proteins. Using an “in silico” approach, we were able to identify different structural domains, among them three ubiquitin binding domains (UBDs), and we aimed to characterise its role on USP25m function. By generating a collection of deletion and punctual mutants of the regions of interest, we conclude that USP25m is monoubiquitinated and that the UBDs modulate this modification. The preferential site for monoubiquitination is lysine 99 (K99), a residue that has been reported to undergo sumoylation (SUMO conjugation, being SUMO an UbL). According to our results, mutation of the K99 residue diminishes the deubiquitinating function, proposing a mechanistic model for USP25m regulation based on alternative conjugation of Ub and SUMO on the same residue, K99. Futhermore, while seeking new protein interactions of USP25m we identified Makorin Ring finger protein 1 (MKRN1), which belongs to an ubiquitin ligase family, as a putative interactor. We were capable of characterise its interaction and propose different cellular scenarios were they could interact.

    image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/ Diposit Digital de l...arrow_drop_down
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    Authors: Bosch Farré, Cristina;

    To determine the prevalence of Active and Healthy Ageing (AHA) in the province of Girona and 14 European countries according to various models, to analyze the association between health variables and social determinants of health. This was a cross-sectional, observational analysis of a representative sample of population aged 50 years and older in Girona and Europe consisted of 55.278 participants. The data were obtained by MESGI50 and SHARE studies. AHA was measured using Rowe Kahn model (AHA-RK) and a model based on the WHO definition (AHA-WHO). The prevalence was 23.5% in AHA-RK model and 38.8% in AHA-WHO model. In the geographic analysis, there was a north-central to south-east Europe gradient. In both models, AHA was significantly associated with: self-perception of excellent-very good health status; high-very high quality of life; less use of health services. AHA was more strongly associated with socioeconomic status, mainly with to work and not financial difficulties. L’objectiu és determinar la prevalença de l’Envelliment Actiu i Saludable (EAS) a la província de Girona i a 14 països d’Europa segons diferents models i analitzar l’associació de l’EAS amb variables de salut i determinants socials de la salut. Estudi transversal observacional analític d’una mostra representativa de població de 50 i més anys de la província de Girona i Europa de 55.278 participants. S’analitzaren dades de MESGI50 i SHARE. Es va mesurar l’EAS amb el model Rowe i Kahn i amb un model basat en la definició de l’OMS. Les prevalences d’EAS eren 23,5% model EAS-RK i 38,8% model EAS-OMS. Hi havia un gradient geogràfic Nord-Centre amb Sud-Est d’Europa. En els dos models l’EAS s’associava significativament amb: salut autopercebuda excel•lent o molt bona; qualitat de vida alta o molt alta; menys ús de recursos sanitaris. L’EAS està fortament associat a les condicions socioeconòmiques, principalment treballar i no tenir dificultats econòmiques.

    image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/ Recolector de Cienci...arrow_drop_down
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      image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/ Recolector de Cienci...arrow_drop_down
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    Authors: Districte 4. Les Corts;

    Presentat al Consell Plenari del Districte de Les Corts de 02-12-2009

    image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/ Recolector de Cienci...arrow_drop_down
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      image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/ Recolector de Cienci...arrow_drop_down
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    Authors: Programa d'Harmonització Farmacoterapèutica;

    Alzheimer; Registre del tractament farmacològic; Població atesa Alzheimer; Register of pharmacological treatment; Population attended Alzheimer; Registro del tratamiento farmacológico; Población atendida La malaltia d’Alzheimer (MA) és un trastorn neurodegeneratiu progressiu i irreversible normalment de desenvolupament lent però sostingut en el temps. La MA és la causa més freqüent de demència (69%). La seva prevalença és d’un 5,1% i augmenta exponencialment amb l’edat amb els valors més elevats al voltant dels 90 anys. La enfermedad de Alzheimer (EA) es un trastorno neurodegenerativo progresivo e irreversible normalmente de desarrollo lento pero sostenido en el tiempo. La MA es la causa más frecuente de demencia (69%). Su prevalencia es de un 5,1% y aumenta exponencialmente con la edad con los valores más elevados en torno a los 90 años. Alzheimer's disease (MA) is a progressive and irreversible neurodegenerative disorder usually a slow but sustained development over time. MA is the most frequent cause of dementia (69%). Its prevalence is 5.1% and increases exponentially with age with the highest values ​​around 90 years.

    image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/ Scientia, Dipòsit d’...arrow_drop_down
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    Authors: Madrid i Fernández, Marisol;

    [cat] Aquest treball és una proposta de model integral per a l'estudi de materials ceràmics en un jaciment arqueològic. Incorpora dues metodologies de treball, l'arqueològica i l'arqueomètrica, cadascuna de les quals presenta un procediment metodològic propi, sense que cap d'elles es vegi condicionada per l'altra. El jaciment és la ciutat romana de Baetulo (Badalona), que va gaudir d'una dinàmica comercial important gràcies a la indústria del vi, i que es troba situada a la Costa Catalana a mig camí entre les dues ciutats més importants del moment, Emporiae i Tarraco. El material són les diferents produccions de terra sigillata comercialitzades a Baetulo i que s'inclourien dins els grups següents: terra sigillata itàlica, gàl·lica, hispànica i el que en aquest treball hem anomenat com a terra sigillata indeterminada, que es correspon al que abans d'aquest treball, a Badalona, classificàvem com a presigillata i prearetina. La fusió i integració dels resultats procedents d'ambdues metodologies permet la resolució del problema arqueològic plantejat inicialment, que és la identificació de les diferents produccions: quantes, la seva provinença, les seves característiques tecnològiques, els seus períodes de circulació a la ciutat i les rutes comercials utilitzades per a la seva comercialització a Baetulo. El contrast amb sigillata procedent d'Emporiae i Tarraco permet, a més, obtenir una visió més àmplia sobre la comercialització d'aquestes produccions a la Costa Catalana.L'estudi arqueològic s'ha fet a partir d'una selecció de contextos que cobreixen diverses etapes des d'inicis del govern d'August fins al segle II d.e. Durant aquest període es documenta sempre la presència de terra sigillata, de vegades contemporània a la formació dels estrats, d'altres residual. Es per això que la discussió cronològica dels contextos s'ha centrat només en aquells considerats de formació contemporània a la circulació de la terra sigillata.A partir d'aquests contextos, el primer pas ha estat la classificació a ull nu de la sigillata dins un dels grans grups definits anteriorment. L'estudi arqueològic del material s'ha completat amb la seva classificació tipològica, així com l'estudi individualitzat dels individus amb marques de ceramista i/o decoracions. L'anàlisi del context arqueològic del material ha permès proposar cronologies per aquests, així com per les estructures amb què es troben relacionats.A partir de l'anàlisi arqueològica es va realitzar un mostreig aleatori de tota la sigillata per a la seva caracterització arqueomètrica. No es van fer distincions entre produccions ni individus; tots van rebre el mateix tractament, independentment de si tenien o no forma, marca o decoració. La mostra està composta de 225 individus procedents de Baetulo, 63 d'Emporiae i 75 de Tarraco.Per als estudis de provinença, basats en la composició química, es van portar a terme anàlisis químiques per Fluorescència de Raigs X i Activació Neutrònica. L'anàlisi mineralògica es va portar a terme per Difracció de Raigs X per als estudis tecnològics. El Microscòpic Electrònic de Rastreig es va utilitzar per als estudis de microestructura i estadi de sinterització. Finalment, es van realitzat tests per a mesurar la resistència del material a la ruptura per definir la qualitat de les vaixelles. L'aplicació d'aquest model a Badalona ha permès la identificació d'un gran nombre de produccions de terra sigillata, moltes de les quals han pogut ser associades a produccions, tallers o àrees de provinença conegudes arqueomètricament. A més, la integració d'ambdues metodologies de treball ha permès establir els seus períodes de circulació a la ciutat: arribada, coexistència i desaparició. El contrast dels resultats de Baetulo amb aquells procedents d'Emporiae i Tarraco permet observar que, malgrat les coincidències, les tres ciutats haurien tingut la seva pròpia dinàmica comercial, el que significa que Baetulo no hauria estat només a remolc d'una gran ciutat. [eng] The aim of this study is the archaeological and archaeometrical analysis of the Indeterminate, Italian (TSI), Gaulish (TSS) and Hispanic (TSH) "Terra Sigillata" recovered from the modern excavations in "Baetulo" in order to identify the different productions included in these main groups. For the archaeological analysis, four recent excavations, in which the oldest stratigraphic levels including "Sigillata" pottery have been documented, were selected. These contexts cover a period from the beginning of the Augustan government to the second half of the 2nd century AD. During this period, Sigillata productions are always documented, in some cases contemporary to the formation of the stratigraphic layers, while in others as residual materials. Even though all individuals are considered in the archaeological and archaeometrical study, the chronological discussion focuses only on those stratigraphic layers contemporary to the ceramic circulation.After the archaeological analysis, a random sampling was conduced and 225 individuals from "Baetulo" were archaeometrically characterized. Besides, 63 individuals from Emporiae and 75 from Tarraco were also characterized in order to get a better knowledge about the TS commercialization in the Catalan coast. For provenance studies based on chemical composition, chemical analyses were performed by means of X Rays Flourescence (XRF) and Neutron Activation (NA). Mineralogical analyses were performed by means of X Rays Diffraction (XRD) for technological studies. Scanning Electronic Microscope (SEM) was used for microstructure and sintering stage studies. Finally, tests for measuring strength to the rupture of the materials were applied in order to define qualities. The study carried out in "Baetulo" allowed us the identification of a great number of "terra sigillata" productions, most of them associated to productions, workshops or provenance areas archaeometrically known. Besides, the integration of the archaeological and archaeometrical results, allows proposing the circulation periods of theses productions: arrival, coexistence and disappearance in "Baetulo". The contrast of the results from "Baetulo" with those from "Emporiae" and "Tarraco" point out that despite the coincidences, the three cities would have had their own commercial dynamic. Therefore, "Baetulo" would not have been just in tow of any great city.

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    Authors: Vilaplana Martínez, Eduard;

    La enfermedad de Alzheimer (EA) se caracteriza neuropatológicamente por la presencia de depósitos extracelulares de ß-amiloide (Aß) y ovillos neurofibrilares intracelulares (proteína tau fosforilada, p-tau) así como fenómenos inflamatorios. Estos procesos se asocian con atrofia cerebral, pérdida neuronal y alteraciones funcionales que acaban produciendo deterioro cognitivo y eventualmente un síndrome clínico de demencia. El depósito de amiloide comienzan décadas antes de que se pueda hacer un diagnóstico de demencia e incluso de la aparición de los primeros síntomas, y constituyen lo que se conoce como EA preclínica (Sperling et al., 2011). En la actualidad podemos estudiar los mecanismos fisiopatológicos que ocurren en la EA preclínica a través de biomarcadores (Dubois et al., 2016). Entender las relaciones entre biomarcadores en la EA preclínica es esencial para entender la fisiopatología de la enfermedad y poder desarrollar terapias que ralenticen o frenen su curso. Sin embargo, estas relaciones distan de estar claras, por ejemplo, la relación de la amiloidosis y la estructura cortical dista de es controvertida (Fortea et al., 2014). El objetivo principal de esta tesis fue estudiar las alteraciones corticales estructurales que ocurren en la enfermedad de Alzheimer preclínica. Concretamente, los objetivos fueron 1) estudiar la relación entre Aß y el grosor cortical y sus posibles interacciones con la proteína p-tau, 2) analizar los cambios estructurales corticales longitudinales de la EA preclínica, 3) investigar la microestructura cortical y entender su relación con la macroestructura en el continuum de la enfermedad y, 4) estudiar el impacto local del depósito de amiloide en la estructura cerebral en la EA preclínica. Para la realización de esta tesis se ha contado con bases de datos públicas americanas (Alzheimer’s Disease Neuroimaging Initiative, http://adni.loni.usc.edu/) y con bases de datos españolas (proyecto SIGNAL, https://www.signalstudy.es/). Los resultados de la tesis han conducido a la propuesta de un modelo bifásico de cambios corticales estructurales en la EA preclínica. El depósito de amiloide en ausencia de tau patológico se asocia a un incremento del grosor cortical, una ralentización de la atrofia longitudinal a 2 años y descensos de difusión cortical. Posteriormente, en presencia de tau patológica, y como resultado del efecto tóxico sinérgico o interacción entre procesos patológicos, se produciría una aceleración de la atrofia e incrementos de difusión que se extenderían siguiendo un patrón característico que ha sido definido como la huella cortical de la EA (Dickerson et al., 2009). Los resultados presentados en esta tesis tienen implicación directa en la investigación y en la práctica clínica. En primer lugar, en relación a los modelos de evolución de biomarcadores de la EA (Jack et al., 2013) ya que esta fase temprana de engrosamiento cortical no está contemplada en los modelos actuales. Nuestro modelo ayudaría a integrar los resultados contradictorios previos en la literatura en relación a los efectos del amiloide sobre la estructura cerebral. Los modelos actuales, no contemplan la interacción/sinergia entre biomarcadores que rigen el mencionado proceso bifásico. En segundo lugar, los resultados tienen implicaciones en el diseño de los ensayos clínicos, tanto en la selección de pacientes como en el uso subrogado de la resonancia como marcador de eficacia, ayudando a entender algunos resultados inesperados de los ensayos clínicos previos con inmunoterapia anti-amiloidea. Finalmente, la difusión cortical podría ser un marcador precoz en el curso de la EA. Futuros estudios multimodales de resonancia magnética y líquido cefalorraquídeo que incorporen PET de inflamación y de Tau con seguimientos longitudinales serán claves para seguir estudiando los procesos fisiopatológicos que subyacen la EA preclínica. The Alzheimer’s disease (AD) neuropathological hallmarks are the presence of extracellular amyloid ß (Aß) deposition and intracellular neurofibrillary tangles (hyperphosphorilated tau protein) as well as inflammation phenomena. These processes are associated with cerebral atrophy, neuronal loss and functional alterations which lead to cognitive dysfunction and, eventually, a clinical syndrome of dementia. These pathophysiological processes begin decades before the diagnosis of the clinical dementia even before the appearance of the first clinical symptoms, and constitute the preclinical AD (Sperling et al, 2011). Nowadays we can study the pathophysiological mechanisms that occur in preclinical AD through biomarkers (Dubois et al., 2016). It is crucial to understand the relationships between biomarkers in preclinical AD to further understand the disease pathophysiology and be able to develop treatments that could slow down or stop its course. However, these relationships are not clear, for example, the relationship between brain amyloidosis and brain structure is controversial (Fortea et al., 2014). The objective of this thesis was to study the cortical structural alterations that occur in preclinical AD. Specifically, 1) to study the relationship between Aß and cortical thickness and its potential interactions with p-tau, 2) to analyze the 2-year cortical longitudinal changes in preclinical AD, 3) to investigate cortical microstructure and understand its relationship with brain macrostructure in the disease continuum and, 4) to assess the local impact of amyloid deposition in brain structure in preclinical AD. In this thesis, we have used data from a public American database (Alzheimer’s Disease Neuroimaging Initiative, http://adni.loni.usc.edu/) and from a Spanish multicentric cohort (proyecto SIGNAL, https://www.signalstudy.es/). The results of this thesis have conducted to the proposal of a biphasic model of structural cortical changes in preclinical AD. Amyloid deposition in the absence of pathological tau levels would be associated with increased cortical thickness, less 2-year longitudinal cortical thinning and cortical diffusivity decreases. Then, in the presence of pathological tau levels, and as a result of the synergic toxic effect or interaction between pathologic processes, there would be an atrophy acceleration and cortical diffusivity increases that would spread following a pattern that has been described as the AD-signature (Dickerson et al., 2009). The results presented in this thesis have direct research and clinical implications. First, they impact on the models of biomarker evolution in AD (Jack et al., 2013), as the cortical thickening phase is not contemplated in previous models. Our model would help to understand previous contradictory results in the literature that assessed the effect of amyloid on brain structure. Current models do not take into account the interaction/synergy effect between biomarkers that define the aforementioned biphasic process. Second, our results have relevance in the design of clinical trials, both in the selection of patients and in the use of MRI as a surrogate marker of efficacy, and might help explain some unexpected results in previous anti-amyloid immunotherapy trials. Finally, cortical diffusivity could be an early marker in the AD course. Further multimodal studies that incorporate tau- and inflammation-PET with longitudinal follow-ups are crucial to further investigate the pathophysiological process that underlies preclinical AD.

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    Authors: Dalmases i Thió, Ignasi de; Jornades transfrontereres seguretat i emergències (2013 : La Jonquera);

    Competències en seguretat i protecció civil .Article 4 del Decret 266/2007 Reglament del Cos d’Agents Rurals sobre els principis d’actuació: els i les membres del cos d’agents rurals quan actuïn com agents de l’autoritat en l’exercici de les serves funcions, han de tenir accés a la informació i han d’integrar-se al sistema de seguretat de Catalunya. El cos d’agents rurals participa en els plans de protecció civil d’acord amb les previsions d’aquest plans.. El cos d’agents rurals exerceix les seves funcions sense perjudici de les competències del departament responsable en matèria de seguretat , protecció civil i prevenció i extinció d’incendis i de les del cossos que exerceixen funcions en aquesta matèria El cos d’agents rurals ha de col·laborar amb els cossos que tenen encomanades funcions de seguretat i prevenció i extinció d’incendis

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  • image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    Authors: Mata Valldaura, Olga;

    Este trabajo trata de encontrar aquellos factores del espacio arquitectónico que influyen en su carácter, identidad, atmósfera o esencia; aquellos que son dificiles de apreciar de manera consciente, a simple vista; pero están presentes en el espacio y son los que acaban definiéndolo. Mediante un estudio del pensamiento de Peter Zumthor, comprendemos los factores esenciales para generar las atmósferas interiores de sus obras. Después de conocer el pensamiento del arquitecto se elabora un análisis de tres obras que han tenido una gran relevancia a lo largo de su trayectoria, donde se refleja la coherencia de las ideas que el arquitecto quiere transmitir al usuario a través de la atmósfera. Aquest treball tracta de buscar aquells factors de l'espai arquitectònic que influeixen en el seu caràcter, identitat, atmosfera o essència; aquells que costa d'apreciar de manera conscient, a simple vista; però estan presents en l'espai i són els que acaban difinint-lo. Mitjançant un estudi del pensament de Peter Zumthor, comprenem els factors essencials per a generar les atmosferes interiors de les seves obres. Després de conèixer el pensament de l'arquitecte s'elabora una anàlisi de tres obres que han tingut una gran rellevància al llarg de la seva trajectòria, on es reflecteix la coherència de les idees que l'arquitecte vol transmetre a l'usuari a través de l'atmosfera. This work seeks to find those factors in the architectural space that influence its character, identity, atmosphere or essence; those which are difficult to consciously appreciate, at first sight; but are present in space and are the ones that define it. Through a study of the thought of Peter Zumthor, we understand the essential factors to generate the interior atmospheres of his works. After learning the architect's thought, and the analysis of three works which have had great significance throughout his career, reflecting the consistency of the ideas that the architect wants to transmit to the user through the atmosphere.

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    Authors: Denuc Isern, Amanda;

    [cat] La present Tesi Doctoral es presenta com una agrupació de quatre publicacions que resumeixen el treball realitzat al Departament de Genètica de la Facultat de Biologia de la Universitat de Barcelona. El principal objectiu és la caracterització funcional de les regions estructurals de la isoforma muscular de l’enzim deubiquitinat USP25, inicialment definides amb eines bioinformàtiques. A més a més, es pretén fer un estudi de noves interaccions moleculars tipus proteïna-proteïna per la cerca de nous substrats o reguladors enzimàtics. La cèl·lula eucariota posseeix, entre altres, un sistema senyalitzador intracel·lular basat en una família de pèptids, el representant dels quals és la ubiquitina. Aquest sistema presenta diferents categories funcionals, entre elles, els enzims deubiquitinants, un centenar a l’espècie humana. Aquests enzims hidrolitzen l’enllaç que uneix la ubiquitina als seus precursors o substrats, mantenint així l’homeostasi d’aquest pèptid dins la cèl·lula. Una alteració de la seva funció pot portar diferents conseqüències depenent de la via metabòlica que es vegi afectada, doncs suposa una desregulació estequiomètrica dels substrats ubiquitinants respecte els no ubiquitinats. L’enzim deubiquitinant USP25 es va descriure en el grup d’investigació d’aquesta tesi durant la cerca de nous gens relacionats amb la síndrome de Down. Un cop caracteritzat funcionalment com una proteasa específica d’ubiquitina, els estudis d’expressió van mostrar l’existència de tres isoformes proteiques, una d’elles, USP25m, restringida al teixit muscular i cardíac. Tenint en compte que en el fenotip dels pacients amb síndrome de Down, entre altres trets, hi ha deficiència cardiovascular i atonia muscular, els esforços del grup es van centrar en la descripció i anàlisi d’aquesta isoforma. Els primers estudis van mostrar la seva situació citosòlica, l’expressió correlativa amb la diferenciació de cèl·lules musculars i la relació específica amb diverses proteines del sarcòmer. En el treball realitzat per la present Tesi Doctoral, s’han caracteritzat funcionalment diferents regions reguladores descrites a nivell bioinformàtic, així com també s’ha analitzat la seva implicació fisiológica a la funció d’USP25m. A més a més, mitjançant un estudi de cerca de nous interactors proteics, s’ha trobat una nova molècula que pertany a la mateixa via senyalitzadora i que es relaciona de manera específica amb USP25m, la lligasa d’ubiquititna MKRN1 (makorin 1) Mitjançant l’ús de diferents construccions amb delecions i mutacions puntuals de la proteïna que afecten a les regions d’interès, s’ha arribat a diferents conclusions, entre elles, que USP25m és monoubiquitinat i té la capacitat d’autodeubiquitinar-se. La monoubiquitinació en regula la seva activitat enzimàtica i es proposa un mecanisme de regulació basat en la conjugació alternativa de SUMO (una altra molècula de la família de la ubiquitina) i ubiquitina, en el mateix residu aminoacídic, la lisina 99 (Lys99). Els dominis d’unió a ubiquitina regulen el reconeixement de substrat i afavoreixen la monoubiquitinació. USP25m oligomeritza dins la cèl·lula i es troba present en diferents formacions proteiques d’elevat pes molecular. S’ha comprovat la relació específica amb la nova lligasa MKRN1 i es suggereixen diferents escenaris moleculars on poden trobar-se inclosos els dos pèptids. [eng] The main aim of the present PhD work, titled “Structural domains and new protein interactions of the deubiquitinating enzyme USP25”, is the functional characterisation of the structural domains of the muscle isoform of USP25, USP25m, as well as the analysis of new protein‐protein interactions. The ubiquitin‐proteasome pathway is widely known as the preferential system to get ride of old or non‐functional proteins. Recently, it has become more apparent that this is not the only function. Ubiquitin (Ub) and all ubiquitin–like (UbLs) molecules acted as regulatory tags involved in different cellular events as subcellular localization, enzyme activation, DNA repair, etc. The intricate Ub‐signalling networks require a tight regulation of both conjugation and deconjugationprocesses, which are controlled by ubiquitin ligases and deubiquitinating enzymes (DUBs), respectively. USP25 is a DUB described while looking for novel genes involved in Down syndrome phenotype. First studies showed that it encoded three alternative protein isoforms, one of them, muscle specific. This muscle isoform, USP25m, is a cytosolic protein, upregulated during myogenesis that interacts in a specific manner with different sarcomeric proteins. Using an “in silico” approach, we were able to identify different structural domains, among them three ubiquitin binding domains (UBDs), and we aimed to characterise its role on USP25m function. By generating a collection of deletion and punctual mutants of the regions of interest, we conclude that USP25m is monoubiquitinated and that the UBDs modulate this modification. The preferential site for monoubiquitination is lysine 99 (K99), a residue that has been reported to undergo sumoylation (SUMO conjugation, being SUMO an UbL). According to our results, mutation of the K99 residue diminishes the deubiquitinating function, proposing a mechanistic model for USP25m regulation based on alternative conjugation of Ub and SUMO on the same residue, K99. Futhermore, while seeking new protein interactions of USP25m we identified Makorin Ring finger protein 1 (MKRN1), which belongs to an ubiquitin ligase family, as a putative interactor. We were capable of characterise its interaction and propose different cellular scenarios were they could interact.

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    Authors: Bosch Farré, Cristina;

    To determine the prevalence of Active and Healthy Ageing (AHA) in the province of Girona and 14 European countries according to various models, to analyze the association between health variables and social determinants of health. This was a cross-sectional, observational analysis of a representative sample of population aged 50 years and older in Girona and Europe consisted of 55.278 participants. The data were obtained by MESGI50 and SHARE studies. AHA was measured using Rowe Kahn model (AHA-RK) and a model based on the WHO definition (AHA-WHO). The prevalence was 23.5% in AHA-RK model and 38.8% in AHA-WHO model. In the geographic analysis, there was a north-central to south-east Europe gradient. In both models, AHA was significantly associated with: self-perception of excellent-very good health status; high-very high quality of life; less use of health services. AHA was more strongly associated with socioeconomic status, mainly with to work and not financial difficulties. L’objectiu és determinar la prevalença de l’Envelliment Actiu i Saludable (EAS) a la província de Girona i a 14 països d’Europa segons diferents models i analitzar l’associació de l’EAS amb variables de salut i determinants socials de la salut. Estudi transversal observacional analític d’una mostra representativa de població de 50 i més anys de la província de Girona i Europa de 55.278 participants. S’analitzaren dades de MESGI50 i SHARE. Es va mesurar l’EAS amb el model Rowe i Kahn i amb un model basat en la definició de l’OMS. Les prevalences d’EAS eren 23,5% model EAS-RK i 38,8% model EAS-OMS. Hi havia un gradient geogràfic Nord-Centre amb Sud-Est d’Europa. En els dos models l’EAS s’associava significativament amb: salut autopercebuda excel•lent o molt bona; qualitat de vida alta o molt alta; menys ús de recursos sanitaris. L’EAS està fortament associat a les condicions socioeconòmiques, principalment treballar i no tenir dificultats econòmiques.

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    Authors: Districte 4. Les Corts;

    Presentat al Consell Plenari del Districte de Les Corts de 02-12-2009

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    Authors: Programa d'Harmonització Farmacoterapèutica;

    Alzheimer; Registre del tractament farmacològic; Població atesa Alzheimer; Register of pharmacological treatment; Population attended Alzheimer; Registro del tratamiento farmacológico; Población atendida La malaltia d’Alzheimer (MA) és un trastorn neurodegeneratiu progressiu i irreversible normalment de desenvolupament lent però sostingut en el temps. La MA és la causa més freqüent de demència (69%). La seva prevalença és d’un 5,1% i augmenta exponencialment amb l’edat amb els valors més elevats al voltant dels 90 anys. La enfermedad de Alzheimer (EA) es un trastorno neurodegenerativo progresivo e irreversible normalmente de desarrollo lento pero sostenido en el tiempo. La MA es la causa más frecuente de demencia (69%). Su prevalencia es de un 5,1% y aumenta exponencialmente con la edad con los valores más elevados en torno a los 90 años. Alzheimer's disease (MA) is a progressive and irreversible neurodegenerative disorder usually a slow but sustained development over time. MA is the most frequent cause of dementia (69%). Its prevalence is 5.1% and increases exponentially with age with the highest values ​​around 90 years.

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    Authors: Madrid i Fernández, Marisol;

    [cat] Aquest treball és una proposta de model integral per a l'estudi de materials ceràmics en un jaciment arqueològic. Incorpora dues metodologies de treball, l'arqueològica i l'arqueomètrica, cadascuna de les quals presenta un procediment metodològic propi, sense que cap d'elles es vegi condicionada per l'altra. El jaciment és la ciutat romana de Baetulo (Badalona), que va gaudir d'una dinàmica comercial important gràcies a la indústria del vi, i que es troba situada a la Costa Catalana a mig camí entre les dues ciutats més importants del moment, Emporiae i Tarraco. El material són les diferents produccions de terra sigillata comercialitzades a Baetulo i que s'inclourien dins els grups següents: terra sigillata itàlica, gàl·lica, hispànica i el que en aquest treball hem anomenat com a terra sigillata indeterminada, que es correspon al que abans d'aquest treball, a Badalona, classificàvem com a presigillata i prearetina. La fusió i integració dels resultats procedents d'ambdues metodologies permet la resolució del problema arqueològic plantejat inicialment, que és la identificació de les diferents produccions: quantes, la seva provinença, les seves característiques tecnològiques, els seus períodes de circulació a la ciutat i les rutes comercials utilitzades per a la seva comercialització a Baetulo. El contrast amb sigillata procedent d'Emporiae i Tarraco permet, a més, obtenir una visió més àmplia sobre la comercialització d'aquestes produccions a la Costa Catalana.L'estudi arqueològic s'ha fet a partir d'una selecció de contextos que cobreixen diverses etapes des d'inicis del govern d'August fins al segle II d.e. Durant aquest període es documenta sempre la presència de terra sigillata, de vegades contemporània a la formació dels estrats, d'altres residual. Es per això que la discussió cronològica dels contextos s'ha centrat només en aquells considerats de formació contemporània a la circulació de la terra sigillata.A partir d'aquests contextos, el primer pas ha estat la classificació a ull nu de la sigillata dins un dels grans grups definits anteriorment. L'estudi arqueològic del material s'ha completat amb la seva classificació tipològica, així com l'estudi individualitzat dels individus amb marques de ceramista i/o decoracions. L'anàlisi del context arqueològic del material ha permès proposar cronologies per aquests, així com per les estructures amb què es troben relacionats.A partir de l'anàlisi arqueològica es va realitzar un mostreig aleatori de tota la sigillata per a la seva caracterització arqueomètrica. No es van fer distincions entre produccions ni individus; tots van rebre el mateix tractament, independentment de si tenien o no forma, marca o decoració. La mostra està composta de 225 individus procedents de Baetulo, 63 d'Emporiae i 75 de Tarraco.Per als estudis de provinença, basats en la composició química, es van portar a terme anàlisis químiques per Fluorescència de Raigs X i Activació Neutrònica. L'anàlisi mineralògica es va portar a terme per Difracció de Raigs X per als estudis tecnològics. El Microscòpic Electrònic de Rastreig es va utilitzar per als estudis de microestructura i estadi de sinterització. Finalment, es van realitzat tests per a mesurar la resistència del material a la ruptura per definir la qualitat de les vaixelles. L'aplicació d'aquest model a Badalona ha permès la identificació d'un gran nombre de produccions de terra sigillata, moltes de les quals han pogut ser associades a produccions, tallers o àrees de provinença conegudes arqueomètricament. A més, la integració d'ambdues metodologies de treball ha permès establir els seus períodes de circulació a la ciutat: arribada, coexistència i desaparició. El contrast dels resultats de Baetulo amb aquells procedents d'Emporiae i Tarraco permet observar que, malgrat les coincidències, les tres ciutats haurien tingut la seva pròpia dinàmica comercial, el que significa que Baetulo no hauria estat només a remolc d'una gran ciutat. [eng] The aim of this study is the archaeological and archaeometrical analysis of the Indeterminate, Italian (TSI), Gaulish (TSS) and Hispanic (TSH) "Terra Sigillata" recovered from the modern excavations in "Baetulo" in order to identify the different productions included in these main groups. For the archaeological analysis, four recent excavations, in which the oldest stratigraphic levels including "Sigillata" pottery have been documented, were selected. These contexts cover a period from the beginning of the Augustan government to the second half of the 2nd century AD. During this period, Sigillata productions are always documented, in some cases contemporary to the formation of the stratigraphic layers, while in others as residual materials. Even though all individuals are considered in the archaeological and archaeometrical study, the chronological discussion focuses only on those stratigraphic layers contemporary to the ceramic circulation.After the archaeological analysis, a random sampling was conduced and 225 individuals from "Baetulo" were archaeometrically characterized. Besides, 63 individuals from Emporiae and 75 from Tarraco were also characterized in order to get a better knowledge about the TS commercialization in the Catalan coast. For provenance studies based on chemical composition, chemical analyses were performed by means of X Rays Flourescence (XRF) and Neutron Activation (NA). Mineralogical analyses were performed by means of X Rays Diffraction (XRD) for technological studies. Scanning Electronic Microscope (SEM) was used for microstructure and sintering stage studies. Finally, tests for measuring strength to the rupture of the materials were applied in order to define qualities. The study carried out in "Baetulo" allowed us the identification of a great number of "terra sigillata" productions, most of them associated to productions, workshops or provenance areas archaeometrically known. Besides, the integration of the archaeological and archaeometrical results, allows proposing the circulation periods of theses productions: arrival, coexistence and disappearance in "Baetulo". The contrast of the results from "Baetulo" with those from "Emporiae" and "Tarraco" point out that despite the coincidences, the three cities would have had their own commercial dynamic. Therefore, "Baetulo" would not have been just in tow of any great city.

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    Authors: Vilaplana Martínez, Eduard;

    La enfermedad de Alzheimer (EA) se caracteriza neuropatológicamente por la presencia de depósitos extracelulares de ß-amiloide (Aß) y ovillos neurofibrilares intracelulares (proteína tau fosforilada, p-tau) así como fenómenos inflamatorios. Estos procesos se asocian con atrofia cerebral, pérdida neuronal y alteraciones funcionales que acaban produciendo deterioro cognitivo y eventualmente un síndrome clínico de demencia. El depósito de amiloide comienzan décadas antes de que se pueda hacer un diagnóstico de demencia e incluso de la aparición de los primeros síntomas, y constituyen lo que se conoce como EA preclínica (Sperling et al., 2011). En la actualidad podemos estudiar los mecanismos fisiopatológicos que ocurren en la EA preclínica a través de biomarcadores (Dubois et al., 2016). Entender las relaciones entre biomarcadores en la EA preclínica es esencial para entender la fisiopatología de la enfermedad y poder desarrollar terapias que ralenticen o frenen su curso. Sin embargo, estas relaciones distan de estar claras, por ejemplo, la relación de la amiloidosis y la estructura cortical dista de es controvertida (Fortea et al., 2014). El objetivo principal de esta tesis fue estudiar las alteraciones corticales estructurales que ocurren en la enfermedad de Alzheimer preclínica. Concretamente, los objetivos fueron 1) estudiar la relación entre Aß y el grosor cortical y sus posibles interacciones con la proteína p-tau, 2) analizar los cambios estructurales corticales longitudinales de la EA preclínica, 3) investigar la microestructura cortical y entender su relación con la macroestructura en el continuum de la enfermedad y, 4) estudiar el impacto local del depósito de amiloide en la estructura cerebral en la EA preclínica. Para la realización de esta tesis se ha contado con bases de datos públicas americanas (Alzheimer’s Disease Neuroimaging Initiative, http://adni.loni.usc.edu/) y con bases de datos españolas (proyecto SIGNAL, https://www.signalstudy.es/). Los resultados de la tesis han conducido a la propuesta de un modelo bifásico de cambios corticales estructurales en la EA preclínica. El depósito de amiloide en ausencia de tau patológico se asocia a un incremento del grosor cortical, una ralentización de la atrofia longitudinal a 2 años y descensos de difusión cortical. Posteriormente, en presencia de tau patológica, y como resultado del efecto tóxico sinérgico o interacción entre procesos patológicos, se produciría una aceleración de la atrofia e incrementos de difusión que se extenderían siguiendo un patrón característico que ha sido definido como la huella cortical de la EA (Dickerson et al., 2009). Los resultados presentados en esta tesis tienen implicación directa en la investigación y en la práctica clínica. En primer lugar, en relación a los modelos de evolución de biomarcadores de la EA (Jack et al., 2013) ya que esta fase temprana de engrosamiento cortical no está contemplada en los modelos actuales. Nuestro modelo ayudaría a integrar los resultados contradictorios previos en la literatura en relación a los efectos del amiloide sobre la estructura cerebral. Los modelos actuales, no contemplan la interacción/sinergia entre biomarcadores que rigen el mencionado proceso bifásico. En segundo lugar, los resultados tienen implicaciones en el diseño de los ensayos clínicos, tanto en la selección de pacientes como en el uso subrogado de la resonancia como marcador de eficacia, ayudando a entender algunos resultados inesperados de los ensayos clínicos previos con inmunoterapia anti-amiloidea. Finalmente, la difusión cortical podría ser un marcador precoz en el curso de la EA. Futuros estudios multimodales de resonancia magnética y líquido cefalorraquídeo que incorporen PET de inflamación y de Tau con seguimientos longitudinales serán claves para seguir estudiando los procesos fisiopatológicos que subyacen la EA preclínica. The Alzheimer’s disease (AD) neuropathological hallmarks are the presence of extracellular amyloid ß (Aß) deposition and intracellular neurofibrillary tangles (hyperphosphorilated tau protein) as well as inflammation phenomena. These processes are associated with cerebral atrophy, neuronal loss and functional alterations which lead to cognitive dysfunction and, eventually, a clinical syndrome of dementia. These pathophysiological processes begin decades before the diagnosis of the clinical dementia even before the appearance of the first clinical symptoms, and constitute the preclinical AD (Sperling et al, 2011). Nowadays we can study the pathophysiological mechanisms that occur in preclinical AD through biomarkers (Dubois et al., 2016). It is crucial to understand the relationships between biomarkers in preclinical AD to further understand the disease pathophysiology and be able to develop treatments that could slow down or stop its course. However, these relationships are not clear, for example, the relationship between brain amyloidosis and brain structure is controversial (Fortea et al., 2014). The objective of this thesis was to study the cortical structural alterations that occur in preclinical AD. Specifically, 1) to study the relationship between Aß and cortical thickness and its potential interactions with p-tau, 2) to analyze the 2-year cortical longitudinal changes in preclinical AD, 3) to investigate cortical microstructure and understand its relationship with brain macrostructure in the disease continuum and, 4) to assess the local impact of amyloid deposition in brain structure in preclinical AD. In this thesis, we have used data from a public American database (Alzheimer’s Disease Neuroimaging Initiative, http://adni.loni.usc.edu/) and from a Spanish multicentric cohort (proyecto SIGNAL, https://www.signalstudy.es/). The results of this thesis have conducted to the proposal of a biphasic model of structural cortical changes in preclinical AD. Amyloid deposition in the absence of pathological tau levels would be associated with increased cortical thickness, less 2-year longitudinal cortical thinning and cortical diffusivity decreases. Then, in the presence of pathological tau levels, and as a result of the synergic toxic effect or interaction between pathologic processes, there would be an atrophy acceleration and cortical diffusivity increases that would spread following a pattern that has been described as the AD-signature (Dickerson et al., 2009). The results presented in this thesis have direct research and clinical implications. First, they impact on the models of biomarker evolution in AD (Jack et al., 2013), as the cortical thickening phase is not contemplated in previous models. Our model would help to understand previous contradictory results in the literature that assessed the effect of amyloid on brain structure. Current models do not take into account the interaction/synergy effect between biomarkers that define the aforementioned biphasic process. Second, our results have relevance in the design of clinical trials, both in the selection of patients and in the use of MRI as a surrogate marker of efficacy, and might help explain some unexpected results in previous anti-amyloid immunotherapy trials. Finally, cortical diffusivity could be an early marker in the AD course. Further multimodal studies that incorporate tau- and inflammation-PET with longitudinal follow-ups are crucial to further investigate the pathophysiological process that underlies preclinical AD.

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