Functional Magnetic Resonance Imaging (fMRI) has consistently highlighted aberrant functional connectivity across brain regions of autism spectrum disorder (ASD) patients. However, the manifestation and neural substrates of these alterations are highly heterogeneous and often conflicting. Moreover, their neurobiological under- pinnings and etiopathological significance remain largely unknown. A deeper understanding of the complex pathophysiological cascade leading to impaired connectivity in ASD can greatly benefit from the use of model organisms where individual pathophysiological or phenotypic components of ASD can be recreated and investigated via approaches that are either off limits or confounded by clinical heterogeneity. In this work, we first describe the intrinsic organization of the mouse brain at the macroscale as seen through resting-state fMRI (rsfMRI). The analysis of a large rsfMRI dataset revealed the presence of six distinct functional modules related to known brainwide functional partitions, including a homologue of the human default-mode network (DMN). Consistent with human studies, interconnected functional hubs were identified in several sub-regions of the DMN, in the thalamus, and in small foci within integrative cortical structures such as the insular and temporal association cortices. We then study the effects of mutations in contactin associated protein-like 2 (Cntnap2), a neurexin-related cell-adhesion protein, on functional connectivity. Homozygous mutations in this gene are strongly linked to autism and epilepsy in humans, and using rsfMRI, we showed that homozygous mice lacking Cntnap2 exhibit aberrant functional connectivity in prefrontal and midline functional hubs, an effect that was associated with reduced social investigation, a core “autism trait” in mice. Notably, viral tracing revealed reduced frequency of prefrontal-projecting neural clusters in the cingulate cortex of Cntnap2−/− mutants, suggesting a possible contribution of defective mesoscale axonal wiring to the observed functional impairments. Macroscale cortico-cortical white-matter organization appeared to be otherwise preserved in these animals. These findings revealed a key contribution of ASD-associated gene CNTNAP2 in modulating macroscale functional connectivity, and suggest that homozygous loss-of-function mutations in this gene may predispose to neurodevelopmental disorders and autism through a selective dysregulation of connectivity in integrative prefrontal areas. Finally, we discuss the role mouse models could play in generating and testing mechanistic hypotheses about the elusive origin and significance of connectional aberrations observed in autism and recent progress towards this goal.

The highly complex nervous system is built upon an intricate network of neurons. In order to make a functional network, the establishment of precise connections is crucial. Neuronal networks are established early during development when neurons send out axons that navigate through complex environments to connect to their target. Chemotropic attractant or repellent cues, cell adhesion molecules, morphogens and a wide range of factors secreted or expressed by guidepost cells enable axon guidance. The leading tip of the axon, the GC is important to sense the environment and integrate extracellular signals to navigate precisely. The axonal GC has a large repertoire of mRNAs that are dynamic in nature. Local regulation of transcripts in navigating axons is suspected to ensure precise pathfinding. However, mechanisms involving regulation of expression of these transcripts within GCs are largely unknown. This thesis investigates whether microRNAs, one of the quintessential posttranscriptional regulators, can regulate axon guidance by fine-tuning mRNA expression within subcellular compartments. To explore microRNA roles in axon guidance, Xenopus laevis visual system was used as a model. Profiling axons of retinal ganglion cells revealed the presence of miRNAs within axons. The most abundant axonal miRNAs, the miR-181 family and miR-182, exhibit distinct roles in regulating axon guidance in vivo. Loss of function analyses suggests that both miRNA families are required for accurate axonal targeting but involve different mechanisms. Thus, specific axonal microRNAs locally regulate mRNAs contributing to error-free pathfinding.

This thesis will describe two functional Magnetic Resonance Imaging (fMRI) experiments and one Voxel-Based Morphometry (VBM) study, each investigating how the human brain identifies objects and their associated properties. In particular, we used three different categories of objects – living (animals), nonliving (tools and nontools) and faces (famous and non-famous) – to examine the type of knowledge attribute in question: one perceptual (movement) and two semantic attributes (typical object location and biographic knowledge). We know from neuropsychological literature that the most anterior portions of the temporal cortices critically support human conceptual knowledge. Unfortunately, the Anterior Temporal Lobe (ATL) is a challenging region for fMRI due to susceptibility artifacts, especially at high fields. For these reasons we established an optimized fMRI protocol (described in the second Chapter) by adjusting key acquisition parameters like phase-encoding gradient polarity, slice thickness, echo time, and slice angle. The protocol gave reliable Blood-Oxygen-Level Dependence (BOLD) signal sensitivity in the ATL. Clinical data describe patients with specific semantic impairments at the level of category (living, nonliving) as well as disproportionate deficits for a modality or type of knowledge (e.g., visual/perceptual knowledge or manipulation knowledge). Functional neuroimaging studies on semantic organization with normal subjects found an “action network†specific for tools rather than living items. In the first experiment (Chapter 3) we devised an fMRI paradigm to investigate the processing of movement (action) and place (encyclopedic) features, and their influence on category-specific activations. Within the “movement network†statistical analyses did not show any significant interaction between categories. These findings suggest that the visuomotor “action network†is not specific for tools because it is also activated when the action related knowledge is elicited for other categories, such as animals. The second and the third experiment (Chapter 4) focus on the processing of faces. Neuropsychological literature attributes semantic and lexical retrieval deficits in patients to ATL lesions. In Part I of Chapter 4, we report data from a VBM study on patients with known lesions in the temporal lobe. Unfortunately, as far as we know, data on patients and functional neuroimaging in healthy individuals has not clarified the differential role of this area in the two mental operations because semantic and lexical processes usually occur simultaneously and automatically. In Part II, we devised an event-related fMRI activation paradigm that allowed us to study the identification (i.e., association of semantic biographical information) of celebrities, with and without the ability to retrieve the proper name. While semantic retrieval reliably activated the ATL, only more posterior areas in the left temporal and temporal-parietal junction were significantly modulated by covert lexical retrieval. These results support findings from patients with ATL lesions and suggest that their anomia is due to semantic rather than lexical retrieval impairment.

The clinical manifestations of Multiple Sclerosis are motor, sensitive, cerebellar and cognitive alterations. It evolves with a high degree of physical and cognitive disability. The “EM-line! Project” has its origins in the need to provide effective treatment for cognitive problems given that a gap in cognitive treatment was detected, especially at the onset of the disease. For this reason, the main objective of the “EM-line! Project” was: To supply free cognitive rehabilitation materials that do not interfere in the professional activity of the patients for use at home from the onset of the disease. Patients participated in a 26 week prospective, randomized, single-blind intervention study and patients were found to improve specifically in the areas of visual memory (learning and long term memory), executive functions (working memory and access to vocabulary), attention, processing speed, and naming ability. The “EM-line Project” is effective in improving cognitive disorder in multiple sclerosis patients. / Las manifestaciones de la esclerosis múltiple son alteraciones motoras, sensitivas, cerebelosas y cognitivas. Evoluciona con un alto grado de discapacidad física y cognitiva. El “Projecte EM-line!” surgió de la necesidad clínica de dar un tratamiento efectivo a los problemas cognitivos ya que se observó un vacío en el tratamiento cognitivo en el inicio de la enfermedad. El objetivo del “Projecte EM-line!” es: - Proporcionar un material de rehabilitación cognitiva gratuito para poder realizar en casa desde el inicio de la enfermedad, sin interferir en las actividades profesionales de los pacientes. Se realizó un estudio prospectivo de intervención , randomizado y simple ciego de 26 semanas de duración y los pacientes mejoraron en memoria visual (aprendizaje y memoria a largo plazo), funciones ejecutivas (memoria de trabajo y acceso al léxico), atención, velocidad de procesamiento y capacidad de denominación. El projecte EM-line es efectivo para mejorar el trastorno cognitivo en la EM.

Depression is the most common type of emotional disorder among the world's population. It is characterized by negative sentiments, the feeling of guilt, low self-esteem, a loss of interest, a high-level process of reflection, and in general by a decrease of the individual's psychic functions. The new non-invasive neuroimaging techniques have increased the ability of studying possible variations in patients' brain activity. In concrete, functional magnetic resonance imaging (fMRI) has become the most important method to study human brain functions in the past two decades, being non-invasive and with no risk for human health. Biswal and others in 1995, and later Lowe and his colleagues in 1998, showed the existence of continous spontaneous activity in the brain's activity at rest. These fluctuations have also been verified in other species like macaques (Vicent JL et l, 2007). Studying the brain's activity at rest (rs-fMRI) by means of neuroimaging techniques has become a powerful tool for the investigation of diseases, since it has demonstrated a better signal to noise ratio concerning task-based approaches on one hand, and since certain patients could have difficulties to perform cognitive, language or motor tasks on the other hand. However, it seems that because of certain inconsistencies found among studies, rs-fMRI techniques would not reach a practical clinical use of a personalised monitoring, prognosis or pre-diagnosis in individuals with depression. In this respect, even if Grecius MD exposed in 2008 the benefits of rs-fMRI techniques, he also commented that the signal to noise ratio remains to be improved to be used in a clinical routine. Grecius suggested to lenghthen the time of the temporal series at rest, and to improve analysis procedures. The aim of this thesis is to elucidate if the existence of certain factors or components in the functional signal at rest could be used at the clinical health level. In order to achieve this, we use rs-fMRI data on two sets of samples. In the first set of samples, composed by 27 patients with major depression (MDD) and 27 individuals as controls, we design descriptors that describe both static and dynamic aspects of the resting-state signal for the construction of prediction models. Conversely, with the second type of samples (48 twins), we analyse the relation between possible genetic and environmental factors which could explain certain depressive components in the activity in resting condition. On the one hand, the results show that depression could simultaneously affect different brain networks located in the prefrontal-limbic area, in the DMN, and between the frontoparietal lobes. Besides, it seems that the alterations in these networks could be explained by both static and dynamic aspects existing in the rest signal. Finally, we achieve the creation of models that would partially explain certain clinical phenomenons present in depressive patients by means of global descriptors in these networks. These network descriptors could be used for personalised monitoring in patients with major depression. On the other hand, using the twin sample, we achieve the construction of a risk model from the amygdalar activity which evaluates the risk or predisposition of an individual from analytical components in the activity at rest. The cerebellum of this sample was also analysed, and the environment was found to be possibly modifying the activity in these regions / La depresión es el tipo de trastorno emocional más común en la población mundial. Se caracteriza por sentimientos de culpa o negativos, baja autoestima, pérdida de interés, alto nivel de reflexión y en general una disminución de las funciones psíquicas del individuo. Las nuevas técnicas de neuroimagen no invasivas han incrementado la habilidad para estudiar posibles variaciones de la actividad cerebral en pacientes. En concreto, las imágenes por resonancia funcional magnética (fRMI) se han convertido en las dos últimas décadas el método más importante, no-invasivo sin riesgo para la salud humana, para el estudio de las funciones cerebrales humanas. Biswal y otros en 1995, y posteriormente Lowe y compañía en 1998, demostraron la existencia de actividad espontanea continua en la actividad cerebral en estado de reposo. Estas fluctuaciones también han sido confirmadas en otras especies como en macacos (Vincent JL y compañía, 2007). El estudio mediante técnicas de neuroimagen sobre la actividad cerebral en reposo (rs-fMRI) se ha convertido en una potente herramienta para el estudio de enfermedades, puesto que, por un lado, se ha demostrado tener una mejor relación señal-ruido respecto a enfoques basados en tareas, y por otro lado, ciertos pacientes podrían tener dificultades para realizar algún tipo de tareas cognitivas, de lenguaje o motoras. Sin embargo, parece ser que debido a ciertas inconsistencias encontradas entre estudios, las técnicas de rs-fMRI no estarían llegando a un uso clínico-práctico para el seguimiento, pronóstico o pre-diagnostico personalizado en individuos con depresión. En línea a esto, aunque Grecius MD en 2008 expuso los beneficios de la técnica rs-fMRI también comentó que para poder ser utilizada en la rutina clínica aún se debería mejorar la relación señal-ruido. Propuso alargar los tiempos de las series temporales en estado de reposo y mejorar los procedimientos de análisis. En esta tesis se trabaja para dilucidar si existen ciertos factores o componentes en la señal funcional en estado de reposo que pudieran ser utilizados para su uso en la salud clínica. Por ello, utilizamos datos de rs-fMRI sobre dos conjunto de muestras. En el primer conjunto, 27 pacientes con depresión mayor (MDD) y 27 individuos como control, diseñamos descriptores que describan aspectos estáticos y dinámicos de la señal de reposo para la construcción de modelos de prónostico. En cambio, con el segundo tipo de muestras, 48 gemelos, analizamos la relación de posibles factores genéticos y de entorno que pudieran explicar ciertos componentes depresivos en la actividad en estado de reposo. Por un lado, los resultados muestran que la depresión pudiera estar afectando diferentes redes cerebrales al mismo tiempo localizadas en la parte prefrontal-limbica, en la red DMN, y entre los lóbulos frontoparietales. Además, parece ser que las alteraciones sobre estas redes pudieran ser explicadas tanto por aspectos estáticos y dinámicos existentes en la señal de reposo. Finalmente, conseguimos crear modelos que explicarían parcialmente ciertos fenómenos clínicos presentes en los pacientes depresivos, mediante descriptores globales de estas redes. Estos descriptores de red pudieran ser utilizados para el seguimiento personalizado en pacientes con depresión mayor. Por otro, utilizando la muestra de gemelos, conseguimos construir un modelo de riesgo a partir de la actividad amigdalar que evalúa el riesgo o propensión de un individuo a partir de componentes analíticas en la actividad de reposo. También sobre esta muestra, se analizó el cerebelo encontrando que el entorno pudiera estar modificando la actividad en estas regiones

In this work we have assessed the possible contribution of the human chromosome-21 gene DYRK1A in the developmental cortical alterations associated with Down Syndrome using the mBACTgDyrk1a mouse, which carries 3 copies of Dyrk1a, and a trisomic model of the syndrome, the Ts65Dn mouse. We show that trisomy of Dyrk1a changes the cell cycle parameters of dorsal telencephalic radial glial (RG) progenitors and the division mode of these progenitors leading to a deficit in glutamatergic neurons that persist until the adulthood. We demonstrate that Dyrk1a is the triplicated gene that causes the deficit in early-born cortical glutamatergic neurons in Ts65Dn mice. Moreover, we provide evidences indicating that DYRK1A-mediated degradation of Cyclin D1 is the underlying mechanism of the cell cycle defects in both, mBACTgDyrk1a and Ts65Dn dorsal RG progenitors. Finally, we show that early neurogenesis is enhanced in the medial ganglionic eminence of mBACTgDyrk1a embryos resulting in an altered proportion of particular cortical GABAergic neuron types. These results indicate that the overexpression of DYRK1A contributes significantly to the formation of the cortical circuitry in Down syndrome. / En aquest treball s'ha avaluat la possible contribució del gen DYRK1A, localitzat en el cromosoma humà 21, en les alteracions del desenvolupament de l’escorça cerebral associades a la Síndrome de down (SD) mitjançant l’estudi de dos models murins: el ratolí mBACTgDyrk1a, el qual conté 3 còpies de Dyrk1a, i el ratolí Ts65Dn, un dels models trisòmics de la SD més ben caracteritzats. Els nostres resultats mostren que la trisomia de Dyrk1A altera alguns paràmetres del cicle cel•lular i el tipus de divisió dels progenitors neurals del telencèfal dorsal, donant lloc a un dèficit de neurones glutamatèrgiques que persisteix fins l’edat adulta. Hem demostrat que Dyrk1a és el gen triplicat responsable del dèficit inicial en la generació de neurones glutamatèrgiques corticals observat en el ratolí Ts65Dn. A més a més, hem proporcionat evidències de que la degradació de Ciclina D1 induïda per DYRK1A és el mecanisme molecular subjacent a les alteracions de cicle cel•lular observades en els progenitors neuronals dels embrions mBACTgDyrk1a i Ts65Dn. Per altra banda, hem demostrat que la neurogènesis inicial està incrementada en l’eminència ganglionar medial dels embrions mBACTgDyrk1a, fet que altera la proporció de subtipus específics d’interneurones GABAèrgiques en l’escorça cerebral adulta. En conclusió, els nostres resultats indiquen que la sobreexpressió de DYRK1A contribueix significativament a la formació dels circuits cortical en la SD.

El cànnabis i l’èxtasi són dues drogues d’ús recreatiu, les quals usualment es solen consumir de forma conjunta. Degut al seu ús combinat, resulta difícil esclarir les conseqüències que té cada droga a nivell neurobiològic. En aquesta tesi hem investigat els mecanismes neurals involucrats en les respostes conductuals produïdes per l’administració de MDMA (èxtasi) i THC (principi actiu del cànnabis) en models animals. L’administració repetida de MDMA produeix alteracions en la motivació per obtenir menjar apetitós, però és necessària l’administració repetida d’altes dosis que produeixen efectes neurotòxics per produir una manca de flexibilitat cognitiva i dèficits transitoris en la memòria de treball. L’administració de dosis neurotòxiques de MDMA produeix una disminució en els nivells de transportador de dopamina així com un dèficit en l’alliberació d’aquest transmissor. Així doncs, aquests resultats suggereixen que les alteracions en les funcions executives provocades per la MDMA estan associades als canvis observats en la neurotransmissió dopaminèrgica. Per altra banda, mitjançant l’ús de ratolins transgènics als quals els manquen els receptors 2A de serotonina hem revelat que aquests receptors modulen les respostes induïdes pel THC. Aquests animals són menys sensibles als efectes amnèsics, ansiolítics i pro-socials del THC i a més presenten un menor síndrome d’abstinència a aquesta substància. En canvi, l’absència de 5-HT2A no modifica les propietats antinociceptives, hipotèrmiques, hipolocomotores i ansiogèniques del THC, ni tampoc redueix els efectes reforçants de l’agonista cannabinoide WIN 55,212-2. Mitjançant estudis moleculars in vitro i assajos ex vivo hem descobert i caracteritzat els heteromers CB1-5-HT2A, els quals presenten unes propietats de senyalització específiques. Pertorbant la formació dels heteromers mitjançant pèptids específics hem aconseguit abolir els efectes amnèsics del THC, mantenint les seves propietats antinociceptives. Aquesta troballa suggereix la possibilitat d’utilitzar els heteromers CB1-5-HT2A com a diana per dissociar els efectes terapèutics del THC dels efectes indesitjables induïts per la seva administració. / Cannabis and ecstasy are popular recreational drugs that are often consumed together. Hence, the combined use of both drugs makes it difficult to elucidate their selective contribution in the neurobiological alterations observed in this population. We investigated the neural mechanisms underlying the behavioural effects of MDMA (ecstasy) and THC administration separately using animal models. Repeated administration of neurotoxic and non-neurotoxic doses of MDMA induced alterations in the motivation for palatable food, while only neurotoxic doses of MDMA induced durable resistance to extinction and cognitive flexibility, and transient deficits in working memory. A decrease in striatal DAT binding, and lower levels of stimulated dopamine release were observed following repeated neurotoxic doses of MDMA. These findings suggest that MDMA induces alterations in executive functioning that are associated with changes in striatal dopaminergic neurotransmission. In transgenic mice lacking 5-HT2A receptors, we found a decrease in the amnesic, anxiolytic, and pro-social-like effects of THC, as well as the manifestations of THC withdrawal syndrome. In contrast, 5-HT2A receptor deletion did not modulate the acute hypolocomotor, hypothermic, anxiogenic and antinociceptive effects of THC or the reinforcing effects of the cannabinoid agonist, WIN 55,212-2. In vitro molecular assays and ex vivo studies in mouse brain slices revealed the formation of CB1-5-HT2A heteromers with specific signaling properties. The disruption of this heteromer with specific transmembrane interference peptides selectively abrogated the memory impairments caused by THC exposure, but not its antinociceptive properties. These findings suggest that the potential therapeutic properties of cannabinoids can be dissociated from their unfavourable side-effects by targeting the CB1-5-HT2A heteromer.

L’origen ambiental i genètic de les diferències individuals en l’aprenentatge de paraules i regles gramaticals és desconegut. Per aquest motiu es van realitzar dos estudis. En el primer, dos grups de bessons, monozigòtics i dizigòtics, varen desenvolupar una tasca d’aprenentatge de paraules i regles. Es va mesurar la similitud entre bessons en l’activitat cerebral i els resultats indicaren que els factors genètics eren poc rellevants. En el segon estudi es va mesurar la diferència entre bessons monozigòtics en la integritat de la matèria blanca i en el nivell d’aprenentatge de paraules i es van correlacionar ambdues mesures. Els resultats mostraren que els factors ambientals que afecten als fascicles arcuat i front-occipital esquerres explicarien, en part, les diferències individuals en l’aprenentatge de paraules. Ambdós estudis suggereixen que les experiències juguen un paper central en el modelatge dels substrats neuronals associats a l’aprenentatge de paraules i regles. / The genetic and environmental origin of individual differences in word and grammar learning is unknown. Two separate studies addressed this issue. In the first study, monozygotic and dizygotic twins were exposed to a word and rule learning task while event-related potentials were recorded. Brain signal similarity between twins was measured, and indicated a weak influence of genetics in both processes. In the second study, white matter integrity estimates were obtained for language-relevant connections in a sample of monozygotic twins that also underwent a statistical word learning task. Twin differences in both white matter integrity and word learning performance were computed and correlated. Significant results in the left arcuate and inferior fronto-occipital fasciculus revealed that the environmental pressures affecting the integrity of these two structures partially explain individual differences in word learning. Taken together, both studies suggest that life experiences play a pivotal role in shaping the neural substrates of word and rule learning.

Nitric oxide (NO) is a molecule that has pleiotropic effects in brain and vascular system. Physiologically, NO induces the translation of the GluN2B subunit of N-methyl Daspartate receptor (NMDARc) by derepressing it 5’untranslated region (5’UTR) effect. This pathway is due to the activation of the heme regulated eIF2α (HRI) kinase and prevents an excess of GluN2B levels, especially at the extrasynaptic areas, where it can trigger excitotoxicity. Pathologically, NO in a pro-oxidant environment such as in Alzheimer’s Disease (AD) reacts with superoxide anion producing peroxynitrite, which can nitrotyrosinates proteins. There are other concomitant oxidative processes that affect AD patient like protein glycation. Therefore the albumin, the most abundant plasmatic protein, in AD patients is more nitrotyrosinated and glycated, which affects its structure. Modified albumin has a reduced ability as an osmolarity buffer and it is hardly uptaken by hepatoma cells. Moreover, modified albumin binds more Aβ, contributing to maintain higher amount of amyloid in brain and plasma. / El óxido nítrico (NO) es una molécula con efectos pleyotrópicos en cerebro y sistema vascular. Fisiológicamente, induce la traducción de la subunidad GluN2B del N-methyl D-aspartate receptor (NMDARc) al revertir la represión de su 5’untranslated region (5’UTR). Este efecto se debe a la activación de la heme regulated eIF2α kinase (HRI) y previene el exceso de GluN2B, especialmente en regiones extrasinápticas, donde desencadena excitotoxicidad. Patológicamente, el NO en un ambiente pro-oxidatvio como el dado en la enfermedad de Alzheimer (AD) reacciona con el anión superóxido produciendo peroxinitrito, y causando entre otros efectos la nitrotirosinación de proteínas. Simultaneamente, las proteínas de pacientes con AD padecen otros procesos oxidativos como la glicación. Por tanto, la albúmina, la proteína plasmática más abundante, en estos pacientes está más nitrotirosinada y glicada, afectando su estructura. La albúmina modificada presenta menos capacidad para tamponar la osmolaridad y apenas es digerida por las células de hepatoma. Además, une más Aβ, contribuyendo a mantener más alta la carga amiloidogénica en cerebro y plasma.

The continuing growth of older age groups worldwide needs an increased understanding of the ageing phenomena. For this reason, the present thesis is aimed at two very important outcomes in the elderly, active ageing (AA) in older adults and health-related quality of life (HRQL) in people with dementia. To do this, I have participated in different studies and used different research methodologies. In the first publication of this thesis, I study the distribution and associations with sociodemographic variables of different definitions of AA in a large adult population sample in Spain, Poland and Finland. The next publication reviews the previous literature on HRQL instruments for dementia in order to understand such complex concept and compare the different instruments in terms of for example data collection method or purpose of assessment. In the last publication, I explore the distribution of HRQL in the very old population in Cambridge by creating a new instrument using an already existing conceptual framework. Note: data from Courage Project (http://www.courageineurope.eu/) used for the thesis. / El continuo envejecimiento de la población mundial hace que sea necesario entender mejor este fenómeno. Por esta razón, la presente tesis doctoral tiene como objetivo estudiar dos variables muy importantes en la gente mayor, envejecimiento activo (AA) en la gente mayor y calidad de vida relacionada con la salud (HRQL) en gente con demencia. Para ello, he participado en diferentes estudios y he utilizado diferentes metodologías de investigación. En la primera publicación de esta tesis, estudio la distribución y asociación de diferentes definiciones de AA con variables sociodemográficas en una amplia muestra poblacional de España, Polonia y Finlandia. En la siguiente publicación llevo a cabo una revisión de la literatura sobre instrumentos para medir HRQL en demencia con tal de entender este complejo concepto y comparar los diferentes instrumentos en cuanto al método de recogida de información o al motivo de evaluación, por ejemplo. En la ultima publicación, exploro la distribución de HRQL en la población de gente muy mayor de Cambridge, creando un nuevo instrumento utilizando un marco conceptual ya existente. Nota: se usan los datos del Proyecto Courage (http://www.courageineurope.eu/).