Diffusion Tensor Imaging in Alzheimer's disease

Attentional control and Information processing speed are central concepts in cognitive psychology and neuropsychology. Functional neuroimaging and neuropsychological assessment have depicted theoretical models considering attention as a complex and non-unitary process. One of its component processes, Attentional set-shifting ability, is commonly assessed using the Trail Making Test (TMT). Performance in the TMT decreases with increasing age in adults, Mild Cognitive Impairment (MCI) and Alzheimer’s Disease (AD). Besides, speed of information processing (SIP) seems to modulate attentional performance. While neural correlates of attentional control have been widely studied, there are few evidences about the neural substrates of SIP in these groups of patients. Different authors have suggested that it could be a property of cerebral white matter, thus, deterioration of the white matter tracts that connect brain regions related to set-shifting may underlie the age-related, MCI and AD decrease in performance. The aim of this study was to study the anatomical dissociation of attentional and speed mechanisms. Diffusion tensor imaging (DTI) provides a unique insight into the cellular integrity of the brain, offering an in vivo view into the microarchitecture of cerebral white matter. At the same time, the study of ageing, characterized by white matter decline, provides the opportunity to study the anatomical substrates speeded or slowed information processing. We hypothesized that FA values would be inversely correlated with time to completion on Parts A and B of the TMT, but not the derived scores B/A and B-A.

MEG networks organization is related to white matter integrity

Many studies have assessed the characterization of anatomical or functional connectivity in mild cognitive impairment (MCI), however it is still unknown how they are related in the course of the pathology. Here we integrate the analysis of magnetoencephalographic (MEG) data with white matter (WM) integrity quantification from diffusion weighted imaging (DWI), to asses whether the damage in the WM tracts disrupt the organization of the functional networks.

Entornos de ayuda a la vida independiente de personas mayores sobre servicios de redes de próxima generación

El progresivo envejecimiento de la población está produciendo una elevada demanda de servicios socio‐asistenciales por parte de las personas mayores para mantener su vida independiente y el consiguiente “envejecimiento activo”. La iniciativa Ambient Assisted Living (AAL) promueve el “envejecimiento activo” a través de las Tecnologías de la Información y las Comunicaciones (TIC) y es en ella donde se centrará el trabajo de esta tesis doctoral. Una característica fundamental de los servicios AAL es su adaptación y personalización a las características y preferencias del usuario y su contexto. Así, el paradigma “context awareness” presenta una gran relevancia en la provisión de servicios AAL y en el soporte a la vida independiente de las personas mayores. Concretamente, la utilización de ontologías permite crear modelos de usuarios y contexto que pueden ser utilizadas para los mecanismos de razonamiento incluidos en los servicios context‐aware. Por otra parte, los usuarios actualmente precisan acceder a un conjunto de servicios desde cualquier red de acceso y desde cualquier dispositivo. Las redes de próxima generación (Next Generation Networks‐NGN) lo hacen posible pues ofrecen una convergencia dispositivo‐red‐servicio. La tecnología IMS (IP Multimedia Subsystem) es una arquitectura que implementa el paradigma NGN y ofrece una serie de servicios de red genéricos llamados servicios habilitadores o enablers que pueden ser reutilizados en cualquier aplicación, soportando mecanismos de interoperabilidad entre aplicaciones y permitiendo un desarrollo robusto, rápido y sencillo. Además, los servicios enablers permiten mecanismos de gestión de la información de usuario para realizar una provisión adaptada del servicio en función de la información del estado del usuario. El objetivo de esta tesis doctoral se centra en establecer un marco de convergencia entre estos dos campos diseñando y desarrollando un conjunto de servicios enablers soportados en una arquitectura IMS implementada para soportar la provisión de aplicaciones AAL bajo el paradigma context‐awareness y la triple convergencia reddispositivo‐ servicio cubriendo así las necesidades y requisitos de las personas mayores. Entre las aportaciones de la presente tesis se destaca la realización de un modelo de plataforma servicios AAL, denominado Residencia Virtual Asistiva, para su provisión en el domicilio de la persona mayor, así como la propuesta de implementación de sus servicios a través de servicios enablers. Por otra parte se define una ontología destinada a modelar servicios AAL así como sus usuarios (personas mayores) para lograr una provisión personalizada y adaptada de servicios AAL. Esta ontología se ha implementado a través del servicio de presencia de la arquitectura IMS para poder crear perfiles de usuario y así poder realizar dicha provisión personalizada. Además, se desarrolla una aplicación de teleconsulta, como ejemplo de servicio AAL, que utiliza una serie de servicios enablers desarrollados para ofrecer funcionalidades avanzadas a la aplicación. Bajo el paradigma contex‐awareness se ha desarrollado y evaluado técnicamente un servicio enabler para ofrecer soporte a la movilidad y a la independencia de las personas mayores con deterioro cognitivo que sufren episodios de desorientación espacial. ABSTRACT The progressive ageing of the population is making elderly people demand sociohealthcare services to maintain an independent living and therefore an “active ageing”. The initiative Ambient Assisted Living (AAL), on which the current PhD thesis is focused, promotes the “active ageing” by means of Information and Communication Technologies (ICT). Essential features of AAL services are the adaptation and personalization to the user’s characteristics and preferences as well as user’s context. Thus, the “context‐awareness” paradigm implies a great importance in the AAL service provision and the elderly independent living support. In particular, the usage of ontologies allows creating user and contexts models to be employed in the reasoning mechanism of context‐aware services. On the other hand, users currently require accessing to a set of services from anywhere and any device. Next‐Generation Networks (NGN) support this need by offering a service‐network‐device convergence. The IP Multimedia Subsystem (IMS) technology is an architecture that implements the NGN paradigm and offers a generic network services know as service enabler which can be reused by any application supporting application interoperability mechanism as well as allowing a simple, fast and robust application development. Furthermore, the service enablers offer user’s information management procedures to achieve and adapt service provision considering the user’s status. The objective of this PhD thesis is focused on establishing a convergence framework between these two previous fields by designing and developing a group of service enablers that will be deployed in an IMS architecture. The enablers developed will support the AAL applications provision from the context‐awareness paradigm and service‐network‐device convergence in order to cover the elderly people’s requirements and needs. Among the contributions achieved in this PhD thesis, the definition of an AAL platform service model, named as “Assited Virtual Nursing Home”, for being deployed in the older adult home is emphasised. In addition, a proposal of service enablers to support the AAL service defined in the model is made. Otherwise, an ontology is defined to model AAL services as well as their users with the aim at achieve a personalized and adapted AAL service. This ontology has been implemented by means of the IMS service presence in order to create users profiles to be used in the personalized AAL services. As an example of AAL service, a teleconsulting application has been developed to employ a group of service enablers developed using a set of advanced functionalities. Considering the context‐paradigm, a service enabler has been developed and technologically evaluated to support the mobility and independence of elderly people with mild cognitive impairment who suffers spatial disorientation episodes.

Identification and characterization of an enzyme involved in the elongation of n-6 and n-3 polyunsaturated fatty acids

The enzymes that are involved in the elongation of fatty acids differ in terms of the substrates on which they act. To date, the enzymes specifically involved in the biosynthesis of polyunsaturated fatty acids have not yet been identified. In an attempt to identify a gene(s) encoding an enzyme(s) specific for the elongation of γ-linolenic acid (GLA) (18:3n-6), a cDNA expression library was made from the fungus Mortierella alpina. The cDNA library constructed in a yeast expression vector was screened by measuring the expressed elongase activity [conversion of GLA to dihomo-GLA (20:3n-6)] from an individual yeast clone. In this report, we demonstrate the isolation of a cDNA (GLELO) whose encoded protein (GLELOp) was involved in the conversion of GLA to dihomo-GLA in an efficient manner (60% conversion). This cDNA contains a 957-nucleotide ORF that encodes a protein of 318 amino acids. Substrate specificity analysis revealed that this fungal enzyme acted also on stearidonic acid (18:4n-3). This report identifies and characterizes an elongase subunit that acts specifically on the two Δ6-desaturation products, 18:3n-6 and 18:4n-3. When this GLELO cDNA was coexpressed with M. alpina Δ5-desaturase cDNA in yeast, it resulted in the conversion of GLA to arachidonic acid (20:4n-6) as well as the conversion of stearidonic acid to eicosopentaenoic acid (20:5n-3). Thus, this GLELO gene may play an critical role in the bio-production of both n-6 and n-3 polyunsaturated fatty acids.

Adenoviral gene transfer of Caenorhabditis elegans n−3 fatty acid desaturase optimizes fatty acid composition in mammalian cells

Omega−3 polyunsaturated fatty acids (PUFAs) are essential components required for normal cellular function and have been shown to exert many preventive and therapeutic actions. The amount of n−3 PUFAs is insufficient in most Western people, whereas the level of n−6 PUFAs is relatively too high, with an n−6/n−3 ratio of >18. These two classes of PUFAs are metabolically and functionally distinct and often have important opposing physiological functions; their balance is important for homeostasis and normal development. Elevating tissue concentrations of n−3 PUFAs in mammals relies on chronic dietary intake of fat rich in n−3 PUFAs, because mammalian cells lack enzymatic activities necessary either to synthesize the precursor of n−3 PUFAs or to convert n−6 to n−3 PUFAs. Here we report that adenovirus-mediated introduction of the Caenorhabditis elegans fat-1 gene encoding an n−3 fatty acid desaturase into mammalian cells can quickly and effectively elevate the cellular n−3 PUFA contents and dramatically balance the ratio of n−6/n−3 PUFAs. Heterologous expression of the fat-1 gene in rat cardiac myocytes rendered cells capable of converting various n−6 PUFAs to the corresponding n−3 PUFAs, and changed the n−6/n−3 ratio from about 15:1 to 1:1. In addition, an eicosanoid derived from n−6 PUFA (i.e., arachidonic acid) was reduced significantly in the transgenic cells. This study demonstrates an effective approach to modifying fatty acid composition of mammalian cells and also provides a basis for potential applications of this gene transfer in experimental and clinical settings.

Étude du polymorphisme rs3846662 de l’HMGCR dans le cerveau et le système périphérique

Dans cette thèse, l’impact du polymorphisme rs3846662 sur l’épissage alternatif de la 3-hydroxy-3-méthylglutaryl coenzyme A réductase (HMGCR) a été investigué in vivo, chez des patients atteints d’hypercholestérolémie familiale (HF) ou de maladie d’Alzheimer (MA). Le premier manuscrit adresse la problématique de la normalisation de la quantification relative des ARNm par PCR quantitative. Les découvertes présentées dans ce manuscrit nous ont permis de déterminer avec un haut niveau de confiance les gènes de référence à utiliser pour la quantification relative des niveaux d’ARNm de l’HMGCR dans des échantillons de sang (troisième manuscrit) et de tissus cérébraux post-mortem (quatrième manuscrit). Dans le deuxième manuscrit, nous démontrons grâce à l’emploi de trois cohortes de patients distinctes, soit la population canadienne française du Québec et les deux populations nord américaines « Alzheimer’s Disease Cooperative Study (ADCS) » et « Alzheimer’s Disease Neuroimaging Initiative (ADNI) », que le génotype AA au locus rs3846662 confère à ces porteurs une protection considérable contre la MA. Les femmes porteuses de ce génotype voient leur risque de MA diminuer de près de 50% et l’âge d’apparition de leurs premiers symptômes retarder de 3.6 ans. Les porteurs de l’allèle à risque APOE4 voient pour leur part leurs niveaux de plaques séniles et dégénérescences neurofibrillaires diminuer significativement en présence du génotype AA. Enfin, les individus atteints de déficit cognitif léger et porteurs à la fois de l’allèle APOE4 et du génotype protecteur AA voient leur risque de convertir vers la MA chuter de 76 à 27%. Dans le troisième manuscrit, nous constatons que les individus atteints d’HF et porteurs du génotype AA ont, contrairement au modèle établi chez les gens normaux, des niveaux plus élevés de cholestérol total et de LDL-C avant traitement comparativement aux porteurs de l’allèle G. Le fait que cette association n’est observée que chez les non porteurs de l’APOE4 et que les femmes porteuses du génotype AA présentent à la fois une augmentation des niveaux d’ARNm totaux et une résistance aux traitements par statines, nous indique que ce génotype influencerait non seulement l’épissage alternatif, mais également la transcription de l’HMGCR. Comme une revue exhaustive de la littérature ne révèle aucune étude abondant dans ce sens, nos résultats suggèrent l’existence de joueurs encore inconnus qui viennent influencer la relation entre le génotype AA, l’épissage alternatif et les niveaux d’ARNm de l’HMGCR. Dans le quatrième manuscrit, l’absence d’associations entre le génotype AA et les niveaux d’ARNm Δ13 ou de protéines HMGCR nous suggère fortement que ce polymorphisme est non fonctionnel dans le SNC affecté par la MA. Une étude approfondie de la littérature nous a permis d’étayer cette hypothèse puisque les niveaux de HNRNPA1, la ribonucléoprotéine influencée par l’allèle au locus rs3846662, sont considérablement réduits dans la MA et le vieillissement. Il est donc proposé que les effets protecteurs contre la MA associés au génotype AA soient le résultat d’une action indirecte sur le processus physiopathologique.

Measuring cognitive impairment with large data sets /

"OM91-0512"--P. [80].

Mapping hippocampal and ventricular change in Alzheimer disease

We developed an anatomical mapping technique to detect hippocampal and ventricular changes in Alzheimer disease (AD). The resulting maps are sensitive to longitudinal changes in brain structure as the disease progresses. An anatomical surface modeling approach was combined with surface-based statistics to visualize the region and rate of atrophy in serial MRI scans and isolate where these changes link with cognitive decline. Fifty-two high-resolution MRI scans were acquired from 12 AD patients (age: 68.4 +/- 1.9 years) and 14 matched controls (age: 71.4 +/- 0.9 years), each scanned twice (2.1 +/- 0.4 years apart). 3D parametric mesh models of the hippocampus and temporal horns were created in sequential scans and averaged across subjects to identify systematic patterns of atrophy. As an index of radial atrophy, 3D distance fields were generated relating each anatomical surface point to a medial curve threading down the medial axis of each structure. Hippocampal atrophic rates and ventricular expansion were assessed statistically using surface-based permutation testing and were faster in AD than in controls. Using color-coded maps and video sequences, these changes were visualized as they progressed anatomically over time. Additional maps localized regions where atrophic changes linked with cognitive decline. Temporal horn expansion maps were more sensitive to AD progression than maps of hippocampal atrophy, but both maps correlated with clinical deterioration. These quantitative, dynamic visualizations of hippocampal atrophy and ventricular expansion rates in aging and AD may provide a promising measure to track AD progression in drug trials. (C) 2004 Elsevier Inc. All rights reserved.