Genetic factors account for about half of Alzheimers Disease (AD) risk and only about a quarter of that heritability is accounted for by known variants. Family based approaches to understanding AD genetics may be an effective way to identify additional risk factors. Here we report the results of whole exome sequencing (WES) and analyses done on pairs of AD affected cousins from 19 families from the Utah Population Database (UPDB) with a statistical excess of AD risk. WES variants passing quality control were additionally filtered by population frequency (minor allele <<> 0.01) and concordance between cousin pairs, resulting in 564 variants shared by at least one pair of cousins. For each of these variants we conducted in depth annotations using Ingenuity Variant Analysis (IVA), Wellderly Data Allele Frequencies, and literature searches. To further aid in variant prioritization we analyzed each variant for association with Age at Onset of AD, AD Risk, CSF AB42, CSF Tau, CSF PTau and Rate of Disease Decline in data from the Alzheimers Disease Genetics Consortium (ADGC) and from the Knight Alzheimers disease research center. Statistical analyses were conducted using PLINK. Twelve variants (rs201665195, rs28933981, rs148294193, rs147599881, rs61729902, rs140129800, rs191804178, rs200290640, rs199752248, rs45541434, rs141402160 and rs140914494) in eight genes (ABCA7, TTR, PELI3, FCHO1, SNAP91, COX6A2, MUC16, PIDD1, SYT5 and NOTCH3) were prioritized using a clear pipeline of IVA filters and the additional analysis information. We propose that these genes and variants are the most interesting for follow-up based on current knowledge.This family-based approach to finding rare AD variants adds to a growing body of research suggesting a role for NOTCH3 in late-onset AD. This approach replicated two known AD risk variants and also implicated novel putative risk AD variants and genes. These results suggest that further application of this method of using pairs of cousins may result in additional insights into AD genetics and the ability to find novel rare, causal AD variants.

Le syndrome CANVAS (Cerebellar Ataxia with Neuropathy and Vestibular Areflexia Syndrome) est une ataxie cérébelleuse rare qui apparaît à l'âge adulte, et se caractérise par des déséquilibres et une neuropathie sensorielle. Des expansions répétées introniques bialléliques dans l’intron 2 du gène RFC1 ont été identifiées comme cause du CANVAS. Le gène RFC1 code pour la plus grande sous-unité du Facteur de Réplication C, important à la réplication et la réparation de l'ADN. Alors que onze répétitions pentanucléotidiques (AAAAG)11 sont normalement retrouvées, les expansions pathogènes comprennent généralement des centaines de répétitions (AAGGG)exp. Toutefois, les mécanismes selon lesquels ces expansions répétées provoquent ce trouble neurologique sont inconnus. Des articles récents ont identifié des mutations de décalage de cadre dans RFC1, suggérant la perte de fonction comme mécanisme pathogénique. De manière intéressante, nous avons montré que rfc1 est exprimé dans le cervelet en développement chez la souris et le poisson-zèbre, ce qui indique qu'il pourrait jouer un rôle crucial dans son développement et son activité. Étant donné que l'inactivation de RFC1 chez les mammifères entraîne une létalité embryonnaire, nous avons généré un modèle de poissons-zèbres avec une perte de fonction rfc1-KO en utilisant la méthode CRISPR/Cas9. Nous avons constaté que les larves rfc1-/- survivent jusqu'à 10 jours après la fécondation (dpf) et présentent un phénotype morphologique sévère à partir de 2 dpf. Plus important encore, nous avons montré que le développement du cervelet est sévèrement affecté avec une diminution de la prolifération associée à une augmentation de l’apoptose dans le cervelet des mutants rfc1-/-, conduisant à une désorganisation des cellules de Purkinje et une perte des cellules granulaires. Grâce au séquençage de l'ARNm à cellule unique (single cell RNA sequencing, scRNAseq), nous avons démontré l'importance de rfc1 pour la neurogenèse cérébelleuse et que sa perte de fonction conduit à de graves défauts de progéniteurs. Ce travail est le premier à générer un modèle de poissons-zèbres rfc1-KO et à montrer que RFC1 est important pour le développement du cervelet, suggérant que CANVAS pourrait être causé par un mécanisme de perte de fonction de RFC1. / The Cerebellar Ataxia with Neuropathy and Vestibular Areflexia Syndrome (CANVAS) is a rare adult-onset ataxia with a prevalence of less than 1 in a million, characterized mainly by imbalance and sensory neuropathy. Although CANVAS remained only clinically defined, recent findings identified a biallelic intronic repeat expansion (AAGGG)exp in the RFC1 gene as a major cause of CANVAS. RFC1 encodes the largest subunit of the Replication Factor C required for DNA replication and repair. Whereas the reference allele contains eleven pentanucleotide (AAAAG)11 repeats, the pathogenic expansion usually comprises hundreds of AAGGG repeats. However, the mechanisms by which this repeat expansion in the second intron of the RFC1 gene is causing this neurological disorder are unknown. Recent papers also identified frameshift mutations in RFC1, suggesting that a loss of function could drive pathogenicity. Interestingly, we showed that rfc1 is expressed in the mice and zebrafish developing cerebellum, indicating that it might play a crucial role in its development and activity. Since knocking-out (KO) RFC1 in mammals leads to embryonic lethality, we generated a zebrafish loss-of-function model of rfc1 using CRISPR/Cas9 mutagenesis. We found that rfc1-/- larvae survive until 10 days post-fertilization (dpf), thus leaving us a convenient time to study neurodevelopment without rfc1. We showed that rfc1-/- embryos depict a severe morphological phenotype from 2 dpf onwards. More importantly, we showed that the development of the cerebellum is severely affected, with decreased proliferation associated with increased apoptosis in the cerebellum of rfc1-/- mutants, as well as disorganization of Purkinje cells and a severe reduction in the number of granule cells at 5 dpf. Using scRNAseq, we have demonstrated the importance of rfc1 for cerebellar neurogenesis and that its loss of function leads to severe progenitor defects. This work is the first to generate a KO-rfc1 zebrafish model. Altogether, our work is the first to show that RFC1 is important for the development of the cerebellum and suggests that RFC1's loss of function mechanisms partially causes CANVAS.

La thèse a pour objectifs d'identifier les besoins et les difficultés des conjoints aidants de personnesprésentant une maladie d'Alzheimer. Elle vise également à mettre en évidence les points communs etles spécificités de la situation d’aide en fonction de l’âge d’apparition de la maladie. L’axe 1 porte sur l’analyse du vécu de couples dont l'un des partenaires présente une démence précoce. Les résultats mettent en évidence une évolution dans le rapport au savoir des aidants et des personnes malades. Ils passent d'un besoin de comprendre les changements occasionnés par l’arrivée de la maladie à une mise à distance après l'annonce du diagnostic. De plus, avec l'avancée des troubles, les aidants éprouvent des difficultés à ajuster leur niveau d’aide, ce qui est source de conflits entre les deux partenaires. Les deux études de l'axe 2 ont pour objectif d’établir une comparaison entre les aidants de personnes malades jeunes et de personnes malades âgées à la fois sur leurs besoins et sur leurs modes d’ajustement. La majorité des besoins et des stratégies est commune à tous les aidants. Néanmoins, les aidants de personnes malades jeunes expriment plus de besoins en termes de maintien de contact, d'adaptation des structures de soins et d'accompagnement dans les démarches administratives. Les aidants de personnes malades âgées utilisent plus l'humour, l'aménagement et la mise à distance de l'entourage comme stratégies d'ajustement. L’axe 3 vise à investiguer l'influence des caractéristiques de la situation d'aide sur la détresse du conjoint aidant à l’aide d’une modélisation structurale. Les paramètres de ce modèle général ont été comparés en fonction de l'âge de début de la maladie et du genre de l'aidant. Cette étude met en évidence 4 facteurs influençant le sentiment de détresse des conjoints aidants : le sentiment d'être préparé, la qualité du support familial, l’évaluation de sa santé et la qualité d’ajustement du couple. Ce dernier facteur est plus important pour les conjoints aidants de personnes malades jeunes. L’analyse de ces résultats permet de spécifier le contenu de programmes d’accompagnement en faveur de modules communs à tous les aidants et de modules spécifiques en fonction de l'âge d'apparition de la maladie. / This thesis aims to identify needs and difficulties of the spouse caregivers of persons with dementia. We also investigate similarities and specificities related to the caregiving situation regarding the age atonset of the disease.The first axis examines the experience of couples in which one member received a diagnosis of earlyon setdementia. The results show an evolution in the relation to knowledge of the caregivers and the persons with dementia. They oscillate between the need to understand the changes caused by the disease and a distancing after the diagnosis. Moreover, with the progression of the disease, the caregivers are not able to adapt their level of assistance, which increases tensions between the two partners. The two studies of the second axis aim to compare needs and coping strategies of spouse caregivers of persons with early and late onset dementia. The majority of needs and strategies are the same for all spouse caregivers. However, the spouse caregivers of persons with early-onset dementia express the greatest number of needs related to maintaining contacts, more need of adapted care structures and more need to be assisted in administrative procedures. The spouse caregivers of persons with late-onset dementia use more humor, re-arranging, and getting away from the entourage. The third axis investigates the influence of the characteristics of the caregiving context on spousal caregiver distress with a structural modelisation. The sittings of this general model were compared regarding the age at onset of the disease and the gender of caregiver. This study demonstrated that 4 factors contribute to spousal caregiver distress: preparedness, family support, self-rated health and the quality of the couple relationship. Dyadic determinants were more important for caregivers of PEOD. The analysis of these results permits to specify the content of support for a common core and specific modules depending on the age at onset of the disease.

Submitted by Vanessa Rocha Ribeiro null (va_rocharibeiro@aluno.ibb.unesp.br) on 2017-03-08T15:02:28Z No. of bitstreams: 1 Dissertação Vanessa Rocha Ribeiro.pdf: 3324263 bytes, checksum: c662d084e05ff3055723d93ba4f2eee2 (MD5) / Approved for entry into archive by LUIZA DE MENEZES ROMANETTO (luizamenezes@reitoria.unesp.br) on 2017-03-13T14:49:32Z (GMT) No. of bitstreams: 1 ribeiro_vr_me_bot.pdf: 3324263 bytes, checksum: c662d084e05ff3055723d93ba4f2eee2 (MD5) / Made available in DSpace on 2017-03-13T14:49:32Z (GMT). No. of bitstreams: 1 ribeiro_vr_me_bot.pdf: 3324263 bytes, checksum: c662d084e05ff3055723d93ba4f2eee2 (MD5) Previous issue date: 2017-02-22 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Introdução: A pré-eclâmpsia (PE) é uma patologia obstétrica e uma das principais causas de morbimortalidade materna e fetal. Na PE ocorre um estado de má adaptação da tolerância imunológica, caracterizada por ativação anormal do sistema imune inato e adaptativo. As células T reguladoras (Treg) representam uma população de linfócitos T responsáveis pela manutenção da tolerância e controle da inflamação, enquanto células Th17 medeiam diferentes tipos de reações inflamatórias. Portanto, o balanço entre células Treg e Th17 pode ser crítico para a tolerância ao feto e prevenção da PE. Objetivo: Avaliar as subpopulações de células T CD4+ (Th1, Th2, Th17 e Treg) e o perfil de citocinas produzido por essas células, em gestantes portadoras de pré-eclâmpsia, classificadas em PE precoce e PE tardia. Métodos: Foram estudadas 60 gestantes, sendo 20 normotensas e 40 portadoras de PE, pareadas pela idade gestacional. As gestantes com PE foram classificadas de acordo com o aparecimento das manifestações clínicas em PE precoce (< 34 semanas de gestação; n=20) e PE tardia (≥ 34 semanas de gestação; n=20). Células mononucleares do sangue periférico (PBMCs), obtidas das gestantes foram avaliadas quanto à produção de citocinas pró e anti-inflamatórias e à expressão de fatores de transcrição envolvidos na caracterização das subpopulações de células T CD4+. A expressão dos fatores de transcrição intracitoplasmáticos de células Th1 (T-bet), Th2 (GATA-3), Th17 (RORc) e Treg (FoxP3) foi avaliada por citometria de fluxo e a expressão gênica desses fatores de transcrição foi determinada por PCR em tempo real com transcrição reversa (RT-qPCR), logo após a colheita de sangue para avaliação da expressão endógena dessas diferentes subpopulações de células T. A determinação das citocinas de perfil Th1 (IFN-γ e TNF-α), Th2 (IL-4), Th17 (IL-6, IL-17 e IL-22) e Treg (IL-10 e TGF-β1) foi realizada no plasma das gestantes pela técnica de ELISA. Os resultados foram analisados por meio de testes paramétricos ou não paramétricos com nível de significância de 5%. Resultados: Os perfis inflamatórios Th1 e Th17 foram identificados por aumento significativo da média de intensidade de fluorescência (MIF) e da percentagem de células expressando os fatores de transcrição específicos nas gestantes portadoras de PE precoce e PE tardia em relação aos grupos de gestantes normotensas com idade gestacional correspondente. A percentagem de células Th17 foi significativamente maior nas gestantes com PE precoce do que nas com PE tardia. Por outro lado, a análise dos perfis anti-inflamatórios Th2 e Treg mostrou que a percentagem de células expressando GATA-3 e FoxP3 foi significativamente menor nos grupos de PE precoce e PE tardia comparados aos grupos de normotensas, enquanto a comparação entre gestantes pré-eclâmpticas mostrou percentagem de células Treg significativamente menor nas gestantes portadoras de PE precoce. A expressão gênica do fator de transcrição T-bet por PBMCs não mostrou diferenças significativas entre os grupos de gestantes pré-eclâmpticas e de normotensas. Aumento significativo da expressão gênica do fator de transcrição RORc e diminuição da expressão dos genes GATA-3 e FoxP3 foram observados nos grupos de gestantes pré-eclâmpticas em relação aos grupos de normotensas de idade gestacional correspondente. Entre as gestantes pré-eclâmpticas, encontrou-se menor nível transcricional do fator de transcrição GATA-3 na PE precoce. Os níveis plasmáticos das citocinas IFN-γ, IL-6, IL-17 e TNF-α foram significativamente maiores nas gestantes portadoras de PE, enquanto as concentrações de IL-10 e TGF-β1 foram significativamente menores em comparação aos grupos de gestantes normotensas correspondentes. Observaram-se ainda, maiores níveis de IL-6, IL-17, TGF-β1 e TNF-α na PE precoce do que na PE tardia. A expressão proteica de IL-4 (perfil Th2) e IL-22 (perfil Th17), não apresentou diferença significativa entre os grupos estudados. Conclusão: Os resultados demonstram que o balanço entre células Treg e Th17 é deficiente na PE, havendo polarização para perfil Th17 na PE precoce. Esse desbalanço pode ser atribuído ao predomínio de citocinas pró-inflamatórias sobre as anti-inflamatórias, presentes na circulação de gestantes portadoras de pré-eclâmpsia. / Introduction: Preeclampsia (PE) is an obstetric pathology and one of the main causes of maternal and fetal morbidity and mortality. In PE there is a state of maladaptation of immunological tolerance, characterized by abnormal activation of the innate and adaptive immune system. Regulatory T cells (Treg) represent a population of T lymphocytes responsible for tolerance maintenance and inflammation control, whereas Th17 cells mediate different types of inflammatory reactions. Therefore, the balance between Treg and Th17 cells may be critical for fetal tolerance and PE prevention. Objective: To evaluate the subpopulations of CD4+ T cells (Th1, Th2, Th17 and Treg) and the cytokine profile produced by these cells in pregnant women with PE, classified in early-onset PE and late-onset PE. Methods: Sixty pregnant women, 20 normotensive and 40 preeclamptic women, matched by gestational age, were studied. Pregnant women with PE were classified according to clinical manifestations in early-onset PE (<34 weeks gestation; n = 20) and late-onset PE (≥ 34 weeks gestation; n = 20). Peripheral blood mononuclear cells (PBMCs) obtained from pregnant women were evaluated for the production of pro and anti-inflammatory cytokines and expression of transcription factors involved in the characterization of CD4+ T cell subpopulations. Expression of the intracytoplasmic transcription factors of Th1 (T-bet), Th2 (GATA-3), Th17 (RORc) and Treg (FoxP3) cells was assessed by flow cytometry and the gene expression of these transcription factors was determined by reverse-transcription quantitative polymerase chain reaction (RT-qPCR) shortly after blood collection to evaluate the endogenous expression of these different T-cell subpopulations. The cytokine profile of Th1 cells (IFN-γ and TNF-α), Th2 (IL -4), Th17 (IL-6, IL-17 and IL-22) and Treg (IL-10 and TGF-β1) were measured in the plasma of the pregnant women by the ELISA. The results were analyzed using parametric or non-parametric tests with a significance level of 5%. Results: Th1 and Th17 inflammatory profiles were identified by a significant increase in mean fluorescence intensity (FMI) and by the percentage of cells expressing specific transcription factors in pregnant women with early-onset PE and late-onset PE in relation to the normotensive groups with corresponding gestational age. The percentage of Th17 cells was significantly higher in early-onset PE than in late-onset PE group. On the other hand, analysis of Th2 and Treg anti-inflammatory profiles showed percentages of cells expressing GATA-3 and FoxP3 significantly lower in the early- and late-onset PE groups compared to the normotensive groups, whereas the comparison between preeclamptic groups showed significantly lower percentage of Treg cells in pregnant women with early-onset PE. The gene expression of the T-bet transcription factor by PBMCs did not show significant differences between the preeclamptic and normotensive pregnant groups. Significant increase in the gene expression of RORc and decrease in the expression of the GATA-3 and FoxP3 genes were observed in both groups of preeclamptic women compared with the normotensive ones of corresponding gestational age. Among the preeclamptic pregnant women lower transcriptional level of GATA-3 transcription factor was detected in early-onset PE. Plasma levels of the cytokines IFN-γ, IL-6, IL-17 and TNF-α were significantly higher in pregnant women with PE, whereas IL-10 and TGF-β1 concentrations were significantly lower than in the normotensive corresponding groups. It was also observed higher levels of IL-6, IL-17, TGF-β1 and TNF-α in early-onset than in late-onset PE group. Protein expression of IL-4 (Th2 profile) and IL-22 (Th17 profile), did not show significant differences between the groups studied. Conclusion: The results show that the balance between Treg and Th17 cells is deficient in PE, with polarization to the Th17 profile in early-onset PE. This imbalance can be attributed to the predominance of pro-inflammatory cytokines over the anti-inflammatory ones present in the circulation of pregnant women with preeclampsia. / FAPESP: 2014/25124-7 / FAPESP: 2012/24697-8

No description available.

Orientador: Maria Terezinha Serrão Peraçoli / Resumo: Introdução: A pré-eclâmpsia (PE) é uma patologia obstétrica e uma das principais causas de morbimortalidade materna e fetal. Na PE ocorre um estado de má adaptação da tolerância imunológica, caracterizada por ativação anormal do sistema imune inato e adaptativo. As células T reguladoras (Treg) representam uma população de linfócitos T responsáveis pela manutenção da tolerância e controle da inflamação, enquanto células Th17 medeiam diferentes tipos de reações inflamatórias. Portanto, o balanço entre células Treg e Th17 pode ser crítico para a tolerância ao feto e prevenção da PE. Objetivo: Avaliar as subpopulações de células T CD4+ (Th1, Th2, Th17 e Treg) e o perfil de citocinas produzido por essas células, em gestantes portadoras de pré-eclâmpsia, classificadas em PE precoce e PE tardia. Métodos: Foram estudadas 60 gestantes, sendo 20 normotensas e 40 portadoras de PE, pareadas pela idade gestacional. As gestantes com PE foram classificadas de acordo com o aparecimento das manifestações clínicas em PE precoce (< 34 semanas de gestação; n=20) e PE tardia (≥ 34 semanas de gestação; n=20). Células mononucleares do sangue periférico (PBMCs), obtidas das gestantes foram avaliadas quanto à produção de citocinas pró e anti-inflamatórias e à expressão de fatores de transcrição envolvidos na caracterização das subpopulações de células T CD4+. A expressão dos fatores de transcrição intracitoplasmáticos de células Th1 (T-bet), Th2 (GATA-3), Th17 (RORc) e Treg (FoxP3) foi avaliada por c... (Resumo completo, clicar acesso eletrônico abaixo) / Mestre

Background: Neonatal sepsis is one of the most important causes of elevated morbidity and mortality rates in neonatal intensive care units worldwide. While the clinical manifestations of neonatal sepsis tend to be nonspecific, its rapid development and life-threatening potential call for reliable markers for early detection. Methods: We conducted a retrospective single-center study including all neonates suspected of having developed neonatal sepsis from 2013 to 2016. Perinatal and clinical characteristics as well as microbiological and laboratory findings were evaluated. Neonatal sepsis was defined as either culture-proven sepsis (positive blood culture) or clinical sepsis (at least one symptom and elevated C-reactive protein (CRP) concentrations within 72 h with negative blood culture). We further differentiated between early-onset (EOS) and late-onset (LOS) sepsis. Results: Microbiological colonization screening by throat and rectal swabs frequently did not detect the organism that subsequently caused the sepsis. Depending on the age of the newborn with sepsis (EOS or LOS), associations between different anamnestic and clinical factors (prenatal or postnatal ones) were found. In particular, the central–peripheral temperature difference showed a strong association with LOS. Laboratory results useful for the early detection of neonatal sepsis included interleukin-6 (IL-6) and CRP concentrations. Conclusions: Elevated IL-6 >100 ng/L was a strong marker for neonatal sepsis. When choosing the antibiotics for treatment, data from microbiological colonization screening should be considered but not solely relied on. Some indicators of infection also depended on postnatal age.

Diagnosis of Alzheimer’s disease is encouraged as a first step towards people planning for their future with the condition. Despite the proposed benefits of diagnosis, it is also widely recognised that Alzheimer’s disease can expose people to stigma. Therefore, this thesis explores the relationship between stigma and future outlook, from the perspective of people affected by early and late-onset Alzheimer’s disease. In order to recognise the physicality of the condition and how psychological and social factors influence experiences, a biopsychosocial perspective is employed throughout. People with Alzheimer’s disease (n=15 people with late-onset, 7 people with early-onset) and their supporters (n=22) completed questionnaires about perceived stigma. This was followed by 14 interviews with a subsample of participants, which explored stigma and future outlook in more depth. Perceived stigma reporting across participants was low in the questionnaires; whereas interviews revealed higher levels of stigma with people discussing mixed, unpredictable reactions from a range of sources. Participants expressed awareness of the unpredictable nature of their futures with the condition. The subsequent lack of control was managed through focusing on ‘one day at a time’ and avoiding looking too far ahead. Across reflections on stigma and future outlook there was a deliberate focus on positive experiences for people affected by early and late-onset Alzheimer’s disease. The similar management of experiences across participants minimised possible age-based differences. These findings are supported by socioemotional selectivity theory, which suggests people are motivated to maintain positive emotional states when facing ‘time-limiting’ conditions irrespective of age. The research suggests people’s experiences of stigma and future outlook interact, with stigma-driven assumptions about the future affecting how people manage their daily lives. The avoidance of looking ahead suggests that policy which encourages future planning should consider its utility and explore ways of helping people to manage both exposure to stigma, and planning for the future, whilst focusing on daily living.

No description available.

Les fonctions cognitives reposent sur la communication dynamique de régions cérébrales interconnectées. Dans la maladie d’Alzheimer (MA), les travaux antérieurs suggèrent que le processus neuropathologique cible de façon précoce un ou plusieurs systèmes anatomo-fonctionnels spécifiques. La dysfonction du réseau par défaut a été objectivée de façon consistante. Cependant, ses relations avec les symptômes cliniques et avec l’atteinte des régions du lobe temporal interne qui lui sont fonctionnellement connectées restent à clarifier. L’IRM fonctionnelle de repos est une technique pertinente pour caractériser in vivo chez l’Homme la connectivité cérébrale.Par une approche des systèmes neuraux, ce travail de thèse a pour objectif de caractériser la réorganisation fonctionnelle neuronale dans la MA, ses corrélats cliniques, ainsi que l’influence de l’âge de début des symptômes. Par le recueil et l’analyse des données neuropsychologiques, en IRMf de repos et en IRM structurale, acquises chez des sujets avec des troubles de la mémoire et avec une forme mnésique légère de MA, notre travail apporte des éclairages : i) sur l’implication du réseau temporal antérieur dans la mémoire déclarative décontextualisée et ses modifications dans le cours de la MA ; ii) sur les similitudes et spécificités des systèmes anatomo-fonctionnels ciblés dans les deux formes cliniques distinctes - à début précoce et tardif - de la MA ; iii) sur la réorganisation de l’organisation topologique cérébrale dans son ensemble de ces deux formes de la maladie. / Cognitive functions rely on the dynamic interplay of connected brain regions. Previous studies suggest that in Alzheimer disease (AD), early pathological changes target one or several specific anatomo-functional networks. Dysfunction of the default mode network is a consistent finding. However, its relationship with clinical symptoms and interconnected medial temporal regions remains to be clarified. Resting state functional MRI (fMRI) is an emerging method aimed at characterizing in vivo brain connectivity in the Human.Using a neural system approach, the aim of this thesis was to characterize neuronal functional reorganization in AD, its clinical correlates, and to determine the influence of age at onset. Neuropsychological data, structural and fMRI were obtained in subjects with early memory impairment and mild “amnestic” AD. This work provides new insights into : i) the functional role of the anterior temporal network in context-free declarative memory and its changes throughout the course of AD; ii) the common and specific features in targeted anatomo-functional networks between early and late onset AD ; iii) the reorganization of whole brain topological properties in the two forms of the disease.