Numerous epidemiological and experimental studies have shown that patients suffering from metabolic disorders such as type 2 diabetes mellitus (TDM2), insulin resistance or obesity are at a higher risk of cognitive functions impairment and developing Alzheimer's disease (AD). Impairment of insulin signalling in the brain could contribute to two pathological changes which leads to AD development that include insoluble senile plaques and neurofibrillary tangles, containing an abnormally hyperphosphorylated tau protein (Tau). This work is focused on investigating of insulin signaling in hippocampi in the brains of mice models of insulin resistence, impact of disturbed insulin signaling on hyperphosphorylation of Tau, and possible benefical efect of insulin sensitizing agents on insulin signaling and Tau phosphorylation in the hippocampi of diabetic mice. The first, we examined insulin signaling and phosphorylation of Tau in hippocampi in two mouse models of TDM2 - lipodystrofic A-ZIP F-1 mice and monosodium glutamate obese mice (MSG mice). We did not observe any changes in insulin signaling and Tau phosphorylation in hippocampi of A-ZIP F-1 mice compared to controls. In the hippocampi of MSG mice there was attenuated phosphorylation of kinases of insulin signalling including Ser9 of glycogen synthase...

5 ABSTRACT This thesis is focused on examining quality and range of care services for people with dementia and their family carers in the region of Ústí. Through the testimony of nine respondents provides a view of social awareness about this diagnosis. It also focuses on providing information of possibilities of prevention, medical treatment and social care that is currently available. Last but not least it deals with possibilities of development of the services within this area. Key words: Alzheimer disease, dementia, social services, healtcare services, family care.

Diese Arbeit verbindet zwei Publikationen, die sich mit beeinträchtigter Krankheitseinsicht (Anosognosie) bei Patienten mit Alzheimer-Demenz (AD) befassen, sowie mit den Erfassungsmethoden und der Frage, ob Anosognosie bestimmte Bereiche besonders betrifft. Die erste Veröffentlichung stellt die Ergebnisse einer systematischen Literaturübersicht zum Forschungsstand zu Anosognosie bei AD und zu den verschiedenen Erfassungsmethoden für die Krankheitseinsicht von AD-Patienten dar. In der zweiten Publikation sind die Ergebnisse einer empirischen Studie zur Anosognosie bei Patienten mit leichter AD veröffentlicht. Die Ergebnisse dieser Studie weisen zum einen darauf hin, dass die drei Erfassungsmethoden für Anosognosie (klinisches Urteil, Diskrepanz zwischen Selbst- und Fremdeinschätzung, Diskrepanz zwischen Selbsteinschätzung und Testleistung) teils unterschiedliche Facetten der Selbsteinschätzung abbilden. Zum anderen deuten die Befunde darauf hin, dass Unterschiede zwischen den Diskrepanzen zwischen Selbst- und Fremdeinschätzung in verschiedenen Symptombereichen maßgeblich auf unterschiedliche Grade der Beeinträchtigung zurückzuführen sind und nicht Ausdruck einer domänenspezifischen Ausprägung der Einsichtsfähigkeit bei AD-Patienten sind. Diese Studienergebnisse werden in der vorliegenden Arbeit im Zusammenhang mit Erklärungsansätzen für Anosognosie bei AD diskutiert.

Cellular mechanisms involved in neurodegeneration and neuroprotection are continuing to be explored, and this paper focuses on some novel discoveries that give further insight into these processes. Oligodendrocytes and activated astroglia are likely generators of the pro-inflammatory cytokines, such as the tumor necrosis factor family and interleukin family, and these glial support cells express adhesion receptors (e.g., VCAM) and release intercellular adhesion molecules (ICAM) that have a major role in neuronal apoptosis. Even brief exposure to some substances, in ontogeny and sometimes in adulthood, can have lasting effects on behaviors because of their prominent toxicity (e.g., NMDA receptor antagonists) or because they sensitize receptors (e.g., dopamine D2 agonists), possibly permanently, and thereby alter behavior for the lifespan. Cell cycle genes which may be derived from microglia, are the most-recent entry into the neuroprotection schema. Neuroprotection afforded by some common substances (e.g., melatonin) and uncommon substances [e.g., nicotine, green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG), trolox], ordinarily thought to be simple radical scavengers, now are thought to invoke previously unsuspected cellular mechanisms in the process of neuroprotection. Although Alzheimer's disease (AD) has features of a continuous spectrum of neural and functional decline, in vivo PET imaging and and functional magnetic resonance imaging, indicate that AD can be staged into an early phase treatable by inhibitors of β and γ secretase; and a late phase which may be more amenable to treatment by drugs that prevent or reverse tau phosphorylation. Neural transplantation, thought to be the last hope for neurally injured patients (e.g., Parkinsonians), may be displaced by non-neural tissue transplants (e.g., human umbilical cord blood; Sertoli cells) which seem to provide similar neurotrophic support and improved behavior-without posing the major ethical dilemma of removing tissue from aborted fetuses. The objective of this paper is to invite added research into the newly discovered (or postulated) novel mechanisms; and to stimulate discovery of additional mechanisms attending neurodegeneration and neuroprotection.

La maladie d’Alzheimer (MA) est actuellement conceptualisée comme un continuum : la démence représentant la conséquence clinique d’une longue période où s’accumule des éléments pathologiques dans le cerveau d’individus indemnes de symptômes comportementaux. Les futures thérapies devront idéalement débuter avant l’apparition des symptômes mais le manque actuel d’outils reproduisant avec pertinence cette phase préclinique empêche leurs développements. Dans ce travail de thèse, nous avons d’abord levé ce verrou technologique. Un nouveau modèle a été créé dans lequel la production de peptides Aβs solubles en quantité faible, mais néanmoins suffisante pour induire une hyper-phosphorylation des protéines Tau, perturbe la fonction cognitive bien avant l’apparition d’éléments caractéristiques de la MA (plaques amyloïdes, dégénérescences neurofibrillaires, inflammation). Cette avancée technologique, nous a ensuite permis d’évaluer l’implication de la protéine kinase DYRK1A et le potentiel thérapeutique de molécules modulant ses fonctions dans l’ensemble de la pathologie Alzheimer. Nos résultats démontrent que l’inhibition de son activité kinase réduit l’hyper-phosphorylation des protéines Tau et améliore la fonction mnésique chez notre animal modélisant la phase préclinique de la MA. A contrario, nous démontrons que DYRK1A est sensible à un clivage protéolytique dans le cerveau de patients atteints de démence Alzheimer et acquiert de nouvelles fonctions biologiques. Dans ce contexte, la prévention de ce clivage réduit l’inflammation et restaure les déficits cognitifs chez la souris modélisant la phase clinique de la MA. En ciblant différentes phases de la MA, ces données ouvrent donc la voie à la médecine personnalisée et à des stratégies de traitement plus ciblées. / Current view conceptualizes Alzheimer’s disease (AD) as a continuum, with dementia representing the clinical outcome of a long period of cumulative pathological events in the brain of individual with free cognitive symptoms. New therapies for AD should ideally be started before the onset of symptoms but the lack of suitable tools mimicking preclinical stage of AD limits their future evaluations. In this work, we break this technological limitation. A new animal model have been developed in which a small amount of soluble Aβs forms able to induce hyper-phosphorylation of Tau is sufficient to disturb cognitive function long before classical lesions occur (amyloid plaques, neurofibrillary tangles and inflammation). This technological breakthrough allows us to evaluate involvement of the protein kinase DYRK1A and therapeutic potential of molecules modifying its functions in different stages of AD. Our results demonstrate that inhibition of its kinase activity reduces hyper-phosphorylation of Tau proteins and alleviates memory function in our preclinical AD-like animal model. In contrast, we provide evidences that DYRK1A undergoes a cleavage in brain of patient with clinical AD and gains new biological functions. Prevention of this proteolysis reduces inflammation and restores cognitive impairments in a clinical AD-like mice model. By targeting distinct phases of the disease, these data open avenue for personalized medicine and more-targeted treatment strategies.

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Yes / To determine whether or not jugular venous reflux (JVR) is associated with structural brain parenchyma changes in individuals with mild cognitive impairment (MCI) and Alzheimer's disease (AD). 16 AD patients (mean (SD): 81.9 (5.8) years), 33 MCI patients (mean (SD): 81.4 (6.1) years) and 18 healthy elderly controls (mean (SD): 81.5 (3.4) years) underwent duplex ultrasonography and magnetic resonance imaging scans to quantify structural brain parenchyma changes. Normalized whole brain (WB), gray matter (GM) and white matter (WM) volumes were collected, together with CSF volume. JVR was strongly associated with increased normalized WB (p = 0.014) and GM (p = 0.002) volumes across all three subject groups. There was a trend towards increased WB and GM volumes, which was accompanied by decreased CSF volume, in the JVR-positive subjects in both the MCI and AD groups. When the MCI and AD subjects were aggregated together significant increases were observed in both normalized WB (p = 0.009) and GM (p = 0.003) volumes for the JVR-positive group. No corresponding increases were observed for the JVR-positive subjects in the control group. Through receiver operating characteristic analysis of the brain volumetric data it was possible to discriminate between the JVR-positive and negative AD subjects with reasonable accuracy (sensitivity = 71.4%; specificity = 88.9%; p = 0.007). JVR is associated with intracranial structural changes in MCI and AD patients, which result in increased WB and GM volumes. The neuropathology of this unexpected and counterintuitive finding requires further investigation, but may suggest that JVR retrogradely transmits venous hypertension into the brain and leads to brain tissues swelling due to vasogenic edema.

Introduction: Many studies have found an association between Toxoplasma gondii seropositivity and behavioral and cognitive changes in animal models and in humans. In addition, early findings have suggested an association between T. gondii seropositivity and Alzheimer's disease (AD). We sought to determine whether there is an association between T. gondii seropositivity and AD as well as cognitive functioning (including memory, working memory, processing speed, language functioning, executive functioning) in a large, well-characterized sample of subjects with AD and matched controls without dementia. Method: Using ELISA assays, we determined anti-T. gondii IgG antibody titers in 114 control subjects and in 105 subjects diagnosed with AD through an Alzheimer's Disease Research Center. We compared the seroprevalence between the two groups using propensity score matching (PSM). We also compared associations between T. gondii seropositivity and cognitive functioning using both PSM and linear regressions. Results: We found no differences between groups in age, ethnicity, or gender. Education and socioeconomic status was slightly higher in the control group. Using PSM, we did not find a significant difference in having AD due to T. gondii seropositivity between the two groups. Using PSM, we found T. gondii seropositivity was associated with worse performance on the WAIS-R Digit Symbol test. Within the AD group, we found T. gondii seropositivity was associated with worse performance on the WAIS Block Design and Trail Making B tests. Conclusion: In this sample, we found no evidence of an association between T. gondii seropositivity and AD in a larger study than previous studies. We found evidence of a negative association between processing speed and T. gondii seropositivity as well as a negative association between processing speed, executive functioning, and T. gondii seropositivity in those with AD.

No description available.