Cette thèse montre que le GHB et les neurostéroïdes protègent efficacement contre la mort neuronale induite par les facteurs étiologiques de la maladie d'Alzheimer, notamment la sur-expression de l'amyloid precursor protein et le stress oxydant. Nous avons identifié un effet additif du GHB et de l'alloprégnanolone qui pourrait résulter de la combinaison des stimulations partielles évoquées par ces molécules sur l'expression des protéines anti-apoptotiques. L'effet du GHB est bloqué par un inhibiteur de l'aromatase, suggérant que le GHB induirait la neuroprotection via la stimulation de la neurostéroïdogenèse. Pour étudier les effets du GHB et des neurostéroïdes sur l’activité des MMP-2 et MMP-9, qui dégradent les peptides amyloïdes, nous avons optimisé un test enzymatique basé sur l’expression de ces protéases dans la levure. Nos résultats préliminaires ne permettent pas encore de conclure mais leur amélioration et combinaison avec des données de RT-qPCR contribueront à déterminer l'action du GHB et des neurostéroïdes sur l'activité et/ou l'expression des MMP. Notre travail suggère que le GHB et les neurostéroïdes pourraient être associés pour élaborer des stratégies neuroprotectrices contre les pertes neuronales provoquées par la maladie d'Alzheimer. / This PhD work showed that GHB and neurosteroids efficiently protect against nerve cell death caused by Alzheimer's disease etiological factors including amyloid precursor protein overexpression and oxidative stress. Interestingly, we identified an additive action of GHB and allopregnanolone that may result from the combination of partial stimulations of anti-apoptotic protein expression induced by both compounds. GHB protective effect was blocked by aromatase inhibitor, suggesting that GHB may also induce neuroprotection via the activation of neurosteroidogenesis. Finally, we have used a yeast-based MMP activity assay to check whether GHB and neurosteroids regulate MMP-2 and MMP-9 activities which control Aβ peptide degradation. We cannot yet conclude from our preliminary results but their improvement and combination with RT-qPCR analyzes will help to determine the modulatory action of GHB and neurosteroids on MMP activity and/or expression. Together, our data suggest that GHB and neurosteroids may be used to develop combined neuroprotective strategies against neuronal loss in AD.

La maladie d’Alzheimer (MA) se caractérise par une perte mnésique progressive et au plan neuropathologique par le dépôt extracellulaire de plaques amyloïdes, résultant de l’agrégation de peptides amyloïdes (Aβ), et par l’apparition d’une dégénérescence neurofibrillaire (DNF) constituée d’agrégats intraneuronaux de protéines Tau hyper et anormalement phosphorylées. L’évolution des déficits cognitifs des patients est particulièrement corrélée à la progression spatio-temporelle de la DNF. A l’heure actuelle, il n’existe aucun traitement curatif de la maladie. Le cholestérol joue un rôle central dans la physiopathologie de la MA. En particulier, l’allèle ε4 du gène de l’apolipoprotéine E, transporteur cérébral essentiel du cholestérol, est le principal facteur de risque génétique des formes sporadiques de la MA. De nombreuses études in vitro montrent qu’une surcharge en cholestérol induit la production d’Aβ pathogènes et qu’inversement, une déplétion en cholestérol entraîne une diminution de la voie amyloïde. Le cholestérol ne peut pas passer librement la barrière hémato-encéphalique (BHE). Le cholestérol cérébral est exclusivement synthétisé in situ. Le cholestérol cérébral en excès doit être exporté dans la circulation sanguine pour être métabolisé. Pour franchir la BHE, sa conversion en 24(S)-hydroxycholestérol est nécessaire, étape contrôlée par la cholestérol 24-hydroxylase (CYP46A1). Deux précédents travaux de thèse effectués dans le laboratoire ont permis de mettre en évidence des connexions étroites entre le métabolisme du cholestérol et la MA in vivo. La surexpression intracérébrale de CYP46A1 dans un modèle murin amyloïde à l’aide d’un vecteur viral adéno-associé (AAV) a conduit à la diminution de la production d’Aβ, des plaques amyloïdes et à l’amélioration des performances mnésiques des animaux. A l’inverse, l’inhibition de l’expression de CYP46A1 dans l’hippocampe de souris sauvages induit la production d’Aβ, la phosphorylation de Tau et des défauts mnésiques chez la souris. L’objectif de mon travail de doctorat a été de déterminer s’il existait un lien direct entre CYP46A1 et la pathologie Tau et si la modulation du métabolisme du cholestérol pourrait avoir un effet bénéfique sur la pathologie Tau associée à la MA. Pour répondre à ces questions, le modèle murin THY-Tau22, qui développe une pathologie Tau de type Alzheimer, a été utilisé. Cette pathologie, essentiellement hippocampique, est évolutive et associée à des déficits mnésiques. Dans l’hippocampe des souris THY-Tau22, le cholestérol libre total n’est pas modifié, alors que l’expression protéique de CYP46A1 est diminuée, et en conséquence le contenu en 24(S)-hydroxycholestérol. L’expression protéique de CYP46A1 dans l’hippocampe est également réduite dans un autre modèle murin de pathologie Tau, le modèle THY-Tau30. Ainsi, la pathologie Tau semble être à l’origine de la diminution de l’expression protéique de CYP46A1. Afin de déterminer si la surexpression de CYP46A1 chez la souris THY-Tau22 pouvait améliorer son phénotype biochimique, neuropathologique et clinique, un vecteur AAV codant pour CYP46A1 a été injecté dans l’hippocampe de souris THY-Tau22 âgées de trois mois et demi. Deux mois et demi après injection, la surexpression de CYP46A1 chez les souris THY-Tau22 induit une restauration de la concentration hippocampique en 24(S)-hydroxycholestérol et une augmentation de l’expression des gènes impliqués dans la synthèse du cholestérol, et plus particulièrement dans la voie du mévalonate. Deux mois et demi et cinq mois et demi post-injection, la surexpression de CYP46A1 entraîne une restauration complète des performances mnésiques des animaux qui s’accompagne d’un rétablissement de la dépression à long terme, de la longueur des dendrites secondaires, de la densité synaptique et de l’expression des gènes d’activité précoce dans l’hippocampe. (...) / Alzheimer’s disease (AD) is characterized by a progressive memory loss and neuropathologically by senile plaques and neurofibrillary tangles (NFTs). Senile plaques are constituted of extracellular amyloid peptide (Aβ) deposits while NFTs result from the accumulation and the aggregation of intracellular hyperphosphorylated Tau proteins. Spatiotemporal progression of NFTs particularly correlates with cognitive impairments. To date, there is no curative treatment for this disease. Cholesterol plays a central role in AD physiopathology. Indeed, the ε4 allele of the apolipoprotein E, the brain’s principal cholesterol-carrier protein, is the main genetic risk factor for sporadic forms of AD. Numerous in vitro studies have shown that cholesterol overload induces production of pathogenic Aβ and conversely, cholesterol depletion causes a reduction of the amyloidogenic pathway. In adult, brain cholesterol is exclusively synthesized in situ. Brain cholesterol is not able to freely cross the blood brain barrier and its major exportable form is 24(S)-hydroxycholesterol generated by the cholesterol 24-hydroxylase (CYP46A1). Two previous thesis works in this laboratory highlighted narrow connections between cholesterol metabolism and AD in vivo. The intracerebral overexpression of CYP46A1 mediated by an adeno-associated viral (AAV) vector, in a murine amyloid model, led to the decrease of Aβ production, senile plaques and improvement of memory abilities. At the opposite, hippocampal CYP46A1 inhibition in wild-type (WT) mice induced Aβ production, Tau phosphorylation and memory impairments. The aim of this thesis work was to determine whether there was a direct link between CYP46A1 and Tau pathology and whether cholesterol metabolism modulation could have a beneficial effect on AD-like Tau pathology. In order to answer these questions, the THY-Tau22 mouse model, that develops AD-like Tau pathology, was used. In this model, the pathology mainly occurs in the hippocampus, it is progressive, and associated with memory deficits. In THY-Tau22 mice, total free cholesterol in the hippocampus was unchanged, whereas both CYP46A1 protein expression and 24(S)-hydroxycholesterol content were decreased. Furthermore, we also demonstrated that CYP46A1 protein expression was reduced in another murine model of Tau pathology, the THY-Tau30 model. Therefore, it may suggest that Tau pathology can be responsible for CYP46A1 decrease. We next determined whether CYP46A1 overexpression in the THY-Tau22 mouse could improve its biochemical, clinical and neuropathologic phenotype. For this purpose, an AAV vector encoding CYP46A1 was injected in the hippocampus of 3.5-month-old WT and THY-Tau22 mice. Two and a half months after injection, hippocampal CYP46A1 overexpression in THY-Tau22 mice induced restoration of hippocampal 24(S)-hydroxycholesterol content and increased expression of genes involved in cholesterol synthesis, more particularly in the mevalonate pathway. Two and a half and five and a half months post-injection, CYP46A1 overexpression resulted in a complete restoration of memory abilities and was accompanied by restoration of long-term depression, length of secondary dendrites, synaptic density and expression of immediate-early genes in hippocampus. Despite this, abnormal Tau hyperphosphorylation and gliosis, that characterizes this model, remained unchanged after CYP46A1 overexpression. Altogether, these results suggest a direct connection between Tau pathology and CYP46A1 in vivo. In other words, Tau pathology could lead to memory deficits via CYP46A1 decrease. These data, together with the fact that CYP46A1 overexpression can modulate the amyloid pathology in mice, suggest that CYP46A1 may be a relevant therapeutic target for AD.

Notre motricité s’adapte plus ou moins facilement aux changements liés, à l’environnement et à l’évolution de nos capacités au cours de nos expériences, de nos apprentissages et de l’avancée dans l’âge. Nous nous efforçons alors de trouver des solutions optimales, pour être plus performants, plus efficaces. Le couplage perception-action est à la base de l’organisation du contrôle moteur. L’Homme perçoit à travers plusieurs systèmes sensoriels des informations intrinsèques, en provenance de l’état du corps lui-même, et des informations extrinsèques, issues de l’environnement. Ces informations sont mises au service du mouvement et des actions de la vie quotidienne à travers les processus cognitivo-moteurs : de prédiction, d’estimation et de planification motrice. Interroger ces mécanismes chez des personnes âgées fragilisées par l’apparition de troubles cognitifs légers en lien avec la maladie d’Alzheimer, permet de mieux comprendre leur capacité d’adaptation et de compensation face à ce vieillissement. Il s’agit par ailleurs de maintenir et de renforcer ces capacités par l’enrichissement réfléchi de l’environnement de stimulation de la personne âgée. Ces interventions préventives représentent un intérêt majeur pour la préservation de l’indépendance fonctionnelle des personnes âgées vulnérables. Ces travaux de thèse proposent le développement d’outils permettant la stimulation et le renforcement des processus cognitivo-moteurs. Il s’agit d’engager le couplage perception-action à travers des exercices moteurs implicites favorisant l’acquisition de nouveaux apprentissages et le renforcement des processus d’adaptation et de compensation au cours de l’évolution de la maladie. / To write, take, walk, talk is a part of our daily. Our motor ability is used to change depending on our environment and our skill, acquired thanks to our experience, learnings, and according to our age. We strive to find optimal solutions, to be more performants, more efficient. But we must be able to discern to act well and act to better discern. This « perception-action » coupling is the basis of the organization of motor control. Human can discern through several sensory systems (Visual, auditory, proprioceptive) intrinsic informations, coming from his own body, and extrinsic informations, from his environment. All of these informations are in the service of the movement and actions of daily life through the cognitivo-motor processes: of prediction, estimation and motor planning. To question these processes in aged people, weakened by mild cognitive impairment related to Alzheimer's disease, first allow to better understand their adaptation and compensatory capacities faced to this pathological aging. These preventive interventions represent a source of major interest, especially in the preservation of functional independence of vulnerable old people.These works of thesis propose development of tools for stimulating and strengthening cognitive-motor processes. It is clearly about engaging the perception-action coupling through implicit motor exercises benefiting the acquisition of new training and strengthen the process of adaptation and compensation during the progression of Alzheimer’s disease. So many of these processes stimulation exercises will be presented to better know the components relates to the action.

Le point nodal de cette recherche porte sur le changement de regard sur la maladie d'Alzheimer et les troubles apparentés. Ce travail de thèse interroge alors le regard porté, à différents niveaux (sociétal, familial et singulier) sur la démence et sur ce que cela engendre sur les personnes qui en sont atteintes et sur son entourage. Nous amènerons ainsi notre réflexion sur les moyens qui pourraient être mis en place pour permettre une modification des représentations portées sur la vie psychique de la personne malade. Le concept de handicap de Wood et la Classification Internationale de Fonctionnement sont des référentiels sur lesquels nous allons nous appuyer comme modèles de compréhension des situations de handicap en s'intéressant tout particulièrement à la question du désavantage sociale. Nous interrogerons alors les effets des regards sur la personne Alzheimer nous conduisant à la question de l'intersubjectivité, c'est-à-dire des enjeux correspondant aux modes d'Alzheimer. Il convient alors de faire un inventaire de ce qui habite, trahi, infléchi le regard dans sa réciprocité et d'identifier tout ce qui caractérise ce regard. Nous faisons ainsi l'hypothèse d'un appel à l'art comme vecteur de changement de regard. L'objectif sera alors d'étudier comment l'art thérapie peut produire autre chose que ce qui fait désavantage. En effet, l'art fait appel à la créativité, il s'agit donc d'une production de la vie psychique. Cela engendre des émotions qui sont brutes, non représentables mettant en exergue ce qui constitue le coeur même de l'identité du sujet. Nous travaillerons sur les articulations entre les incapacités et les désavantages sociaux dans le but de rechercher et d'identifier de nouvelles compétences que les personnes âgées construisent dans leurs situations de malades Alzheimer. / Aging in our current society, in which death is constantly pushed backwards, places the elderly at risk of exclusion from the social sphere. "Aging young": here is the paradox we are facing every day. The way society views the elderly, especially those suffering from Alzheimer's disease, is pejorative, referring to dependence, decline and decay. Alzheimer's disease is often defined as “severing of connections” , often seen as an impediment to communication and relationships, especially with family members. " An individual is a social being" says Norbert Elias, sociologist. So taking into consideration the stigmatization of Alzheimer disease and the social representation that family members may have, it becomes possible to develop tools that would allow a different type of bond in the future. After several months of immersion, observations and meetings in different EHPAD, this study offers an approach to transform and build an alternative outlook on people suffering from Alzheimer's disease through an introduction to artistic and cultural measures.

The aim of this thesis was to study the biomarker homocysteine and other novel potential vascular risk factors for dementia. In an out-patient based study of a cohort of 926 consecutive subjects referred to our Memory Unit during 1996―2000, serum-folate was lower and total plasma homocysteine (tHcy) and serum methyl malonate were higher in subjects being prescribed with B12. In the subgroup diagnosed with dementia and with a positive family history of dementia, tHcy was higher than in the subgroup diagnosed as non-demented. It is necessary to supplement subjects with vitamin B12 deficiency with B12, but our results indicate that it is not sufficient with B12 alone because this gives rise to intracellular folate deficiency. We also found indications of a genetic component in dementia because tHcy was higher in the group with a positive family history of dementia. These findings prompted further studies of homocysteine metabolism. The frequency of mutations in the gene for folate receptor-α (FOLR-1), and the fibrinolytic pattern in dementia and non-dementia were studied in the two cohorts DGM (n=300) and AS (n=389). The DGM cohort is a consecutive series of subjects attending our Memory Care Unit for investigation of suspected cognitive problems or dementia between 2003 - 2007. The AS (= active seniors) cohort comprises retired, apparently healthy subjects from central Sweden, actively participating in study circles. A rare haplotype in the FOLR-1, with mutations in two nearby loci, was discovered, possibly associated with lower serum-folate and higher tHcy concentrations and was more frequent in the DGM group. The transport of folate to the CSF was studied in the DGM-cohort. Dementia with a vascular component was associated with a lower CSF to serum folate ratio indicative of reduced transport of folate to the CSF and further to the brain. The vascular endothelial derived fibrinolytic markers tPA, tPA/PAI-1-complex, and vWF were not only higher in vascular dementia (VaD) but also in Alzheimer’s Disease (AD) when compared to the AS group. The impaired fibrinolytic activity in both vascular dementia and in AD is a novel finding, signifying a vascular component in the development of dementia. In conclusion we found that both hereditary and nutritional background factors were linked to dementia and furthermore that a dysregulated fibrinolysis was linked to both VaD and AD.

Abstract The present study surveyed medical problems and mental health in an unselected population-based series of people with Down syndrome (DS). All people with DS identified in the Intellectual Disability Service Register in the Kainuu region (n=138) were included, and their health and disability case records in the public services were analysed. The severity of intellectual disability was related to age, gender, and recorded medical problems. Adaptive behaviour changes were assessed among adults repeatedly during ten years using the Adaptive Behaviour Scale - Residential and Community, Part I. The study evaluated health surveillance and practices were compared to the national Current Care guidelines. Numerous medical problems and behavioural symptoms were recorded in this population. Surgical treatments were used extensively. The number of medical problems varied to a great degree among participants. Health problems were extensive from birth to old age. Many health concerns were age-related. The degree of intellectual disability related to visual and neurological impairments. Depression, and among participants in their forties and older, Alzheimer’s disease were the most common underlying reasons for changes in adaptive behaviour. A gradual functional decline and dementia affected many participants at a relatively early age. Visual acuity and hearing should be regularly monitored in all individuals with DS because of a high prevalence of visual impairment and hearing loss in this population. There was a general lack of evidence that the health care guidelines initiated five years ago were being followed. This suggests that possibilities to enhance health have not been optimally implemented. Therefore, further efforts are needed to diagnose and treat medical problems in people with DS. / Tiivistelmä Tutkimuksessa kuvattiin todettujen terveysongelmien yleisyyttä ja terveysseurannasta annettujen suositusten toteutumista Downin oireyhtymässä. Nykyisin Kainuussa elävien Down -henkilöiden tietojen lisäksi alueella aiemmin asuneiden saatavissa olevat sairaus- ja huoltokertomustiedot analysoitiin (n=138). Kehitysvammaisuuden vaikeusasteen, iän, sukupuolen ja todettujen sairauksien yhteyksiä selvitettiin. Aikuisten ja ikääntyvien Down -henkilöiden toimintakykyä seurattiin kymmenen vuoden ajan käyttäen Adaptiivisen käyttäytymisen asteikkoa. Käypä hoito -suosituksen toteutumista terveysseurannan osalta arvioitiin. Down -henkilöillä oli todettu lukuisia terveysongelmia ja käytösoireita kaikissa ikäryhmissä. Kirurgisia hoitoja oli tehty paljon. Yksilölliset erot sairastavuudessa ja toimintakyvyssä olivat erittäin huomattavat. Monet terveysongelmista liittyivät tiettyyn ikään. Vaikeasti kehitysvammaisilla todettiin enemmän silmäsairauksia ja näön ongelmia sekä neurologisia sairauksia kuin lievästi tai keskivaikeasti kehitysvammaisilla. Masennus ja yli 40 vuoden ikäisillä Alzheimerin tauti olivat yleisimmät toimintakyvyn heikentymisen syyt. Toimintakykvyn heikentyminen alkoi usein 40 ikävuoden jälkeen ja moni sairastui suhteellisen nuorena dementiaan. Kaikkien Down -henkilöiden kuuloa ja näköä tulisi seurata säännöllisesti, koska kuulon alentuminen ja näön ongelmat ovat yleisiä ja jäävät usein toteamatta. Hoitosuositukset eivät toteutuneet ainakaan säännöllisen kuulon ja kilpirauhasen toiminnan seurannan osalta viiden vuoden kuluessa suositusten antamisesta. Terveysseurannan parempi toimeenpano terveyden edistämiseksi on mahdollista. Down henkilöiden sairauksien toteamisen ja hoidon kehittäminen vaatii edelleen työtä.

Bien que la maladie d’Alzheimer (MA) soit la cause de démence la plus fréquente, lesmécanismes qui sous-tendent les déficits cognitifs chez les patients restent mal connus.Cependant, les peptides amyloïdes (Aβ) semblent être un acteur majeur impliqué dansl’apparition des troubles mnésiques au cours de l’évolution de la maladie, notamment de parleur capacité à induire un hypofonctionnement du système cholinergique associé au déclinmnésique. Sur la base de ces observations, le rôle joué par les récepteurs cholinergiquesnicotiniques α7 (α7-nAChRs) a été largement étudié, au vue de leur capacité à interagir avecles Aβ, sans toutefois dégager un consensus quant à l’implication de ces récepteurs dans lesdéficits mnésiques induits par les Aβ.Afin d’améliorer notre compréhension quant aux mécanismes sous-tendant les effetsdélétères induits par les Aβ dans les déficits mnésiques, notre travail visait à identifier le rôlejoué par les récepteurs α7-AChRs via une approche comportementale, pharmacologique etmoléculaire. Ainsi, nous avons utilisé un modèle « souris » basé sur des injections de formesoligomériques d’Aβ(1-42) (Aβo(1-42)) dans la région CA1 de l’hippocampe dorsal (dCA1),structure cérébrale impliquée dans les processus mnésiques, atteinte de manière précoce dansla MA et exprimant fortement les récepteurs α7-nAChRs.La première partie de cette étude a consisté à mettre au point et à valider notre modèleanimal d’étude des effets induits par les Aβo(1-42) dans le dCA1 par une approchecomportementale et moléculaire. Nous montrons que les injections répétées d’Aβo(1-42) dans ledCA1 induisent une perturbation spécifique de la mémoire de travail alors que la mémoirespatiale est préservée lorsque les performances mnésiques sont évaluées 7 jours après ladernière injection. Nous avons également montré que cette perturbation de la mémoire detravail est associée à une absence d’activation/phosphorylation de ERK1/2 au sein du réseauhippocampo-frontal et septo-hippocampique. Ces données nous ont permis de valider notremodèle expérimental permettant d’étudier spécifiquement l’impact des Aβo(1-42) dansl’hippocampe dorsal.Dans une seconde partie, nous nous sommes focalisés sur le rôle joué par lesrécepteurs α7-nAChRs dans les perturbations mnésiques induites par les Aβo(1-42). Nosrésultats montrent que (1) les souris KOα7 ne présentent pas de déficits de mémoire de travailconsécutivement aux injections intra-dCA1 d’Aβo(1-42), (2) les déficits mnésiques ainsi que lala perturbation de l’activation de ERK1/2 induits par les Aβo(1-42) sont compensés par destraitements pharmacologiques agoniste partiel et antagoniste des récepteurs α7-nAChRs, (3)le traitement par un agoniste complet des récepteurs α7-nAChRs ne permet pas de prévenir lesdéficits mnésiques. Au regard de ces résultats, le récepteur α7-nAChRs semble être essentielau développement des déficits mnésiques induits par les Aβo(1-42), et l’utilisationd’antagonistes de ces récepteurs pourraient être une cible potentielle pour le développementde nouvelles stratégies thérapeutiques. / Although Alzheimer’s disease (AD) has been considered as one of the major causesfor dementia, the mechanisms by which cognitive decline appear still remain unclear.However, amyloid-β peptides (Aβ) seem to play a central role in the appearance of memoryimpairments in the time course of the disease, inducing down-regulation of the cholinergicsystem which is associated with cognitive decline. Based on these observations, the role of α7nicotinic receptors (α7-nAChRs) which can interact with Aβ was widely studied withoutconsensus about the involvement of these receptors in memory deficits induced by Aβ.In order to improve our knowledge about the mechanisms involved in Aβ side effects,our work aims at identify the role of α7-nAChRs via behavioral and molecular approaches.Thus, we used a mice model based on injections of oligomeric assemblies of Aβo(1-42) (Aβo(1-42)) in the CA1 field of the dorsal hippocampus (dCA1) which is a brain structure stronglyinvolved in memory processes, precociously affected in the AD and with a high density of α7-nAChRs.The first part of this study was to develop and validate this animal model to studythe effects induced by Aβo(1-42) in the dCA1 by behavioral and molecular approaches. Weshow that repeated injections of Aβo(1-42) in the dCA1 induce a specific disruption of workingmemory 7 days after the last injection whereas spatial memory is spared. We also showed thatworking memory disturbance is associated with decreased activation / phosphorylation ofERK1 / 2 in the hippocampo-frontal and septo-hippocampal networks. These data allowed usto validate our experimental model to specifically study the impact of Aβo(1-42) into the dorsalhippocampus.In the second part, we focused on the role played by the α7- nAChRs receptors inmemory disturbances induced by Aβo(1-42). Our results show that (1) KOα7 mice do notexhibit working memory deficits consecutively to intra-dCA1 Aβo(1-42) injections, (2) thememory deficits and decreasing activation of ERK1/2 induced by Aβo(1-42) are offset bypharmacological treatments partial agonist and antagonist of α7-nAChRs receptors, (3)treatment with a full agonist of α7-nAChRs receptors does not prevent memory deficits .Given these results, the α7-nAChRs receptor appears to be essential to the development ofmemory deficits induced by Aβo(1-42), and the use of antagonists of these receptors might be apotential target for developing new therapeutic strategies for AD.

Professional and personal caregivers of persons with Alzheimer’s disease (AD) receive little or no training with regards to the nature, course and accompanying communication challenges of this illness (Haak, 2003). The main aim of the research study was to investigate the interaction between nursing home staff and persons with AD with in a nursing home context, before and after attending a communication-orientated educational workshop for the nursing home staff. Research was carried out by using multiple single case studies. A pre-experimental design was used as the research method. The four participants’ communication skills (verbal, nonverbal and paralinguistic) were evaluated by using the Pragmatic Protocol (Prutting and Kirchner, 1987). Their listening skills were observed and scored according to the Checklist of listening behaviours (Hartley, 1995). A questionnaire was designed to measure the participants’ knowledge and perceptions of different AD aspects. Various shortcomings were identified in the interaction process which highlights the importance of training staff to become competent in using communication strategies that facilitate more successful interaction with persons with AD. The communication-orientated educational workshop (event of the study) was designed according to the data that was collected and based on the person-centred approach of Kitwood (1997). The participants’ communication and listening skills, knowledge and perceptions were evaluated again in the posttest (after the workshop) to determine whether or not there had been a change in these areas. A general view of all the participants’ results showed that there was a significant change in their communication and listening skills. The interaction process was more appropriate during the posttest in comparison to the results that were obtained in the pretest. The participants’ interaction were based more on the principles of the person-centred approach to dementia care than the pretest. There had been a noticeable increase after the workshop in the participants’ knowledge and change to a more positive perception towards persons with AD and the illness. The conclusion has been reached that attendance and participation in a communication-orientated educational workshop leads to more positive interaction with persons with AD. This study has motivated the need for dementia care that is based on the principles of the person-centred approach. It is suggested that an increase in the person-centred approach leads to improvement in quality of life of persons with AD as well as the decrease of the effect of institutionalization in a nursing home setting. Suggestions for future research include that attention should be given to educational programmes with regards to communication strategies for persons with AD. It has furthermore been suggested to approach managers of nursing homes regarding future inservice training of their nursing home staff. / Dissertation (M(Communication Pathology))--University of Pretoria, 2007. / Speech-Language Pathology and Audiology / unrestricted

The aim of this study was to investigate the relationship between noncognitive symptoms and premorbid temperament in a group with Alzheimer’s disease. The relationship between premorbid temperament and noncognitive symptoms can be used to understand symptom susceptibility and risk, caregiver burdens, as well as providing insights into the neuroanatomical substrates of temperament and noncognitive behaviour. Sixty-three primary caregivers of Alzheimer’s patients fulfilled the eligibility criteria for this study. Information regarding the noncognitive symptoms and premorbid temperament was procured from the primary caregivers. In fifty-one cases, a secondary caregiver also provided information about the premorbid temperament of the Alzheimer’s patient. The latter was obtained to enhance the reliability of retrospective data. The Behaviour Rating Scale for Dementia, the Formal Characteristics of Behaviour-Temperament Inventory, and the Blessed Dementia scale were used to elicit data on noncognitive symptomatology, premorbid temperament, and current cognitive status, respectively. ii Noncognitive symptoms were grouped into two clusters namely neuropsychiatric and neurobehavioural disturbances. The neuropsychiatric cluster included mood and psychotic symptoms and the neurobehavioural cluster included vegetative and overall behavioural dysregulatory symptoms. Results showed that there is a wide spectrum of noncognitive symptom manifestation in patients’ profiles and that the neurobehavioural dysregulatory symptoms are more common than the neuropsychiatric symptoms in this Alzheimer’s cohort. With regard to symptom manifestation and cognitive status, a Pearson product moment correlational analysis showed that a lower level of cognitive functioning is significantly associated with aggressive episodes and a higher level of cognitive functioning with manifestations of depressive symptoms. In terms of interrater concordance on premorbid temperament ratings, intraclass correlations were significant for five of the six temperament domains, thus indicating a reliable estimate of premorbid disposition. Canonical correlational analysis yielded two significant variates. The first variate indicated that Alzheimer’s disease patients with a proclivity for aggressive behaviours and general behavioural deregulation but lower depressive profiles, were premorbidly more emotionally reactive, had low sensory thresholds (high sensitivity), and greater cognitive deficit. The second variate showed that patients with Alzheimer’s disease who tended to manifest with depressive and dysregulatory behaviour appear to have been premorbidly perseverative in temperament with a low sensory threshold (high sensitivity) and the tendency to maintain and attain a low level of activity (stimulation). Taken together, the significant variates revealed a dimensional relationship between depressive symptoms, aggressive symptoms, and behavioural dysregulation; and sensory sensitivity, emotional reactivity, perseverance, and activity, with cognitive status serving as a moderating variable. In conclusion, the study indicated a dimensional relationship between specific premorbid temperament traits and noncognitive symptoms, thereby highlighting the possible predictive influence of premorbid temperament on noncognitive manifestations in Alzheimer’s disease patients. / Thesis (PhD (Psychology))--University of Pretoria, 2005. / Psychology / unrestricted

Apart from the personal and socioeconomic burdens of dementia, the immense, intangible emotional and psychological suffering endured by dementia patients, their carers and families are difficult to quantify. Alzheimer’s dementia (AD) accounts for over 50% of all dementias and is responsible for a large percentage of morbidity and mortality in older adults. It is also recognised as a disease qualitatively distinct from the normal ageing process. Identified almost 95 years ago by Alois Alzheimer, it poses a seminal problem, which in the twenty-first century is compounded by the predicted extension in human longevity. Caregivers thus bear a considerable financial, social and emotional burden due to the progressive debilitating nature of the disease. It is hypothesised that social support buffers the individual from the negative emotional effects of stressful circumstances associated with the caregiving process; and although the inevitable course of the disease cannot be stopped, improving support to caregivers may decrease feelings of isolation and improve psychological health. Caregivers of AD patients often report experiencing a lack of social support due to the nature and progression of this disease. This study thus aims to investigate the relationship between real and/or perceived social support and psychological health (depression, loneliness, and perceived burden of care) amongst a cohort of Alzheimer’s caregivers. The following standardised measuring instruments were used to elicit data: the Zarit Burden Interview (ZBI), the Beck Depression Inventory (BDI-II), UCLA Loneliness Scale, Personal Resource Questionnaire (PRQ85) and a biographical questionnaire. Data were analysed using correlation and regression statistical techniques. The main findings of this study were that there is a significant positive correlation between loneliness and depression; loneliness and personal strain (burden) as well as both role and personal strain (burden) with depression. A significant negative correlation was also found between perceived social support and loneliness. Additional findings were that participants with higher educational qualifications experienced more personal strain and role strain (burden); caregivers with patients in the two younger age groups scored higher on the BDI-II; and the cognitive status of the patient correlated with the burden experienced by the caregiver. A significant negative correlation between summaries of reactions (burden) and duration of caregiving was also reported. / Dissertation (MA)--University of Pretoria, 2008. / Psychology / unrestricted