Alzheimer’s disease (AD) is a neurodegenerative disorder, with extensive evidence implicating the misfolding, aggregation and deposition of the amyloid-β (Aβ) peptide as central to the pathogenesis. Heparan sulfate (HS) is an interactive glycosaminoglycan, attached to core proteins as HS proteoglycans (HSPGs). HSPGs are present on cell surfaces and in the extracellular matrix where they facilitate multiple signaling functions, but HS is also consistently present in all amyloid deposits, including those of AD. In amyloidosis HS has been studied as an aggregation template, promoting fibril formation and serving a scaffold function in the resulting deposits. The objective of this thesis was to assess how cell surface HS is potentially implicated in Aβ amyloidosis and the associated neuroinflammation of AD.   In AD brain we determined that HS predominantly accumulated in Aβ deposits with dense cores and found glial-expressed HSPGs within these deposits. Aβ elevated HSPG levels in primary glial cultures, implicating activated glia as one source of the Aβ-associated HS. Next, we determined that microglial HSPGs are critical for the upregulation of interleukin-1β and tumor necrosis factor-α following exposure to lipopolysaccharide, an established inflammatory insult. Together these results raise the possibility that Aβ-induced expression of microglial HSPGs may promote neuroinflammation.   Multiple mechanisms of Aβ toxicity have been proposed and different Aβ assemblies exert their toxicity through alternative routes. We found that three different preparations of Aβ aggregates all exhibited HS-dependent cytotoxicity, which in part correlated with Aβ internalization. Furthermore, heparin treatment attenuated Aβ cytotoxicity and uptake. In Aβ-positive AD microvasculature, HS deposited with Apolipoprotein E (ApoE) and its receptor, the low density lipoprotein receptor-related protein 1 (LRP1). In cell culture, HS and LRP1 co-operated in Aβ interactions and the addition of ApoE increased the levels of cell-associated Aβ in a HS- and LRP1-dependent manner. This ApoE-mediated increase in cell-associated Aβ may promote toxicity and vascular degeneration, but equally HS-mediated internalization of Aβ could represent a clearance route across the blood-brain-barrier. The findings presented here illustrate multiple roles for cell-surface HSPGs in interactions relevant to the pathogenesis of AD.

Vascular risk factors inducing a state of chronic cerebral hypoperfusion and metabolic stress are thought to influence the onset and progression of Alzheimer’s disease (AD). To investigate the complex molecular changes underpinning cellular adaptation to metabolic stress, the first aim of this thesis was to define the proteomic response of the SH-SY5Y human neuroblastoma cell line after exposure to the metabolic challenge of oxygen glucose deprivation (OGD). 958 proteins across multiple subcellular compartments were detected and quantified by label-free liquid chromatography mass spectrometry (LC-MS). The levels of 130 proteins were significantly increased (P<0.01) after OGD and the levels of 63 proteins were significantly decreased (P<0.01) while expression of the majority of proteins (765) was not altered. Ingenuity Pathway Analysis identified novel protein-protein interactomes involved with mitochondrial energy production, protein folding, and protein degradation, indicative of coherent and integrated proteomic responses to the metabolic challenge. Approximately one third (61) of the differentially expressed proteins were associated with the endoplasmic reticulum and mitochondria. Electron microscopic analysis of these subcellular structures showed morphologic changes consistent with the identified proteomic alterations. Pertinent to AD research, amyloid binding alcohol dehydrogenase (ABAD) was found to be significantly increased in response to OGD. ABAD is emerging as a key player in mitochondrial dysfunction in AD, yet full understanding of the biochemical pathways in which this protein is involved remain elusive. Using immunoprecipitation coupled to LC-MS (IP-MS), the second aim of the thesis was to characterise the ABAD protein interactome in SH-SY5Y cells and its response to metabolic stress. 67 proteins were identified as potential ABAD interactors under control conditions, and 69 proteins were identified as potential ABAD interactors under OGD conditions. The Database for Annotation, Visualization and Integrated Discovery (DAVID) was used to determine the subcellular locations and biological functions of the ABAD interacting proteins in control and OGD conditions. DAVID identified the nuclei and mitochondria to contain the greatest number of changes in ABAD interacting proteins following OGD. “Glucose Metabolic Process” (GO:0006006) was the top functional cluster for ABAD interacting proteins in both control and OGD conditions. Independent immunoprecipitations, western blotting, immunohistochemistry and electron microscopy were used to validate specific protein interactions. OGD was found to initiate a novel interaction between ABAD and glucose-regulated protein 75 (GRP75), a finding confirmed in human AD tissue. GRP75 is a mitochondrial protein and marker of the mitochondrial associated membrane (MAM), a specialised region between the mitochondria and the ER. The MAM is known to be enriched with presenilin proteins, involved in the proteolytic cleavage of amyloid precursor protein (APP). These data were used to generate an “ABAD-GRP75-MAM hypothesis of mitochondrial dysfunction in AD”, which might provide a novel link between chronic metabolic stress, ABAD, mitochondrial dysfunction and the onset / progression of AD. The third aim of the thesis was to test this novel hypothesis. Western blotting revealed APP to be significantly decreased following OGD, concurrent with an increase in ABAD protein levels. Over-expression of ABAD protein in SH-SY5Y cells was used to test whether the increased levels of ABAD following OGD were the driving force behind APP down-regulation. ABAD over-expression in SH-SY5Y cells was found to have no detectable effect on APP. Conversely, electron microscopy revealed a dynamic response of the MAM to metabolic stress. This result, along with the interaction of ABAD with GRP75, and the enrichment of presenilins at the MAM, suggests that this specialised membrane region may have an important role to play in AD.

The increasing prevalence of Alzheimer’s disease poses a considerable socioeconomic challenge in the years ahead. There are few clinical treatments available and none capable of halting or slowing the progressive nature of the condition. Despite decades of experimental research and testing over 300 interventions in transgenic mouse models of the condition, clinical success has remained elusive. Deepening our understanding of how such studies have been conducted is likely to provide insights which could inform future preclinical and clinical research. Therefore I performed a systematic review and meta-analysis on interventions tested in transgenic mouse models of Alzheimer’s disease. My systematic search was performed by electronically searching for publications reporting the efficacy of interventions tested in transgenic models of Alzheimer's disease. Across these publications I extracted data regarding study characteristics and reported study quality alongside outcome data for pathology (i.e. plaque burden, amyloid beta species, tau, cellular infiltrates and neurodegeneration) and neurobehaviour. From these data I calculated estimates of efficacy using random effects meta-analysis and subsequently investigated the potential impact of study quality and study characteristics on observed effect size. My search identified 427 publications, 357 interventions and 55 transgenic models representing 11, 688 animals and 1774 experiments. There were a number of principal concerns regarding the dataset: (i) the reported study quality of such studies was relatively low; less than 1 in 5 publications reported blinded assessment of outcome or random allocation to group and no studies reported a sample size calculation, (ii) the depth of data on any individual intervention was relatively poor-only 16 interventions had outcomes described in 5 or more publications and (iii) publication bias analyses suggested 1 in 5 pathological and 1 in 7 neurobehavioural experiments remain unpublished. Where I inspected relationships between outcomes, meta-regression identified a number of notable associations. Changes in amyloid beta 40 were reflective of changes in amyloid beta 42 (R2 = 0.84, p<0.01) and within the Morris water maze changes in the ‘training’ acquisition phase could explain 44% of the changes in the probe ‘test’ phase (p<0.05). Additionally, I identified measures of neurodegeneration as the best pathological predictors of changes in neurobehaviour (R2 = 0.72, p<0.01). Collectively this work identifies a number of potential weaknesses within in vivo modelling of Alzheimer’s disease and demonstrates how the use of empirical data can inform both preclinical and clinical studies.

Cerebral hypoperfusion can occur in normal ageing and is proposed to underlie white matter disturbances observed in the ageing brain. Moreover, cerebral hypoperfusion and white matter attenuation are early events in the progression of Alzheimer’s disease (AD). White matter mostly consists of myelinated axons which have distinct protein architecture, segregated into defined regions; the axon initial segment (AIS), the node of Ranvier, paranode, juxtaparanode, and internode. These sites are essential for action potential initiation and/or propagation and subsequently effective brain function. At the outset of the studies in the thesis there was evidence that the different regions within the myelinated axons are vulnerable to injury and disease. Thus it is hypothesised that in response to normal ageing and/or cerebral hypoperfusion these structures are altered and associated with cognitive impairment and that these effects are exacerbated in a transgenic mouse model (APPSw,Ind, J9 line) which develops age-dependent amyloid-β (Αβ) pathology. The first study aims to investigate the effect of normal ageing and Aβ deposition on myelinated axons and on learning and memory. To address this, the effects of normal ageing on the integrity of the AIS, nodes of Ranvier, myelin, axons, synapses and spatial working memory are examined in young and aged wild-type and TgAPPSw,Ind mice. A significant reduction in the length of nodes of Ranvier is demonstrated in aged wild-type and TgAPPSw,Ind mice. In addition, the length of AIS, is significantly reduced in the aged wild-type animals while the young TgAPPSw,Ind have significantly shorter AIS than the young wild-type mice. These effects are not influenced by the presence of Aβ. Myelin integrity is affected by age but this is more prominent in the wild-type animals whilst axonal integrity is intact. Moreover, there is an age-related decrease of presynaptic boutons only in the TgAPPSw,Ind mice. Contrary to the original hypothesis, working memory performance is not altered with age or influenced by increasing Aβ levels. The second study aims to examine the effects of cerebral hypoperfusion in combination with Αβ pathology and/or ageing on cognitive performance and the structure of myelinated axons. To address this, the effects of surgically induced cerebral hypoperfusion on the integrity of the nodes of Ranvier, paranodes, myelin, axons and spatial working memory performance are investigated in young and aged wild-type and TgAPPSw,Ind mice. A decrease in nodal length is observed in response to hypoperfusion in young and aged animals. This effect is shown to be exacerbated in the young TgAPPSw,Ind animals. Moreover, the disruption of the nodal domain is shown to occur without any gross alterations in myelin and axonal integrity. It is also demonstrated that in response to hypoperfusion, spatial working memory performance is defected in young and aged animals of both genotypes. This deficit is exacerbated in the young TgAPPSw,Ind. The observed changes in the nodal structure are associated with poor working memory performance indicating functional implication for the nodal changes. These data highlight that structures within myelinated axons are vulnerable to ageing and cerebral hypoperfusion. Therefore, the development of strategies that minimize injury or drive repair to these regions is necessary together with therapeutic approaches against the vascular insults that induce hypoperfusion and lead to white matter attenuation and cognitive decline. In the future, it would be interesting to investigate how alterations at the AIS/nodes of Ranvier affect neuronal excitability.

Background: Dementia impairs cognitive functions, such as memory and speech, changing a person’s life forever. Providing person-centred care to these persons intend to retain their identities, dignity and autonomy. Such care demands time, devotion and good knowledge of the caring nurse. Dementia is expected to increase in the future and therefore nurses will have to face new challenges. Aim: To describe nurses’ experience of providing person-centred care for people with dementia. Method: A literature review of 15 articles, published between 2009-2016, that have been read and analysed through content-analysis. Results: Nurses experience a positive change in their attitudes, when providing person-centred care to people with dementia, as they gained better understanding of their patients’ dignity and integrity. Education, training and support from management were seen as key factors for providing up-to-date care. Time was viewed as a hindrance for person-centred care, and often led to nurses prioritizing other routines. Two common outcomes of person-centred care were increased satisfaction as well as emotional burnout. Conclusion: Since dementia is increasing and nurses find person-centred care time-consuming, there is a risk of such care becoming poor. To prevent this nurses need good leadership and education. / Bakgrund: Demenssjukdomar försämrar den kognitiva funktionen, så som minne och tal, vilket förändrar en persons liv för alltid. Att ge personcentrerad vård till dessa personer ämnar behålla deras identitet, värdighet och autonomi. En sådan typ av vård kräver tid, hängivenhet och god kunskap av den behandlande sjuksköterskan. I framtiden förväntas alltfler att insjukna i demenssjukdom och sjuksköterskan kommer därför att behöva möta nya utmaningar. Syfte: Att beskriva sjuksköterskans upplevelse av att ge personcentrerad vård till personer med demenssjukdom. Metod: En litteraturstudie där 15 artiklar, publicerade mellan 2009-2016, har blivit lästa och analyserade genom innehållsanalys. Resultat: Sjuksköterskor upplevde en positiv förändring i sin inställning när de gav personcentrerad vård till personer med demenssjukdom. Framförallt då de fick ökad förståelse för deras patienters värdighet och integritet. Utbildning, övning och stöd från ledningen sågs som nyckelfaktorer för att kunna ge aktuell vård. Tiden sågs som ett hinder för personcentrerad vård och ledde ofta till att sjuksköterskorna prioriterade andra rutiner. Två vanliga följder av vårdandet rapporterades vara såväl ökad tillfredsställelse som emotionell utmattning. Konklusion: Eftersom demenssjukdomar ökar och sjuksköterskor finner personcentrerad vård som tidskrävande, finns det en risk att sådan vård fallerar. För att förhindra detta behöver sjuksköterskor gott ledarskap och utbildning.

Intact white matter is critical for normal cognitive function. In traumatic brain injury (TBI), chronic cerebral hypoperfusion and Alzheimer’s disease (AD) damage to white matter is associated with cognitive impairment. However, these conditions are associated with grey matter damage or with other pathological states and the contribution of white matter damage in isolation to their pathogenesis is not known. Furthermore, TBI is a risk factor for AD and cerebral hypoperfusion is an early feature of AD. It is hypothesised that white matter damage following TBI or chronic cerebral hypoperfusion will be associated with cognitive deficits and that white matter changes after injury contribute to AD pathogenesis. To investigate this, this thesis examined the contribution of white matter damage to cognitive deficits after TBI and chronic cerebral hypoperfusion and furthermore, investigated the role of white matter damage in the relationship between TBI and AD. Three studies addressed these aims. In the first, mild TBI was induced in wild-type mice and the effects on axons, myelin and neuronal cell bodies examined at time points from 4 hours to 6 weeks after injury. Spatial reference learning and memory was tested at 3 and 6 weeks after injury. Injured mice showed axonal damage in the cingulum, close to the injury site in the hours after injury and at 6 weeks, damage in the thalamus and external capsule were apparent. Injured and sham animals had comparable levels of neuronal damage and no change was observed in myelin. Injured animals showed impaired spatial reference learning at 3 weeks after injury, demonstrating that selective axonal damage is sufficient to impair cognition. In the second study mild TBI was induced in a transgenic mouse model of AD and the effects on white matter pathology and AD-related proteins examined 24 hours after injury. There was a significant increase in axonal damage in the cingulum and external capsule and parallel accumulations of amyloid were observed in these regions. There were no changes in tau or in overall levels of AD-related proteins. This suggests that axonal damage may have a role in mediating the link between TBI and AD. The third study used a model of chronic cerebral hypoperfusion in wild type mice and investigated white matter changes after one and two months of hypoperfusion as well as a comprehensive assessment of learning and memory. Chronic cerebral hypoperfusion resulted in diffuse myelin damage in the absence of ischaemic neuronal damage at both 1 and 2 months after induction of hypoperfusion. Hypoperfused animals also showed minimal axonal damage and microglial activation. Cognitive testing revealed a selective impairment in spatial working memory but not spatial reference or episodic memory in hypoperfused animals, showing that modest reductions in blood flow have effects on white matter sufficient to cause cognitive impairment. These results demonstrate that selective damage to white matter components can have a long-term impact on cognitive function as well as on the development of AD. This suggests that minimisation of axonal damage after TBI is a target for reducing subsequent risk of AD and that repair or prevention of white matter damage is a promising strategy for rescuing cognitive function in individuals who have experienced mild TBI or chronic cerebral hypoperfusion.

La maladie d’Alzheimer est une maladie neurodégénérative, elle représente 70% des formes de démences et affecte près de 860 000 personnes en France. Cette maladie est caractérisée par deux lésions neuropathologiques : les Dégénérescences neurofibrillaires et les Plaques séniles. Ces dernières sont principalement constituées de peptides amyloïdes (A&#946;) résultant du clivage d’une protéine membranaire appelée Précurseur du peptide amyloïde (APP). L’étude des formes familiales monogéniques a montré que des mutations des gènes de l’APP et des Présénilines 1 et 2 conduisaient systématiquement à une augmentation de la production d’A&#946;. Cette observation a permis l’élaboration de la cascade amyloïde plaçant le métabolisme de l’APP au centre du processus physiopathologique. Même si aujourd’hui ce métabolisme commence à être relativement bien connu, plusieurs zones d’ombres subsistent encore. Dans l’optique de caractériser de nouveaux acteurs intervenant dans ce métabolisme, nous avons émis une hypothèse qui repose sur deux constatations : (i) les protéines impliquées dans l’étiologie de la maladie sont différentiellement exprimées entre les cerveaux des patients et ceux des témoins (ii) dans le cerveau, de nombreuses métalloprotéases participent aux même mécanismes que l’APP (adhésion cellulaire, neuroinflammation, plasticité neuronale...), certaines sont aussi directement actrices du métabolisme de l’APP en tant qu’&#945;-sécrétase (ADAM9, ADAM10 et ADAM17) ou en dégradant l’A&#946; (NEP, IDE, MMP2, MMP3 et MMP9). Nous avons donc supposé que les métalloprotéases présentant une différence d’expression entre le tissu cérébral des malades et celui des témoins soient des candidates intéressantes pour moduler le métabolisme et le trafic de l’APP. Une première analyse transcriptomique par biopuce, à partir d’ARN totaux issus des cerveaux de 12 malades et de 12 témoins, nous a permis d’identifier quatre métalloprotéases présentant une différence d’expression significative (p<10-5) : ADAMTS16, ADAM17, ADAM30 et ADAM33. Nous avons cherché à confirmer ce résultat par une autre technologie sur un plus grand nombre d’échantillons (malades n=52 et témoins n=42). Seules ADAM30 et ADAM33 ont pu être validées. Nous avons également pu observer que l’expression d’ADAM30 dans le tissu cérébral des malades est inversement proportionnelle à la quantité d’A&#946;42 déposée dans la parenchyme (A&#946;42 la forme d’A&#946; la plus neurotoxique). De plus, au niveau cérébral, l’expression d’ADAM30 est restreinte aux neurones, cellules sièges du métabolisme de l’APP. Nous avons donc sélectionné ADAM30 comme intervenante potentielle dans le métabolisme de l’APP. Pour tester notre hypothèse, nous avons sous- et sur-exprimé ADAM30 dans deux modèles cellulaires différents. Nous avons mis en évidence que la sur-expression d’ADAM30 entraîne une diminution de l’ensemble des produits du métabolisme de l’APP. En mutant le site catalytique de cette protéase, nous avons remarqué que cette action sur le métabolisme de l’APP est dépendante de cette activité catalytique. De manière cohérente, une sous-expression d’ADAM30 entraîne une augmentation de l’ensemble des produits du métabolisme de l’APP. En utilisant les inhibiteurs alcalisant, nous avons démontré que l’effet d’ADAM30 sur le métabolisme de l’APP met en jeu la dégradation par le lysosome. Des expériences d’immunofluorescence ont attesté qu’ADAM30 est localisée dans le réticulum endoplasmique et l’appareil de Golgi et qu’elle co-localise fortement avec l’APP dans ces organites. Au vu des résultats obtenus durant ces quatre années, nous pensons qu’ADAM30 pourrait être une protéine clé de la régulation de l’APP en inhibant son acheminement jusqu’à la membrane plasmique et en favorisant sa dégradation par le lysosome. [...] / Alzheimer’s disease (AD) is the most common neurodegenerative disorder of the old age, characterized by the presence of two major neuropathological features : neurofibrillary tangles and senile plaques. These plaques are composed of the A&#946; peptides cleavage product of the amyloid precursor protein (APP). Proteolytic processing of APP is modulated by the action of enzymes &#945;-, &#946;- and &#947;-secretases with the latter two mediating the amyloidogenic pathway. Suggesting that processing of APP is a key step in the pathology of AD. However, even if extensively studied, this APP metabolism is still not fully characterized. With this background, we postulate that the characterization of new actors of the APP metabolism might help for a more subtle understanding of this APP metabolism and trafficking. We focused on the ADAMs and related proteins with the hypothesis that ADAMs and related proteins, under- or over-expressed in the brain of AD cases compared with the one of controls, may be of particular interest. Beyond the obvious implication of several ADAMs as &#945;-secretases, this hypothesis was also driven by several observations : (i) ADAMs have been involved in numerous biological processes including brain development, plasticity and repair as APP; (ii) several metalloproteases (MMP-2, -3 and -9) have been described to degrade A&#946; peptides. Using microarray to screen the expression of 117 ADAMs and MMPs was analyzed using total RNA extracted from cerebral tissue of 12 AD cases and 12 controls. We observed that 4 ADAMs were differentially expressed. We first confirmed that the ADAM30 expression was decreased in AD brains and we observed that ADAM30 under-expression was correlated with an increase in A&#946;42 deposition in AD brains. Consistently, over-expression of ADAM30 led to decrease APP metabolism and as a consequence, A&#946; secretion in two different cell lines (Moreover, under-expressed ADAM30 increases APP processing and A&#946; generation). This modification of the APP metabolism was directly linked to the ADAM30 catalytic properties. Our data suggest that catalytic activity of ADAM30 takes an important place in APP processing in a lysosome dependent manner and AD pathophysiological process.

Neuropsychological testing is one method used in the diagnosis of Alzheimer’s disease and other cognitive disorders. However, the testing process may be affected by subtle external factors which if not controlled for may have the ability to affect the scores obtained. The primary aim of this thesis was to investigate the effects of some of these external factors, namely caffeine, non-oily fish consumption and time of day. A secondary aim was to evaluate the use of a novel virtual assessment as a possible tool for the early detection of AD. Healthy elderly participants over the age of sixty with no existing cognitive impairment or neurological condition were recruited to take part. For each external factor investigated participants were required to undertake a cognitive assessment. The results demonstrated that subtle external factors present during a typical testing session have the ability to significantly affect the scores obtained. Scores on one part of the virtual test correlated with existing tests used for the early detection of cognitive impairment and were significantly lower in participants classified as mildly impaired. With further modification this test has the potential to be used as an early detection tool. The results have implications for the interpretation of neuropsychological test scores which may be considered when classifying participants, determining treatment interventions, selecting participants for research and making a diagnosis. These findings have important considerations for psychological and cognitive research that investigates human brain function.

La maladie d'Alzheimer (MA) est une maladie neurodégénérative irréversible et progressive entraînant des troubles cognitifs et comportementaux. L'inflammation est caractéristique de la MA. L'interleukine-10 (IL-10), une cytokine anti-inflammatoire a été associée à un risque plus faible de développer la MA. Cependant le lien entre l'IL-10 et la progression de la MA n'a jamais été étudié. Le but de cette thèse a été d'étudier le rôle de l'IL-10 dans le développement ainsi que dans la progression de la MA. Pour mener à bien cette étude, 31 sujets atteints par la MA et 20 sujets contrôles cognitivement intacts ont été recrutés. En fonction de la vitesse de diminution du test de Mini-Mental State Examination et de l’évolution des troubles cognitifs sur deux ans, les patients souffrant de la MA ont été divisés en deux sous-groupes: les patients avec une progression lente (MA lent) et ceux avec une progression rapide (MA rapide). Les analyses se sont portées sur la concentration d’IL-10 en périphérie (plasma, production par les cellules mononuclées du sang périphérique (PBMCs) après stimulation par les peptides Aβ) ainsi que le polymorphisme de son promoteur en position -592, -819 et -1082. En complément, d’autres cytokines impliquées dans l’inflammation ont été étudiées : l’IL-6 (sa concentration plasmatique, sa production par les PBMCs à la suite d’une stimulation par les peptides Aβ et son polymorphisme en position -174) et les polymorphismes du TGF-β1 (-10 et - 25), de l’IFN-γ (-874) et du TNF-α (-308) ainsi que le gène de l'apolipoprotéine E (ApoE). Une étude de la longueur des télomères, liée à l’inflammation, a été aussi réalisée. Les résultats ont montré une association entre le génotype AA et l’allèle A du polymorphisme de l’IFN-γ en position -874 avec la progression rapide de la MA. Une augmentation statistiquement significative de la production d'IL-10 après stimulation par les peptides Aβ a été montrée chez les patients atteints avec une progression lente (MA lent). Une longueur significativement plus courte des télomères a été aussi associée aux patients MA lent. L’ensemble de ces travaux suggère qu’un profil de forte production de l’IL-10 ainsi qu’un profil génétique d’IFN-γ (TT -874) pourrait ralentir la progression de la MA. Il est aussi apparu que la longueur des télomères pourrait être un marqueur du déficit cognitif. Il est clair que ces résultats préliminaires ont besoin d’être confirmés par une étude de plus grande envergure, avec un nombre de patients plus élevé. / Alzheimer’s disease (AD) is an irreversible and progressive neurodegenerative disorder leading to cognitive and behavioral impairment. Inflammation is hallmark of AD although the exact mechanisms involved and the roles of the different inflammatory components are far less clear. Interleukin-10 (IL-10) is a key anti-inflammatory cytokine and IL-10 -1082 A > G polymorphism has been associated with a lower risk of developing AD although the link between IL-10 and the AD progression have never been studied. The aim of this study is to study the role of IL-10 in the risk of developing AD and its role in AD progression. In order to complete successfully this study, 31 AD patients and 20 cognitively intact controls were recruited. Depending of the rate of decrease of mini-mental state test examination (MMSE) and evolution of cognitive disorders, AD patients were divided in two subgroups: patients with slow progression (AD slow) and those with fast progression (AD fast). Analysis were focused on periphery concentration of IL-10 (plasma and and its production by peripheral blood mononuclear cells (PBMCs) after Aβ peptides stimulation) as well as its promoter polymorphism in position -592, -819 and -1082. In addition, other cytokines involved in inflammation were studied: IL-6 (its plasma concentration, its production by PBMCs following stimulation with Aβ peptides and its polymorphism at position -174) and polymorphisms of TGF-β1 (-10 to - 25), IFN-γ (-874) and TNF-α (-308) as well as the gene polymorphisms of Apolipoprotein E (ApoE). A study of telomere length, link to inflammation, was also performed. Results showed IFNγ -874AA genotype and -874A allele was associated with AD fast progression. A statistically significant increase of IL-10 production by PBMCs stimulated with Aβ peptides was shown in AD slow patients. A significantly shorter telomere length was also associated with AD slow patients. All of this work suggests that a profile with high IL-10 production and high IFN-γ (-874 TT) genotype could confer a slower AD progression. It was also found that telomere length may be a marker of cognitive impairment. It is clear that these preliminary results need to be confirmed in a larger study with a larger number of patients.

INTRODUCTION. Les troubles neurocognitifs sévères ou démences sont notamment définis par la CIM-10 et le DSM-5. Ils englobent un cadre nosographique large : démence d’Alzheimer, démence vasculaire, démence à corps de Lewy, dégénérescence lobaire fronto-temporale, etc. Chaque type de démence possède des critères diagnostiques propres et des facteurs de risque partiellement identifiés. Identifier les troubles cognitifs dans les grandes bases de données est une question complexe, qui doit tenir compte de l’évolution des connaissances. Notre premier objectif était de décrire l’évolution des codages de démences dans la base nationale du Programme de Médicalisation des Systèmes d’Information (PMSI) de court séjour, au fil de l’évolution des critères diagnostiques. Notre deuxième objectif était d’énumérer les principaux facteurs associés connus de maladie d’Alzheimer. Notre troisième objectif était de déterminer les facteurs associés à l’apparition d’une maladie d’Alzheimer dans la base nationale du PMSI de court séjour.METHODES. Pour le premier travail, nous avons utilisé les diagnostics principaux sur le site ScanSanté pour le PMSI de court séjour de 2007 à 2017. Pour le deuxième travail, nous avons effectué une synthèse des revues de littérature et méta-analyses en utilisant les moteurs de recherche PubMed et LiSSa. Pour le troisième travail, nous avons réalisé une étude analytique par fouille de données dans la base nationale du PMSI de court séjour chez les patients âgés de 55 ans ou plus en 2014 : nous avons sélectionné 137 variables explicatives potentielles en 2008 ; la variable à expliquer était la maladie ou démence d’Alzheimer en 2014.RESULTATS. Notre premier travail sur l’identification des démences met en évidence une diminution des séjours hospitaliers avec pour diagnostic principal une maladie ou démence d’Alzheimer, avec un glissement vers d’autres troubles mentaux organiques ; une stabilité des séjours hospitaliers avec pour diagnostic principal une démence vasculaire mais avec une modification des sous-diagnostics (diminution des diagnostics principaux d’infarctus multiples et augmentation de tous les autres sous-types) ; une augmentation importante des séjours hospitaliers avec pour diagnostic principal une démence ou autre trouble cognitif persistant ou tardif liés à la consommation d’alcool ; une évolution homogène sur l’ensemble du territoire français. Ces résultats sont en faveur d’un codage respectueux des évolutions de la littérature. Nos deux travaux suivants sur l’identification des populations à risque permettent d’identifier plusieurs facteurs associés à la maladie ou démence d’Alzheimer, notamment l’âge, le sexe féminin, le diabète de type 2, la dépression, la dénutrition, les troubles bipolaires, psychotiques et anxieux, le faible niveau de scolarité, l’excès d’alcool, l’épilepsie, les chutes après 75 ans et l’hypertension intracrânienne. Ces facteurs associés peuvent être des facteurs de risque, des symptômes précoces, révélateurs ou précipitants.CONCLUSION. Identifier les troubles cognitifs dans les grandes bases de données implique de bien comprendre l’évolution des codages de démence, qui semble respecter l’évolution des connaissances. L’identification des patients ayant des facteurs associés aux démences permet un repérage précoce plus ciblé, puis une bonne identification du diagnostic étiologique nécessaire à une prise en charge adaptée. / INTRODUCTION. Severe neurocognitive disorders or dementias are defined by ICD-10 and DSM-5. They encompass a broad nosographic framework: Alzheimer's dementia, vascular dementia, Lewy body dementia, frontal-temporal lobar degeneration, etc. Each type of dementia has its own diagnostic criteria and partially identified risk factors. Identifying cognitive disorders in large databases is a complex issue, which must take into account changes in knowledge. Our first objective was to describe the evolution of dementia coding in the national database of the Medicalization of Information Systems Program (PMSI) for short stays, as diagnostic criteria evolved. Our second objective was to summarize the main known associated factors of Alzheimer's disease. Our third objective was to determine the factors associated with the onset of Alzheimer's disease in the national database of the short stay PMSI.METHODS. For the first work, we used the main diagnoses on the ScanSanté site for the short stay PMSI from 2007 to 2017. For the second work, we synthesized the literature reviews and meta-analyses using the PubMed and LiSSa search engines. For the third work, we conducted an analytical study by data mining in the national database of the short stay PMSI for patients aged 55 years or older in 2014: we selected 137 potential explanatory variables in 2008; the dependant variable was Alzheimer's disease or dementia in 2014.RESULTS. Our first work on the identification of dementias shows a decrease in inpatient stays with a main diagnosis of Alzheimer's disease or dementia, with a shift towards other organic mental disorders; stability of inpatint stays with a main diagnosis of vascular dementia but with a modification of under-diagnosis (decrease in main diagnoses of multiple heart attacks and increase in all other subtypes); a significant increase in inpatient stays with a main diagnosis of dementia or other persistent or late cognitive disorders related to alcohol consumption; a homogeneous evolution throughout the French territory. These results support a coding that respects the evolution of the literature. Our next two studies on the identification of at-risk populations identify several factors associated with Alzheimer's disease or dementia, including age, gender, diabetes mellitus, depression, undernutrition, bipolar, psychotic and anxiety disorders, low education, excess alcohol, epilepsy, falls after age 75 and intracranial hypertension. These associated factors may be risk factors, early, revealing or precipitating symptoms.CONCLUSION. Identifying cognitive disorders in large databases requires a good understanding of the evolution of dementia coding, which seems to respect the evolution of knowledge. The identification of patients with factors associated with dementia allows a more focused early identification and then proper identification of the etiological diagnosis necessary for appropriate management.