Émotions et nouvelles technologies apparaissent le plus souvent comme une alliance impossible. Pourtant, ces dernières années, les nouvelles technologies, telles que les capteurs portés et les logiciels de reconnaissance d’activités, ont permis une évaluation plus fine des émotions. A travers cette thèse notre objectif était de développer et de tester divers instruments technologiques permettant l’évaluation et la prise en charge des émotions que ce soit au niveau comportemental, physiologique ou cognitif. Nous avons commencé par faire un état des lieux des nouvelles technologies disponibles pour l’évaluation et la prise en charge des troubles émotionnels. Nous avons ensuite recueilli les recommandations d’experts pour leur utilisation ainsi que l’avis des internes de psychiatrie et des médecins généralistes. Au sein de notre deuxième étude, nous avons développé un test informatisé permettant de mesurer les défauts de ressenti et de régulation des émotions propres aux composantes physiologique et cognitive des émotions. Notre troisième étude a consisté à élaborer une prise en charge des troubles émotionnels dans ces deux composantes par une immersion sensori-virtuelle et à étudier l’effet de cette dernière sur le langage de patients avec et sans troubles cognitifs. Enfin, notre quatrième étude a visé à développer une plateforme automatisée d’évaluation et de prise en charge des troubles émotionnels dans la composante comportementale. Nous avons développé et évalué l’intérêt des algorithmes de reconnaissance d’activité pour leur détection et des solutions non pharmacologiques basées sur l’aromathérapie, la musicothérapie et les serious games pour leur prise en charge. / Emotions and new technologies often sound as an impossible association. However, in recent years, new Information and Communication Technologies (nICT) such as wearable sensors and software for activity recognition have enabled to assess emotions more accurately. This dissertation aimed at developing and testing various nICT-based tools allowing a better assessment and management of emotions, either at the behavioral, physiological or cognitive level. I started with a literature review of the existing nICT for the assessment and management of emotional disorders. I then gathered recommendations for the use of nICT from experts in the field, as well from interns in psychiatry and general practitioners (Study 1). Next, I developed a computerized test to assess impairments in emotional experience and emotion regulation at the physiological and cognitive level (Study 2). Study 3 consisted in developing a tool to manage emotional disorders at the physiological and cognitive level by means of a multisensory, virtual immersion, and assessing the effects of this immersion on the verbal ability of patients with and without cognitive impairment. Finally, in Study 4 I developed an automated platform for the assessment and management of emotional disorders at the behavioral level. In this context, I developed and evaluated the interest of employing activity recognition algorithms for the detection of behavioral emotional disorders, and I evaluated the effects of nonpharmacological solutions based on aromatherapy, music therapy and serious games for the management of these disorders.

Cette thèse avait pour objectif de tester la théorie de la rétrogenèse appliquée au langage des personnes atteintes de la maladie d’Alzheimer, afin de tirer des conclusions permettant d’adapter notre comportement aux patients et de mettre en place des méthodes de maintient dans le langage plus appropriées.Pour ce faire, trois tâches ont été mises en place : une tâche de fluence verbale (phonémique (lettre initiale P) puis sémantique (animaux)), une tâche de dénomination d’images, ainsi qu’une tâche de répétition de phrases. Trois groupes de participants ont été créés : un groupe de 80 personnes atteintes de la maladie d’Alzheimer, un groupe de 60 enfants, âgés de 3 à 11 ans, puis un groupe contrôle de personnes âgées saines. Le groupe des patients était divisé en 4 sous-groupes en fonction de leur score au MMSE. Il en était de même pour les enfants, répartis en trois sous-groupes.Les analyses effectuées par le biais de modèles mixtes, ont permis de montrer que le déclin du langage dans la maladie d’Alzheimer semble bien suivre un ordre symétrique à celui de son acquisition. L’effet d’AoA permet souvent d’expliquer ce phénomène. Toutefois, des différences entre les enfants et les personnes Alzheimer sont également observables : si le langage semble suivre une involution symétrique à celle de l’enfant, il n’en est pas moins que les processus sous-jacents impliqués ne sont pas les mêmes que chez l’enfant. / The aim of this thesis was to test retrogenesis hypothesis applied to the language of people with Alzheimer's disease, in order to draw conclusions allowing us to adapt our behavior to patients and to implement appropriate methods of maintaining language.To do this, three tasks were established: a verbal fluency task (phonemic (initial letter P) and then semantic (animals)), an picture naming task, and a sentence repetition task. Three groups of participants were created: a group of 80 people with Alzheimer's disease, a group of 60 children, aged 3 to 11, and a healthy elderly control group. The patient group was divided into 4 subgroups based on their MMSE score. It was the same for children, divided into three subgroups.Analyzes conducted runing mixed models have shown that the decline of language in Alzheimer's disease seems to follow a symmetrical order to that of its acquisition. The effect of AoA can often explain this phenomenon. However, differences between children and Alzheimer's patients are also observable: if the language seems to follow an involution symmetrical to that of the child, it is nonetheless that the underlying processes involved are not the same as in the child.

Active learning strategies are important for facilitating deep learning that may be carried throughout life, but which is still finding its way into the college setting. Educators are not often trained in effective learning practices, which reduces the cognitive and proficiency gains of their students. By providing such guidance in the formative years of a teacher’s training, we hypothesize that the learning environment will be greatly enriched and enhanced. On the opposite end of the spectrum of life and cognition, the plague of dementia also warrants examination. Alzheimer’s disease (AD), an incurable neurodegenerative disorder progressing from the medial temporal lobe, is the most common form of dementia diagnosed in people over age 65, afflicting 30-40% of those 85 years and older. Despite its prevalence, effective treatments are limited because the principal causes and triggers of AD are not entirely understood. Growing evidence demonstrates that oxidative stress (OS) is an important factor contributing to the initiation and progression of AD. A key player contributing to this OS is iron, an essential trace mineral which is required for proper neuronal function, but which generates reactive oxygen species during redox transitions. Intracellular labile iron pool (LIP) levels are strictly regulated by proteins such as transferrin (import), ferroportin (export), and ferritin (storage). However, when these proteins become dysregulated, excess iron associates with other proteins such as amyloid beta (Aβ) and tau, aggregations of which are hallmarks of AD. In our hypothetical model, under extensive or prolonged OS, as occurs in AD, much larger Aβ plaques form because the stress does not abate. Hyperphosphorylated tau is the last resort to protect the cell against free iron, and aggregates when the LIP is elevated because neither iron storage in ferritin nor iron export through ferroportin can relieve the neurons of the free iron.

Fluorodeoxyglucose Positron Emission Tomography (FDG PET) and Magnetic Resonance Imaging (MRI) are commonly used in a clinical setting as an examination in Alzheimer’s Disease (AD) patients. FDG PET is an imaging tool to evaluate hypometabolism; meanwhile, the MRI observes the brain volume. However, it is still unclear which examination better reflects the tau tangles, which have been known as the hallmark’s pathology of AD. Therefore, this study was conducted to compare FDG PET and MRI in assessing tau pathology in AD, by utilizing a database from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). The presence of tau tangles was confirmed by using the Tau-PET images. In total, 275 cognitively impaired subjects were included as well as a subgroup of 147 subjects with positive amyloid status. Based on the analysis, it was observed that higher Tau-PET is significantly associated with FDG PET hypometabolism and MRI atrophy. A similar result was also seen in the amyloid positive subgroups. By comparing the spearman’s correlation coefficients, it was found that that the correlation was stronger between Tau PET and FDG PET (r=-0.414, p<0.001, and r=-0.475, p<0.001 in the positive amyloid subgroup) compared to Tau-PET and MRI (r=-0.331, p<0.001 and r=-0.440, p<0.001 in the positive amyloid subgroup). Inconclusion, FDG PET better reflects the tau pathology compared to MRI in AD.

Alzheimer’s disease (AD) is a multifactorial neurological condition associated with genetic profiles that are still not completely understood. We performed a family-based low-density genome-wide association analysis of age at onset (AAO) in AD (244 patients and their relatives) using Illumina 6 K single-nucleotide polymorphisms (SNPs) panel and the FBAT-logrank statistic. We observed 10 SNPs associated with AAO in AD with p < 2 × 10−3. The most significant hit within a known gene, the neuronal protein astrotactin 2 (ASTN2), was SNP rs1334071 (p = 8.74 × 10−4). ASTN2 has been implicated in several neuropsychiatric disorders, including cognitive disorders, autism and schizophrenia. We then conducted a replication study focusing on ASTN2 gene in a Canadian sample of 791 AD patients and 782 controls using the logrank test. Five ASTN2 SNPs (highest association is rs16933774 with p = 0.0053) showed associations with AAO in this Canadian sample (p < 0.05). Furthermore, Kaplan–Meier survival analysis of SNP rs16933774 showed that the AAO of AD in individuals heterozygous for AG genotype of rs16933774 (median of AAO = 68.5 years) was approximately 4.5 years earlier than those individuals having the AA genotype (median of AAO = 73 years). In conclusion, a significant association of ASTN2 genetic variants with AAO of AD in two independent samples demonstrates a role for ASTN2 in the pathogenesis of AD. Future functional studies of this gene may help to characterize the genetic architecture of the AAO of AD. Genetic factors in AAO may be a critical factor for early AD intervention and prevention efforts.

No study has focussed on the longitudinal effect of APOE-ε4 genotype on the logical memory delayed recall total (LDELTOTAL) score in late-onset Alzheimer’s disease (AD). The LDELTOTAL scores were collected at baseline, 12, 24, 36 and 48 months from 382 participants with AD, 503 with cognitive normal (CN), 1293 with mild cognitive impairment (MCI) in the Alzheimer's Disease Neuroimaging Initiative (ADNI). A linear mixed model (LMM) was used to investigate the effect of APOE-ε4 on the longitudinal changes in the LDELTOTAL scores adjusted for age, gender, education and baseline Mini Mental State Examination score. There were significant differences in LDELTOTAL scores among AD, CN, and MCI (P < 0.0001) and among APOE-ε4 alleles at baseline (P < 0.0001). In the multivariable LMM, elders with 75+ years (P = 0.0051), females (P < 0.0001), lower education (P < 0.0001), AD and MCI (both P values < 0.0001) were associated with decreased LDELTOTAL values, while the individuals with 1 or 2 APOE-ε4 allele revealed significantly lower LDELTOTAL scores (both P values <0.0001) compared with individuals without APOE-ε4 allele. Further, APOE-ε4 alleles had significant interactions with four follow-up visits, where all follow-up visits showed significantly higher LDELTOTAL score. In addition, gender showed interaction with age, education and APOE-ε4 with follow-up visits. Our findings provide the first evidence of the effect of APOE-ε4 genotype on the logical memory declines related to AD. Further, APOE-ε4 alleles showed interactions with gender and follow-up visits.

Ammonia is a toxic by-product of protein catabolism and is involved in changes in glutamate metabolism. Therefore, ammonia metabolism genes may link a range of diseases involving glutamate signaling such as Alzheimer’s disease (AD), major depressive disorder (MDD), and type 2 diabetes (T2D). We analyzed data from a National Institute on Aging study with a family-based design to determine if 45 single nucleotide polymorphisms (SNPs) in glutaminase (GLS), carbamoyl phosphate synthetase 1 (CPS1), or glutamate-ammonia ligase (GLUL) genes were associated with AD, MDD, or T2D using PLINK software. HAPLOVIEW software was used to calculate linkage disequilibrium measures for the SNPs. Next, we analyzed the associated variations for potential effects on transcriptional control sites to identify possible functional effects of the SNPs. Of the SNPs that passed the quality control tests, four SNPs in the GLS gene were significantly associated with AD, two SNPs in the GLS gene were associated with T2D, and one SNP in the GLUL gene and three SNPs in the CPS1 gene were associated with MDD before Bonferroni correction. The in silico bioinformatic analysis suggested probable functional roles for six associated SNPs. Glutamate signaling pathways have been implicated in all these diseases, and other studies have detected similar brain pathologies such as cortical thinning in AD, MDD, and T2D. Taken together, these data potentially link GLS with AD, GLS with T2D, and CPS1 and GLUL with MDD and stimulate the generation of testable hypotheses that may help explain the molecular basis of pathologies shared by these disorders.

The cyanobacterial toxin β-N-methylamino-l-alanine (BMAA) now appears to be a cause of Guamanian amyotrophic lateral sclerosis/parkinsonism dementia complex (ALS/PDC). Its production by cyanobacteria throughout the world combined with multiple mechanisms of BMAA neurotoxicity, particularly to vulnerable subpopulations of motor neurons, has significantly increased interest in investigating exposure to this non-protein amino acid as a possible risk factor for other forms of neurodegenerative illness. We here provide a brief overview of BMAA studies and provide an introduction to this collection of scientific manuscripts in this special issue on BMAA.

Genome-wide association studies (GWASs) have reported numerous associations between risk variants and Alzheimer’s disease (AD). However, these associations do not necessarily indicate a causal relationship. If the risk variants can be demonstrated to be biologically functional, the possibility of a causal relationship would be increased. In this article, we reviewed all of the published GWASs to extract the genome-wide significant (p < 5×10−8) and replicated associations between risk variants and AD or AD-biomarkers. The regulatory effects of these risk variants on the expression of a novel class of non-coding RNAs (piRNAs) and protein-coding RNAs (mRNAs), the alteration of proteins caused by these variants, the associations between AD and these variants in our own sample, the expression of piRNAs, mRNAs and proteins in human brains targeted by these variants, the expression correlations between the risk genes and APOE, the pathways and networks that the risk genes belonged to, and the possible long non-coding RNAs (LncRNAs) that might regulate the risk genes were analyzed, to investigate the potential biological functions of the risk variants and explore the potential mechanisms underlying the SNP-AD associations. We found replicated and significant associations for AD or AD-biomarkers, surprisingly, only at 17 SNPs located in 11 genes/snRNAs/LncRNAs in eight genomic regions. Most of these 17 SNPs enriched some AD-related pathways or networks, and were potentially functional in regulating piRNAs and mRNAs; some SNPs were associated with AD in our sample, and some SNPs altered protein structures. Most of the protein-coding genes regulated by the risk SNPs were expressed in human brain and correlated with APOE expression. We conclude that these variants were most robust risk markers for AD, and their contributions to AD risk was likely to be causal. As expected, APOE and the lipoprotein metabolism pathway possess the highest weight among these contributions.

La personne de confiance, créée par la loi du 4 mars 2002, permet au patient non communiquant, de transmettre sa parole au médecin, pour l'aider dans sa prise de décision. Dix ans après, la désignation de la personne de confiance reste rare, même en gériatrie, y compris pour les patients atteints de maladie d’Alzheimer. Plusieurs enquêtes par questionnaires et entretiens et une recherche-action ont été réalisés auprès des différents acteurs du soin gériatrique : patients, aidants, gériatres, médecins traitants et associations de patients, pour appréhender comment les professionnels de gériatrie se sont approprié la notion juridique de personne de confiance et ont modifié leurs pratique Les résultats montrent que les acteurs ne connaissent pas bien la loi et n’ont rien fait pour la mettre en œuvre, même s’ils en attendent beaucoup. Les équipes de soin peuvent cependant s’approprier le sujet et donner à la personne de confiance la place prévue par la loi. Des risques de dérives sont décrits : prise de pouvoir de la personne de confiance sur le patient, décharge de la responsabilité médicale, écartement des proches au profit de la seule personne de confiance, poids extrême pouvant peser sur cette dernière. Les professionnels trouvent que la procédure prend beaucoup de temps, qu’un document écrit n’est pas toujours adapté, que cela représente une charge supplémentaire, alors qu’ils sont déjà surchargés. Le manque de pratique entraine le manque d’utilisation. Les patients présentent parfois des difficultés de communication, limitant la possibilité de désigner. L’information sur la personne de confiance et sa désignation provoquent souvent une angoisse supplémentaire du patient face à sa possible mort prochaine. Il lui est parfois difficile de choisir entre ses enfants. Les professionnels pressentent que la personne de confiance n’a pas la même utilité pour tous. Elle est intéressante en soins d’urgence et de réanimation, mais les patients n’ont souvent pas le temps de la désigner avant d’en avoir besoin. Elle prend tout son sens dans les maladies chroniques, dont la maladie d’Alzheimer, pour lesquelles la désignation de la personne de confiance pourrait être anticipée par rapport à l’arrivée à l’hôpital. Il ne semble pas y avoir de limite, autre que celle de l’a priori moral des professionnels, à la possibilité de désigner une personne de confiance, même pour un patient atteint de maladie d’Alzheimer, la personne de confiance permettant alors au patient d’exprimer ses volontés au-delà de son handicap, en prenant au mieux en compte son ancienne personnalité et ses désirs actuels. Cette réflexion amène à certaines réserves éthiques. Le patient, sa personne de confiance et le médecin peuvent-ils conclure une alliance thérapeutique en médecine aiguë, alors que la patient est dépendant du médecin, par le fait même de sa maladie et de la proximité de la mort ? La logique des droits des patients a-t-elle une limite, puisque tous les patients n’ont pas accès à la désignation de leur personne de confiance ? Le risque de routinisation de la procédure est majeur, si le sens même de cette désignation n’est pas perçu par les différents acteurs. La réflexion autour de la prise de décision montre que le patient en semble souvent absent et pas toujours représenté par la personne de confiance. Le tuteur ne semble pas être le représentant idéal du patient, qui ne peut légalement plus désigner sa personne de confiance. Une amélioration du processus par le biais de bonnes pratiques de la désignation de la personne de confiance sont proposées : améliorer l’information de la population et des patients, former les professionnels aux conditions de désignation optimale pour le patient, informer la personne de confiance sur son rôle et sur sa responsabilité vis-à-vis du patient, de l’aidant familial et de la famille, extension de la procédure de désignation partout où il y a du soin / The Act of March 4th, 2002, has created a new actor in the doctor-patient relationship: the health care surrogate. This person can be designated by every patient at the beginning of the hospitalization, except patients under legal protection. This person can escort the patient to receive the medical information, so with a derogation of medical confidentiality. This person can also tell the doctor what the patient would want, if the patient is not able to communicate. So this health care surrogate could be the witness, who allows the patient who can no longer communicate, to advise the medical decision. Ten years after the law, few health care surrogates are designated, even in geriatric care and for people suffering from Alzheimer disease. Different studies have been done with people acting in geriatric care: patients, caregivers, geriatricians, general practioners, and patient’s associations. The aim of these studies was to appreciate how professional of geriatrics appropriated the juridical notion of health care surrogate and how they changed their practices. Results showed that the role and missions of the health care surrogate are insufficiently known by the patients and also by the professionals. But professionals can be trained and can give to the health care surrogate his right place. Some risks are described: health care surrogate taking power on the patient, discharge from medical responsibility, spacing proxies in the benefit of the health care surrogate, burden to the surrogate. Professionals found that the procedure is time consuming, that a written document is not always adapted and that it’s an additional burden, so they are already exhausted. The lack of practice leads to a lack of use. Designation is often difficult for patients that are then faced with their own death and particularly for those who had communication difficulties. Sometimes patients did not want to choose between their children, who will be their surrogate. Health care surrogate designation was interesting in acute care and emergency room but people did not have often enough time to do it. It makes sense in chronicle diseases, for which the designation may be anticipated before patient’s arrival in the hospital. It does not seem to be any limit to designate health care surrogate, other than the moral prejudices of professionals, even for patients with Alzheimer disease. Health care surrogates allowed Alzheimer patient to express himself his will, taking care of his old personality and his actual wishes. This reflexion leads to some ethical reserves. Can patient, health care surrogate and doctors make a therapeutic alliance in acute care? Thus patient is under medical power, due to his illness and the possibility to die. Do the patient’s rights have a limit, as some patients are not allowed to designate their surrogate? The risk of routine is extreme if the sense itself of the designation is lost or not seen by professionals. Patients are often excluded from the decision process. The legal protector of the patient does not seem to be the ideal health care surrogate. This could be ameliorated by good practice recommendations: improving population and patient information, improving professional’s training, informing the health care surrogates, caregivers and families. The designation’s procedure can be extended everywhere where care is done: home, networks, nursing homes… the tools for information and designation must be adapted to everyone, and be as different as patients can be. Progressive appropriation of the concept of the health care surrogate by the care system can be done, with help of the peer’s societies and patient’s associations