Introduction : Ces dernières années, les auteurs se sont attachés à créer une théorie générale de la problématique de la relation d’aide afin de mettre en évidence l’importance de la place occupée par les familles auprès du sujet âgé souffrant de la maladie d’Alzheimer. Il peut toutefois être intéressant de replacer l’aidant dans sa singularité de sujet affecté par d’autres questionnements que ceux relatifs à l’aide, afin de déterminer les facteurs influençant son vécu. Problématique : Dans quelle mesure la personnalité, les représentations du vieillissement, le lien de parenté et la qualité des relations passées vont influencer le vécu du rôle d’aidant principal d’un parent ou conjoint âgé en perte d’autonomie psychique, que ce dernier réside à domicile ou en institution ? Objectifs : Dans un premier temps, ce travail a pour objectif, d’établir les relations entre les différentes dimensions du vécu de l’aidant familial (difficultés, satisfactions et stratégies). Il se propose ensuite d’étudier l’influence sur ce vécu du lien de parenté et de l’entrée en institution d’une part, et de la personnalité (modèle en Cinq dimensions) et des représentations de la vieillesse d’autre part. Méthodologie : Pour ce faire, nous avons mené une étude auprès de 113 participants, dont 80 enfants et 33 conjoints. La première moitié accompagnait un proche à son domicile, la seconde en institution. Dans une première partie de l’étude, les participants ont rempli un questionnaire sociodémographique accompagné d’échelles évaluant la qualité des relations passées (QRASA), le fardeau (ZBI), les difficultés (CADI), satisfactions ressenties (CASI) et stratégies utilisées (CAMI) dans la relation d’aide, la personnalité (NEO PI-R) et la dépression (BDI). Dans un second temps, dix-sept participants ont été vus en entretien semi-directif afin d’appréhender qualitativement leur expérience d’aidant, les relations qu’ils entretiennent avec la personne accompagnée ainsi que leurs représentations de la vieillesse. Résultats : Les résultats de cette étude montrent que les difficultés, satisfactions ressenties et stratégies utilisées dans la relation d’aide sont liées entre elles, créant un équilibre nécessaire pour que l’aidant familial puisse investir son rôle. Cet équilibre est influencé aussi bien par des facteurs situationnels (lieu de résidence de la personne malade), relationnels (qualité des relations avec la personne accompagnée) que personnels (personnalité et représentations liées au vieillissement). Conclusion : Les implications en termes d’accompagnement et de prévention auprès de cette population sont discutées. / Introduction: Over the past years, authors have proposed a general theory of the caregiving relationship in order to highlight the importance of the place occupied by the families, who have an elderly relative suffering from Alzheimer's disease. However, it may be interesting to consider the caregiver with all his specificities, and as an individual affected by other problems than only the caregiving. We wonder to what extent the personality of a caregiver, the representations of the ageing process, the family relationship and the quality of the past relationships can influence the experience of caregiving. The studied caregivers were children or spouses of a patient losing his psychic autonomy, living at home or in an institution. Methods: We realized a study with 113 subjects (80 children and 33 spouses of an Alzheimer’s patient). Half of the patients were living at home and the other half in an institution. First, all caregivers filled a socio-demographic questionnaire and different clinical scales, assessing: the quality of the passed relationships (QRASA) ; the burden (ZBI) ; the difficulties (CADI ), satisfactions (CASI ) and strategies they used (CAMI) in the caregiving situations ; the personality (NEO PI-R) and the depression (BDI ). Second, 17 subjects have been seen in a semi-structured interview in order to qualitatively assess their experience of the caregiving, the past and present relationship they have with their parent or spouse. Results: The results of this study showed that the difficulties, the satisfactions which are experienced, and the strategies which are used in the caregiving relation are linked together. A balance between these variables is required for the family caregiver to invest his role. This balance is influenced by situational factors (the place where the patient lives), relational factors (the quality of the present and past relationship with the patient) as well as personal factors (personality and representations linked to the ageing process). Conclusion: The implications in terms of support and prevention for this population of caregivers are discussed.

Alzheimer’s disease (AD) is associated with amyloid-beta peptide deposition and loss of mitochondrial function. Using a transgenic C. elegans AD worm model expressing amyloid-beta in body wall muscle, we determined that supplementation with either of the forms of vitamin B2, flavin mononucleotide (FMN) or flavin adenine dinucleotide (FAD) protected against amyloid-beta mediated paralysis. FMN and FAD were then assayed to determine effects on ATP, oxygen consumption, and reactive oxygen species (ROS) with these compounds not significantly improving any of these mitochondrial bioenergetic functions. Knockdown of the daf-16/FOXO transcriptional regulator or the FAD synthase enzyme completely abrogated the protective effects of FMN and FAD, while knockdown of the mitochondrial unfolded protein response factors ubl-5 or atfs-1 also blocked the protective effects. Therefore, vitamin B2 supplementation could lead to the activation of conserved signaling pathways in humans to delay the onset and progression of neurodegenerative diseases such as AD.

Discovery of Novel Serum Biomarkers for Diagnosing and Staging Alzheimer’s DiseaseDipti Jigar ShahDepartment of Chemistry and Biochemistry, BYUDoctor of PhilosophyAlzheimer’s disease (AD) is an untreatable neurologic disease affecting more than 5 million Americans, most over 60 years of age. Protein plaques and neurofibrillary tangles typify AD brain pathology and are thought to cause the progressive dementia and brain shrinkage observed in AD. Currently there are no methods to diagnose the disease at a time before damage becomes irreversible.Biochemical tests for AD using cerebrospinal fluid analysis or neuroimaging are not yet sufficiently sensitive and specific, and they are invasive. This points to a need for a more easily applied and more sensitive diagnostic test. Although the gross anatomical changes are localized to the brain, AD is likely to involve changes throughout the body. As a result of this, changes in the abundance of certain biomolecules present in the circulation system are likely to occur. Consequently, a serum proteomics approach able to measure such changes, when applied to AD, would likely find quantitative changes in relevant molecules that can help diagnose the disease correctly, ideally early in the disease process. The goal of this work was to discover and validate novel diagnostic serum biomarkers for AD. For biomarker discovery and validation, we used a novel serum proteomics approach involving reversed phase capillary-liquid chromatography-electrospray ionization-quadrupole-time of flight mass spectrometry. Our samples were protein depleted, which helped us survey low molecular weight species in the serum without ion suppression from larger proteins like albumin. We were able to observe more than 8000 molecular species in a single run. The overall project was comprised of four studies: (i) discovery of novel potential serum AD markers, (ii) blinded validation of diagnostically promising biomarkers found in the initial study, with their further chemical identification, (iii) exploring gender-based serum AD biomarkers, and (v) discovery of biomarkers that distinguish early versus moderate stage AD. In the first study, the approach found 38 significant (p < 0.05) biomarkers and 21 near significant (p = 0.05 to 0.099) biomarkers. On using the forward selection approach, we built multi-marker panels with specificities and sensitivities higher than 80%.The second study reports on a blinded validation study that was performed on a new set of serum samples. We focused on the 13 most promising AD biomarkers found as part of the initial study. We successfully validated 4 of these biomarkers that showed highly significant statistical p-values. As part of this study, research was conducted to identify these 4 biomarkers, which was accomplished using tandem mass spectrometry with fragmentation experiments. The third study used data from the initial study but looked at gender specific biomarkers. We found 31 significant and near significant serum AD biomarkers for women, 16 for men, and 25 that were gender independent. Multi-marker panels of AD biomarkers for women or men had sensitivities of >60% and specificities >85%.In the fourth study, cases with moderate AD were compared to cases with very mild or mild AD to find novel biomarkers that could be used for staging. We found 44 significant and near significant biomarkers that were quantitatively different between mild and severe AD. In conclusion, we were successful in accomplishing the goal of this work of finding, validating and identifying novel serum biomarkers that diagnose AD.

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In the literature, the experience of ‘care’ and ‘caregiving’ has been well documented and widely researched. Caregivers are recognized as people (family and friends) who provide unpaid substantial care for family members. Over time, research has increased awareness of caregivers as a distinct social group and has also contributed to caregiving being a widely recognized social issue. However, despite this increased awareness and continued concern for caregivers, much of the literature focuses on adult caregivers. As a result, the experiences of other caregiving populations, such as the youth and young adults, continues to be overlooked and underrepresented. Therefore, there is a need to explore and understand the unique experience of this population and how they give meaning to their experiences. Young caregivers (YCs) are children (5-18) and young adults (18-25) who provide substantial (unpaid) care for a family member who has an illness or disability (Stamatopoulos, 2016). Research on this population is scant and there exists many notable gaps in the literature in terms of diversity, age-based differences, programming and best practices for intervention. More specifically, there is a gap in understanding the experiences of young caregivers who are affected by progressive and incurable chronic brain diseases such as Alzheimer’s Disease or a Related Dementia. As such, this dissertation explores the experiences of YACs affected by ADRD, in terms of their personal experiences with ADRD (knowledge, dementia care and care practices), perceptions of their caregiving role and how they navigate the caregiving role. It builds on scholarship on young caregivers to broaden existing knowledge by using a phenomenological approach, known as Interpretive Phenomenological Analysis, to explore their caregiving experiences and the meaning they give to these experiences in-depth (n=12). It also aims to challenge the dominant assumptions about young caregivers by giving voice to this population by situating the young caregivers as the experts in their own lives. Findings indicate that the caregiving experience for YACs is complex, and situated within a larger socio-political context, which impacts the overall experience of care. Overall, the findings contribute to knowledge on the experiences of care among YACs and highlight the need for more inclusive research and practices on addressing caregiving among this group. / Dissertation / Candidate in Philosophy / This dissertation explores the lived experiences of young adult caregivers (YACs) caring for an older adult with Alzheimer’s Disease or a Related Dementia. Research on this group of caregivers is limited, particularly YACs (ages 18-25) who provide substantial (unpaid) caregiving for an older adult affected by Alzheimer’s or a Related Dementia. Therefore, a key aim of this research is to generate awareness and shed light on the nature of caregiving as experienced by this overlooked population of caregivers. As such, this dissertation aims to understand how young caregivers give meaning to, interpret and make sense of their caregiving experience. To understand the caregiving experience of YACs, I conducted interviews with 12 YACs from Canada and the United States and analyzed their perspectives in detail. The findings shed light on the many factors that shape the caregiving experiences. In addition, the findings show that more research is needed to understand the differences amongst young caregivers to better support their needs. In general, the research can contribute to existing knowledge on young adult caregivers, as well as relevant programs and policies.

This critical synopsis of prior work by Clive Beggs is submitted in support of a PhD by published work. The work focuses on venous and cerebrospinal fluid (CSF) anomalies associated with multiple sclerosis (MS) and other neurological diseases. MS is characterized by focal inflammatory lesions, which are often venocentric. Recently a vascular syndrome, chronic cerebrospinal venous insufficiency (CCSVI) has been linked with MS. This syndrome, which is characterized by constricted cerebral venous outflow, has become mired in controversy, with various studies producing conflicting findings, with the result that the science associated with CCSVI has become obscured. Clive Beggs work seeks to bring clarity to the debate surrounding CCSVI by characterizing physiological changes associated with constricted cerebral venous outflow. The work submitted here involves collaborative studies with Robert Zivadinov (University of Buffalo), Paolo Zamboni (University of Ferrara), and Chih- Ping Chung (National Yang Ming University of Medicine). The key findings of these studies are: (i) MS patients, diagnosed with CCSVI, exhibit greatly increased hydraulic resistance of the cerebral venous drainage system; (ii) MS patients experience loss of the small cerebral veins; (iii) MS patients exhibit reduced CSF bulk flow, consistent with mild venous hypertension; (iv) MS patients exhibit increased CSF pulsatility in the Aqueduct of Sylvius, which appears to be linked with mild venous hypertension associated with CCSVI; and (v) jugular venous reflux is associated with white matter and parenchymal volumetric changes in Alzheimer’s patients. Collectively, these findings suggest that extracranial venous anomalies are associated with changes in the intracranial physiology.

Alzheimer’s disease (AD) drugs in therapy are limited to acetylcholine esterase inhibitors and memantine. Newly developed drugs against a single target structure have an insufficient effect on symptomatic AD patients. Results: Novel aromatically anellated pyridofuranes have been evaluated for inhibition of AD-relevant protein kinases cdk1, cdk2, gsk-3b and Fyn. Best activities have been found for naphthopyridofuranes with a hydroxyl function as part of the 5-substituent and a hydrogen or halogen substituent in the 8-position. Best results in nanomolar ranges were found for benzopyridofuranes with a 6-hydroxy and a 3-alkoxy substitution or an exclusive 6-alkoxy substituent. Conclusion: First lead compounds were identified inhibiting two to three kinases in nanomolar ranges to be qualified as an innovative approach for AD multitargeting.

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Extracellular accumulation of Aβ in β-amyloid plaques is thought to be associated with the neurodegeneration observed in Alzheimer’s disease (AD) patients, although a lack of correlation with cognitive decline raised doubts on this hypothesis. In different transgenic mouse models Aβ accumulates inside the cells and mice develop behavioral deficits well before visible extracellular β-amyloid accumulation. Here we show that intracellular Aβ accumulates in flotillin-1 positive endocytic vesicles. We also demonstrate that flotillin-1 is not only associated with intracellular Aβ in transgenic mice but also with extracellular β-amyloid plaques in AD patient brain sections. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

La maladie d’Alzheimer est majoritairement sporadique et peu est connu sur les mécanismes déclenchant le développement de cette forme de la maladie. Les études sur la forme familiale ont attribué une importance particulière à la bêta-amyloïde (Aβ), un produit de clivage du précurseur de la protéine amyloïde (APP). Plusieurs facteurs de risques ont été identifiés comme déclencheurs potentiels du développement de la maladie d’Alzheimer dont le diabète de type II (T2D). En effet, la déficience de la signalisation de l’insuline par la désensibilisation des récepteurs de l’insuline (IR) dans le cerveau semble être une caractéristique commune aux deux maladies. Les effets à long terme de la résistance à l’insuline sur l’accumulation d’Aβ et sur la phosphorylation de Tau ont été étudiés, mais les effets de la perturbation aiguë des IR sont moins bien caractérisés. Aussi, les désordres métaboliques sont également des caractéristiques communes aux deux maladies. Le but de notre étude est de déterminer si la perturbation aiguë des IR peut affecter le clivage de l’APP et si la privation énergétique par le jeûne peut sensibiliser ce clivage à la perturbation aiguë des IR. Pour évaluer ceci, nous avons utilisé la Tyrphostin AG1024 à faible dose pour simuler une perturbation des IR plutôt qu’un blocage complet des récepteurs. Pour quantifié le clivage de l’APP, nous avons mesuré les changements de la quantité d’APP taille pleine totale par immunobuvardage de type Western. Pour s’assurer que les changements de la quantité d’APP taille pleine traduisait bien un clivage, nous avons développé un système de lecture par luciférase. Ce système nous permet de suivre le clivage de l’APP via l’expression de la luciférase Firefly puisque le facteur de transcription GAL4 est lié à la portion C-terminale de l’APP . Tout d’abord, nous avons observé que la perturbation aiguë des IR par la Tyrphostin mène au clivage de l’APP et que le jeûne augmente la vulnérabilité au clivage de l’APP suite à une plus petite dose de Tyrphostin. Ce clivage serait imputable à la voie amyloïdogénique puisque l’inhibition de la β-secrétase et de la γ-secrétase empêche le clivage de l’APP. Nous avons aussi montré que la perturbation des IR est nécessaire alors que la perturbation spécifique des IGF-1R n’est pas suffisante. De plus, ni l’autophagie, ni les caspases et ni le protéasomes ne semblent impliqués dans le clivage de l’APP suivant la combinaison du jeûne et de la petite perturbation des IR. L’activité de mTOR n’est également pas requise. Cependant, l’activité de la GSK3 est nécessaire au clivage et semble affecter le clivage par la γ-secrétase. Nous avons ensuite confirmé dans des cultures primaires neuronales que la combinaison du jeûne et de la perturbation aiguë des IR cause le clivage de l’APP et que la GSK3 est encore une fois fortement active. Ainsi, nos résultats suggèrent que la perturbation de la signalisation de l’insuline tel qu’observé dans le T2D augmente le clivage de l’APP via la voie amyloïdogénique et, donc, contribue à la pathologie de la maladie d’Alzheimer. / Little is known about the mechanisms that trigger the onset of Alzheimer’s disease (AD), a primarily sporadic disease. Studies on the familial form of AD attributed a particular importance to Amyloid beta (Aβ), a cleavage product of the Amyloid precursor protein (APP). Many risk factors have been identified as potential triggers of the development of AD including Type 2 diabetes (T2D). Indeed, the impairment of insulin signaling by the desensitization of insulin receptors (IR) in the brain seems to be a common hallmark of both diseases. The long term effects of IR resistance on the accumulation of Aβ and Tau hyperphosphorylation have been studied, but the acute effects of IR perturbation is less characterized. Also, both diseases show metabolic defects. Our research aimed to determine whether acute perturbation of IR signaling affects APP processing and if starving (energy deprivation) could sensitize this processing to acute perturbation of IR. To assess this, we used small doses of Tyrphostin AG1024 to simulate IR perturbations rather than a complete blocakade of the receptors. To quantify APP processing, we measured the change of total full- lenght APP by Western blot. To ensure that this change reflected APP processing we developed a luciferase based readout system. This system allowed us to monitor the occurrence of APP cleavage via GAL4-UAS Firefly luciferase driven expression because we linked GAL4 transcription factor to the C-terminal region of APP. First, we showed that IR perturbation with Tyrphostin leads to APP processing and that starving increased IR susceptibility to a smaller doses of Tyrphostin. This APP processing occurs via the amyloidogenic pathway because inhibition of β- and γ-secretase inhibited APP processing. We showed that this processing absolutely requires IR perturbation, while IGF-1R perturbation alone is insufficient. Furthermore, neither autophagy, caspases nor proteasome seemed to be implicated in APP processing following starvation and small IR perturbation. The activity of mTOR is also not required. On the contrary, GSK3 activation is necessary for the processing and seems to affect γ-secretase cleavage. We then confirmed in primary cultured neurons that the combination of acute starvation and small IR perturbation causes APP cleavage and GSK3 is again strongly activated. Taken together, our results suggest that the impairment of IR signalling seen in T2D increases the processing of APP via the amyloidogenic pathway and thereby contributes to the pathology of AD.