New strategies for integrating sample pretreatment with chemical analyses under a single format is required for rapid, sensitive and enantioselective analyses of low abundance metabolites in complex biological samples. Capillary electrophoresis (CE) offers a unique environment for controlling analyte/reagent band dispersion and electromigration properties using a discontinuous electrolyte system allowing for highly efficient separations to be achieved. A fundamental study of the thermodynamic and electrokinetic parameters influencing enantioselectivity in chiral CE separation is first examined. A new strategy for single-step analysis of low abundance metabolites via online sample preconcentration with chemical derivatization by CE (SPCD-CE) is then detailed within. In-capillary sample preconcentration serves to enhance concentration sensitivity via electrokinetic focusing of long sample injection volumes for lower detection limits, whereas chemical derivatization by zone passing of single or multiple reagents is used to expand detectability and selectivity, notably for enantiomeric resolution of metabolites lacking intrinsic chromophores. Together, on-line SPCD-CE can provide over a 100-fold improvement in concentration sensitivity, shorter total analysis times, reduced sample handling and improved reliability for a variety of biologically relevant amino acid and amino sugar metabolites, which is also amenable to automated high-throughput screening. The basic method development and optimization parameters relevant to SPCD-CE, including applications to bacterial metabolite flux and biomarker analyses are discussed. Insight into the mechanism of analyte focusing and labelling during electromigration by SPCD-CE is also presented, as well as future directions for continued research using this unique integrated analytical platform. / Thesis / Doctor of Philosophy (PhD)

In clinical trials, placebo response is considered a beneficial effect arising from multiple factors, including the patient’s expectations for the treatment. Due to the presence of placebo response, the classical parallel design often fails to declare an efficacious treatment. The Sequential Parallel Comparison Design (SPCD), a two-stage design where the first stage is a classical parallel trial, followed by another parallel trial among placebo patients from the first stage, was proposed to mitigate the placebo response. In SPCD, in lieu of treatment effect, a weighted average of the mean treatment difference in Stage I among all randomized patients and the mean treatment difference in Stage II among placebo non-responders was proposed as the efficacy measure. However, by mixing two possibly different populations, this weighted average lacks interpretability, the choice of weight remains controversial, and the classification of patients into placebo responders and non-responders via hard criterion-based rule warrants careful consideration. In this work, we first elaborate and study the shortcomings surrounding this efficacy measure, which motivates us to propose causal estimands for clinically meaningful principal strata under the principal stratification framework. To make the estimands identifiable, we invoke a set of assumptions and introduce two sensitivity parameters. Meanwhile, in the absence of a clinically proven criterion for classifying responders and non-responders, we additionally suggest estimating the response status and sensitivity parameters via the Expectation-Maximization (EM) algorithm by treating the principal strata as full latent characteristics. Next, we further refine and alternatively propose a more consistent and sophisticated EM procedure for classification, point estimation, and hypothesis testing. Finally, we evaluate our methods with extensive simulation studies and apply them to an actual SPCD study of antidepressant therapy to assess the benefit of low-dose aripiprazole adjunctive to antidepressant therapy treatment, the ADAPT-A trial. In conclusion, we believe this is an important step toward a more rigorous and transparent approach to evaluating the treatment benefit in the presence of placebo response. / 2025-09-18T00:00:00Z

La maladie d’Alzheimer (MA) est la plus répandue des maladies neurodégénératives. Elle se caractérise par une déficience cognitive puis fonctionnelle souvent associée à des Symptômes Psychologiques et Comportementaux des Démences (SPCD). Les études longitudinales de corrélations physiopathologiques des SPCD sont rares et difficiles à évaluer en raison de grandes hétérogénéités dans les populations étudiées. Associée à l’expertise clinique, la neuroimagerie fournit des indices cruciaux pour comprendre les corrélats neuroanatomiques des SPCD les plus invalidants dans la MA. Dans les travaux de recherche, il apparaît déterminant de considérer la MA associée à certaines co-pathologies neurodégénératives et vasculaires. En effet, alors que les patients jeunes sont les plus touchés par des lésions pures, le vieillissement favorise l'apparition de co-lésions liées à la MA et aux Maladies à Corps de Lewy (MCL) et Maladies CérébroVasculaires (MCV).Soutenu par un travail bibliographique sur la MA et ses co-lésions, ce travail de thèse s’appuie sur 3 études complémentaires. La 1ière porte sur une revue de littérature ayant pour objectif d’évaluer les corrélats neuroradiologiques des SPCD dans la MA. Différents moteurs de recherche de données bibliographiques ont permis d’identifier 118 études évaluant cet objectif. Un modèle global des corrélats cérébraux des SPCD a été proposé pour soutenir la forte implication de la région frontale. Aussi, des stratégies méthodologiques ont été suggérées pour aider à diriger de futures recherches. La 2ième étude avait pour objectif d’évaluer si le profil d’atrophie cérébrale pouvait déterminer le risque de développer des SPCD dans la MA. Une analyse volumétrique de données IRM a été effectuée pour évaluer l’atrophie régionale en incluant 53 patients MA sans SPCD significatifs à l’inclusion et 40 contrôles. Vingt-quatre structures dans les régions frontale, temporale, pariétale, occipitale et sous-corticale ainsi que dans le cervelet ont été identifiées comme associées aux SPCD. L'atrophie frontale semble être le prédicteur le plus significatif des SPCD. La 3ième étude s’inscrit en continuité et en perspective de ce travail de thèse. Elle a pour but d’explorer ces questions chez des patients atteints de MA associée à des co-lésions de MCL et MCV / Alzheimer's disease (AD) is the most common neurodegenerative disease. AD is characterized by cognitive and functional impairment often associated with Behavioural and Psychological Symptoms of Dementia (BPSD). Longitudinal studies of pathophysiological correlations of BPSD are rare and difficult to evaluate due to large heterogeneities in the populations studied. Associated with clinical expertise, neuroimaging provides crucial clues to understand the neuroanatomic correlates of the most disabling BPSD in AD. It seems important to consider in the research, AD with some neurodegenerative and vascular co-pathologies. Indeed, while young patients are the most affected by pure lesions, aging favors the appearance of co-lesions related to AD and Lewy body disease and cerebrovascular diseases.Supported by a bibliographic work on AD and its co-lesions, this work is based on 3 complementary studies. The first concerns a literature review aimed at evaluating neuroradiological correlates of BPSD in AD. Bibliographic search has led to 118 studies evaluating this objective. A global pattern of cerebral cortical brain regions has been proposed to support the strong involvement of the frontal region. Also, methodological strategies have been suggested to help direct future research. The aim of the second study was to evaluate whether the profile of cerebral atrophy could determine the risk of developing BPSD in AD. A volumetric analysis of MRI data was performed to evaluate regional atrophy by including 53 patients with no significant BPSD at baseline and 40 controls. Twenty-four structures in the frontal, temporal, parietal, occipital and subcortical regions as well as in the cerebellum were identified as associated with BPSD. Frontal atrophy appears to be the most significant predictor of BPSD. The third study is in continuity of this work of thesis. It is intended to explore these issues in patients with AD associated with co-lesions