Neuroimaging biomarkeurs of structural and functional connectivity in Parkinson's disease
Institution:
Paris 6Disciplines:
Directors:
Abstract EN:
Parkinson’s disease (PD) is a debilitating neurodegenerative disorder involving progressive motor dysfunction, most commonly affecting elderly individuals. A hallmark of disease pathology is a loss of dopaminergic neurons in the substantia nigra and their terminals in the striatum. Neurodegeneration is thought to lead to a destabiliation of the normal signalling that occurs between these, and other cortical and subcortical brain regions. An important challenge for neuroscience lies in differentiating PD neuropathology from similar disorders, as well as those impairments that occur as part of normal aging. The purpose of this thesis was to apply neuroimaging, specifically magnetic resonance imaging (MRI), to identify and evaluate biomarkers of PD. Biomarkers are objective measures of biological state that can be used to quantify a disease, including the symptoms associated with its appearance and progression. Three standalone studies formed the basis of this work. In the first study, outliers in diffusion weighted MRI (DW-MRI) were probed using simulations and real data analyses, to understand their impact on candidate biomarker metrics. Metrics were found to be highly sensitive to error, and data correction was recommended to minimise bias in further analyses. A q-space interpolation method was proposed for identifying and correcting corruptionaffected data, and a decision support system outlined with which to treat this data. In the second study, candidate biomarkers in DW-MRI and resting state functional MRI (rsfMRI) were evaluated to determine their performance as metrics of structural and functional connectivity. A unique, multimodal paradigm demonstrated that anatomical and functional deficits could be attributed to PD for particular connections relevant to the sensorimotor circuit. In the third study, validation of the candidate biomarkers identified in PD was performed in a group of healthy subjects. Here, the objective was to understand the effects of aging on the same associative, limbic and sensorimotor circuitry connecting cortical and subcortical brain regions. Age-related variations in anatomical connectivity were found to differentially affect certain circuits, and nuances in biomarker metrics were observed for particular brain structures. Interestingly, associative circuit functional connections also appeared strengthened. Overall, this thesis successfully identified and evaluated several new candidate biomarkers for PD, as well as furthered an understanding of brain structure and function as it relates to PD, through the development of new analytical pipelines. In addition, tentative conclusions could be drawn regarding the differentiation of PD dysfunction from brain function in healthy elderly subjects.
Abstract FR:
La maladie de Parkinson (MDP) est une maladie neurodégénérative qui atteint le plus souvent les personnes âgées et qui se manifeste par des troubles moteurs qui s’aggravent au cours du temps. L'objectif de cette thèse était d'identifier et d'évaluer des biomarqueurs de la MDP grâce à l'imagerie par résonance magnétique (IRM). Ce travail est constitué de trois différentes études. La première étude visait à mieux comprendre l'influence de la qualité des données acquises sur les mesures de biomarqueurs candidats en IRM pondérée en diffusion (IRM-DW) en utilisant un jeu de données simulées dans un premier temps, puis un jeu de données réelles dans un deuxième temps. Dans la deuxième étude, les patrons de connectivité structurelle et fonctionnelle ont été évalués en IRM-DW et en IRM fonctionnelle au repos (IRMf-rs) pour déterminer leur efficacité en tant que biomarqueurs candidats. Un paradigme multimodal unique a permis d'isoler des déficits anatomiques et fonctionnels qui concernaient des connexions isolées du circuit sensorimoteur particulièrement touchées dans la MDP. Dans la troisième étude, la validation des biomarqueurs candidats identifiés précédemment a été effectuée dans un groupe de volontaires sains. Les changements de connectivité anatomiques liés à l'âge affectaient différemment les trois circuits corticales-souscorticales. Dans l'ensemble, cette thèse a permis d'une part d'identifier et d'évaluer plusieurs nouveaux biomarqueurs dans la MDP, d'autre part d'approfondir notre compréhension du rapport entre les anomalies structurelles et fonctionnelles du cerveau en ce qui concerne la MDP, tout en développant de nouveaux outils analytiques de neuroimagerie.