<strong>Background</strong>. Pathological processes in Parkinson’s disease (PD) start long before the first symptoms appear and by the time the disease is clinically established the results of neurodegeneration may be irreversible. Efforts to prevent or stem disease progression need to start in early disease and good characterization and new markers of early PD are urgently needed. <strong>Objectives</strong>. This thesis aims to characterize early disease stages in three projects. Firstly, clinical features of PD within 3 years of diagnosis will be explored in an incident cohort of patients and controls, using a range of tools to cover the whole breadth of clinical presentation of PD. Secondly, functional imaging studies in PD published so far will be examined through a meta-analysis to identify the most robust functional imaging markers. Thirdly, a functional MRI resting-state study in early PD will be performed to identify reproducible differences between patients and matched control subjects. <strong>Results</strong>. The cohort analysis found that age was a strong predictor of disease severity, independent of disease duration, while gender was seen to affect disease severity depending on the body region. A meta-analysis of all published functional imaging studies across all disease stages showed abnormal activations in the Basal Ganglia but also in a wide range of motor and non-motor brain areas. Dopamine supplementation normalized activations in the Basal Ganglia and some other areas, while other circuits remained resistant to medication suggesting non-dopaminergic abnormality. In the resting-state study, the Basal Ganglia Network showed greatly reduced connectivity in early PD compared to controls, which normalized on administration of dopaminergic medication. Reduced BGN connectivity was also validated on a separate group of PD subjects achieving very good separation of patients from controls. <strong>Conclusions</strong>. The effect of gender and age on early presentation of PD has potential significance for early diagnosis and choice of outcome measures for clinical trials. Within the realm of imaging, traditional task-based fMRI studies fail to show a clear and reproducible pattern of activations making this method unfeasible for early diagnostic testing. In contrast, resting-state fMRI connectivity in the Basal Ganglia Network appears to be a promising and reliable method even in the early stages of PD. Clinical profiling and resting imaging changes offer avenues for developing future biomarkers in early PD.

En médecine personnalisée, les mesures et les descriptions radiologiques jouent un rôle important. En particulier, elles facilitent aux cliniciens l’établissement du diagnostic, la prise de décision thérapeutique ainsi que le suivi de la réponse au traitement. On peut citer à titre d’exemple, les critères d’évaluation RECIST (en anglais Response Evaluation Criteria in Solid Tumors). De nombreuses études de corrélation en radiologie-pathologie montrent que les caractéristiques d'imagerie quantitative et qualitative sont associées aux altérations génétiques et à l'expression des gènes. Par conséquent, une gestion appropriée des phénotypes d'imagerie est nécessaire pour faciliter leur utilisation et leur réutilisation dans de multiples études concernant les mesures radiologiques. En littérature, les mesures radiologiques qui caractérisent les processus biologiques des sujets imagés sont appelées biomarqueurs d'imagerie. L'objectif principal de cette thèse est de proposer une conceptualisation ontologique des biomarqueurs d'imagerie pour rendre leur sens explicite et formel, améliorer le reporting structuré des images. La première partie de la thèse présente une ontologie générique qui définit les aspects fondamentaux du concept de biomarqueur d'imagerie, à savoir : les caractéristiques biologiques mesurées, les protocoles de mesure et les rôles des biomarqueurs imagerie dans la prise de décision. La deuxième partie de la thèse traite des problèmes de modélisation sémantique liés à la description des données d’observation en neuro-imagerie en utilisant les connaissances biomédicales existantes. Ainsi, elle propose des solutions ''pertinentes'' aux situations les plus typiques qui doivent être modélisées dans le glioblastome. / In personalized medicine, radiological measurements and observations play an important role; in particular they help clinicians in making their diagnosis, selecting the appropriate treatment and monitoring the therapeutic response to an intervention as for example the Response Evaluation Criteria in Solid Tumors (RECIST). Many radiology-pathology correlation studies show that quantitative and qualitative imaging features are associated to genetic alterations and gene expression. Therefore, suitable management of imaging phenotypes is needed to facilitate their use and reuse in multiple studies regarding radiological measurements. In litterature, radiological measurements that characterize biological processes of imaged subjects are called imaging biomarkers. The main objective of this thesis is to propose an ontological conceptualisation of imaging biomarkers to make their meaning explicit and formal, improve structured reporting of images. The first part of the thesis presents a generic ontology that defines basic aspects of the imaging biomarker concept, namely; measured biological characteristic, measurement protocols and role in decision making application. The second part of the thesis adresses important semantic modeling challenges related to the description of neuro-imaging data using existing biomedical knowledge, as well as it proposes some “relevant” solutions to the most typical situations that need to be modeled in glioblastoma.

Radiological imaging already has a key role in the detection and management of patients with metastatic colorectal cancer (mCRC). With the evolution of personalised medicine there is a need for non-invasive imaging biomarkers that can detect early tumour response to targeted therapies. Translation from bench to bedside requires a multicentre approach that follows an agreed development roadmap to ensure that the proposed biomarker is precise (reproducible/ repeatable) and accurate in its characterisation of a meaningful physiological, pathological or post treatment response. The following thesis (organized in the alternative format with experimental studies written as individual complete manuscripts) investigates methods to improve precision and accuracy of the Apparent Diffusion Coefficient (ADC), a proposed quantitative imaging biomarker with a potential role in characterisation of post treatment responses in mCRC. The first objective was to establish baseline multicentre reproducibility (n=20) for ADC. A change in ADC greater than 21.1% was required to determine a post treatment response. Using a statistical error model, the dominating factors that influenced reproducibility were motion artefact and tumour volume. In the second study these factors were addressed using a single centre cohort with pre and post treatment data. Correcting for errors due to motion and tumour volume improved sensitivity from 30.3% to 1.7%, so a post treatment response was detected in 6/12 tumours compared to 0/12 using the baseline approach. In the third study, motion correction was implemented and the statistical error model was applied successfully to a multicentre cohort of 15 patients (1.9% sensitivity). The results of this thesis highlights that with careful consideration and correction of factors that negatively influence sensitivity, ADC is a potential imaging biomarker for use in post treatment response for patients with mCRC.

Background: Drugs targeting angiogenic pathway remain the mainstay of treatment for metastatic renal cell carcinoma (mRCC). Tyrosine Kinase Inhibitors (TKI) as Sunitinib, Pazopanib as single agents and humanised monoclonal antibody bevacizumab (Bev) in combination with Interferon- α2a (IFN) have established as the first-line therapy for mRCC. Despite improvements in treatment, there are multiple questions which remain unanswered. In the combination of Bev and IFN, the respective role of each drug and whether any additional anti-angiogenic activity is gained by adding IFN to Bev remains unknown. As the clinical benefit obtained with these cytostatic agents does not always correlate with the conventional response assessment techniques as RECIST, it is necessary to reconsider the methods by which we assess benefit from these therapies. In this thesis, I report three studies aiming to answer these questions. Methods: With the clinical trial reported here, I explore whether Bev induced changes in vascular parameters measured by Dynamic Contrast Enhanced MRI (DCE-MRI) is significantly enhanced by the addition of IFN. In a phase II, randomised, open labelled, multicentre trial, treatment naïve mRCC patients were randomised to receive Bev on its own or in combination with a low dose (3MU) or standard dose (9MU) IFN. DCE-MRI was used to assess the changes in vascularity with the primary endpoint being, changes in transfer coefficient (Ktrans) after six weeks of treatment. I also report two retrospective imaging-based studies, using contrast-enhanced CT scans, performed to improve the methodology of response assessment for these antiangiogenic therapeutics. Here I explore the use of a) combining changes in size and arterial phase contrast enhancement measured using CT scan and b) changes in CT texture as methods of therapeutic response assessment in mRCC patients treated with TKI. Results: With the phase 2 clinical trial, we faced significant difficulty in recruitment as a result of restrictions in access to treatment in NHS, other competing studies and restrictions proposed by the DCE-MRI inclusion criteria. With slow recruitment, an unplanned analysis was performed after 21 patients were recruited. Analysis of primary endpoint showed no trend in the difference between arms with no correlation found between change in Ktrans and addition of IFN to bevacizumab. Effect size analysis performed due to the small numbers recruited failed to show any significance in the observed difference in Ktrans. Change in Ktrans and Kep may identify a group of patients likely to have PFS > 6 months, but this observation needs to evaluation in a larger sample size. Measuring size and change in arterial phase enhancement retrospectively using CT, a new criterion "modified" Choi, which prerequisite a combination of a decrease in arterial phase density by 15% and a decrease in size by 10% for response was proposed. Response assessment was measured with RECIST, Choi and modified Choi individually in 20 evaluable patients retrospectively and clinical benefit compared with Kaplan-Meier statistics and Log-Rank test. Response assessment as defined by the modified Choi criteria successfully identified patients who received clinical benefit from the treatment. Time to progression (TTP) was 448 days for the partial response and 89 days for stable disease as per the new criteria which were statistically significant with a p-value of 0.002. The second retrospective analysis explored the textural changes in enhanced CT scan. Performed in collaboration with researchers from Brighton University who developed the software algorithm used to assess changes in entropy and uniformity, 87 metastases from 39 patients with mRCC were analysed at baseline and after two cycles of TKI treatment. Textural parameters and response assessment criteria were correlated with TTP. After two cycles of TKI, the decrease in tumour entropy was 3%-45%, and increase in uniformity was 5%-21%. At a threshold change of -2% with uniformity, on a coarse scale of 2.5, the textural change was able to separate responders from non-responders. With Kaplan-Meier analysis comparing all four criteria, the percentage change in uniformity was statistically more significant than for RECIST, Choi, and Modified Choi criteria. Cox regression analysis showed that texture uniformity was an independent predictor of time to progression. Discussion: With the studies reported here, I was able to demonstrate the importance of improving the methodology in assessment of therapeutic response to targeted anti-angiogenic therapy in metastatic renal cell carcinoma. Even though the clinical trial, terminated early due to slow recruitment, did not reach its primary endpoint, changes in other vascular parameters as Kep combined with changes Ktrans showed tendency towards identifying a group of patients who derived clinical benefit of >6months with these therapies. This is particularly exciting as given the vascular stabilisation effect proposed for bevacizumab, the effusion parameter Kep may be a better tool in assessing response rather than Ktrans and warrants further assessment in a larger cohort. Modified choi criterion and textural analysis are two important methodological improvements in response assessment of cytostatic anti-angiogenic therapy. In the analyses reported here, both techniques have shown superiority over RECIST in response assessment and differentiating mRCC patients who is likely to gain clinical benefit by TKI therapy. Validation of these criteria on a larger patient cohort is important. As these criterions are assessed on standard enhanced CT scans, incorporating these criteria, especially modified choi criterion, as part of standard CT assessment could be performed and will provide a real world validation. Retrospective assessment using larger cohort of patients from previous phase 3 trials or inclusion of these parameters prospectively in phase 3 trials would also help us in evaluating these modalities further.

L’hypothèse prédominante de cette thèse est que les changements métaboliques tumoraux mesurés par FDG-PET/CT sous l’influence des traitements anticancéreux, apparaissent plus précocement et parfois exclusivement par rapport aux modalités d’imagerie morphologique classique. L’imagerie multimodale, en combinant les avantages de chacune des techniques, dépasse leur limitations et pourrait permettre (i) une évaluation du bénéfice du traitement plus rapide et plus adéquate ;(ii) de modifier les algorithmes thérapeutiques à différents stades de cancer colorectal et (iii) d’améliorer la compréhension des mécanismes d’échappement aux traitements anticancéreux. Pour évaluer l’apport de l’imagerie multimodale dans l’évaluation de la réponse au traitement des cancers colorectaux (CCR), nous avons poursuivi 3 séries d’expérimentation cliniques.<p><p>1) Le premier projet explore l’imagerie multimodale comme un outil d’individualisation pour la radio-embolisation (microsphères chargées en 90Yttrium) chez des patients porteurs d’un CCR métastatique au niveau du foie, pour laquelle l’imagerie morphologique classique est incapable de mesurer l’effet thérapeutique. Nous montrons que l’usage non sélectif de la radio-embolisation améliore l’histoire clinique de ces patients, bien que certains d’entre eux ne semblent pas en bénéficier. Ensuite, par une analyse multimodale lésion par lésion intégrant angiographie-CT Scan, FDG-PET/CT et scintigraphie aux macro-agrégats d’albumine marqués au 99mTechnetium, nous démontrons que la distribution pré-thérapeutique des macro-agrégats d’albumine est hétérogène entre les différentes lésions des patients et prédictive de la réponse métabolique au sein de ces lésions, permettant le développement d’un outil de prédiction et de planification pour la radio-embolisation.<p><p>2) Le deuxième projet explore le domaine du CCR métastatique traité par chimiothérapie palliative. (i) Nous démontrons d’abord que la réponse métabolique (RM) tumorale après une cure de chimiothérapie cytolytique prédit plus vite et plus adéquatement que l’imagerie morphologique basée sur les critères RECIST les bénéfices cliniques du traitement. La RM précoce a une excellente valeur prédictive négative sur l’absence de réponse morphologique et met en évidence une variabilité de réponse inter-lésionnelle chez une proportion importante des patients. (ii) L’étude SoMore explore ensuite des patients présentant un CCR avancé et réfractaire, traités par capecitabine et sorafenib, et confirme l’importance pronostique des RM mixtes, suggérant une méthodologie de classification clinique basée sur la consistance de la RM. (iii) Cette classification cherche confirmation dans l’étude RegARd-C, encore en cours, évaluant les effets du regorafenib, et explorant également la signification génomique et épigénétique de la variabilité de RM. <p><p>3) Le troisième projet cherche à utiliser les propriétés de l’imagerie métabolique pour modifier l’algorithme de traitement adjuvant des patients porteurs d’un cancer du côlon de stade III. Ce projet, encore en cours, fait l’hypothèse que l’absence de RM de la lésion primitive après une cure de chimiothérapie prédit l’absence de bénéfice du traitement adjuvant complet. Une analyse intérimaire en démontre la faisabilité et confirme la présence de 40% de tumeurs présentant des caractéristiques métaboliques de chimio-résistance.<p><p>En conclusion, pour des patients porteurs d’un CCR, l’imagerie multimodale comprenant une évaluation du métabolisme tumoral permet une évaluation plus précoce et plus adéquate du bénéfice au traitement anticancéreux pour différentes modalités thérapeutiques comme la radio-embolisation, la chimiothérapie cytotoxique et les agents biologiques. L’imagerie multimodale permet de prédire et planifier les radio-embolisations et se révèle très prometteuse pour les traitements chimiothérapiques cytotoxiques ou combinés à des biologiques en situation adjuvante ou métastatique. Elle démontre par ailleurs une importante variabilité de réponse métabolique inter-lésionnelle qui représente un axe de recherche majeur sur les mécanismes moléculaires d’hétérogénéité génomique tumorale et de résistance aux traitements anti-cancéreux.<p> / Doctorat en Sciences médicales / info:eu-repo/semantics/nonPublished