Dissertations / Theses on the topic 'Imaging marker'

PET image degradation imposed by patient respiratory motion is a well-established problem in clinical oncology; strategies exist to study and correct this. Some attempt to minimise or arrest patient motion through restraining hardware; their effectiveness is subject to the comfort and compliance. Another practice is to gate PET data based on signals acquired from an external device. This thesis presents several contributions to the field of respiratory motion correction research in PET imaging. First and foremost, this thesis presents a framework which allows a researcher to process list mode data from a Siemens Biograph mCT scanner and reconstruct sinograms of which in the open source image reconstruction package STIR. Secondly, it demonstrates the viability of a depth camera for respiratory monitoring and gating in a clinical environment. It was demonstrated that it was an effective device to capture anterior surface motion. Similarly, it has been shown that it can be used to perform respiratory gating. The third contribution is the design, implementation and validation of a novel respiring phantom. It has individually programmable degrees of freedom and was able to reproduce realistic respiration motion derived from real volunteers. The final contribution is a new gating algorithm which optimises the number and width of gates based on respiratory motion data and the distribution of radioactive counts. This new gating algorithm iterates on amplitude based gating, where gates as positioned based on respiratory pose at a given instant. The key improvement is that it considers the distribution of counts as a consequence of the distribution of motion in a typical PET study. The results show that different studies can be optimised with a unique number of gates based on the maximum extent of motion present and can take into account shifts in baseline position due to patient perturbation.

Image-guided neurosurgery interventions are becoming sur- gical procedure routines. We suggest a novel method for automatic marker localization in X-ray images for Leksell SurgiPlan® which is an image-based neurosergical treat- ment planning software provided by Elekta Instrument AB. We implemented an algorithm for fiducial marker localiza- tion based on feature detection, classification and prior geo- metrical knowledge of the markers. Automatic localization ca help to decrease the human error associated with manual registration of these fiducial markers which is the current applied method for X-ray images in Leksell SurgiPlan®.

The pumping performance of the heart is affected by the mechanical properties of the muscle fibre part of the cardiac wall, the myocardium. The myocardium has a complex structure, where muscle fibres have different orientations at different locations, and during the cardiac cycle, the myocardium undergoes large elastic deformations. Hence, myocardial strain pattern is complex. In this thesis work, a computation method for myocardial strain and a detailed map of myocardial transmural strain during the cardiac cycle are found by the use of surgically implanted metallic markers and beads. The strain is characterized in a local cardiac coordinate system. Thereafter, non-invasive phase contrast magnetic resonance imaging (PC-MRI) is used to compare strain at different myocardial regions. The difference in resolution between marker data and PC-MRI data is elucidated and some of the problems associated with the low resolution of PC-MRI are given.

The gold standard of vascular access is the arteriovenous fistula (AVF). Unfortunately it is associated with high rates of failing to mature. Therefore the ability to predict AVF outcomes would change clinical practice. Predictive markers of AVF outcomes were assessed in chapter 2. The literature and our study showed numerous contradictions. In chapter 3 we assessed a multifactorial approach with a systematic review on predictive models of maturation. The review found few models and the disparity between each one limits the development of a unified model. Recent development in infrared thermal imaging (IRTI) technology has made it portable and easy to use. In Chapter 4, we proved that IRTI is a valid and user-friendly method of measuring skin temperature and is comparable to traditional methods of thermometry. IRTI can be used to quantity reactive hyperaemia following a vascular occlusion test (chapter 5). In Chapter 6 we showed that IRTI is an accurate tool in predicting AVF outcome. It was shown to have superiority to intra-operative thrill and other independent patient factors. In conclusion IRTI has a definite role in patients with vascular access. There is also potential for its use in patients with other conditions such as peripheral vascular disease.

Introduction: A portfolio of studies is presented aimed at understanding the clinical and pathophysiological significance of cerebral microbleeds (CMBs) in stroke patients. CMBs are the radiological marker of microscopic haemosiderin deposits on iron-sensitiveMRI sequences (mainly gradient-recalled echo [GRE] T2* MRI). They are common in patients with cerebrovascular disease and are hypothesised to be a biomarker for brain small vessel diseases, including hypertensive arteriopathy and cerebral amyloid angiopathy (CAA). Important questions relating to CMBs include their use as a prognostic marker for antithrombotic-related intracerebral haemorrhage (ICH) and cognitive impairment. Our aims were to address the pathophysiological and clinical relevance of CMBs using longitudinal, case-control and cross-sectional studies. Methods: Patients were ascertained from prospective databases of admissions to the stroke service at the National Hospital for Neurology and Neurosurgery and at University College London Hospital’s (UCLH) NHS Trust. Magnetic resonance imaging data was collected and analysed for markers of small vessel disease including CMBs. Clinical and radiological associations of CMBs were determined using appropriate statistical tests. Objectives: First, ways of improving microbleed detection and reporting were explored through the development of a visual rating scale (theMicrobleed Anatomical Rating Scale, MARS) aimed at reliably rating CMBs. Second, the prognostic relevance of CMBs was investigated for antiplatelet-related ICH in a case-comparison study. Third, the detection of new CMBs over time and the factors that influence this were explored. Fourth, the impact of CMBs on cognitive impairment was studied in a cross-sectional study. Finally, the association between CMBs and acute silent ischaemia on diffusion-weighted MRI was investigated via a multi-centre cross-sectional MRI study of patients with ICH. Main findings: 1. MARS is a reliable scale with good intra- and inter-rater agreement for rating CMBs presence and number in any brain location. 2. Lobar CMBs, especially if numerous, are a risk factor for antiplatelet-related ICH independent of the extent of white matter changes. 3. CMBs accumulate over time in stroke patients, and the risk is related to baseline systolic blood pressure. 4. Lobar CMBs are an independent predictor of frontal executive impairment; this suggests that CAA is a potential underlying contributor to cognitive impairment. 5. Silent acute infarcts are frequent in patients within 3 months of ICH, especially in those with probable CAA, and are associated with markers of small vessel disease severity, including CMBs. Conclusion: These studies provide new information on detection, clinical impact and associations of CMBs in stroke patients. They suggest that CMBs have useful roles in understanding pathophysiology, diagnosis and prognosis in patients with small vessel diseases. Further studies are required to determine the direct therapeutic consequences of CMBs, but the present work suggests several promising areas for future research.

Bildgesteuerte, perkutane Interventionen stellen bei vielen diagnostischen und therapeutischen Fragestellungen eine Alternative zum chirurgischen Vorgehen dar. Hierbei kommen bevorzugt die Sonographie und die Computertomographie (CT) zum Einsatz. Zu den Indikationen für eine gezielte Nutzung der Magnetresonanztomographie (MRT) zählen Befunde, die sich mit anderen Modalitäten nicht ausreichend darstellen lassen, die fehlende Strahlenexposition (CT) sowie Alleinstellungsmerkmale wie der hervorragende native Weichteilkontrast oder die Möglichkeiten zur Darstellung von Temperaturen oder Diffusionsprozessen. Zu den Nachteilen zählen die langen Messzeiten, das starke Magnetfeld sowie die räumliche Enge in den meist röhrenförmigen Geräten, die ein interventionelles Vorgehen oft erschweren. Stereotaktische Führungs- und Navigationshilfen sind kein notwendiger Bestandteil der interventionellen Ausrüstung, ermöglichen jedoch oft eine gezieltere Planung, bessere Visualisierung oder vereinfachte Durchführung, insbesondere gegenüber einer rein kognitiven Einbeziehung der MRT-Informationen. Assistenzsysteme für geschlossene MRT-Geräte sind meist rahmenbasiert und beschränken sich auf bestimmte Regionen, z. B. die Mamma, die Prostata oder das muskuloskelettale System. Diese Arbeit beschreibt hingegen eine leistungsstarke rahmenlose Assistenztechnik (Navigation), die sich praktisch in beliebigen Körperregionen einsetzen lässt. Der Operateur orientiert sich dabei anhand von hochwertigen MRT-Ansichten, die gemäß der in Echtzeit erfassten Nadellage aus einem kurz zuvor erhobenen Referenzdatensatz reformatiert werden. Ausgehend von der Implementierung an einem speziellen offenen MRT-System (0,5 T) werden interventionelle Komponenten und Methoden beschrieben, die erfolgreich auf ein herkömmliches MRT-System (1,5 T) übertragen wurden. Die Einschränkungen des geschlossenen Systems führten dabei zu einer speziellen Registrierungstechnik mit Hilfe einer kompakten, frei positionierbaren Referenzplatte mit resonanten Miniatur-Hochfrequenzspulen (semiaktiv) als MR-Positionsmarker. Im Vordergrund stand die systematische Prüfung der Marker hinsichtlich Signalverhalten und Sicherheit sowie die Zuverlässigkeit und Genauigkeit einer vollautomatischen, bildbasierten 3D-Lokalisation unter experimentellen und klinischen Randbedingungen. Gegenüber herkömmlichen, passiven (Kontrastmittel-) Markern zeichnet sich die semiaktive Technik dadurch aus, dass sie gleichzeitig, auch mehrere, beliebig über das gesamte Messvolumen verteilte Marker, praktisch unabhängig von sämtlichen anatomischen Strukturen lokalisieren kann. Sowohl die Festlegung einer Position (ein Marker) oder einer Ebene (drei Marker) wie auch die navigierte Platzierung einer Nadel zeigten im Experiment ausreichend hohe Genauigkeiten. Auf Basis einer zeitlich optimierten (Subsekunden-) Markerbildgebung konnte experimentell eine robotisch geführte Nadel direkt im MRT bildgebend verfolgt werden, was weitere Anwendungen der Lokalisationstechnik in Aussicht stellt. Navigierte Biopsien an einem Gewebephantom zeigten nach ausschließlich stereotaktischer Positionierung – ohne Kontrollbildgebung – unabhängig vom Erfahrungsgrad der medizinischen Anwender ausreichend hohe Trefferquoten. Gleichzeitig lieferte die Studie wertvolle, auch anwenderspezifische Erkenntnisse über die Bedienbarkeit sowie den Zeitbedarf für einzelne Interventionsschritte. Im Vergleich mit anderen prototypischen oder kommerziellen Systemen zeigte sich die vorgestellte Assistenztechnik – am Beispiel muskuloskelettaler Interventionen – als klinisch flexibel einsetzbar.

Contesto e scopo: La proproteina convertasi subtilisina/kexina di tipo 9 (PCSK9), uno dei principali regolatori del metabolismo del recettore delle LDL, è stata associata allo sviluppo di aterosclerosi. Diversi studi hanno confermato tale associazione attraverso vie lipidiche e non lipidiche. Tuttavia, le relazioni dirette tra PCSK9 circolante e marcatori di aterosclerosi subclinica e clinica sono ancora da chiarire. Pertanto, abbiamo valutato le relazioni tra i livelli plasmatici di PCSK9 ed alcuni indici di aterosclerosi subclinica (marcatori di imaging) e clinica (eventi vascolari; EV). Un altro obiettivo è stato l'identificazione dei determinanti indipendenti di PCSK9, con particolare attenzione ai lipidi e ai biomarcatori infiammatori. Infine, abbiamo anche valutato la relazione tra alcuni marcatori di imaging e quattro SNPs del gene PCSK9, noti per essere associati alla presenza di bassi livelli di colesterolo LDL. Per validare i risultati ottenuti in quest’ultima parte, le analisi genetiche sono state replicate in una coorte indipendente reclutata nel Regno Unito (UK). Metodi: Lo studio è stato realizzato sfruttando le banche dati, biobanche e la banca di immagini dello studio IMPROVE. 3,703 soggetti europei (54-79 anni; 48% uomini), privi di EV al basale e definiti ad alto rischio per la presenza di almeno tre fattori di rischio vascolare, sono stati reclutati e seguiti per 36 mesi. PCSK9 è stata misurata tramite ELISA e trasformata in logaritmo prima delle analisi. I marcatori di imaging convenzionali [spessore medio-intimale carotideo (cIMT, dall’inglese intima-media thickness) e dimensione della placca carotidea] ed emergenti [cambiamento di cIMT nel tempo, ecolucenza dello spessore del complesso medio intimale della carotide comune misurato in zone libere da placca (PF CC-IMTmean), ecolucenza della placca più grande rilevata in tutto l'albero carotideo e punteggio di calcio carotideo (cCS, dall’inglese carotid calcium score)] sono stati misurati su scansioni ultrasonografiche conservate nella banca di immagini. In particolare, l'ecolucenza è stata misurata in termini di mediana della scala dei grigi (GSM, dall’inglese grey scale median) della distribuzione dei pixel di una specifica regione d’interesse, mentre il cCS è stato calcolato come somma delle lunghezze dei coni d’ombra acustici generati dal calcio all'interno delle placche carotidee. I lipidi sono stati misurati con metodi enzimatici (ad eccezione del colesterolo LDL che è stato calcolato con la formula di Friedewald). Tra i marcatori infiammatori, la proteina C reattiva ad alta sensibilità (hs-PCR) è stata misurata con la turbidimetria, mentre il conteggio dei globuli bianchi (WBC, dall’inglese white blood cells) e la formula leucocitaria sono stati misurati localmente. Tutti i soggetti dello studio IMPROVE e della coorte UK (n=22,179; 48 % uomini) sono stati genotipizzati. Risultati: Nell'analisi univariata, PCSK9 correlava positivamente con colesterolo totale, LDL e HDL e con trigliceridi e basofili (tutte le p <0.0001), mentre correlava negativamente con neutrofili ed eosinofili (entrambe le p=0.04). Le correlazioni positive osservate con hs-PCR e con il conteggio dei WBC erano solo vicine alla significatività statistica (p=0.060 e 0.064, rispettivamente). Le terapie con fibrati o statine (positivamente; entrambe le p <0.0001), così come sesso maschile e storia familiare di diabete (negativamente; entrambe le p <0.05) erano i predittori indipendenti più forti dei livelli plasmatici di PCSK9. Nell'analisi non aggiustata, si osservava una correlazione negativa tra PCSK9 e variabili basali di cIMT (IMTmean, IMTmax, IMTmean-max, e PF CC-IMTmean), una correlazione negativa tra PCSK9 e la variazione di cIMT nel tempo (Fastest-IMTmax-progr) e cCS (tutte le p ≤0.01), mentre si osservava un trend positivo tra PCSK9 e GSM sia del PF CC-IMTmean che della placca carotidea (entrambe le p ≤0.0001). Il cCS (positivamente) e il GSM del PF CC-IMTmean (positivamente) erano associati significativamente (o vicini alla significatività) a PCSK9 in diversi modelli multivariati (tutte le p ≤0.064). Tutte le correlazioni osservate all’analisi univariata tra PCSK9 e le variabili basali di cIMT, Fastest-IMTmax-progr e GSM della placca carotidea perdevano la significatività statistica dopo aggiustamento delle stesse per età, sesso, latitudine ed altri potenziali confondenti. Durante il follow-up [mediana (intervallo interquartile): 3.01 (2.98; 3.12) anni], sono stati registrati 215 EV: 125 coronarici, 73 cerebrali e 17 EV periferici. Tra questi, 37 erano eventi hard (infarto miocardico, morte improvvisa ed ictus). Nell'analisi non aggiustata, PCSK9 era associata positivamente ad eventi combinati e coronarici (entrambe le p <0.01), ma non ad eventi cerebrovascolari. Anche in questo caso, tuttavia, tutte le associazioni osservate perdevano la significatività statistica dopo aggiustamento delle analisi per età, sesso e stratificazione per latitudine. La mancanza di associazione con EV era confermata anche nel modello aggiustato per tutti i fattori confondenti considerati e nelle analisi focalizzate sugli eventi hard. Per quanto riguarda il ruolo delle varianti genetiche, nessuno dei quattro SNPs considerati correlava con cIMT (IMTmean, IMTmax, IMTmean-max) quando l'analisi era effettuata nei soggetti reclutati nello studio IMPROVE. La variante rs11591147, invece, correlava negativamente con l’IMTmax misurato nella popolazione UK (p=0.002). Combinando le quattro varianti genetiche in uno score, la relazione con cIMT era non significativa nello studio IMPROVE, mentre era negativa e significativa nella popolazione UK (tutte le p <0.01). Conclusioni: I livelli plasmatici di PCSK9 non sono associati a EV. Per quanto riguarda i marcatori dell'aterosclerosi subclinica, i livelli plasmatici di PCSK9 non sono associati né alla dimensione della lesione, né all'ecolucenza della placca carotidea, ma sono associati all'ecolucenza dello spessore della parete carotidea e al carotid calcium score. Ulteriori studi sono pertanto necessari per comprendere meglio il ruolo di tale proproteina nell'ecolucenza dello spessore della parete carotidea e nel carotid calcium score. La terapia con fibrati o statine, così come il sesso maschile e la storia familiare di diabete sono i predittori indipendenti più forti di PCSK9 circolante. È stata inoltre confermata l'associazione, precedentemente osservata, tra PCSK9 circolante e alcuni marcatori lipidici ed infiammatori. La relazione tra i livelli plasmatici di PCSK9 ed altri marcatori infiammatori (neutrofili, basofili ed eosinofili) merita ulteriori indagini, così come merita ulteriori indagini l’associazione tra le quattro varianti genetiche di PCSK9 selezionate e il cIMT nella coorte britannica, in quanto lascia intravvedere un possibile ruolo di SNPs o polimorfismi genici di PCSK9 nell’aterosclerosi e nelle strategie della sua prevenzione.
Background and purpose: Proprotein convertase subtilisin/kexin type 9 (PCSK9), one of the main regulators of LDL receptor metabolism, has been associated with atherosclerosis development. Several studies have confirmed such association through both lipid and non-lipid pathways. However, the direct relationships between circulating PCSK9 and markers of subclinical and clinical atherosclerosis are still matter of debate. Therefore, we investigated the relationships between plasma PCSK9 levels and some indexes of subclinical (imaging markers) and clinical (vascular events; VEs) atherosclerosis. Another objective was the identification of the independent determinants of PCSK9, with particular attention to lipids and inflammatory biomarkers. Finally, we also assessed the relationship between some imaging markers and four SNPs of the PCSK9 gene, known to be associated with the presence of low levels of LDL-cholesterol. In order to validate the results obtained in this last part, the genetic analyses were replicated in an independent cohort recruited in the United Kingdom (UK). Methods: The study was carried out taking advantage of databases, biobanks and imaging-bank of the IMPROVE study. 3,703 European subjects (54-79 years; 48% men), free of VEs at baseline and defined at high risk for the presence of at least three vascular risk factors, were recruited and followed-up for 36 months. PCSK9 was measured by ELISA and log-transformed prior to analyses. Conventional imaging markers [carotid intima-media thickness (cIMT) and carotid plaque-size], and emerging imaging markers [cIMT change over time, echolucency of the intima-media thickess of common carotid measured in plaque free areas (PF CC-IMTmean), echolucency of the biggest plaque detected in the whole carotid tree, and carotid calcium score (cCS)] were measured on ultrasonographic scans stored in the imaging-bank. In particular, echolucency was measured in terms of grey scale median (GSM) of pixels distribution of a specific region of interest, whereas cCS was calculated as sum of lengths of acoustic shadow cones generated by calcium within carotid plaques. Lipids were measured with enzymatic methods (except for LDL-cholesterol, which was calculated by Friedewald's formula). Among inflammatory markers, high-sensitivity C-reactive protein (hs-CRP) was measured by turbidimetry, whereas white blood cells (WBC) count and the leukocyte formula had already been measured locally. All the IMPROVE study and UK (n=22,179; 48% men) subjects have been genotyped. Results: In the univariate analysis, PCSK9 was positively correlated with total, LDL-, and HDL-cholesterol, and with triglycerides and basophils (all p <0.0001), whereas was negatively correlated with neutrophils and eosinophils (both p=0.04). The positive correlations observed with hs-CRP and WBC count were just close to the statistical significance (p=0.060 and 0.064, respectively). Fibrates or statins therapies (positively; both p <0.0001), as well as male sex and family history of diabetes (negatively; both p <0.05) were the strongest independent predictors of plasma PCSK9 levels. In the unadjusted analysis, a negative correlation was observed between PCSK9 levels and basal cIMT variables (i.e. carotid IMTmean, IMTmax, IMTmean-max, and PF CC-IMTmean), a negative correlation between PCSK9 and cIMT change over time (Fastest-IMTmax-progr) and cCS (all p ≤0.01), whereas a positive trend was observed between PCSK9 and GSM of both PF CC-IMTmean and carotid plaque (both p ≤0.0001). The cCS (positively) and the GSM of PF CC-IMTmean (positively) were significantly (or almost significantly) associated with PCSK9 in several multivariate models (all p ≤0.064). All correlations observed in the univariate analysis between PCSK9 and basal cIMT variables, Fastest-IMTmax-progr and GSM of carotid plaque lost the statistical significance after adjustment for age, sex, latitude, and other potential confounders. During the follow-up [median (interquartile range): 3.01 (2.98; 3.12) years], 215 VEs were recorded: 125 coronary, 73 cerebral and 17 peripheral VEs. Among these, 37 were hard events (i.e. myocardial infarction, sudden death and stroke). In the unadjusted analysis, PCSK9 was positively associated with combined and coronary events (both p <0.01), but not with cerebrovascular events. Also in this case, however, all the associations observed lost the statistical significance after adjustment of the analyses for age, sex, and stratification for latitude. The lack of association with VEs was confirmed also in the model adjusted for all confounding factors considered, and in the analyses focused on hard events. With regard to the role of genetic variants, none of the four SNPs considered was correlated with cIMT (i.e. IMTmean, IMTmax, IMTmean-max) when the analysis was performed in the subjects recruited in the IMPROVE study. The rs11591147 variant, by contrast, was negatively correlated with IMTmax measured in the UK population (p=0.002). By combining the four genetic variants in a score, the relationship with cIMT was not significant in the IMPROVE study, whereas was negative and significant in the UK population (all p <0.01). Conclusions: Plasma PCSK9 levels are not associated with VEs. Regarding markers of subclinical atherosclerosis, PCSK9 levels are associated neither with lesion size, nor with carotid plaque echolucency, but are associated with echolucency of carotid wall thickness and with carotid calcium score. Therefore, further studies are needed to better understand the role of such circulating proprotein in carotid wall thickness echolucency and in carotid calcium score. Fibrates or statins therapies, as well as male sex and family history of diabetes are the strongest independent predictors of PCSK9 levels. The associations, previously observed, between circulating PCSK9 and some lipid and inflammatory markers have been confirmed. The relationship between plasma levels of PCSK9 and other inflammatory markers (neutrophils, basophils and eosinophils) deserves further investigation, as does the association between the four selected PCSK9 variants and cIMT in the UK cohort, as it suggests a possible role of PCSK9 SNPs or gene polymorphisms in atherosclerosis and in its preventive strategies.

Die Verbesserung der Früherkennung des Urothelkarzinoms ist derzeit der einzige Weg zur Senkung der Mortalität dieser Tumorentität. Bisher fehlen Screeeningparameter für das Blasenkarzinom vergleichbar dem Prostata-spezifischen Antigen (PSA) zur Diagnostik des Prostatakarzinoms. Jedoch scheint auf Grund vielversprechender diagnostischer Ansätze und einer Vielzahl potentieller Urin- und Serummarker die Entwicklung eines Screeningverfahrens in der Zukunft möglich. Zur Bestätigung eines Tumorverdachts (z.B. bei schmerzloser Makrohämaturie) erscheint die ALS (5-Aminolävulinsäure)- Fluoreszenzzystoskopie trotz der aktuellen Diskussionen derzeit als die einzige diagnostische Alternative zur Standardweißlichtzystoskopie. Der klinische Wert eines zukünftigen ausschließlich auf der Laser- induzierten Autofluoreszenz (LIF) basierenden bildgebenden Verfahrens ist derzeit unklar. Vorstellbar wäre auch eine Kombination aus LIF- und ALS- Fluoreszenzzystoskopie mit Erhöhung der Spezifität der Fluoreszenzmethode. Die Ergebnisse der in dieser Habilitation vorgestellten Untersuchungen belegen, dass eine nicht- bzw. minimal- invasive Diagnostik des Blasenkarzinoms möglich ist. Die Kombination von verschiedenen diagnostischen Verfahren würde eine den klinischen Erfordernissen entsprechende Charakterisierung des Tumors ermöglichen. Als Vision für die Zukunft wäre die Möglichkeit einer "optischen Biopsie", d.h. die in vivo Diagnostik ohne die Notwendigkeit der Gewebeentnahme, ein neuer Ansatz und hätte mehrere entscheidende Vorteile: 1. Es findet keine Zerstörung des Urothels bzw. des Karzinoms statt. Bei gleichzeitigem Einsatz schonender Therapieverfahren (z.B. Lasertherapie) bestünde kaum die Gefahr einer Tumorzellstreuung. 2. Es könnte eine unbegrenzte Anzahl von "Biopsien" durchgeführt werden mit möglicher Verbesserung der diagnostischen Sensitivität. 3. Im Gegensatz zur herkömmlichen Endoskopie und Mikroskopie erlaubt der kombinierte Einsatz von optischer Kohärenztomographie (OCT), Ultraschall und konfokaler Laser- Rastermikroskopie (CLSM) erstmals eine dreidimensionale Begutachtung des Gewebes. 4. Die Diagnostik erfolgt in vivo ohne Biopsie-, Fixierungs- oder Färbungs-bedingte Artefakte. 5. Der diagnostische und auch der finanzielle Aufwand (Fixierung, H/E- Färbung, Personal etc.) wären geringer. 6. Die Diagnosestellung erfolgt intraoperativ. Dies hat z.B. den Vorteil, dass bei der Diagnose eines muskelinvasiven Tumors und entsprechender Indikation für die radikale Zystektomie auf eine vorherige TURB verzichtet werden könnte. 7. Durch Automatisierung könnte der diagnostische Prozess objektiviert und beschleunigt werden. Die Ergebnisse wären erstmals vergleichbar und reproduzierbar. Nach Meinung des Autors ist die "optische Biopsie" zur Diagnostik maligner Epithelveränderungen in der Zukunft möglich. Sinnvoll erscheint die Kombination aus einem sensitiven orientierenden Verfahren (z.B. ALA/LIF), einer Staging- Methode mit ausreichender Eindringtiefe (z.B. Sonographie, OCT) und einer Grading- Methode mit mikroskopischer Bildauflösung (CLSM). Am Ende der Entwicklung sollte ein Multisensorendoskop stehen, welches die verschiedenen bildgebenden Verfahren in sich vereint. Der Einsatzbereich eines solchen Gerätekonzepts geht weit über den Bereich der Urologie hinaus und wird die Diagnostik und Therapie von Neoplasien in der Zukunft maßgeblich beeinflussen.
At present, the only way to lower the mortality rate of urothelial carcinoma is the improvement of early detection. Screening parameters like prostate specific antigen (PSA) for the diagnosis of prostate cancer are missing. However, promising potential markers in urine and serum make the development of a screening method in the future possible. In order to confirm the suspicion of bladder cancer (e.g. macrohematuria) currently fluorescence cystoscopy with 5-aminolevulinic-acid (ALA) appears as the only alternative to standard white light endoscopy. To date, the clinical value of a diagnostic method solely based on laser- induced autofluorescence (LIF) is unclear. Possible seems the combination of LIF and ALA-fluorescence cystoscopy. The results of the studies described in this "Habilitation" demonstrate that a non- or minimal- invasive diagnosis of bladder carcinoma is achievable. The combination of different diagnostic methods would be sufficient to characterize a tumor in vivo. As a vision for future "optical biopsies", that means the in vivo diagnosis of cancer without the need for excisional biopsies would have several advantages: 1. There is no destruction of the urothelium or the tumor. Therefore the risk of tumor cell seeding is minimal. 2. One could take an unlimited number of "biopsies" with possible improvement of the diagnostic sensitivity. 3. In contrast to traditional white light endoscopy which allows only two-dimensional surface imaging, the combination of optical coherence tomography (OCT), ultrasound (US) and endoscopic confocal microscopy may enable three-dimensional high resolution imaging of tissue structure at depth. 4. One could study human tissue in real time and in its original in vivo state without artifacts caused by biopsy forceps, cautery or fixation. 5. For hospitals the cost of performing histological studies on excised tissue is a significant expense, which optical techniques may reduce by replacing or reducing the number of biopsies. 6. The diagnosis will be determined in the OR. In case of an muscle- invasive tumor this could spare the patient an invasive transurethral resection (TURB) prior to radical cystectomy. 7. Through automation of the diagnostic process the results were more objective and comparable. In conclusion we believe that the concept of "optical biopsies" is a realistic vision, which could eventually change the way we diagnose and treat diseased tissue. The combination of a sensitive orientating method (e.g. ALA/LIF), a staging method (e.g. OCT, US) and a grading method with microscopic resolution (e.g. CLSM) would be necessary. The end point should be the development of a multi-sensor endoscope, which would have applications in almost all clinical disciplines.

L'étude du milieu sous-marin nécessite des avancées technologiques importantes notamment en ce qui concerne le développement des véhicules sous-marins autonomes et en particulier, leurs capteurs de perception. Le travail de cette thèse avait pour objectif d'apporter des solutions permettant d'améliorer la qualité des images sous-marines dans le but de promouvoir l'emploi des robots sous-marins autonomes. La rapidité de calcul est un point très essentiel, car les robots autonomes sont limités par les contraintes d'énergie, la capacité de calcul et de stockage. Dans ce contexte, une méthode rapide et efficace d'amélioration de la qualité d’images sous-marines a été proposée. D'une part, cette méthode utilise un système optique d'imagerie polarimétrique pour réduire les effets de diffusion lors de l'acquisition d'images. D'autre part, elle est basée sur une version optimisée de la méthode DCP (dark channel prior) qui est très répondue pour le débrumage d’images sous-marines.Dans cette thèse, nous nous intéressons également à la détection et à l'identification de marqueurs utilisés pour le docking automatique d'un véhicule sous-marin avec une station immergée. Le succès de cette tâche nécessite un bon contraste dans la zone où se situe le marqueur. Pour résoudre ce problème, une méthode de débrumage orientée-objet est proposée pour optimiser le contraste des marqueurs. La stratégie proposée exploite les caractéristiques de texture dérivées du filtrage multicanal de Gabor pour la segmentation d'images. Une fois que les différents objets de l’image sont séparés, une version optimisée du Dark Channel Prior (DCP) est appliquée pour optimiser le contraste de chaque objet. Les résultats obtenus, sur une large base de données d’images de marqueurs, montrent que la méthode proposée améliore sensiblement la détection et l'identification des marqueurs en environnement sous-marin
Study of the underwater environment requires significant technological advances, particularly, in the development of autonomous underwater vehicles, and their perception sensors. This thesis is dealing with the development of a real time solution for underwater image quality improvement in order to promote the use of autonomous underwater vehicles. Developing a fast image processing algorithms are required due the limitations of these kinds of vehicles in terms of energy, computing capacity and storage. In this context, a fast and effective method of underwater image quality improvement has been proposed. On the one hand, this method uses a polarimetric imaging optical system to reduce the diffusion effects on the image acquisition.On the other hand, it is based on an optimized version of the dark channel prior (DCP) method that has received a great deal for image dehazing.In this thesis, we are also interested in the detection and the identification of markers used for the automatic docking of an underwater vehicle with a submerged station. The success of this task requires a good contrast in the area where the marker is located. To solve this problem, an object-oriented dehazing method is proposed to optimize the contrast of markers. The proposed strategy exploits the texture features derived by Gabor multichannel filtering for image segmentation. Once different objects of the image are separated, an optimized Dark Channel Prior dehazing method is applied to optimize the contrast of each individual object. The system has been tested on a large image dataset and the obtained results show that the object-oriented dehazing improves the markers identification in underwater environment

Joint damage in osteoarthritis (OA) involves characteristic changes in multiple joint tissue types, with alterations in the shape of subchondral bone and composition of synovial fluid occurring concomitantly with cartilage damage. Systemic risk factors such as obesity and local biomechanical processes that determine joint loading have long been shown to predispose to the disease, and more recent evidence suggests that specific genetic loci and inflammatory processes may make contributions, but the exact mechanisms driving the initiation and progression of the disease are yet to be elucidated. Advances in imaging that allow visualisation of minute changes in structures such as cartilage composition and subchondral bone shape have enabled longitudinal tracking of early disease development. It is hoped that the identification of early imaging biomarkers for later disease will not only assist in clarifying disease pathogenesis, but facilitate the development of disease-modifying interventions by shortening the lead time for assessing their effectiveness. This thesis aimed to clarify the current information on the utility of imaging biomarkers in research into the pathogenesis and treatment of osteoarthritis, and investigate potential imaging markers in the two regions that contribute the most to the disease burden of osteoarthritis; the knee and the hand. It utilises data from three clinical studies; a cross-sectional survey on quality of life indices in patients with arthritis, and the ongoing KANON (Knee Anterior Cruciate Ligament Non-operative vs. Operative Treatment) and COMBO (Combined Conservative Therapies on Clinical Outcomes in Thumb Base Osteoarthritis) trials. The chapters are presented in mixed manuscript form and journal format owing to differing stages of publication, and are designed to be read independently. Chapter one presents an introduction to the current understanding of the pathogenesis of OA and the role of imaging in clinical research. Chapter two presents published data from a cross-sectional survey that included 1039 participants via an online platform and utilised the validated ICOAP (Measure of Intermittent and Constant Osteoarthritis Pain) and EQ5D scores. The data identified the knees and hands as the regions in which pain was the most common, and in which arthropathy was the most detrimental to activities of daily living. This regional distribution differed slightly from studies in which participants were drawn from clinician referral, rather than from a convenience sample, raising points on the potential advantages of online platforms, and framing the subsequent focus on research into imaging biomarkers for OA of the knees and hands. Chapter three provides a further introduction to magnetic resonance imaging (MRI) to provide a background for the subsequent two chapters, and consists of a published book chapter that focuses on MRI as an imaging modality that enables direct visualisation of changes in both structure and composition in different joint tissues through the modification of contrast and sequences. In chapter four, post-traumatic osteoarthritis is discussed in two published manuscripts in terms of its value in investigating disease pathogenesis through imaging. Traumatic joint injury, and anterior cruciate ligament (ACL) rupture in particular, is strongly linked to the subsequent development of osteoarthritis, so provides an opportunity to track pathological changes from a defined starting point, and therefore potentially identify early imaging markers for subsequent disease. Chapter five presents data from serial MRIs in the KANON trial, which included 121 individuals who had sustained an acute anterior cruciate ligament (ACL) rupture to a previously uninjured knee. In the trial, 62 participants were randomised to undergo early ACL reconstruction and structured rehabilitation, and 59 were allocated to undergo structured rehabilitation alone, with an optional delayed ACL reconstruction. MRIs of the knee were obtained for all participants at baseline, two years, and five years, and for a subgroup of 63 participants, additional MRIs were performed at 3, 6, and 12 months. The serial MR imaging has enabled the effects of concomitant injuries such as osteochondral fractures and meniscal tears to be tracked, as well as providing longitudinal measurements of changes in cartilage and subchondral bone that can then be correlated with clinical outcomes. Data on the regional changes in the area of bone covered by cartilage (cAB) as a potential biomarker for disease, and the effects of baseline injuries to other joint structures, are presented. In chapter six, data on radiographic markers in trapeziometacarpal (base of thumb) osteoarthritis are presented from the COMBO trial. It includes two manuscripts – one published and one in the process of review – that present data from the first 100 participants included in the COMBO trial. Radiographic markers have traditionally had a poor correlation with symptomatic and functional outcomes, so generalised estimating equations are used for bilateral data to minimize the influence of interpersonal confounding factors and account for the fact that within-person measurements are not independent. The radial subluxation ratio is investigated in the manuscripts as a marker for structural and functional osteoarthritis progression, and radiographic markers of disease severity are analysed in relation to pain and functional outcomes in symptomatic disease. In summary, magnetic resonance imaging and radiographic markers are investigated in relation to their utility as indicators of osteoarthritis progression, and in acting as outcomes for the assessment of potential interventions in clinical trials.

There is rapidly increasing interest in functional imaging for the diagnosis and monitoring of disease. In particular, Dynamic Contrast Enhanced (DCE) Mag- netic Resonance Imaging (MRI) is of enormous, and growing importance in medical imaging, fundamentally because it provides a powerful tool for assessing tumour vasculature. Furthermore it has been proposed as a means of moni- toring disease progression and for identifying potential markers for predicting patient response to therapy. In principle, DCE-MRI data can be quantified us- ing pharmacokinetic models, enabling extraction of physiologically meaningful parameters. Although the combination of DCE-MRI sequencing and pharmacokinetic mod- elling promises quantitative analysis of response, as well as providing the clinician with parametric information (such as Ktrans and kep), there are a number of fun- damental problems to be addressed. When we applied the published models to clinical colorectal cancer MRI data sets, we observe that many voxels within the tumour volume fail to produce identifiable pharmacokinetic information. We ad- dress the root causes of this problem as a necessary precursor to moving beyond calculating average pharmacokinetic values for a region of interest to observing and quantifying tumour heterogeneity. We find a high dependence of the pharmacokinetic model on uncorrected motion in the MR images, and on estimation of the pre-contrast Tl tissue relaxation time. We quantify the effects of each of these, and derive a more reliable means of generating concentration curves, necessary as a precursor to pharmacokinetic modelling. Next, we look at the standard two compartment model for DCE-MRI. While the functional form of the compartment model is known, computation of the amount of contrast agent depends critically upon knowing the arterial input function. We demonstrate a high dependence of the pharmacokinetic model on the choice of arterial input function. We quantify the effects of model and population- averaged parameter choice and find that the standard image based methods used for individual arterial input function extraction, based on identifying an artery or reference region, are unsuitable on clinical data whose temporal resolution is low. We propose an alternative method to extract the plasma concentration from the tissue of interest. We assess the new method on both simulated and clinical data; the results show a more robust estimation of the pharmacokinetic parameters. The literature suggests DCE-MRI has applications in predicting the response of tumours to neoadjuvant chemoradiotherapy. For colorectal cancer, only 70% of patients demonstrate response to therapy with 10-20% responding completely. By clustering parameters across patients to infer blood flow patterns common for different subsets of tumour, we attempt to find a suitable description of.

The research presented in this thesis focused on the investigation of platinum(II) and iridium(III) complexes in bacterial imaging. The use of the complexes as luminescent probes to image live bacteria has been demonstrated with different approaches including confocal or super-resolution microscopy and ion-nanoscopy, showing how structurally diverse metal complexes could readily penetrate the cell envelope of live bacteria, enabling the visualisation of different cellular sub-structures.

La maladie d’Alzheimer (MA) est la première cause de démence dégénérative. Elle est ‏définie par l’accumulation anormale des protéines Tau et myloïdes, constituant des plaques‏ amyloïdes. Alors que l’atteinte neuro-pathologique de la MA est stéréotypée chez les malades, son ‏expression clinique et son pronostic sont hétérogènes. Les facteurs modulant l’expression de la ‏maladie sont actuellement peu connus.‏ Dans ce travail, nous avons analysé deux facteurs modulateurs de l’expression de la ‏maladie : l’âge et l’activation microgliale que nous avons étudié au sein d’une population de sujets‏ atteints de la MA (aux stades débutant et sévère) et de témoins, définis sur des critères‏ diagnostiques clinico-biologiques.‏Nous avons tout d’abord analysé l’effet de l’âge sur la modification de la morphologie des ‏sillons corticaux au cours de la MA. Nous avons mesuré l’ouverture des sillons corticaux ainsi que ‏le volume hippocampique sur l’IRM cérébrale de sujets MA jeunes (<65 ans), de sujets MA plus ‏âgés (>65 ans) ainsi que chez des sujets témoins appariés à l’âge. Dans un second temps, nous étudié ‏l’activation microgliale en quantifiant la fixation du ligand [18F]-DPA-14, grâce à la tomographie ‏par émission de positrons (TEP) au sein d’une population de sujets MA et de témoins suivis‏ cliniquement pendant deux ans. Finalement, nous avons mesuré et comparé l’évolution de‏ l’activation microgliale au cours du temps entre des sujets MA et des témoins, qui ont bénéficié de ‏la réalisation d’un second examen TEP. ‏Nos hypothèses étaient (1) que l’étude de la morphologie des sillons corticaux était plus ‏performante que la mesure du volume hippocamique pour distinguer les formes jeunes de MA des‏ formes du sujet âgé, (2) qu’en comparaison aux témoins, l’activation microgliale était plus‏ importante chez les sujets MA et qu’elle influait sur la progression clinique de la maladie, et (3)‏qu’il existait différents profils évolutifs d’activation microgliale.‏Nos résultats montrent (1) que la mesure de l’ouverture des sillons corticaux est un meilleur ‏marqueur diagnostique que la mesure du volume hippocampique dans le groupe de sujets MA jeune,‏ dès le stade débutant de la maladie. A l’inverse, elle entraîne un risque de diagnostic par excès chez ‏le patient de plus de 65 ans, où l’effet de l’âge se confond avec celui de la maladie ; (2) l'activité‏ microgliale est augmentée précocement au cours de la MA et est associée à une stabilité cognitive et fonctionnelle de la MA. Finalement, (3) qu’il existe différents profils d’activation microgliale‏ au cours du temps, avec des retentissements distincts sur la progression de la MA. ‏ Au total, ces travaux confirment l'hétérogéneité de la maladie d'Alzheimer. L'étude des‏effets de l'âge et de l'activation microgliale au sein d'une population atteinte d'une MA met en‏ évidence des sous-types de malades avec une expression et des trajectoires évolutives distinctes ; ‏les sujets jeunes présentent une expression corticale de la maladie plus étendue et les sujets avec‏ une faible activation de la microglie ont une dégradation fonctionnelle et cognitive plus sévère. ‏Ces facteurs de variabilité ouvrent des pistes de recherche clinique mais aussi‏ thérapeutiques. Ils pourraient être pris en compte dans les protocoles thérapeutiques ultérieurs. ‏
No abstract

Aims: I investigate potential MRI markers in cerebral small vessel disease (SVD), to determine their relationship to cognitive impairment and investigate whether they are feasible for use as surrogate outcome measures in clinical trials by estimating their sensitivity to longitudinal change and calculating sample sizes for a hypothetical clinical trial. I also carry out pilot work to investigate the potential use of 7T MRI in SVD. Methods: Data from the prospective St Georges Cognition and Neuroimaging in Stroke (SCANS) study of patients with symptomatic SVD was used (n=121). Neuropsychological testing was performed annually for a period of 3 years. Multimodal MRI was also acquired annually to evaluate brain volume, T2 White Matter Hyperintensities (WMH) volume, lacunes and white matter damage on diffusion tensor imaging (DTI). Results: At baseline, lacunes and brain volume were found be important predictors of cognitive impairment on conventional MRI. There is a specific association between lacunes in the anteromedial thalamus and impaired processing speed (Chapter 3). Perivascular spaces (PvS) were not associated with cognitive impairment but were associated with other MRI markers of SVD (Chapter 4). Over 3 years, longitudinal change was detectable in MRI markers but not in cognitive measures. WMH volume and diffusion tensor imaging parameters were most sensitive to change and therefore had the smallest sample size estimates for a hypothetical clinical trial (Chapter 5). The presence of new lacunes was the only MRI marker able to predict longitudinal change in cognition over a 3 year follow-up period (Chapter 6). Conclusion: Quantitative MRI markers could significantly reduce the size of clinical trials to screen treatments for efficacy in SVD, although further validation from studies with longer follow-up is required. 7T MRI has the potential to provide new information on underlying disease mechanisms and more specific surrogate markers of SVD progression (Chapter 7).

In this research, a series of iridium(III) tetrazolato complexes were synthesised and their photophysical and biological properties investigated. Both the cyclometalated and the ancillary ligands were systematically modified by substitution of functional groups or by increasing the extension of the  conjugation. This approach allowed a more systematic rationalisation of the structure-activity relationship, highlighting how variations in the chemical structure and charge might influence the biological behaviour of these complexes.

Abstract

 

Camera phones are moving into the rapid growth stage and they will rapidly be the most common image capture device in the world. Analysis agencies Gartner, ABI-Research and Future Image estimate that over 650 million camera phones were shipped in 2007 and that by the end of the decade there will be a global population of over one billion mobile imaging handsets -- more than double the number of digital still cameras (DSC).

 

Although handset shipments are flourishing, consumers are not using their camera phones to the fullest extent. Researchers reveal that the number of photos taken, shared, and printed is relatively very low compared with DSC, resulting in a significant unrealised revenue potential for the mobile imaging industry.

 

Despite the current limitations, recent researches done by Nokia marketing reveal that 40% of camera phone users indicate the camera phone is their primary camera. The researches suggest that with improvements in functionality, quality, usability and usage model, camera phones have the potential to be the most common and most frequently used type of camera.

 

We believe the industry needs to stimulate more photo activity among camera phone owners to speed up (1) handset purchases, (2) picture taking, and (3) sharing, storing and printing services.

 

To achieve this we believe companies with niche imaging technologies; such as faster decoding, less memory usage, minor processor (CPU) demands, rich features, and rich user experience have slightly high chance to outstand itself in this market. Also companies within the mobile imaging sphere which should have a competitive edge are the one who can solve inhibitors.

 

Five out of every six sold cameras will be embedded in mobile phones. We believe the dominance of camera-phones will impact the imaging market in a variety of ways that will benefit the industry.

 

This report aims to initiate a simple approach to give a high level view for companies aiming and searching for mobile imaging opportunities and should help extending the mobile focus thinking and area.

 

Initiating a study on mobile imaging has been a challenge and this is due to two main reasons; the speed of development within this particular industry and the access to credible sources whether commercial or scientific. There is a significant fierce competition in the industry and it has been a great advantage to the authors to have had access to commercial reports and information sources first hand.

 

When it comes to theories and methods, they have been taped from both the mainstream marketing literature and guerrilla marketing. There has been no obvious advantage to exclude mainstream marketing theories for this fast growing and quickly changing industry and methods described has proven worth while for the outcome of this study.

The mainstream marketing literature has been utilised in the market analysis performed on the materiel obtained and when looking to the future possibilities and opportunities as well.

The MIO model or the MIO-perspective, has been an excellent tool to help digest the information in a structural way and the three perspectives that are the foundation of the model; Market, Interaction and Organisation are all needed in any successful Marketing activity whether it is a fast moving business like the mobile image one or a more traditional industry e.g. the car industry. The model identifies the present situation, the future, strategy and action plan, all important components in forming the business plan.

When describing both the present environment and when searching for new opportunities, the usage of the classic 4P’s is outstanding. Product, Price, Promotion and Place are all important parameters to elaborate on and as the MIO model points out, one should first focus on the industry as a whole and not once own enterprise in order to find profitable ways to develop the business.

 

Some conclusions drawn from the study are; the more megapixels camera phone are released the more the customers’ awareness and education is raised and refined. This leads to better customers inconvenience to get the best out of their phones and the myth of getting a free digital camera does not live any more. The customers are getting better informed and they want their right to one converged high quality device where the camera is as important as the call functions of a phone device.

Cognitive impairment and fatigue are prevalent and impactful symptoms of multiple sclerosis (MS). Effective markers are required by clinical studies to accurately test the efficacy of treatments for these symptoms. Graph analysis of brain networks based on magnetic resonance imaging (MRI) data can feasibly provide useful candidate markers of cognitive impairment and fatigability in MS which may be more objective, reliable and specific than existing markers. My original contribution to knowledge is therefore an exposition of the following hypothesis: “summary graph-theoretic descriptors of brain network organisation are good candidate markers of cognition or fatigue in MS”. To achieve this, network metrics were assessed based on three main criteria: reliability (“are the measurements the same across time and settings?”), validity (“do they measure what they are supposed to measure?”) and responsiveness (“are they altered when a change in cognitive state is induced?”). The applicability of the graph-theoretic approach was first established with a spatial meta-analysis of tract integrity and its relevance to cognition and disability. Reliability over time in healthy subjects was assessed by systematic review and reliability between different scanners and between MS and control groups was assessed in two longitudinal datasets by measuring intra-class correlation (ICC) of graph metrics. The validity criterion was assessed in an analysis of covariance and linear regression of cognitive and fatigue measures with brain network metrics in people with MS. Finally, an exploration of network dynamics during a sustained attention task with a sliding-window approach was performed to test the immediate responsiveness of the measures to alterations in cognitive state. Spatial meta-analysis of white matter tract degradation was performed using the Signed Differential Mapping method. Statistical maps were gathered from the original authors of studies which performed voxelwise correlations between fractional anisotropy (a measure of white matter integrity based on diffusion tensor imaging data) and measures of either cognitive impairment or physical disability. The combined sample included 495 people with MS and 253 controls from 12 studies. MS diagnosis was significantly associated with widespread lower tract fractional anisotropy. Distributions of voxels with significantly lower fractional anisotropy in relation to cognition and physical disability were only minimally overlapping. The number of and effect sizes for significant clusters in the cognition comparison were greater than those for the physical disability comparison, suggesting a greater relevance of cerebral white matter damage to cognition. The main results remained significant when using a stringent p-value threshold of 0.00001 to control for false positives. The next analysis was a systematic review of the reproducibility of graph metrics over time in healthy people. Online databases were searched for articles reporting ICCs for graph metrics based on imaging data and information was recorded on the sample size, acquisition method, inter-scan interval and reported ICCs. Twenty-six articles were included, with a combined sample size of 676. Overall, reproducibility over time was rated as “good”, but heterogeneity of methods precluded in-depth quantitative analysis. A qualitative synthesis of results highlighted the main methodologic factors affecting reproducibility, which included: ICC type, retest interval, fibre tracking algorithm, graph metric type, image processing strategy, region of interest size, graph threshold and acquisition method. Reliability of brain network metrics between scanners was tested using a travelling-subjects dataset in which 5 subjects each underwent a resting-state functional MRI scan at 10 sites. Graph metrics were calculated for each scan and then tested for ICC across sites. Reproducibility was “poor” for most metrics (characteristic path length ICC=0.23, global efficiency ICC=0.18, modularity ICC=0.24) and “fair” for two (clustering coefficient ICC=0.43, small-worldness ICC=0.42). There was limited evidence that some subjects tended to produce less reliable results and that magnets with higher field strengths did not produce more reliable results. The main implication is that multi-site studies using graph analysis of brain MRI data should investigate inter-site reproducibility beforehand. To investigate the validity of graph metrics as markers of cognitive impairment and fatigue, MRI and neurocognitive data were first gathered from 37 people with MS and 23 matched controls. The sample was characterised in detail and comprised a range of cognitive abilities. Data quality was investigated and the small-world structure of the data was confirmed by comparison to random and lattice graphs. Analysis of covariance controlling for age, sex and education showed significant group differences for all but one graph metric. Linear regression models predicted the main measures of cognitive impairment in the MS group, but not in the control group. Measures of fatigue were not well-explained by graph metrics. The direction of the relationships indicated that greater levels of cognitive impairment were related to increased network clustering and modularity, longer average path lengths, lower small-worldness, lower levels of education, old age and sleep disturbance. Finally, responsiveness of graph metrics was investigated in an analysis of functional network dynamics during performance of a sustained attention task. A “sliding-window” approach was taken, in which network metrics were calculated for 84 100-second windows at increments along the fMRI timeseries. Reaction times in the task showed a learning effect for both groups, but were consistently slower for the MS group. Plots of graph metrics over time showed differing responses to the task and to the transition between task and rest periods between groups. The small-worldness and clustering coefficient metrics were correlated with reaction times for both MS (small-worldness: r=0.623, < 0.001; clustering coefficient: r=0.554, p= < 0.001) and control (small-worldness: r=0.586, < 0.001; clustering coefficient: r=0.627, p= < 0.001) groups, but the characteristic path length metric was not (MS: r=-0.154, p=0.313; control: r=0.343, p=0.021). Disconnection of cortical areas by degradation of white matter is a viable explanation for cognitive symptoms in MS. There is some evidence that increased network segregation and decreased network integration may explain cognitive symptomatology. Graph theoretic summary brain network metrics do have potential for use as complimentary information to existing markers of cognitive impairment in clinical studies.

Today we are collecting a large amount of tissue samples to store for future studies of different health conditions, in hopes that the focus in health care will shift from treatments to early detection and prevention, by the use of biomarkers. To make sure that the storing of tissue is done in a reliable way, where the molecular profile of the samples are preserved, we first need to characterise how these changes occur. In this thesis, data from mice brains were collected using MALDI imaging mass spectrometry (IMS) and an analysis pipeline for robust MALDI IMS data handling and evaluation was implemented. The finished pipeline contains two reduction algorithms, catching images with interesting intensity features, while taking the spatial information into account, along with a robust similarity measurement, for measuring the degree of co-localisation. It also includes a clustering algorithm built upon the similarity measurement and an amino acid mass comparer, iteratively generating combinations of amino acids for further mass comparisons with mass differences between cluster members. Availability: The source code is available at https://github.com/stephanieherman/thesis

This study aims at the development of materials for biodegradable fiducial markers for X-ray based medical imaging and their anchorage in soft tissue. Towards this goal a degradable polymer matrix of poly(L-lactide-co-ε-caprolactone) (P[LAcoCL]) was combined with barium sulfate (BaSO₄) and hydroxyapatite (HAp) as radio-opaque fillers. Low pressure plasma treatment was applied to the composite materials to improve cell adhesion and subsequent tissue integration. In particular, the effects of oxygen and ammonia plasmas were evaluated and compared using X-ray photoelectron spectroscopy, atomic force microscopy and dynamic water contact angle measurements as well as in vitro studies using the murine fibroblast cell line L929. To exclude the cytotoxic effects of degradation products of P[LAcoCL] and released BaSO₄ or HAp cytotoxicity assays with the degradation products of the composite materials were conducted. The results obtained by this broad range of analytical techniques suggest the application of composites of P[LAcoCL] with BaSO₄ and HAp as promising material systems for innovative fiducial markers for soft tissue in X-ray based medical imaging.

The main objective of the thesis is to use advanced MRI techniques to look for biomarkers that separate neuromyelitis optica spectrum disorders (NMOSD) from MS to improve diagnosis. NMOSD, a severe inflammatory disease which causes demyelination of the central nervous system, is characterised by optic neuritis (ON) and acute myelitis. Because of similarities with MS, NMOSD is not always correctly diagnosed at onset. As it is both more aggressive and faster progressing than MS, an early accurate diagnosis is crucial. For this thesis, three different MRI techniques were used, together with clinical assessments, to gain a better understanding of the differences between the two diseases. The first was neurite orientation dispersion and density imaging (NODDI), a diffusion MR technique used to analyse the microstructure of dendrites and axons. When applied to a single-shell dataset of RRMS patients, it was shown to detect more regions of diffusion abnormalities than FA maps. The second technique used is phase-sensitive inversion recovery (PSIR), to look for grey matter lesions. This first application to NMOSD patients led to the detection of grey matter lesions in nearly 50% of this group, as well as showing differences in leucocortical and juxtacortical lesions between NMOSD and MS, with juxtacortical lesions emerging as potential markers to differentiate between these diseases. The final part applies magnetisation transfer ratio (MTR) to the optic nerve to assess myelin integrity in both MS and NMOSD patients, together with optic coherence tomography (OCT) for the macula the retinal nerve fibre layer and visual assessments. Significant differences in MTR and OCT values were found in MS and NMOSD patients with ON compared to healthy controls (HC). Significant differences were found between the unaffected nerve of NMOSD patients and HC, but not between groups for either MTR values (after correction for age) and OCT measurements.

Thesis (M.Sc (Radiography))--Cape Peninsula University of Technology, 2016.
Multiple sclerosis (MS) affects the central nervous system (CNS) and is characterized by multiple demyelinating lesions. It is in this context that a need arises for reliable biomarkers such as Magnetic Resonance Imaging (MRI), which could lead to the early diagnosis and therapeutic intervention when maximum potential impact is possible. This study examines the impact of MRI as a marker and the sequences that give the best images to aid in evaluation of disease progression (which can indirectly be seen as disability) and the early diagnosis of MS which will, in turn, lead to more effective management of the disease. METHOD: Sixteen subjects underwent a neurological examination, the Expanded Disability Status Scale (EDSS), blood tests for iron parameters and a 3Tesla Magnetic Resonance Imaging (MRI) scan. In a study of MS, 11 had MRI data that could be analysed by using tract-based spatial statistics (TBSS). Subjects were divided according to the EDSS score (8 of the subjects had an EDSS score of ≤ 3 while 3 subjects had scores of ≥ 6). Diffusion tensor imaging (DTI), the fused Proton Density and Fluid Attenuation Recovery (FLAIR) was utilised to compute the lesion numbers and standard laboratory procedures were used to measure other biochemical markers (serum iron, % transferrin saturation, ferritin, haemoglobin) in subjects with disability and simultaneously assess the disease process. RESULTS: The FA of white matter tracts (WMTs) as a parameter of myelin integrity was lower in subjects with MS only in those who had high EDSS scores. An association between FA and iron parameters, especially percentage transferrin saturation (% Tf) sat were observed, which suggests that iron availability to the WM may be a requirement for optimal myelin functionality. CONCLUSION: The FA of WMTs as a parameter of myelin integrity was lower only in those MS subjects who had high EDSS scores. Subjects who had EDSS scores < 3 (i.e. who had a “benign” disease outcome) had FA values similar to control values and this finding was not related to their age or disease duration. The association found between FA and iron parameters, especially % Tf sat, suggests that iron availability to the WM may be a requirement for optimal myelin functionality. Results also suggest that serum iron concentration, ferritin and % Tf sat had an effect on myelination. The lack of association between FA and Hb suggests that the iron in this protein is not available for WM function.

Multiple sclerosis is a leading cause of neurological disability in young adults which affects more than 2.5 million people worldwide. An important substrate of disability accrual is the loss of neurons and connections between them (neurodegeneration) which can be captured by serial brain imaging, especially in the cerebral grey matter. In this thesis in four separate subprojects, I aimed to assess the strength of imaging-derived grey matter volume as a biomarker in the diagnosis, predicting the evolution of multiple sclerosis, and developing a staging system to stratify patients. In total, I retrospectively studied 1701 subjects, of whom 1548 had longitudinal brain imaging data. I used advanced computational models to investigate cross-sectional and longitudinal datasets. In the cross-sectional study, I demonstrated that grey matter volumes could distinguish multiple sclerosis from another demyelinating disorder (neuromyelitis optica) with an accuracy of 74%. In longitudinal studies, I showed that over time the deep grey matter nuclei had the fastest rate of volume loss (up to 1.66% annual loss) across the brain regions in multiple sclerosis. The volume of the deep grey matter was the strongest predictor of disability progression. I found that multiple sclerosis affects different brain areas with a specific temporal order (or sequence) that starts with the deep grey matter nuclei, posterior cingulate cortex, precuneus, and cerebellum. Finally, with multivariate mechanistic and causal modelling, I showed that brain volume loss causes disability and cognitive worsening which can be delayed with a potential neuroprotective treatment (simvastatin). This work provides conclusive evidence that grey matter volume loss affects some brain regions more severely, can predict future disability progression, can be used as an outcome measure in phase II clinical trials, and causes clinical and cognitive worsening. This thesis also provides a subject staging system based on which patients can be scored during multiple sclerosis.

The aim of this thesis is to assess the ever challenging role of MRI in predicting disability in relapse-onset Multiple Sclerosis (MS) patients. It consists of four parts. In part one a brief overview of MS is given, looking at the most up-to-date knowledge on aetiology, pathogenesis, most common clinical presentations and the evolution in diagnostic process, prognosis and ever increasing treatment options for MS patients. Then, a brief review of the basic physics concepts and the techniques used to assess disability in MS is given using both conventional and non-conventional MRI. In part two, the relationship of T2 white matter lesion volume (T2WMLV) with long-term disability is assessed in a unique cohort of MS patients seen from the disease onset with a clinically isolated syndrome and followed up with clinical and MRI data every 5 years up to 20 years. In part three, using cross-sectional data from the same cohort of patients, the role of tissue specific i.e. grey matter and white matter changes in predicting disability at 20 years is assessed, using both atrophy measurements and magnetisation transfer ratio. Comparisons between sub-group of MS patients and controls are also assessed. Furthermore, the relationship of longitudinal T2WMLV changes with atrophy measurements at 20 years is also explored. In the fourth and final part of this thesis, a summary of the main findings of this work is given and there is discussion on what the future holds for the role of imaging in predicting disability in MS.

Ce travail de thèse concerne le traitement d’image fDOT (fDOT pour fluorescence diffuse optical tomography) suit vers deux axes. Le recalage d'images fDOT à l’aide de l’imagerie TEP (tomographie par émission de positons) et l’amélioration des reconstructions fDOT à l’aide de miroirs pour collecter des projections complémentaires. Il est présenté en deux parties : Dans la première partie, une méthode automatique pour recaler les images de fDOT avec les images de Tomographie par Emission de Positons (TEP) développée dans le but de corréler l’ensemble des informations issues de chaque modalité. Cette méthode de recalage est basée sur une détection automatique de marqueurs fiduciaires présents dans les deux modalités. La particularité de cette méthode est l’utilisation de l’image de surface obtenue en fDOT, qui sert à identifier la position en Z des marqueurs fiduciaires dans les images optiques. Nous avons testé cette méthode sur un modèle de souris porteuses de xénogreffes de tumeurs de cellules cancéreuses MEN2A qui imitent un carcinome thyroïdien médullaire humain, après une double injection de traceur radioactif : [18F]2-fluoro-2-Deoxy-D-glucose (FDG) pour l’imagerie TEP et un traceur optique d’infrarouge fluorescent, le Sentidye. Grâce à la précision de notre méthode, nous arrivons à démontrer que le signal Sentidye est présent à la fois dans la tumeur et les vaisseaux environnants [1]. La qualité des images fDOT est dégradée selon l’axe Z du fait d’un nombre limité de projections pour la reconstruction. Dans la deuxième partie, le travail s’est orienté vers une nouvelle méthode de reconstruction d’images fDOT à partir d’un nouveau système d’acquisition multi-angulaire avec deux miroirs placés de chaque côté de l’animal. Ce travail a été mené en collaboration avec le département CS d’University College London (UCL), partenaire du projet Européen FMT-XCT. Le logiciel TOAST développé par cette équipe a été utilisé comme source pour l’algorithme de reconstruction, et modifié pour s’adapter à notre problématique. Après plusieurs essais concernant l’ajustement des paramètres du programme, nous avons appliqué cette méthode sur un fantôme réaliste des tissus biologiques et chez la souris. Les résultats montrent une amélioration de l’image reconstruite d’un fantôme semi-cylindrique et de l’image de rein chez la souris, pour lesquelles la méthode des miroirs est supérieure à la méthode classique sans miroir. Malgré tout, nous avons observé que les résultats étaient très sensibles à certains paramètres, d’où une performance de reconstruction variable d’un cas à l’autre. Les perspectives futures concernent l’optimisation des paramètres afin de généraliser l’approche multi-angle
This thesis concerns the image processing of fluorescence diffuse optical tomography (fDOT), following two axes: FDOT image co-registration with PET (positron emission tomography) image and improvement of fDOT image reconstructions using mirrors to collect additional projections. It is presented in two parts:In the first part, an automatic method to co-register the fDOT images with PET images has been developed to correlate all the information from each modality. This co-registration method is based on automatic detection of fiducial markers (FM) present in both modalities. The particularity of this method is the use of optical surface image obtained in fDOT imaging system, which serves to identify the Z position of FM in optical images. We tested this method on a model of mice bearing tumor xenografts of MEN2A cancer cells that mimic a human medullary thyroid carcinoma, after a double injection of radiotracer [18F] 2-fluoro-2-Deoxy-D-glucose ( FDG) for PET imaging and optical fluorescent infrared tracer Sentidye. With the accuracy of our method, we can demonstrate that the signal of Sentidye is present both in the tumor and surrounding vessels.The fDOT reconstruction image quality is degraded along the Z axis due to a limited number of projections for reconstruction. In the second part, the work is oriented towards a new method of fDOT image reconstruction with a new multi-angle data acquisition system in placing two mirrors on each side of the animal. This work was conducted in collaboration with the CS Department of University College London (UCL), a partner of the European project FMT-XCT. TOAST software developed by this team was used as source code for the reconstruction algorithm, and was modified to adapt to the concerned problem. After several tests on the adjustment of program parameters, we applied this method on a phantom that simulating the biological tissue and on mice. The results showed an improvement in the reconstructed image of a semi-cylindrical phantom and the image of mouse kidney, for which the reconstruction of the mirrors geometry is better than that of conventional geometry without mirror. Nevertheless, we observed that the results were very sensitive to certain parameters, where the performance of reconstruction varies from one case to another. Future prospectives concern the optimization of parameters in order to generalize the multi-angle approach

Aims : Patients with mild heart failure (HF) who are clinically compensated may have normal left ventricular (LV) stroke volume (SV). Despite this, altered intra-ventricular flow patterns have been recognized in these subjects. We hypothesized that, compared with normal LVs, flow in myopathic LVs would demonstrate a smaller proportion of inflow volume passing directly to ejection and diminished the end-diastolic preservation of the inflow kinetic energy (KE). Methods and results : In 10 patients with dilated cardiomyopathy (DCM) (49 ± 14 years, six females) and 10 healthy subjects (44 ± 17 years, four females), four-dimensional MRI velocity and morphological data were acquired. A previously validated method was used to separate the LV end-diastolic volume (EDV) into four flow components based on the blood's locations at the beginning and end of the cardiac cycle. KE was calculated over the cardiac cycle for each component. The EDV was larger (P = 0.021) and the ejection fraction smaller (P < 0.001) in DCM compared with healthy subjects; the SV was equivalent (DCM: 77 ± 19, healthy: 79 ± 16 mL). The proportion of the total LV inflow that passed directly to ejection was smaller in DCM (P = 0.000), but the end-diastolic KE/mL of the direct flow was not different in the two groups (NS). Conclusion : Despite equivalent LVSVs, HF patients with mild LV remodelling demonstrate altered diastolic flow routes through the LV and impaired preservation of inflow KE at pre-systole compared with healthy subjects. These unique flow-specific changes in the flow route and energetics are detectable despite clinical compensation, and may prove useful as subclinical markers of LV dysfunction.

Magnetic resonance imaging (MRI) is regularly used to obtain anatomical images, greatly advancing biomedical research and clinical health care today, but its full potential in providing functional, physiological, and molecular information is only beginning to emerge. The goal of magnetic resonance molecular imaging is to utilize MRI to acquire information on the molecular level. This dissertation is focused on ways to increase the use of MRI for molecular imaging using superparamagnetic iron oxide (SPIO) nanoparticle induced MRI contrast. This work is divided into three main sections: 1) Elucidation of the contribution of size and coating properties to magnetic nanoparticle induced proton relaxation. To maximize contrast generated without increasing particle size, new methods to increase effects on relaxivity must be developed. Experimental data obtained on a new class of biocompatible particles are presented, along with simulated data. The effects of coating size, proton exchange, and altered diffusion are examined. Simulations are presented confirming the effect of particle coatings on clustering-induced relaxivity changes, and an experimental system demonstrating the clustering effect is presented. 2) Development of a diffusion-dependent, off-resonance imaging protocol for magnetic nanoparticles. This work demonstrates an alternative approach, off-resonance saturation (ORS), for generating contrast sensitive to SPIO nanoparticles. This method leads to a calculated contrast that increases with SPIO concentration. Experimental data and a mathematical model demonstrate and characterize this diffusion-dependent, off-resonance effect. Dependence on off-resonance frequency and power are also investigated. 3) Development of a genetic MRI marker via in vivo magnetic nanoparticle synthesis. This work seeks to provide a gene expression marker for MRI based on bacterial magnetosomes, tiny magnets produced by naturally occurring magnetotactic bacteria. Here, magA is expressed in a commonly used human cell line, 293FT, resulting in the production of magnetic, iron oxide nanoparticles by these cells. MRI shows these particles can be formed in vivo utilizing endogenous iron and can be used to visualize cells positive for magA. These results demonstrate magA alone is sufficient to produce magnetic nanoparticles and that it is an appropriate candidate for an MRI reporter gene.

Proust em imagens é uma reescritura ou uma tradução intersemiótica de fragmentos da obra Em busca do tempo perdido de Marcel Proust e de sua crítica, sob a forma de uma exposição de artes plásticas. Além disso, seu texto consiste em uma busca pessoal, da minha vocação de artista espelhada na do narrador da Recherche e na do próprio autor, Marcel Proust; em um projeto de exposição e em uma reflexão sobre as duas linguagens: literatura e artes plásticas ou texto e imagem. Por fim, acrescento a análise de uma frase do caderno manuscrito 39 do mesmo autor, sob uma ótica da crítica genética e da pintura, o quadro Vista de Delft de Vermeer e seu pedacinho de muro amarelo
Proust in images is a rewrite or intersemiotic translation of fragments of the work In Search of Lost Time by Marcel Proust and his criticism in an exhibition of visual arts. Also, this text consists of a personal quest, my vocation as an artist mirrored in the narrator of the In Search of Lost Time and the authors own Marcel Proust; of a exhibition projects and of a reflection on the two languages : literature and visual arts or text and image. Finally, I add the analysis of a sentence of 39 notebook manuscript by the same author, in a perspective of genetic criticism and painting, the Vermeer painting and his little piece of yellow wall

Cardiovascular disease varies by ethnicity in the UK. South Asians (SA) have higher coronary heart disease (CHD) and diabetes prevalence, while African-Caribbeans (AfC) have greater stroke, but intriguingly lower CHD rates despite higher blood pressures and diabetes risk than Europeans. Conventional risk factors do not fully explain such differences. This cross-sectional study tested the hypothesis that the hormones, vitamin D measured as 25(OH)D and aldosterone, would be independently associated with intermediate cardiovascular outcome markers in these ethnic groups. Community-dwelling men 40-80 years old (AfC: n=67, 55±10yr; SA: n=68, 55±10yr; European: n=63, 57±8yr) were sampled from Greater Manchester’s multi-ethnic population. The intermediate markers examined were aortic pulse wave velocity (aPWV), left ventricular (LV) mass and function, and carotid intima media thickness (CIMT), measured non-invasively by ultrasound, and hemodynamic profiling methods (the Arteriograph) in the total sample and by magnetic resonance imaging (MRI) in a subsample of 50. Adjusted for age, systolic blood pressure and diabetes, mean(SE) aPWV by the Arteriograph, was 0.5(0.2) m/s higher in SA than AfC and Europeans (p=0.01), which paralleled known cross-ethnic CHD risk differences in the UK. By MRI, aPWV along the descending aorta in SA was 0.7(0.3) and 0.8(0.3) m/s higher than that in AfC and Europeans, but aPWV along the aortic arch was not significantly different. Unlike aldosterone, 25(OH)D was independently and inversely correlated with aPWV (unstandardised B(SE)=-0.013[0.004] m/s, p<0.001), and partly explained the ethnic variation in aPWV. Similar inverse correlations were found between 25(OH)D and LV concentricity measured by echocardiography and MRI. Compared to Europeans, SA and AfC, had 21(3) and 14(3) nmol/L lower mean(SE) 25(OH)D, respectively (p<0.01). Mean(SE) of relative wall thickness, an index of LV concentricity by echocardiography, was 0.05(0.01) higher in SA and AfC than Europeans. Lower 25(OH)D levels were also associated with higher myocardial deformation rates measured by MRI myocardial tagging (n=50), supporting previous animal experimental evidence. A one standard deviation (SD) decrease in 25(OH)D was associated with a 0.38 SD increase in absolute systolic strain rate (p=0.003) and 0.22 SD rise in diastolic strain rate (p=0.04). Right and left CIMT showed different relations with 25(OH)D and aldosterone. Left-right CIMT differences varied by ethnicity and were related to SA ethnicity and aldosterone levels. Two related technical studies investigated the relatively new method of hemodynamic profiling, the Arteriograph, used here. The results suggested a standardisation method of aortic length estimation for purely central aPWV, which significantly improved aPWV agreement between the Arteriograph and MRI (reference method here), and was used for calibrating the Arteriograph aPWV in the above-mentioned results for the total sample. Future well-designed trials are necessary to investigate any cause-effect relationship between vitamin D deficiency and the unfavourable cardiovascular intermediate outcomes found here in a cross-sectional design and multi-ethnic background.

La Malattia di Alzheimer (AD) è la forma più comune di demenza nella popolazione anziana e affligge più 35 milioni di persone nel mondo. Ad oggi, le uniche terapie approvate per la sua cura sono dirette a ridurre i sintomi. Lo sviluppo di nuovi farmaci è lungo e costoso. Il processo di scoperta è arduo in quanto i trial clinici coinvolgono un ampio campione di pazienti e implicano dei follow-up troppo lunghi. Inoltre il valore predittivo dei modelli sperimentali è limitato a causa della mancanza di marcatori omologhi nell’uomo e nei modelli animali. Questo lavoro si inserisce in Pharmacog, un progetto europeo che vede la collaborazione di università ed industrie allo scopo di identificare biomarcatori affidabili e sensibili alla progressione di malattia in pazienti affetti da decadimento cognitivo lieve (MCI) e modelli animali di AD allo scopo di colmare il vuoto tra risultati clinici e preclinici. Nell’uomo, i marcatori di neuroimmagine sono tra i più promettenti candidati nel tracciare la progressione di malattia. Innovazioni nelle tecniche di risonanza magnetica (MRI) rendono possibile l’identificazione di marcatori omologhi nell’uomo e nel topo. Prima dello studio di neuroimmagine nei pazienti MCI, è necessario verificare che eventuali cambiamenti individuati siano dovuti all’effettiva progressione di malattia e non causati dalla variabilità intra e tra i diversi scanner utilizzati nel progetto. Il primo scopo di questo lavoro è lo studio dei cambiamenti morfometrici e di diffusione in tre diversi modelli murini di Malattia Alzheimer (TASTPM, TauPS2APP e PDAPP da 3 a 22 mesi) tramite l’utilizzo di tecniche MRI. A nove mesi abbiamo trovato una significativa riduzione rispetto ai controlli del volume del caudato-putamen e della corteccia frontale nei TASTPM e nei TauPS2APP (p< 0.001). L’assottigliamento della corteccia entorinale era significativo alla stessa età in tutte e tre i modelli (p< 0.001). Abbiamo inoltre individuato delle anormalità dipendenti dall’età anche in diverse regione di sostanza bianca. Quelle più precoci erano nella commissura anteriore e nel corpo calloso dei TASTPM di 13 mesi (p< 0.001). I danni dei TASTPM sono associabili al pesante carico di amiloide ed alla marcata attivazione della glia e degli astrociti. Il secondo scopo dello studio è la valutazione e la comparazione della riproducibilità di misure volumetriche e di spessore tra test e retest ottenute utilizzando due diversi metodi di processazione esistenti (Freesurfer sulla singola acquisizione o Freesurfer longitudinale). Inoltre abbiamo saggiato la riproducibilità di un’analisi per le immagini di diffusione messa a punto nel nostro laboratorio. A questo scopo ognuno degli otto centri europei coinvolti nel progetto e con diversi scanner a 3T ha arruolato un gruppo di 5 volontari sani e anziani sottoponendoli a 2 acquisizioni di risonanza ad almeno una settimana di distanza l’una dall’altra. Abbiamo trovato che la variabilità intra e tra i diversi centri nei volumi estratti da queste acquisizioni era inferiore al 3% per le strutture più grandi (come il talamo) e minore del 6% per quelle più piccole (es. amigdala). La variabilità degli spessori era meno del 6% e le variazioni dei parametri di diffusione erano prevalentemente nell’intervallo del 2-3%. In conclusione, abbiamo identificato nei modelli analizzati dei marcatori di immagine sensibili alla progressione dell’AD simili a quelli visti nell’uomo e questo apre la strada al possibile utilizzo di una “distintiva collezione” di marcatori murini di immagine nei trial clinici. I dati collezionati nella parte umana mostrano un più altra riproducibilità dei risultati morfometrici ottenuti con l’analisi longitudinale rispetto a quella sulla singola acquisizione (p< 0.01). Infine, abbiamo dimostrato che l’analisi delle immagini di diffusione messa a punto nel nostro laboratorio dà risultati ugualmente riproducibili a quelli riportati in letteratura.
Alzheimer’s disease (AD) is the most common form of dementia in elderly population, affecting more than 35 million people worldwide. To date, the only approved therapies for AD focus on symptomatic relief. The development of new therapeutic agents is time consuming and costly. Drug discovery process is arduous because clinical trials are currently involving too wide sample of patients and long follow-up. Moreover, the predicting value of experimental models used nowadays is limited due to the lack of homologous markers in humans and animals. This work is a branch of Pharmacog, an industry-academic European project aimed at identifying reliable biomarkers that are sensitive to disease progression in patients with Mild Cognitive Impairment (MCI) and in AD animal models in order to bridge the gap between preclinical and clinical outcomes. Human neuroimaging markers are among the most promising candidates to track disease progression. In addition, advanced magnetic resonance imaging (MRI) allow the identification of homologous biomarkers in humans and mice. Prior to investigate neuroimaging biomarkers on MCI patients, we have to test that there is no significant effect of within and across MRI sites variability on brain AD-related longitudinal changes. The first aim of this work is the study of the morphometric and diffusion changes in three different AD mouse model (TASTPM, TauPS2APP and PDAPP from 3 to 22 months of age) through MRI. We found significant volume reduction starting at 9 months in the caudate-putamen and frontal cortex of TASTPM and TauPS2APP (p< 0.001) compared to non transgenic mice. The decrease in the enthorinal cortex thickness was significantly lower in all the strains (p< 0.001). We also found age-related diffusion abnormalities in different white matter regions of TASTPM. The earlier changes were found in the corpus callosum and anterior commissure of 13 months old mice (p< 0.001). In TASTPM, deficits detected with MRI are related to heavy amyloid pathology, marked gliosis and astrocitosys. The second aim of this study is the evaluation and comparison of test-retest reproducibility of brain volumes and thicknesses by two existing Freesurfer pipelines (longitudinal and cross-sectional). Moreover, we assessed the reliability of a diffusion pipeline developed in our lab. Eight different 3T MRI sites in Europe enrolled a group of 5 healthy elderly subjects scanned twice at least a week apart. We found that the within and across sites variability of volumes was less than 3% for larger brain structures (such as thalamus) and less than 6% for smaller regions (i.e., hippocampus). The thickness variability was less than 6% and diffusion indices variations were mostly within the range 2-3%. In conclusion, the present data identify imaging biomarkers of disease progression in mice similar to that seen in humans and pave the way of a murine “imaging signature” usefulness in clinical trials. Human data show significantly higher reproducibility of brain morphometry using the longitudinal pipeline than using the cross-sectional one (p< 0.01). Finally, we demonstrated that the reliability of the analysis of brain diffusion we implemented in our lab is comparable to data reported in the literature.

Somatic cells can be reprogrammed into induced pluripotent stem (iPS) cells by over expression of the transcription factors OCT4, SOX2, KLF4 and c-MYC. Using serial live cell immunofluorescence imaging of human fibroblasts undergoing reprogramming, we traced the emergence of nascent iPS cell colonies among heterogeneous cell populations and defined the kinetics of marker expression. We identified distinct colony types that morphologically resemble embryonic stem (ES) cells yet differ in molecular phenotype and differentiation potential. By analyzing expression of pluripotency markers, methylation at the OCT4 and NANOG promoters, and differentiation into teratomas, we determined that only one colony type represented bona fide iPS cells, whereas the others represented reprogramming intermediates. Proviral silencing and expression of TRA-1-60, DNMT3B, and REX1 distinguished the fully reprogrammed state, whereas Alkaline Phosphatase, SSEA-4, GDF3, hTERT and NANOG proved insufficient as markers. Reprogramming in chemically defined medium favored formation of bona fide iPS cell colonies relative to partially reprogrammed colonies. These data highlight the need for rigorous characterization and standardization of putative iPS cells.

In recent times, the Internet revolution has spawned numerous innovative enterprises-virtual companies, and electronic markets. Electronic markets (or digital markets) are scalable web-based platforms for buyers, sellers, marketmakers, and brokers to carry out business transactions. Over the last two years, there has been a proliferation of such E-Markets on the web. In this thesis, we develop an E-marketplace, which we call IMAGINE (Intelligent Market with AGents and Integrative NEgotiations) that improves upon the existing state-of-the-art in several non-trivial ways. IMAGINE combines the best features of existing E-marketplaces with several innovations. The thesis describes the conceptualization, analysis, and design of IMAGINE and provides details of implementation of a prototype of IMAGINE at the Electronic Enterprises Laboratory, Department of Computer Science and Automation, Indian Institute of Science. IMAGINE is a collaborative, co-operative, intelligent E-Market that maximizes the combined utility value of the all traders involved. IMAGINE has several distinctive features: • It uses an innovative business model, which is intelligent in the sense of perceiving the nature of the market and market forces and using this market intelligence in matching buyers with sellers and in determining the prices. • It uses integrative negotiations, which make it attractive for buyers and sellers to reveal their true business interests and valuations. • A sound and robust software architecture for a web-based implementation using best practices in object technology. • Implementation of a prototype of IMAGINE has been carried out using leading edge Internet technologies such as multi-agent technology, Jini, and Javaspaces.

Biomarker research is of great interest in the field of traumatic brain injury (TBI), since there are numerous potential markers that may indicate central nervous system damage, yet the brain is normally well isolated and discovery is at its infancy. Traditional methods for biomarker discovery include time consuming multi step chromatographic mass spectrometery (MS) techniques or pre-defined serial probing using traditional assays, making the identification of biomarker panels limiting and expensive. These shortfalls have motivated the development of a MS based probe that can be embedded into 3D neural cultures and obtain temporal and spatial information about the release of biomarkers. Using the high sensitivity MS ionization method of nano-electrospray ionization (nano-ESI) with an in-line microdialysis (MD) unit allows us to use MS to analyze low concentrations of TBI biomarkers from within cell cultures with no need for off-line sample manipulation. This thesis goes through the development of the probe by studying the theoretical principles, simulations and experimental results of the probe's capability to sample small local concentrations of a marker within cell culture matrix, the MD unit's sample manipulation capabilities, and the ability to detect markers using in-line MD-nano-ESI MS.

Soft tissue infection in a diabetic foot with an ulcer is often clinically obvious but the diagnosis of osteomyelitis underlying a diabetic foot ulcer is challenging. It has been calculated that there are over 1 million amputations worldwide for diabetes related complications every year, many preceded by an ulcer complicated by osteomyelitis.
This research encompasses two studies attempting to add to the ways in which osteomyelitis is diagnosed.
The first was examining the role of inflammatory blood markers in recognising and separating ulcers with cutaneous infection from both suspected and proven osteomyelitis. The response of the body to produce these markers when an injury occurs is well known but arguments exist as to the capacity of the individual with diabetes to do so. Despite the recognition and allowance for common confounding factors no trend was found. This study may have been more difficult than originally thought due to the many interactions of the diseased state of diabetes, the drugs used to control it and the many other confounders that would have influenced the inflammatory process and as such the level of the markers.
The second study was comparing a new form of scanning technique (SPECT/CT) to the technique most commonly used as a ‘gold standard’ – MRI. The results of each type of scan were compared to the clinical diagnosis and each other. The SPECT/CT scan appears to show some good results and may be a more suitable scan for individuals who are unable to have a MRI for example due to the need to introduce a renally excreted drug to help make the images clearer but it does mean introducing a small amount of radiation into the individual.

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.

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.

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.

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.

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.

Doctorat en Sciences médicales
info:eu-repo/semantics/nonPublished