Non-invasive visualization of amyloid-beta deposits in Alzheimer amyloidosis mice using magnetic resonance imaging and fluorescence molecular tomography

Abnormal cerebral accumulation of amyloid-beta peptide (Aβ) is a major hallmark of Alzheimer's disease. Non-invasive monitoring of Aβ deposits enables assessing the disease burden in patients and animal models mimicking aspects of the human disease as well as evaluating the efficacy of Aβ-modulating therapies. Previous in vivo assessments of plaque load have been predominantly based on macroscopic fluorescence reflectance imaging (FRI) and confocal or two-photon microscopy using Aβ-specific imaging agents. However, the former method lacks depth resolution, whereas the latter is restricted by the limited field of view preventing a full coverage of the large brain region. Here, we utilized a fluorescence molecular tomography (FMT)-magnetic resonance imaging (MRI) pipeline with the curcumin derivative fluorescent probe CRANAD-2 to achieve full 3D brain coverage for detecting Aβ accumulation in the arcAβ mouse model of cerebral amyloidosis. A homebuilt FMT system was used for data acquisition, whereas a customized software platform enabled the integration of MRI-derived anatomical information as prior information for FMT image reconstruction. The results obtained from the FMT-MRI study were compared to those from conventional planar FRI recorded under similar physiological conditions, yielding comparable time courses of the fluorescence intensity following intravenous injection of CRANAD-2 in a region-of-interest comprising the brain. In conclusion, we have demonstrated the feasibility of visualizing Aβ deposition in 3D using a multimodal FMT-MRI strategy. This hybrid imaging method provides complementary anatomical, physiological and molecular information, thereby enabling the detailed characterization of the disease status in arcAβ mouse models, which can also facilitate monitoring the efficacy of putative treatments targeting Aβ

New frontiers in time-domain diffuse optics, a review

The recent developments in time-domain diffuse optics that rely on physical concepts (e.g., time-gating and null distance) and advanced photonic components (e.g., vertical cavity source-emitting laser as light sources, single photon avalanche diode, and silicon photomultipliers as detectors, fast-gating circuits, and time-to-digital converters for acquisition) are focused. This study shows how these tools could lead on one hand to compact and wearable time-domain devices for point-of-care diagnostics down to the consumer level and on the other hand to powerful systems with exceptional depth penetration and sensitivity

Imaging workflow and calibration for CT-guided time-domain fluorescence tomography

In this study, several key optimization steps are outlined for a non-contact, time-correlated single photon counting small animal optical tomography system, using simultaneous collection of both fluorescence and transmittance data. The system is presented for time-domain image reconstruction in vivo, illustrating the sensitivity from single photon counting and the calibration steps needed to accurately process the data. In particular, laser time- and amplitude-referencing, detector and filter calibrations, and collection of a suitable instrument response function are all presented in the context of time-domain fluorescence tomography and a fully automated workflow is described. Preliminary phantom time-domain reconstructed images demonstrate the fidelity of the workflow for fluorescence tomography based on signal from multiple time gates

Algoritmy pro multi-modální radiografii s novými zobrazovacími detektory.

Zobrazování v medicíně je technika, která nám umožňuje bez operativních zásahů vizua- lizovat vnitřní struktury lidského těla, abychom mohli diagnostikovat nemoci. Umožňuje nám taky monitorování fyzikálních procesů a funkcí různých orgánů v těle. Obor medi- cínského zobrazování obsahuje širokou škálu metod založených na různých fyzikálních principech. Součástí tohoto oboru jsou i metody používající ionizující záření. Kvalita na- měřených snímků silně závisi na použitých zobrazovacích detektorech. Existuje celá řada různých typů detektorů, od čistě analogových (filmy) až po plně digitální detektory jako jsou flat panely, které jsou v dnešní době nejrozšířenější. Novější typy dektorů využívají technologie počítání fotonů a nejmodernější experimentální detektory jako například Me- dipix jsou schopné detekovat a analyzovat jednotlivé fotony. Tato práce studuje vlastnoti, parametery a možné aplikační využití nejvnovejšího detek- toru Timepix3 z rodiny detektorů Medipix v různých zobrazovacích modalitách. Nejprve byl vyvinut nový vyčítací hardware a akviziční software společně s novými kalibračními a korekčními metodami. Poté byly postupně prozkoumány různé módy Timepix3 detek- toru: velmi rychlá spektrální radiografie, která demonstruje velmi rychlé měření "barev- ných"rentgenových obrázků; jednofotovná...Medical imaging is a technique that allows us to visualize non surgically the internal structure of the human body in order to diagnose or treat medical conditions. It permits also monitoring of physical processes or functions of different organs inside the body. The medical imaging encompasses wide range of techniques based on different physical prin- ciples, including techniques using ionizing radiation. The quality of the images depends significantly on the quality of the used imaging detectors. There are many types of the detectors, from old analog devices (e.g. films) to fully digital detectors such as flat panels, that are the most widely used today. The newer technology is being developed and the techniques such as photon counting explored. However, the state of the art technology is the single photon counting, where the experimental detectors such as Medipix are able to count and process each individual photon. This works studies the properties, features and applications of the newest detector from the Medipix family Timepix3 in different imaging modalities. Firstly, a design of a new hardware readout interface for Timepix3 is presented together with data acquisition software and new analysis and calibration algorithms. Then, different applications of Timepix3 detector were explored: very...Ústav patologické fyziologie 1. LF UKInstitute of Pathological Physiology First Faculty of Medicine Charles University1. lékařská fakultaFirst Faculty of Medicin

NONINVASIVE MULTIMODAL DIFFUSE OPTICAL IMAGING OF VULNERABLE TISSUE HEMODYNAMICS

Measurement of tissue hemodynamics provides vital information for the assessment of tissue viability. This thesis reports three noninvasive near-infrared diffuse optical systems for spectroscopic measurements and tomographic imaging of tissue hemodynamics in vulnerable tissues with the goal of disease diagnosis and treatment monitoring. A hybrid near-infrared spectroscopy/diffuse correlation spectroscopy (NIRS/DCS) instrument with a contact fiber-optic probe was developed and utilized for simultaneous and continuous monitoring of blood flow (BF), blood oxygenation, and oxidative metabolism in exercising gastrocnemius. Results measured by the hybrid NIRS/DCS instrument in 37 subjects (mean age: 67 ± 6) indicated that vitamin D supplement plus aerobic training improved muscle metabolic function in older population. To reduce the interference and potential infection risk on vulnerable tissues caused by the contact measurement, a noncontact diffuse correlation spectroscopy/tomography (ncDCS/ncDCT) system was then developed. The ncDCS/ncDCT system employed optical lenses to project limited numbers of sources and detectors on the tissue surface. A motor-driven noncontact probe scanned over a region of interest to collect boundary data for three dimensional (3D) tomographic imaging of blood flow distribution. The ncDCS was tested for BF measurements in mastectomy skin flaps. Nineteen (19) patients underwent mastectomy and implant-based breast reconstruction were measured before and immediately after mastectomy. The BF index after mastectomy in each patient was normalized to its baseline value before surgery to get relative BF (rBF). Since rBF values in the patients with necrosis (n = 4) were significantly lower than those without necrosis (n = 15), rBF levels can be used to predict mastectomy skin flap necrosis. The ncDCT was tested for 3D imaging of BF distributions in chronic wounds of 5 patients. Spatial variations in BF contrasts over the wounded tissues were observed, indicating the capability of ncDCT in detecting tissue hemodynamic heterogeneities. To improve temporal/spatial resolution and avoid motion artifacts due to a long mechanical scanning of ncDCT, an electron-multiplying charge-coupled device based noncontact speckle contrast diffuse correlation tomography (scDCT) was developed. Validation of scDCT was done by imaging both high and low BF contrasts in tissue-like phantoms and human forearms. In a wound imaging study using scDCT, significant lower BF values were observed in the burned areas/volumes compared to surrounding normal tissues in two patients with burn. One limitation in this study was the potential influence of other unknown tissue optical properties such as tissue absorption coefficient (µa) on BF measurements. A new algorithm was then developed to extract both µa and BF using light intensities and speckle contrasts measured by scDCT at multiple source-detector distances. The new algorithm was validated using tissue-like liquid phantoms with varied values of µa and BF index. In-vivo validation and application of the innovative scDCT technique with the new algorithm is the subject of future work

Development and Performance Evaluation of High Resolution TOF-PET Detectors Suitable for Novel PET Scanners

Tesis por compendio[ES] La Tomografía por Emisión de Positrones (PET) es una de las técnicas más importantes en la medicina de diagnóstico actual y la más representativa en el campo de la Imagen Molecular. Esta modalidad de imagen es capaz de producir información funcional única, que permite la visualización en detalle, cuantificación y conocimiento de una variedad de enfermedades y patologías. Áreas como la oncología, neurología o la cardiología, entre otras, se han beneficiado en gran medida de esta técnica. A pesar de que un elevado número de avances han ocurrido durante el desarrollo del PET, existen otros que son de gran interés para futuras investigaciones. Uno de los principales pilares actualmente en PET, tanto en investigación como en desarrollo, es la obtención de la información del tiempo de vuelo (TOF) de los rayos gamma detectados. Cuando esto ocurre, aumenta la sensibilidad efectiva del PET, mejorando la calidad señal-ruido de las imágenes. Sin embargo, la obtención precisa de la marca temporal de los rayos gamma es un reto que requiere, además de técnicas y métodos específicos, compromisos entre coste y rendimiento. Una de las características que siempre se ve afectada es la resolución espacial. Como discutiremos, la resolución espacial está directamente relacionada con el tipo de centellador y, por lo tanto, con el coste del sistema y su complejidad. En esta tesis, motivada por los conocidos beneficios en imagen clínica de una medida precisa del tiempo y de la posición de los rayos gamma, proponemos configuraciones de detectores TOF- PET novedosos capaces de proveer de ambas características. Sugerimos el uso de lo que se conoce como métodos de "light-sharing", tanto basado en cristales monolíticos como pixelados de tamaño diferente al del fotosensor. Estas propuestas hacen que la resolución espacial sea muy alta. Sin embargo, sus capacidades temporales han sido muy poco abordadas hasta ahora. En esta tesis, a través de varios artículos revisados, pretendemos mostrar los retos encontrados en esta dirección, proponer determinadas configuraciones y, además, indagar en los límites temporales de éstas. Hemos puesto un gran énfasis en estudiar y analizar las distribuciones de la luz centellante, así como su impacto en la determinación temporal. Hasta nuestro conocimiento, este es el primer trabajo en el que se estudia la relación de la determinación temporal y la distribución de luz de centelleo, en particular usando SiPM analógicos y ASICs. Esperamos que esta tesis motive y permita otros muchos trabajos orientados en nuevos diseños, útiles para instrumentación PET, así como referencia para otros trabajos. Esta tesis esta organizada como se describe a continuación. Hay una introducción compuesta por tres capítulos donde se resumen los conocimientos sobre imagen PET, y especialmente aquellos relacionados con la técnica TOF-PET. Algunos trabajos recientes, pero aún no publicados se muestran también, con el objetivo de corroborar ciertas ideas. En la segunda parte se incluyen las cuatro contribuciones que el candidato sugiere para el compendio de artículos.[CA] La Tomografia per Emissió de Positrons (PET) és una de les tècniques més importants en la medicina de diagnòstic actual i la més representativa en el camp de la Imatge Molecular. Esta modalitat d'imatge és capaç de produir informació funcional única, que permet la visualització en detall, quantificació i coneixement d'una varietat de malalties i patologies. Àrees com l'oncologia, neurologia o la cardiologia, entre altres, s'han beneficiat en gran manera d'aquesta tècnica. Tot i que un elevat nombre d'avanços han ocorregut durant el desenvolupament del PET, hi ha altres que són de gran interés per a futures investigacions. Un dels principals pilars actuals en PET, tant en investigació com en desenvolupament, és l'obtenció de la informació del temps de vol (TOF en anglès) dels raigs gamma detectats. Quan açò ocorre, augmenta la sensibilitat efectiva del PET, millorant la qualitat senyal-soroll de les imatges. No obstant això, l'obtenció precisa de la marca temporal dels raigs gamma és un repte que requerix, a més de tècniques i mètodes específics, compromisos entre cost i rendiment. Una de les característiques que sempre es veu afectada és la resolució espacial. Com discutirem, la resolució espacial està directament relacionada amb el tipus de centellador, i per tant, amb el cost del sistema i la seua complexitat. En aquesta tesi, motivada pels coneguts beneficis en imatge clínica d'una mesura precisa del temps i de la posició dels raigs gamma, proposem nouves configuracions de detectors TOF-PET capaços de proveir d'ambduess característiques. Suggerim l'ús del que es coneix com a mètodes de "light-sharing", tant basat en cristalls monolítics com pixelats de diferent tamany del fotosensor. Aquestes propostes fan que la resolució espacial siga molt alta. No obstant això, les seues capacitats temporals han sigut molt poc abordades fins ara. En aquesta tesi, a través de diversos articles revisats, pretenem mostrar els reptes trobats en aquesta direcció, proposar determinades configuracions i, a més, indagar en els límits temporals d'aquestes. Hem posat un gran èmfasi a estudiar i analitzar les distribucions de la llum centellejant, així com el seu impacte en la determinació temporal. Fins al nostre coneixement, aquest és el primer treball en què s'estudia la relació de la determinació temporal i la distribució de llum de centelleig, en particular utilitzant SiPM analògics i ASICs. Esperem que aquesta tesi motive i permeta molts altres treballs orientats en nous dissenys, útils per a instrumentació PET, així com referència per a altres treballs. Aquesta tesi esta organitzada com es descriu a continuació. Hi ha una introducció composta per tres capítols on es resumeixen els coneixements sobre imatge PET i, especialmente, aquells relacionats amb la tècnica TOF-PET. Alguns treballs recents, però encara no publicats es mostren també, amb l'objectiu de corroborar certes idees. La segona part de la tesi conté els quatre articles revisats que el candidat suggereix.[EN] Positron Emission Tomography (PET) is one of the greatest tools of modern diagnostic medicine and the most representative in the field of molecular imaging. This imaging modality, is capable of providing a unique type of functional information which permits a deep visualization, quantification and understanding of a variety of diseases and pathologies. Areas like oncology, neurology, or cardiology, among others, have been well benefited by this technique. Although numerous important advances have already been achieved in PET, some other individual aspects still seem to have a great potential for further investigation. One of the main trends in modern PET research and development, is based in the extrapolation of the Time- Of-Flight (TOF) information from the gamma-ray detectors. In such case, an increase in the effective sensitivity of PET is accomplished, resulting in an improved image signal-to-noise ratio. However, the direction towards a precise decoding of the photons time arrival is a challenging task that requires, besides specific approaches and techniques, tradeoffs between cost and performance. A performance characteristic very habitually compromised in TOF-PET detector configurations is the spatial resolution. As it will be discussed, this feature is directly related to the scintillation materials and types, and consequently, with system cost and complexity. In this thesis, motivated by the well-known benefits in clinical imaging of a precise time and spatial resolution, we propose novel TOF-PET detector configurations capable of inferring both characteristics. Our suggestions are based in light sharing approaches, either using monolithic detectors or crystal arrays with different pixel-to-photosensor sizes. These approaches, make it possible to reach a precise impact position determination. However, their TOF capabilities have not yet been explored in depth. In the present thesis, through a series of peer-reviewed publications we attempt to demonstrate the challenges encountered in these kinds of configurations, propose specific approaches improving their performance and eventually reveal their limits in terms of timing. High emphasis is given in analyzing and studying the scintillation light distributions and their impact to the timing determination. To the best of our knowledge, this is one of the first works in which such detailed study of the relation between light distribution and timing capabilities is carried out, especially when using analog SiPMs and ASICs. Hopefully, this thesis will motivate and enable many other novel design concepts, useful in PET instrumentation as well as it will serve as a helpful reference for similar attempts. The present PhD thesis is organized as follows. There is an introduction part composed by three detailed sections. We attempt to summarize here some of the knowledge related to PET imaging and especially with the technique of TOF-PET. Some very recent but still unpublished results are also presented and included in this part, aiming to support statements and theories. The second part of this thesis lists the four peer-reviewed papers that the candidate is including.This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement No 695536). It has also been supported by the Spanish Ministerio de Economía, Industria y Competitividad under Grants No. FIS2014-62341-EXP and TEC2016-79884-C2-1-R. Efthymios Lamprou has also been supported by Generalitat Valenciana under grant agreement GRISOLIAP-2018-026.Lamprou, E. (2021). Development and Performance Evaluation of High Resolution TOF-PET Detectors Suitable for Novel PET Scanners [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/162991TESISCompendi

Video-Rate Fluorescence Molecular Tomography for Hand-held and Multimodal Molecular Imaging

In the United States, cancer is the second leading cause of death following heart disease. Although, a variety of treatment regimens are available, cancer management is complicated by the complexity of the disease and the variability, between people, of disease progression and response to therapy. Therefore, advancements in the methods and technologies for cancer diagnosis, prognosis and therapeutic monitoring are critical to improving the treatment of cancer patients. The development of improved imaging methods for early diagnosis of cancer and of near real-time monitoring of tumor response to therapy may improve outcomes as well as the quality of life of cancer patients. In the last decade, imaging methods including ultrasound, computed tomography: CT), magnetic resonance imaging: MRI), single photon emission computed tomography: SPECT), and positron emission tomography: PET), have revolutionized oncology. More recently optical techniques, that have access to unique molecular reporting strategies and functional contrasts, show promise for oncologic imaging This dissertation focuses on the development and optimization of a fiber-based, video-rate fluorescence molecular tomography: FMT) instrument. Concurrent acquisition of fluorescence and reference signals allowed the efficient generation of ratio-metric data for 3D image reconstruction. Accurate depth localization and high sensitivity to fluorescent targets were established to depths of \u3e10 mm. In vivo accumulation of indocyanine green dye was imaged in the region of the sentinel lymph node: SLN) following intradermal injection into the forepaw of rats. These results suggest that video-rate FMT has potential as a clinical tool for noninvasive mapping of SLN. Spatial and temporal co-registration of nuclear and optical images can enable the fusion of the information from these complementary molecular imaging modalities. A critical challenge is in integrating the optical and nuclear imaging hardware. Flexible fiber-based FMT systems provide a viable solution. The various imaging bore sizes of small animal nuclear imaging systems can potentially accommodate the FMT fiber imaging arrays. In addition FMT imaging facilitates co-registering the nuclear and optical contrasts in time. In this dissertation, the feasibility of integrating the fiber-based, video-rate FMT system with a commercial preclinical NanoSPECT/CT platform was established. Feasibility of in vivo imaging is demonstrated by tracking a monomolecular multimodal-imaging agent: MOMIA) during transport from the forepaw to the axillary lymph nodes region of a rat. These co-registered FMT/SPECT/CT imaging results with MOMIAs may facilitate the development of the next generation preclinical and clinical multimodal optical-nuclear platforms for a broad array of imaging applications, and help elucidate the underlying biological processes relevant to cancer diagnosis and therapy monitoring. Finally, I demonstrated that video-rate FMT is sufficiently fast to enable imaging of cardiac, respiratory and pharmacokinetic induced dynamic fluorescent signals. From these measurements, the image-derived input function and the real-time uptake of injected agents can be deduced for pharmacokinetic analysis of fluorescing agents. In a study comparing normal mice against mice liver disease, we developed anatomically guided dynamic FMT in conjunction with tracer kinetic modeling to quantify uptake rates of fluorescing agents. This work establishes fiber-based, video-rate FMT system as a practical and powerful tool that is well suited to a broad array of potential imaging applications, ranging from early disease detection, quantifying physiology and monitoring progression of disease and therapies