The characterization of a mouse model of transient stroke using ex vivo MR microscopy and in vivo MR imaging

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2009.Includes bibliographical references (p. 141-152).Disrupted blood-brain barrier after an ischemic attack can cause vasogenic edema and increase the risk of hemorrhagic transformation. Therefore, early detection and monitoring of BBB damage is important in the pathological understanding and therapeutic treatment of stroke. Currently, MR contrast agents have been widely used in clinics for disease diagnosis and treatment evaluation, and in basic research to achieve better anatomical structure visualization and to understand pathological mechanisms of various human diseases in animal models. Thus, the central theme of this thesis to exploit the use of MR contrast agents in the study of ischemic stroke using both in vivo and ex vivo MR techniques. Specifically, the overall goals of this thesis are twofold: (1) to exploit the multiple relaxation mechanisms and varying tissue-dependent affinities of different MR contrast agents for better structure delineation, tissue differentiation, and image contrast manipulation in magnetic resonance microscopy (MRM) staining, and (2) to develop an MRI technique that employs intrinsic water as a biomarker for qualitative and quantitative monitoring of blood-brain barrier (BBB) integrity alteration in a mouse model of stroke using an intravascular long-circulating MRI contrast agent. Despite the great success of MRM in anatomical studies, MRM images based on intrinsic tissue contrast lack the flexibility and target-specificity offered by conventional histological staining. Therefore, the first focus of this thesis was on the development of MRM staining method by utilizing the different tissue relaxation ability and tissue biophysical/biochemical properties of different MR contrast agents. Two common MR contrast agents, Gd-DTPA and MnCl2 were used in this thesis. The ability of MR contrast agents to increase SNR and enhance image contrast was first tested in a relatively simple in vitro glioma spheroid (diameter ' 400 um) system.(cont.) We then fully characterized the relaxation mechanisms and tissue-dependent staining properties of these contrast agents in the brain tissue, and demonstrated that their unique relaxation and tissue properties led to differentiated MR staining in the ex vivo mouse brains, which greatly enhanced the ability of MRM to delineate tissue structures in addition to providing improved SNR. This MRM staining method was then applied to the Kif2la knockout mouse model for the anatomical phenotyping of the new born Kif2la knockout mice. The BBB damage is usually detected through the spatial leakage profiles of extrinsically administrated markers such as staining dyes, fluoresceins, radiolabeled compounds, or gadolinium based compound, which are only possible when BBB is compromised to the extent that allows extravasation of these markers. It is therefore desirable to develop a technique that allows the early detection of BBB damage. In the second part of thesis, we first presented the theoretical background of measuring trans vascular water exchange based on a two-compartment water exchange model. Parameters affecting the quantitative BBB water exchange measurement were initially characterized using computer simulations. We then performed graded hypercapnia and Mannitol-induced BBB-opening experiments to test the ability of this novel MRI technique to detect and monitor the changes of BBB integrity and cerebral blood volume (CBV). Upon the characterization of this MRI technique, we measured baseline BBB water exchange and other MRI-derived cerebrovascular parameters in the eNOS knockout mice, and showed that there is basal increase of trans vascular water exchange in addition to the morphological changes in the vasculature of eNOS knockout mice.(cont.) After developing and characterizing these ex vivo and in vivo MR techniques, we applied the in vivo MRI BBB water exchange detection technique and the ex vivo MRM staining method to a mouse model of transient stroke. We demonstrated the importance of CBV restoration in the BBB integrity change at acute stage after reperfusion, and showed that MRM staining may have a great potential in histopathological studies of ischemic brain injury.by Shuning Huang.Ph.D

Accomplishments and challenges in stem cell imaging in vivo.

Stem cell therapies have demonstrated promising preclinical results, but very few applications have reached the clinic owing to safety and efficacy concerns. Translation would benefit greatly if stem cell survival, distribution and function could be assessed in vivo post-transplantation, particularly in patients. Advances in molecular imaging have led to extraordinary progress, with several strategies being deployed to understand the fate of stem cells in vivo using magnetic resonance, scintigraphy, PET, ultrasound and optical imaging. Here, we review the recent advances, challenges and future perspectives and opportunities in stem cell tracking and functional assessment, as well as the advantages and challenges of each imaging approach

Medical Imaging of Microrobots: Toward In Vivo Applications

Medical microrobots (MRs) have been demonstrated for a variety of non-invasive biomedical applications, such as tissue engineering, drug delivery, and assisted fertilization, among others. However, most of these demonstrations have been carried out in in vitro settings and under optical microscopy, being significantly different from the clinical practice. Thus, medical imaging techniques are required for localizing and tracking such tiny therapeutic machines when used in medical-relevant applications. This review aims at analyzing the state of the art of microrobots imaging by critically discussing the potentialities and limitations of the techniques employed in this field. Moreover, the physics and the working principle behind each analyzed imaging strategy, the spatiotemporal resolution, and the penetration depth are thoroughly discussed. The paper deals with the suitability of each imaging technique for tracking single or swarms of MRs and discusses the scenarios where contrast or imaging agent's inclusion is required, either to absorb, emit, or reflect a determined physical signal detected by an external system. Finally, the review highlights the existing challenges and perspective solutions which could be promising for future in vivo applications

Magnetic resonance microimaging of the spinal cord in the SOD1 mouse model of amyotrophic lateral sclerosis detects motor nerve root degeneration

Amyotrophic lateral sclerosis (ALS) is characterized by selective degeneration of motor neurons. Current imaging studies have concentrated on areas of the brain and spinal cord that contain mixed populations of sensory and motor neurons. In this study, ex vivo magnetic resonance microimaging (MRM) was used to separate motor and sensory components by visualizing individual dorsal and ventral roots in fixed spinal cords. MRM at 15 pm in plane resolution enabled the axons of pure populations of sensory and motor neurons to be measured in the lumbar region of the SOD1 mouse model of ALS. MRM signal intensity increased by 38.3% (p < 0.05) exclusively in the ventral motor nerve roots of the lumbar spinal cord of ALS-affected SOD1 mice compared to wildtype littermates. The hyperintensity was therefore limited to white matter tracts arising from the motor neurons, whereas sensory white matter fibers were unchanged. Significant decreases in ventral nerve root volume were also detected in the SOD1 mice, which correlated with the axonal degeneration observed by microscopy. These results demonstrate the usefulness of MRM in visualizing the ultrastructure of the mouse spinal cord. The detailed 3D anatomy allowed the processes of pure populations of sensory and motor neurons to be compared. (C) 2011 Elsevier Inc. All rights reserved

Cardiovascular Magnetic Resonance Imaging in Experimental Models

Cardiovascular magnetic resonance (CMR) imaging is the modality of choice for clinical studies of the heart and vasculature, offering detailed images of both structure and function with high temporal resolution

Toolbox for in vivo imaging of host-parasite interactions at multiple scales

Animal models have for long been pivotal for parasitology research. Over the last few years, techniques such as intravital, optoacoustic and magnetic resonance imaging, optical projection tomography, and selective plane illumination microscopy developed promising potential for gaining insights into host-pathogen interactions by allowing different visualization forms in vivo and ex vivo. Advances including increased resolution, penetration depth, and acquisition speed, together with more complex image analysis methods, facilitate tackling biological problems previously impossible to study and/or quantify. Here we discuss advances and challenges in the in vivo imaging toolbox, which hold promising potential for the field of parasitology