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.
| Identifer | oai:union.ndltd.org:MIT/oai:dspace.mit.edu:1721.1/47853 |
| Date | January 2009 |
| Creators | Huang, Shuning, Ph. D. Massachusetts Institute of Technology |
| Contributors | Bruce R. Rosen., Harvard University--MIT Division of Health Sciences and Technology., Harvard University--MIT Division of Health Sciences and Technology. |
| Publisher | Massachusetts Institute of Technology |
| Source Sets | M.I.T. Theses and Dissertation |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | 152 p., application/pdf |
| Rights | M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission., http://dspace.mit.edu/handle/1721.1/7582 |
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