Document Type dissertation Author Name Bennett, David G URN etd-081707-080430 Title Osmotic- and Stroke-Induced Blood-Brain Barrier Disruption Detected by Manganese-Enhanced Magnetic Resonance Imaging Degree PhD Department Biomedical Engineering Advisors Christopher Sotak, Ph.D., Advisor George Pins, Ph.D., Committee Member Yitzhak Mendelson, Ph.D., Committee Member Karl Helmer, Ph.D., Committee Member Peter Grigg, Ph.D., Committee Chair Keywords rat brain osmotic shock blood-brain barrier manganese-enhanced MRI Date of Presentation/Defense 2007-06-08 Availability unrestricted
Manganese (Mn2+) has recently gained acceptance as a magnetic resonance imaging (MRI) contrast agent useful for generating contrast in the functioning brain. The paramagnetic properties of Mn2+, combined with the cellâ€™s affinity for Mn2+ via voltage-gated calcium channels, makes Mn2+ sensitive to cellular activity in the brain. Compared with indirect measures of brain function, such as blood oxygenation level dependent (BOLD) functional MRI, manganese-enhanced MRI (MEMRI) can provide a direct means to visualize brain activity.
MEMRI of the brain typically involves osmotic opening of the blood-brain barrier (BBB) to deliver Mn2+ into the interstitial space prior to initiation of a specific neuronal stimulus. This method assumes that the BBB-disruption process itself does not induce any apparent stimuli or cause tissue damage that might obscure any subsequent experimental observations. However, this assumption is often incorrect and can lead to misleading results for particular types of MRI applications.
One aspect of these studies focused on characterizing the confounding effects of the BBB-opening process on MRI measurements typically employed to characterize functional activity or disease in the brain (Chapters 4 and 5). The apparent diffusion coefficient (ADC) of tissue water was found to decrease (relative to the undisrupted contralateral hemisphere) following BBB opening, obscuring similar ADC changes associated with ischemic brain tissue following stroke. Brain regions exhibiting reduced ADC values following osmotic BBB disruption also experienced permanent tissue damage, as validated by histological measures in the same vicinity of the brain. Non-specific MEMRI-signal enhancement was also observed under similar conditions and was found to be correlated to regions with BBB opening as verified by Evans Blue histological staining. In this case, MEMRI may prove to be a useful alternative for monitoring BBB-permeability changes in vivo.
MEMRI was also investigated as a method for visualizing regions of BBB damage following ischemic brain injury (Chapter 6). BBB disruption following stroke has been investigated using gadolinium-based MRI contrast agents (e.g., Gd-DTPA). However, as an extracellular MRI contrast agent, Gd-DTPA is not expected to provide information regarding cell viability or function as part of MR image contrast enhancement. By comparison, brain regions with ischemia-induced BBB damage, and blood-flow levels sufficient to deliver Mn2+, show MEMRI-signal enhancement that correlates to regions with tissue damage as verified by histological staining. This approach should allow us to better understand the factors responsible for ischemia-induced BBB damage. Furthermore, MEMRI should be a useful tool for monitoring therapeutic interventions that might mitigate the damage associated with BBB disruption following stroke.
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