Hi, I'm Krista and I'm a medical student in Dr. Mack's lab. I'm going to be discussing work that we did in the combined labs of Dr. Mack and Dr. Zolkovic. The title of my presentation is Experimental Chronic Cerebral Hypoperfusion Results in Increased Blood-Brain Barrier Permeability and White Matter Injury. There are no disclosures. Chronic cerebral hypoperfusion can result in small-vessel white matter ischemic injury and cognitive deficits. Bilateral carotid artery stenosis, or BCAS, is an experimental model of cerebral hypoperfusion. Previously, our lab investigated both blood-brain barrier dysfunction and pericyte coverage in the corpus callosum of mice following BCAS using histological analysis. We measured blood-brain barrier permeability with Evans blue extirpation. Overall, we found an increase in blood-brain barrier permeability with a concomitant decrease in pericyte coverage that was greatest on day 3. The aim of this study was to further characterize the temporal pattern of blood-brain barrier integrity and white matter injury with MRI following murine chronic cerebral hypoperfusion secondary to BCAS. We sought to expand upon previous results and used MRI to eliminate intersubject variability. MRI allowed for sequential observation of the same animal longitudinally and increased the resolution of the cerebrovasculature. Mice were split equally into two cohorts with five mice in each cohort. They underwent either BCAS or sham surgeries on day 0. In BCAS surgeries, a midline cervical incision was made and microcoils were placed around the common carotid arteries bilaterally. For sham surgeries, the common carotid arteries were exposed without further intervention. MRIs were performed on days 1, 3, 7, and 30 postoperatively. T2-weighted MRI was used to characterize anatomical changes. Mice were injected intravenously with gadolinium-based contrast for dynamic contrast enhance or DCE MRI to characterize blood-brain barrier permeability. Dynamic susceptibility contrast or DSC MRI and time-of-flight angiography measured cerebral and vessel blood flow respectively. DCE and DSC MRI were analyzed with rocket ship software. We discovered a temporal pattern of blood-brain barrier dysfunction. Blood-brain barrier permeability was increased on postoperative days 1, 3, and 7 in BCAS mice compared to sham mice. Blood-brain barrier breakdown was the greatest on day 3 with recovery by day 30 in the corpus callosum of BCAS mice. The same pattern was seen in the hippocampus with a peak of blood-brain barrier permeability on day 3 and recovery by day 30 in BCAS mice. At day 30 there were white matter hyperintensities visualized on T2-weighted MRI scans in BCAS mice but not in sham mice. The bottom figure shows a representative example of a T2-weighted MRI image that demonstrates a white matter hyperintensity in the corpus callosum of a BCAS mouse. In comparison, the corpus callosum of the sham mouse was free of hyperintensities. We also wanted to investigate the effect of cerebral hiboperfusion on the cerebrovasculature. We discovered decreased blood flow in the middle cerebral artery in the BCAS cohort compared to the sham cohort with significant decreases on days 3 and 7. Conversely, blood flow in the posterior cerebral artery increased in BCAS mice on day 30. In conclusion, chronic cerebral hiboperfusion temporally increases blood-brain barrier permeability with a peak on day 3 and recovery by day 30. This is the first study to report in vivo permeability in the BCAS model of chronic cerebral hiboperfusion. Our lab also showed expected decreases in middle cerebral artery blood flow following BCAS. The observed increase in posterior cerebral artery flow may compensate for decreased anterior flow. Overall, blood-brain barrier breakdown precedes white matter injury and may therefore contribute to its pathogenesis following chronic cerebral hiboperfusion. I would like to thank my mentor Dr. Mack and everyone in his lab that has assisted with this project. I would also like to thank Dr. Zolkovic and his lab for their contribution to this project. Thank you.

chronic cerebral hypoperfusion

blood-brain barrier integrity

white matter injury

MRI

BCAS mice