Brain Blood-brain Barrier Permeability Research Articles

Abstract TMP75: Blood Brain Barrier Disruption And Neurologic Outcomes In Intracranial Hemorrhage Patients

Introduction: Patients with primary intracerebral hemorrhage (ICH) are known to demonstrate disruption of the blood-brain barrier (BBB) particularly in peri-hematomal regions. However, disruption of the BBB may also occur throughout the brain, even in areas remote from the acute bleed. We aimed to study the clinical significance of this finding. Methods: We performed a retrospective review of our prospectively collected ICH database from January 2020 to January 2022 to identify consecutive patients who had MR perfusion study performed within 5 days from admission. BBB permeability data was analyzed blinded to the clinical data. Baseline demographics, admission systolic blood pressure and NIH stroke scale (NIHSS) score were collected during the hospitalization. A measure of whole brain BBB permeability was computed from the perfusion MR scans. Primary outcome was good neurologic outcome defined as a modified Rankin Scale (mRS) score of 0-3 at 90 days. We examined the association between the BBB permeability and clinical outcome. Results: A total of 24 ICH patients were identified. Median age was 60 years old (Interquartile range (IQR) 57-70), with 11 females (45.8%) and 13 males (54.2%). Median hematoma volume was 40.3mL (IQR 14.9-53.2mL), with a median admission NIHSS of 17.5 (IQR 15-22). Thirteen out of 24 patients achieved a good neurologic outcome at 3 months (54.2%). Patients who achieved a good neurologic outcome were more likely to have a lower admission NIHSS (16 vs 20 p=0.04), smaller baseline hematoma volume (24.6mL vs 48.4 mL), (p=0.02), and a lower NIHSS at discharge (4 vs 19), (p=0.003). Median whole brain BBB permeability was insignificantly lower in patients who achieved a better neurologic outcome (1.8 vs 2.1, p=0.17). However, a threshold of whole brain BBB permeability less than 1.9% significantly correlated with improved neurologic outcome at 3 months (Odds Ratio=0.11, 95% Confidence Interval (0.02-0.71), p=0.02). Additionally, the same threshold was significantly associated with a lower NIHSS at discharge (5 vs 17.5, p=0.03). Conclusion: Diffuse disruption of the BBB in the days after presenting with ICH is associated with worse clinical outcome if the disruption is severe.

Pigment Epithelium-Derived Factor Improves Paracellular Blood-Brain Barrier Integrity in the Normal and Ischemic Mouse Brain.

Pigment epithelium-derived factor (PEDF) is a neurotrophic factor with neuroprotective, antiangiogenic, and antipermeability effects. In the brain, blood-brain barrier (BBB) function is essential for homeostasis. Its impairment plays a crucial role in the pathophysiology of many neurological diseases, including ischemic stroke. We investigated (a) whether PEDF counteracted vascular endothelial growth factor (VEGF)-induced BBB disruption in the mouse brain, (b) the time course and route of BBB permeability and the dynamics of PEDF expression after cerebral ischemia, and (c) whether intraventricular infusion of PEDF ameliorated brain ischemia by reducing BBB impairment. C57Bl6/N mice received intraparenchymal injections of CSF, VEGF, or a combination of VEGF and PEDF. PEDF increased paracellular but not transcellular BBB integrity as indicated by an increase in the tight junction protein claudin-5. In another group of mice undergoing 60-min middle cerebral artery occlusion (MCAO), transcellular BBB permeability (fibrinogen staining in the absence of a loss of claudin-5) increased as early as 6h after reperfusion. PEDF immunofluorescence increased at 24h, which paralleled with a decreased paracellular BBB permeability (claudin-5). PEDF after MCAO originated from the blood stream and endogenous pericytes. In the third experiment, the intraventricular infusion of PEDF decreased edema and cell death after MCAO, potentially mediated by the improvement of the paracellular route of BBB permeability (claudin-5) in the absence of an amelioration of Evans Blue extravasation. Together, our data suggest that PEDF improves BBB function after cerebral ischemia by affecting the paracellular but not the transcellular route. However, further quantitative data of the different routes of BBB permeability will be required to validate our findings.