Increased apparent diffusion coefficients on MRI linked with matrix metalloproteinases and edema in white matter after bilateral carotid artery occlusion in rats
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Published on: January 23, 2019
Rohit Sood1, Yi Yang, Saeid Taheri
1Department of Neurology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131, USA. rsood@salud.unm.edu
Abstract:
White matter (WM) injury after bilateral common carotid artery occlusion (BCAO) in rat is associated with disruption of the blood-brain barrier (BBB) by matrix metalloproteinases (MMPs). We hypothesized that WM injury as seen on magnetic resonance imaging (MRI) would correlate with regions of increased MMP activity. MRI was performed 3 days after BCAO surgery in rats. Apparent diffusion coefficients (ADC) were calculated and vascular permeability was quantified by the multiple-time graphical analysis (MTGA) method, using gadolinium-diethylenetriamine pentaacid (Gd-DTPA). After MRI, one group of animals had BBB permeability measured in the WM with (14)C-sucrose, and another had Evans blue (EB) injected for fluorescent microscopy for MMP-2, MMP-9, tight junction proteins (TJPs), and in situ zymography. We found that ADC values were increased in WM in BCAO rats compared with controls (P<0.05). WM with increased ADC had leakage of EB. MMP-2 and MMP-9 activity on in situ zymograms corresponded with leakage of EB. Although increased permeability to EB could be visualized, permeability quantification with (14)C-sucrose and Gd-DTPA failed to show increases and TJPs were intact. We propose that increased ADC, which is a marker of vasogenic edema, is related to activity of MMP-2 and MMP-9. MRI provides unique information that can be used to guide tissue studies of WM injury.
Insights
White matter injury after carotid artery occlusion involves blood-brain barrier disruption by matrix metalloproteinases (MMPs). Magnetic resonance imaging (MRI) revealed increased apparent diffusion coefficients (ADC) correlating with MMP activity in white matter.
Area of Science:
- Neuroscience
- Biochemistry
- Medical Imaging
Background:
- White matter (WM) injury following bilateral common carotid artery occlusion (BCAO) in rats is linked to blood-brain barrier (BBB) disruption.
- Matrix metalloproteinases (MMPs) are implicated in the breakdown of the BBB.
Purpose of the Study:
- To investigate the correlation between white matter injury, assessed by MRI, and matrix metalloproteinase (MMP) activity.
- To determine if increased MMP activity contributes to blood-brain barrier (BBB) disruption in white matter post-BCAO.
Main Methods:
- Magnetic resonance imaging (MRI) was used to measure apparent diffusion coefficients (ADC) in rat white matter 3 days after BCAO.
- Vascular permeability was assessed using gadolinium-diethylenetriamine pentaacid (Gd-DTPA) with multiple-time graphical analysis (MTGA), (14)C-sucrose, and Evans blue (EB) leakage.
- MMP-2 and MMP-9 activity was evaluated using in situ zymography, alongside tight junction protein (TJP) analysis.
Main Results:
- Increased ADC values, indicating vasogenic edema, were observed in the white matter of BCAO rats compared to controls.
- Evans blue leakage in white matter correlated with increased MMP-2 and MMP-9 activity.
- Despite visible EB leakage, quantitative permeability measurements using (14)C-sucrose and Gd-DTPA did not show significant increases, and TJPs remained intact.
Conclusions:
- Increased apparent diffusion coefficients (ADC) in white matter, a marker of vasogenic edema, are associated with matrix metalloproteinase (MMP) activity.
- Magnetic resonance imaging (MRI) offers valuable insights for guiding further tissue-based investigations of white matter injury.
