Application of Delayed Contrast Extravasation Magnetic Resonance Imaging for Depicting Subtle Blood–Brain Barrier Disruption in a Traumatic Brain Injury Model

Sigal Liraz Zaltsman*, Shirley Sharabi, David Guez, Diann Daniels, Itzik Cooper, Chen Shemesh, Dana Atrakchi, Orly Ravid, Liora Omesi, Daniel Rand, Abigail Livny, Michal Schnaider Beeri, Yael Friedman-Levi, Esther Shohami, Yael Mardor, David Last

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

The blood–brain barrier (BBB) is composed of brain microvasculature that provides selective transport of solutes from the systemic circulation into the central nervous system to protect the brain and spinal microenvironment. Damage to the BBB in the acute phase after traumatic brain injury (TBI) is recognized as a major underlying mechanism leading to secondary long-term damage. Because of the lack of technological ability to detect subtle BBB disruption (BBBd) in the chronic phase, however, the presence of chronic BBBd is disputable. Thus, the dynamics and course of long-term BBBd post-TBI remains elusive. Thirty C57BL/6 male mice subjected to TBI using our weight drop closed head injury model and 19 naïve controls were scanned by magnetic resonance imaging (MRI) up to 540 days after injury. The BBB maps were calculated from delayed contrast extravasation MRI (DCM) with high spatial resolution and high sensitivity to subtle BBBd, enabling depiction and quantification of BBB permeability. At each time point, 2–6 animals were sacrificed and their brains were extracted, sectioned, and stained for BBB biomarkers including: blood microvessel coverage by astrocyte using GFAP, AQP4, ZO-1 gaps, and IgG leakage. We found that DCM provided depiction of subtle yet significant BBBd up to 1.5 years after TBI, with significantly higher sensitivity than standard contrast-enhanced T1-weighted and T2-weighted MRI (BBBd volumes main effect DCM/T1/T2 p < 0.0001 F(2,70) = 107.3, time point p < 0.0001 F(2,133, 18.66) = 23.53). In 33% of the cases, both in the acute and chronic stages, there was no detectable enhancement on standard T1-MRI, nor detectable hyperintensities on T2-MRI, whereas DCM showed significant BBBd volumes. The BBBd values of TBI mice at the chronic stage were found significantly higher compared with age matched naïve animals at 30, 60, and 540 days. The calculated BBB maps were histologically validated by determining significant correlation between the calculated levels of disruption and a diverse set of histopathological parameters obtained from different brain regions, presenting different components of the BBB.

Cumulative evidence from recent years points to BBBd as a central component of the pathophysiology of TBI. Therefore, it is expected that routine use of highly sensitive non-invasive techniques to measure BBBd, such as DCM with advanced analysis methods, may enhance our understanding of the changes in BBB function after TBI. Application of the DCM technology to other CNS disorders, as well as to normal aging, may shed light on the involvement of chronic subtle BBBd in these conditions.

Original languageAmerican English
Pages (from-to)430-446
Number of pages17
JournalJournal of Neurotrauma
Volume41
Issue number3-4
DOIs
StatePublished - Feb 2024

Bibliographical note

Publisher Copyright:
© 2024 Mary Ann Liebert Inc.. All rights reserved.

Keywords

  • MRI
  • TBI
  • blood-brain barrier disruption
  • delayed contrast MRI

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