Blood-brain barrier breakdown in brain ischemia: Insights from MRI perfusion imaging

Abstract

Brain ischemia is a major cause of neurological dysfunction and mortality worldwide. It occurs not only acutely, such as in acute ischemic stroke (AIS), but also in chronic conditions like cerebral small vessel disease (cSVD). Any other conditions resulting in brain hypoperfusion can also lead to ischemia. Ischemic events can cause blood-brain barrier (BBB) disruption and, ultimately, white matter alterations, contributing to neurological deficits and long-term functional impairments. Hence, understanding the mechanisms of BBB breakdown and white matter injury across various ischemic conditions is critical for developing effective interventions and improving patient outcomes. This review discusses the proposed mechanisms of ischemia-related BBB breakdown. Moreover, magnetic resonance imaging (MRI) based perfusion-weighted imaging (PWI) techniques sensitive to BBB permeability changes are described, including dynamic contrast-enhanced (DCE-MRI) and dynamic susceptibility contrast MRI (DSC-MRI), two perfusion-weighted imaging (PWI). These PWI techniques provide valuable insights that improve our understanding of the complex early pathophysiology of brain ischemia, which can lead to better assessment and management. Finally, in this review, we explore the implications of the mentioned neuroimaging findings, which emphasize the potential of neuroimaging biomarkers to guide personalized treatment and inform novel neuroprotective strategies. This review highlights the importance of investigating BBB changes in brain ischemia and the critical role of advanced neuroimaging in improving patient care and advancing stroke research.

Keywords: Acute ischemic stroke; Brain ischemia; Cerebral small vessel disease; Dynamic contrast-enhanced; Dynamic susceptibility contrast; Magnetic resonance imaging.

Fig. 1

Drawing representing ischemic core and penumbra in a brain. The ischemic core represents the area of irreversible damage due to severe blood flow reduction. The penumbra is the region surrounding the ischemic core that is at risk but potentially recoverable. Image created with biorender.com.

Fig. 2

Overview of BBB breakdown and white matter alterations in AIS. Occlusion of a cerebral artery leads to ischemia in the brain parenchyma. The resulting BBB disruption, characterized by impaired tight junctions and endothelial damage, allows the infiltration of peripheral immune cells, neurotoxic substances, and fluid into the extracellular space. Simultaneously, white matter undergoes demyelination and axonal damage due to excitotoxicity, oxidative stress, and inflammation. Activated microglia and infiltrating peripheral immune cells release pro-inflammatory mediators, contributing to both BBB dysfunction and white matter injury and ultimately leading to necrosis in the brain parenchyma. Image created with biorender.com.

Fig. 3

Example of using PWI parameters for assessing cSVD. Representative slice of FLAIR (a), normalized CBF map (c), Mean Transit Time (MTT) map (e), and K^trans (a combination parameter of blood flow and permeability) map (g) in a subject with mild lesion load. In (b, d, f), these perfusion parameter maps are also overlaid on FLAIR image showing co-localization. Reproduced with permission from Dewey et al., AJNR, 2021 [102].

Fig. 4

Example of arrival-time corrected K2 assessment in a patient with cSVD. Panel a shows a K2-based heat map overlain on the DSC source image from which it was generated. The color code shows the increasing permeability within the white matter lesions. Panels b–e show the signal change (ΔR2∗) over time (at each dynamic) of the recorded signal (red dashed line) and the normal average signal (solid blue line) before and after applying the arrival time correction (ATC). Panels b and d are for a voxel with a K 2 of 0.1 ​% (a green voxel from panel a). Panels c and e are for a voxel with a K2 value of 3.5 ​% (a red voxel in panel a). Note that in the setting of BBB disruption, the dashed line is pulled down below the baseline due to the T1 effects from contrast leakage into the tissue. Reproduced with permission from Dewey et al., AJNR, 2021 [102].