Developing an image biomarker for assessing blood-brain barrier permeability

Abstract

The blood-brain barrier (BBB) is a protective covering surrounding the brain vessels, tightly regulating the movement of substances entering the brain tissue. The integrity of this barrier decreases with age and various pathologies. A safe and repeatable imaging biomarker could be an essential tool for assessing the health of this barrier and identifying early changes in its functionality. This thesis is based on three research papers that focus on developing an image biomarker for BBB permeability assessment using a contrast-agent-free MRI approach called multiple echo time arterial spin labeling (multi-TE ASL). The research conducted in this thesis evaluates crucial aspects of this biomarker, including test-retest repeatability, sensitivity, and response to a drug. These evaluations are particularly significant as this has not been tested in humans before.

In this context, the first paper addresses a limitation in the computational model regarding the instantaneous arrival of labeled water for exchange. A modification is introduced by adding a delay time within the voxel to account for transit through vessels offering limited or no exchange. Furthermore, the impact of this modification through simulations and in vivo data was evaluated. Lastly, the test-retest reproducibility of the biomarker was assessed at three different levels — intra-session, inter-session, and inter-visit to evaluate the robustness and stability.

Further evaluations investigate the sensitivity of the biomarker to detect age-related changes in BBB permeability in two different age groups. The results showed that the biomarker was able to detect significant differences in BBB permeability, which increased with age, as reported in the literature.

Finally, an evaluation was performed to assess the performance of the biomarker in a perturbed physiological state induced by a drug. Caffeine, a known vasoconstrictor reported to decrease cerebral perfusion, was used for this test. The results revealed that BBB permeability increased in response to caffeine ingestion, possibly to compensate for the decrease in perfusion and to maintain homeostasis in the resilient brain tissue.