Quantitative imaging assessment of blood-brain barrier permeability in humans

Abstract

The blood-brain barrier (BBB) is a functional and structural barrier separating the intravascular and neuropil compartments of the brain. It characterizes the vascular bed and is essential for normal brain functions. Dysfunction in the BBB properties have been described in most common neurological disorders, such as stroke, traumatic injuries, intracerebral hemorrhage, tumors, epilepsy and neurodegenerative disorders. It is now obvious that the BBB plays an important role in normal brain activity, stressing the need for applicable imaging and assessment methods. Recent advancements in imaging techniques now make it possible to establish sensitive and quantitative methods for the assessment of BBB permeability. However, most of the existing techniques require complicated and demanding dynamic scanning protocols that are impractical and cannot be fulfilled in some cases. We review existing methods for the evaluation of BBB permeability, focusing on quantitative magnetic resonance-based approaches and discuss their drawbacks and limitations. In light of those limitations we propose two new approaches for BBB assessment with less demanding imaging sequences: the "post-pre" and the "linear dynamic" methods, both allow semi-quantitative permeability assessment and localization of dysfunctional BBB with simple/partial dynamic imaging protocols and easy-to-apply analysis algorithms. We present preliminary results and show an example which compares these new methods with the existing standard assessment method. We strongly believe that the establishment of such "easy to use" and reliable imaging methods is essential before BBB assessment can become a routine clinical tool. Large clinical trials are awaited to fully understand the significance of BBB permeability as a biomarker and target for treatment in neurological disorders.

Figures

Figure 1

Pre-post comparison method. The enhancement-distribution histograms of three representing regions (ROIs): eyeball, muscle and a blood vessel. Black line represents an enhancement distribution in the muscle ROI (temporal muscle), green line for eyeball ROI (vitreous humor) and red line demonstrates blood ROI (superior sagittal sinus). Author:

Figure 2

Semi-quantitative assessment for pre-post comparison method. (A) Enhancement distribution at range of 20%-100% defined with muscle ROI. (B) Brain masking: CSF – blue, grey matter – red, white matter – green. (C) Permeable pixels at region defined by total brain region mask. (D) Permeable pixels at region defined by brain tissue mask, excluding pixels relating to ventricles and subarachnoid space appearing in C. (E) Clustering procedure applied to D. Single pixels and regions smaller than minimal size of 10 pixels were removed.

Figure 3

The linear dynamic method. A comparison of normalization methods and effect on the estimated parameters. The slope and intercept are displayed on an arbitrary scale (different scale for each method), whereas the R2 is always scaled in the range of 0–1. The parameters maps are smoothed using a median filter with a kernel of 3x3 voxels for display purpose.

Figure 4

Signal intensity changes in different tissues. Intensity is relative to the intensity in the first scan.

Figure 5

A comparison of the permeability constant Ktrtans,( min-1) from Toft’s model (A), the normalized slope (sec-1) from the linear model (B) and the difference percentage from the post-pre method (C). Quantitative comparison between the 3 methods is not trivial, so a qualitative comparison is shown. False color scales reflect Ktrtans (A), normalized slope (B) and percent difference (C).