Blood–brain barrier permeability measured using dynamic contrast‐enhanced magnetic resonance imaging: a validation study

Abstract

Key points The blood–brain barrier (BBB) is an important and dynamic structure which contributes to homeostasis in the central nervous system.BBB permeability changes occur in health and disease but measurement of BBB permeability in humans is not straightforward.Dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI) can be used to model the movement of gadolinium contrast into the brain, expressed as the influx constant K i.Here evidence is provided that K i as measured by DCE‐MRI behaves as expected for a marker of overall BBB leakage.These results support the use of DCE‐MRI for in vivo studies of human BBB permeability in health and disease. AbstractBlood–brain barrier (BBB) leakage can be measured using dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI) as the influx constant K i. To validate this method we compared measured K i with biological expectations, namely (1) higher K i in healthy individual grey matter (GM) versus white matter (WM), (2) GM/WM cerebral blood volume (CBV) ratio close to the histologically established GM/WM vascular density ratio, (3) higher K i in visibly enhancing multiple sclerosis (MS) lesions versus MS normal appearing white matter (NAWM), and (4) higher K i in MS NAWM versus healthy individual NAWM. We recruited 13 healthy individuals and 12 patients with MS and performed whole‐brain 3D DCE‐MRI at 3 T. K i and CBV were calculated using Patlak modelling for manual regions of interest (ROI) and segmented tissue masks. K i was higher in control GM versus WM (P = 0.001). CBV was higher in GM versus WM (P = 0.005, mean ratio 1.9). K i was higher in visibly enhancing MS lesions versus MS NAWM (P = 0.002), and in MS NAWM versus controls (P = 0.014). Bland–Altman analysis showed no significant difference between ROI and segmentation methods (P = 0.638) and an intra‐class correlation coefficient showed moderate single measure consistency (0.610). K i behaves as expected for a compound marker of permeability and surface area. The GM/WM CBV ratio measured by this technique is in agreement with the literature. This adds evidence to the validity of K i measured by DCE‐MRI as a marker of overall BBB leakage.

MRI measurement of blood–brain barrier leakage: minding the gaps

“…The article by Varatharaj et al . () published in the current issue of The Journal of Physiology therefore contributes welcome proof‐of‐principle evidence of biological validity. They performed DCE‐MRI in MS subjects and in healthy controls.…”

“…()) will be familiar to fellow researchers in the field, as will the phenomenon of negative K i estimates (Figure 4, Varatharaj et al . ()).…”

“…The difficulty of probing low‐level BBB leakage is also nicely illustrated in the article: signal changes that are small in relation to the temporal noise level (Figure 3, Varatharaj et al . ()) will be familiar to fellow researchers in the field, as will the phenomenon of negative K i estimates (Figure 4, Varatharaj et al . ()).…”

Blood-Brain Barrier Disruption in Neuro-Oncology: Strategies, Failures, and Challenges to Overcome

“…Contrastingly, static contrast-enhanced MRI based on changes of gadolinium enhancement is relatively non-invasive in comparison to angiography and SPECT has often been used to assess BBB permeability in the modern imaging era. However, we advocate for DCE-MRI, in which several images are acquired in rapid succession enabling dynamic assessment of changes in contrast while also providing parameters pertinent to perfusion and permeability ( 73 ). Limitations of DCE-MRI, as stated in the MRgFUS discussion, include the spatial resolution and the ability to correlate dynamic variations in contrast enhancement with pharmacokinetic properties of test agents.…”

Corrigendum

“…In the article by Varatharaj et al . (2019), there is an error in the labelling of Figure 1, Panel C.…”