Dynamic monitoring of blood-brain barrier integrity using water exchange index (WEI) during mannitol and CO2 challenges in mouse brain.
The integrity of the blood-brain barrier (BBB) is critical to normal brain function. Traditional techniques for the assessment of BBB disruption rely heavily on the spatiotemporal analysis of extravasating contrast agents. However, such methods based on the leakage of relatively large molecules are not suitable for the detection of subtle BBB impairment or for the performance of repeated measurements in a short time frame. Quantification of the water exchange rate constant (WER) across the BBB using strictly intravascular contrast agents could provide a much more sensitive method for the quantification of the BBB integrity. To estimate WER, we have recently devised a powerful new method using a water exchange index (WEI) biomarker and demonstrated BBB disruption in an acute stroke model. Here, we confirm that WEI is sensitive to even very subtle changes in the integrity of the BBB caused by: (i) systemic hypercapnia and (ii) low doses of a hyperosmolar solution. In addition, we have examined the sensitivity and accuracy of WEI as a biomarker of WER using computer simulation. In particular, the dependence of the WEI-WER relation on changes in vascular blood volume, T1 relaxation of cellular magnetization and transcytolemmal water exchange was explored. Simulated WEI was found to vary linearly with WER for typically encountered exchange rate constants (1-4 Hz), regardless of the blood volume. However, for very high WER (>5 Hz), WEI became progressively more insensitive to increasing WER. The incorporation of transcytolemmal water exchange, using a three-compartment tissue model, helped to extend the linear WEI regime to slightly higher WER, but had no significant effect for most physiologically important WERs (WER < 4 Hz). Variation in cellular T1 had no effect on WEI. Using both theoretical and experimental approaches, our study validates the utility of the WEI biomarker for the monitoring of BBB integrity.
Health Science and Technology (HST), Massachusetts Institute of Technology, Cambridge, MA, USA; Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, USA.
Shuning
S
Huang
Christian T
CT
Farrar
Guangping
G
Dai
Seon Joo
SJ
Kwon
Alexei A
AA
Bogdanov
Bruce R
BR
Rosen
Young R
YR
Kim
D000818:Animals; D001810:Blood Volume / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology*; D002245:Carbon Dioxide / Q000494:pharmacology*; D003198:Computer Simulation; D008279:Magnetic Resonance Imaging; D008297:Male; D008353:Mannitol / Q000494:pharmacology*; D008810:Mice, Inbred C57BL; D014867:Water / Q000737:chemistry*
D014867:Water; D002245:Carbon Dioxide; D008353:Mannitol