APPLICATION OF THE DOUBLE-INDICATOR TECHNIQUE FOR MEASUREMENT OF BLOOD-BRAIN-BARRIER PERMEABILITY IN HUMANS

This review examines and evaluates the double-indicator technique for utilization in quantitative measurements of the transport of substance s across the human brood-brain barrier (BBB). The classic double-indic ator method and its limitations are described along with a new approac h for correction of capillary heterogeneity and tracer backflux. This approach considers the total course of the venous outflow curves and i nvolves a short-time experiment model that incorporates calculations o f parameters for transport from the blood into the brain and from the brain back to the blood, for the uptake of neurons and glia cells, and for the tracer distribution volume. A modification of the double-indi cator technique with intravenous instead of intracarotid bolus injecti on is discussed along with advantages and limitations of this techniqu e. The application of the method is described and examples are given f or D-glucose as well as for some large neutral amino acids and flow tr acers, On the basis of the model, it is demonstrated that after crossi ng the BBB, D-glucose distributes in the brain interstitial fluid volu me, and already at the peak of the glucose outflow curves, the apparen t extraction is significantly influenced by backflux from the brain. F or large neutral amino acids, the permeability from the interstitial f luid space back to the blood is similar to 10 times higher than the pe rmeability from the blood into the brain, Such a difference in permeab ilities across the BBB can almost entirely be ascribed to the effect o f a nonlinear transport system combined with a relatively small brain amino acid metabolism. This high and rapid backflux causes methodologi cal problems when estimating blood-to-brain transfer of amino acids wi th traditional in vivo methods. The method is also evaluated for high- permeable substances. Water and the two flow tracers ethyl cysteinate dimer and hexamethylpropyleneamine oxime and the obtained values for b rain extraction and distribution volume compare well with those obtain ed by other methods. Finally, ethical aspects and the future role and possibilities of the double-indicator technique are discussed and rela ted to other methods for determination of BBB permeabilities in the li ving human brain.