MICROVASCULAR RESEARCH 39, 28-49 (19%) Kinetic Analysis of Blood-Brain Barrier Transport of D-Glucose in Man: Quantitative Evaluation in the Presence of Tracer Backflux and Capillary Heterogeneity GITTE Moos KNUDSEN,* KAREN D. PErrtoaEw,t OLAF B. PAULSON,* MARIANNE M. HERTZ,$ AND CLIFFORD S. PATLAK§ Departments of *Neurology and Psychiatry, Rigshospitalet, DK-2100 Copenhagen, Denmark; TDivision of Biometry and Applied Sciences, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892; and SDepartment of Neurological Surgery, Health Sciences Center, State University of New York, Stony Brook, New York 11794 Received April 27, 1989 The present study deals with the analysis of double-indicator curves for blood-brain barrier studies. Two mathematical models which provide for the estimation of backflux of tracer from brain to blood in conjunction with heterogeneity of the cerebral capillary and large-vessel transit times were used for the analysis of o-glucose transport on the basis of cerebral venous outflow curves. The two models, nonmixed and well mixed, arise from differing assumptions regarding the effective region surrounding the capillary lumen. An approximate solution for the well-mixed model was developed to increase computation speed. Fourteen n-glucose outflow curves and their reference curves were obtained from nine patients and subsequently analyzed by the two models. Further, in five patients data were obtained under different physiological conditions: normal, decreased, and increased cerebral blood flow rates. The results support the appropriateness of the well-mixed model and heterogeneity of the cerebral capillary transit times. The median value for the average extraction was 0.18 and the median distribution space was 0.14. The latter value is similar to the brain extracellular space that has been estimated by other methods. The extraction values calculated from the peak of the venous outflow curves were significantly smaller than the whole-brain average extraction values estimated with the well-mixed model (0.157 vs 0.178, P < 0.0005). In summary: (a) capillary heterogeneity is present in the human brain and changes with cerebral blood flow; (b) after crossing the blood-brain barrier, D- glucose distributes in the brain extracellular fluid; and (c) the extraction curve is significantly influenced by backflux. Q 1990 Academic press, IN. INTRODUCTION The double-indicator method, introduced more than 30 years ago (Chinard and Flexner, 1951), has gained widespread use in studies of capillary permeability and has been a major tool for the investigation of the passage of various sub- stances from blood to brain (Crone, 1965; Yudilevich and de Rose, 1971; Lassen et al., 1971; Hertz and Paulson, 1980). To interpret the double-indicator curves, the single-capillary model has commonly been used. The application of this model, however, presents two problems for the correct calculation of brain unidirectional uptake of substances: tracer backflux and capillary heterogeneity. With the single-capillary model, the extraction of the test compound in the 28 00%2862/9tl $3.00 Copyright 0 19Sll by Academic Press. Inc. All rights of reproduction in any form reserved. Printed in U.S.A.