Comparison of Cerebral Glucose Metabolic Rates Measured with Fluorodeoxyglucose and Glucose Labeled in the 1, 2, 3–4, and 6 Positions Using Double Label Quantitative Digital Autoradiography

Abstract

Summary:We compared local cerebral glucose meta bolic rates (LCMR g 1u) that were determined with [ 18 FJfluorodeoxyglucose (FDG) and [ 14 C]glucose labeled in the 1, 2, 3-4, and 6 positions. Double label digital auto radiography was used with published kinetic models to determine LCMR gl u for FDG and glucose in the same an imals. Glucose showed metabolic rate dependent under estimation of LCMR gl u compared to FDG, which wors ened with increasing experimental times. The least un derestimation occurred with glucose labeled in the 6 Kinetic models have been proposed for the mea surement of local cerebral metabolic rate of glucose (LCMRg1u) with both radiolabeled glucose (Hawkins et aI., 1979; Lu et aI., 1983; Hawkins et aI., 1985) and glucose analogs such as deoxyglu cose (DG) (Sokoloff et aI., 1977) and fluorodeoxy glucose (FDG) (Reivich et aI., 1979; Phelps et aI., 1979;Miller and Kiney, 1981; Lear et aI., 1984; Olds et aI., 1985; Sako et aI., 1985; Lear and Ack ermann, 1988). DG and FDG cross the blood-brain barrier using the same facilitated transport system as glucose. In the brain, DG and FDG are phosphorylated by hexokinase to DG-6-phosphate (DGP) and FDG 6-phosphate (FDGP), as glucose is metabolized to Received December 22, 1987; accepted March 22, 1988. Address correspondence and reprint requests to Dr. J. L.Lear, at Nuclear Medicine (A034) , University of Colorado Health Sciences Center, 4200 E. 9th Ave., Denver, CO 80262 U.S.A.Abbreviations used: DO, deoxyglucose; DOP, deoxyglucose 6-phosphate; FDO, fluorodeoxyglucose; FDOP, fluorodeoxyglu cose 6-phosphate; LCMR gt u, local cerebral glucose metabolic rates. 575position at 6 min, reaching 10% in areas of high metabo lism. Labeling in the I position, the 2 position and the 3-4 position caused progressively worse underestimation at all times. In addition, some structures showed differ ences not directly related to metabolic rate, indicating re gional variations in relationships between individual ki netic constants of FDG and glucose. Key Words: Deoxy glucose-Fluorodeoxyglucose-Glucose-Autoradiog raphy -LCMR gl u-Metabolism. glucose 6-phosphate. Unlike glucose 6-phosphate, however, further metabolism of DGP and FDGP is extremely slow; therefore DGP and FDGP accu mulate within brain cells at a rate proportional to metabolism. Thus over time, the radio tracer in the brain will change from predominantly precusor (DG or FDG) to predominantly metabolic product (DGP or FDGP). DG and FDG generally are allowed to circulate for approximately 45 min, so that by the end of the experiment the majority of the radioac tivity in the brain is DGP or FDGP. This is impor tant because neither position emission tomography scanning nor autoradiography can differentiate be tween unmetabolized DG or FDG and the com pound of interest, DGP or FDGP. After estimation of the fraction of total brain activity which is DGP or FDGP, a "lumped constant" is then used to re late cerebral DGP or FDGP concentration to glu cose metabolism. This lumped constant represents the steady-st...

Fueling and Imaging Brain Activation

“…Uncertainties in the true values of rate constants have a negligible effect in routine 30–45 min assays, but they do have a large influence on estimates of precursor level in shorter assays with labelled DG and glucose (Adachi et al, 1995) and on the tissue integrated specific activity (see Figure 10 in Sokoloff, 1986). For this reason, the results of 5–10 min in vivo autoradiographic assays with either tracer may not be as accurate as desired (Brondsted and Gjedde, 1988; Lear and Ackermann, 1988; Adachi et al, 1995), but levels of labelled precursor and products can be directly measured in tissue extracts to avoid errors in their estimates. Also, the plasma time-activity integral can be used to calculate the minimal metabolic rate (at short experimental times the plasma integral exceeds that in brain due to restricted tracer entry into brain across the blood–brain barrier; Sokoloff et al, 1977).…”

Brain Glucose Levels in Portacaval-Shunted Rats with Chronic, Moderate Hyperammonemia: Implications for Determination of Local Cerebral Glucose Utilization

“…This value is relatively high, i.e., �45% of the total 14C in normal, con scious rats at 5 min after the pulse and � 18% at 10 min (Hawkins and Miller, 1978), and errors in the estimate of e4C]glucose in the precursor pool can have a large influence on the calculated lCMRglc • Values obtained in many brain structures with [2_14C]glucose are too low (Hawkins et al, 1985;Lear and Ackermann, 1988), and rate constants used to calculate lCMRglC with [6-14C]glucose are estimated using a relation between T max and values for lCMRglc that were assayed with [2_14C]glucose (Hawkins et aI., 1983;Hawkins and Mans, 1989). Underestimation of lCMR Ie with e4C]glucose compared with [14C]DG or e l P]fluorodeoxyglucose is evident at 6 min; the magnitude of underestima tion rises as the duration of the experimental period and metabolic rate increase, and varies with posi tion of the 14C label on e4C]glucose (Collins et aI., 1987;Br�ndsted and Gjedde, 1988;Lear and Ack ermann, 1988;Ackermann and Lear, 1989).…”

Mapping brain function in freely moving subjects

“…Since glucose itself is metabolized too rapidly for adequate study, use of radiolabeled glucose analogues, e.g. [ 14 C]-2-deoxyglucose ([ 14 C]-2-DG) [50] [51], allow measurement of brain metabolism. 2-Deoxyglucose (2-DG) crosses the blood-brain barrier and is phosphorylated by the hexokinase system to DG-6-phosphate, similarly to glucose.…”