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Objective: Parameters of a pharmacokinetic-pharmacodynamic (PK-PD) model of levodopa have been claimed to reflect the magnitude of the dopaminergic deficit in patients with Parkinson's disease. The aim of this study was to correlate such parameters with positron emission tomography (PET) with levodopa tagged with 6-fluorine 18, an established imaging method for striatal dopaminergic neurons., Methods: Twenty-three patients in different disease stages (Hoehm and Yahr stage 2.5-5 [Hoehn MM, Yahr MD. Parkinsonism: onset, progression and mortality. Neurology 1967;4:427-42]; median duration, 12 years) were studied. PK-PD modeling followed a single oral dose of levodopa/benserazide. The sum score of the Columbia Rating Scale (CURSSigma) was used for clinical assessments. A nonparametric effect compartment approach assuming a sigmoidal E(max) model was applied to the PK-PD analysis of plasma levodopa concentrations and corresponding CURSSigma. Thereafter 6-[18F]levodopa PET was performed, and the influx rate constants (k(c)) for the putamen and the caudatus region were correlated with the median effective concentration (EC(50)) and the equilibrium half-life (T(eq)) of the PK-PD model., Results: (1) A significant correlation was observed between PK-PD parameters or with k(c) putamen as the dependent variable and the duration of the disease as the independent variable, which explains 33% of the variability of the EC(50), 42% of the variability of T(eq), and 36% of the variability of k(c). (2) Significant correlations were observed between k(c) and either EC(50) or T(eq), yielding the closest correlation for the putamen region (r = -0.47, P <.05; and r = 0.55, P <.01; respectively)., Conclusions: Our findings show that key parameters of a PK-PD model of levodopa were in fairly close agreement with imaging of dopaminergic neurons by 6-[18F]levodopa PET. However, although PK-PD modeling of levodopa has been proven as a useful investigation of approaches aimed to restore dopaminergic deficits or to monitor disease progression, this modeling cannot serve as a pathomorphologic surrogate for the loss of striatal dopaminergic neurons.

We used positron emission tomography and [11C]flumazenil to analyze the benzodiazepine receptor binding in symptomatic and asymptomatic carriers of the Huntington's disease gene. We found an inverse relationship between [11C]flumazenil and [11C]raclopride binding in the putamen of symptomatic patients, and interpret this result as GABA receptor upregulation.

Unlabelled: Toxicity of abundant copper is the main cause of brain and liver tissue damage in patients with Wilson's disease (WD). However, there is also evidence of a disturbed iron metabolism in this genetically determined disorder. This PET study was undertaken to assess cerebral iron metabolism in WD patients., Methods: We used 52Fe-citrate, which converts to 52Fe-transferrin in blood plasma, to study basic pharmacokinetic features of the cerebral iron transport in 6 WD patients and in 16 healthy volunteers (control subjects). A 2-tissue-compartment model and multiple time graphic plotting were used to calculate 52Fe-transferrin distribution volumes and transport rates., Results: Net iron uptake (Ki) from plasma into brain tissue was significantly (P < 0.001) higher in WD patients (Ki [mean +/- SEM] = 15.1E-05 +/- 7.13E-05 [1/min]) than in healthy volunteers (Ki = 2.66E-05 +/- 0.351E-05 [1/min]). There was no difference of tracer iron distribution in the cerebral plasma volume between patients and healthy volunteers. Iron uptake values resulting from 2 methods to model PET data of patients and healthy volunteers were highly correlated (P < 0.001)., Conclusion: An abnormally increased cerebral 52Fe-transferrin uptake was found in WD patients.

Administration of the N-methyl-D-aspartate (NMDA) antagonist S-ketamine in normals produces a psychosis-like syndrome including several positive and negative symptoms of schizophrenic disorders (Abi-Saab WM, D'Souza DC, Moghaddam B, Krystal JH. The NMDA antagonist model for schizophrenia: promise and pitfalls. Pharmacopsychiatry 1998;31:104-109). Given the clinical efficacy of dopamine (DA) D2 receptor antagonists in the treatment of positive symptoms, it is conceivable that S-ketamine-induced psychotic symptoms are partially due to a secondary activation of dopaminergic systems. To date, animal and human studies of the effects of NMDA antagonists on striatal DA levels have been inconsistent. The present study used positron emission tomography (PET) to determine whether a psychotomimetic dose of S-ketamine decreases the in vivo binding of [11C]raclopride to striatal DA D2 receptors in humans (n = 8). S-ketamine elicited a psychosis-like syndrome, including alterations in mood, cognitive disturbances, hallucinations and ego-disorders. S-ketamine decreased [11C]raclopride binding potential (BP) significantly in the ventral striatum (-17.5%) followed by the caudate nucleus (-14.3%) and putamen (-13.6%), indicating an increase in striatal DA concentration. The change in raclopride BP in the ventral striatum correlated with heightened mood ranging from euphoria to grandiosity. These results provide evidence that the glutamatergic NMDA receptor may contribute to psychotic symptom formation via modulation of the DA system.

Unlabelled: Dexamethasone (DEX) is frequently used in brain tumor management. This study investigated the effect of DEX treatment and plasma glucose levels on 18F-fluorodeoxyglucose (FDG) uptake in patients with malignant gliomas (16 glioblastoma, 3 anaplastic astrocytoma)., Methods: Fifteen DEX-treated patients (mean relative dose 0.23 +/- 0.15 mg(-1) x kg(-1) x day(-1), range 0.07-0.53), four patients not treated with DEX and nine healthy subjects were studied using PET and FDG. PET data obtained from tumors and the contralateral cortex were fitted to a standard two-tissue compartment model. The FDG transport and phosphorylation rates, distribution volume (DV), steady-state accumulation (Ki), deoxyglucose metabolism (R), plasma volume as well as standardized uptake values (SUVs) and tumor-to-brain ratios were determined. In addition, the tumor size was estimated from the maximal area of contrast-enhancing tumor on computed cranial tomography (CCT) scans or MRI., Results: FDG uptake was depressed in the contralateral cortex of patients and was related to tumor size. With increasing relative DEX dose, a decrease in the DV of tumors (linear regression p = 0.021) and in the DV (p = 0.109) and plasma volume (p = 0.010) of contralateral cortex was found. R, Ki and SUVs in tumors and contralateral cortex were not related to the relative DEX dose. With increasing plasma glucose levels, differential decreases in Ki and SUVs in tumors (p = 0.057 and p = 0.733, respectively) and contralateral cortex (p = 0.001 and p = 0.029, respectively) were observed., Conclusion: The data suggest that DEX affects FDG uptake in malignant gliomas through interaction with cerebral blood vessels and extracellular space, whereas FDG metabolism in tumors is not influenced substantially. This is of practical importance for patients having serial brain tumor imaging for treatment evaluation because patients may receive different DEX doses at different time points in the course of their disease. By contrast, the plasma glucose level must be considered a confounding variable when SUVs, tumor-to-brain ratios or Ki are used for treatment evaluation.

We studied a patient with juvenile pilocytic astrocytoma (JPA) using positron emission tomography (PET), 18F-fluorodeoxyglucose (FDG), 11C-methionine (MET), and 82Rubidium (RUB). Non-linear fitting and multiple time graphical plotting of the dynamic PET data revealed values for tumor plasma volume, blood-brain barrier transport rate constants and tracer distribution volume in the range of glioblastomas and meningiomas, or higher. Likewise, the steady-state accumulation of MET and FDG was increased. With regard to the known vascular composition of JPA, our data suggest that increased transport and distribution considerably contribute to the high net tracer uptake observed in this tumor.

Iron and transferrin are required for DNA synthesis and cell division. Cellular iron uptake is mediated by transferrin receptors. In order to investigate whether iron uptake in brain tumors is associated with their histological grade, we studied 24 patients (5 astrocytoma, 11 glioblastoma, 8 meningioma) using positron emission tomography and 52Fe-citrate. Tracer uptake from blood into brain and tumor tissue was assessed 1. using multiple time graphical analysis yielding a measure for unidirectional net tracer uptake (Ki) and 2.) testing a one- and two-tissue kinetic compartment model, where K1 denotes tracer uptake from blood into tissue, k2 efflux from tissue into plasma, and k3 specific tracer binding. In the plasma, 52Fe was bound to a 80 kD protein (transferrin). Ki (in units of 10(-5)/min) was higher in glioblastomas (Ki mean +/- SD 13.6 +/- 6.1) compared with astrocytomas (4.8 +/- 3.5, Mann Whitney p = 0.015) and contralateral brain (2.2 +/- 0.9, Mann Whitney p = 0.009). Highest values were found in meningiomas (no blood-brain barrier (BBB); Ki 33.4 +/- 16.5, Mann Whitney p = 0.008 compared with glioblastomas). Among the compartment models, fitting with K1 and regional plasma volume explained the data best (one-tissue model), data fits were not significantly improved by addition of a k2 or k3 parameter. K1 and Ki values were significantly correlated (Spearman Rank, p = 0.0006). We conclude that 52Fe accumulation in tumors is governed by tracer uptake at the BBB, and does not reflect number of transferrin receptors at the level of tumor cells.