Showing papers by "Nora D. Volkow published in 1994"

Decreased dopamine transporters with age in healthy human subjects

Abstract: The effects of aging on brain dopamine transporters was evaluated in 26 healthy male volunteers (age range, 21-63 years) using positron emission tomography and { 11 C}cocaine. The radio of the distribution volume for { 11 C}cocaine in basal ganglia to that in cerebellum was used as a model parameter for dopamine transporter availability and showed a significant negative correlation with age (r=0.65, p<0.0005). This results document an age-related decline in dopamine transporters in healthy individuals

Recovery of brain glucose metabolism in detoxified alcoholics.

Abstract: Objective: To differentiate withdrawal-related abnormalities in brain glucose metabolism among alcoholics from abnormalities that may be irreversible or antedate alcohol use, the authors evaluated metabolic recovery during alcohol detoxification. Method: Regional brain glucose metabolism was measured with positron emission tomography and 2-deoxy-2[l8Fjfluoro-D-glucose in 10 male alcoholics at 8-15 days, 16-30 days, and 31-60 days after last use of alcohol. The alcoholics’ metabolic values were compared with those of 1 0 agematched male healthy volunteers. Results: Brain metabolism increased significantly during detoxification. There were significant differences in global and regional measures between the first and last time points but not between the second and third points, suggesting that recovery occurred predominantly within 16-30 days. Regional increases in metabolism were greater in the frontal regions. Whereas during the first evaluation the alcoholics showed significantly lower metabolism in various brain regions than the comparison group, at the end of detoxif ication the alcoholics showed significantly lower absolute and relative metabolic values in the basalganglia and lower relative metabolic values in the parietal cortex. Among the alcoholics, but not the comparison group, metabolism in the frontal, parietal, and left temporal cortexes was negatively correlated with years of alcohol use and with age. Conclusions: This study shows significant increases in brain metabolism during alcohol withdrawal and documents persistent low metabolic levels in the basal ganglia of detoxified alcoholics. (Am J Psychiatry 1 994; 1 S 1:178-183)

Effects of blood flow on [11C]raclopride binding in the brain : model simulations and kinetic analysis of PET data

Abstract: To assess the stability of different measures of receptor occupancy from [11C]raclopride (a D2 antagonist) studies with positron emission tomography, we analyze data from five test/retest studies in normal volunteers in terms of individual model parameters from a three-compartment model, the distribution volume (DV) and the ratio of DVs from a receptor-containing region of interest to a non-receptor-containing region. Large variations were found in the individual model parameters, limiting their usefulness as an indicator of change in receptor systems. The DV ratio showed the smallest variation. Individual differences were reflected in the greater intersubject variation in DV than intrasubject variation. The potential effects of blood flow on these measurements were addressed both experimentally and by simulation studies using three models that explicitly incorporate blood flow into a compartmental model that also includes receptor-ligand binding. None of the models showed any variation in the DV with changes in blood flow as long as flow was held constant during the simulation. Experimentally, blood flow was significantly reduced by hyperventilation in a human subject. The DV was found to be reduced relative to baseline in the hyperventilation study, but the DV ratio remained unchanged. The effect of elevated and reduced flow was also tested in two baboon experiments in which PCO2 was varied. Some variability in the DV ratio was observed but was not correlated with changes in blood flow. This raises the possibility that other factors indirectly related to changes in blood flow (or PCO2) may cause changes in DV, and these effects need to be considered when evaluating experimental results.

Slow recovery of human brain MAO B after L-Deprenyl (Selegeline) withdrawal

Abstract: L-Deprenyl (Selegeline) is an enzyme-activated irreversible inhibitor of monoamine oxidase B (MAO B; EC 1.4.3.4). It is used to treat Parkinson's disease at a dose of 5 mg twice a day. Since enzyme inhibition is irreversible, the recovery of functional enzyme activity after withdrawal from L-deprenyl requires the synthesis of new enzyme. We have measured a 40 day half-time for brain MAO B synthesis in Parkinson's disease and in normal subjects after withdrawal from L-deprenyl. This is the first measurement of the synthesis rate of a specific protein in the living human brain. L-Deprenyl is currently used by 50,000 patients with Parkinson's disease in the United States and its use is expected to increase with reports that it may be beneficial in Alzheimer's disease. The slow turnover of brain MAO B suggests that the current clinical dose of L-deprenyl may be excessive and that the clinical efficacy of reduced dosing should be evaluated. Such an evaluation may have mechanistic importance as well as an impact on reducing the side effects and the costs arising from excessive drug use. © 1994 Wiley-Liss, Inc.1

Intersubject Variability of Brain Glucose Metabolic Measurements in Young Normal Males

Abstract: This study evaluates intersubject variability on regional glucose metabolic values in a group of 50 healthy right-handed males between 20 and 40 yr of age. Methods: Brain glucose metab olism was measured using PET and 2-deoxy-2[18F]fluoro-Dglucose under resting conditions and was separately assessed for subjects in their twenties (n = 34) and those in their thirties (n = 16). Results: Regional brain metabolic values showed significant intersubject variability with coefficients of variation (CV) that ranged between 11.1% to 15.2% (twenties) and 7.2% to 12.6% (thirties). Relative measures (regional/global)were less variable than absolute measures and the CV ranged between 4.1% to 8.3% (twenties) and 3.9% to 10% (thirties). Whereas global brain metabolic rate for subjects in their twenties was not significantly different from that of subjects in their thirties, the metabolic rate in left frontal regions was significantly lower in the older subjects. Conclusion: The correlations between age and absolute and relative metabolism in the left frontal region were r = 0.438, p < 0.002 and r = 0.447, p < 0.001, respectively.This study shows significant intersubject variability for regional brain

Pharmacokinetics and in vivo specificity of [LLC]dl-threo-methylphenidate for the presynaptic dopaminergic neuron

Abstract: dl-threo-Methylphenidate (Ritalin) was labeled with carbon-11 (t1/2:20.4 minutes) in order to measure its pharmacokinetics, to evaluate it as a radiotracer for the presynaptic dopaminergic neuron, and to examine its sensitivity to the loss of dopaminergic neurons. Positron emission tomographic (PET) studies were carried out in the baboon to determine specificity for the presynaptic dopaminergic neuron and in humans to assess sensitivity to neuronal loss. Studies with [11C]dl-threo-methylphenidate ([11C]MP) in baboon demonstrated high regional uptake in the striatum. Peak uptake (0.04%/cc) occurred at 5-15 minutes post-injection. The half-time for clearance from peak uptake for [11C]MP was 60 minutes and the ratio between the radioactivity in the striatum and that in the cerebellum (ST/CB) ranged from 2.2 to 2.6 at 40 minutes. Repeated measures in the same baboon showed < or = 8% variability in the ST/CB ratio. Pretreatment with unlabeled methylphenidate (0.5 mg/kg) or GBR12909 (1.5 mg/kg) 30 minutes prior to [11C]MP injection markedly reduced the striatal but not the cerebellar uptake of [11C]MP, demonstrating the saturable and specific binding of [11C]MP to a site on the dopamine transporter in the brain. In both cases, the ratio of striatum to cerebellum (ST/CB) after pretreatment was reduced by about 43%. The ratios of distribution volumes at the steady-state for the striatum to cerebellum (ST/CB) for these two separate studies in the same baboon were reduced by 37 and 38%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Diminished cerebral metabolic response to motor stimulation in schizophrenics: a PET study.

Abstract: Positron emission tomography (PET) and the deoxyglucose method were used to measure cerebral metabolism in 14 normals and 13 schizophrenics at rest and during performance of simple and complex finger-movement sequences. The normals, but not the schizophrenics, showed significant metabolic activation in mesial frontal and contralateral sensorimotor and premotor regions during the complex movement. The relative metabolism of schizophrenics was significantly lower than normal in frontal regions and higher than normal in thalamus and basal ganglia underall scanning conditions. The results suggest that schizophrenics may have a brain dysfunction which limits their capacity to produce a focal metabolic response to stimulation in several functionally distinct brain regions.

PET studies of cocaine inhibition of myocardial norepinephrine uptake.

Abstract: Positron emission tomography (PET), [11C]cocaine, and (–)-6-[18F]fluoronorepinephrine [(-)-6-[18F]NE] were used to determine the extent to which the binding of labeled cocaine in the baboon heart represents binding to the norepinephrine transporter and to characterize the functional consequences of cocaine administration on the norepinephrine transporter. Peak heart binding of [11C] cocaine was high (0.038-0.055%/g) and clearance was rapid (t1/2 from peak: 2.5–9 min) for both tracer doses and a pharmacological dose. The binding of a tracer dose of labeled cocaine could not be inhibited by desipramine, tomoxetine, cocaine, nomifensine, or benztropine. The behavior of a pharmacological dose of [11C]cocaine could not be distinguished from a tracer dose and also could not be inhibited by tomoxetine. However, pretreatment with cocaine profoundly inhibited norepinephrine uptake as assessed by (–)-6-[18F]NE. Recovery was slow with only 48% of the baseline (–)-6-[18F]NE uptake being recovered by 78 minutes after cocaine administration. [11C]Benzoylecgonine, a vasoactive metabolite of cocaine, showed negligible retention in heart. The results of this study (i.e., the rapid clearance of cocaine from the heart, the inability to inhibit cocaine binding with desipramine and tomoxetine, and its relatively long-lasting effects on norepinephrine uptake) reinforce the need to understand the link between cocaine pharmacokinetics and norepinephrine transporter function and its relationship to cardiotoxicity. © 1994 Wiley-Liss, Inc.