Showing papers by "Nora D. Volkow published in 1992"

Long-term frontal brain metabolic changes in cocaine abusers.

Abstract: Neurological complications from cocaine use are well recognized. We propose that chronic cocaine use can also cause clinically silent brain dysfunction. We investigated brain glucose metabolism with positron emission tomography (PET) and 2-deoxy-2[18F] fluoro-D-glucose (FDG) in 21 neurologically intact chronic cocaine abusers (C) and 18 normal controls (N). The cocaine abusers were tested 1-6 weeks after the last use of cocaine and seven were retested after a 3 month drug-free period. Global cerebral glucose metabolism was not significantly different between controls and cocaine abusers (N = 38.4 +/- 3, C = 36.5 +/- 5 mumol/100 g of tissue, min). However, cocaine abusers had significantly (P less than 0.05) lower metabolic activity in 16 of the 21 left frontal regions and 8 of the 21 right frontal regions. These decreases persisted after 3-4 months of detoxification and were correlated with the dose (P less than or equal to 0.01) and the years of cocaine use (P less than or equal to 0.05). This study shows reduced rates of frontal metabolism in neurologically intact cocaine abusers that persist even after 3-4 months of detoxification.

Topography of Cross-sectional and Longitudinal Glucose Metabolic Deficits in Alzheimer's Disease: Pathophysiologic Implications

Abstract: • Positron emission tomographic studies of cerebral glucose metabolism have shown high diagnostic specificity in distinguishing among the degenerative dementias and differentiating between Alzheimer's disease (AD) and normal aging. The current investigation was undertaken to characterize the regional glucose metabolic deficits in AD, using cross-sectional and longitudinal study designs. All subjects met the National Institute of Neurological and Communicative Disorders and Stroke—Alzheimer's Disease and Related Disorders Association criteria for AD (n=45) or were normal (n=20), and the AD subjects were subdivided into incipient and mild AD and moderate plus moderately severe subgroups based on the Global Deterioration Scale. The subjects underwent a non—contrast computed tomographic scan and a positron emission tomographic (PETT VI) scan. The AD subjects (n=14) and normal control subjects (n=15) received evaluations 2 to 3 years after baseline study. The brain regions that show glucose metabolic deficits cross-sectionally (temporal and parietal association areas, with lesser degrees of deficit in subcortical gray matter structures), over the stages of AD, also show further deficits longitudinally within the same AD subjects. The reduction in glucose metabolism is greater than would be expected from the degree of brain atrophy. The glucose metabolic deficits are discussed in the context of neuropathologic findings and neurotransmitter deficits in AD.

Decreased brain metabolism in neurologically intact healthy alcoholics.

Abstract: Objective: The extent to which cerebral dysfunction in alcoholics is related to the direct effects of alcohol in the brain rather than to indirect mechanisms and/or alcohol withdrawal remains unclear. The purpose of this study was to evaluate whether healthy alcoholics with no evidence ofalcohol-associated complications showed changes in brain glucose metabolism. Method: Positron emission tomography and [18F]-fluorodeoxyglucose were used to measure regional brain metabolism. The study group consisted of 22 normal, healthy, right-handed volunteers and 22 neurologically intact, healthy, right-handed alcoholics tested 6 to 32 days after alcohol discontinuation. Results: Alcoholics showed significantly lower whole brain metabolism than normal control subjects. Normalization of regional metabolic values to the whole brain metabolic rate revealed that the left parietal and right frontal cortices were the most affected regions. Although the whole brain metabolic rate was correlated with the amount of time since alcohol discontinuation, the “normalized” decreases in left parietal and right f rontal glucose metabolism were not. Conclusions: These findings support the contribution of the direct effect of alcohol as well as alcohol withdrawal on the changes in regional brain metabolism seen in alcoholics. They also provide evidence of cerebral changes in neurologically intact healthy alcoholics.

PET scanning of iodine-124-3F9 as an approach to tumor dosimetry during treatment planning for radioimmunotherapy in a child with neuroblastoma.

Abstract: A patient with advanced neuroblastoma who had failed chemotherapy presented with a large abdominal mass and virtually total bone marrow replacement by tumor on repeated marrow biopsies. She was considered a candidate for a Phase I 131I-3F8 radioimmunotherapy trial, (MSKCC 89-141A). As a potential aid to treatment planning, a test dose of 124I-3F8 was injected and the patient was imaged over the 72 hr postinjection using two BGO based PET scanners of different designs. Time activity curves were obtained, and the cumulated activity concentration of radiolabeled 3F8 in tumor was determined. Based on MIRD, an estimated radiation absorbed dose for 131I-3F8 was 7.55 rad/mCi, in the most antibody avid lesions. Because of low uptake and unfavorable dosimetry in some bulky tumor sites, it was decided not to treat the patient with radiolabeled antibody. Positron emission tomography of 124I-labeled antibodies can be used to measure cumulated activity or residence time in tumor for more accurate estimates of radiation absorbed tumor dose from radioiodinated antibodies and can help guide management decisions in patients who are candidates for radioimmunotherapy.

Low cerebellar metabolism in medicated patients with chronic schizophrenia.

Abstract: Because of the frequent association of cerebellar structural defects with schizophrenia, the authors reanalyzed the metabolic brain images of patients with chronic schizophrenia to assess if they had abnormalities in cerebellar metabolism. They used carbon-11-2-deoxyglucose and positron emission tomography to study 18 medicated patients with chronic schizophrenia and 12 normal comparison subjects. Patients with schizophrenia showed significantly lower absolute and relative metabolism in the cerebellum than normal subjects.

Distribution and kinetics of carbon-11-cocaine in the human body measured with PET.

Abstract: The extent to which the toxic properties of cocaine are related to its accumulation in various organs is not known. This study investigates cocaine uptake in the human body using 11C-cocaine and PET in 14 healthy males. The rate of uptake and clearance of 11C-cocaine varied among organs: peak uptake occurred in the lungs at 45 sec, in the heart and kidneys at 2-3 min, in the adrenals at 7-9 min, and in the liver at 10-15 min. Half-peak clearances were 90 sec in the lungs, 10 min in the heart and kidneys and 22 min in the adrenals. Liver radioactivity plateaued 10-15 min after injection and remained constant thereafter (40 min). Lung radioactivity paralleled that of plasma. The average uptake at peak was 0.007% (s.d., 0.001) dose/cc in the heart, 0.014% (s.d., 0.002) dose/cc in the kidney, 0.014% (s.d., 0.002) dose/cc in the liver and 0.034% (s.d., 0.001) dose/cc in the adrenals. The significant accumulation of cocaine in human heart, kidneys, adrenals and liver could contribute to its toxicity.

Regional distribution and kinetics of haloperidol binding in human brain: a PET study with [18F]haloperidol.

Abstract: The regional distribution and the kinetics of haloperidol uptake in human brain were examined using [18F]haloperidol and PET in 9 controls and 5 schizophrenics while on haloperidol medication and after haloperidol washout. The regional distribution of [18F]N-methylspiroperidol, a tracer for D2 receptors, was measured in 1 normal subject for comparison. The uptake of [18F]haloperidol in the whole brain in normals was high (6.6% of the injected dose at 2 hr), and regional distribution was much more extensive than could be accounted for by the distribution of dopamine D2 receptors. In normals, the cerebellum, basal ganglia, and thalamus showed a greater concentration than the cortex, and there was minimal clearance of 18F from the brain during the 10-hr period of the study. Medicated schizophrenics showed a total brain uptake of 4.0% and had a significant clearance of [18F]haloperidol from brain and a higher concentration of [18F]haloperidol in plasma. After withdrawal from medication, [18F]haloperidol clearance from brain became slower than while on medication. These results are discussed in terms of the pharmacokinetics of haloperidol in the human brain and its binding to dopamine D2 receptors and to sigma receptors.

Comparative PET studies of the kinetics and distribution of cocaine and cocaethylene in baboon brain

Abstract: Recent studies have suggested that cocaethylene, an active metabolite of cocaine found in blood and postmortem brain of individuals self-administering cocaine and alcohol, may play a role in the increased toxicity seen when coadministering these 2 drugs. We have used positron emission tomography (PET) and carbon-11 (t1/2:20.4 min) labeled cocaine and cocaethylene to compare the short-term kinetics of cocaine and cocaethylene in baboon brain. The regional uptake of [11C]cocaine cocaethylene in baboon brain. The regional uptake of [11C]cocaine ([11C]COC) and [11C]cocaethylene ([11C]CE), 5-8 mCi and 4-6 micrograms, in baboon brain (n = 7) were similar but clearance from whole brain (global, GL) and from striatum (SR), thalamus (TH), and cerebellum (CB) was slower for cocaethylene. Steady-state distribution volumes (DV) were not significantly different in the striatum but were greater for cocaethylene in the thalamus, cerebellum, and whole brain. Debenzoylation of cocaethylene proceeded at about one-third the rate of cocaine, as determined by in vitro incubation of labeled cocaethylene and labeled cocaine with baboon plasma and with purified horse butyryl-cholinesterase (EC 3.1.1.8). Even though the slower clearance of cocaethylene could lead to longer tissue exposures and potentially accentuated or different physiological effects relative to cocaine, the difference between the 2 drugs is not large. Thus it is more likely that the direct actions of cocaine and alcohol on some organs, rather than cocaethylene, account for this enhanced toxicity.

Quantitative autoradiography of cocaine binding sites in human brain postmortem

Abstract: Quantitative autoradiography was used to study cocaine binding sites in the human brain postmortem. Tritiated cocaine was applied to brain sections from three drug- and disease-free subjects at a low (10 nM) concentration and at a high (1 microM) concentration, the latter being in the range of brain concentrations of cocaine found in users of the drug. Nonspecific binding was assessed in the presence of 100 microM unlabeled cocaine. At low (10 nM) concentrations of labeled cocaine, the basal ganglia exhibit the highest density of binding sites, with considerably lower densities in thalamus, cortex, and hippocampus. Cocaine binding at high (1 microM) concentrations displayed a different distribution pattern, more homogeneous with some cortical regions exhibiting binding site densities close to those seen in the basal ganglia. Preliminary competition experiments with several drugs indicate that dopamine uptake inhibitors completely block cocaine binding to the basal ganglia, while serotonin uptake inhibitors were more effective in the hippocampus. These findings suggest that cocaine binds to dopamine uptake sites in the human basal ganglia postmortem but that it also interacts with other classes of binding sites, depending on the concentration and brain region examined.

Alcohol inoxication does not change [11C]cocaine pharmacokinetics in human brain and heart

Abstract: There is increasing evidence that the combined use of cocaine and alcohokl produces enhanced behaviroal and toxic effects. We have used PET and tracer doses of [11C]cocaine in 7 normal human volunteers to assess if the dostribution and clearance of cocaine are altered by alcohlol intoxication. Each subject received 2 PET studies with [11C]cocaine (3–11 mg), one before and one during alcohol intoxication (1 g/kg). Regions of interest included dthe brain (n= 3) and heart (n = 4). arterial plasma was assayed for unchanged cocaine and for labelaed cocaethylene, a metabolite of cocaine found in individuals usig cocaine and alcohol in combination (hearn et al., 1991a). Alcohol intoxication did not change uptake and clearance or the steady-state distribution volume of [11C]cocaine in brain (striatum, thalamus, and cerebellum) or in heart. Moreover, labeled cocaethylene was not detedted in the 10 minute plasma sample. These results suggest that the acute dnhancement of behavior and toxicity associated with the combined use of cocaine and alcohol is not due to an alteration in cocaine's organ distribution or to cocaethylene formation but may be related to an additive effect resulting from the direct actaons of each of these drugs. Published 1992 Wiley-Liss, Inc.

Brain imaging of an alcoholic with MRI, SPECT, and PET.

Abstract: A medically healthy chronic alcoholic without evidence of neurological and neuropsychological impairment was studied with magnetic resonance imaging (MRI), single photon emission computerized tomography (SPECT), and positron emission tomography (PET). An age-matched normal volunteer was evaluated with the same scans for comparison. The MRI of the alcoholic revealed prominent ventricles and mild cortical atrophy. SPECT and PET revealed predominant involvement of the frontal cortex as shown by decreased frontal blood flow and metabolism. This case illustrates the sensitivity of brain imaging techniques in detecting cerebral abnormalities even in the absence of neurologic and/or neuropsychological impairments.

Spatial low frequency pattern analysis in positron emission tomography: a study between normals and schizophrenics.

Abstract: Using the two-dimensional Fourier transform and the brain's centroidal principal axis, a method is developed for the analysis of PET metabolic brain images without the use of predefined anatomic regions of interest. We applied the method to images from a group of 11 normal and 12 medicated schizophrenics tested under resting conditions and under a visual task. A cortical/subcortical spatial pattern was found to be significant in two directions| anterior/posterior and chiasmatic (left-anterior/right-posterior). The best individual clinical classification (Jackknife classification) occurred under visual task at two axial brain levels: at the basal ganglia with correct classification rates of 91% and 84%, while the cerebellum had rates of 82% and 92%. These high classification rates were obtained using only the four coefficients of the lowest spatial frequency. These results point to the generalized brain dysfunction of regional glucose metabolism in chronic medicated schizophrenics both at rest and at a visual image-tracking task

Positron emission tomography instrumentation: a review and update.

Abstract: Positron Emission Tomography (PET) has evolved into a powerful modality for in vivo functional imaging of the brain and the heart. Developments in PET technology and instrumentation have occurred rapidly during the last 20 years and have been driven by the requirements for improved resolution and image quality necessary for clinical and research applications. Clinical applications of PET have now been validated for the heart and the brain, and new research in the mapping of receptor density in the brain is being explored. PET cameras have developed into sophisticated imaging devices capable of both clinical and research applications. This review article updates the previous overview on PET instrumentation written by the authors with an added emphasis on performance evaluation of PET cameras. A short summary of current PET cameras available commercially is included for the purpose of comparing some important specifications between different systems.

A theory of the mind/brain dichotomy with special reference to the contribution of positron emission tomography.

Abstract: Throughout history, human beings have found it difficult to understand their conscious, free, and rational qualities in light of biological developments that continue to present the human condition as constituted chiefly of \"mindless, meaningless, physical particles.\" This seeming inconsistency or paradox led to theories (most particularly the Cartesian perspective) that split these processes into two zones or truly separable realms: \"mental\" phenomena, which usually included thoughts and feelings, and \"physical\" phenomena, which consist of mass, weight, texture, and motion of objects in the world [2]. Over the centuries, attempts have been made to deemphasize one portion of this dichotomy over the other. In the current century, biophysiologists and philosophers have mustered strong arguments against the intrinsic character of mental things [3]. Of particular importance in this area have been the contributions of the neurosciences. Advances have related biological processes to phenomena such as the transmission of sensation and information over neurons, and have disclosed specific locations in the brain that deal with perception, emotion, cognition, and speech [4, 5]. However, these arguments have not been completely successful in refuting the existence of a separate \"mental\" entity [6]. This failure can be attributed to biological as well as philosophical reasons. The biological reasons have to do with the way neuroscientific knowledge has been obtained. Until recently, most of the studies were conducted either on