Decreased [18F]spiperone binding in putamen in dystonia.
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Adult↗
Biomedical subjects
J S Perlmutter
Publications and source records attributed to J S Perlmutter.
PET measurement of dopamine D2 receptor-mediated changes in striatopallidal function.
This study was designed to validate an in vivo measurement of the functional sensitivity of basal ganglia neuronal circuits containing dopamine D2 receptors. We hypothesized that a D2 agonist would decrease striatopallidal neuronal activity, and hence regional cerebral blood flow (rCBF) over the axon terminals in the globus pallidus. Quantitative pallidal blood flow was measured using positron emission tomography (PET) with bolus injections of H215O and arterial sampling in six baboons before and after intravenous administration of the selective D2 agonist U91356a. We also tested whether the response to U91356a was modified by previous acute administration of various antagonists. Another baboon had serial measurements of blood flow under identical conditions, but received no dopaminergic drugs. In all animals that received U91356a, pallidal flow decreased in a dose-related manner. Global CBF had a similar response, but the decline in pallidal flow was greater in magnitude and remained significant after accounting for the global effect. A D2 antagonist, but not antagonists of D1, serotonin-2, or peripheral D2 receptors, prevented this decrease. This work demonstrates and validates an in vivo measure of the sensitivity of D2-mediated basal ganglia pathways. It also supports the hypothesis that activation of the indirect striatopallidal pathway, previously demonstrated using nonselective D2-like agonists, can be mediated specifically by D2 receptors. We speculate that the U91356a-PET technique may prove useful in detecting functional abnormalities of D2-mediated dopaminergic function in diseases such as parkinsonism, dystonia, Tourette syndrome, or schizophrenia.
Aminoquinolines↗
Decreased [18F]spiperone binding in putamen in idiopathic focal dystonia.
In this study we have investigated the pathophysiology of two idiopathic focal dystonias: hand cramp with excessive cocontractions of agonist and antagonist hand or forearm muscles during specific tasks, such as writing, and facial dystonia manifested by involuntary eyelid spasms (blepharospasm) and lower facial and jaw spasms (oromandibular dystonia). We used positron emission tomography (PET) to measure the in vivo binding of the dopaminergic radioligand [18F]spiperone in putamen in 21 patients with these two focal dystonias and compared the findings with those from 13 normals. We measured regional cerebral blood flow and blood volume in each subject as well as the radiolabeled metabolites of [18F]spiperone in arterial blood. A stereotactic method of localization, independent of the appearance of the images, was used to identify the putamen in all of the PET images. We analyzed the PET and arterial blood data with a validated nonsteady-state tracer kinetic model representing the in vivo behavior of the radioligand. An index of binding called the combined forward rate constant was decreased by 29% in dystonics, as compared with normals (p < 0.05). There were no significant differences between dystonics and normals in regional blood flow, blood volume, nonspecific binding, permeability-surface area product of [18F]spiperone or the dissociation rate constant. These findings are consistent with a decrease of dopamine D2-like binding in putamen and are the first demonstration of a receptor abnormality in idiopathic dystonia. These results have important implications for the pathophysiology of dystonia as well as for function of the basal ganglia.
Adult↗
Radiation dosimetry of [18F] (N-methyl)benperidol as determined by whole-body PET imaging of primates.
Radiation absorbed doses due to IV administration of [18F](N-methyl) benperidol ([18F]NMB) were estimated by whole-body PET imaging of nonhuman primates. Time-activity curves were obtained for nine compartments (striatum, eyes, heart, lungs, liver, gallbladder, intestines, kidneys, bladder) by using dynamic PET scans of three different baboons given the radiotracer. These time-activity curves were used to calculate the residence times of radioactivity in these tissues. Human absorbed dose estimates were calculated using the updated MIRDOSE 3 S values and assuming the same biodistribution. Based on an average of three studies, the critical organs were the lower large intestine, gallbladder, and liver, receiving doses of 585, 281, and 210 mrad/mCi, respectively. The brain received a dose of 13 mrad/mCi; other organs received doses between 32-77 mrad/mCi. These results indicate that up to 8.5 mCi of [18F]NMB can be safely administered to human subjects for PET studies of D2 receptor binding.
Animals↗
In vivo kinetics of [18F](N-methyl)benperidol: a novel PET tracer for assessment of dopaminergic D2-like receptor binding.
A novel D2-like receptor-binding radioligand, [18F](N-methyl)benperidol ([18F]NMB), was evaluated via positron emission tomographic (PET) imaging studies of baboons. [18F]NMB rapidly localized in vivo within dopaminergic receptor-rich cerebral tissues, and striatum-to-cerebellum ratios as high as 35 were achieved after 3 hours. Pretreatment of an animal with unlabeled receptor-specific antagonists before injection of [18F]NMB confirmed that the radioligand bound specifically to central D2-like receptors in vivo, and not to S2- or D1-like receptors. Unlabeled eticlopride displaced striatal [18F]NMB in vivo, showing that D2-like binding is reversible. Receptor-binding by the radioligand was resistant to competitive displacement by synaptic dopamine, as illustrated by the lack of effect of intravenous d-amphetamine on the in vivo localization of [18F]NMB. Studies involving sequential intravenous administration of [18F]NMB, d-amphetamine, and eticlopride show that the radioligand does not undergo agonist-mediated internalization with subsequent trapping. The feasibility of applying a three-compartment non-steady state model for quantification of [18F]NMB receptor binding was demonstrated. These in vivo characteristics give [18F]NMB distinct advantages over the PET radiopharmaceuticals currently used for clinical investigation of D2-like receptor binding.
Animals↗
MPTP induces dystonia and parkinsonism. Clues to the pathophysiology of dystonia.
The pathophysiology of dystonia is unclear, but several clues implicate striatal dopamine dysfunction. In contrast, the causal relationship between striatal dopamine deficiency and parkinsonism is well defined. We now suggest that parkinsonism or dystonia may occur following striatal dopamine deficiency. Baboons treated with intracarotid 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) developed transient hemidystonia prior to hemiparkinsonism. The day after MPTP treatment, most animals had spontaneous ipsilateral turning. Within a few days, all developed contralateral hemidystonia, with the arm and leg extended and externally rotated. This transient dystonia preceded hemiparkinsonism with flexed posture, bradykinesia, and postural tremor that persisted for up to 1.5 years. Dystonia corresponded temporally with a decreased striatal dopamine content and a transient decrease in D2-like receptor number. The time course of dystonia and parkinsonism is analogous to lower limb dystonia as the first, frequently transient, symptom of Parkinson's disease in humans. The association of striatal dopamine deficiency with dystonia and parkinsonism implies that other factors influence clinical manifestations.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
Septuagenarian Sydenham's with secondary hypomania.
A 74-year-old man with a remote history of Sydenham's chorea but no personal or family history of mood disorder had simultaneous onset of severe, generalized chorea and a mild manic syndrome in clear consciousness. Both chorea and hypomania improved after treatment with sodium valproate and clonazepam. Agitated delirium or mood lability have been described in Sydenham's, but this case is the first report of criteria-based secondary mania with probable Sydenham's chorea, as well as the longest reported remission between symptomatic Sydenham's episodes. The parallel course of this patient's hypomania and chorea supports current pathophysiologic theories of idiopathic mania.
Aged↗
Dynamic changes in striatal dopamine D2 and D3 receptor protein and mRNA in response to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) denervation in baboons.
Loss of nigrostriatal neurons leads to striatal dopamine deficiency and subsequent development of parkinsonism. The effects of this denervation on D2-like receptors in striatum remain unclear. Most studies have demonstrated increases in striatal dopamine D2-like receptors in response to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-mediated denervation, but others have found either decreases or no change in binding. To clarify the response to denervation, we have investigated the time-dependent changes in dopamine D2, D3, and D4 receptor protein and mRNA levels in unilaterally MPTP-lesioned baboons. MPTP (0.4 mg/kg) was infused into one internal carotid artery, producing a contralateral hemi-parkinsonian syndrome. After MPTP treatment, the animals were maintained for 17-480 d and then euthanized. MPTP decreased ipsilateral dopamine content by >90%, which did not change with time. Ipsilateral D2-like receptor binding in caudate and putamen initially decreased then increased two- to sevenfold over the first 100 d and returned to near baseline levels by 480 d. Relative levels of D2 mRNA were essentially unchanged over this period. D4 mRNA was not detected. In contrast, D3 mRNA increased sixfold by 2 weeks and then decreased. At the peak period of increase in binding sites, all D2-like receptors were in a micromolar affinity agonist-binding state, implying an increase in uncoupled D2 but not D3 receptor protein. Taken together, these data suggest that MPTP-induced changes in D2-like dopamine receptors are complex and include translational or post-translational mechanisms.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
Specific, reversible binding of [18F]benperidol to baboon D2 receptors: PET evaluation of an improved 18F-labeled ligand.
[18F]Benperidol ([18F]BP), a positron-emitting analogue of the dopaminergic D2 antagonist benperidol, was evaluated as a radiopharmaceutical for use with positron emission tomography (PET). PET imaging of baboons after i.v. injection of [18F]BP indicated that the radiofluorinated ligand rapidly localized in vivo within dopaminergic receptor-rich cerebral tissues, and that selective disposition was retained for over 2 h. Pretreatment of an animal with unlabeled receptor-specific antagonists prior to injection of [18F]BP confirmed that the radioligand bound specifically to central D2 receptors in vivo, and not to S2 or D1 receptors. [18F]BP bound to D2 receptors in a reversible manner; unlabeled eticlopride displaced D2 receptor-bound [18F]BP in vivo. The radioligand was metabolized in the periphery to polar metabolites which are not expected to cross the blood-brain barrier. [18F]BP has advantages over other tracers as a radiopharmaceutical for PET study of central D2 receptor activity, and can be applied for noninvasive evaluation of the interaction of unlabeled drugs with central D2 receptor sites.
Animals↗
Tracer-kinetic analysis for measuring regional cerebral blood flow by dynamic nuclear magnetic resonance imaging.
Measurement of regional cerebral blood flow in vivo has proved useful in the study of normal and diseased states in the brain. This circumstance has led to a variety of techniques for its quantitative determination and has continued to motivate the search for ever safer and more accurate methods of measurement. Recently, the use of nuclear magnetic resonance (NMR) in medical imaging has stimulated efforts to make it the basis for a non-invasive method of measuring flow in the brain. New advances in fast NMR imaging (MRI) provide data potentially amenable to analysis by tracer-kinetic methods. Such an analysis has not previously been available. In this paper we present theoretical results that may permit measurement of brain blood flow by NMR. The data interpreted by our model are those generated by a novel MRI protocol developed by Perman et al. (1992, Magn. Reson. Med. 28, 74-83; Radiology 185(P), Abstr. 154, 127) that is entirely compatible with existing routine MRI procedures. These data are fast dynamic NMR signals that reflect passage of an intravenously administered paramagnetic contrast agent serving as a plasma tracer. Our equations show how to use such data sequences to determine plasma mean transit time, plasma volume, and plasma and whole-blood flow in arbitrarily selected regions of interest in the brain. The theory accounts rigorously for recirculation of tracer to the imaged regions. Our analysis provides an explanation for the linear relationship observed experimentally by others between regional vascular volumes and time integrals of vascular-tracer residue curves, and shows that this relationship remains valid in the presence of tracer recirculation.
Brain↗
First-pass extraction fraction of iodine-123 labeled perfusion tracers in living primate brain.
The cerebral extraction and retention of three radioiodinatéd SPECT perfusion tracers were measured using residue detection in a baboon. A permeability-surface area product PS' with special relevance to SPECT was calculated from the retention of tracer in the brain after 10 min. PS' differs from the traditional PS value, which is calculated from the tracer clearance curve at 2 min. The PS' values ranged from 50 to 95 mL/min/100 g, decreased in the order [123I]IMP > [123I]iodoperidol approximately [123I]HIPDM, and did not differ for specific activities of 10 MBq/mmol to 74 TBq/mmol. These radioiodinated compounds exhibited extraction characteristics superior to those of [99mTc]HMPAO but underestimated cerebral blood flow when flows were above 20-30 mL/min/100 g, underscoring the need for development of a more ideal SPECT perfusion tracer.
Animals↗
Assessment of fetal tissue transplantation in Parkinson's disease: does PET play a role?
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Animals↗
A half-Fourier gradient echo technique for dynamic MR imaging.
Recently we developed the simultaneous dual FLASH (SDFLASH) pulse sequence that simultaneously obtains sequential images from the brain and the internal-carotid arteries in the neck with 1-sec temporal resolution using a standard MR scanner. The high temporal resolution (1 sec) of the SDFLASH technique was achieved partly by using a low number of phase-encoding views which thereby limited our in-plane spatial resolution to 6.25 x 3.12 mm pixels. To overcome this limitation we have developed a calibration technique which corrects distortions in signal intensity and object shape when using gradient echo half-Fourier spin warp imaging. Using this calibration technique, the operator can use the 41% decrease in scan time to either double the spatial or temporal resolution. We have successfully used this technique to acquire SDFLASH images of the head and neck with 1.0 sec temporal resolution and 3.12 x 1.6 mm spatial resolution.
Brain↗
New techniques in neuroimaging: when are pretty pictures clinically useful?
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Brain Diseases↗
Abnormal cortical responses in patients with writer's cramp.
We evaluated sensorimotor processing in patients with writer's cramp using PET and H2(15)O blood flow scans. The study included six right-handed patients with unilateral writer's cramp and eight right-handed normals. Subjects had blood flow scans at rest and during vibration of either the "affected" or "unaffected" hand. Vibration produced a consistent peak response in primary sensorimotor area (PSA) and supplementary motor area (SMA), both contralateral to the vibrated hand. Both responses were significantly reduced approximately 25% in patients with writer's cramp (PSA, p = 0.002; SMA, p = 0.02) whether vibrating the affected or unaffected hand. This indicates that patients with unilateral writer's cramp have bilateral brain dysfunction. These data provide objective evidence of abnormal central sensorimotor processing in writer's cramp.
Adult↗
Specific binding of 3N-(2'-[18F]fluoroethyl)benperidol to primate cerebral dopaminergic D2 receptors demonstrated in vivo by PET.
3N-(2'-[18F]Fluoroethyl)benperidol ([18F]FEB) an 18F-labeled analogue of the D2 antagonist benperidol, was evaluated as a tracer for positron emission tomography (PET). PET imaging of a living baboon showed that the fluorinated ligand rapidly localized in vivo within D2 receptor-rich brain tissue, with selective retention lasting over 2 h after tracer injection. Pretreatment of the animal with unlabeled D2-specific antagonist eticlopride (4 mg/kg, i.v.) 1 h before [18F]FEB completely abolished the selective disposition of the radioligand, whereas the regional cerebral blood flow, blood volume and peripheral metabolism/protein binding of [18F]FEB were not changed. Tracer localization when the baboon was pretreated with unlabeled ketanserin (0.55 mg/kg, i.v.) or SCH 23390 (1.1 mg/kg, i.v.) was identical to that for the control case, indicating that the [18F]FEB did not bind to S2 of D1 receptors in vivo. [18F]FEB has advantages compared to previously used PET tracers, and may be an excellent radioligand for non-invasive study of D2 receptor binding.
Animals↗
Binding of 5-(2'-[18F]fluoroethyl)flumazenil to central benzodiazepine receptors measured in living baboon by positron emission tomography.
5-(2'-[18F]Fluoroethyl)flumazenil ([18F]FEF), a fluorine-18-labeled analogue of the benzodiazepine antagonist flumazenil, was evaluated for use with positron emission tomography (PET). PET imaging of a baboon after i.v. injection of [18F]FEF showed that the radiofluorinated ligand rapidly localized in vivo within benzodiazepine receptor-rich cerebral tissues, and that selective disposition was retained for over 2 h. Coinjection of unlabeled flumazenil (0.55 mg/kg i.v.) abolished the heterogeneous cerebral distribution of the tracer; receptor-specific uptake was reduced by approximately 95%. The fluorinated benzodiazepine antagonist was degraded in vivo only to polar radiometabolites that do not cross the blood-brain barrier. [18F]FEF has advantages over existing PET radiopharmaceuticals, and is a promising radioligand for non-invasive evaluation of central benzodiazepine receptor binding in vivo.
Animals↗
Simultaneous MR acquisition of arterial and brain signal-time curves.
Regional cerebral blood flow (rCBF) provides important information about local neuronal functional and cerebrovascular status. Determination of rCBF requires sequential measurements of tracer concentration in arterial blood and brain tissue unless the tracer is trapped in the brain in proportion to rCBF. Since gadopentate dimeglumine is not trapped within brain tissue, we have developed the simultaneous dual FLASH pulse sequence (SDFLASH) which sequentially measures the MR signal change in both the internal carotid artery and brain parenchyma simultaneously during the passage of a bolus of paramagnetic contrast material.
Animals↗