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ABSTRACT: In vivo imaging of the dopamine transporter (DAT) with single photon emission computed tomography (SPECT) is a quantitative biomarker for Parkinson's disease (PD) onset and severity. This study has examined and compared the loss of striatal DAT in PD and multiple system atrophy (MSA) using [(123)I]beta-CIT SPECT imaging. One hundred and eighty-three patients (157 PD and 26 MSA) were studied. Clinical rating scales (Hoehn and Yahr stage and Unified Parkinson's Disease Rating Scale [UPDRS] scores) demonstrated that the MSA patients were more severely impaired than the PD patients. The striatal [(123)I]beta-CIT SPECT uptake was markedly reduced in both the PD and MSA groups. In addition, MSA patients showed more symmetric DAT loss compared with the PD patients, consistent with the more symmetric clinical motor dysfunction observed in MSA. While the loss of DAT was significantly reduced in all regions in both MSA and PD, comparison of the relative loss of the DAT did not significantly improve diagnostic accuracy in distinguishing between PD and MSA.
Movement Disorders 12/2001; 16(6):1023-32. · 4.51 Impact Factor
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ABSTRACT: Nicotine and other constituents of tobacco smoke elevate dopamine (DA) and serotonin (5-HT) levels in brain and may cause homeostatic adaptations in DA and 5-HT transporters. Since sex steroids alter DA and 5-HT transporter expression, the effects of smoking on DA and 5-HT transporter availability may differ between sexes. In the present study, DA and 5-HT transporter availabilities were quantitated using single photon emission computed tomography (SPECT) imaging approximately 22 h after bolus administration of [123I]beta-CIT, an analog of cocaine which labels DA and 5-HT transporters. Forty-two subjects including 21 pairs of age-, race-, and gender-matched healthy smokers and nonsmokers (12 female and 9 male pairs) were imaged. Regional uptake was assessed by the outcome measures, V3", which is the ratio of specific (i.e., ROI-cerebellar activity) to nondisplaceable (cerebellar) activity, and V3, the ratio of specific to free plasma parent. Overall, striatal and diencephalic [123I]beta-CIT uptake was not altered by smoking, whereas brainstem [123I]beta-CIT uptake was modestly higher (10%) in smokers vs. nonsmokers. When subgrouped by sex, regardless of smoking status, [123I]beta-CIT uptake was higher in the striatum (10%), diencephalon (15%), and brainstem (15%) in females vs. males. The sex*smoking interaction was not significant in the striatum, diencephalon, or brainstem, despite the observation of 20% higher brainstem [123I]beta-CIT uptake in male smokers vs. nonsmokers and less than a 5% difference between female smokers and nonsmokers. The results demonstrate higher DA and 5-HT transporter availability in females vs. males and no overall effect of smoking with the exception of a modest elevation in brainstem 5-HT transporters in male smokers. Although these findings are preliminary and need validation with a more selective 5-HT transporter radiotracer, the results suggest that brainstem 5-HT transporters may be regulated by smoking in a sex-specific manner.
Synapse 10/2001; 41(4):275-84. · 2.94 Impact Factor
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ABSTRACT: Approximately 40% of patients treated with curative intent for colorectal carcinoma eventually recur. In about one third of these patients, the lesion is localized and potentially resectable. Typically, the recurrence is characterized by findings on diagnostic imaging studies and may be accompanied by a rise in the serum carcinoembryonic antigen (CEA) levels. In a few patients, however, the asymptomatic rise in CEA is not accompanied by diagnostic findings on computed tomography (CT). We report a case herein, of a patient with rising CEA, noted 1 year after completion of adjuvant chemotherapy for node-positive colorectal cancer. CT and laparoscopic exploration were nondiagnostic. In order to further evaluate the rise in CEA, positron emission tomography (PET) was performed. PET revealed an area of increased uptake in the right lobe of the liver. Resection of the metastatic liver lesion resulted in a subsequent drop in the CEA levels.
Clinical Colorectal Cancer 09/2001; 1(2):117-20. · 1.68 Impact Factor
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ABSTRACT: Image processing techniques were applied to interictal positron emission tomography (PET) and single-photon emission computed tomography (SPECT) brain images to aid in the localization of epileptogenic foci by calculating a functional image that represents the degree of coupling between perfusion and metabolism. Uncoupling of these two functions has been demonstrated to be a characteristic of epileptogenic tissue in temporal lobe epilepsy and has the potential to serve as a diagnostic measure for localization in other areas as well.
Interictal PET ((18)F-FDG) and interictal SPECT ((99m)Tc-HMPAO) scans were acquired from 11 epilepsy patients. The metabolism and perfusion images were three-dimensionally spatially registered, and a functional ratio-image was computed. These functional maps are overlaid onto a three-dimensional rendering of the same patient's magnetic resonance imaging anatomy.
In all patients, an average uniform perfusion-to-metabolism ratio showed approximately constant values throughout most of the whole brain. However, the epileptogenic area (confirmed on surgery) demonstrated an area of elevated perfusion/metabolism in the grey matter.
Although hypometabolism in the PET image was observed in most of these patients, the calculation of a functional ratio-image demonstrated localized foci that in some cases could not be observed on the PET image alone. The ratio-image also yields a quantitative measure of the uncoupling phenomenon.
Epilepsia 01/2001; 41(12):1560-6. · 3.96 Impact Factor
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ABSTRACT: The iodinated analog (S)-5-[123I]iodo-3-(2-azetidinylmethoxy)pyridine of A-85380 is a new potential SPECT tracer specific for the alpha4beta2 subtype nicotinic acetylcholine receptors, which play an important role in neurodegenerative diseases and in tobacco dependence. To evaluate the possibility of using this tracer for the in vivo quantification of these receptors, an accurate measurement of the plasma concentration of the parent compound is necessary. In human or nonhuman primate whole blood as well as in plasma, the parent compound is only stable for approximately 5 min, after which it decomposes. The radioligand is stable in the injection solution and in protein-free ( >30 K M.W.) plasma ultrafiltrate for at least 18 h. To preserve the parent compound in plasma the radioactive plasma must be mixed with equal volumes of acetonitrile within 5 min after its collection or, alternatively, radioactive blood should be collected and mixed with sodium azide (3 mg/ml blood). The in vivo metabolism of [123I]5-IA resulted in two components: a radiometabolite that is less lipophilic than the parent compound and a polar radiometabolite that is not free radioiodide because of the absence of radioactivity accumulation in the thyroid.
Nuclear Medicine and Biology 01/2001; 28(1):91-6. · 3.02 Impact Factor
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C H van Dyck,
J C Soares,
P Z Tan,
J K Staley,
R M Baldwin,
L A Amici,
X Fu,
P K Garg, J P Seibyl,
D S Charney,
R B Innis
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ABSTRACT: [(18)F]Altanserin has emerged as a promising positron emission tomography (PET) ligand for serotonin-2A (5-HT(2A)) receptors. The deuterium substitution of both of the 2'-hydrogens of altanserin ([(18)F]deuteroaltanserin) yields a metabolically more stable radiotracer with higher ratios of parent tracer to radiometabolites and increased specific brain uptake than [(18)F]altanserin. The slower metabolism of the deuterated analog might preclude the possibility of achieving stable plasma and brain activities with a bolus plus constant infusion within a reasonable time frame for an (18)F-labeled tracer (T(1/2) 110 min). Thus, the purpose of this study was to test the feasibility in human subjects of a constant infusion paradigm for equilibrium modeling of [(18)F]deuteroaltanserin with PET. Seven healthy male subjects were injected with [(18)F]deuteroaltanserin as a bolus plus constant infusion lasting 10 h postinjection. PET acquisitions and venous blood sampling were performed throughout the infusion period. Linear regression analysis revealed that time-activity curves for both specific brain uptake and plasma [(18)F]deuteroaltanserin concentration stabilized after about 5 h. This permitted equilibrium modeling and estimation of V(')(3) (ratio of specific uptake to total plasma parent concentration) and the binding potential V(3) (ratio of specific uptake to free plasma parent concentration). Cortical/cerebellar ratios were increased by 26% relative to those we previously observed with [(18)F]altanserin using similar methodology in a somewhat older subject sample. These results demonstrate feasibility of equilibrium imaging with [(18)F]deuteroaltanserin and suggest that it may be superior to [(18)F]altanserin as a PET radioligand.
Nuclear Medicine and Biology 12/2000; 27(8):715-22. · 3.02 Impact Factor
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ABSTRACT: Evidence of a relationship between genotype and binding availability was assessed for the dopamine and serotonin transporter genes.
The authors assessed dopamine transporter genotype at the SLC6A3 3' variable number of tandem repeats (VNTR) polymorphism and serotonin transporter genotype at the SLC6A4 promotor VNTR polymorphism in 30 healthy subjects who also underwent single photon emission computed tomography with [(123)I]beta-CIT.
Subjects homozygous for the 10-repeat allele at the SLC6A3 locus demonstrated significantly lower dopamine transporter binding than carriers of the nine-repeat allele. There was no effect of SLC6A4 genotype upon serotonin transporter binding.
These findings suggest that genetic variation at the SLC6A3 3' VNTR polymorphism may modify dopamine transporter function.
American Journal of Psychiatry 11/2000; 157(10):1700-3. · 12.54 Impact Factor
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ABSTRACT: Nicotinic acetylcholine receptors (nAChRs) play an important role in tobacco dependence and a potential therapeutic role in neuropsychiatric disorders such as Alzheimer's disease. [123I]5-iodo-3-[2(S)-2-azetidinylmethoxy]pyridine (5-I-A-85380) is a new SPECT tracer that labels alpha4beta2 nAChRs. The purpose of this study was to assess the usefulness of this tracer to measure regional nAChR binding in baboon brain using both a bolus/kinetic paradigm and also a bolus plus constant infusion/equilibrium paradigm.
A pair of bolus/kinetic and bolus plus constant infusion/equilibrium studies was performed in each of 3 isoflurane-anesthetized baboons. Bolus studies were performed by intravenous injection of 191-226 MBq [123I]5-I-A-85380 and image acquisition for 289-367 min. The data were analyzed with 1- and 2-tissue compartment models. Bolus plus constant infusion/equilibrium studies were performed by a bolus injection (74-132 MBq) followed by a 468- to 495-min infusion with a bolus/infusion ratio (B/I) of 4.8-5.0 h. The distribution volumes in the thalamus were measured in these 2 paradigms. To study whether the cerebellum was appropriate as a receptor-poor region, displacement studies were done in 2 baboons using the B/I paradigm with subcutaneous injection of (-)-cytisine (0.8 and 1.0 mg/kg).
The kinetics of this tracer was best described by the 1-tissue compartment model. The 2-compartment model showed poor identifiability of rate constants. The total (specific plus nondisplaceable compartments) distribution volumes (V(T)') agreed between bolus and B/I paradigms (average percentage difference in V(T)', 16.8%). (-)-Cytisine (0.8 and 1.0 mg/kg) displaced 70% and 72% of the radioactivity in the thalamus and 36% and 55% in the cerebellum, respectively, indicating that the latter was not appropriate as a receptor-poor region.
These results show the feasibility of quantifying alpha4beta2 nAChRs using [123I]5-I-A-85380 and support the use of V(T)' as an appropriate outcome measure.
Journal of Nuclear Medicine 10/2000; 41(9):1552-60. · 6.38 Impact Factor
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J K Staley,
G Tamagnan,
R M Baldwin,
M Fujita,
M S Al Tikriti,
L Eshima,
J Thornback,
D Roe,
L Lu, J P Seibyl,
R B Innis
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ABSTRACT: The suitability of an (123)I-labeled form of the putative D(4) receptor ligand L750,667 as a radiotracer for single photon emission computed tomography imaging was assessed in nonhuman primates. [(123)I]L750,667, labeled by iododestannylation, was administered to baboons in bolus and bolus plus constant infusion paradigms and imaged for 6 h. Total [(123)I]L750,667 brain uptake peaked (2.3% injected dose) at 15 min postinjection. [(123)I]L750,667 uptake was observed in all brain regions measured including diencephalon, brainstem, basal ganglia, cingulate cortex, and cerebellum, and slightly lower levels were noted in the frontal, parietal, temporoinsular, and occipital cortices. Administration of the D(4) receptor antagonist NGD 94-1 (2 mg/kg) did not displace radioactivity from any of the brain regions examined. Thus, while L750,667 is selective for the D(4) receptor in vitro, because brain [(123)I]L750,667 uptake was not displaced by NGD 94-1 at receptor saturating doses, [(123)I]L750,667 does not appear to be a suitable radiotracer for in vivo imaging of the D(4) receptor.
Nuclear Medicine and Biology 09/2000; 27(6):547-56. · 3.02 Impact Factor
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ABSTRACT: This study evaluated the test-retest reproducibility of D2 receptor quantification in the thalamus and temporal cortex using [123I]epidepride SPECT.
Ten healthy volunteers (4 men, 6 women; age range, 19-46 y) underwent 2 SPECT studies (interval, 2-26 d) using a bolus-plus-constant-infusion paradigm (bolus-to-infusion ratio = 6 h; infusion time = 9 h). Plasma clearance (in liters per hour) and free fraction (f1) of the parent tracer were measured. Radioactivity (in becquerels per gram) in the thalamus, temporal cortex, and cerebellum were normalized to the infusion rate (in becquerels per hour). Normalized striatal radioactivity was also measured to assess reproducibility in regions with a high density of receptors and better counting statistics. The outcome measures obtained were V3 (receptor density [Bmax]/equilibrium dissociation constant [KD]), V3' (f1 x Bmax/KD), and RT (specific-to-nondisplaceable tissue ratio).
Test-retest variability and reliability (intraclass correlation coefficient) were 10.8% and 0.88, respectively, for plasma clearance and 15.3% and 0.77, respectively, for f1. The test-retest variability of brain-specific (target minus nondisplaceable) radioactivity was higher in the thalamus and temporal cortex than in the striatum, although reliability was comparable. Among the outcome measures, V3' showed better test-retest variability and reliability in the thalamus (13.3% and 0.75, respectively) and temporal cortex (13.4% and 0.86, respectively).
Brain radioactivity was the main source of variability for quantification of extrastriatal D2 receptors with [123I]epidepride. The reproducibility of outcome measures in extrastriatal regions was good. However, because receptor density was lower in extrastriatal regions than in the striatum, the counting statistics in these regions were low and reproducibility was affected by the higher test-retest variability of brain-specific radioactivity. Compared with V3 and V3', RT showed less test-retest variability in the thalamus and temporal cortex but lower reliability. Moreover, measurement of RT may be affected by the presence of potential lipophilic metabolites entering the brain.
Journal of Nuclear Medicine 09/2000; 41(8):1343-51. · 6.38 Impact Factor
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ABSTRACT: Increased dopaminergic neurotransmission has been implicated in the pathophysiology of bipolar disorder. However, it remains unclear whether the abnormality is due to increased dopamine release or enhanced postsynaptic receptor sensitivity. In this study, dopamine receptor imaging combined with a pharmacological challenge of amphetamine was used to assess both pre- and postsynaptic aspects of dopamine neurotransmission in euthymic bipolar disorder patients.
Thirteen patients with bipolar disorder (seven medication free and six receiving mood stabilizer therapy) who had been euthymic for more than 4 weeks and 13 age- and gender-matched healthy comparison subjects were included in the study. Single photon emission computed tomography scans were obtained with the striatal dopamine (D(2)/D(3)) receptor radiotracer iodobenzamide ([(123)I]IBZM) before and after an intravenous amphetamine challenge (0.3 mg/kg). Reduction in striatal [(123)I]IBZM binding potential from the first scan to the second scan was used as an indirect measure of the amount of dopamine released. Behavioral response to amphetamine was measured with the Brief Psychiatric Rating Scale, Young Mania Rating Scale, and visual analogue scales.
Bipolar patients and healthy subjects did not differ in terms of mood state or striatal D(2) receptor binding at baseline. Amphetamine challenge led to a significantly greater behavioral response in bipolar patients than in healthy subjects. However, there was no significant difference between the two groups in the amphetamine-induced decrease in striatal [(123)I]IBZM binding.
In a group of euthymic patients with bipolar disorder, this study did not find evidence for increased striatal dopamine release. Instead, these data are consistent with enhanced postsynaptic dopamine responsivity in patients with bipolar disorder.
American Journal of Psychiatry 08/2000; 157(7):1108-14. · 12.54 Impact Factor
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ABSTRACT: Recent work has underscored the role of serotonergic neurotransmission in chronic neural adaptations to cocaine dependence. The authors tested for evidence of serotonergic dysfunction during acute abstinence from cocaine, a period of high risk for relapse in cocaine dependence.
Binding availability of dopamine transporters and serotonin transporters was measured in 15 cocaine-dependent subjects during acute abstinence and in 37 healthy comparison subjects by using [(123)I]beta-CIT and single photon emission computed tomography.
Significant increases in diencephalic and brainstem serotonin transporter binding (16.7% and 31.6%, respectively) were observed in cocaine-dependent subjects. Brainstem serotonin transporter binding was significantly inversely correlated with age across diagnostic groups.
These findings provide further evidence of serotonergic dysfunction during acute abstinence from chronic cocaine use. Age-related decline in brainstem serotonin transporter binding may underlie the poor response to selective serotonin reuptake inhibitor antidepressants seen in some elderly depressed patients.
American Journal of Psychiatry 08/2000; 157(7):1134-40. · 12.54 Impact Factor
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ABSTRACT: Increased regional cerebral blood flow (rCBF) at the epileptogenic site has been consistently reported for single photon emission computed tomography (SPECT) injections made during seizure activity, and the increased rCBF has been shown to remain elevated at the epileptogenic site in some cases, even when SPECT injections are made after seizure termination (postictal). A sustained increase in rCBF after seizure cessation was recently confirmed, but for no more than 100 s from seizure onset [Avery, R.A., Spencer, S.S., Spanaki, M.V., Corsi, M., Seibyl, J.P., Zubal, I.G., 1999. Effect of injection time on postictal SPET perfusion changes in medically refractory epilepsy. Eur. J. Nucl. Med. 26, 830-836]. In the current study, it is examined whether ictal SPECT injections demonstrate a similar change in rCBF around 100 s from seizure onset. Twenty-one patients with medically refractory epilepsy and a known area of seizure onset receiving ictal and interictal 99mTc-Hexamethyl-propyleneamineoxime (HMPAO) SPECT scans were studied. The results of SPECT subtraction analysis which visualize increased and decreased rCBF were compared to seizure duration and HMPAO injection time. Five patients received ictal SPECT injections (during ongoing seizure activity) more than 90 s after seizure onset and demonstrated decreased rCBF. Two of these patients also demonstrated areas of increased rCBF. Decreased rCBF was localized to the epileptogenic lobe in four of the five patients. By examining ictal SPECT injections made 90 s after seizure onset, evidence was found that reduced rCBF may exist during ictus. The change in rCBF around 90 s is also observed in postictal injections, suggesting a common metabolic mechanism may be responsible.
Epilepsy Research 07/2000; 40(1):53-61. · 2.29 Impact Factor
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ABSTRACT: The effect of endogenous dopamine on in vivo measurement of dopamine D(2) receptors in extrastriatal regions (thalamus and temporal cortex) was evaluated with single photon emission computed tomography and the high affinity ligand [123I]epidepride by comparing the binding potential before and after acute dopamine depletion. Dopamine depletion was achieved by per-oral administration of 5.5 g/70 kg body weight alpha-methyl-para-tyrosine given in 37 h. The alpha-methyl-para-tyrosine treatment increased the binding potential significantly in the temporal cortex (13+/-15%, P=0.036) but not in the thalamus (2+/-9%). The increase of the binding potential in the temporal cortex correlated strongly with the increase of dysphoric mood evaluated by the Positive and Negative Symptom Scale (PANSS) (rho=0.88, P=0.004). These results imply that [123I]epidepride, coupled with acute dopamine depletion might provide estimates of synaptic dopamine concentration.
European Journal of Pharmacology 02/2000; 387(2):179-88. · 2.52 Impact Factor
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ABSTRACT: Peri-ictal single-photon emission tomography (SPET) difference images co-registered to magnetic resonance imaging (MRI) visualize regional cerebral blood flow (rCBF) changes and help localize the epileptogenic area in medically refractory epilepsy. Few reports have examined the reproducibility of SPET difference image results. Epilepsy patients having two peri-ictal and at least one interictal SPET scan who later underwent surgical resection were studied. Localization accuracy of peri-ictal SPET difference images results, interictal electroencephalography (EEG), and ictal EEG from the first (seizure 1) and second (seizure 2) seizure, as well as MRI and positron emission tomography (PET) findings, were compared using surgical resection site as the standard. Thirteen patients underwent surgical resection (11 temporal lobe and 2 extratemporal). SPET results from seizure 1 were localized to the surgical site in 12/13 (92%) patients, while SPET results from seizure 2 were localized in 13/13 (100%) patients. All other modalities were less accurate than the SPET results interictal EEG--seizure 1 6/13 (46%); ictal EEG--seizure 1 5/13 (38%); interictal intracranial EEG--seizure 2 4/9 (44%); ictal intracranial EEG--seizure 2 results 8/9 (89%); MRI 6/13 (46%); PET 9/13 (69%)[. SPET results were reproducible in 12/13 (92%) patients. SPET difference images calculated from two independent peri-ictal scans appear to be reproducible and accurately localize the epileptogenic area. While SPET difference images visualize many areas of rCBF change, the quantification of these results along with consideration of injection time improves the diagnostic interpretation of the results.
European Journal of Nuclear Medicine 02/2000; 27(1):50-5.
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ABSTRACT: Previously we have shown that twelve weeks of repeated low-dose d-amphetamine (AMPH) exposure in rhesus monkeys induces a long-lasting enhancement of behavioral responses to acute low-dose challenge. The present study was designed to investigate the behavioral and neurochemical consequences of a six-week regimen of low-dose AMPH exposure (0.1-1.0 mg/kg, i.m., b.i.d.) in rhesus monkeys. SPECT imaging of AMPH's (0.4 mg/kg) ability to displace [123I]IBZM bound to D2 dopamine receptors in the striatum of saline control and AMPH-treated animals prior to and following chronic treatment was accomplished using a bolus/constant infusion paradigm. Following chronic AMPH treatment, all monkeys showed an enhanced behavioral response to acute AMPH challenge and a significant decrease in the percent of AMPH-induced displacement of [123I]IBZM in striatum compared to their pretreatment scans. These findings suggest that relatively small changes in presynaptic dopamine function may be reflected in significant alterations in the behavioral response to acute AMPH challenge.
Neuropsychopharmacology 02/2000; 22(1):4-13. · 7.99 Impact Factor
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M Fujita, J P Seibyl,
N P Verhoeff,
M Ichise,
R M Baldwin,
S S Zoghbi,
C Burger,
J K Staley,
N Rajeevan,
D S Charney,
R B Innis
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ABSTRACT: Quantitative SPECT measures of dopamine D(2) like receptors with [(123)I]epidepride is complicated by its high affinity and lipophilic metabolites. The purpose of this study was to use both parent (P) and lipophilic metabolites (M) as input functions in a kinetic paradigm and in comparison to the results of equilibrium studies. Kinetic studies on eleven healthy human subjects, ages 32+/- 10 were performed following i.v. injection of approximately 370 MBq of [(123)I]epidepride. Images were acquired for 13.5+/-1.0 hours. Equilibrium studies were done on seven of eleven subjects with a bolus injection of approximately 140 MBq, bolus/infusion ratio of 10 hours, and infusion for 30-32 hours. High (striatum) and low (temporal cortex) density regions were studied. Two (P and M) and one (P) input function models were applied in the kinetic studies. In receptor-rich regions, the distribution volumes in nondisplaceable compartments were fixed to those in cerebellum. In addition, in the two input function model, K(1)(P)/K(1)(M) was fixed to the values in the cerebellum. The one input function model provided V'(3) values (=f(1)*B'(max)/K(D)) which were consistent with those obtained in equilibrium studies in both receptor-rich regions, while the two input function model provided consistent values only in striatum. Poor identifiability of the rate constants of metabolites seemed to be the source of errors in the two input function model. These results suggest that correct V'(3) values can be obtained with the one input function model both in high- and low-density regions.
Synapse 01/2000; 34(4):290-304. · 2.94 Impact Factor
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ABSTRACT: To evaluate effects of vigabatrin (VGB) by using [123I]iomazenil single-photon emission computed tomography (SPECT) to estimate central gamma-aminobutyric acid (GABA(A))/benzodiazepine receptors (BZRs), and magnetic resonance spectroscopy (MRS) to assess tissue GABA levels.
Six patients with partial seizures had both SPECT and MRS before and 25-84 days after starting VGB (3 g p.o., q.d.). SPECT was acquired by using the constant-infusion method and, after nonuniform attenuation correction, coregistered with T1-weighted MR Imaging (MRI) A volume of interest (VOI) of 3 x 2 x 2 cc over the occipital cortex, used for MRS acquisition, was positioned on both MRI and coregistered SPECT. Occipital activity was divided by either total plasma activity or plasma [123I]iomazenil concentration to estimate BZR distribution volume (V(T)-p and V'(T), respectively). Wilcoxon's test was used for VOI differences in GABA levels, BZR V(T)-p or V'(T). SPM96 (either no global normalization or proportional scaling) was used to compare BZR V(T)-p changes in the patients with and without VGB with test-retest data in eight healthy age-matched controls.
Occipital GABA levels were increased threefold (without VGB, 1.1+/-0.1 micromol/g; with VGB, 2.9+/-0.5 micromol/g; p = 0.027). BZR distribution volumes showed no change, when estimated by either V(T)-p (without VGB, 6.00+/-0.91 ml/g; with VGB, 5.86+/-0.44 ml/g; p = 0.92) or V(T) (without VGB, 41.1+/-11.2 ml/g; with VGB, 41.2+/-9.9 ml/g; p = 0.75). No significant changes were detected by SPM96.
A clinically effective dose of VGB caused a threefold increase in tissue GABA levels but was not associated with a substantial BZR downregulation.
Epilepsia 11/1999; 40(10):1433-8. · 3.96 Impact Factor
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J P Seibyl
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ABSTRACT: The known dopaminergic abnormalities in Parkinson's disease have facilitated the development of radiolabeled biomarkers for diagnostic and research applications in humans. Presynaptic, intrasynaptic, and postsynaptic imaging now is possible using single-photon emission computed tomography. In particular, the development of new radiotracers that target the dopamine transporter located on degenerating dopamine neurons in Parkinson's disease and related disorders is directly relevant to improved clinical diagnosis, disease monitoring, and assessment of putative neuroprotective strategies in patients. In addition, the ability to characterize in vivo neuronal degeneration in these disorders provides a powerful research tool to better understand the natural course of these disorders and could provide clues to etiology.
Journal of Neuroimaging 11/1999; 9(4):223-8. · 1.51 Impact Factor
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N P Verhoeff,
J C Soares,
C D D'Souza,
R Gil,
K Degen,
A Abi-Dargham,
S S Zoghbi,
M Fujita,
N Rajeevan, J P Seibyl,
J H Krystal,
C H van Dyck,
D S Charney,
R B Innis
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ABSTRACT: Deficient inhibitory neurotransmission of gamma-aminobutyric acid (GABA) has been implicated in the pathophysiology of schizophrenia based on postmortem studies. However, in vivo studies have shown predominantly negative or conflicting results. The goal of this study was to better characterize possible changes of the regional GABA(A)-benzodiazepine receptor distribution volume (BZR V3-p) in schizophrenia in vivo, using a larger sample size than previous studies. Single photon emission computed tomography (SPECT) with [123I]iomazenil was used with a constant infusion paradigm to measure the BZR V3-p under sustained radiotracer equilibrium conditions. Twenty-five patients with schizophrenia and 24 matched healthy control subjects were studied. Positive and Negative Syndrome Scale (PANSS) ratings were done in all subjects. Statistical parametric mapping (SPM) 96 was used to compare patients and control subjects as well as to study the relationship between SPECT results and composite PANSS scores based on two factorial models: the pentagonal model (positive, negative, dysphoric mood, activation, and autistic preoccupation factors) and the taxometric model (disorganized dimension). On the basis of 'absolute' values of V3-p with no normalization for total brain uptake, the schizophrenic patients showed no significant differences in BZR levels compared to the healthy control subjects. With a global normalization procedure, which is more sensitive to relative regional differences in activity, BZR V3-p was significantly decreased in the patients in the left precentral gyrus (BA 6). The relative BZR V3-p showed a significant positive correlation with duration of illness in the superior occipital gyri (BA 19). No significant correlations were observed between either absolute or relative BZR V3-p and either age or any of the composite PANSS scores based on any of the two factorial models in either patients or control subjects. No significant differences were observed between cigarette smoking vs. non-smoking patients, nor between the patients on atypical antipsychotics vs. on typical antipsychotics vs. not on any antipsychotics. In general, no significant differences in BZR V3-p were observed between patients and control subjects, except for a decrease in relative BZR V3-p in the left precentral gyrus. Grey matter atrophy is unlikely to be the cause for this decrease. However, we could not exclude that possibility. The positive correlation with duration of illness might reflect the relative preservation of neurons expressing BZR in the superior occipital gyri as compared to other cortical brain regions in schizophrenia.
Psychiatry Research 11/1999; 91(3):163-73. · 2.52 Impact Factor
