Dopamine D2 receptor binding before and after treatment of major depression measured by [123I]IBZM SPECT

Fifteen patients fulfilling DSM-IV criteria for major depression were investigated with the specific dopamine D₂ receptor antagonist [¹²³I]iodobenzamide (IBZM). Two single photon emission computed tomography (SPECT) examinations were performed before and after 6 weeks of treatment with a selective serotonin re-uptake inhibitor (SSRI). Striatal D₂ receptor binding was calculated and normalized to the cerebellum. In a non-psychiatric control group (n=17), which was investigated once with [¹²³I]IBZM and SPECT, striatal IBZM binding decreased significantly with age (0.092 per decade). The age-dependent correlation was lower in subjects with major depression and did not reach statistical significance. There was no significant difference in mean IBZM binding between depressives and control subjects. Age-corrected baseline IBZM binding in the striatum was significantly lower in treatment responders than in depressed non-responders and control subjects. Furthermore, in the depressive group there was a significant linear correlation between treatment response and change of D₂ receptor binding during treatment in the basal ganglia. IBZM binding increased in treatment responders and decreased in non-responders. In accordance with animal studies, the results suggest an association between changes in the dopaminergic system and treatment response in major depression.     

Striatal dopamine transporter in different disability stages of Parkinson's disease studied with [(123)I]beta-CIT SPECT

Six healthy controls and eighteen patients with Parkinson's disease in different disability stages were studied with SPECT using [(123)I]beta-CIT to label the striatal dopamine transporter. The mean uptake of [(123)I]beta-CIT in the putamen was reduced to 54% of the control mean and to 65% of the average control value in the caudate nucleus. In patients with totally, or predominantly unilateral symptoms the reduction was greater on the side opposite to the predominant symptoms (to 56% of the control mean in the contralateral putamen and to 77% in the ipsilateral putamen). There was a significant negative correlation between [(123)I]beta-CIT uptake in the putamen and the Hoehn and Yahr stage (r = -0.81, p < 0.0001). An analysis of covariance was performed using age and disease duration as covarianes, and the correlation between putaminal [(123)I]beta-CIT uptake and parkinsonian disability according to the Hoehn and Yahr stage remained significant (r = -0.75, p = 0.02). A similar correlation was seen in the caudate nucleus (r = -0.79, p < 0.0001) between the uptake of [(123)I]beta-CIT and the Hoehn and Yahr stage. The correlation also remained significant after correction for the duration of disease and age of the patients (r= -0.76, p = 0.02). The present results show that [1231],Q-CIT SPECT is a useful method to study the function of presynaptic dopaminergic terminals in PD, and might be used in the early diagnosis and follow-up of the disease.     

Benzodiazepine receptor quantification in Huntington's disease with [(123)I]omazenil and SPECT

OBJECTIVES: Increasing evidence suggests that metabolic changes predate neuronal death in Huntington's disease and emission tomography methods (PET and SPECT) have shown changes in glucose consumption and receptor function in early and possibly even presymptomatic disease. Because the GABA(A)-benzodiazepine receptor complex (BZR) is expressed on virtually all cerebral neurons BZR density images may be used to detect neuronal death. In this study the regional cerebral [(123)I]iomazenil binding to BZR was determined in patients with Huntington's disease and normal controls by a steady state method and SPECT. METHODS: Seven patients mildly to moderately affected by Huntington's disease and seven age matched controls were studied. Brain CT was performed on all subjects. In each subject two [(123)I]iomazenil-SPECT measurements were acquired-one with and one without infusion of flumazenil. The affinity constant of flumazenil (Kd) was calculated from the paired distribution volumes (DV) and the free plasma flumazenil concentration. The distribution volume of [(123)I]iomazenil in the unblocked condition (DV(0)) reflects the ratio between BZR density and Kd. RESULTS: Flumazenil Kd was similar in the Huntington's disease group and the control group (11.3 v 11.2 mM). For the Huntington's disease group a 31% reduction in striatal DV(0) (p=0.03) was found. In the cortical regions, DV(0) was similar in patients and in controls. In Huntington's disease, DV(0) correlated significantly with functional capacity (p=0.04) and chorea symptoms (p=0.02). The clinically least affected patients displayed DV(0)s within the range of those of the control group (19-35 ml/ml). CONCLUSIONS: The finding of an unchanged Kd of flumazenil in patients indicates that the BZR is functionally intact in Huntington's disease. That is, the reduction in DV(0) for BZR represents a selective decrease in the number of striatal BZRs. DV(0) significantly correlated with functional loss and [(123)I]iomazenil-SPECT could be an important tool for validation of the effect of future therapeutic strategies aimed at limiting oxidative stress and free radicals in Huntington's disease.     

Striatal [123I] FP-CIT SPECT demonstrates dopaminergic deficit in a sporadic case of Creutzfeldt-Jakob disease

Background – The frequent occurrence of movement disorders such as myoclonus, parkinsonism and dystonia, strongly suggests an involvement of the dopaminergic system in sporadic Creutzfeldt‐Jakob disease (sCJD), but this issue has not been specifically addressed yet. Methods – We report a patient who after a sub‐acute focal clinical onset, developed the full clinical picture of probable sCJD. Given the early unilateral right extrapyramidal rigidity, the patient was assessed by single‐photon emission computed tomography of the dopamine transporter (DAT) using [123I] FP‐CIT. Results – DAT‐scan demonstrated reduced values of presynaptic receptorial trace in the putamen, particularly on the left side, consistent with functional putaminal dopaminergic presynaptic alteration. Conclusions – The present observation emphasizes the possible role of DAT imaging studies in the investigation of the pathogenesis of movement disorders in CJD.     

SPECT tracer [(123)I]IBZM has similar affinity to dopamine D2 and D3 receptors

Emission tomography investigations of the pathophysiological involvement of the cerebral dopaminergic transmitter system in the living human brain relies heavily on a careful selection of the most suitable radioligand. In recent years, many clinical studies have employed [(123)I]IBZM in SPECT studies. The aim of the present study was to characterize the binding of IBZM to dopaminergic receptor subtypes as a means of elucidating which receptor subtypes are visualized and examined by [(123)I]IBZM. The affinity of IBZM for each of the major human dopamine receptors (D1, D2(short), D3, D4(4. 2), and D5 receptor) was determined by competitive radioligand binding assay using membranes prepared from clonal cell lines expressing the different subtypes. Radioligands with high affinity for the D1(A) and D5 receptors ([(3)H]SCH-23390), dopamine D2(short) and D4(4.2) receptors ([(3)H]Spiroperidol), and dopamine D3 receptor ([(3)H]7-OH-DPAT) were used to measure specific binding. Corresponding unlabeled displacing ligands for determination of nonspecific binding were employed. Assays were performed at 25 degrees C. These experiments show that for IBZM K(i) values were 1.6 nM for dopamine D2(s) receptors and 2.2 nM for dopamine D3 receptors. There was no binding of IBZM to D1(A), D5, or D4(4.2) receptors. In conclusion, when [(123)I]IBZM is used as SPECT tracer, the studies reflect dopaminergic D2 as well as D3 receptor binding.     

Dopamine D(2) receptor quantification in extrastriatal brain regions using [(123)I]epidepride with bolus/infusion

The iodinated benzamide epidepride, which shows a picomolar affinity binding to dopamine D(2) receptors, has been designed for in vivo studies using SPECT. The aim of the present study was to apply a steady-state condition by the bolus/infusion approach with [(123)I]epidepride for the quantification of striatal and extrastriatal dopamine D(2) receptors in humans. In this way the distribution volume of the tracer can be determined from a single SPECT image and one blood sample. Based on bolus experiments, an algorithm using conventional convolution arguments for prediction of the outcome of a bolus/infusion (B/I) experiment was applied. It was predicted that a B/I protocol with infusion of one-third of the initial bolus per hour would be appropriate. Steady-state conditions were attained in extrastriatal regions within 3-4 h but the infusion continued up to 7 h in order to minimize the significance of individual differences in plasma clearance and binding parameters. A steady-state condition, however, could not be attained in striatal brain regions using a B/I protocol of 20 h, even after 11 h. Under near steady-state conditions a striatal:cerebellar ratio of 23 was demonstrated. Epidepride has a unique signal-to-noise ratio compared to [(123)I]IBZM but present difficulties for steady-state measurements of striatal regions. The bolus/infusion approach is particularly feasible for quantification of the binding potential in extrastriatal regions.     

Cerebral benzodiazepine receptors in depressed patients measured with [123I]iomazenil SPECT.

BACKGROUND: A recent magnetic resonance spectroscopy (MRS) study revealed low gamma-aminobutyric acid (GABA) levels in the occipital cortex of depressed patients. No in vivo study has been reported to measure postsynaptic GABA receptors in the patients. METHODS: Cortical benzodiazepine (BZ) binding to GABA(A) receptors was measured with [(123)I]iomazenil and single photon emission computed tomography in unmedicated patients with unipolar major depression (n = 13) and healthy subjects (n = 19). Group differences were evaluated by means of statistical parametric mapping (SPM) with partial volume correction for gray matter. Occipital GABA levels were determined by proton MRS in a subgroup (n = 6) of the patients. RESULTS: No evidence of altered BZ binding was found in patients with depression compared with healthy control subjects in the SPM analysis. Although reduction in gray matter volume was observed in the frontal cortex and amygdala of the patients, partial volume correction of the atrophy did not change the result of unaltered BZ binding. GABA levels were found lower in the occipital cortex; however, BZ binding did not show significant relationship to GABA levels. CONCLUSIONS: GABA(A) receptor binding measured in vivo with BZ radioligand binding are not altered in patients with depression.     

Striatal amphetamine-induced dopamine release in patients with schizotypal personality disorder studied with single photon emission computed tomography and [123I]iodobenzamide.

BACKGROUND: Previous imaging studies demonstrated that schizophrenia is associated with increased amphetamine-induced dopamine (DA) release in the striatum, most pronounced during episodes of illness exacerbation. Schizotypal personality disorder (SPD) is a schizophrenia spectrum disorder, genetically related to schizophrenia. The goal of this study was to investigate striatal DA function in patients with SPD. METHODS: In our study, 13 SPD patients and 13 matched healthy control subjects underwent single photon emission computed tomography (SPECT) scan during bolus plus constant infusion of the D2/3 radiotracer [123I]iodobenzamide (IBZM). Striatal specific to nonspecific equilibrium partition coefficient (V(3)") was measured at baseline and following amphetamine administration (.3 mg/kg). RESULTS: No significant differences were observed in baseline V(3)" between groups. Amphetamine induced a larger decrease in [123I]IBZM V(3)" in SPD patients (-12 +/- 5%) compared with control subjects (-7 +/- 5%, p =.03). CONCLUSIONS: The reduction in [123I]IBZM V(3)" induced by amphetamine in SPD was similar to that observed in remitted schizophrenia patients (-10 +/- 9%, n = 17), but significantly lower than that observed during illness exacerbation (-24 +/- 13%, n = 17). This suggests that DA dysregulation in schizophrenia spectrum disorders might have a trait component, present in remitted patients with schizophrenia and in SPD, and a state component, associated with psychotic exacerbations but not SPD.     

(123)I]beta-CIT SPECT is a useful method for monitoring dopaminergic degeneration in early stage Parkinson's disease

OBJECTIVES: To examine the validity of [(123)I]beta-CIT SPECT for monitoring the progression of dopaminergic degeneration in Parkinson's disease; to investigate the influence of short term treatment with D(2)receptor agonists on striatal [(123)I]beta-CIT binding; and to determine the sample size and frequency of SPECT imaging required to demonstrate a significant effect of a putative neuroprotective agent. METHODS: A group of 50 early stage Parkinson's disease patients was examined. Two SPECT imaging series were obtained, 12 months apart. The mean annual change in the ratio of specific to non-specific [(123)I]beta-CIT binding to the striatum, putamen, and caudate nucleus was used as the outcome measure. RESULTS: A decrease in [(123)I]beta-CIT binding ratios between the two images was found in all regions of interest. The average decrease in [(123)I]beta-CIT binding ratios was about 8% in the whole striatum, 8% in the putaminal region, and 4% in the caudate region. Comparison of scans done in nine patients under two different conditions-in the off state and while on drug treatment-showed no significant alterations in the expression of striatal dopamine transporters as measured using [(123)I]beta-CIT SPECT. Power analysis indicated that to detect a significant (p < 0.05) effect of a neuroprotective agent with 0.80 power and 30% of predicted protection within two years, 216 patients are required in each group when the effects are measured in the whole putamen. CONCLUSIONS: [(123)I]beta-CIT SPECT seems to be a useful tool to investigate the progression of dopaminergic degeneration in Parkinson's disease and may provide an objective method of measuring the effectiveness of neuroprotective treatments. Short term treatment with a D(2)agonist does not have a significant influence on [(123)I]beta-CIT binding to dopamine transporters. If the latter finding is replicated in larger groups of patients, it supports the suitability of [(123)I]beta-CIT SPECT for examining the progression of neurodegeneration in patients being treated with D(2)receptor agonists.     

Iodolisuride and iodobenzamide,two ligands for SPECT exploration of the dopaminergic D2 receptors: A comparative study

Iodobenzamide (IBZM) and iodolisuride (ILIS), which belong to different chemical families, are two radioligands used for SPECT imaging of dopamine D2 receptors. We have compared their cerebral biodistribution in control rats and their ability to detect quantitative modifications of D2 receptors in experimental models. IBZM and ILIS have a similar cerebral distribution in vivo in control rats and permitted the detection of upregulation of striatal dopamine D2 receptors in a model of chronic haloperidol treatment. Moreover, we observed that 1 h after injection of a saturating dose of haloperidol, IBZM uptake was 72% displaced from the striatum, while ILIS uptake was 50% displaced. In an experimental model of excitotoxic striatal lesion, the in vivo accumulation of IBZM was 30% decreased on the lesioned side, in agreement with a decrease in dopamine D2 receptor density. By contrast, the accumulation of ILIS was identical in the lesioned and in the intact striatum. From the results, it appears that IBZM and ILIS, which are both used to image dopamine D2 receptors in vivo, behave differently in pathological experimental models. The ligand for human exploration should then be chosen according to the suspected pathology. © 1996 Wiley-Liss, Inc.     

SPECT imaging of the dopamine transporter with [(123)I]-beta-CIT reveals marked decline of nigrostriatal dopaminergic function in Parkinson's disease with urinary dysfunction.

We studied a correlation of urinary dysfunction with nigrostriatal dopaminergic deficit in Parkinson's disease (PD) by single-photon emission computed tomography (SPECT) imaging of dopamine transporter with [123I]-2beta-carbomethoxy-3beta-(4-iodophenyl)tropane (beta-CIT). Eleven patients were enrolled in the study, including four men and seven women, with a mean age of 64 years. Seven patients had urinary symptoms 1-5 years after the onset of motor disorder, which included nighttime frequency in six, urinary retardation in four, daytime frequency in one and urge urinary incontinence in one. Using a SPECT camera, the ratio specific to nondisplaceable [123I]-beta-CIT uptake, designated as "striatal V3" was obtained in the caudate, anterior and posterior putamen 24 h after the tracer injection. The striatal V3 was compared in patients with and without urinary dysfunction, and between men and women, using unpaired Student's t-test. Correlation of motor dysfunction and duration of illness with urinary dysfunction, was also analyzed. In the patients, there was a reduction of [123I]-beta-CIT binding in the striatum on both sides, particularly in the putamen contralateral to the affected body side. The striatal V3 of the caudate (p<0.01, Rt; p<0.05, Lt), anterior putamen (p<0.05, Rt) and posterior putamen (p<0.05, Rt) in patients with urinary dysfunction was significantly reduced than those without urinary dysfunction. No sex difference was seen in reduction of [123I]-beta-CIT binding. Urinary dysfunction in PD was more common in patients with higher Unified Parkinson's Disease Rating Scale (UPDRS) score, higher Hoehn-Yahr grade, but not in those with longer duration of disease, although there was no statistical significance. It is likely that our results reflect the association of urinary dysfunction and degeneration of the nigrostriatal dopaminergic cells in PD.     

99mTc]TRODAT-1/[123I]IBZM SPECT studies of the dopaminergic system in Tourette syndrome

The good clinical effectiveness of dopamine depleter and receptor antagonists on tics suggests dopaminergic hyperactivity in Tourette syndrome (TS). In this case-control study of 10 TS patients and 15 age-matched healthy controls, we evaluated (i) presynaptic and postsynaptic striatal dopaminergic function using [(99m)Tc]TRODAT-1/[(123)I]IBZM single photon emission computed tomography (SPECT) and (ii) correlations between dopamine transporter (DAT)/D2 receptor binding sites and tic severity scores. Patients 1-5 were pretreated with haloperidol and were drug free for at least 3 months before SPECT imaging. Patients 6-10 were drug-na?ve. We found no significant difference in DAT and D2 receptor binding sites between TS patients and healthy controls nor any association between striatal DAT or D2 receptor binding sites and tic severity assessed using the Modified Rush Videotape Rating Scale. Our findings provided no direct evidence of abnormally available striatal DAT or dopamine D2 receptors in TS. However, functional abnormalities of the dopaminergic system, e.g., alterations in the synaptic release of endogenous dopamine, cannot be completely ruled out.     

Striatal Dopamine transporter in Parkinson's disease: A Study With a New Radioligand, [(123)I]B-CIT-FP

Six healthy controls and 12 patients with Parkinson's disease in different disability stages were studied with SPECT using [(123)I]-N-(3-fluoropropyl)-2beta-carbomethoxy-3beta-(4-iodo-phenyl)-nortropane ([(123)I]beta-CIT-FP), a novel tracer, to label the striatal dopamine transporter. The mean uptake of [(123)I]beta-CIT-FP in the putamen was reduced to 60% of the control mean and to 80% of the average control value in the caudate nucleus. In patients with totally, or predominantly unilateral symptoms the reduction was greater on the side opposite to the predominant symptoms. There was a significant negative correlation between [(123)I]beta-CIT-FP uptake and the Hoehn and Yahr stage both in the putamen (r = - 0.70, p = 0.01) and caudate nucleus (r = - 0.81, p = 0.001). The present results show that SPECT with [(123)I]beta-CIT-FP is a useful method to study the function of presynaptic dopaminergic terminals in PD. Whether [(123)I]beta-CIT-FP provides advantages over widely used [(123)I]beta-CIT other than a shorter scan time and a lower striatal radiation exposure remains to be seen.     

Striatal dopaminergic D2 receptor occupancy and clinical efficacy in psychosis exacerbation: a 123I-IBZM study with ziprasidone and haloperidol

OBJECTIVE: The aim of this study was to compare striatal dopaminergic D2 receptor occupancy (D2 RO) induced by ziprasidone and haloperidol and its relationship with clinical response and extrapyramidal side effects (EPS) in patients with acute psychosis exacerbation. METHOD: Twenty patients hospitalized with an acute psychosis exacerbation were randomised in a single-blind study to receive either ziprasidone (80-120 mg/day) or haloperidol (5-20 mg/day) for more than 2 weeks. When stable doses were achieved, data on 123I-IBZM single-photon emission computed tomography (SPECT), as well as data on clinical efficacy (positive and negative symptoms scale [PANSS]) and EPS (Simpson Angus scale [SAS]), were compared between the two groups of patients. Clinical response was defined as a percentage of change of >30% in PANSS. Striatal D2 RO and clinical data were also compared between responders and nonresponders on each treatment group. RESULTS: All patients on haloperidol and four patients on ziprasidone showed EPS. Mean D2 RO was significantly higher in the haloperidol (74.7+/-3.5) than in the ziprasidone (60.2+/-14.4) group (Mann Whitney U-test [M-W U-test] 8.50; p=0.002). Five patients were responders, and five were nonresponders on each group of treatment. Haloperidol responders and nonresponders did not differ in D2 RO, duration of treatment, doses or EPS. Ziprasidone responders were on higher doses than nonresponders and showed higher D2 RO although below 74%. A positive correlation of ziprasidone D2 RO was found with dose (r Spearman 0.87; p=0.001) and with SAS scores (r Spearman 0.88; p=0.001). CONCLUSIONS: Ziprasidone induces lower D2 RO and EPS than haloperidol, which is consistent with an atypical antipsychotic profile. A direct relationship of ziprasidone D2 RO with dose, clinical efficacy and EPS has been found in this study. These data suggest that high ziprasidone doses might be more beneficial in patients with psychosis exacerbation and claim for caution regarding EPS appearance with such high dosages.     

Dopamine transporter density in the basal ganglia in obsessive-compulsive disorder, measured with [123I]IPT SPECT before and after treatment with serotonin reuptake inhibitors

It has been suggested that dopamine as well as serotonin are associated with the pathophysiology of obsessive-compulsive disorder (OCD). 5-Hydroxytryptophan inhibits dopamine release in healthy persons as well as in patients with OCD, and serotonin tonic inhibition affects dopamine function in basal ganglia, indicating a close relationship between serotonin and the dopamine system. Using iodine-123-labeled N-(3-iodopropen-2-yl)-2 beta-carbomethoxy-3beta-(4-chlorophenyl) tropane ([(123)I]IPT) single photon emission computed tomography (SPECT), we investigated the dopamine transporter (DAT) density in the basal ganglia of patients with OCD. The test consists of two measurements before and after treatment with serotonin reuptake inhibitors (SRIs). Ten patients with OCD before and after treatment with SRIs were included. We performed brain SPECT 2 h after intravenous administration of [(123)I]IPT using a dual-head SPECT camera (Vertex, ADAC, Calif., USA) and analyzed the SPECT data, reconstructed for the assessment of the specific/nonspecific DAT binding ratio in the basal ganglia. We then examined the correlation between the scores of OCD symptom changes, assessed with the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), and DAT binding ratio. Patients with OCD after treatment with SRIs showed a significantly decreased DAT binding ratio in the right basal ganglia compared with baseline. A significant correlation was found between the total scores and compulsion score changes of the Y-BOCS and the changes of the DAT binding ratio of the right basal ganglia. These findings suggest that the dopaminergic neurotransmitter system of the basal ganglia could play an important role in the symptom improvement of OCD patients.     

A case of Cotard syndrome: (123)I-IBZM SPECT imaging of striatal D(2) receptor binding

A case of 'dèlire de nègation' that suddenly appeared in a 43-year-old male is presented. No alteration in regional cerebral blood, as measured by (99m)Tc-HMPAO-SPECT, was found, but (123)I-IBZM-SPECT analysis showed reduced striatal D(2) receptor binding that further decreased after treatment.