No significant effects of single intravenous,single oral and subchronic oral administration of acetylcholinesterase inhibitors on striatal [<Superscript>123</Superscript>I]FP-CIT binding in rats

Purpose [¹²³I]FP-CIT SPECT is a valuable diagnostic tool to discriminate Lewy body dementia from Alzheimer’s dementia. To date, however, it is uncertain whether the frequently used acetylcholinesterase inhibitors (AChEIs) by demented patients, have an effect on [¹²³I]FP-CIT binding to dopamine transporters (DATs). Earlier animal studies showed a decline of DAT availability after acute intravenous injection of AChEIs. The aim of this study was to investigate effects of single intravenous, single oral and subchronic oral administration of AChEIs on DAT availability in the rat brain as measured by [¹²³I]FP-CIT. Methods Biodistribution studies were performed in Wistar rats (n = 5–16 per group). Before [¹²³I]FP-CIT injection, rats were injected intravenously with a single dose of the AChEI rivastigmine (2.5 mg/kg body weight) or donepezil (0.5 mg/kg), the DAT-blocker methylphenidate (10 mg/kg) or saline. A second group was orally treated with a single dose of rivastigmine or donepezil (2.5 mg/kg), methylphenidate (10 mg/kg) or saline before injection of [¹²³I]FP-CIT. Studies were also performed in rats that were orally treated during 14 consecutive days with either rivastigmine (1 mg/kg daily), donepezil (1.5 mg/kg daily), methylphenidate (2.5 mg/kg) or saline. Brain parts were assayed in a gamma counter, and specific striatum/cerebellum ratios were calculated for the [¹²³I]FP-CIT binding to DATs. Results No significant effects of either single intravenous, single oral or subchronic oral administration of AChEIs on striatal FP-CIT binding could be detected. Single pretreatment with methylphenidate resulted in an expected significantly lower striatal FP-CIT binding. Conclusion We conclude that in rats, single intravenous and single or subchronic oral administration of the tested AChEIs does not lead to an important alteration of [¹²³I]FP-CIT binding to striatal DATs. Therefore, it is unlikely that these drugs will induce large effects on the interpretation of [¹²³I]FP-CIT SPECT scans in routine clinical studies.     

[<Superscript>123</Superscript>]FP-CIT SPECT scans initially rated as normal became abnormal over time in patients with probable dementia with Lewy bodies

Purpose

Decreased striatal dopamine transporter (DAT) binding on SPECT imaging is a strong biomarker for the diagnosis of dementia with Lewy bodies (DLB). There is still a lot of uncertainty about patients meeting the clinical criteria for probable DLB who have a normal DAT SPECT scan (DLB/S?). The aim of this study was to describe the clinical and imaging follow-up in these patients, and compare them to DLB patients with abnormal baseline scans (DLB/S+).

Methods

DLB patients who underwent DAT imaging ([¹²³I]FP-CIT SPECT) were selected from the Amsterdam Dementia Cohort. All [¹²³I]FP-CIT SPECT scans were evaluated independently by two nuclear medicine physicians and in patients with normal scans follow-up imaging was obtained. We matched DLB/S-? patients for age and disease duration to DLB/S+ patients and compared their clinical characteristics.

Results

Of 67 [¹²³I]FP-CIT SPECT scans, 7 (10.4?%) were rated as normal. In five DLB/S? patients, a second [¹²³I]FP-CIT SPECT was performed (after on average 1.5 years) and these scans were all abnormal. No significant differences in clinical characteristics were found at baseline. DLB/S? patients could be expected to have a better MMSE score after 1 year.

Conclusion

This study was the first to investigate DLB patients with the initial [¹²³I]FP-CIT SPECT scan rated as normal and subsequent scans during disease progression rated as abnormal. We hypothesize that DLB/S? scans could represent a relatively rare DLB subtype with possibly a different severity or spread of alpha-synuclein pathology (“neocortical predominant subtype”). In clinical practice, if an alternative diagnosis is not imminent in a DLB/S? patient, repeating [¹²³I]FP-CIT SPECT should be considered.

     

Diagnostic value of asymmetric striatal D<Subscript>2</Subscript> receptor upregulation in Parkinson’s disease: an [<Superscript>123</Superscript>I]IBZM and [<Superscript>123</Superscript>I]FP-CIT SPECT study

Introduction Striatal postsynaptic D₂ receptors in Parkinson’s disease (PD) are thought to be upregulated in the first years of the disease, especially contralateral to the clinically most affected side. The aim of this study was to evaluate whether the highest striatal D₂ binding is found contralateral to the most affected side in PD, and whether this upregulation can be used as a diagnostic tool. Methods Cross-sectional survey was undertaken of 81 patients with clinically asymmetric PD, without antiparkinsonian drugs and with a disease duration of ≤5 years and 26 age-matched controls. Striatal D₂ binding was assessed with [¹²³I]IBZM SPECT, and severity of the presynaptic dopaminergic lesion with [¹²³I]FP-CIT SPECT. Results The mean striato-occipital ratio of [¹²³I]IBZM binding was significantly higher in PD patients (1.56 ±0.09) than in controls (1.53 ±0.06). In PD patients, higher values were found contralateral to the clinically most affected side (1.57 ±0.09 vs 1.55 ±0.10 ipsilaterally), suggesting D₂ receptor upregulation, and the reverse was seen using [¹²³I]FP-CIT SPECT. However, on an individual basis only 56% of PD patients showed this upregulation. Conclusion Our study confirms asymmetric D₂ receptor upregulation in PD. However, the sensitivity of contralateral higher striatal [¹²³I]IBZM binding is only 56%. Therefore, the presence of contralateral higher striatal IBZM binding has insufficient diagnostic accuracy for PD, and PD cannot be excluded in patients with parkinsonism and no contralateral upregulation of D₂ receptors, assessed with [¹²³I]IBZM SPECT.     

European multicentre database of healthy controls for [123I]FP-CIT SPECT (ENC-DAT): age-related effects, gender differences and evaluation of different methods of analysis

Purpose

Dopamine transporter (DAT) imaging with [¹²³I]FP-CIT (DaTSCAN) is an established diagnostic tool in parkinsonism and dementia. Although qualitative assessment criteria are available, DAT quantification is important for research and for completion of a diagnostic evaluation. One critical aspect of quantification is the availability of normative data, considering possible age and gender effects on DAT availability. The aim of the European Normal Control Database of DaTSCAN (ENC-DAT) study was to generate a large database of [¹²³I]FP-CIT SPECT scans in healthy controls.

Methods

SPECT data from 139 healthy controls (74 men, 65 women; age range 20?–?83 years, mean 53 years) acquired in 13 different centres were included. Images were reconstructed using the ordered-subset expectation-maximization algorithm without correction (NOACSC), with attenuation correction (AC), and with both attenuation and scatter correction using the triple-energy window method (ACSC). Region-of-interest analysis was performed using the BRASS software (caudate and putamen), and the Southampton method (striatum). The outcome measure was the specific binding ratio (SBR).

Results

A significant effect of age on SBR was found for all data. Gender had a significant effect on SBR in the caudate and putamen for the NOACSC and AC data, and only in the left caudate for the ACSC data (BRASS method). Significant effects of age and gender on striatal SBR were observed for all data analysed with the Southampton method. Overall, there was a significant age-related decline in SBR of between 4 % and 6.7 % per decade.

Conclusion

This study provides a large database of [¹²³I]FP-CIT SPECT scans in healthy controls across a wide age range and with balanced gender representation. Higher DAT availability was found in women than in men. An average age-related decline in DAT availability of 5.5 % per decade was found for both genders, in agreement with previous reports. The data collected in this study may serve as a reference database for nuclear medicine centres and for clinical trials using [¹²³I]FP-CIT SPECT as the imaging marker.     

Does combined imaging of the pre- and postsynaptic dopaminergic system increase the diagnostic accuracy in the differential diagnosis of parkinsonism?

Purpose We hypothesized that combining pre- and postsynaptic quantitative information about the dopaminergic system would provide a higher diagnostic accuracy in the differential diagnosis of parkinsonism than specific striatal D₂ receptor binding alone. Therefore, the aim of the study was to introduce new semi-quantitative parameters and evaluate their ability to discriminate between Parkinson’s disease (IPS) and non-idiopathic parkinsonian syndromes (non-IPS). Methods In 100 patients (69 IPS, 31 non-IPS), postsynaptic [¹²³I]IBZM and presynaptic [¹²³I]FP-CIT SPECT scans were evaluated by observer-independent techniques. The diagnostic performances of striatal dopamine transporter (DAT) and D₂ receptor binding, their respective asymmetries, and a combination of pre- and postsynaptic asymmetry were evaluated with ROC analyses. A logistic regression model was generated combining factors to calculate the probability for each patient of belonging to either diagnostic group. Results D₂ receptor binding provided a sensitivity of 87.1% and a specificity of 72.5% with an area under the curve (AUC) of 0.866. The AUCs of other single parameters were lower than that of D₂ binding. A gain of diagnostic power (p = 0.026) was reached with a model combining pre- and postsynaptic asymmetries and D₂ binding (sensitivity 90.3%, specificity 73.9%, AUC 0.893). Conclusion The combination of quantitative parameters of presynaptic DAT and postsynaptic D₂ receptor binding demonstrates superior diagnostic power in the differentiation of patients with IPS and non-IPS than the established approach based on D₂ binding alone. Striatal D₂ receptor binding and the combination of DAT and IBZM binding asymmetries are the factors contributing most in separating these diagnostic groups.     

Dopamine transporter imaging and the effects of deep brain stimulation in patients with Parkinson’s disease

Purpose Single-photon emission computed tomography (SPECT) with [¹²³I]FP-CIT is a marker for loss of presynaptic dopamine transporters in the striatum in Parkinson’s disease (PD). We used [¹²³I]FP-CIT SPECT in order to evaluate binding to the dopamine transporter before and after neurosurgical treatment with bilateral stimulation in the subthalamic nucleus (STN). Methods Thirty-five patients with levodopa-responsive PD were examined with [¹²³I]FP-CIT SPECT pre-operatively (baseline scan: mean 3 months before surgery), and 3 and 12 months after surgery. Results Pre-operatively, all patients already had substantial signs of severe nigrostriatal neuronal loss as determined from the [¹²³I]FP-CIT SPECT scans. One year after surgery the specific [¹²³I]FP-CIT binding to the striatum was significantly reduced by 10.3% compared with the pre-operative baseline scan. The mean time span from the baseline scan before surgery to the follow-up scan 1 year after surgery was 16.2 months. Hence, the rate of reduction equals a mean annual reduction of 7.7%. A comparable control group of patients with PD who did not undergo surgery was also examined longitudinally. In this group the specific binding of [¹²³I]FP-CIT was reduced by 6.7% per year. Conclusion The specific binding of [¹²³I]FP-CIT was reduced equally in the STN-stimulated patients and a group of non-operated PD patients with advanced disease. Our study does not support the notion that electrode implantation and STN stimulation exert a neuroprotective effect by themselves.     

Quantitation of dopamine transporter blockade by methylphenidate: first in vivo investigation using [123I]FP-CIT and a dedicated small animal SPECT

Purpose The aim of this study was to investigate the feasibility of assessing dopamine transporter binding after treatment with methylphenidate in the rat using a recently developed high-resolution small animal single-photon emission computed tomograph (TierSPECT) and [¹²³I]FP-CIT.Methods [¹²³I]FP-CIT was administered intravenously 1 h after intraperitoneal injection of methylphenidate (10 mg/kg) or vehicle. Animals underwent scanning 2 h after radioligand administration. The striatum was identified by superimposition of [¹²³I]FP-CIT scans with bone metabolism and perfusion scans obtained with ^99mTc-DPD and ^99mTc-tetrofosmin, respectively. As these tracers do not pass the blood–brain barrier, their distribution permits the identification of extracerebral anatomical landmarks such as the orbitae and the harderian glands. The cerebellum was identified by superimposing [¹²³I]FP-CIT scans with images of brain perfusion obtained with ^99mTc-HMPAO.Results Methylphenidate-treated animals and vehicle-treated animals yielded striatal equilibrium ratios (V₃) of 0.24±0.26 (mean ± SD) and 1.09±0.42, respectively (t test, two-tailed, p<0.0001). Cortical V₃ values amounted to 0.05±0.28 (methylphenidate) and 0.3±0.39 (saline, p=0.176). This first in vivo study of rat dopamine transporter binding after pre-treatment with methylphenidate showed a mean reduction of 78% in striatal [¹²³I]FP-CIT accumulation.Conclusion The results can be interpreted in terms of a pharmacological blockade in the rat striatum and show that in vivo quantitation of dopamine transporter binding is feasible with [¹²³I]FP-CIT and the TierSPECT. This may be of future relevance for in vivo investigations on rat models of attention deficit/hyperactivity disorder. Furthermore, our findings suggest that investigations in other animal models, e.g. of Parkinsons and Huntingtons disease, may be feasible using SPECT radioligands and small animal imaging systems.     

Repeated administration of D-amphetamine induces loss of [123I]FP-CIT binding to striatal dopamine transporters in rat brain: a validation study

In recent years, several PET and SPECT studies have shown loss of striatal dopamine transporter (DAT) binding in amphetamine (AMPH) users. However, the use of DAT SPECT tracers to detect AMPH-induced changes in DAT binding has not been validated. We therefore examined if repeated administration of D-AMPH or methamphetamine (METH) may induce loss of binding to striatal DATs in rats by using an experimental biodistribution study design and a SPECT tracer for the DAT ([123I]FP-CIT). METHODS: Groups of male rats (n = 10 per group) were treated with D-AMPH (10 mg/kg body weight), METH (10 mg/kg body weight), or saline, twice a day for 5 consecutive days. Five days later, [123I]FP-CIT was injected intravenously, and 2 h later, the rats were sacrificed and radioactivity was assayed. RESULTS: In d-AMPH but not METH-treated rats, striatal [123I]FP-CIT uptake was significantly lower (approximately 17%) than in the control group. CONCLUSION: These data show that [123I]FP-CIT can be used to detect AMPH-induced changes in DAT binding and may validate the use of DAT radiotracers to study AMPH-induced changes in striatal DAT binding in vivo.     

Implementation of the European multicentre database of healthy controls for [<Superscript>123</Superscript>I]FP-CIT SPECT increases diagnostic accuracy in patients with clinically uncertain parkinsonian syndromes

Purpose

Even though [¹²³I]FP-CIT SPECT provides high accuracy in detecting nigrostriatal cell loss in neurodegenerative parkinsonian syndromes (PS), some patients with an inconclusive diagnosis remain. We investigated whether the diagnostic accuracy in patients with clinically uncertain PS with previously inconclusive findings can be improved by the use of iterative reconstruction algorithms and an improved semiquantitative evaluation which additionally implemented a correction algorithm for patient age and gamma camera dependency (EARL-BRASS; Hermes Medical Solutions, Sweden).

Methods

We identified 101 patients with inconclusive findings who underwent an [¹²³I]FP-CIT SPECT between 2003 and 2010 as part of the diagnostic process of suspected PS at the University of Munich, and re-evaluated these scans using iterative reconstruction algorithms and the new corrected EARL-BRASS. Clinical follow-up was obtained in 62 out of the 101 patients and constituted the gold standard for the re-evaluation to assess the possible improvement in diagnostic accuracy.

Results

Clinical follow-up confirmed the diagnosis of PS in 11 of the 62 patients. In patients in whom both visual and semiquantitative analysis showed concordant findings (48 patients), a high negative predictive value (93 %), positive predictive value (100 %) and accuracy (94 %) were found, and thus a correct diagnosis was obtained in 45 of the 48 patients. Among the 14 patients with discordant findings, the additional semiquantitative analysis correctly identified all five of nine patients patients without PS by nonpathological semiquantitative findings in visually pathological or inconclusive scans. In contrast, four of the remaining five patients with decreased semiquantitative values but visually normal scans did not show a PS during follow-up.

Conclusion

The age-corrected and camera-corrected mode of evaluation using EARL-BRASS provided a notable improvement in the diagnostic accuracy of [¹²³I]FP-CIT SPECT in PS patients with previously inconclusive findings. The gain in accuracy might be achieved by better discrimination between physiological low striatal [¹²³I]FP-CIT binding due to age-related loss of the dopamine transporter or pathological loss of binding.

     

Differential Diagnosis of Patients with Inconclusive Parkinsonian Features Using [18F]FP-CIT PET/CT

Purpose

It is often difficult to differentiate parkinsonism, especially when patients show uncertain parkinsonian features. We investigated the usefulness of dopamine transporter (DAT) imaging for the differential diagnosis of inconclusive parkinsonism using [¹⁸F]FP-CIT PET.

Methods

Twenty-four patients with inconclusive parkinsonian features at initial clinical evaluation and nine healthy controls were studied. Patients consisted of three subgroups: nine patients whose diagnoses were unclear concerning whether they had idiopathic Parkinson’s disease or drug-induced parkinsonism (‘PD/DIP’), nine patients who fulfilled neither the diagnostic criteria of PD nor of essential tremor (‘PD/ET’), and six patients who were alleged to have either PD or atypical parkinsonian syndrome (‘PD/APS’). Brain PET images were obtained 120 min after injection of 185 MBq [¹⁸F]FP-CIT. Imaging results were quantified and compared with follow-up clinical diagnoses.

Results

Overall, 11 of 24 patients demonstrated abnormally decreased DAT availability on the PET scans, whereas 13 were normal. PET results could diagnose PD/DIP and PD/ET patients as having PD in six patients, DIP in seven, and ET in five; however, the diagnoses of all six PD/APS patients remained inconclusive. Among 15 patients who obtained a final follow-up diagnosis, the image-based diagnosis was congruent with the follow-up diagnosis in 11 patients. Four unsolved cases had normal DAT availability, but clinically progressed to PD during the follow-up period.

Conclusion

[¹⁸F]FP-CIT PET imaging is useful in the differential diagnosis of patients with inconclusive parkinsonian features, except in patients who show atypical features or who eventually progress to PD.     

Reproducibility of [<Superscript>123</Superscript>I]PE2I binding to dopamine transporters with SPECT

Purpose The iodinated cocaine derivative [¹²³I]PE2I is a new selective ligand for in vivo studies of the dopamine transporter (DAT) with SPECT. Recently, a bolus/infusion (B/I) protocol for [¹²³I]PE2I measurements of DAT density was established [Pinborg LH et al. J Nucl Med 2005;46:1119–271]. The aims of this study were, firstly, to evaluate the test–retest variability using the B/I protocol and, secondly, to evaluate the B/I approach in a new group of healthy subjects using two outcome parameters, BP₁ (C_ROI/C_plasma) and BP₂ (C_ROI/C_REF). Methods Seven healthy subjects were subjected to [¹²³I]PE2I SPECT scanning twice. For both studies, the two outcome parameters BP₁ and BP₂ were calculated based on two different methods for region of interest (ROI) delineation, namely manual delineation and probability map-based automatic delineation with MRI co-registration. Results With manual delineation, striatal test–retest variability (absolute difference between first and second scan as a percentage of the mean) of BP₁ and BP₂ was 13.9% (range 1.8–35.7%) and 4.1% (range 0.5–9.7%) respectively. The probability map-based automatic delineation resulted in striatal test–retest variability of 17.2% (range 4.3–40.5%) and 5.2% (range 0.1–10.9%) respectively. The B/I approach provided stable brain activity from 120 to 180 min post injection in both high- and low-count regions with a mean % change/hour in striatal BP₂ of 10.6. Conclusion [¹²³I]PE2I SPECT with the B/I approach yields a highly reproducible measure of striatal dopamine transporter binding. The appropriateness of a B/I protocol with a B/I ratio of 2.7 h (i.e. with a bolus worth 2.7 h of infusion) was confirmed in an independent sample of healthy subjects.     

Effect of age and gender on dopamine transporter imaging with [123I]FP-CIT SPET in healthy volunteers

Dopamine transporter imaging is a valuable tool to investigate the integrity of the dopaminergic neurons. To date, several reports have shown an age-associated decline in dopamine transporters in healthy volunteers. Although animal studies suggest an effect of gender on dopamine transporter density, this gender effect has not yet been confirmed in human studies. To study the influence of age and gender on dopamine transporter imaging in healthy volunteers, we performed single-photon emission tomography imaging with [¹²³I]FP-CIT to quantify dopamine transporters. Forty-five healthy volunteers (23 males and 22 females) were included, ranging in age from 18 to 83 years. SPET imaging was performed 3 h after injection of ±110 MBq [¹²³I]FP-CIT. An operator-independent volume of interest analysis was used for quantification of [¹²³I]FP-CIT binding in the striatum. The ratio of specific striatal to non-specific [¹²³I]FP-CIT binding was found to decrease significantly with age. Moreover, we found a high variance in [¹²³I]FP-CIT binding in young adults. Finally, females were found to have significantly higher [¹²³I]FP-CIT binding ratios than males. This effect of gender on [¹²³I]FP-CIT binding ratios was not related to age. The results of this study are consistent with findings from previous studies, which showed that dopamine transporter density declines with age. The intriguing finding of a higher dopamine transporter density in females than in males is in line with findings from animal studies. Received 29 January 2000 and in revised form 27 March 2000     

IBZM tool: a fully automated expert system for the evaluation of IBZM SPECT studies

Purpose Visual reading of [¹²³I]IBZM SPECT scans depends on the experience of the interpreter. Therefore, semi-quantification of striatal IBZM uptake is commonly considered mandatory. However, semi-quantification is time consuming and prone to error, particularly if the volumes of interest (VOIs) are positioned manually. Therefore, the present paper proposes a new software tool (“IBZM tool”) for fully automated and standardised processing, evaluation and documentation of [¹²³I]IBZM SPECT scans. Methods The IBZM tool is an easy-to-use SPM toolbox. It includes automated procedures for realignment and summation of multiple frames (motion correction), stereotactic normalisation, scaling, VOI analysis of striatum-to-reference ratio R, classification of R and standardised display. In order to evaluate the tool, which was developed at the University of Hamburg, the tool was transferred to the University of Hannover. There it was applied to 27 well-documented subjects: eight patients with multi-system atrophy (MSA), 12 patients with Parkinson’s disease (PD) and seven controls. The IBZM tool was compared with manual VOI analysis. Results The sensitivity and specificity of the IBZM tool for the differentiation of the MSA subjects from the controls were 100% and 86%, respectively. The IBZM tool provided improved statistical power compared with manual VOI analysis. Conclusion The IBZM tool is an expert system for the detection of reduced striatal D₂ availability on [¹²³I]IBZM SPECT scans. The standardised documentation supports visual and semi-quantitative evaluation, and it is useful for presenting the findings to the referring physician. The IBZM tool has the potential for widespread use, since it appears to be fairly independent of the performance characteristics of the particular SPECT system used. The tool is available free of charge.     

Effect of cyclosporin A administration on the biodistribution and multipinhole μSPECT imaging of [<Superscript>123</Superscript>I]R91150 in rodent brain

Purpose  P-glycoprotein (Pgp) is an efflux protein found amongst other locations in the blood–brain barrier. It is important to investigate the effect of Pgp modulation on clinically used brain tracers, because brain uptake of the tracer can be altered by blocking of the Pgp efflux transporter. The function of Pgp can be blocked with cyclosporin A. Methods  We investigated the effect of cyclosporin A administration on the biodistribution of [¹²³I]R91150 in rodents, and the effect of Pgp blocking on the quality of multipinhole μSPECT imaging with [¹²³I]R91150. The influence of increasing doses of cyclosporin A on the brain uptake of [¹²³I]R91150 was investigated in NMRI mice. A biodistribution study with [¹²³I]R91150 was performed in male Sprague-Dawley rats pretreated with cyclosporin A and not pretreated. Brain uptake of [¹²³I]R91150 after cyclosporin A injection was compared to the brain uptake in untreated animals, and a displacement study with ketanserin was performed in both groups. A multipinhole μSPECT brain imaging study was also performed using a Milabs U-SPECT-II camera in male Sprague-Dawley rats. To exclude the effect of possible metabolites, a metabolite study was also performed. Results  At the highest cyclosporin A dose (50 mg/kg), a sevenfold increase in brain radioactivity concentration was observed in NMRI mice. Also, a dose-response relationship was established between the dose of cyclosporin A and the brain uptake of [¹²³I]R91150 in mice. Compared to the control group, a five-fold increase in [¹²³I]R91150 radioactivity concentration was observed in the brain of Sprague-Dawley rats after cyclosporin A treatment (50 mg/kg). Radioactivity concentration in the frontal cortex increased from 0.24±0.0092 to 1.58±0.097% injected dose per gram of tissue after treatment with cyclosporin A (at the 1-h time-point). Blood radioactivity concentrations did not increase to the same extent. The cortical activity was displaced by administration of ketanserin. A metabolite study confirmed that there was no increased metabolism of [¹²³I]R91150 due to cyclosporin A. The visual quality of multipinhole μSPECT images with [¹²³I]R91150 in Sprague-Dawley rats improved markedly after cyclosporin A pretreatment. Conclusion  From the results obtained in the biodistribution studies, it can be concluded that [¹²³I]R91150 is a substrate for Pgp in rodents. A relationship between the administered dose of cyclosporin A and the increase in [¹²³I]R91150 brain radioactivity concentration was established. The overall quality of our multipinhole μSPECT images with [¹²³I]R91150 in rats improved markedly after pretreatment of the animals with cyclosporin A.     

Long-term assessment of striatal dopamine transporters in parkinsonian patients with intrastriatal embryonic mesencephalic grafts

Purpose Single-photon emission computed tomography (SPECT) of striatal dopamine transporters (DAT) has been used to demonstrate presynaptic dopaminergic dysfunction and to monitor the progression of Parkinson’s disease. In parkinsonian patients who were implanted with embryonic mesencephalic tissue in the striatum, positron emission tomography (PET) has shown an increase in striatal [¹⁸F]dopa uptake as an indicator of graft survival and striatal reinnervation. The aim of this study was to investigate two patients who had undergone bilateral intrastriatal transplantation of human embryonic mesencephalic tissue using SPECT and the ¹²³I-labelled DAT ligand N-(3-iodopropen-2-yl)-2β-carbomethoxy-3β-(4-chlorophenyl) tropane (IPT). Methods Two patients were subjected to [¹²³I]IPT SPECT according to a standardised protocol prospectively and repeatedly up to 8 years after transplantation. Results From baseline to year 3 after transplantation, mean striatal DAT availability increased by a mean of 61% (93% and 29% in patients 1 and 2, respectively). It then remained relatively stable up to 8 years in patient 2, but increased further by another 77% of baseline values in patient 1. Clinically, both patients experienced a moderate improvement in motor performance but developed moderate (patient 2) to severe (patient 1) off-medication dyskinesias. Conclusion Our data indicate that DAT imaging using IPT and SPECT can be used to demonstrate graft survival following dopaminergic tissue implantation. Because SPECT with DAT ligands is widely available in the routine clinical setting, this methodology may be a useful alternative to [¹⁸F]dopa PET for repeated scanning of grafted parkinsonian patients. The relevance of the long-term increase in DAT binding for the development of off-medication dyskinesias remains to be elucidated further. An editorial commentary on this paper is available at     

[123I]FP-CIT binding in rat brain after acute and sub-chronic administration of dopaminergic medication

The recently developed radioligand [¹²³I]FP-CIT is suitable for clinical single-photon emission tomography (SPET) imaging of the dopamine (DA) transporter in vivo. To date it has remained unclear whether dopaminergic medication influences the striatal [¹²³I]FP-CIT binding. The purpose of this study was to investigate the influence of this medication on [¹²³I]FP-CIT binding in the brain. We used an animal model in which we administered dopaminomimetics, antipsychotics and an antidepressant. In vivo [¹²³I]FP-CIT binding to the DA and serotonin transporters was evaluated after sub-chronic and acute administration of the drugs. The administered medication induced small changes in striatal [¹²³I]FP-CIT binding which were not statistically significant. As expected, the DA reuptake blocker GBR 12,909 induced a significant decrease in [¹²³I]FP-CIT binding. [¹²³I]FP-CIT binding in the serotonin-rich hypothalamus was decreased only after acute administration of fluvoxamine. The results of this study suggest that dopaminergic medication will not affect the results of DA transporter SPET imaging with [¹²³I]FP-CIT. Received 15 August and in revised form 15 October 1999     

Comparison between a dual-head and a brain-dedicated SPECT system in the measurement of the loss of dopamine transporters with [<Superscript>123</Superscript>I]FP-CIT

BACKGROUND: Dual-head SPECT systems are used by many clinical departments for [(123)I]FP-CIT SPECT imaging, while triple-head or brain-dedicated systems with better imaging performance are more commonly used by research institutions. There are limited data comparing the capability of the two types of system to measure dopamine transporter (DAT) loss in vivo. PURPOSE: The aim of this study was to compare the ability of a dual-head and a brain-dedicated SPECT system to estimate the degree of DAT loss in different movement disorders with variable nigrostriatal impairment, with [(123)I]FP-CIT. MATERIALS AND METHODS: Four patients with essential tremor, 24 with Parkinson's disease (PD), six with spinocerebellar ataxia type 2 and six controls were studied with [(123)I]FP-CIT. SPECT scans were performed on a dual-head (E.CAM-Siemens) and subsequently on a brain-dedicated system (Ceraspect-DSI). RESULTS: Striatal DAT outcome measures on the E.CAM and the Ceraspect were strongly correlated and the putamen-to-caudate ratios were almost identical. Although the measured values were lower by 52 +/- 25% in caudate and by 51 +/- 31% in putamen on the E.CAM (p < 0.0001), the average striatal DAT decrease in each patient group compared with controls was similar for both systems. In PD patients, similar correlations (p < 0.05) were found between motor UPDRS or Hoehn and Yahr stage and striatal DAT density. CONCLUSIONS: Despite underestimation of striatal DAT outcome measures, the E.CAM showed similar capability as the Ceraspect in measuring the degree of nigrostriatal dopaminergic deficit and assessing the correlation between DAT outcome measures and clinical variables of PD severity and stage.     

Spatial Normalization Using Early-Phase [18F]FP-CIT PET for Quantification of Striatal Dopamine Transporter Binding

PurposeThe precise quantification of dopamine transporter (DAT) density on N-(3-[¹⁸F]Fluoropropyl)-2β-carbomethoxy-3β-(4-iodophenyl) nortropane positron emission tomography ([¹⁸F]FP-CIT PET) imaging is crucial to measure the degree of striatal DAT loss in patients with parkinsonism. The quantitative analysis requires a spatial normalization process based on a template brain. Since the spatial normalization method based on a delayed-phase PET has limited performance, we suggest an early-phase PET-based method and compared its accuracy, referring to the MRI-based approach as a gold standard.MethodsA total of 39 referred patients from the movement disorder clinic who underwent dual-phase [¹⁸F]FP-CIT PET and took MRI within 1 year were retrospectively analyzed. The three spatial normalization methods were applied for quantification of [¹⁸F]FP-CIT PET-MRI-based anatomical normalization, PET template-based method based on delayed PET, and that based on early PET. The striatal binding ratios (BRs) were compared, and voxelwise paired t tests were implemented between different methods.ResultsThe early image-based normalization showed concordant patterns of putaminal [¹⁸F]FP-CIT binding with an MRI-based method. The BRs of the putamen from the MRI-based approach showed higher agreement with early image- than delayed image-based method as presented by Bland-Altman plots and intraclass correlation coefficients (early image-based, 0.980; delayed image-based, 0.895). The voxelwise test exhibited a smaller volume of significantly different counts in putamen between brains processed by early image and MRI compared to that between delayed image and MRI.ConclusionThe early-phase [¹⁸F]FP-CIT PET can be utilized for spatial normalization of delayed PET image when the MRI image is unavailable and presents better performance than the delayed template-based method in quantitation of putaminal binding ratio.     

Human biodistribution and dosimetry of [123I]FP-CIT: a potent radioligand for imaging of dopamine transporters

This study reports on the biodistribution and radiation dosimetry of iodine-123-labelled N-ω-(flu- oropropyl)-2β-carbomethoxy-3β-(4-iodophenyl)tropane ([¹²³I]FP-CIT), a promising radioligand for the imaging of dopamine transporters. In 12 healthy volunteers, conjugate whole-body scans were performed up to 48 h following intravenous injection of approximately 100 MBq [¹²³I]FP-CIT. Attenuation correction was performed using a transmission whole-body scan obtained prior to injection of the radioligand, employing a ¹²³I flood source. Blood samples were taken and urine was freely collected up to 48 h after injection of the radiotracer. For each subject, the percentage of injected activity measured in regions of interest over brain, striatum, lungs and liver were fitted to a multicompartmental model to give time-activity curves. The cumulative urine activity curve was used to model the urinary excretion rate and, indirectly, to predict faecal excretion. Using the MIRD method, nine source organs were considered in estimating absorbed radiation doses for organs of the body. The images showed rapid lung uptake and hepatobiliary excretion. Diffuse uptake and retention of activity was seen in the brain, especially in the striatum. At 48 h following the injection of [¹²³I]FP-CIT, mean measured urine excretion was 60%±9% (SD), and mean predicted excretion in faeces was 14%±1%. In general, the striatum received the highest absorbed dose (average 0.23 mGy/MBq), followed by the urinary bladder wall (average 0.054 mGy/MBq) and lungs (average 0.043 mGy/MBq). The average effective dose equivalent of [¹²³I]FP-CIT was estimated to be 0.024 mSv/MBq. The amount of [¹²³I]FP-CIT required for adequate dopamine transporter imaging results in an acceptable effective dose equivalent to the patient. Received 14 July and in revised form 26 September 1997     

Human biodistribution and dosimetry of iodine-123-fluoroalkyl analogs of β-CIT

Two new N-ω-fluoroalkyl analogs of [¹²³I]2β-carbomethoxy-3β-(4-iodophenyl)tropane ([¹²³I]β-CIT), the fluoroethyl and fluoropropyl compounds ([¹²³I]FE-CIT and [¹²³I]FP-CIT, respectively), have been shown to have faster kinetics and better selectivity for the dopamine transporter than [¹²³I]β-CIT. We examined the organ biodistribution and radiation safety of these two compounds in six healthy volunteers who received an injection with each of the two compounds 2 weeks apart. Data were obtained on the Strichman 860 whole-body scanner. Transmission scans were obtained in all subjects prior to the injection of the radiotracer with a line source and used to derive organ-specific attenuation correction factors. Whole-body planar images were acquired every hour for the first 6 h, and at 24 h. Attenuation-corrected regional conjugate counts were converted into units of activity using a calibration factor obtained for each subject by dividing whole-body conjugate decay-corrected counts from the first acquisition by the injected activity. Radiation dose estimates were on average higher for [¹²³I]CIT-FE than for [¹²³I]CIT-FP, with the lower large intestine receiving the highest exposure: 0.15±13% mGy/MBq (mean ±COV) and 0.12±14% mGy/MBq for [¹²³I]FE-CIT and [¹²³I]FP-CIT, respectively, followed by the upper large intestine and the spleen. Received 7 May and in revised form 7 August 1997