Morten Ziebell

Serotonin Transporters in Dopamine Transporter Imaging: A Head-to-Head Comparison of Dopamine Transporter SPECT Radioligands 123I-FP-CIT and 123I-PE2I

Current SPECT radioligands available for in vivo imaging of the dopamine transporter (DAT) also show affinity for monoamine transporters other than DAT, especially the serotonin transporter (SERT). The effect of this lack of selectivity for in vivo imaging is unknown. In this study, we compared the SPECT radioligands 123I-2-β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)nortropane (123I-FP-CIT) and 123I-N-(3-iodoprop-2E-enyl)-2-β-carbomethoxy-3β-(4-methylphenyl) (123I-PE2I). 123I-FP-CIT has a 10-fold higher selectivity than 123I-FP-CIT for DAT versus SERT. Methods: Sixteen healthy individuals were scanned in random order with both radioligands. The radioligands were administered according to standard recommendations: 123I-FP-CIT was given as a bolus injection, and the ratio between the striatum and reference tissue was measured after 3 h. 123I-PE2I was administered in a bolus–infusion setup, and the nondisplaceable binding potential (BPND) was measured after 2 h. To assess the contribution of SERT to the overall SPECT signal, SERT was blocked by intravenous citalopram in 6 of the individuals. Results: The striatum-to-reference ratio − 1 of 123I-FP-CIT was on average 18% higher than the striatal BPND of 123I-PE2I. Equal doses of radioactivity resulted in 3 times higher counting rates for 123I-FP-CIT than for 123I-PE2I, both in target and in reference brain regions. Citalopram infusion led to significant reductions in both striatal (22.8% ± 20.4%, P < 0.05) and thalamic (63.0% ± 47.9%, P < 0.05) 123I-FP-CIT binding ratios, whereas BPND of 123I-PE2I was unaltered. Likewise, blocking of SERT led to increased (21% ± 30.1%, P < 0.001) plasma 123I-FP-CIT, probably as a result of significant blocking of peripheral SERT binding sites. By contrast, plasma 123I-PE2I remained stable. Conclusion: 123I-FP-CIT and 123I-PE2I had approximately the same target-to-background ratios, but per injected megabecquerel, 123I-FP-CIT gave rise to 3-fold higher cerebral counting rates. We found that 123I-FP-CIT, but not 123I-PE2I, brain images have a highly interindividual but significant signal contribution from SERT. Whether the SERT signal contribution is of clinical importance needs to be established in future patient studies.

Striatal dopamine transporter binding correlates with serum BDNF levels in patients with striatal dopaminergic neurodegeneration

Compelling evidence has shown, that neurotrophins responsible for the regulation of neuronal growth, survival, and differentiation are involved in neurodegenerative diseases. Whereas lower serum levels of brain derived neurotrophic factor (BDNF) have been observed in patients with Parkinsons disease, no studies have directly related the degree of striatal neurodegeneration of dopaminergic neurons (DA) with serum BDNF levels. In this study we examined the relationship between striatal neurodegeneration as determined with (123)I-PE2I-single photon emission computer tomography (SPECT) and serum BDNF levels in patients with parkinsonism. Twenty-one patients with abnormal in vivo striatal dopamine transporter (DAT) binding as evidenced with [(123)I]PE2I SPECT brain scanning were included. Samples for serum BDNF levels were collected at the time of the SPECT scanning, and BDNF was measured with enzyme-linked immunosorbent assay (ELISA). The striatal binding potential of non-displaceable [(123)I]PE2I was calculated. We found a positive correlation between serum BDNF levels and striatal DAT availability (p < 0.01, R(2) = 0.36). We find that in patients with striatal dopaminergic neurodegeneration serum BDNF levels decrease along with loss in striatal DAT binding.

No correlation between body mass index and striatal dopamine transporter availability in healthy volunteers using SPECT and [123I]PE2I.

Dopamine plays an important role in both the rewarding and conditioning effects of food. These effects involve mesolimbic, mesocortical, and nigrostriatal pathways. In humans, the most consistent finding has been reduced striatal dopamine D2/3 receptor availability. In striatum, dopamine is inactivated by reuptake via the dopamine transporter (DAT). The aim of the study was to test the hypothesis of lower DAT availability in obese healthy subjects using a selective DAT radiotracer in a sample of subjects with a wide range of BMI values.

Striatal Dopamine Transporter Binding Does Not Correlate with Clinical Severity in Dementia with Lewy Bodies

Patients who have dementia with Lewy bodies (DLB) show both clinical and histopathologic overlap with Alzheimer disease patients and Parkinson disease patients. In this study, we correlated the core features of DLB (dementia, parkinsonism, hallucinations, and fluctuations) with striatal dopamine transporter (DAT) availability as assessed with SPECT and 123I-N-(3-iodoprop-2E-enyl)-2-β-carbomethoxy-3β-(4-methylphenyl) nortropane (123I-PE2I) in patients with newly diagnosed DLB. Methods: Two hundred eighty-eight patients were consecutively included in the study as they were referred for diagnostic SPECT scanning of DAT with 123I-PE2I. Of those patients, 51 had, on the basis of clinical guideline criteria, a probable-DLB diagnosis at follow-up 16 ± 11.6 mo later. Before or on the day of the SPECT scan, DLB patients had a routine neurologic examination including Hoehn and Yahr grading and were cognitively evaluated with the Mini Mental State Examination. Results: There was no correlation between Mini Mental State Examination, Hoehn and Yahr score, fluctuations or hallucinations, and striatal DAT availability as measured with 123I-PE2I and SPECT. Conclusion: In patients with newly diagnosed DLB, symptoms are not associated with a reduction in striatal DAT despite its firm involvement in DLB pathology.

No difference in striatal dopamine transporter availability between active smokers, ex-smokers and non-smokers using [123I]FP-CIT (DaTSCAN) and SPECT

BackgroundMesolimbic and nigrostriatal dopaminergic pathways play important roles in both the rewarding and conditioning effects of drugs. The dopamine transporter (DAT) is of central importance in regulating dopaminergic neurotransmission and in particular in activating the striatal D2-like receptors. Molecular imaging studies of the relationship between DAT availability/dopamine synthesis capacity and active cigarette smoking have shown conflicting results. Through the collaboration between 13 SPECT centres located in 10 different European countries, a database of FP-CIT-binding in healthy controls was established. We used the database to test the hypothesis that striatal DAT availability is changed in active smokers compared to non-smokers and ex-smokers.MethodsA total of 129 healthy volunteers were included. Subjects were divided into three categories according to past and present tobacco smoking: (1) non-smokers (n = 64), (2) ex-smokers (n = 39) and (3) active smokers (n = 26). For imaging of the DAT availability, we used [123I]FP-CIT (DaTSCAN) and single photon emission computed tomography (SPECT). Data were collected in collaboration between 13 SPECT centres located in 10 different European countries. The striatal measure of DAT availability was analyzed in a multiple regression model with age, SPECT centre and smoking as predictor.ResultsThere was no statistically significant difference in DAT availability between the groups of active smokers, ex-smokers and non-smokers (p = 0.34). Further, we could not demonstrate a significant association between striatal DAT and the number of cigarettes per day or total lifetime cigarette packages in smokers and ex-smokers.ConclusionOur results do not support the hypothesis that large differences in striatal DAT availability are present in smokers compared to ex-smokers and healthy volunteers with no history of smoking.

Source localization of rhythmic ictal EEG activity: A study of diagnostic accuracy following STARD criteria

Although precise identification of the seizure‐onset zone is an essential element of presurgical evaluation, source localization of ictal electroencephalography (EEG) signals has received little attention. The aim of our study was to estimate the accuracy of source localization of rhythmic ictal EEG activity using a distributed source model.

Validation of a Method for Accurate and Highly Reproducible Quantification of Brain Dopamine Transporter SPECT Studies

In nuclear medicine brain imaging, it is important to delineate regions of interest (ROIs) so that the outcome is both accurate and reproducible. The purpose of this study was to validate a new time-saving algorithm (DATquan) for accurate and reproducible quantification of the striatal dopamine transporter (DAT) with appropriate radioligands and SPECT and without the need for structural brain scanning. Methods: In a reconstructed DAT SPECT image, DATquan automatically calculated the ratio at steady state of specifically bound radioligand to nondisplaceable radioligand in tissue (BPND) within striatal ROIs that were delineated by use of a semiautomatic template-based alignment approach. DATquan was tested with 123I-N-(3-iodoprop-2E-enyl)-2-β-carbomethoxy-3β-(4-methylphenyl) SPECT images from 15 patients. In each image, ROIs were first manually delineated, and then corresponding BPND values were derived by an experienced physician. Afterward, 2 independent novice operators used DATquan to analyze the same 15 images. The resulting DATquan-derived BPND data were compared with the data retrieved by manual delineation to assess the accuracy and reproducibility of DATquan. Also, the operational aspects of DATquan were assessed on the basis of measurements of the mean running time of the algorithm as well as on the basis of quantification of the overlap of the DATquan-delineated ROIs obtained by the 2 operators. Results: The mean algorithm running time was 3 min, and the operators’ striatal ROIs had a mean overlap of more than 82%. DATquan-derived BPND values obtained by the 2 operators showed high agreement (the mean difference was 0.00 [SD, 0.05] in the striatum, 0.02 [SD, 0.26] in the putamen, and 0.03 [SD, 0.43] in the caudate nucleus). The interoperator variability was 2.2% (SD, 1.3%) in the striatum, 11.7% (SD, 9.9%) in the putamen, and 12.9% (SD, 4.0%) in the caudate nucleus. DATquan-derived BPND values showed high agreement with the values manually derived by the experienced delineator. Conclusion: DATquan is a freely available, accurate, and highly reproducible method for quantification of DAT binding in the brain by SPECT. Once implemented in clinics, DATquan will serve as a useful and time-saving tool.

MRI-Guided Region-of-Interest Delineation Is Comparable to Manual Delineation in Dopamine Transporter SPECT Quantification in Patients: A Reproducibility Study

A particularly sensitive step in the quantification of SPECT images of the dopamine transporter (DAT) is a correct delineation of the region of interest (ROI). In this study, we primarily compared the reproducibility of the following different approaches for ROI delineation in SPECT images of the DAT: the use of manual delineation (MD) on high-count striatal slides directly on the SPECT image, ROI delineation based on individual MR images (MRD), and oversized striatal ROIs—that is, the striatal volume of interest (SVI), as described previously. We also assessed the ability of the different approaches to identify striatal pathology in patients with parkinsonism. Methods: Eight patients with highly variable reductions in cerebral DAT availability were SPECT-scanned twice with 123I-labeled N-(3-iodoprop-(2E)-enyl)-2β-carboxymethoxy-3β-(4′-methylphenyl) nortropane bolus infusion setup and once with an MRI scanner. For SPECT/MRI coregistration, we used external fiducial markers visible on both MRI and SPECT. With the MD and MRD methods, the outcome parameters for DAT availability were the binding potentials and the ratio at equilibrium of specifically bound radioligand to nondisplaceable radioligand in tissue (BPND). For the SVI method, the outcome parameter was the specific binding ratio (SBR). Results: No statistically significant difference in striatal BPND intraobserver reproducibility was seen among any of the 3 methods. The intraobserver reproducibility average ± SD for MD was 7.0% ± 4.1%; for MRD, 5.7% ± 5.4%; and for SVI, 6.7% ± 6.0%. Mean intrasubject variability, as determined from the test–retest scans, did not differ with the 3 delineation methods used. The average (±SD) intrasubject variability of striatal BPND was 11.9% ± 10.0% with MD and 14.6% ± 15.3% with MRD. With the SVI method, the intrasubject variability of striatal specific binding ratio was 10.0% ± 10.2%. BPND values obtained with the MD and MRD methods were similar (paired t test, P > 0.4). Conclusion: In patients with reduced striatal DAT binding, the reproducibility of the outcome from ROI MD is comparable to both that obtained by delineation of ROI on individual MR images, followed by coregistration to the SPECT image, and that obtained with the SVI-based approach.

The impact of reconstruction and scanner characterisation on the diagnostic capability of a normal database for [ 123 I]FP-CIT SPECT imaging

BackgroundThe use of a normal database for [123I]FP-CIT SPECT imaging has been found to be helpful for cases which are difficult to interpret by visual assessment alone, and to improve reproducibility in scan interpretation. The aim of this study was to assess whether the use of different tomographic reconstructions affects the performance of a normal [123I]FP-CIT SPECT database and also whether systems benefit from a system characterisation before a database is used.Seventy-seven [123I]FP-CIT SPECT studies from two sites and with 3-year clinical follow-up were assessed quantitatively for scan normality using the ENC-DAT normal database obtained in well-documented healthy subjects. Patient and normal data were reconstructed with iterative reconstruction with correction for attenuation, scatter and septal penetration (ACSC), the same reconstruction without corrections (IRNC), and filtered back-projection (FBP) with data quantified using small volume-of-interest (VOI) (BRASS) and large VOI (Southampton) analysis methods. Test performance was assessed with and without system characterisation, using receiver operating characteristics (ROC) analysis for age-independent data and using sensitivity/specificity analysis with age-matched normal values. The clinical diagnosis at follow-up was used as the standard of truth.ResultsThere were no significant differences in the age-independent quantitative assessment of scan normality across reconstructions, system characterisation and quantitative methods (ROC AUC 0.866–0.924). With BRASS quantification, there were no significant differences between the values of sensitivity (67.4–83.7%) or specificity (79.4–91.2%) across all reconstruction and calibration strategies. However, the Southampton method showed significant differences in sensitivity between ACSC (90.7%) vs IRNC (76.7%) and FBP (67.4%) reconstructions with calibration. Sensitivity using ACSC reconstruction with this method was also significantly better with calibration than without calibration (65.1%). Specificity using the Southampton method was unchanged across reconstruction and calibration choices (82.4–88.2%).ConclusionsThe ability of a normal [123I]FP-CIT SPECT database to assess clinical scan normality is equivalent across all reconstruction, system characterisation, and quantification strategies using BRASS quantification. However, when using the Southampton quantification method, performance is sensitive to the reconstruction and calibration strategy used.

Experimental determination of the weighting factor for the energy window subtraction-based downscatter correction for I-123 in brain SPECT studies

Correction for downscatter in I-123 SPECT can be performed by the subtraction of a secondary energy window from the main window, as in the triple-energy window method. This is potentially noise sensitive. For studies with limited amount of counts (e.g. dynamic studies), a broad subtraction window with identical width is preferred. This secondary window needs to be weighted with a factor higher than one, due to a broad backscatter peak from high-energy photons appearing at 172 keV. Spatial dependency and the numerical value of this weighting factor and the image contrast improvement of this correction were investigated in this study. Energy windows with a width of 32 keV were centered at 159 keV and 200 keV. The weighting factor was measured both with an I-123 point source and in a dopamine transporter brain SPECT study in 10 human subjects (5 healthy subjects and 5 patients) by minimizing the background outside the head. Weighting factors ranged from 1.11 to 1.13 for the point source and from 1.16 to 1.18 for human subjects. Point source measurements revealed no position dependence. After correction, the measured specific binding ratio (image contrast) increased significantly for healthy subjects, typically by more than 20%, while the background counts outside of all subjects were effectively removed. A weighting factor of 1.1-1.2 can be applied in clinical practice. This correction effectively removes downscatter and significantly improves image contrast inside the brain.