Gerda Thomsen

Imaging of dopamine transporters and D2 receptors in patients with Parkinson’s disease and multiple system atrophy

PurposeThe aim of this study was to ascertain whether combined presynaptic and postsynaptic dopaminergic single-photon emission computed tomography (SPECT) scanning is useful for differentiation between patients with idiopathic Parkinson’s disease (IPD), patients with multiple system atrophy of the striatonigral type (MSA) and healthy subjects.MethodsSPECT measurements of the dopamine transporter (DAT) were done with 123I-β-CIT, while for determination of the dopamine D2-like receptors (D2), 123I-epidepride was used. Clinical evaluation and SPECT scans were carried out in 14 patients with IPD, eight patients with MSA and 11 healthy age-matched control subjects.ResultsPutaminal DAT binding was reduced to 32% of control values in IPD and to 19% of control values in MSA . Significantly higher striatal asymmetry in DAT binding was found in MSA than in controls, but IPD patients had significantly higher asymmetry than MSA patients. Striatal D2 binding did not differ significantly between patients and healthy controls but the ratio between caudate DAT and D2 binding was significantly higher in patients with IPD than in those with MSA, even when disease severity was taken into account.ConclusionPatients with reduced striatal 123I-β-CIT binding and a side-to-side difference greater than 15% are likely to suffer from IPD. Patients with reduced striatal 123I-β-CIT binding and a side-to-side difference of between 5% and 15% are more likely to have MSA. 123I-epidepride SPECT measurements may add further diagnostic information, since the ratio between DAT and D2 receptor binding is significantly higher in IPD than in MSA.

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.

Value of Semiquantitative Analysis for Clinical Reporting of 123I-2-β-Carbomethoxy-3β-(4-Iodophenyl)-N-(3-Fluoropropyl)Nortropane SPECT Studies

Clinical 123I-2-β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)nortropane (123I-FP-CIT) SPECT studies are commonly performed and reported using visual evaluation of tracer binding, an inherently subjective method. Increased objectivity can potentially be obtained using semiquantitative analysis. In this study, we assessed whether semiquantitative analysis of 123I-FP-CIT tracer binding created more reproducible clinical reporting. A secondary aim was to determine in what form semiquantitative data should be provided to the reporter. Methods: Fifty-four patients referred for the assessment of nigrostriatal dopaminergic degeneration were scanned using SPECT/CT, followed by semiquantitative analysis calculating striatal binding ratios (SBRs) and caudate-to-putamen ratios (CPRs). Normal reference values were obtained using 131 healthy controls enrolled on a multicenter initiative backed by the European Association of Nuclear Medicine. A purely quantitative evaluation was first performed, with each striatum scored as normal or abnormal according to reference values. Three experienced nuclear medicine physicians then scored each striatum as normal or abnormal, also indicating cases perceived as difficult, using visual evaluation, visual evaluation in combination with SBR data, and visual evaluation in combination with SBR and CPR data. Intra- and interobserver agreement and agreement between observers and the purely quantitative evaluation were assessed using κ-statistics. The agreement between scan interpretation and clinical diagnosis was assessed for patients with a postscan clinical diagnosis available (n = 35). Results: The physicians showed consistent reporting, with a good intraobserver agreement obtained for the visual interpretation (mean κ ± SD, 0.95 ± 0.029). Although visual interpretation of tracer binding gave good interobserver agreement (0.80 ± 0.045), this was improved as SBRs (0.86 ± 0.070) and CPRs (0.95 ± 0.040) were provided. The number of striata perceived as difficult to interpret decreased as semiquantitative data were provided (30 for the visual interpretation; 0 as SBR and CPR values were given). The agreement between physicians’ interpretations and the purely quantitative evaluation showed that readers used the semiquantitative data to different extents, with a more experienced reader relying less on the semiquantitative data. Good agreement between scan interpretation and clinical diagnosis was seen. Conclusion: A combined approach of visual assessment and semiquantitative analysis of tracer binding created more reproducible clinical reporting of 123I-FP-CIT SPECT studies. Physicians should have access to both SBR and CPR data to minimize interobserver variability.

Cerebral blood flow, oxidative metabolism and cerebrovascular carbon dioxide reactivity in patients with acute bacterial meningitis

Background: The optimal arterial carbon dioxide tension (PaCO2) in patients with acute bacterial meningitis (ABM) is unknown and controversial. The objective of this study was to measure global cerebral blood flow (CBF), cerebrovascular CO2 reactivity (CO2R), and cerebral metabolic rates (CMR) of oxygen (O2), glucose (glu), and lactate (lac), in patients with ABM and compare the results to those obtained in healthy volunteers.

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.

TSPO Imaging in Glioblastoma Multiforme: A Direct Comparison Between 123I-CLINDE SPECT, 18F-FET PET, and Gadolinium-Enhanced MR Imaging

Here we compare translocator protein (TSPO) imaging using 6-chloro-2-(4′-123I-iodophenyl)-3-(N,N-diethyl)-imidazo[1,2-a]pyridine-3-acetamide SPECT (123I-CLINDE) and amino acid transport imaging using O-(2-18F-fluoroethyl)-l-tyrosine PET (18F-FET) and investigate whether 123I-CLINDE is superior to 18F-FET in predicting progression of glioblastoma multiforme (GBM) at follow-up. Methods: Three patients with World Health Organization grade IV GBM were scanned with 123I-CLINDE SPECT, 18F-FET PET, and gadolinium-enhanced MR imaging. Molecular imaging data were compared with follow-up gadolinium-enhanced MR images or contrast-enhanced CT scans. Results: The percentage overlap between volumes of interest (VOIs) of increased 18F-FET uptake and 123I-CLINDE binding was variable (12%–42%). The percentage overlap of MR imaging baseline VOIs was greater for 18F-FET (79%–93%) than 123I-CLINDE (15%–30%). In contrast, VOIs of increased contrast enhancement at follow-up compared with baseline overlapped to a greater extent with baseline 123I-CLINDE VOIs than 18F-FET VOIs (21% vs. 8% and 72% vs. 55%). Conclusion: Our preliminary results suggest that TSPO brain imaging in GBM may be a useful tool for predicting tumor progression at follow-up and may be less susceptible to changes in blood–brain barrier permeability than 18F-FET. Larger studies are warranted to test the clinical potential of TSPO imaging in GBM, including presurgical planning and radiotherapy.

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.