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A large set of patients with Parkinson's disease (PD), and normal healthy control subjects, were studied using the dopamine transporter tracer [99mTc]TRODAT-1 and single photon emission tomography (SPECT). The sample used in this study was comprised of 81 PD patients (mean ageplusmnSD, 63.4plusmn10.4 y; age range, 39.0-84.2 y), and 94 healthy controls (mean ageplusmnSD, 61.8plusmn11.0 y; age range, 40.9-83.3 y). A standardized template containing six regions-of-interest (ROIs) was transposed onto subregions of the right and left basal ganglia. In addition, all images were coregistered to a standard [99mTc]TRODAT-1 template. The three slices corresponding to the striatum were extracted and summed into a single transverse slice. These single-slice images were used in a human observer study, using four experienced investigators. Each observer was asked to rate their confidence that each randomly selected image had the appearance of a healthy control subject, or a patient with PD. The data from the observer study was analyzed using a receiver operating characteristic (ROC) analysis. The area under the ROC curve (AUC) indicated the accuracy with which each observer identified each subject. In a similar manner, the ROI data was also analyzed using a ROC curve. The observer analysis gave a more accurate diagnosis (AUC=0.93plusmn0.02) than the ROI technique (AUC=0.90plusmn0.02). This suggests that the human observers are visually acquiring more information from the images than is contained in the quantitative striatal uptake alone. Indeed, it is likely that the pattern of uptake of the tracer is of more significance than the absolute uptake, which has implications for the analysis of radionuclide images using quantitative techniques

Rationale and Objectives Introduction of suicide genes, such as herpes simplex virus type1 thymidine kinase (HSV1-tk), in tumor cells has provided a useful method for tumor gene therapy. Several L-nucleosides, such as Lamivudine (3TC) and Clevudine (L-FMAU), have been successfully tested as high-potency antiviral agents. To investigate the potential differences between D- and L-isomers of nucleosides, [125/123I]-2’-fluoro-2’-deoxy-1β-D/L-arabino-furanosy-5-iodo-uracil (D/L-FIAU) have been synthesized and evaluated as potential SPECT agents for imaging HSV1-tk gene expression. Materials and Methods [125/123I]D- and L-FIAU were prepared by iododestannylation of the respective tin precursors with 125/123I-sodium iodide. In vitro cell uptake studies were performed by incubation of [125I]D- and L-FIAU in RG2 cells expressing HSV1-tk (RG2TK+). In vivo studies including biodistribution and SPECT were performed in RG2TK+ and RG2TK− tumor-bearing nude mice using [123I]D- and L-FIAU. Results Cell uptake and biodistribution studies indicated that [125/123I]L-FIAU did not show any high accumulation (sensitivity) or uptake ratios (selectivity) in HSV1-TK-positive (RG2TK+) tumors as compared to control tumors. In contrast, [125/123I]D-FIAU displayed both sensitivity and selectivity to RG2TK+ tumors. The selective in vivo accumulation of [123I]D-FIAU increased with time and the tumor uptake ratios (RG2TK+/RG2TK−) for 2, 4, and 24 hours averaged 6.2, 22.7, and 58.8, respectively. High-resolution SPECT of four nude tumor-bearing mice demonstrated a very high uptake of [123I]D-FIAU in the RG2TK+ tumor, while no significant tracer accumulation was observed in the RG2TK− tumor and other organs. Conclusion The data suggest that only the D-isomer of [123I]FIAU is useful for imaging HSV1-tk gene expression in mice by high-resolution SPECT imaging.

Quantification provides the link between the concentrations of radioactivity measured in tissue and the underlying physiologic processes occurring in the organ. It relates the rate at which radioactivity levels in the body change over time to quantitative parameters such as absolute rate glucose metabolism, regional blood flow, or concentrations of receptors or other binding sites. Absolute measurement of physiologic parameters generally requires accurate measurement of activity concentrations in arterial blood, which provides the input function to the kinetic model. Although absolute quantification can be a difficult process, simplifications of these invasive techniques, involving reference tissues or normalization approaches (eg, SUV), have been applied with some success. Any simplified model of tracer behavior must be validated against the full model to test for bias and systematic errors.

Imaging serotonin transporters (SERT) is an emerging research tool potentially useful to cast light on the mechanisms of drug action as well as to monitor the treatment of depressed patients. We have prepared two new derivatives of 3, 2-(2-(dimethylaminomethyl)phenoxy)-5-iodophenylamine (4) and 2-(2-(dimethylaminomethyl)benzyl)-5-iodophenylamine (5) (K(i) for SERT = 0.37 and 48.6 nM, respectively). Both [(125)I]4 and [(125)I]5 displayed excellent brain uptakes in rats, and they showed a highest uptake in hypothalamus (between 60 and 240 min), a region populated with the highest density of SERT. The specific uptake of [(125)I]4 in the hypothalamus resulted in a target to nontarget ratio ([hypothalamus-cerebellum]/cerebellum) of 4.3 at 2 h. Autoradiography of rat brain sections (ex vivo at 2 h) of [(125)I]4 showed an excellent regional distribution pattern consistent with known SERT localization. These data suggest that [(123)I]4 may be useful for imaging SERT binding sites in the brain by single photon emission computed tomography (SPECT).

Multiple system atrophy (MSA), a disorder causing autonomic dysfunction, parkinsonism, and cerebellar dysfunction, is difficult to differentiate from other movement disorders, particularly early in the course of disease. This study evaluated whether [99mTc]TRODAT-1 binding to the dopamine transporter differentiates MSA from other movement disorders. Single-photon emission computed tomographic brain scans were acquired in 25 MSA patients, 48 age-matched controls, and 130 PD patients, 3 h after the injection of 740 MBq (20 mCi) of [99mTc]TRODAT-1. Regions of interest (ROIs) were placed manually on subregions of both basal ganglia and distribution volume ratios (DVRs) were calculated. Regional DVRs were compared between study groups in MSA patients. Student’s t tests were used to compare MSA patients with other study groups. Spearman correlations were used to compare DVRs with NP measures. Based upon various motor scores, MSA and PD patients had comparable motor impairment, and were significantly impaired compared with controls. Mean DVRs in the basal ganglia of MSA patients were significantly less than those of controls, but generally higher (p

Molecular imaging of small animals in vivo is vital in the study of mouse and rat models of human diseases, and will provide important clues to the pathogenesis, progression and treatment of many disorders. Functional imaging of small animals using ultra-high resolution single photon emission tomography (SPECT) should be a valuable tool in the molecular imaging armamentarium. SPECT has been used to study cerebral binding sites, to image the expression of reporter genes, and in applications in cardiology and oncology. In this review, we summarize the most recent developments in SPECT imaging of small animals, with particular reference to the types of systems available, their application, and some of the potential limitations.

Functional imaging of small animals, such as mice and rats, using ultra-high-resolution positron emission tomography (PET) and single-photon emission tomography (SPET) should be a valuable tool in studies of drug occupancy of cerebral binding sites. In this study we aimed to demonstrate the feasibility of using ultra-high-resolution SPET to measure the occupancy of dopamine D2 receptors by a competing drug, using the dopamine D2 receptor-specific radioligand iodine-123 5-iodo-7-N-[(1-ethyl-2-pyrrolidinyl) methyl] carboxamido-2,3-dihydrobenzofuran ([123I]IBF). Fourteen normal male mice (CD-1) were jugular vein-cannulated and a bolus infusion protocol was used to deliver 360 MBq [123I]IBF into the mouse (bolus-to-infusion ratio 1.8:1). The mice were scanned using an ultra-high-resolution triple-headed SPET system equipped with pinhole collimators. After sustained equilibrium had been achieved, varying doses of raclopride, a potent dopamine D2 receptor antagonist, were injected through the tail vein and the tracer was allowed to regain equilibrium. A simple equilibrium ratio of striatum to cerebellum provided a measure of D2 receptor binding both before and after injection of raclopride. Following raclopride administration, the system returned to equilibrium with lower specific binding in the striatum, while the counts in the cerebellum were unaffected. Receptor occupancy was 5.2% +/- 2.9% (control), 52.1% +/- 11.1% (0.3 mg/kg), 79.3% +/- 4.8% (1.0 mg/kg), and 94.7% +/- 2.2% (3.0 mg/kg), which gave an ED50=0.26 +/- 0.03 mg/kg using a single receptor site saturation model. This study has demonstrated clearly that ultra-high-resolution SPET of small animals is capable of measuring displacement and occupancy of dopamine D2 receptors by competing ligands.

Methylphenidate (MPH) is an effective symptomatic treatment of attention deficit hyperactivity disorder (ADHD), but the mechanisms of its therapeutic action have not been fully elucidated. To address this issue, we assessed the effects of discontinuation of chronic MPH treatment on regional cerebral blood flow (rCBF) in ADHD patients.Twenty-two prepubescent boys with ADHD (age range, 8.2-11.5 y) and 7 healthy volunteers were studied with SPECT on and off MPH. Their rCBF data were automatically normalized to whole-brain counts and coregistered with standard anatomic space. rCBF changes were evaluated with statistical parametric mapping based on voxel-by-voxel ANOVA.When the subjects were not taking MPH, rCBF was higher in the motor, premotor, and the anterior cingulate cortices (Brodmann's areas 4, 6, and 32).Brief discontinuation of MPH treatment is associated with increased motor and anterior cingulate cortical activity. Our findings suggest that MPH treatment modulates motor and anterior cingulate cortical activity directly or indirectly. Alternatively, our findings may be related to MPH withdrawal. These data provide novel information on the potential mechanisms of the therapeutic action of MPH. Furthermore, they are clinically relevant to the commonly occurring brief interruptions in MPH treatment.

Depression is a recognized feature of epilepsy. This study tested the hypothesis that depression arising in patients with epilepsy would be associated with decreased activity in brain regions previously demonstrated to be hypoperfused both in primary depression and in depression secondary to movement disorders. Two groups of patients with temporal lobe epilepsy were studied, one of which also met DSM IV criteria for a major depressive episode. All underwent a SPECT scan using the blood flow marker, 99m Tc-HMPAO. An automated voxel-based analysis demonstrated no regions of relatively decreased activity in the depressed compared with the non-depressed patients. Sites of relative hyperactivity in the depressed group were concentrated in the left hemisphere, particularly in dorsolateral prefrontal cortex, striatum, thalamus and temporo-parietal regions. Comparison of these data with normal population data revealed that in the depressed epilepsy group regional activities were within the normal range whilst corresponding results from the non-depressed group were below it. Depressed patients with epilepsy have cerebral regions with greater perfusion than non-depressed people with epilepsy, although they are not hyperperfused compared with normals. Our results suggest that depression in people with epilepsy may arise from a mechanism which differs from that underlying the development of depression in patients with movement disorders.

Positron emission tomography (PET) and single-photon emission tomography (SPET) imaging of the dopaminergic system is a powerful tool for distinguishing groups of patients with neurodegenerative disorders, such as Parkinson's disease (PD). However, the differential diagnosis of individual subjects presenting early in the progress of the disease is much more difficult, particularly using region-of-interest analysis where small localized differences between subjects are diluted. In this paper we present a novel pixel-based technique using logistic discriminant analysis to distinguish between a group of PD patients and age-matched healthy controls. Simulated images of an anthropomorphic head phantom were used to test the sensitivity of the technique to striatal lesions of known size. The methodology was applied to real clinical SPET images of binding of technetium-99m labelled TRODAT-1 to dopamine transporters in PD patients (n=42) and age-matched controls (n=23). The discriminant model was trained on a subset (n=17) of patients for whom the diagnosis was unequivocal. Logistic discriminant parametric maps were obtained for all subjects, showing the probability distribution of pixels classified as being consistent with PD. The probability maps were corrected for correlated multiple comparisons assuming an isotropic Gaussian point spread function. Simulated lesion sizes measured by logistic discriminant parametric mapping (LDPM) gave strong correlations with the known data (r(2)=0. 985, P0.001). LDPM correctly classified all PD patients (sensitivity 100%) and only misclassified one control (specificity 95%). All patients who had equivocal clinical symptoms associated with early onset PD (n=4) were correctly assigned to the patient group. Statistical parametric mapping (SPM) had a sensitivity of only 24% on the same patient group. LDPM is a powerful pixel-based tool for the differential diagnosis of patients with PD and healthy controls. The diagnosis of disease even before clinical symptoms become apparent may be possible, and ultimately this technique could be most useful in differentiating between several neurodegenerative disorders, incorporating images of multiple neuroreceptor systems.

A new radioligand, 5-iodo-2-[[2-2-[(dimethylamino)methyl]phenyl]thio]benzyl alcohol ([(123)I]IDAM), has been developed for selective single-photon emission tomography (SPET) imaging of SERT. In vitro binding studies suggest a high selectivity of IDAM for SERT (K(i)=0.097 nM), with considerably lower affinities for norepinephrine and dopamine transporters (NET K(i)= 234 nM and DAT K(i)10 microM, respectively). In this study the biodistribution of SERT in the baboon brain was investigated in vivo using [(123)I]IDAM and SPET imaging. Dynamic sequences of SPET scans were performed on three female baboons (Papio anubis) after injection of 555 MBq of [(123)I]IDAM. Displacing doses (1 mg/kg) of the selective SERT ligand (+)McN5652 were administered 90-120 min after injection of [(123)I]IDAM. Similar studies were performed using a NET inhibitor, nisoxetine, and a DAT blocker, methylphenidate. After 60-120 min, the regional distribution of tracer within the brain reflected the characteristic distribution of SERT, with the highest uptake in the midbrain area (hypothalamus, raphe nucleus, substantia nigra), and the lowest uptake in the cerebellum (an area presumed free of SERT). Peak specific binding in the midbrain occurred at 120 min, with a ratio to the cerebellum of 1.80+/-0.13. At 30 min, 85% of the radioactivity in the blood was metabolite. Following injection of a competing SERT ligand, (+)McN5652, the tracer exhibited rapid washout from areas with high concentrations of SERT (dissociation rate constant in the midbrain, averaged over three baboons, k(off)=0. 025+/-0.002 min(-1)), while the cerebellar activity distribution was undisturbed (washout rate 0.0059+/- 0.0003 min(-1)). Calculation of tracer washout rate pixel-by-pixel enabled the generation of parametric images of the dissociation rate constant. Similar studies using nisoxetine and methylphenidate had no effect on the distribution of [(123)I]IDAM in the brain. These results suggest that [(123)I]IDAM is suitable for selective SPET imaging of SERT in the primate brain, with high contrast, favorable kinetics, and negligible binding to either NET or DAT.

Accurate quantification of neuroreceptors requires full kinetic modeling of the dynamic single-photon emission tomography (SPET) or positron emission tomography (PET) images, with highly invasive arterial blood sampling. This study investigated the application of a reference region kinetic model to the dynamics of [99mTc]TRODAT-1 in nonhuman primates, obviating the need for blood sampling. A series of dynamic SPET scans were performed on two baboons following the injection of approximately 700 MBq of [99mTc]TRODAT-1. Rapid arterial blood samples were taken automatically during scanning. Reconstructed SPET images were coregistered with magnetic resonance imaging (MRI) scans of the baboons, and regions of interest (ROIs) placed on the striatum, cerebellum and cerebral hemispheres. The ROI data were combined with metabolite-corrected blood data, and fitted to a three-compartment kinetic model using nonlinear least squares techniques. The same data were also used in a simplified reference region model, in which the input function was derived from the nondisplaceable tissue compartment. In addition, semiquantitative blinded analysis was performed by three raters to determine the point of transient equilibrium in the specific binding curves. All methods generated values for the ratio of the kinetic rate constants k3/k4, which gives an estimate of the binding potential, BP. These were compared with the full kinetic model. The mean values of k3/k4 for the three different analysis techniques for each baboon were: 1.17 +/- 0.21 and 1.12 +/- 0.13 (full kinetic model), 0.93 +/- 0.13 and 0.90 +/- 0.07 (reference region model), and 0.97 +/- 0.18 and 0.92 +/- 0.08 (equilibrium method). The reference region method gave significantly lower results than the full kinetic model (P = 0.01), but it also produced a much smaller spread and better quality fits to the kinetic data. The reference region model results for k3/k4 correlated very strongly with the full kinetic analysis (r2 = 0.992, P < 0.001), and with the equilibrium model (r2 = 0.88, P = 0.002). The subjectivity inherent in the equilibrium method produces inferior results compared with both kinetic analyses. It is suggested that the self-consistency of the reference region model, which requires no arterial blood sampling, provides a more precise and reliable estimate of the binding of [99mTc]TRODAT-1 to dopamine transporters than full kinetic modeling. The reference region method is also better suited to a routine clinical environment, and would be able to distinguish smaller differences in dopaminergic function between patient groups.

The segmentation of medical images is one of the most important steps in the analysis and quantification of imaging data. However, partial volume artefacts make accurate tissue boundary definition difficult, particularly for images with lower resolution commonly used in nuclear medicine. In single-photon emission tomography (SPET) neuroreceptor studies, areas of specific binding are usually delineated by manually drawing regions of interest (ROIs), a time-consuming and subjective process. This paper applies the technique of fuzzy c-means clustering (FCM) to automatically segment dynamic neuroreceptor SPET images. Fuzzy clustering was tested using a realistic, computer-generated, dynamic SPET phantom derived from segmenting an MR image of an anthropomorphic brain phantom. Also, the utility of applying FCM to real clinical data was assessed by comparison against conventional ROI analysis of iodine-123 iodobenzamide (IBZM) binding to dopamine D2/D3 receptors in the brains of humans. In addition, a further test of the methodology was assessed by applying FCM segmentation to [123I]IDAM images (5-iodo-2-[[2-2-[(dimethylamino)methyl]phenyl]thio] benzyl alcohol) of serotonin transporters in non-human primates. In the simulated dynamic SPET phantom, over a wide range of counts and ratios of specific binding to background, FCM correlated very strongly with the true counts (correlation coefficient r2>0.99, P

One early effect of the treatment of tumours by the new modality photodynamic therapy (PDT) is a reduction in tumour glucose levels. We have employed the widely used positron-emitting glucose analogue flurorine-18 fluoro-2-deoxy-D-glucose ([18F]-FDG), to determine whether, in principle, PDT-induced injury might be delineated non-invasively and quantitatively by positron emission tomography (PET). The scanner was of the high-density avalanche-chamber (HIDAC) type with a resolution of 2.6 mm. Subcutaneous T50/80 mouse mammary tumours, sensitised by haematoporphyrin ester, were illuminated by graded doses of interstitial 630 nm light. Thirty hours later, any remaining viable tumour was detected (a) by region-of-interest analysis of the PET images and (b) by gamma counting the excised tumour. PET measurements of % uptake of [18F]-FDG into tumour correlated closely with ex vivo gamma counting (slope=0.976, r2=0. 995), validating the in situ method. Uptake into untreated, control tumours was 3.8%+/-1.1% of the injected activity. Uptake of [18F]-FDG into treated tumours decreased by 0.7% for every 100 mm3 reduction in remaining viable histological volume. Outcome was further compared with that measured by (a) T2-weighted proton imaging on a 4.7-T magnetic resonance imaging (MRI) system and (b) histological analysis of subsequently sectioned tumours. PET using [18F]-FDG described the absolute volume of surviving tumour histological mass to the same degree as high-resolution MRI. The conclusion of these initial studies is that PET with [18F]-FDG, although non-specific, quantitatively described at early times the extent of tumour destruction by PDT.

This paper describes the application of a multivariate statistical technique to investigate striatal dopamine D2 receptor concentrations measured by iodine-123 iodobenzamide (123I-IBZM) single-photon emission tomography (SPET). This technique enables the automatic segmentation of dynamic nuclear medicine images based on the underlying time-activity curves present in the data. Once the time-activity curves have been extracted, each pixel can be mapped back on to the underlying distribution, considerably reducing image noise. Cluster analysis has been verified using computer simulations and phantom studies. The technique has been applied to SPET images of dopamine D2 receptors in a total of 20 healthy and 20 schizophrenic volunteers (22 male, 18 female), using the ligand 123I-IBZM. Following automatic image segmentation, the concentration of striatal dopamine D2 receptors shows a significant left-sided asymmetry in male schizophrenics compared with male controls. The mean left-minus-right laterality index for controls is -1.52 (95% CI -3.72-0.66) and for patients 4.04 (95% CI 1.07-7.01). Analysis of variance shows a case-by-sex-by-side interaction, with F=10.01, P=0. 005. We can now demonstrate that the previously observed male sex-specific D2 receptor asymmetry in schizophrenia, which had failed to attain statistical significance, is valid. Cluster analysis of dynamic nuclear medicine studies provides a powerful tool for automatic segmentation and noise reduction of the images, removing much of the subjectivity inherent in region-of-interest analysis. The observed striatal D2 asymmetry could reflect long hypothesized disruptions in dopamine-rich cortico-striatal-limbic circuits in schizophrenic males.

6motile sperm cells per mL, the inclusion criterion for the use of ICSI in the Netherlands. Both oligozoospermic (n=69) and azoospermic (n=11) men were included. All patients were karyotyped, and a consecutive subgroup (n=58) was also tested for Y-chromosomal deletions and CFTR mutations. We found an abnormal karyotype in peripheral blood lymphocytes in seven (8·8%) of 80 patients, ten-fold more than the overall population incidence of 0·85% 2 (p

1. Acton PD, Choi SR, Plossl K, Kung HF. Quantification of dopamine transporters in the mouse brain using ultra-high resolution single photon emission tomography. Eur J Nucl Med 2002; DOI 10.1007/s00259-002-0776-7 2. Rosen GD, Williams AG, Capra JA, Connolly MT, Cruz B, Lu L, Airey DC, Kulkarni K, Williams RW. The Mouse Brain Library @ www.mbl.org. Int Mouse Genome Conference 2000; 14: 166 Paul D. Acton (✉) Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA e-mail: pacton@sunmac.spect.upenn.edu Tel.: +1-215-349-8374, Fax: +1-215-349-5035 Image of the month