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Purpose: Scans without evidence of dopaminergic deficit (SWEDD) have been initially described in a minority of subjects with suspected Parkinson's disease (PD). Although a highly controversial entity, longitudinal studies showed that SWEDD cases mostly involve non-degenerative conditions mimicking PD or misattribution of scan images to normal status. Using the Parkinson's Progression Markers Initiative (PPMI) cohort, we undertook a case-controlled analysis of [123I]N-ω-fluoropropyl-2β-carbomethoxy-iodophenyl nortropane ([123I]FP-CIT) single photon emission computed tomography (SPECT) images to measure extrastriatal serotonergic transporter (SERT) density in SWEDD and PD. Procedures: We included 37 SWEDD cases (mean age 60 years, 33 % female) with available [123I]FP-CIT SPECT imaging and high-resolution T1-weighted magnetic resonance imaging (MRI) for coregistration. Sixty-one controls and 62 similarly aged PD subjects were included for group comparisons. Regional [123I]FP-CIT was extracted with PETPVE12 using geometric transfer matrix and partial volume effect correction. Results: PD subjects showed significantly lower [123I]FP-CIT binding in both striatal (caudate nucleus and putamen) and extrastriatal regions (pallidum and insula) compared with controls and SWEDD (all between-group p < 0.0001). PD group also showed lower binding in the thalamus relative to controls (p = 0.007). Receiver operating characteristics (ROC) area under the curve (AUC) did not show a significant difference when using extrastriatal region in addition to striatal ROIs for the separation of SWEDD and PD (95 % ROC-AUC for both methods, p = 0.52). In addition, striatal [123I]FP-CIT binding contralateral to the clinically more affected side was usually lower for PD (> 75 %) but not for SWEDD (< 49 %, p < 0.002). No significant difference regarding [123I]FP-CIT binding was observed between SWEDD and controls. Conclusion: These findings corroborate the view that SWEDD cases represent a heterogeneous group of conditions not involving dopaminergic and serotonergic terminals. Further studies are warranted to be assessed whether using extrastriatal [123I]FP-CIT evaluation can be of help in the assessment of degenerative parkinsonism. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this multicenter trial was to generate a [123I]FP-CIT SPECT database of healthy controls from the common SPECT systems available in Japan.Methods: This study included 510 sets of SPECT data from 256 healthy controls (116 men and 140 women; age range, 30-83 years) acquired from eight different centers. Images were reconstructed without attenuation or scatter correction (NOACNOSC), with only attenuation correction using the Chang method (ChangACNOSC) or X-ray CT (CTACNOSC), and with both scatter and attenuation correction using the Chang method (ChangACSC) or X-ray CT (CTACSC). These SPECT images were analyzed using the Southampton method. The outcome measure was the specific binding ratio (SBR) in the striatum. These striatal SBRs were calibrated from prior experiments using a striatal phantom.Results: The original SBRs gradually decreased in the order of ChangACSC, CTACSC, ChangACNOSC, CTACNOSC, and NOACNOSC. The SBRs for NOACNOSC were 46% lower than those for ChangACSC. In contrast, the calibrated SBRs were almost equal under no scatter correction (NOSC) conditions. A significant effect of age was found, with an SBR decline rate of 6.3% per decade. In the 30-39 age group, SBRs were 12.2% higher in women than in men, but this increase declined with age and was absent in the 70-79 age group.Conclusions: This study provided a large-scale quantitative database of [123I]FP-CIT SPECT scans from different scanners in healthy controls across a wide age range and with balanced sex representation. The phantom calibration effectively harmonizes SPECT data from different SPECT systems under NOSC conditions. The data collected in this study may serve as a reference database. [ABSTRACT FROM AUTHOR]

ABSTRACT The reuptake and release of dopamine (DA) can be estimated using in vivo imaging methods by assessing the competition between endogenous DA and an administered exogenous DA transporter (DAT) and D2 receptor (D2R) radioligand, respectively. The aim of this study was to investigate the comparative roles of DA release vs DA reuptake in the rat striatum with small animal SPECT in relation to l-DOPA-induced behaviors. DAT and D2R binding, together with behavioral measures, were obtained in 99 rats in response to treatment with either 5 or 10 mg/kg l-DOPA or vehicle. The behavioral parameters included the distance travelled, and durations and frequencies of ambulation, sitting, rearing, head-shoulder motility, and grooming. Data were subjected to a cluster analysis and to a multivariate principal component analysis. The highest DAT binding (i.e., the lowest DA reuptake) was associated with the highest, and the lowest DAT binding (i.e., the highest DA reuptake) was associated with the lowest motor/exploratory activity. The highest and the lowest D2R binding (i.e., the lowest and the highest DA release, respectively) were merely associated with the second highest and second lowest levels of motor/exploratory activity. These findings indicate that changes in DA reuptake in response to fluctuating DA levels offer a better prediction of motor activity than the release of DA into the synaptic cleft. This dissociation, as reflected by in vivo DAT and D2R binding data, may be accounted for by the regulatory sensitization meachnisms that occur at D2R binding sites in response to altered levels of DA. Synapse 70:369-377, 2016. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Background: Little is known about the underlying mechanisms of clinical symptoms in dementia with Lewy bodies. The aim of this study was to explore the association between loss of striatal dopamine transporter binding and symptoms in dementia with Lewy bodies.Methods: Thirty-five patients with dementia with Lewy bodies underwent single-photon emission computerized tomography brain imaging with N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane ([(123) I]FP-CIT). Associations between striatal binding ratios and motor (UPDRS), psychiatric (Neuropsychiatric Inventory; [NPI]), and cognitive (Mini-Mental State Examination [MMSE] and neuropsychological tests) symptoms were assessed by linear regression analysis.Results: The explorative analysis showed that the motor UPDRS was negatively associated with putamen dopamine transporter binding, whereas no association with striatal dopamine transporter binding was found for total NPI, hallucinations, apathy, depression, anxiety, and MMSE scores. However, in post-hoc analysis, executive impairment was positively associated with dopamine transporter loss after adjustment of age and gender.Conclusions: Dopamine deficiency in patients with dementia with Lewy bodies was associated with severity of motor symptoms, but did not correlate significantly with ratings of neurobehavioral disturbances or overall cognition. [ABSTRACT FROM AUTHOR]

ABSTRACT Objectives Aim of this study was to quantify the binding of [123I]FP-CIT in striatum of healthy tree shrews. [123I]FP-CIT is widely used in clinical SPECT imaging to reveal nigrostriatal degeneration in aid of the diagnosis of clinically uncertain parkinsonian syndromes. Despite its wide clinical use, the saturation binding parameters of [123I]FP-CIT for the dopamine transporter (DAT) have not yet been determined in any mammalian brain. Tree shrews are genetically and neuroanatomically more similar to humans than are rodents and might therefore be a valuable animal model for research of neurological disorders involving brain dopamine. Experimental Design Quantitative in vitro autoradiography with [123I]FP-CIT was performed with brains of healthy tree shrews and, for comparison, brains of healthy rats. Dopamine D2/3 receptor autoradiography with [3H]raclopride was also performed. Principal observations Saturation analysis revealed high specificity of [123I]FP-CIT for DAT in the striatum with considerably higher affinity in tree shrews than in rats ( KD = 10.3 versus 36.4 nM). The density of DAT binding sites also was higher in tree shrews than in rats ( Bmax = 2499 versus 1495 pmol/g wet weight (ww)). [3H]raclopride revealed D2/3 receptors in the tree shrew striatum with about the same density as in rats ( Bmax = 78.4 versus 84.1 pmol/g ww), but with slightly lower affinity in tree shrews ( KD = 1.27 versus 0.59 nM). Conlusions The higher affinity in combination with the higher abundance of DAT binding sites compared to rat striatum predicts substantially higher binding of [123I]FP-CIT in SPECT studies of living tree shrews. Synapse 69:497-504, 2015. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

ABSTRACT Cognitive impairment in Parkinson's disease (PD) is common and does directly impact patients' everyday functioning. However, the underlying mechanisms of early cognitive decline are not known. This study explored the association between striatal dopaminergic deficits and cognitive impairment within a large cohort of early, drug-naïve PD patients and tested the hypothesis that executive dysfunction in PD is associated with striatal dopaminergic depletion. A cross-sectional multicenter cohort of 339 PD patients and 158 healthy controls from the Parkinson's Progression Markers Initiative study was analyzed. Each individual underwent cerebral single-photon emission CT (SPECT) and a standardized neuropsychological assessment with tests of memory as well as visuospatial and executive function. SPECT imaging was performed with [123I]FP-CIT, and specific binding ratios in left and right putamen and caudate nucleus were calculated. The association between specific binding ratios, cognitive domain scores, and age was analyzed using Pearson's correlations, partial correlation, and conditional process analysis. A small, but significant, positive association between total striatal dopamine transporter binding and the attention/executive domain was found (r = 0.141; P = 0.009) in PD, but this was not significant after adjusting for age. However, in a moderated mediation model, we found that cognitive executive differences between controls and patients with PD were mediated by an age-moderated striatal dopaminergic deficit. Our findings support the hypothesis that nigrostriatal dopaminergic deficit is associated with executive impairment, but not to memory or visuospatial impairment, in early PD. © 2014 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

ABSTRACT OBJECTIVE To review [123I]FP-CIT (Ioflupane I 123, DaTscan) SPECT imaging and its role in clinical practice. BACKGROUND [123I]FP-CIT is a radiopharmaceutical that binds reversibly to striatal presynaptic dopamine transporters. METHODS We review the two principal multicenter clinical trials of [123I]FP-CIT SPECT imaging and provide additional, previously unreported information. Study 1 was a trial of [123I]FP-CIT SPECT in patients with early suspected parkinsonism that compared baseline scans to the consensus clinical diagnosis established 3 years later. Study 2 was a trial of [123I]FP-CIT SPECT in patients with established diagnoses of parkinsonian syndrome (PS) or essential tremor (ET). RESULTS In Study 1, positive percent agreement (abnormal baseline scan and clinical diagnosis of PS at 36 months [ n= 71]) was 78-79%. Negative percent agreement (normal baseline scan and a clinical diagnosis of non-PS at 36 months [ n= 28]) was 97%. In study 2, positive percent agreement (abnormal scan and a clinical diagnosis of PS [ n= 158]) was 92-97%. Negative percent agreement (normal scan and a clinical diagnosis of ET [ n= 27]) was 74-96%. CONCLUSION [123I]FP-CIT SPECT brain imaging is used to assist in the evaluation of adult patients with suspected PS and may help differentiate ET from PS as an adjunct to other diagnostic evaluations. [ABSTRACT FROM AUTHOR]

The mechanisms by which deep brain stimulation (DBS) of the subthalamic nucleus (STN) leads to clinical benefit in Parkinson’s disease (PD), especially with regard to dopaminergic transmission, remain unclear. Therefore, the objective of our study was to evaluate alterations of synaptic dopaminergic signaling following bilateral STN-DBS in advanced PD within a one-year follow-up. We used [123I]FP-CIT single-photon emission computed tomography (SPECT) to measure dopamine transporter (DAT) availability and [123I]IBZM SPECT to assess dopamine D2 receptor (D2R) availability (stimulator ON condition). Patients (n = 18) showed a tendency towards a better suppression of symptoms after STN-DBS (Unified Parkinson’s Disease Rating Scale motor score with medication decreased from 24. 1 ± 16. 1 to 15. 4 ± 7. 45; p = 0. 002) while medication was strongly reduced (61 % reduction of levodopa equivalent units; p < 0. 0001). No changes of striatal [123I]FP-CIT binding and an increase of [123I]IBZM binding up to 16 % (p < 0. 05) between pre-surgery and follow-up investigations were noticed. These data show that clinical improvement and reduction of dopaminergic drugs in patients with advanced PD undergoing bilateral STN-DBS are paralleled by stable DAT and recovery of striatal D2R availability 12 months after surgery. [ABSTRACT FROM AUTHOR]

Single-photon emission computed tomography (SPECT) markers allow measuring the integrity of the brain dopaminergic system in vivo. We used dopamine transporter (DAT) SPECT with [123I]FP-CIT and dopamine D2/D3 receptor SPECT with [123I]IBZM to evaluate whether there is a reduction of DAT and/or D2/D3 receptor SPECT in treated and untreated patients with Parkinsonian syndrome (PS). We found that almost a quarter of our patients treated with anti-Parkinsonian medication prior to SPECT imaging did not show evidence of a presynaptic dopaminergic deficit while 37% of untreated patients were diagnosed as having Parkinson’s disease. 17% of treated patients had additional loss of D2/D3 receptor binding capacity in concordance with the clinical follow-up diagnoses of multiple system atrophy, progressive nuclear palsy, and vascular Parkinsonism. Apart from 38% clinically uncertain cases, SPECT was in concordance with 75% of initial clinical diagnoses. 25% were reclassified as indicated by SPECT findings and confirmed by a 1.5-year clinical follow-up. We conclude that dopamine SPECT may support establishing or refuting the clinical diagnosis and, therefore, help to make the decision for or against dopaminomimetic treatment in cases with PS. [ABSTRACT FROM AUTHOR]

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 &verbar;123&verbar;FP-CIT. Methods: &verbar;123&verbar;FP-CIT was administered intravenously 1 h after intrapentoneal injection of methylphenidate (10 mg/kg) or vehicle. Animals underwent scanning 2 h after radioligand administration. The striatum was identified by superimposition of &verbar;123&verbar;FP-CIT scans with hone metabolism and perfusion scans obtained with 99mTcDPD and 99mTc-tetrofosmin, respectively. As these tracers do not pass the blood-brain harrier, their distribution permits the identification of extracerebral anatomical landmarks such as the orbitae and the harderian glands. The cerebellum was identified by superimposing &verbar;123&verbar;FP-CIT scans with images of brain perfusion obtained with 99mTc-HMPAO. Results: Methyl-phenidate-treated animals and vehicle-treated animals yielded striatal equilibrium ratios (V"3) of 0.24±0.26 (mean ± SI)) and 1.09±0.42, respectively (t test, two-tailed, p<0.0001). Cortical V"3 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 &verbar;123&verbar;FP-CIT accumulation. Conclusion: The results can he interpreted in terms of a pharmacological blockade in the rat striatum and show that in vivo quantitation of dopamine transporter binding is feasible with &verbar;123&verbar;FP-CIT and the TierSPECT. This may he of future relevance br in vivo investigations on rat models of attention deficit/hyperactivity disorder. Furthermore, our lindings suggest that investigations in other animal models, e.g. of Parkinson's and Huntington's disease, may be feasible using SPECT radioligands and small animal imaging systems. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]