Validation of a standardized normalization template for statistical parametric mapping analysis of 123I-FP-CIT images.

(123)I-FP-CIT ((123)I-N-omega-fluoropropyl-2beta-carbomethoxy-3beta-(4-iodophenyl)nortropane) is a SPECT dopamine transporter (DAT) tracer that probes dopaminergic cell loss in Parkinson's disease (PD). Quantification of (123)I-FP-CIT images is performed at equilibrium using a ratio (BR) of specific (striatal) to nonspecific (occipital) uptake with values obtained from regions of interest drawn manually over these structures. Statistical parametric mapping (SPM) is a fully automated voxel-based statistical approach that has great potential in the context of DAT imaging. However, the accuracy of the spatial normalization provided by SPM has not been validated for (123)I-FP-CIT images. Our first aim was to create an (123)I-FP-CIT template that does not require the acquisition of patient-specific MRI and to validate the spatial normalization procedure. Next, we hypothesized that this customized template could be used by different SPECT centers without affecting the outcomes of imaging analyses. METHODS: The spatial normalization to the customized template created with SPM (template A1) was validated using (123)I-FP-CIT images obtained from 6 subjects with essential tremor (ET) with normal DAT status and 6 PD patients. Variability in BR values due to the normalization was evaluated using striatal volume of interest (VOI). To determine whether different SPECT centers could use a unique (123)I-FP-CIT template, we generated 3 other (123)I-FP-CIT templates using different subjects and image-processing schemes. The interchangeability of these templates was assessed using (a) putamen BR values analyzed with the intraclass correlation coefficient (ICC) and the Bland-Altman graphical analysis, and (b) SPM analysis comparing the results of group comparisons-that is, ET versus PD, obtained after normalization to each of the 4 templates. RESULTS: There was no significant difference between pre- and post-normalization striatal BR values in our study. The mean variability calculated with putamen VOI values after normalization to each template was <10%, with the lowest ICC of 98%. Intergroup analyses performed with VOI and SPM approaches provided similar results independently of the template used. CONCLUSION: SPM normalization was accurate even in subjects with low striatal (123)I-FP-CIT uptake, making it a promising approach for automatic analysis of (123)I-FP-CIT images using a single customized template at different centers.     

Is iterative reconstruction an alternative to filtered backprojection in routine processing of dopamine transporter SPECT studies?

In general, striatal dopamine transporter (DAT) binding is assessed by use of data reconstructed by filtered backprojection (FBP). The aim of this study was to investigate whether the use of an iterative reconstruction algorithm (ordered-subset expectation maximization [OSEM]) may provide results comparable to or even better than those obtained by standard FBP. METHODS: In 50 patients with parkinsonian syndromes, SPECT scans were acquired 4 h after injection of 185 MBq of (123)I-fluoropropyl-2beta-carbomethoxy-3beta-(4-iodophenyl)tropane ((123)I-FP-CIT) by use of a triple-head gamma-camera fitted with low-energy, high-resolution fanbeam collimators. After reconstruction by FBP and OSEM, data were filtered with a Butterworth filter and corrected for attenuation. Patient studies were automatically fitted to a mean template with a corresponding 3-dimensional (3D) volume-of-interest map covering the striatum, caudate, and putamen as well as an occipital reference region to calculate specific DAT binding. In addition, studies with an anthropomorphic 3D striatal phantom were performed to mimic different pathologies. RESULTS: Visual assessment of phantom and patient data suggested a better separation between the caudate and the putamen in studies reconstructed by OSEM than in those reconstructed by FBP. There was an excellent correlation between specific DAT binding assessed by OSEM and that assessed by FBP (R(2) values: striatum, 0.999; caudate, 0.998; putamen, 0.998). Mean specific striatal binding obtained by OSEM was approximately 6% lower than that obtained by FBP. In no case was diagnostic information from OSEM inferior to that from FBP. CONCLUSION: Iterative reconstruction of (123)I-FP-CIT SPECT studies for the assessment of DAT is feasible in routine clinical practice. A close correlation between FBP and OSEM data suggested that the latter also allow reliable quantification of DAT binding. Because of a better separation between the caudate and the putamen in the visual evaluation, as suggested by phantom and patient studies, OSEM may even be considered the preferable approach.     

Clinical correlation of the binding potential with <Superscript>123</Superscript>I-FP-CIT in de novo idiopathic Parkinson’s disease patients

Purpose  The aim of this study was to evaluate the accuracy of different single-photon emission computed tomography (SPECT) reconstruction techniques in measuring striatal N-ω-fluoropropyl-2β-carbomethoxy-3β-4-[¹²³I]iodophenyl-nortropane (¹²³I-FP-CIT) binding in de novo Parkinson’s disease (PD) patients, in order to find a correlation with clinical scales of disease severity in the initial phases of disease. Methods  Thirty-six de novo PD patients underwent ¹²³I-FP-CIT SPECT and MRI scan. SPECT data were reconstructed with filtered back projection (FBP), with an iterative algorithm (ordered subset expected maximization, OSEM) and with a method previously developed in our institution, called least-squares (LS) method. The ratio of specific to non-specific striatal ¹²³I-FP-CIT binding (binding potential, BP) was used as the outcome measure with all the reconstruction methods (BP_FBP, BP_OSEM, BP_LS). Results  The range of values of striatal BP_LS was significantly greater than BP_FBP and BP_OSEM. For all striatal regions, estimates of BP_FBP correlated well with BP_OSEM (r = 0.84) and with BP_LS (r = 0.64); BP_OSEM correlated significantly with BP_LS (r = 0.76). A good correlation was found between putaminal BP_LS and Hoen and Yahr, Unified PD Rating Scale (UPDRS) and lateralized UPDRS motor scores (r = −0.46, r = −0.42, r = −0.39, respectively). Neither putaminal BP_FBP nor putaminal BP_OSEM correlated with any of these motor scores. Conclusions  In de novo PD patients, ¹²³I-FP-CIT BP values derived from FBP and OSEM reconstruction techniques do not permit to differentiate PD severity. The LS method instead finds a correlation between striatal BP and disease severity scores. The results of this study support the use of ¹²³I-FP-CIT BP values estimated with the LS method as a biomarker of PD severity.     

Reproducibility of dopamine transporter density measured with<Superscript>123</Superscript>I-FPCIT SPECT in normal control and Parkinson’s disease patients

The objective of this study was to evaluate the reproducibility of 123I-FPCIT SPECT by using whole striatal region of interest (ROI) and subdivided ROI in normal controls (NC) and Parkinson's disease (PD) patients. METHODS: Ten NC and 6 PD received a SPECT scan for 6 hours postinjection of FPCIT. The distribution volume ratio (R(V)) and specific-nonspecific tissue activity ratio (RT) were measured as an outcome measure. The test/retest reproducibility of R(V) and R(T) was evaluated by calculating the test/retest difference, variability, and reliability. RESULTS: There were no significant test/retest differences for any regions in either the NC or PD. The test/retest variability/reliability of Rv was 5.53+/-4.12%/0.89 in NC, 4.50+/-5.31%/0.99 in PD with whole striatal ROI, 4.29+/-0.78%/ 0.94+/-0.03 in NC, and 6.87+/-1.23 %/0.98+/-0.01 in PD with subdivided ROI. The test/retest variability/reliability of RT was 11.1+/-10.4%/0.59 in NC, 7.84+/-8.94%/0.95 in PD with whole striatal ROI, 11.9+/-1.22%/0.65+/-0.06 in NC, and 12.2+/-4.00%/0.95+/-0.03 in PD with subdivided ROI. CONCLUSION: R(V) is highly reproducible and reliable compared with RT in both NC and PD as an outcome measure.     

Progression of dopaminergic degeneration in dementia with Lewy bodies and Parkinson’s disease with and without dementia assessed using 123I-FP-CIT SPECT

Purpose The objective of this study was to investigate the rate of progression of nigrostriatal dopaminergic loss in subjects with dementia with Lewy bodies (DLB), Parkinsons disease (PD) and PD with dementia (PDD) using serial ¹²³I-FP-CIT SPECT imaging. We hypothesised that striatal rates of decline in patients would be greater than in controls, and that DLB and PDD would show similar rates, reflecting the similarity in neurobiological mechanisms of dopaminergic loss between the two disorders.Methods We studied 20 patients with DLB, 20 with PD, 15 with PDD and 22 healthy age-matched controls. Semi-automated region of interest (ROI) analysis was performed on both baseline and repeat scans for each subject and mean striatal uptake ratios (caudate, anterior and posterior putamen) were calculated.Results Rates of decline in striatal binding between groups were assessed using ANCOVA. Significant differences between patients and controls were observed in caudate (DLB, PD, PDD, p0.01), anterior putamen (DLB, PDD, p0.05; PD, p=0.07) and posterior putamen (DLB, PD, PDD, p<0.006). Rates of decline were similar between DLB, PD and PDD.Conclusion In conclusion, this is the first study to show that significant progressive dopaminergic loss occurs in DLB and PDD using serial ¹²³I-FP-CIT SPECT. Dementia severity and motor impairment were correlated with decline, suggesting that dopaminergic loss may play an important role in cognitive as well as motor features.     

123I-FP-CIT SPECT imaging of dopamine transporters in patients with cerebrovascular disease and clinical diagnosis of vascular parkinsonism.

The purpose of our study was to prospectively evaluate the striatal uptake of 123I-labeled N-(3-fluoropropyl)-2beta-carbomethoxy-3beta-(4-iodophenyl)nortropane (FP-CIT) and the response to l-dopa therapy in patients with cerebrovascular disease (CVD) who develop clinical symptoms of vascular parkinsonism (VP). METHODS: Twenty consecutive patients who developed VP in the course of CVD were prospectively enrolled in the study. All patients had CT evidence of CVD (17 patients had lacunar infarcts, 3 patients had territorial strokes). The clinical stage of the patients was assessed using the Hoehn and Yahr scale, and the severity of the symptoms was measured using the Unified Parkinson's Disease Rating Scale score. Ten age-matched subjects were used as controls. SPECT was performed 180 min after injection of 185 MBq 123I-FP-CIT using a dual-head gamma-camera. The ratio of the mean specific-to-nonspecific striatal binding for the entire striatum, caudate, and putamen was calculated in all patients and compared with that of controls. Putamen-to-caudate binding ratios were compared as well. The response to therapy was compared between patients with normal and abnormal 123I-FP-CIT binding. RESULTS: No correlation was found between any of the clinical variables and response to therapy in patients with VP. Nine patients had normal striatal 123I-FP-CIT binding with no significant differences in striatal or subregional binding ratios compared with those of the controls. In contrast, 11 patients had significantly diminished striatal binding compared with that of controls (P < 0.001). Subanalyses showed significantly decreased binding in the caudate (P < 0.04 and P < 0.01 for the right and left caudate, respectively), diminished binding in the putamen (P < 0.04 and P < 0.01 for the right and left putamen, respectively), and a decreased putamen-to-caudate ratio on the right side (P < 0.001). The latter ratio was not significant on the left. Two of the 3 patients with territorial strokes had significantly diminished striatal 123I-FP-CIT binding in the hemisphere contralateral to the CT lesion. All 9 patients with normal scan findings had a poor response to L-dopa. Six of 11 patients with abnormal studies had no response to L-dopa, whereas 5 patients had a good response (P < 0.03). CONCLUSION: The diagnosis of VP cannot be accurately confirmed on the basis of clinical features alone because CVD may alter the typical presentation of PD. Functional imaging with 123I-FP-CIT is highly recommended in patients with CVD who develop symptoms of VP to confirm or exclude the existence of nigrostriatal dopaminergic degeneration. Identifying a subset of patients with reduced 123I-FP-CIT binding in the striatum is important for better treatment selection.     

Clinical testing of an optimized software solution for an automated, observer-independent evaluation of dopamine transporter SPECT studies.

A lack of standardized evaluation procedures for dopamine transporter (DAT) SPECT investigations impairs both intra- and interindividual comparisons as well as multicenter trials-for example, for assessment of disease progression or the response to various drug treatments. Therefore, the aim of this study was to evaluate a novel automated method, which has been specifically developed for a standardized quantification of N-(3-fluoropropyl)-2beta-carbomethoxy-3beta-(4-iodophenyl)nortropane (123I-FP-CIT) SPECT studies. METHODS: DAT binding ratios of 155 (123)I-FP-CIT SPECT studies in 14 control subjects and 141 patients referred to confirm or exclude a presynaptic dopaminergic deficit were determined manually and by a fully automated technique. The latter included coregistration of patient studies to an 123I-FP-CIT mean template of controls with specialized, nonrigid adjustment for variation in striatal location, followed by calculation of specific striatal DAT binding using a standardized 3-dimensional volume-of-interest (VOI) map. The map is based on a MR scan and covers the striatum (S), caudate (C), putamen (P), and an occipital reference region. The semiquantitative ratios of both methods were compared with the visual findings. RESULTS: Excellent linear correlations were observed between manually and automatically determined results (S: r = 0.99; C: r = 0.99; P: r = 0.99; P < 0.001, respectively). Automated evaluations delivered highly reproducible and visually exact coregistrations. Individual variations in striatal anatomy (e.g., atrophy) were considered and VOI positions were corrected before quantification. Both the manual and the automated method showed identical accuracy in supporting the visual diagnoses. CONCLUSION: In a large patient population, excellent agreement was observed between quantitative DAT results using a time-consuming, observer-dependent, conventional manual method and the objective, automated evaluation specifically developed for a standardized evaluation of 123I-FP-CIT SPECT studies. It is suggested that the novel automated technique may substantially facilitate both intra- and interindividual comparisons as well as multicenter trials.     

Quantification of striatal dopamine transporters with 123I-FP-CIT SPECT is influenced by the selective serotonin reuptake inhibitor paroxetine: a double-blind, placebo-controlled, crossover study in healthy control subjects.

Dopamine transporter (DAT) imaging with (123)I-FP-CIT ((123)I-N-omega-fluoropropyl-2beta-carbomethoxy-3beta-(4-iodophenyl)nortropane) SPECT is frequently used to detect loss of nigrostriatal cells in parkinsonism. Recent (123)I-beta-CIT ((123)I-2beta-carbomethoxy-3beta-(4-iodophenyl)tropane) studies have shown a significant increase in striatal-to-nonspecific beta-CIT binding ratios after treatment with selective serotonin reuptake inhibitors (SSRIs). Due to similarities between (123)I-beta-CIT and (123)I-FP-CIT (both are derived from cocaine and show relatively high affinity for the DAT and the serotonin transporter [SERT]), we hypothesized that quantification of striatal (123)I-FP-CIT binding may be influenced by SSRIs. Moreover, we hypothesized that (123)I-FP-CIT in humans binds not only to DATs but also to central and peripheral SERTs. METHODS: To study the influence of the SSRI paroxetine on (123)I-FP-CIT binding to DATs in the striatum, we conducted a double-blind, placebo-controlled, crossover study with paroxetine in 8 healthy young male control subjects. In addition, we studied whether paroxetine was able to block (123)I-FP-CIT binding in SERT-rich brain areas and in lung tissue, as lung tissue contains a considerable amount of SERTs. Participants were pretreated for 2 d with paroxetine (20 mg/d) or placebo at 2 sessions (crossover design), and brain SPECT was performed 1 and 3 h after (123)I-FP-CIT injection, whereas lung uptake was measured 2 h after injection. RESULTS: Compared with placebo pretreatment, we found after paroxetine pretreatment a statistically significant increase (approximately 10%) in specific striatal-to-nonspecific (123)I-FP-CIT binding ratios at 3 h after injection, a time point at which striatal (123)I-FP-CIT binding ratios are stable. In addition, after paroxetine treatment, statistically significantly lower binding ratios were found in SERT-rich brain areas (e.g., at 1 h after injection, midbrain-to-cerebellar ratios were approximately 90% lower) as well as significantly lower uptake in lung tissue was found (approximately 40% lower after paroxetine). CONCLUSION: In this study we show that the quantification of striatal (123)I-FP-CIT binding to DAT is significantly increased by the SSRI paroxetine in humans. To our knowledge, this is the first study which shows that (123)I-FP-CIT binds in vivo in humans not only to DATs but also to central SERTs and SERTs in lung tissue.     

Investigating dopaminergic neurotransmission with 123I-FP-CIT SPECT: comparability of modern SPECT systems.

With (123)I-labeled N-omega-fluoropropyl-2-beta-carbomethoxy-3-beta-(4-iodophenyl)nortropane (FP-CIT) SPECT increasingly gaining access into routine patient care, the comparability of the results of different SPECT systems in the quantification of receptor binding is important for accurate clinical decision making and the translation of imaging results between institutions (e.g., as part of multicenter therapy trials). METHODS: In a series of studies using phantoms (containing target cylinders of 2- and 2.8-cm diameter) and (123)I-FP-CIT patient studies (n = 49), we compared target-to-background (T/BG) and (123)I-FP-CIT striatal uptake ratios recovered by a conventional triple-head SPECT system and a dedicated high-resolution brain SPECT system. All patient studies were acquired on both SPECT systems successively (<15-min interscan gap) using a single-injection protocol (group A [n = 20] was first scanned on the triple-head SPECT system, and group B [n = 29] was first scanned on the dedicated brain SPECT system). RESULTS: In phantom studies, the T/BG ratios recovered by both systems correlated strongly with the true T/BG ratios (R(2) > 0.96), with the linear regression slopes being 0.86-1.17 and 0.41-0.52 (less steep for smaller target size and lower T/BG ratios) for the dedicated brain SPECT and the triple-head SPECT system, respectively. Although both systems yielded markedly different results, they showed a high linear correlation with each other (R(2) > 0.95, no significant effect from target size). In (123)I-FP-CIT patient studies, a similar linear intersystem correlation was found (R(2) [A/B] = 0.79/0.80, 0.52/0.68, and 0.83/0.85 for the uptake ratios of the striatum, caudate, and putamen, respectively, to the occipital reference region). CONCLUSION: A linear transformation of striatal uptake ratios between different SPECT systems appears to be achievable for ligands such as (123)I-FP-CIT. An evaluation is needed of whether the present method can do this with sufficient accuracy for clinical purposes or whether methodologic adaptations are necessary. Proper study timing has to be ensured.     

The effect of levodopa therapy on dopamine transporter SPECT imaging with 123I-FP-CIT in patients with Parkinson’s disease

Purpose The aim of this study was to evaluate, by means of ¹²³I-FP-CIT SPECT, the effect of chronic treatment with levodopa on striatal dopamine transporter (DAT) in patients with Parkinsons disease.Methods Fifteen patients under stable levodopa/carbidopa monotherapy were imaged twice: at baseline on medication and after at least 20 days of treatment wash-out. DAT levels were assessed from SPECT imaging for the entire striatum, the right and left striatum, the right and left putamen and the right and left caudate, as a ratio of regional brain activities using the formula: (striatal region of interest–occipital)/occipital.Results During levodopa wash-out, despite a worsening in patients clinical disability (H&Y mean stage 2.53±0.58 versus 1.73±0.45 on therapy, p<0.001), striatal ¹²³I-FP-CIT levels were not significantly different from those at baseline in any of the brain regions examined.Conclusion The results of this study suggest that levodopa does not affect ¹²³I-FP-CIT brain imaging and confirm that it is not necessary to withdraw this medication to measure DAT levels with SPECT.     

Quantitation of iodine-123-beta-CIT dopamine receptor uptake in a phantom model.

OBJECTIVE: The purpose of this study was to determine the effects of technical factors such as collimation and filtration on the measurement of 123I-beta-CIT uptake in the striatum. METHODS: All SPECT studies were performed using a brain phantom containing striata within a bone- and tissue-equivalent skull. The effects of collimator resolution and septal penetration were assessed from 99mTc and 123I studies containing variable activities in the striata and background regions. Optimum attenuation coefficients (mu) were determined from studies containing uniform activity in the brain. RESULTS: For 99mTc, mu was 0.095 cm-1 and 0.07 cm-1 for parallel-hole and fanbeam collimators, respectively. For 123I, these values dropped to 0.09 cm-1 and 0.00 cm-1 (zero) for medium-energy and fanbeam collimators, respectively. Striatal uptake was significantly underestimated, particularly for medium-energy and general-purpose collimators. With 99mTc, fanbeam collimation gave a 50% increase in the measured striatal uptake, compared to medium-energy collimation. However, with 123I, this gain was eliminated by septal penetration and scatter. Increasing transaxial slice thickness, ROI size and decreasing filter cutoff frequency all degraded apparent striatal uptake. CONCLUSION: Partial volume effects, combined with the averaging effects of increasing slice thickness and ROI size, are the most significant factors affecting measurement of striatal uptake of 123I-beta-CIT. The increased resolution of low-energy high-resolution collimators, compared to a medium-energy collimator, is offset by the increased septal penetration and scatter.     

Automatic segmentation of dynamic neuroreceptor single-photon emission tomography images using fuzzy clustering.

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<0.0001). Similarly, FCM gave segmentation of the [123I]IBZM data comparable with manual ROI analysis, with the binding ratios derived from both methods significantly correlated (r2=0.83, P<0.0001). Fuzzy clustering is a powerful tool for the automatic, unsupervised segmentation of dynamic neuroreceptor SPET images. Where other automated techniques fail completely, and manual ROI definition would be highly subjective, FCM is capable of segmenting noisy images in a robust and repeatable manner.     

Optimization of automated quantification of 123I-IBZM uptake in the striatum applied to parkinsonism.

Evaluation of therapies for parkinsonism by dopamine receptor SPECT requires a reproducible, optimized quantitation technique. This study presents a new, objective, automated technique for semiquantitative analysis of dopamine receptor density, as applied to the differential diagnosis of parkinsonism. METHODS: Dopamine receptor density measured by 123I-iodobenzamide (IBZM) SPECT was retrospectively analyzed in nonidiopathic parkinsonism (NIPS), in Parkinson's disease (PD), and in healthy volunteers (n = 19, 38, and 13, respectively). A mean template was created from coregistered control studies. Registration errors were assessed using studies with simulated binding deficits. Patient studies were registered to the mean template, and striatal binding was calculated from a corresponding map of 3-dimensional regions of interest (ROIs). The striatal binding ratio and deficits determined by voxelwise comparison with the normal template were investigated and tested with various 3-dimensional ROI sizes and positions. Separation of patient groups was determined by tscore after automatically processing all studies. Results were compared with manual ROI analyses. RESULTS: The automatic method was completely reproducible in 64 of 70 cases. The best diagnostic discriminator was the minimum binding ratio of the 2 striatal nuclei, with the following values: NIPS, 1.33+/-0.13; PD, 1.50+/-0.12; healthy volunteers, 1.49+/-0.08 (+/-SD). The deficit size from voxelwise analysis was: NIPS, 20.5+/-8.2 mL; PD, 9.5+/-8.3; healthy volunteers, 8.9+/-6.0 (+/-SD). The accuracy, measured by receiver operating characteristic areas, was 0.85+/-0.05, 0.77+/-0.06, and 0.80+/-0.06 (+/-SE) for the optimal predictor (automated) and 2 blinded observers (manual), respectively. CONCLUSION: A new 3-dimensional, automated technique has been developed to semiquantitate receptor density that dramatically improves reproducibility. The optimal diagnostic discriminator of parkinsonism determined by the automatic technique has good accuracy compared with the manual technique.     

123I-FP-CIT semi-quantitative SPECT detects preclinical bilateral dopaminergic deficit in early Parkinson's disease with unilateral symptoms

BACKGROUND AND AIM: 123I-FP-CIT SPECT has been successfully used to detect the loss of dopaminergic nigrostriatal neurons in Parkinson's disease at an early stage. In this study we evaluated the capacity of 123I-FP-CIT SPECT to assess bilateral dopamine transporter (DAT) loss in de-novo hemi-Parkinson's disease (PD) patients with one-sided clinical symptoms. PATIENTS AND METHODS: Twenty-nine de-novo hemi-PD patients at an early stage (Hoehn & Yahr stage 1) and 18 gender and age matched healthy subjects were studied. SPECT imaging was always performed at 4 h post-injection. The ratios of striatal (S) to non-specific occipital (O) binding for the entire striatum (S/O), caudate nuclei (C/O), putamina (P(put)/O), and the putamen to caudate nucleus index (P(put)/C) were calculated in both the basal ganglia. RESULTS: In PD patients S/O, C/O and P(put)/O ratio values contralateral to the clinically affected side were significantly lower (P<0.001) than in the control group (-38%, -34% and -42%, respectively). A significant reduction (P<0.001) of the striatal binding ratios was also found ipsilaterally (S/O, -31%; C/O, -28%; P(put)/O, -33%). The P(put)/C index was also bilaterally significantly reduced (P<0.01). DAT loss was significantly greater (P<0.001) in the contralateral than in the ipsilateral S; and putamen bilaterally presented a higher dopaminergic deficit than did caudate. CONCLUSION: Our results indicate that semi-quantitative 123I-FP-CIT SPECT detects a bilateral dopaminergic deficit in early PD with unilateral symptoms and preclinical DAT loss in the ipsilateral striatal binding, corresponding to the side not yet affected by motor signs. Semi-quantitative analysis may thus be used to diagnose PD at an early stage as well as to identify individuals developing bilateral dopaminergic damage.     

New semiquantitative assessment of123I-FP-CIT by an anatomical standardization method

We evaluated a new semiquantitative procedure to more easily and objectively estimate the striatal uptake of 123I-FP-CIT in patients with Parkinsonian syndrome (PS) and essential tremor (ET), using an anatomical standardization method, the Neurostat. METHODS: Eleven patients with PS and 8 with ET were examined by clinical assessment and 123I-FP-CIT SPECT imaging. The modified Hoehn and Yahr Staging Scale and Unified Parkinson's Disease Rating Scale (UPDRS) were used to assess the stage and severity of the disease. The co-registered MR and SPECT images were created with fusion software included in Neurostat. On the cross section, which shows the largest area of striate, irregular shaped regions of interest corresponding to the striate and occipital cortex were drawn. Then the ratio of specific striatal uptake to non-specific occipital cortex, V3"(F), was calculated. Another calculation was done by VOIClassic, which is a software included in Neurostat to estimate the counts per voxel of anatomically defined regions such as caudate nucleus, putamen, occipital cortex, and total cortex. Using these count data, the ratio of specific striatal uptake to non-specific occipital cortex, V3"(OC), and total cortex, V3"(TC), was calculated. RESULTS: A fair linear correlation was observed between V3"(OC) and V3"(F) (y = 1.53x + 1.40; r = 0.756; p < 0.01), as well as between V3"(TC) and V3"(F) (y = 1.24x + 1.43; r = 0.713; p < 0.01). Both V3"(OC) and V3"(TC) yielded similar tendencies. Concerning discrimination between ET and PS, there was a significant difference between the mean V3" of PS and ET (p < 0.01). Concerning the correlation between V3" value and the severity of PS, the UPDRS motor score significantly correlated with the V3"(F) value (rs = -0.816). However, V3"(OC) and V3"(TC) correlated less with UPDRS (rs = -0.667 and -0.645, respectively). CONCLUSIONS: Semiquantitative parameters, V3"(OC) and V3"(TC), calculated by VOIClassic including the Neurostat system are useful and easily calculable parameters as well as V3"(F) for the differential diagnosis of PS from ET.     

Dual-isotope single-photon emission computed tomography for dopamine and serotonin transporters in normal and parkinsonian monkey brains

IntroductionParkinson's disease (PD) affects both dopaminergic and serotonergic systems. In this study, we simultaneously evaluated dopamine and serotonin transporters in primates using dual-isotope single-photon emission computed tomography (SPECT) imaging and compared the results with traditional single-isotope imaging.MethodsFour healthy and one 6-OHDA-induced PD monkeys were used for this study. SPECT was performed over 4 h after individual or simultaneous injection of [^99mTc]TRODAT-1 (a dopamine transporter imaging agent) and [¹²³I]ADAM (a serotonin transporter imaging agent).ResultsThe results showed that the image quality and uptake ratios in different brain regions were comparable between single- and dual-isotope studies. The striatal [^99mTc]TRODAT-1 uptake in the PD monkey was markedly lower than that in normal monkeys. The uptake of [¹²³I]ADAM in the midbrain of the PD monkey was comparable to that in the normal monkeys, but there were decreased uptakes in the thalamus and striatum of the PD monkey.ConclusionsOur results suggest that dual-isotope SPECT using [^99mTc]TRODAT-1 and [¹²³I]ADAM can simultaneously evaluate changes in dopaminergic and serotonergic systems in a PD model.     

Absolute quantification in dopaminergic neurotransmission SPECT using a Monte Carlo-based scatter correction and fully 3-dimensional reconstruction.

Dopamine transporter (DAT) ligands have been developed for in vivo imaging of the dopaminergic system in SPECT. Although the visual analysis of SPECT images is, in general, suitable for clinical assessment, the accurate quantification of the striatal uptake might increase the sensitivity of the technique and help in the early diagnosis, follow-up, and eventual treatment response of Parkinson's disease (PD). This work is focused on assessment of the quantification of specific uptake of (99m)Tc-DAT ligands when compensation for all degrading phenomena is performed. METHODS: The SimSET Monte Carlo (MC) code was used to generate a set of SPECT projections of a numeric striatal phantom with different specific uptake ratios (SURs). An absolute quantification method (AQM), which performs a MC-based scatter compensation and a fully 3-dimensional (3D) reconstruction, was implemented. The scatter estimate was included in the reconstruction algorithm. RESULTS: The use of attenuation, point-spread-function (PSF), and scatter corrections resulted in an improvement in the value of the SUR of 37% on average with respect to the reconstruction without corrections. The magnitude of each improvement corresponded to 7% for the attenuation correction, 12% for the PSF correction using a 2-dimensional reconstruction algorithm and a further 11% for the PSF correction using a 3D reconstruction algorithm, and 7% for the scatter correction. CONCLUSION: Our findings indicate that the PSF correction plays a major role in the quantification of striatal uptake in comparison with the attenuation correction and the scatter correction. The implemented method also provides an absolute quantification procedure based on MC methods that do not depend on empiric approximations. The relative quantification results using the proposed AQM accounted for 96%-97% of the nominal SUR, whereas the limit achieved using only primary photons attained 98%-99%. The volumetric activity values obtained using the AQM converged toward the nominal values.     

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.     

Usefulness of rCBF analysis in diagnosing Parkinson’s disease: supplemental role with MIBG myocardial scintigraphy

(123)I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy is a useful tool for differentiating idiopathic Parkinson's disease (PD) from parkinsonism (PS) caused by other disorders. However, cardiac MIBG uptake is affected by various causes. Alternatively, hypoperfusion in the occipital lobe of PD is reported recently. OBJECTIVE: The objective is to clarify the correlation between regional cerebral blood flow (rCBF) alteration and cardiac MIBG uptake in PD. In addition, we examined whether additional brain perfusion analysis improved the differential diagnostic ability for PD from PS when compared with MIBG scintigraphy alone. METHODS: Forty-nine patients with PD (27 mild groups: Hoehn and Yahr stages I, II; 22 severe groups: Hoehn and Yahr stages III, IV) and 28 patients with PS participated. We compared absolute rCBF values between PD and PS. In addition, we determined correlation between MIBG parameters and each rCBF value. Finally, we compared the diagnostic ability for the differentiation of PD from PS between two diagnostic criteria, each MIBG index abnormality alone [heart-to-mediastinum ratio, H/M (E) < 1.9, H/E (D) < 1.7, washout rate > 40%] and each MIBG index abnormality or occipital lobe hypoperfusion (<36 ml/100 g per min). RESULTS: Absolute rCBF value of occipital lobe was significantly lower in severe PD as compared with PS or mild PD. In the correlation analysis, rCBF of occipital lobe correlated positively with MIBG parameters (H/M). Regarding the diagnostic ability, sensitivity improved by accounting for occipital hypoperfusion as compared with MIBG indices alone. In contrast, neither specificity nor accuracy improved by adding occipital lobe analysis. CONCLUSIONS: MIBG parameters (H/M) correlated positively with occipital hypoperfusion in PD. In the differential diagnosis between PD and PS, although its usefulness might be limited, analysis of rCBF in the occipital lobe added to (123)I-MIBG myocardial imaging can be recommended.     

The cost effectiveness of <Superscript>123</Superscript>I-FP-CIT SPECT imaging in patients with an uncertain clinical diagnosis of parkinsonism

PURPOSE: (123)I-N-omega-fluoropropyl-2-beta-carboxymethoxy-3beta-(4-iodophenyl)nortropane ((123)I-FP-CIT) Single-photon emission computed tomography (SPECT) has been suggested to be a useful diagnostic adjunct in patients with clinically uncertain parkinsonism. We developed a pharmaco-economic (PE) model, evaluating the cost effectiveness of adding (123)I-FP-CIT SPECT to the diagnostic workup. As the model was developed before application of the diagnostic technique in real practice, a predictive validity assessment was performed based on data from a large nationwide patient registry in these patients. METHODS: A PE model, using a Markov state transition model, was created, based on literature-derived and clinical expert panel data. Effects were expressed as adequately treated years (ATY). Key input data were compared to the real-life patterns in a nationwide multi-centre clinical setting, based on a complete national registry of 1,701 consecutive patients. The change in initial diagnosis and alteration of management of the patient after SPECT were registered. RESULTS: In the PE model, it was calculated that management would change in 48.5% of patients by SPECT and that, over a 5-year period, 1.2 ATYs could be gained at a yearly additional cost of 72. From the studied 1,701 patients, nigrostriatal degeneration was observed in 59.8%, the initial diagnosis was changed in 51.5%, management was altered in 49%, and cost effectiveness was increased to 358 per ATY. CONCLUSION: Good correspondence between assumed and observed changes in patient management was found, indicating that (123)I-FP-CIT SPECT is influential in diagnosis and management of patients with uncertain clinical diagnosis of parkinsonism. This can be achieved at a marginal added cost to the health insurance and leads to a significant gain in ATY.