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INTRODUCTION: This study aimed to investigate whether regional cerebral perfusion patterns on early-phase 18F-FP-CIT PET scans, which is typically coupled to cerebral metabolism, predict the long-term prognosis of Parkinson's disease (PD). METHODS: We enrolled 397 drug-naïve patients with early-stage PD who underwent dual-phase 18F-FP-CIT PET scans. After quantifying the early-phase 18F-FP-CIT PET images, cluster analysis was performed to delineate the PD subtypes according to the patterns of regional cerebral perfusion. We compared the risk of developing levodopa-induced dyskinesia (LID), wearing-off, freezing of gait (FOG), and dementia between the PD subtypes. RESULTS: Cluster analysis classified patients into three subtypes: cluster 1 (relatively preserved cortical uptake; n = 175), cluster 2 (decreased uptake in the frontal, parietal, and temporal regions; n = 151), and cluster 3 (decreased uptake in more extensive regions, additionally involving the lateral occipital regions; n = 71). Cluster 1 was characterized by a younger age-of-onset, less severe motor deficits, less severely decreased 18F-FP-CIT binding in the caudate, and better cognitive performance. Cluster 3 was characterized by an older age-of-onset, more severe motor deficits, and poorer cognitive performance. Cluster 2 was intermediate between clusters 1 and 3. Cox regression analyses demonstrated that clusters 2 and 3 had a higher risk for dementia conversion than cluster 1, whereas the risk for developing LID, wearing-off, and FOG did not differ among the clusters. CONCLUSION: The patterns of regional cerebral perfusion can provide information on long-term prognosis with regards to cognitive, but not motor aspects of patients with early-stage PD.

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BACKGROUND: To investigate whether the cingulate island sign (CIS) ratio (i.e., the ratio of regional uptake in the posterior cingulate cortex relative to the precuneus and cuneus on cerebral perfusion scans) is associated with early dementia conversion in Parkinson's disease (PD). METHODS: We enrolled 226 patients with newly diagnosed PD and 48 healthy controls who underwent dual-phase 18 F-FP-CIT PET scans. Patients with PD were classified into three groups according to the CIS ratio on early-phase 18 F-FP-CIT PET images: a PD group with CIS or high CIS ratios (PD-CIS; n = 96), a PD group with inverse CIS or low CIS ratios (PD-iCIS; n = 40), and a PD group consisting of the remaining patients with normal CIS ratios (PD-nCIS; n = 90). We compared the risk of dementia conversion within a 5-year time point between the groups. RESULTS: There were no significant differences in age, sex, education, or baseline cognitive function between the PD groups. The PD-CIS group had higher Unified Parkinson's Disease Rating Scale (UPDRS) motor scores and more severely decreased dopamine transporter availability in the putamen. The PD-iCIS group had a smaller hippocampal volume compared with the other groups. The risk of dementia conversion in the PD-CIS group did not differ from that in the PD-iCIS and PD-nCIS groups. Meanwhile, the PD-iCIS group had a higher risk of dementia conversion than the PD-nCIS group. CONCLUSION: The results of this study suggest that inverse CIS, rather than CIS, is relevant to early dementia conversion in patients with PD.

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We describe 5 cases of patients who presented atypical parkinsonian syndrome (APS), including gait disturbance, postural instability, decreasing facial expression, dyskinesia, and subjective cognitive impairment. The patients underwent 18F-FP-CIT PET and 18F-FDG PET consecutively for differential diagnosis of APS. Through PET imaging examination, it was possible to offer a suggestive diagnosis and determine individual strategic management for patients with APS.

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We are aimed to evaluate the diagnostic performances of quantitative indices obtained from dual-phase 18F-FP-CIT PET/CT for differential diagnosis of atypical parkinsonian syndromes (APS) from Parkinson's disease (PD). We analyzed 172 subjects, including 105 non-Parkinsonism, 26 PD, 8 PSP, 1 CBD, 8 MSA-P, 9 MSA-C, and 15 DLB retrospectively. Two sequential PET/CT scans were acquired at 5 min and 3 h. We compared subregional binding potentials, putamen-to-caudate nucleus ratio of the binding potential, asymmetry index, and degree of washout. To differentiate APS, all BPs in both early and late phases (except late BPbrainstem) and all factors of the percent change except for putamen in APS significantly differed from PD. When a cut-off for early BPcerebellum was set as 0.79, the sensitivity, specificity (SP), positive predictive value (PPV), negative predictive value (NPV), and accuracy for differentiating APS 73.2%, 91.7%, 93.8%, 66.7%, and 80.0%. The early BPcerebellum showed significantly greater SP and PPV than the late quantitative indices. Combined criteria regarding both early and late indices exhibited only greater NPV. The quantitative indices showed high diagnostic performances in differentiating APS from PD. Our findings provide the dual-phase 18F-FP-CIT PET/CT would be useful for differentiating APS from PD.

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OBJECTIVE: 18F-labeled fluoropropyl-carbomethoxylodopropyl-nor-ß-tropane ([18F]FP-CIT) positron emission tomography (PET) is a useful tool for evaluating disease progression in Parkinson's disease (PD) patients. We evaluated the test-retest reproducibility of [18F]FP-CIT PET measures in essential tremor (ET) and PD patients. METHODS: Fifteen ET (68.9 ± 6.6 years) and 10 PD patients (70.5 ± 6.3 years; Hoehn and Yahr stage, 2.3 ± 0.8) underwent two [18F]FP-CIT PET/CT scans with an interval of 48 ± 7 day. For both the test and retest studies, standardized uptake value ratios were estimated for 90-min and 3-h acquisitions for the caudate, anterior putamen, and posterior putamen using T1-MRI-based normalization (automatic) and fixed-VOI (manual) methods, with the occipital lobe as a reference. Reproducibility was evaluated by the bias, variability, percent test-retest, within-subject coefficient of variation, repeatability coefficient, and intraclass correlation coefficient (ICC). RESULTS: Reproducibility was excellent, with low variability (ET: 6.99-8.02%, PD: 3.51-6.94%) and high reliability (ICC; ET: 0.88-0.96, PD: 0.98-0.99). The ET group showed higher variability and lower ICCs than the PD group. The variability in the 90-min images (ET: 7.85-8.59%, PD: 1.52-2.75%) was comparable to that in the 3-h images (ET: 6.99-8.02%, PD: 3.51-6.94%). There were no differences in variability among the subregions in the ET group. In the PD group, the variability was high in the posterior putamen (automatic method: 6.94%, manual method: 11.80%). The test-retest variability and ICCs were similar for the manual and automatic methods. CONCLUSION: [18F]FP-CIT PET is reproducible for the quantitative measurement of DAT binding in both ET and PD individuals, independent of the acquisition time or analysis method. Also, the automatic method is more suitable for evaluating early loss of DAT binding in patients with PD.

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PURPOSE: The precise quantification of dopamine transporter (DAT) density on N-(3-[18F]Fluoropropyl)-2ß-carbomethoxy-3ß-(4-iodophenyl) nortropane positron emission tomography ([18F]FP-CIT PET) imaging is crucial to measure the degree of striatal DAT loss in patients with parkinsonism. The quantitative analysis requires a spatial normalization process based on a template brain. Since the spatial normalization method based on a delayed-phase PET has limited performance, we suggest an early-phase PET-based method and compared its accuracy, referring to the MRI-based approach as a gold standard. METHODS: A total of 39 referred patients from the movement disorder clinic who underwent dual-phase [18F]FP-CIT PET and took MRI within 1 year were retrospectively analyzed. The three spatial normalization methods were applied for quantification of [18F]FP-CIT PET-MRI-based anatomical normalization, PET template-based method based on delayed PET, and that based on early PET. The striatal binding ratios (BRs) were compared, and voxelwise paired t tests were implemented between different methods. RESULTS: The early image-based normalization showed concordant patterns of putaminal [18F]FP-CIT binding with an MRI-based method. The BRs of the putamen from the MRI-based approach showed higher agreement with early image- than delayed image-based method as presented by Bland-Altman plots and intraclass correlation coefficients (early image-based, 0.980; delayed image-based, 0.895). The voxelwise test exhibited a smaller volume of significantly different counts in putamen between brains processed by early image and MRI compared to that between delayed image and MRI. CONCLUSION: The early-phase [18F]FP-CIT PET can be utilized for spatial normalization of delayed PET image when the MRI image is unavailable and presents better performance than the delayed template-based method in quantitation of putaminal binding ratio.

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Parkinsonism has heterogeneous nature, showing distinctive patterns of disease progression and prognosis. We aimed to find clusters of parkinsonism based on 18 F-fluoropropyl-carbomethoxyiodophenylnortropane (FP-CIT) PET as a data-driven approach to evaluate heterogenous dopaminergic neurodegeneration patterns. Two different cohorts of patients who received FP-CIT PET were collected. A labeled cohort (n = 94) included patients with parkinsonism who underwent a clinical follow-up of at least 3 years (mean 59.0 ± 14.6 months). An unlabeled cohort (n = 813) included all FP-CIT PET data of a single-center. All PET data were clustered by a dimension reduction method followed by hierarchical clustering. Four distinct clusters were defined according to the imaging patterns. When the diagnosis of the labeled cohort of 94 patients was compared with the corresponding cluster, parkinsonism patients were mostly included in two clusters, cluster "0" and "2." Specifically, patients with progressive supranuclear palsy were significantly more included in cluster 0. The two distinct clusters showed significantly different clinical features. Furthermore, even in PD patients, two clusters showed a trend of different clinical features. We found distinctive clusters of parkinsonism based on FP-CIT PET-derived heterogeneous neurodegeneration patterns, which were associated with different clinical features. Our results support a biological underpinning for the heterogeneity of neurodegeneration in parkinsonism.

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INTRODUCTION: Patients with Parkinson's disease (PD) present a variety of non-motor symptoms. However, it remains unclear whether dopamine depletion is related to non-motor symptoms, and which non-motor symptoms are significantly dependent on dopaminergic deficit. METHODS: Forty-one patients with PD who underwent positron emission tomography imaging of dopamine transporters (DATs) were recruited for this study. The striatum was divided into 12 subregions, and DAT activity, as striatal dopaminergic concentration, was calculated in each subregion. In addition to measuring motor symptoms using the Unified Parkinson's Disease Rating Scale-part III (UPDRS-III), various non-motor symptoms were assessed using the Montreal cognitive assessment, frontal assessment battery, Beck depression inventory (BDI), Beck anxiety inventory, PD sleep scale (PDSS), PD fatigue scale, and non-motor symptoms scale (NMSS) for PD. RESULTS: For simple linear regression analyses, dopaminergic depletion in all striatal subregions was negatively correlated with the UPDRS-III score. The most relevant non-motor symptom assessment related to dopaminergic loss in the 12 subregions was NMSS, followed by BDI and PDSS. However, following multiple linear regression analyses, dopaminergic depletion in the 12 striatal subregions was not related with any of the non-motor symptoms. Conversely, dopaminergic deficit in the right anterior and posterior putamen was associated with the UPDRS-III score. CONCLUSIONS: Striatal dopaminergic depletion was not significantly correlated with any of the various non-motor symptoms in PD. Our findings suggest that non-dopaminergic systems are significantly implicated in the pathogenesis of non-motor symptoms in patients with PD.

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PURPOSE: The purpose of this study was to evaluate whether the pattern of striatal dopamine transporter (DAT) availability could differentiate between progressive supranuclear palsy (PSP) and frontotemporal dementia (FTD) in the first few years of the disease. METHODS: We enrolled patients who had Parkinsonism and frontal dysfunction and/or language deficit, visited the clinic within 2 years of the onset of symptoms, and had been followed-up for longer than 5 years; thus resulting in 26 patients with PSP and 24 patients with FTD. By quantitatively analyzing N-(3-[18F]fluoropropyl)-2ß-carbon ethoxy-3ß-(4-iodophenyl) nortropane PET, we compared the pattern of DAT availability at the time of the baseline evaluation between the two groups. The discriminatory power of variables including DAT activity and clinical parameters was investigated by receiver operating characteristics (ROC) analyses. Additionally, we analyzed the correlation between striatal subregional DAT availability and cognitive profiles. RESULTS: Patients with PSP and FTD had significantly lower DAT availability than normal controls in the whole striatum and in each striatal subregion. When comparing the two groups, DAT availability was significantly lower in patients with PSP than those with FTD in all striatal subregions. The PSP and FTD groups had generally similar subregional patterns of DAT activity in terms of the anteroposterior and ventrodorsal gradients and asymmetry, except for a different preferential involvement in the caudate. The ROC analysis showed that the DAT activity of the whole striatum had an excellent discriminatory power relative to Parkinsonism or neurocognitive profiles. Correlation analysis showed that verbal memory was significantly correlated with DAT availability in the whole striatum and the putaminal subregion only in patients with PSP. CONCLUSIONS: DAT scans have prognostic value in determining whether patients with Parkinsonism and behavioral and/or language dysfunction will develop features of PSP or FTD later in the disease course.

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PURPOSE: Dopamine transporter imaging is suggested to be a useful imaging biomarker for Parkinson's disease (PD) progression and monitoring drug effects. We investigated the longitudinal decline characteristics of striatal [18F]FP-CIT uptake in PD. METHODS: We retrospectively reviewed 35 PD patients and 9 non-PD patients. All patients underwent [18F]FP-CIT PET at the initial diagnosis and follow-up. PET images were spatially normalized and analyzed with eight striatal and one occipital VOI templates. We measured the specific to non-specific binding ratio (SNBR) of the striatal subregions and calculated the absolute annual reduction (AAR) and relative annual reduction (%RAR) of the SNBRs. RESULTS: Total striatal SNBRs in PD patients were significantly lower than those in non-PD patients, with the most significant difference in the posterior putamen. Both AAR (0.26 ± 0.14 vs. 0.09 ± 0.19, p < 0.05) and %RAR (6.9 ± 3.5 vs. 1.2 ± 2.7, p < 0.001) of total striatal SNBRs were significantly greater in PD than non-PD patients. There were no significant differences in the AAR and %RAR of total striatal SNBRs between elderly and young onset PD. The AARs of the posterior putamen were higher in early PD than in advanced PD. Conversely, the %RARs were not significantly different between early and more advanced PD. The disease duration was significantly negatively correlated with the AAR but not with the %RAR of the posterior putamen. CONCLUSIONS: The longitudinal decline of striatal [18F]FP-CIT uptake in PD was nonlinear and significantly faster than that in non-PD, with a different rate of decline among the striatal subregions.

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PURPOSE: Dopamine transporter imaging is suggested to be a useful imaging biomarker for Parkinson's disease (PD) progression and monitoring drug effects.We investigated the longitudinal decline characteristics of striatal [¹⁸F]FP-CIT uptake in PD.METHODS: We retrospectively reviewed 35 PD patients and 9 non-PD patients. All patients underwent [¹⁸F]FP-CIT PET at the initial diagnosis and follow-up. PET images were spatially normalized and analyzed with eight striatal and one occipital VOI templates. We measured the specific to non-specific binding ratio (SNBR) of the striatal subregions and calculated the absolute annual reduction (AAR) and relative annual reduction (%RAR) of the SNBRs.RESULTS: Total striatal SNBRs in PD patients were significantly lower than those in non-PD patients, with the most significant difference in the posterior putamen. Both AAR (0.26 ± 0.14 vs. 0.09 ± 0.19, p < 0.05) and %RAR (6.9 ± 3.5 vs. 1.2 ± 2.7, p < 0.001) of total striatal SNBRs were significantly greater in PD than non-PD patients. There were no significant differences in the AAR and %RAR of total striatal SNBRs between elderly and young onset PD. The AARs of the posterior putamen were higher in early PD than in advanced PD. Conversely, the %RARs were not significantly different between early and more advanced PD. The disease duration was significantly negatively correlated with the AAR but not with the %RAR of the posterior putamen.CONCLUSIONS: The longitudinal decline of striatal [¹⁸F]FP-CIT uptake in PD was nonlinear and significantly faster than that in non-PD, with a different rate of decline among the striatal subregions.

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BACKGROUND AND PURPOSE: During Vietnam War, many Korean soldiers were dispatched to fight in the war where they were exposed to Agent Orange. Until now, there exist only limited evidence on existence of association between exposure to Agent Orange and Parkinson's disease (PD). To elucidate the effects of Agent Orange exposure on PD, we compared the clinical characteristics and radiolabeled 18F-FP-CIT PET uptake between patients with Agent Orange exposure and patients with Agent Orange no-exposure. METHODS: We retrospectively evaluated 143 patients exposed to Agent Orange and 500 patients with no exposure to Agent Orange from our movement clinics database. The differences between clinical characteristics and pattern of 18F-FP-CIT PET uptake were investigated. RESULTS: Among Unified Parkinson's Disease Rating Scale III motor subscales, tremor at rest, rigidity, finger taps, and rapid alternating movement was significantly higher in patients exposed to Agent Orange as compared to patients with no exposure to Agent Orange. The facial expression score was significantly lower in patients exposed to Agent Orange as compared to patients with no exposure to Agent Orange. Compared to patients not exposed to Agent Orange, all basal ganglia areas (contra- and ipsilateral caudate nucleus, anterior putamen, and posterior putamen) showed a lower18F-FP-CIT uptake and higher asymmetry index of anterior and posterior putamen was found in patients exposed to Agent Orange. The caudate/putamen ratio was significantly lower in patients exposed to Agent Orange as compared to patients with no exposure to Agent Orange. CONCLUSIONS: This study showed a different clinical profile and FP-CIT PET findings between patients exposed to Agent Orange as compared to patients with no exposure to Agent Orange. This finding suggests the possibility of different pathophysiology of PD in patients exposed to Agent Orange from idiopathic PD.

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BACKGROUND AND PURPOSE: During Vietnam War, many Korean soldiers were dispatched to fight in the war where they were exposed to Agent Orange. Until now, there exist only limited evidence on existence of association between exposure to Agent Orange and Parkinson's disease (PD). To elucidate the effects of Agent Orange exposure on PD, we compared the clinical characteristics and radiolabeled 18F-FP-CIT PET uptake between patients with Agent Orange exposure and patients with Agent Orange no-exposure. METHODS: We retrospectively evaluated 143 patients exposed to Agent Orange and 500 patients with no exposure to Agent Orange from our movement clinics database. The differences between clinical characteristics and pattern of 18F-FP-CIT PET uptake were investigated. RESULTS: Among Unified Parkinson's Disease Rating Scale III motor subscales, tremor at rest, rigidity, finger taps, and rapid alternating movement was significantly higher in patients exposed to Agent Orange as compared to patients with no exposure to Agent Orange. The facial expression score was significantly lower in patients exposed to Agent Orange as compared to patients with no exposure to Agent Orange. Compared to patients not exposed to Agent Orange, all basal ganglia areas (contra- and ipsilateral caudate nucleus, anterior putamen, and posterior putamen) showed a lower18F-FP-CIT uptake and higher asymmetry index of anterior and posterior putamen was found in patients exposed to Agent Orange. The caudate/putamen ratio was significantly lower in patients exposed to Agent Orange as compared to patients with no exposure to Agent Orange. CONCLUSIONS: This study showed a different clinical profile and FP-CIT PET findings between patients exposed to Agent Orange as compared to patients with no exposure to Agent Orange. This finding suggests the possibility of different pathophysiology of PD in patients exposed to Agent Orange from idiopathic PD.

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BACKGROUNDS: Leukoaraiosis may present with slowly progressive parkinsonism indistinguishable from primary degenerative parkinsonism. Both leukoaraiosis and degenerative parkinsonism are an age-related disorder. Thus, comorbidity is expected to be common in elderly patients with parkinsonism. However, no systematic study has been reported on the clinical features indicating concomitant nigrostriatal dopaminergic denervation (NDD) in parkinsonian patients with leukoaraiosis. METHODS: We performed [(18)F] FP-CIT positron emission tomography studies in 42 consecutive parkinsonian patients with diffuse leukoaraiosis, but no basal ganglia vascular lesions. RESULTS: Twenty (48%) of the 42 patients had coexisting NDD. Compared to parkinsonian patients with isolated leukoaraiosis, those with coexisting NDD more frequently had asymmetric onset. They had similar degree of parkinsonian motor deficits in the legs, but greater rigidity and resting tremor in the arms. Consequently, they had less prominent lower body parkinsonism. They more frequently showed favorable response to levodopa treatment. They had similar burden of regional and total leukoaraiosis. Among a variety of clinical variables and MRI findings, only asymmetric onset and more than 30% improvement in UPDRS motor score by levodopa treatment were valuable indicators of coexisting NDD. CONCLUSIONS: We would like to recommend dopaminergic functional imaging studies for all parkinsonian patients with leukoaraiosis. Further studies are needed to confirm sensitivity and specificity of asymmetric onset and good levodopa response for the prediction of coexisting NDD in a different group of parkinsonian patients with leukoaraiosis.

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BACKGROUND: The characteristics of clinical features and nigrostriatal dopaminergic dysfunction in patients with combined postural and resting tremors have been less clearly reported. METHODS: The present study examined 43 patients with a visible persistent bilateral postural tremor and a unilateral/bilateral resting tremor involving the hands and forearms. The patients had experienced tremors for more than 3 years, with no evidence of Parkinson's disease or other parkinsonian disorders. Visual and quantitative analyses of [18F] N-(3-fluoropropyl)-2beta-carbon ethoxy-3beta-(4-iodophenyl) nortropane (FP-CIT) PET in 36 patients were performed. Seventeen age-matched normal controls were also studied. RESULTS: On visual analysis, 28 patients (78%) showed normal [18F] FP-CIT uptake and eight (22%) showed significantly reduced uptake, suggesting nigrostriatal dopaminergic neuronal degeneration. The reduced [18F] FP-CIT uptake was significantly associated with earlier age-at-onset of tremor and asymmetric presentation of resting tremor. On quantitative analysis, there were statistically significant differences in the [18F] FP-CIT uptake ratio in the posterior putamen between patients with reduced uptake (2.37 ± 1.83) and patients with normal uptake (6.39 ± 1.35) (P < 0.001). However, posterior putamen uptake levels in patients with normal [18F] FP-CIT uptake on visual analysis were similar to those in normal controls (7.22 ± 1.29) (P = 0.291). CONCLUSION: The nigrostriatal dopaminergic dysfunction in patients with combined postural and resting tremors may be associated with earlier age-at-onset of tremor and asymmetric pattern of resting tremor, which might help to correctly diagnose patients with mixed tremors.

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PURPOSE: (18)F-FP-CIT positron emission tomography (PET) is an effective imaging for dopamine transporters. In usual clinical practice, (18)F-FP-CIT PET is analyzed visually or quantified using manual delineation of a volume of interest (VOI) for the striatum. In this study, we suggested and validated two simple quantitative methods based on automatic VOI delineation using statistical probabilistic anatomical mapping (SPAM) and isocontour margin setting. METHODS: Seventy-five (18)F-FP-CIT PET images acquired in routine clinical practice were used for this study. A study-specific image template was made and the subject images were normalized to the template. Afterwards, uptakes in the striatal regions and cerebellum were quantified using probabilistic VOI based on SPAM. A quantitative parameter, QSPAM, was calculated to simulate binding potential. Additionally, the functional volume of each striatal region and its uptake were measured in automatically delineated VOI using isocontour margin setting. Uptake-volume product (QUVP) was calculated for each striatal region. QSPAM and QUVP were compared with visual grading and the influence of cerebral atrophy on the measurements was tested. RESULTS: Image analyses were successful in all the cases. Both the QSPAM and QUVP were significantly different according to visual grading (P < 0.001). The agreements of QUVP or QSPAM with visual grading were slight to fair for the caudate nucleus (κ = 0.421 and 0.291, respectively) and good to perfect to the putamen (κ = 0.663 and 0.607, respectively). Also, QSPAM and QUVP had a significant correlation with each other (P < 0.001). Cerebral atrophy made a significant difference in QSPAM and QUVP of the caudate nuclei regions with decreased (18)F-FP-CIT uptake. CONCLUSION: Simple quantitative measurements of QSPAM and QUVP showed acceptable agreement with visual grading. Although QSPAM in some group may be influenced by cerebral atrophy, these simple methods are expected to be effective in the quantitative analysis of (18)F-FP-CIT PET in usual clinical practice.