Usefulness of a dopamine transporter PET ligand [(18)F]beta-CFT in assessing disability in Parkinson's disease

OBJECTIVES: The usefulness of a novel dopamine transporter PET ligand, [(18)F]beta-CFT in assessing disability in Parkinson's disease was studied. METHODS: Twenty seven patients with Parkinson's disease in different disability stages (of which nine were patients with early disease) and nine healthy controls were studied. The regions of interest were drawn on a magnetic resonance image resliced according to the PET image. RESULTS: There was a significant reduction in [(18)F]beta-CFT uptake in the posterior putamen (to 18% of the control mean, p<0.00001), anterior putamen (28%, p<0.00001), and caudate nucleus (51%, p<0.00001) in the total population of patients with Parkinson's disease. The reduction in [(18)F]beta-CFT uptake was more pronounced with more severe disability of the patients, the correlations between the total motor score of the unified Parkinson's disease rating scale (UPDRS) and [(18)F]beta-CFT uptake being significant in the posterior putamen (r=-0.62 p=0.0005), anterior putamen (r=-0.64, p=0.0003), and the caudate nucleus (r=-0.62, p=0.0006). There was a significant negative correlation with putaminal [(18)F]beta-CFT uptake and the hypokinesia and rigidity scores, but not with the tremor score of the UPDRS motor part. In nine patients with early disease and without any antiparkinsonian medication the reduction in the [(18)F]beta-CFT uptake (average of ipsilateral and contralateral side) was reduced in the total putamen to 34% of the mean control value (p<0.00001). The corresponding figures in the other brain areas were: posterior putamen 21% (p<0.00001), anterior putamen 43% (p<0.00001), and caudate nucleus 76% (p<0.01). The reductions in [(18)F]beta-CFT uptake were more severe in the contralateral than in the ipsilateral side. Individually, [(18)F]beta-CFT uptake in the putamen in all patients was below 3 SD from the control mean. CONCLUSIONS: [(18)F]beta-CFT is a sensitive marker of nigrostriatal dopaminergic dysfunction in Parkinson's disease and can be used in the diagnosis, assessment of disease severity, and follow up of patients.     

Striatal subregional 6-[18F]fluoro-L-dopa uptake in early Parkinson's disease: a two-year follow-up study.

Thirty-one drug-naive patients with Parkinson's disease (PD) underwent 6-[18F]fluoro-L-dopa (F-dopa) positron emission tomography (PET) scan at the time of the diagnosis (baseline) and 2 years later in order to investigate F-dopa uptake in striatal and extrastriatal regions during the first years of early PD. Twenty-four healthy controls underwent one F-dopa PET scan. The regional differences in the striatal and extrastriatal regions were analyzed with statistical parametric mapping and automated region of interest analyses. Our study shows that the F-dopa uptake in unmedicated early PD is most severely decreased in the dorsal part of caudal putamen but significant decrease can be seen throughout the striatum compared with controls. During the first years of PD, there is a progressive regional decline in striatal F-dopa uptake, the dorsal part of caudal putamen being still the most severely affected region. The absolute decline is equal between the striatal subregions. This suggests that the decline of dopamine function starts from the dorsocaudal putamen, but once started, the rate of progression is equal between the subregions of the striatum. In contrast to the striatal decline, the increased cortical F-dopa uptake prevails at least during the first years of PD.     

Clinical and [18F] dopa PET findings in early Parkinson's disease.

Twenty seven patients with recent onset (mean symptom duration 22 (SD 14) months, Hoehn and Yahr score 1.8 (SD 0.7)) Parkinson's disease were studied with [18F]dopa PET. There was a correlation between putamen influx (Ki) and clinical rating, but not symptom duration. In 11 patients with hemi-Parkinson's disease of recent onset there were significant differences between normal (mean 0.0123 (SD 0.0023)), asymptomatic (mean 0.0099 (0.0020)) and symptomatic (mean 0.0070 (00.014)) putamen Kis. This suggests that Parkinson's disease has a widely variable rate of progression, and is most compatible with a short preclinical period. Symptom onset was estimated at a putamen Ki of between 57% and 80% of normal. Most ipsilateral putamen Ki values in early asymmetric Parkinson's disease fell within the normal range. The implication is that either the disease is not established in the ipsilateral putamen or that the technique is insufficiently sensitive to detect it. Discriminant analysis completely separated the normal and Parkinson's disease cohorts, but when a discriminant function from a previous study was used predictively four of the 27 patients with Parkinson's disease were incorrectly classified as normal.     

Parametric mapping of [18F]FPCIT binding in early stage Parkinson's disease: a PET study

We have shown that fluorinated N-3-fluoropropyl-2-beta-carboxymethoxy-3-beta-(4-iodophenyl) nortropane ([(18)F]FPCIT) and PET offer a valuable means of quantifying regional abnormality in dopamine transporter (DAT) imaging associated with Parkinson's disease (PD). The objective of this study was to delineate the topographic distribution of DAT binding in early stage idiopathic PD using statistical parametric analysis of [(18)F]FPCIT PET data. We performed dynamic PET studies in 15 hemi-parkinsonian (Hoehn & Yahr I) patients and 10 age-matched normal volunteers over 100 min and calculated images of [(18)F]FPCIT binding ratios on a pixel-by-pixel basis. Statistical parametric mapping (SPM) was then used to localize binding reductions in PD and to compute the absolute change relative to normal. [(18)F]FPCIT binding decreased significantly in the contralateral posterior putamen of the PD group (P < 0.001, corrected). A significant reduction was also seen in the ipsilateral putamen, which was smaller in extent but localized more posteriorly. A quantitative comparison of DAT binding in the two clusters showed that the onset of motor symptoms in PD was associated with an approximate 70% loss relative to the normal mean in the contralateral posterior putamen. These results suggest that SPM analysis of [(18)F]FPCIT PET data can be used to quantify and map abnormalities in DAT activity within the human striatum. This method provides a useful tool to track the onset and progression of PD at its earliest stages.     

Rate of progression in Parkinson's disease: a 6-[18F]fluoro-L-dopa PET study.

The aim of this study was to investigate the rate of progression in Parkinson's disease (PD) with 6-[(18)F]fluoro-L-dopa (FDOPA) positron emission tomography (PET). We investigated 21 patients with PD and eight healthy controls. Ten of the patients were de novo at the time of the first PET scan and antiparkinsonian medication was started thereafter, with a favourable response. A FDOPA PET scan was carried out twice at an approximately 5-year interval. The regions of interest were drawn on individual magnetic resonance imaging (MRI) images, matched with the PET images. At the first PET scan, in PD patients the mean k(i)(occ) (x 10(-3) min(-1)) in the anterior putamen was 5.6 +/- 2.7 (mean +/- S.D.; 55% of the control mean) and in the posterior putamen 4.5 +/- 2.4 (45% of the control mean). The k(i)(occ) value for the caudate nucleus was 7.5 +/- 2.1 (x 10(-3) min(-1); 76% of the control mean). The FDOPA uptake declined by the time of the second PET scan and the annual rate of decline was 8.3 +/- 6.3% (P < 0.001) of the baseline mean in the anterior putamen and 10.3 +/- 4.8% (P < 0.001) in the posterior putamen. In the caudate nucleus, FDOPA uptake decreased by 5.9 +/- 5.1% (P < 0.001) of the baseline mean per year. The estimated preclinical period was longest for the posterior putamen being 6.5 years. For the anterior putamen the preclinical period was 4.6 years. In the caudate nucleus, the estimated FDOPA uptake was at normal level at disease onset. In healthy controls, there was no significant decline in FDOPA uptake in any striatal subregion. Our results suggest that the disease process in PD first affects posterior putamen, followed by the anterior putamen and the caudate nucleus, but once started, the absolute rate of decline is the same. In healthy controls, no significant decline in FDOPA was detected.     

Striatal and extrastriatal dopamine release measured with PET and [18F] fallypride

The amphetamine challenge, in which positron emission tomography (PET) or single photon emission computed tomography radioligand binding following administration of amphetamine is compared to baseline values, has been successfully used in a number of brain imaging studies as an indicator of dopaminergic function, particularly in the striatum. [¹⁸F] fallypride is the first PET radioligand that allows measurement of the effects of amphetamine on D2/D3 ligand binding in striatum and extra‐striatal brain regions in a single scanning session following amphetamine. We scanned 15 healthy volunteer subjects with [¹⁸F] fallypride at baseline and following amphetamine (0.3 mg/kg) using arterial plasma input‐based modeling as well as reference region methods. We found that amphetamine effect was robustly detected in ventral striatum, globus pallidus, and posterior putamen, and with slightly higher variability in other striatal subregions. However, the observed effect sizes in striatum were less than those observed in previous studies in our laboratory using [¹¹C] raclopride. Robust effect was also detected in limbic extra‐striatal regions (hippocampus, amygdala) and substantia nigra, but the signal‐to‐noise ratio was too low to allow accurate measurement in cortical regions. We conclude that [¹⁸F] fallypride is a suitable ligand for measuring amphetamine effect in striatum and limbic regions, but it is not suitable for measuring the effect in cortical regions and may not provide the most powerful way to measure the effect in striatum. Synapse 64:350–362, 2010. © 2009 Wiley‐Liss, Inc.     

Progression of dopaminergic hypofunction in striatal subregions in Parkinson's disease using [18F]CFT PET

The aim of this study was to investigate the progression of dopaminergic hypofunction in striatal subregions in Parkinson's disease (PD). We studied 12 patients with early PD and 11 healthy controls with a dopamine transporter ligand 2beta-carbomethoxy-3beta-(4-[(18)F]-fluorophenyl)tropane ([(18)F]CFT) positron emission tomography (PET). The PET scan was carried out twice with an average interval of 2.2 years. The regions of interest (anterior and posterior putamen, caudate nucleus, and cerebellum) were drawn on individual magnetic resonance imaging (MRI) images, matched with the PET images, and copied onto the PET images. At the first PET scan in PD patients, the [(18)F]CFT uptake in the anterior putamen was 1.92 +/- 0.67, which was 45% of the control mean, and in the posterior putamen 1.02 +/- 0.55, being only 27% of the control mean. For the caudate nucleus the corresponding figure was 2.55 +/- 0.58 (71% of the control mean). The uptake ratios had declined significantly by the time of the second PET scan and the absolute annual rate of decline of the tracer uptake was 0.23 +/- 0.14 (P < 0.001) in the anterior putamen, 0.13 +/- 0.13 (P = 0.005) in the posterior putamen, and 0.20 +/- 0.15 (P < 0.001) in the caudate nucleus. There was a statistically significant difference of the decline in the tracer uptake between the anterior and posterior putamen (P = 0.033). When the rate of progression was calculated compared to the normal control mean, the rate of annual decline was 5.3% in the anterior putamen, 3.3% in the posterior putamen, and 5.6% in the caudate nucleus, without significant changes among striatal subregions (P = 0.10). When ipsi- and contralateral sides were analyzed separately, the absolute decline of [(18)F]CFT uptake in the putamen was higher in the side ipsilateral to the predominant symptoms than in the contralateral side (P = 0.035 for anterior putamen and P = 0.026 for posterior putamen). In the caudate nucleus the absolute decline was not different between ipsi- and contralateral sides (P = 0.76). In healthy controls, no significant decline of [(18)F]CFT uptake was detected. The results are suggestive of slower progression in the posterior putamen, where the disease is more advanced, but studies to follow up the same patient at several time points are needed to resolve this question. Synapse 48:109-115, 2003.     

Progression in Parkinson's disease: a positron emission tomography study with a dopamine transporter ligand [18F]CFT

We studied the rate of progression of striatal dopamine transporter function in Parkinson's disease (PD). Eight patients with early PD without antiparkinsonian medication and 7 healthy volunteers were investigated with [18F]CFT positron emission tomography (PET). The PET scan was carried out twice at an approximate 2-year interval. The uptake of [18F]CFT was calculated as a region-cerebellum:cerebellum ratio at 180 to 210 minutes after injection. At the first PET scan, the [18F]CFT uptake in PD patients in the putamen was 1.45 +/- 0.45 (mean +/- SD) (42% of the control mean) and 2.43 +/- 0.59 in the caudate nucleus (76% of the control mean). The ratios declined by the time of the second PET scan, and the rate of annual decline of the baseline mean in PD patients was 13.1% in the putamen and 12.5% in the caudate nucleus. In controls, the corresponding figures were 2.1% for the putamen and 2.9% for the caudate nucleus. The decline in [18F]CFT uptake was significantly higher in PD patients than in controls. Thus, dopamine transporter ligands such as [18F]CFT seem to be sensitive markers for the rate of progression in PD.     

Striatal [18F]fluorodopa utilization after COMT inhibition with entacapone studied with PET in advanced Parkinson's disease

Summary The effect of peripheral catechol-O-methyltransferase (COMT) inhibition with entacapone on striatal uptake of 6-[¹⁸F]fluoro-L-dopa (FDOPA) was studied with PET both without and with entacapone in fifteen advanced parkinsonian patients and six healthy controls. Entacapone significantly enhanced the fraction of unmetabolized FDOPA in plasma from 16% to about 50% at 80 minutes after FDOPA injection in all subjects. The striatal to occipital ratios and the striatal FDOPA uptake, expressed as a modified decarboxylation coefficient (k₃R₀), was significantly increased in healthy controls, whereas in parkinsonian patients the increase was significant only in the caudate. On the other hand, the influx constant (K_i) decreased significantly in the caudate and putamen in parkinsonian patients; in healthy controls the K_i remained virtually unchanged.Effective peripheral COMT inhibition markedly increased the fraction of FDOPA in plasma and thus its availability in the brain for decarboxylation both in patients and control subjects. However, the change in striatal FDOPA uptake was modest in the advanced parkinsonian patients as compared to that in control subjects, because of the advanced disease, decreased storage capacity, or both.     

Uptake of 6-[18F]fluoro-L-dopa and [18F]CFT reflect nigral neuronal loss in a rat model of Parkinson's disease

In order to characterize the sensitivity of an analog of levodopa and a dopamine transporter ligand to detect defects in nigrostriatal function, the uptake of [(18)F]FDOPA and [(18)F]CFT was studied ex vivo in a rat model of Parkinson's disease. The brains of these rats were unilaterally lesioned with an intranigral injection of 6-hydroxydopamine. The lesioned animals were divided into three groups subject to their behavior after pharmacological challenges. Circling behavior was recorded after amphetamine, apomorphine, and L-DOPA challenge in order to predict lesion size. The spatial distribution of radioactivity after [(18)F]FDOPA or [(18)F]CFT injection in brain sections was determined with digital autoradiography. Regions of interest were left/right striatum, left/right substantia nigra, and cerebellum. The degree of unilateral lesion for each animal was confirmed by counting of nigral tyrosine hydroxylase-positive cell bodies. With both tracers the uptake in the lesioned side was lower than in the intact side in the striatum and in the substantia nigra. In conclusion, both tracers clearly demonstrated nigrostriatal dopaminergic hypofunction and correlated with the number of nigral dopaminergic neurons. However, [(18)F]FDOPA showed a much higher unspecific uptake of radioactivity, due to extensive metabolism; therefore, this tracer was less sensitive than the transporter tracer [(18)F]CFT to detect these defects.     

The metabolic anatomy of Parkinson's disease: complementary [18F]fluorodeoxyglucose and [18F]fluorodopa positron emission tomographic studies

We studied the metabolic anatomy of typical Parkinson's disease (PD) using [18F]fluorodeoxyglucose (FDG) and [18F]fluorodopa (FDOPA) and positron emission tomography (PET). Fourteen PD patients (mean age 49 years) had FDG/PET scans, of which 11 were scanned with both FDOPA and FDG. After the injection of FDOPA, brain uptake and arterial plasma radioactivity were monitored for 2 h. Striatal FDOPA uptake was analyzed with regard to a two-compartment model, and target-to-background ratios (TBRs) and TBR-versus-time slopes were also calculated. Regional patterns of metabolic covariation were extracted from FDG/PET data using the Scaled Subprofile Model (SSM). SSM pattern weights, FDOPA uptake constants (Ki), TBRs, and TBR slopes were correlated with clinical measures for bradykinesia, rigidity, tremor, gait disturbance, left-right asymmetry, dementia, and overall disease severity. In PD patients, rate constants for FDOPA uptake correlated with individual measures of bradykinesia (p = 0.001) and gait disability (p less than 0.05). SSM analysis revealed a distinct pattern of regional metabolic asymmetries, which correlated with motor asymmetries (p less than 0.001) and left-right differences in Ki (p less than 0.01). Our data suggest that in PD patients, FDG/PET and FDOPA/PET may provide unique and complementary information about underlying disease processes.     

Striatal Presynaptic Dopamine in Schizophrenia,Part II: Meta-Analysis of [18F/11C]-DOPA PET Studies

Background: Alterations in striatal dopamine neurotransmission are central to the emergence of psychotic symptoms and to the mechanism of action of antipsychotics. Although the functional integrity of the presynaptic system can be assessed by measuring striatal dopamine synthesis capacity (DSC), no quantitative meta-analysis is available. Methods: Eleven striatal (caudate and putamen) [¹¹C/¹⁸F]-DOPA positron emission tomography studies comparing 113 patients with schizophrenia and 131 healthy controls were included in a quantitative meta-analysis of DSC. Demographic, clinical, and methodological variables were extracted from each study or obtained from the authors and tested as covariates. Hedges’ g was used as a measure of effect size in Comprehensive Meta-Analysis. Publication bias was assessed with funnel plots and Egger’s intercept. Heterogeneity was addressed with the Q statistic and I² index. Results: Patients and controls were well matched in sociodemographic variables (P > .05). Quantitative evaluation of publication bias was nonsignificant (P = .276). Heterogeneity across study was modest in magnitude and statistically nonsignificant (Q = 19.19; P = .078; I² = 39.17). Patients with schizophrenia showed increased striatal DSC as compared with controls (Hedges’ g = 0.867, CI 95% from 0.594 to 1.140, Z = 6.222, P < .001). The DSC schizophrenia/control ratio showed a relatively homogenous elevation of around 14% in schizophrenic patients as compared with controls. DSC elevation was regionally confirmed in both caudate and putamen. Controlling for potential confounders such as age, illness duration, gender, psychotic symptoms, and exposure to antipsychotics had no impact on the results. Sensitivity analysis confirmed robustness of meta-analytic findings. Conclusions: The present meta-analysis showed consistently increased striatal DSC in schizophrenia, with a 14% elevation in patients as compared with healthy controls.     

Comparison of [99mTc]HMPAO SPECT with [18F]fluoromethane PET in cerebrovascular disease

Positron emission tomography (PET) of [18F]fluoromethane (FM) and single-photon emission tomography (SPECT) of [99mTc]hexamethylpropyleneamine oxime (HMPAO) were performed under identical conditions within 2 h in 22 patients suffering from cerebrovascular disease (8 ischemic infarction, 2 intracerebral hemorrhages, 7 transient ischemic attacks, and 5 multi-infarct syndrome). While gross pathological changes could be seen in the images of either procedure, focal abnormalities corresponding to transient ischemic deficits or to lesions in multi-infarct syndrome and areas of functional deactivation were sometimes missed on SPECT images. Overall, HMPAO SPECT images showed less contrast between high and low activity regions than the FM PET images, and differences between lesions and contralateral regions were less pronounced (6.4 vs 13.3% difference). Regional cerebral blood flow (rCBF) was calculated from FM PET studies in 14 large territorial regions and the pathological lesion, and the regional values relative to mean flow were compared to the relative HMPAO uptake in an identical set of regions defined on the SPECT images. Among individual patients, the Spearman rank-correlation coefficient between relative rCBF and HMPAO uptake varied between 0.48 and 0.89, with a mean of 0.70. While an underestimation of high flow with SPECT--which was demonstrated in a curvilinear relationship between all relative regional PET and SPECT values--could be corrected by linearization taking into account HMPAO efflux from the brain before metabolic trapping, correspondence of SPECT data with PET rCBF values was not improved since this procedure also increased the variance in high flow areas. In the cerebellum, however, a high HMPAO uptake in SPECT always overestimated CBF in relation to forebrain values; this finding might be due to high capillary density in the cerebellum. The differences observed between SPECT and PET data may be explained by technical and physical properties of the methods and by the incomplete first-pass extraction of HMPAO. Additionally, HMPAO or its metabolites may leak through a damaged blood-brain barrier (as observed in one infarct and in the surrounding of hemorrhages), impairing the contrast between lesion and normal tissue. The presented data indicate that the quantification of rCBF by HMPAO SPECT is limited.