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.     

Reproducibility and effect of levodopa on dopamine transporter function measurements: a [18F]CFT PET study.

The objective of this article was to study the reproducibility and effect of levodopa on dopamine transporter function measurements using 2beta-carbomethoxy-3beta-(4-[18F]fluorophenyl)tropane ([18F]CFT) positron emission tomography (PET). Seven de novo patients with Parkinson's disease (PD) were studied twice, before and after three months of levodopa medication. Eight healthy volunteer subjects participated in the reproducibility study. The [18F]CFT PET scan was done twice with an interval of approximately 2.5 months. 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. The [18F]CFT uptake was calculated as the region-cerebellum:cerebellum ratio at 180 to 210 minutes. Three-month levodopa treatment in PD patients had no significant effect on [18F]CFT uptake in any striatal subregion between the two PET scans. In PD patients, the percent change from baseline was 4.1% in the anterior putamen, 1.9% in the posterior putamen, and 4.0% in the caudate nucleus. No significant differences in [18F]CFT uptake between the first and second PET scan in any striatal subregion occurred in healthy controls. The intraclass correlation, indicating the reproducibility of the PET scan within subjects, was 0.94 for the anterior putamen, 0.86 for the posterior putamen, and 0.91 for the caudate nucleus. The percent change from baseline was 4.0% in the anterior putamen, 1.1% in the posterior putamen, and 2.8% in the caudate nucleus. Long-term levodopa treatment in PD patients had no effect on the [18F]CFT uptake in the striatum and the test-retest reproducibility was very high. These findings confirm [18F]CFT as a suitable ligand to monitor progression of PD.     

An FDOPA PET study in patients with periodic limb movement disorder and restless legs syndrome

The authors investigated nine drug-naive patients with periodic limb movement disorder and restless legs syndrome (PLMD-RLS) and 27 healthy controls with PET using 6-[18F]fluoro-L-dopa (FDOPA). In the patients, the FDOPA uptake (Ki(occ)) in the caudate nucleus was 88% and in the putamen 89% of the control mean values. This equal affection of the caudate and the putamen differs, for example, from the dopaminergic dysfunction in Parkinson's disease, which affects the putamen earlier and more severely than the caudate. The current results indicate mild nigrostriatal presynaptic dopaminergic hypofunction in PLMD-RLS.     

<Superscript>18</Superscript>F-FP-CIT PET imaging and SPM analysis of dopamine transporters in Parkinson’s disease in various Hoehn &; Yahr stages

To investigate the usefulness of 18F-FP-CIT PET for assessing the severity of Parkinson’s disease (PD) at various clinical stages, 41 patients with PD were divided into early (Hoehn&Yahr I-II, n = 23) and advanced (Hoehn&Yahr III-IV, n = 18) subgroups. 18F-FP-CIT PET was performed in these patients and 12 normal subjects. 18F-FP-CIT uptake in striatal subregions and its correlation with UPDRS were first evaluated by ROI analysis, and between-group differences were also analyzed by Statistical Parametric Mapping (SPM). Our results showed that striatal 18F-FP-CIT binding were significantly reduced to 70.9% (caudate), 46.8% (anterior putamen) and 24.0% (posterior putamen) in early PD compared with that of the control, and to 52.0%, 34.5% and 16.5% correspondingly in advanced PD, respectively. There was significant negative correlation between total motor UPDRS score of all parkinsonian patients and 18F-FP-CIT uptake in caudate nucleus (r = −0.53, p < 0.001), anterior putamen (r = −0.53, p < 0.001) and posterior putamen (r = −0.61, p < 0.001). SPM comparison of 18F-FP-CIT uptake between early or advanced PD and the control group showed significant decline in striatum, predominantly localized on the contralateral side and in the dorsal-posterior putamen. These results indicate that 18F-FP-CIT PET can serve as a suitable biomarker to represent the severity of PD in early and advanced stages. Received in revised form: 11 June 2006     

Dopaminergic correlates of metabolic network activity in Parkinson's disease

Parkinson's disease (PD) is associated with distinct metabolic covariance patterns that relate to the motor and cognitive manifestations of the disorder. It is not known, however, how the expression of these patterns relates to measurements of nigrostriatal dopaminergic activity from the same individuals. To explore these associations, we studied 106 PD subjects who underwent cerebral PET with both ¹⁸F‐fluorodeoxyglucose (FDG) and ¹⁸F‐fluoro‐L‐dopa (FDOPA). Expression values for the PD motor‐ and cognition‐related metabolic patterns (PDRP and PDCP, respectively) were computed for each subject; these measures were correlated with FDOPA uptake on a voxel‐by‐voxel basis. To explore the relationship between dopaminergic function and local metabolic activity, caudate and putamen FDOPA PET signal was correlated voxel‐wise with FDG uptake over the entire brain. PDRP expression correlated with FDOPA uptake in caudate and putamen (P < 0.001), while PDCP expression correlated with uptake in the anterior striatum (P < 0.001). While statistically significant, the correlations were only of modest size, accounting for less than 20% of the overall variation in these measures. After controlling for PDCP expression, PDRP correlations were significant only in the posterior putamen. Of note, voxel‐wise correlations between caudate/putamen FDOPA uptake and whole‐brain FDG uptake were significant almost exclusively in PDRP regions. Overall, the data indicate that PDRP and PDCP expression correlates significantly with PET indices of presynaptic dopaminergic functioning obtained in the same individuals. Even so, the modest size of these correlations suggests that in PD patients, individual differences in network activity cannot be explained solely by nigrostriatal dopamine loss. Hum Brain Mapp 36:3575–3585, 2015. © 2015 Wiley Periodicals, Inc.     

Differing patterns of striatal 18F-dopa uptake in Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy

Using positron emission tomography (PET), we studied regional striatal 18F-dopa uptake in 16 patients with L-dopa-responsive Parkinson's disease (PD), 18 patients with multiple system atrophy, and 10 patients with progressive supranuclear palsy. Results were compared with those of 30 age-matched normal volunteers. The patients with PD showed significantly reduced mean uptake of 18F-dopa in the caudate and putamen compared to controls, but while function in the posterior part of the putamen was severely impaired (45% of normal), function in the anterior part of the putamen and in the caudate was relatively spared (62% and 84% of normal). Mean 18F-dopa uptake in the posterior putamen was depressed to similar levels in all patients. Unlike patients with PD, the patients with progressive supranuclear palsy showed equally severe impairment of mean 18F-dopa uptake in the anterior and posterior putamen. Caudate 18F-dopa uptake was also significantly lower in patients with progressive supranuclear palsy than in patients with PD, being depressed to the same level as that in the putamen. Mean 18F-dopa uptake values in the anterior putamen and caudate in patients with multiple system atrophy lay between PD and progressive supranuclear palsy levels. Locomotor disability of individual patients with PD or multiple system atrophy correlated with decline in striatal 18F-dopa uptake, but this was not the case for the patients with progressive supranuclear palsy. We conclude that patients with PD have selective nigral pathological features with relative preservation of the dopaminergic function in the anterior putamen and caudate, whereas there is progressively more extensive nigral involvement in multiple system atrophy and progressive supranuclear palsy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Striatal uptake of a novel PET ligand, [18F]beta-CFT, is reduced in early Parkinson's disease

[18F] beta-CFT is a novel PET ligand for dopamine reuptake sites. In this study, [18F]beta-CFT uptake was studied in nine patients with early Parkinson's disease (PD) without antiparkinsonian medication and in six age-matched controls. The uptake of [18F]beta-CFT was calculated as a (region-cerebellum)/cerebellum ratio at 150-210 min after injection. The mean uptake in the putamen contralateral to the predominant symptoms (1.04+/-0.40, mean +/- SD; P<0.001) was reduced to 31% of the mean control value. In the "ipsilateral" putamen, the ratio in PD patients (1.50+/-0.50, P<0.001) was reduced to 45% of the control mean (3.33+/-0.61). Individually, all PD patients had [18F]beta-CFT uptake values below 2 SD from the control mean in the contralateral putamen. The decline in [18F]beta-CFT uptake in the caudate nucleus was milder than that seen in the putamen. The uptake was reduced contralaterally (2.19+/-0.47, P<0.01) to 67% and ipsilaterally (2.49+/-0.54, P<0.05) to 77% of the control mean (3.17+/-0.61). In the medial frontal cortex or dorsolateral prefrontal cortex, no significant difference in [18F]beta-CFT uptake between patients and controls was seen. In conclusion, [18F]beta-CFT is a powerful ligand to demonstrate presynaptic dopaminergic defect in PD and shows a clear separation of patient and control values.     

Decreased striatal monoaminergic terminals in Huntington disease

OBJECTIVE: To evaluate the integrity of the dorsal striatal dopaminergic innervation in rigid and choreic Huntington disease (HD). BACKGROUND: Some patients with HD have an akinetic-rigid phenotype. It has been suggested that nigrostriatal in addition to striatal pathology is present in this subgroup. The authors sought to determine whether in vivo measures of striatal vesicular monoamine transporter type-2 (VMAT2) binding could distinguish patients with akinetic-rigid (HDr) from typical choreiform (HDc) HD. METHODS: Nineteen patients with HD (mean age 48 +/- 16 years) and 64 normal controls (mean age 50 +/- 14 years) underwent (+)-alpha-[11C]dihydrotetrabenazine (DTBZ) PET imaging. DTBZ blood to brain ligand transport (K1) and tissue to plasma distribution volume (DV) in the caudate nucleus, anterior putamen, and posterior putamen were normalized to the occipital cortex. RESULTS: The normalized striatal specific DV was reduced in HDr (n = 6) when compared with controls: caudate nucleus -33% (p < 0.001), anterior putamen -56% (p < 0.0001), and posterior putamen -75% (p < 0.0001). Patients with HDc (n = 13) also had reduced striatal DV: caudate nucleus -6% (NS), anterior putamen -19% (p < 0.01), and posterior putamen -35% (p < 0.0001). Patients with HDr had significantly lower striatal (+)-alpha-[11C]DTBZ binding than HDc patients. After correction for tissue atrophy effects, normalized DV differences were less significant, with values somewhat increased in the caudate, slightly reduced in the anterior putamen, and moderately decreased in the posterior putamen. There were no significant regional differences in K1 reductions among caudate, anterior, and posterior putamen in HD. CONCLUSIONS: Reduced striatal VMAT2 binding suggests nigrostriatal pathology in HD, most severely in the HDr phenotype. Striatal DV reductions were most prominent in the posterior putamen, similar to PD.     

A longitudinal study of motor performance and striatal [18F]fluorodopa uptake in Parkinson��s disease

Although [(18)F]fluoro-L: -dopa [FDOPA] positron emission tomography (PET) has been used as a surrogate outcome measure in Parkinson's disease therapeutic trials, this biomarker has not been proven to reflect clinical status longitudinally. We completed a retrospective analysis of relationships between computerized sampling of motor performance, FDOPA PET, and clinical outcome scales, repeated over 4?years, in 26 Parkinson's disease (PD) patients and 11 healthy controls. Mixed effects analyses showed that movement time and tongue strength best differentiated PD from control subjects. In the treated PD cohort, motor performance measures changed gradually in contrast to a steady decline in striatal FDOPA uptake. Prolonged reaction and movement time were related to lower caudate nucleus FDOPA uptake, and abnormalities in hand fine force control were related to mean striatal FDOPA uptake. These findings provide evidence that regional loss of nigrostriatal inputs to frontostriatal networks affects specific aspects of motor function.     

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.     

Cognitive impairment and the brain dopaminergic system in Parkinson disease: [18F]fluorodopa positron emission tomographic study

OBJECTIVE: To investigate the role of the brain dopaminergic system in cognitive impairment in patients with Parkinson disease (PD). DESIGN: We studied 28 patients with PD and 16 age-matched healthy control subjects using [18F] fluorodopa (fluorodopa F 18) positron emission tomography. Patients with PD showed a variable degree of cognitive impairment, which was assessed using the Mini-Mental State Examination and detailed neuropsychologic assessment, including tests sensitive for frontal lobe function. RESULTS: [18F] Fluorodopa uptake was reduced in the putamen (to 36% of the control mean; P<.001), the caudate nucleus (to 61% of the control mean; P<.001), and the frontal cortex (to 45% of the control mean; P<.001) in patients with PD compared with controls. There was no significant association between the degree of overall cognitive impairment of patients and [18F] fluorodopa uptake values. The influx constant (Ki(occ)) in the caudate nucleus had a negative association with performance in the attention-demanding Stroop interference task, especially with the interference time. The Ki(occ) in the frontal cortex had a positive correlation with performance in the digit span (backwards), verbal fluency, and verbal immediate recall tests. Thus, the better the patient performed in tasks demanding immediate and working memory and executive strategies, the better the [18F] fluorodopa uptake in the frontal cortex. In the putamen, no significant correlation was seen between the Ki(occ) value and any of the cognitive tests. The severity of the motor symptoms of PD and [18F]fluorodopa uptake showed a negative correlation in the putamen (r = -0.38; P = .04), and in the caudate nucleus a similar trend was seen (r = -0.36; P = .06). CONCLUSIONS: Reduced [18F]fluorodopa uptake in PD in the caudate nucleus (and frontal cortex) is related to impairment in neuropsychologic tests measuring verbal fluency, working memory, and attentional functioning reflecting frontal lobe function. This indicates that dysfunction of the dopamine system has an impact on the cognitive impairment of patients with PD. However, our results do not exclude the possibility of more generalized cognitive impairment in PD, the pathophysiology of which is probably different and more generalized.     

Differentiation of dementia with Lewy bodies from Alzheimer's disease using a dopaminergic presynaptic ligand

BACKGROUND: Dementia with Lewy bodies (DLB) is one of the main differential diagnoses of Alzheimer's disease (AD). Key pathological features of patients with DLB are not only the presence of cerebral cortical neuronal loss, with Lewy bodies in surviving neurones, but also loss of nigrostriatal dopaminergic neurones, similar to that of Parkinson's disease (PD). In DLB there is 40-70% loss of striatal dopamine. OBJECTIVE: To determine if detection of this dopaminergic degeneration can help to distinguish DLB from AD during life. METHODS: The integrity of the nigrostriatal metabolism in 27 patients with DLB, 17 with AD, 19 drug naive patients with PD, and 16 controls was assessed using a dopaminergic presynaptic ligand, (123)I-labelled 2beta-carbomethoxy-3beta-(4-iodophenyl)-N-(3-fluoropropyl)nortropane (FP-CIT), and single photon emission tomography (SPET). A SPET scan was carried out with a single slice, brain dedicated tomograph (SME 810) 3.5 hours after intravenous injection of 185 MBq FP-CIT. With occipital cortex used as a radioactivity uptake reference, ratios for the caudate nucleus and the anterior and posterior putamen of both hemispheres were calculated. All scans were also rated by a simple visual method. RESULTS: Both DLB and PD patients had significantly lower uptake of radioactivity than patients with AD (p<0.001) and controls (p<0.001) in the caudate nucleus and the anterior and posterior putamen. CONCLUSION: FP-CIT SPET provides a means of distinguishing DLB from AD during life.     

Striatal monoamine terminals in Lewy body dementia and Alzheimer's disease

We used positron emission tomography (PET) with (+)-[(11)C]dihydrotetrabenazine ([+]-[(11)C]DTBZ) to examine striatal monoaminergic presynaptic terminal density in 20 patients with dementia with Lewy bodies (DLB), 25 with Alzheimer's disease (AD), and 19 normal elderly controls. Six DLB patients developed parkinsonism at least 1 year before dementia (DLB/PD) and 14 developed dementia before parkinsonism or at about the same time (DLB/AD). Striatal mean binding potential was decreased by 62 to 77% in the DLB/PD group and 45 to 67% in the DLB/AD compared to AD and control. Binding was lower in the DLB/PD group than the DLB/AD, but the differences reached only marginal significance in the caudate nucleus. No differences were found between AD and control groups though a few AD patients had binding values below the range of the controls. Subsequent neuropathological examination in one AD patient revealed both AD and DLB changes despite the absence of clinical parkinsonism. Both DLB groups had an anterior to posterior binding deficit gradient relative to controls, largest in posterior putamen, smaller in anterior putamen, smallest in caudate nucleus. The DLB/AD group showed significant binding asymmetry only in posterior putamen. We conclude that PET with (+)-[(11)C]DTBZ differentiates DLB from AD, and decreased binding in AD may indicate subclinical DLB pathology in addition to AD pathology.     

PET imaging of the dopamine transporter in progressive supranuclear palsy and Parkinson's disease

OBJECTIVE: To differentiate the patterns of dopamine transporter loss between idiopathic PD and progressive supranuclear palsy (PSP). METHODS: We used the radiotracer [11C]-WIN 35,428 and PET. Regional striatal dopamine transporter binding was measured in the caudate, anterior putamen, and posterior putamen of six patients with L-dopa-responsive stage 2 PD, six patients with PSP, and six age-comparable healthy controls. RESULTS: In patients with idiopathic PD, the most marked abnormality was observed in the posterior putamen (77% reduction), whereas transporter density in the anterior putamen (60% reduction) and the caudate (44% reduction) was less affected. Unlike the patients with PD, the PSP group showed a relatively uniform degree of involvement in the caudate (40% reduction), anterior putamen (47% reduction), and posterior putamen (51% reduction). When posterior putamen/caudate ratios were calculated, these values were significantly lower in patients with PD than they were in patients with PSP (p = 0.0008) and the control group (p < 0.0001). CONCLUSIONS: Patients with PD have a more pronounced loss of dopamine transporters in the posterior putamen due to a subdivisional involvement of nigrostriatal dopaminergic projections in idiopathic PD. This technique is useful in the determination of neurochemical changes underlying PD and PSP, thus differentiating between them.     

Striatal dopa and glucose metabolism in PD patients with freezing of gait.

In Parkinson's disease (PD), freezing suggests sudden and transient blocks of motor behavior during initiating or continuous repetitive movements. Its underlying pathophysiology remains unclear. The objective of this study is to compare striatal dopamine metabolism and cerebral glucose metabolism between PD patients with and without freezing of gait (FOG). A total of 10 PD patients with FOG at off and 7 PD patients without FOG underwent brain positron emission tomography with (18)[F]-6-fluoro-levodopa (FDOPA) and (18)[F]-fluordesoxyglucose (FDG). Striatum decarboxylase activity was expressed by metabolic influx constants of the striatum related to the occipital lobe (Kocc). FDG uptake in caudate and putamen was normalized to global FDG uptake. Region of interest (ROI) analysis of striatal regions was used, as well as voxel-based analysis by statistical parametric mapping (SPM). ROI analysis did not reveal differences in striatal FDOPA and FDG uptake between the groups. SPM showed lower putaminal FDOPA uptake (P = 0.05 uncorrected) with increased FDG uptake (P = 0.01 uncorrected) in freezing PD, whereas caudate uptake of the two tracers was reduced. Freezing-related cortical FDG decrease was found in (right) parietal regions. In conclusion, in freezing PD, caudate uptake of FDG and FDOPA was reduced, whereas putamen FDOPA decrease was associated with FDG increase. Right hemisphere circuitry seemed to be more affected in freezing patients.     

PET shows that striatal dopamine D1 and D2 receptors are differentially affected in AD

OBJECTIVE: To study dopamine D1 and D2 receptors in the putamen and the caudate nucleus in patients with AD and age-matched healthy controls by means of PET. METHODS: A dopamine D1 receptor antagonist ([11C]NNC 756) and a D2 receptor antagonist ([11C]raclopride) were used as ligands. The uptake of these ligands was calculated as a distribution volume ratio of the putamen and the caudate nucleus to the cerebellum. RESULTS: The mean [11C]NNC 756 uptake in AD was reduced by 14% from the mean control value both in the putamen (p = 0.004) and the caudate nucleus (p = 0.009). There was no significant reduction in the mean [11C]raclopride uptake in either the putamen or the caudate nucleus in AD. There was no correlation between [11C]NNC 756 or [11C]raclopride uptake and Mini-Mental State Examination or motor Unified PD Rating Scale scores in patients with AD. CONCLUSIONS: There are changes in striatal D1 but not in D2 receptors in AD.     

Putamen FDOPA uptake and its relationship tot cognitive functioning in PD

Impaired executive functioning is frequently found in PD patients. As a result, impairments in the executive components of other cognitive functions such as memory, visuo-spatial functions and fluency are also present. From a neuroanatomical point of view, different loops are mediating cognitive, emotional and motor functions. The putamen is part of the motor loop, while the caudate nucleus is part of the motor loop but also of the cognitive loop. In PD, multiple neurotransmitter systems are involved in cognitive functioning, including the dopaminergic system. Cognitive functioning in PD is related to striatal FDOPA uptake. This is particularly true for the caudate nucleus, but also for the putamen. We found a relationship between putaminal FDOPA uptake and measures for executive functioning, memory and fluency in a group of 28 non-demented advanced PD patients. This is a surprising finding since the putamen is part of the motor loop, but not the cognitive loop. One possible explanation is that the putamen is involved in motor actions after cognitive switching and is therefore related to neuropsychological test scores, as these require motor responses.     

Dopamine storage capacity in caudate and putamen of patients with early Parkinson's disease: correlation with asymmetry of motor symptoms.

Conventional graphical analysis of positron emission tomography (PET) recordings of the cerebral uptake of the DOPA decarboxylase substrate [(18)F]fluorodopa (FDOPA) assumes irreversible trapping of [(18)F]fluorodopamine formed in the brain. However, 4-h long PET recordings allow the estimation of a rate constant for elimination of [(18)F]fluorodopamine from the brain (k(loss)), from which can be calculated an effective distribution volume (EDV(1)), which is an index of [(18)F]fluorodopamine storage capacity. We earlier developed a method employing 2-h long FDOPA recordings for the estimation of k(loss) and EDV, here defined as EDV(2). This method is based on subtraction of the calculated brain concentrations of the FDOPA metabolite O-methyl-FDOPA, rather than the subtraction of the entire radioactivity in a reference region. We now extend this method for the parametric mapping of these parameters in the brain of healthy aged volunteers and patients with Parkinson's disease (PD), with asymmetry of motor symptoms. For parametric mapping, we use a novel application of a multilinear solution for the two-tissue compartment FDOPA model. We also test a new application of the Logan graphical analysis for mapping of the FDOPA distribution volume at equilibrium. The estimates of k(loss) and EDV(2) were more sensitive for the discrimination of biochemical abnormality in the putamen of patients with early PD relative to healthy aged subjects, than was the conventional net influx estimate. Of the several methods, multilinear estimates of EDV(2) were most sensitive for discrimination of PD and normal putamen. However, k(loss) was most sensitive for detecting biochemical asymmetry in the putamen of PD patients, and only k(loss) also detected in the caudate of PD patients a decline in the retention of [(18)F]fluorodopamine relative to healthy aged control subjects.     

Blinded positron emission tomography study of dopamine cell implantation for Parkinson's disease

We assessed nigrostriatal dopaminergic function in Parkinson's disease (PD) patients undergoing a double-blind, placebo-controlled surgical trial of embryonic dopamine cell implantation. Forty PD patients underwent positron emission tomography (PET) imaging with [18F]fluorodopa (FDOPA) prior to randomization to transplantation or placebo surgery. The 39 surviving patients were rescanned one year following surgery. Images were quantified by investigators blinded to treatment status and clinical outcome. Following unblinding, we determined the effects of treatment status and age on the interval changes in FDOPA/PET signal. Blinded observers detected a significant increase in FDOPA uptake in the putamen of the group receiving implants compared to the placebo surgery patients (40.3%). Increases in putamen FDOPA uptake were similar in both younger (age < or = 60 years) and older (age > 60 years) transplant recipients. Significant decrements in putamen uptake were evident in younger placebo-operated patients (-6.5%) but not in their older counterparts. Correlations between the PET changes and clinical outcome were significant only in the younger patient subgroup (r = 0.58). The findings suggest that patient age does not influence graft viability or development in the first postoperative year. However, host age may influence the time course of the downstream functional changes that are needed for clinical benefit to occur.