Striatal 6-[18F]fluorodopa accumulation after combined inhibition of peripheral catechol-O-methyltransferase and monoamine oxidase type B: Differing response in relation to presynaptic dopaminergic dysfunction

The aim was to investigate the effects of inhibition of monoamine oxidase type B (MAO-B) with selegiline alone and the combined inhibition of peripheral catechol-O-methyltransferase (COMT) with entacapone and MAO-B with selegiline on striatal 6-[¹⁸F]fluorodopa (FDOPA) accumulation, and whether the effect of entacapone + selegiline on FDOPA uptake differed depending on the severity of the presynaptic dopaminergic dysfunction. Thus, eight healthy controls, eight de novo patients with Parkinson's disease (PD), and 18 levodopa-treated PD patients were investigated with positron emission tomography (PET). Half of the subjects in each population belonged to the selegiline group and half to the entacapone + selegiline group. Both groups were studied twice with PET using FDOPA. After the first (baseline) FDOPA PET investigation, both groups were on 2 weeks of selegiline treatment, 10 mg daily. Thereafter, the second FDOPA PET was performed for all subjects with a premedication administered 60 min before the PET imaging; one group received 10 mg of selegiline, and the other group received a single 400 mg dose of entacapone coadministered with 10 mg of selegiline. Selegiline treatment alone had no significant influence on striatal FDOPA metabolism. The FDOPA accumulation, expressed as striatal-to-occipital ratios and modified decarboxylation coefficients (k₃R₀), increased significantly after entacapone + selegiline administration in all subject populations. The FDOPA uptake rate constant (K_i) remained virtually unchanged in controls and in de novo patients but decreased significantly in levodopa-treated PD patients after entacapone + selegiline intake. Entacapone + selegiline administration did not influence significantly the unidirectional blood-to-brain clearance for FDOPA (K₁^D) or the relative dopadecarboxylase activity (k₃^D). The changes in the studied parameters after entacapone + selegiline administration probably reflect the effects of entacapone, since entacapone alone has caused similar changes in previous PET studies. Response in FDOPA accumulation to entacapone + selegiline was higher in controls and de novo patients compared with levodopa-treated PD patients. The milder response in levodopa-treated patients might reflect the reduced ability of the degenerated dopaminergic neurons to utilize the prolonged FDOPA availability, produced by entacapone. Synapse 27:336–346, 1997. © 1997 Wiley-Liss, Inc.     

Cerebral 6-[F]fluoro-l-DOPA uptake in rhesus monkey: pharmacological influence of aromatic amino acid decarboxylase (AAAD) and catechol-O-methyltransferase (COMT) inhibition

FDOPA/PET scans were performed in one rhesus monkey to study the influence of three catechol-O-methyltransferase (COMT) inhibitors (CGP 28014, OR-611 and Ro 40-7592) on FDOPA pharmacokinetics. COMT inhibitors were administered in combination with carbidopa, a peripherally acting inhibitor of the aromatic amino acid decarboxylase (AAAD). FDOPA was administered intravenously and its metabolic fate in plasma was determined using an HPLC system with an on-line γ-γ coincidence detector. Cerebral tracer uptake was assessed in the striatum and in a non-dopaminergic brain region (occipital cortex). In the periphery, the pharmacokinetic efficiency of FDOPA was increased due to the combined inhibition of COMT and AAAD activity. All three COMT inhibitors reduced the FDOPA methylation rate constant in plasma, with complete suppression obtained in the case of Ro 40-7592. In the brain, specific ¹⁸F radioactivity (striatal minus brain reference radioactivity) increased as a result of the increase in FDOPA plasma availability following the administration of COMT and AAAD inhibitors. We established a significant linear correlation between striatal radioactivity and FDOPA plasma levels (r=0.924±0.048, P<0.0001 for total striatal and r=0.948±0.054, P<0.0001 for specific striatal radioactivity). Using plasma FDOPA radioactivity as input, we found that the striatal FDOPA uptake rate constant K_i^FD was not changed by any of the inhibitors. Thus, the enhancement of striatal radioactivity after application of enzyme inhibitors is a consequence of the increase in plasma FDOPA that becomes available for conversion to fluorodopamine in the striatal dopaminergic nerve terminals. By contrast, using the radioactivity in a non-dopaminergic region (cortex) as input, we found that the striatal FDOPA uptake rate constant K_i^ref was significantly (P<0.0001) increased following pretreatment with COMT inhibitors. Our analysis demonstrated that K_i^ref and the 3-OMFD contribution to the cerebral radioactivity were inversely correlated.     

Detection of response to COMT inhibition in FDOPA PET in advanced Parkinson's disease requires prolonged imaging

The aim was to investigate whether the improved 6-[(18)F]fluoro-L-dopa (FDOPA) availability induced by catechol-O-methyltransferase (COMT) inhibition can be more clearly seen during late than during standard (early) imaging in FDOPA uptake in Parkinson's disease (PD) patients with severe dopaminergic hypofunction. Six PD patients and six healthy controls were investigated up to 3.5 h after FDOPA injection with and without a single 400-mg dose of a peripheral COMT inhibitor, entacapone. Prolonged (late) imaging showed a significantly higher increase in FDOPA uptake than standard 1.5 h (early) imaging after entacapone both in controls and in PD patients. The increase in the (putamen-occipital):occipital ratios was 37.4% during early and 70.4% during late imaging in controls. In PD patients, there was no significant change in the ratios during early imaging, but the late imaging showed a significant increase in the putamen-to-occipital ratio of 54.2% after COMT inhibition. Late imaging reveals more clearly the prolonged FDOPA availability induced by COMT inhibition leading to higher cumulated striatal activity compared with early imaging. This might be worth considering in FDOPA studies, especially if investigations are planned to do without blood sampling. Late imaging shows the storing potential of FDA better than is seen during early FDOPA PET imaging after entacapone administration. In patients with severe presynaptic dopaminergic hypofunction, its detection requires prolonged imaging.     

6-[18F]fluoro-L-DOPA PET studies of the turnover of dopamine in MPTP-induced parkinsonism in monkeys

This report describes a method to assess, in vivo, the turnover of dopamine (DA) and describes its application to the evaluation of DA function in normal monkeys and monkeys with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced lesions of the DA nigro–striatal pathway. Using positron emission tomography with the tracer of presynaptic DA function, 6-[¹⁸F]fluoro-L -DOPA (FDOPA), and an extension of the graphical method of analysis, we measured the striatal FDOPA uptake rate constant, K_i, and the rate of reversibility of FDOPA trapping k_loss in normal and MPTP-treated monkeys, either neurologically normal or displaying a parkinsonian symptomatology. An index of effective DA turnover was defined as the ratio of k_loss/K_i. Compared to normal controls, K_i was decreased and k_loss was increased in the MPTP-lesioned monkeys. The index of DA turnover was significantly increased in the monkeys displaying a parkinsonian symptomatology as compared to the controls and the neurologically normal MPTP-treated monkeys. The DA turnover index was also significantly increased in the neurologically normal MPTP-lesioned animals compared to normals. This suggests that an increase in DA turnover develops early in the disease process and may be one of the compensatory mechanisms partly responsible for the delay in the development of the clinical manifestations in Parkinson's disease. Synapse 29:225–232, 1998. © 1998 Wiley-Liss, Inc.     

6-[18F]fluoro-L-DOPA-PETstudies show partial reversibility of long-term effects of chronic amphetamine in monkeys

The acute and long-term effects of chronic amphetamine administration on the striatal dopamine system in monkeys were assessed with 6-[¹⁸F]fluoro-L-DOPA (FDOPA) and positron emission tomography (PET). Vervet monkeys (Cerecopithecus aethiops) were administered amphetamine doses, i.m., that increased from 4 mg/kg/d to 18 mg/kg/d over a 10 day period. Post-amphetamine FDOPA-PET scans at 1–2, 3–4, and 6 week time points in individual subjects showed persistent decrements in dopamine synthesis capacity as reflected by FDOPA influx rate constant (K_i) values being ∼30% that of pre-drug assessment. In other animals that were administered the same drug regimen, biochemical analysis of striatal regions at 1–2 weeks post-drug indicated that dopamine concentrations were decreased by ∼95% throughout caudate and putamen regions, while the homovanillic acid/dopamine level ratio was increased 3–10-fold. Post-drug FDOPA-PET K_i values remained consistently low up to 6 weeks; however, at the 5–6 month time point, relative increases in FDOPA-K_i values (∼53% of pre-drug values) were observed for all subjects, indicative of partial recovery of striatal dopamine synthesis capacity. These results demonstrate that FDOPA-PET can reveal temporal activity changes within the striatal dopamine system of individual subjects. The apparent, partial reversibility of amphetamine's neurotoxic effects suggests a plasticity of dopaminergic function that may include regeneration of dopaminergic terminals and compensatory increases in residual dopamine synthesis rates. The persistence of the partial decrement in dopamine synthesis capacity, however, may indicate a long term component of amphetamine's toxic effects. © 1996 Wiley-Liss, Inc.     

Longitudinal Positron Emission Tomography of Dopamine Synthesis in Subjects with GBA1 Mutations

Mutations in GBA1, the gene mutated in Gaucher disease, are a common genetic risk factor for Parkinson disease, although the penetrance is low. We performed [¹⁸F]-fluorodopa positron emission tomography studies of 57 homozygous and heterozygous GBA1 mutation carriers (15 with parkinsonism) and 98 controls looking for early indications of dopamine loss using voxelwise analyses to identify group differences in striatal [¹⁸F]-fluorodopa uptake (K_i). Forty-eight subjects were followed longitudinally. Cross-sectional and longitudinal comparisons of K_i and K_i change found significant effects of Parkinson disease. However, at baseline and over time, striatal [¹⁸F]-fluorodopa uptake in mutation carriers without parkinsonism did not significantly differ from controls. ANN NEUROL 2020;87:652–657     

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.     

Effect of catechol-O-methyltransferase inhibition on brain uptake of [18F]fluorodopa: Implications for compartmental modelling and clinical usefulness

The efficacy of levo-DOPA in the treatment of Parkinson's disease is potentiated by blockade of its peripheral metabolism with inhibitors of catechol-O-methyltransferase (COMT). Some COMT inhibitors may act entirely in the periphery (nitecapone, OR-462), while others may also have some activity in brain (entacapone, OR-611). We used positron emission tomography (PET) to test the effects of these two COMT inhibitors on the plasma kinetics and brain metabolism of the levo-DOPA analog 6-[¹⁸F]fluoro-L-dopa (FDOPA) in cynomolgus monkeys, employing a compartmental model for the assay of DOPA decarboxylase activity in living brain. Four monkeys each underwent two PET scans in the baseline condition, one PET scan after treatment with OR-462 (15 mg/ kg, i.v.), and one PET scan after treatment with OR-611 (15 mg/ kg, i.v.). Pharmacokinetic analysis of FDOPA metabolism in plasma indicated that these compounds blocked peripheral COMT activity by 80% for at least 60 minutes. Both COMT inhibitors increased the net availability of FDOPA in circulation, and increased the ratio of the radioactivity concentrations in striatum and occipital cortex, suggesting that [¹⁸F]fluorodopamine synthesis in striatum was potentiated. However, OR-611 treatment reduced the unidirectional (K) and net (K_i) blood-brain clearances of FDOPA, and also inhibited the rate of decarboxylation (k) of FDOPA in striatum. These observations suggest that high doses of OR-611 may partially antagonize the cerebral utilization of levo-DOPA. We used the present data to test the sensitivity of the compartmental model to the physiological constraint that the blood-brain permeabilities of the O-methylated plasma metabolite and FDOPA have a fixed ratio. In the groups with COMT inhibition, the estimates of k were insensitive to the magnitude of the permeability ratio. In the control group, the estimate of k increased by 40% as the magnitude of the constrained permeability ratio increased in the range of published estimates. Synapse 30:351–361, 1998. © 1998 Wiley-Liss, Inc.     

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.     

Effects of peripheral and central catechol-O-methyltransferase inhibition on striatal extracellular levels of dopamine: a microdialysis study in freely moving rats

Tolcapone is a mixed (peripheral and central) catechol-O-methyltransferase (COMT) inhibitor, whereas entacapone is a preferential peripheral COMT inhibitor. Both drugs are able to decrease the peripheral conversion of L-DOPA into 3-O-methyl-DOPA and thereby increase plasma and cerebral levels of L-DOPA, the precursor of dopamine (DA). Tolcapone may also impair the extraneuronal catabolism of DA by inhibiting COMT activity in the brain. To evaluate the role played by peripheral and central COMT inhibition, we compared the effects of tolcapone and entacapone on COMT activity in peripheral tissues, and on striatal extracellular levels of L-DOPA and DA in rats. Tolcapone and entacapone, at the dose of 15 mg/kg p.o., were almost equally effective in inhibiting COMT activity in duodenum and liver. Tolcapone decreased striatal extracellular levels of homovanillic acid (HVA), thus confirming its central COMT inhibitory effect, whereas entacapone did not alter HVA efflux. Following L-DOPA/benserazide administration (50/15 mg/kg p.o.), both COMT inhibitors significantly increased striatal levels of L-DOPA and DA compared with saline. The levels of L-DOPA were similar after treatment with either COMT inhibitors, whereas the increase in DA output was significantly greater in rats given tolcapone compared to those given entacapone. We conclude that the blockade of central DA catabolism by tolcapone contributes to the greater increase in striatal DA levels achieved with this drug.     

Decreased single-photon emission computed tomographic {123I}β-CIT striatal uptake correlates with symptom severity in parkinson's disease

Previous studies have utilized single-photon emission computed tomography (SPECT) to demonstrate decreased {¹²³I}β-CIT striatal uptake in idiopathic Parkinson disease (PD) patients. The present study extendss this work by examining SPECT outcome measures in a larger group of PD patients with varying disease severity. Twenty-eight l-dopa-responsive PD patients (Hoehn-Yahr stages 1–4) and 27 healthy controls had SPECT scans at 18 to 24 hours after injection of {¹²³I}β-CIT. Specific to nondisplaceable striatal uptake ratios (designated V_3″) were correlated with Hoehn-Yahr stage and Unified Parkinson's Disease Rating Scale (UPDRS) subscores. Linear discriminant function analyses utilizing striatal uptakes, putamen-to-caudate ratios, and ipsilateral-contralateral asymmetry indices were performed. Decreased striatal tracer uptake (V_3″) was correlated with total UPDRS score for both contralateral and ipsilateral striatum. Putamen uptake was relatively more reduced than caudate with mean putamen:caudate ratios of 0.50 ± 0.17 and 0.82 ± 0.09 for PD patients and controls, respectively. Ipsilateral:contralateral asymmetry was significantly greater in PD patients than controls. Discriminant function analysis utilizing V_3″ for ipsilateral and contralateral caudate and putamen correctly classified all 55 cases. These data demonstrate Marchked differences in {¹²³I}β-CIT SPECT measures in healthy controls and PD patients. The significant correlation of SPECT measures with motor severity suggests {¹²³I}β-CIT may be a useful Marchker of disease severity in PD.     

Longitudinal Behavioral and 6-[F]Fluoro- -DOPA-PET Assessment in MPTP-Hemiparkinsonian Monkeys

Biochemical and behavioral criteria were established to determine the long-term stability of a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced unilateral striatal dopamine deficiency in the vervet monkey. At time points over a 12-month period, post-MPTP striatal dopamine synthesis capacity was indexed with 6-[¹⁸F]fluoro- -DOPA (FDOPA)-positron emission tomography. For the MPTP-treated subjects (n = 4), an intrasubject FDOPA influx rate constant (K_i) ratio method of right (lesioned) striatum/left (unlesioned) striatum values was used to assess changes in striatal activity. Striatal FDOPAK_iratios differed less than 5% between studies conducted at 1–2, 5–7, and 9–11 months post-MPTP; these results indicated a stable MPTP-induced striatal lesion over this time period. At the 5–7 and 9–11 month time points, behavioral indices of the MPTP-induced deficits were obtained within a species-typical group setting. For three of the four subjects, persistent decrements in motoric, affiliative, and vigilance behavior were observed while the frequency of aggression toward group members was increased. At the 9–11 month time point, one subject showed a 30% improvement in the social measures, indicative of a partial recovery from the MPTP-induced behavioral decrements although its striatal FDOPAK_iratio remained unchanged. Thus, behavioral and noninvasive biochemical methods can provide complementary indices to assess individual differences in sensitivity to MPTP-induced deficits. Both types of data are required to determine lesion stability and, subsequently, the efficacy of interventions designed to restore normal function in this primate Parkinsonian model.     

Longitudinal Behavioral and 6-[F]Fluoro-l-DOPA-PET Assessment in MPTP-Hemiparkinsonian Monkeys

Biochemical and behavioral criteria were established to determine the long-term stability of a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced unilateral striatal dopamine deficiency in the vervet monkey. At time points over a 12-month period, post-MPTP striatal dopamine synthesis capacity was indexed with 6-[¹⁸F]fluoro-l-DOPA (FDOPA)-positron emission tomography. For the MPTP-treated subjects (n = 4), an intrasubject FDOPA influx rate constant (K_i) ratio method of right (lesioned) striatum/left (unlesioned) striatum values was used to assess changes in striatal activity. Striatal FDOPAK_iratios differed less than 5% between studies conducted at 1–2, 5–7, and 9–11 months post-MPTP; these results indicated a stable MPTP-induced striatal lesion over this time period. At the 5–7 and 9–11 month time points, behavioral indices of the MPTP-induced deficits were obtained within a species-typical group setting. For three of the four subjects, persistent decrements in motoric, affiliative, and vigilance behavior were observed while the frequency of aggression toward group members was increased. At the 9–11 month time point, one subject showed a 30% improvement in the social measures, indicative of a partial recovery from the MPTP-induced behavioral decrements although its striatal FDOPAK_iratio remained unchanged. Thus, behavioral and noninvasive biochemical methods can provide complementary indices to assess individual differences in sensitivity to MPTP-induced deficits. Both types of data are required to determine lesion stability and, subsequently, the efficacy of interventions designed to restore normal function in this primate Parkinsonian model.     

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.     

Striatal [11C]-N-methyl-spiperone binding in patients with focal dystonia (torticollis) using positron emission tomography

Summary Specific binding of [¹¹C]-N-methyl-spiperone to striatal dopamine D2 receptors was assessed using positron emission tomography (PET) in 6 patients with adult-onset focal dystonia (predominantly spasmodic torticollis) and in 5 healthy subjects. No significant difference in average specific striatal tracer uptake between patients and healthy subjects was found. However, in the 5 patients showing lateralisation of clinical signs a trend to higher striatal tracer uptake in the contralateral hemisphere was observed.     

The effect of peripheral enzyme inhibitors on levodopa concentrations in blood and CSF

Levodopa combined with a dopa‐decarboxylase inhibitor, such as carbidopa, shifts the metabolism to the COMT pathway. Adding the peripheral acting COMT inhibitor entacapone provides improvement for patients with PD suffering from motor fluctuations. We studied the effects of the enzyme inhibitors entacapone and carbidopa on the levodopa concentrations in CSF and in blood. Five PD patients with wearing‐off underwent lumbar drainage and intravenous microdialysis. Samples were taken 12 h daily for 3 days. Day 1; intravenous levodopa was given, day 2; additional oral entacapone 200 mg tid, day 3; additional oral entacapone 200 mg tid and carbidopa 25 mg bid. Levodopa in CSF and in dialysates was analysed. The AUC for levodopa increased both in blood and CSF when additional entacapone was given alone and in combination with carbidopa. The C_max of levodopa in both CSF and blood increased significantly. Additional entacapone to levodopa therapy gives an increase of C_max in CSF and in blood. The increase is more evident when entacapone is combined with carbidopa. © 2010 Movement Disorder Society     

A dual‐tracer study of extrastriatal 6‐[18F]fluoro‐m‐tyrosine and 6‐[18F]‐fluoro‐l‐dopa Uptake in Parkinson's disease

6‐[¹⁸F]‐Fluoro‐l ‐dopa (FDOPA) has been widely used as a biomarker for catecholamine synthesis, storage, and metabolism—its intense uptake in the striatum, and fainter uptake in other brain regions, is correlated with the symptoms and pathophysiology of Parkinson's disease (PD). 6‐[¹⁸F]fluoro‐m‐tyrosine (FMT), which also targets l ‐amino acid decarboxylase, has potential advantages over FDOPA as a radiotracer because it does not form catechol‐O‐methyltransferase (COMT) metabolites. The purpose of the present study was to compare the regional distribution of these radiotracers in the brains of PD patients. Fifteen Parkinson's patients were studied with FMT and FDOPA positron emission tomography (PET) as well as high‐resolution structural magnetic resonance imaging (MRI). MRI's were automatically parcellated into neuroanatomical regions of interest (ROIs) in Freesurfer ( http://surfer.nmr.mgh.harvard.edu ); region‐specific uptake rate constants (K_occ) were generated from coregistered PET using a Patlak graphical approach. The essential findings were as follows: (1) regional K_occ were highly correlated between the radiotracers and in agreement with a previous FDOPA studies that used different ROI selection techniques; (2) FMT K_occ were higher in extrastriatal regions of relatively large uptake such as amygdala, pallidum, brainstem, hippocampus, entorhinal cortex, and thalamus, whereas cortical K_occ were similar between radiotracers; (3) while subcortical uptake of both radiotracers was related to disease duration and severity, cortical uptake was not. These results suggest that FMT may have advantages for examining pathologic changes within allocortical loop structures, which may contribute to cognitive and emotional symptoms of PD. Synapse 68:325–331, 2014 . © 2014 Wiley Periodicals, Inc.     

Impaired somatosensory discrimination of shape in Parkinson's disease: Association with caudate nucleus dopaminergic function

Tactile discrimination of macrogeometric objects in a two‐alternative forced‐choice procedure represents a demanding task involving somatosensory pathways and higher cognitive processing. The objects for somatosensory discrimination, i.e., rectangular parallelepipeds differing only in oblongness, were presented in sequential pairs to normal volunteers and 12 parkinsonian patients. The performance of patients was significantly impaired compared to normal volunteers. From a biochemical point of view, the patients were characterized by a severely reduced 6‐[¹⁸F]‐fluoro‐L‐dopa (FDOPA) tracer metabolism in the basal ganglia, as measured using positron emission tomography (PET). Furthermore, reduced specific FDOPA metabolism in the putamen was consistent with the impaired motor capacities of the patients. The reduced specific FDOPA‐uptake within the caudate nucleus was associated with additionally diminished somatosensory discrimination. This association, of low perception during task performance and decreased FDOPA‐uptake, provides direct evidence for the role of the caudate nucleus in the cognitive part of the task. We suggest that directed attention and working memory were critically involved as a result of disturbed interactions between the head of the caudate nucleus and the dorsolateral prefrontal cortex. Furthermore, there were indications of an additional involvement of the mesolimbic system, which might be of importance during challenging situations such as forced choice. We conclude that differential effects on parts of the basal ganglia, during evolution of the degenerative process characteristic of Parkinson's disease, have profound consequences on the performance of skills, as shown here for a somatosensory discrimination task. Hum. Brain Mapping 8:1–12, 1999. © 1999 Wiley‐Liss, Inc.     

Temporal administration of entacapone with slow release <Emphasis Type="SmallCaps">L</Emphasis>-dopa: pharmacokinetic profile and clinical outcome

Abstract. Entacapone is a specific, peripherally acting catechol-O-methyltransferase (COMT) inhibitor that prevents peripheral degradation of L-dopa, thus improving its bioavailability. Entacapone is known to have pharmacokinetics similar to standard L-dopa but not to that of controlled-release (CR) L-dopa. The aim was to determine whether delayed entacapone administration may prolong CR L-dopa half-life in comparison to the co-administration modality. We compared plasma L-dopa concentrations after co-administration of CR L-dopa and entacapone or after administration of CR and a delayed (30 and 90 minutes) entacapone dose in 10 parkinsonian patients. The area under the concentration-time curve and other pharmacokinetic parameters were not changed by the delayed administration of entacapone. Different temporal modalities of entacapone administration had similar effects on CR L-dopa pharmacokinetics and on L-dopa-induced clinical improvement.     

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.