FluoroDOPA PET shows the nondopaminergic as well as dopaminergic destinations of levodopa

Brown, William D.; Taylor, Michael D.; Roberts, Andrew; Oakes, Terrence R.; Schueller, Michael; Holden, James E.; Malischke, Lisamarie; DeJesus, Onofre T.; Nickles, Robert J.

doi:10.1212/wnl.53.6.1212

Cited by 79 publications

(63 citation statements)

References 33 publications

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“…Furthermore, the magnitude of K was also elevated in extrastriatal structures, i.e., amygdala and midbrain of the patients. Trapping of DOPA decarboxylase substrates may also be associated with serotonin innervations in ex- trastriatal regions (Cumming et al, 1997;Brown et al, 1999). Thus, the extrastriatal findings in the present study may in part reflect the composite contributions of serotonin and dopamine fibers to FDOPA metabolism, especially, perhaps, in the amygdala.…”

Section: Discussionmentioning

confidence: 56%

Elevated [¹⁸F]Fluorodopamine Turnover in Brain of Patients with Schizophrenia: An [¹⁸F]Fluorodopa/Positron Emission Tomography Study

Kumakura¹,

Cumming²,

Vernaleken³

et al. 2007

J. Neurosci.

145

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Previous positron emission tomography (PET) studies with levodopa analogs have revealed a modestly increased capacity for dopamine synthesis in the striatum of patients with schizophrenia compared with healthy age-matched control subjects. We hypothesized that not just the synthesis but also the turnover of radiolabeled dopamine is elevated in patients. To test the hypothesis, we reanalyzed 2-h-long

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Section: Discussionmentioning

confidence: 56%

Elevated [¹⁸F]Fluorodopamine Turnover in Brain of Patients with Schizophrenia: An [¹⁸F]Fluorodopa/Positron Emission Tomography Study

Kumakura¹,

Cumming²,

Vernaleken³

et al. 2007

J. Neurosci.

145

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“…It should also be noted that the resolution of the PET technique did not allow us to distinguish between ventral tegmental area and nigral dopamine neurons in the midbrain. Third, although FDOPA is primarily taken up and metabolized in dopamine neurons, a considerably lesser degree of FDOPA metabolism is also possible within serotonin and noradrenalin neurons (37). However, because of the predominance of FDOPA uptake in dopaminergic neurons, particularly in the midbrain, together with basic research documenting that the activity of midbrain dopamine neurons is the prime modulator of the reward system and the prefrontal cortex in particular (38), we believe that our results likely predominantly reflect dopaminergic regulation.…”

Section: Discussionmentioning

confidence: 99%

Age-related changes in midbrain dopaminergic regulation of the human reward system

Dreher

Meyer‐Lindenberg

Kohn

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

208

153

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The dopamine system, which plays a crucial role in reward processing, is particularly vulnerable to aging. Significant losses over a normal lifespan have been reported for dopamine receptors and transporters, but very little is known about the neurofunctional consequences of this age-related dopaminergic decline. In animals, a substantial body of data indicates that dopamine activity in the midbrain is tightly associated with reward processing. In humans, although indirect evidence from pharmacological and clinical studies also supports such an association, there has been no direct demonstration of a link between midbrain dopamine and rewardrelated neural response. Moreover, there are no in vivo data for alterations in this relationship in older humans. Here, by using 6-[ 18 F]FluoroDOPA (FDOPA) positron emission tomography (PET) and event-related 3T functional magnetic resonance imaging (fMRI) in the same subjects, we directly demonstrate a link between midbrain dopamine synthesis and reward-related prefrontal activity in humans, show that healthy aging induces functional alterations in the reward system, and identify an age-related change in the direction of the relationship (from a positive to a negative correlation) between midbrain dopamine synthesis and prefrontal activity. These results indicate an age-dependent dopaminergic tuning mechanism for cortical reward processing and provide system-level information about alteration of a key neural circuit in healthy aging. Taken together, our findings provide an important characterization of the interactions between midbrain dopamine function and the reward system in healthy young humans and older subjects, and identify the changes in this regulatory circuit that accompany aging.aging ͉ dopamine ͉ fMRI ͉ PET ͉ reinforcement S uccessful aging has become one of the most crucial public health challenges of our time. Achieving an understanding of age-related changes in the neurobiology of key brain circuits, such as the reward system, is an integral part of rising to this challenge. Detecting, predicting, and responding to reward information are fundamental capabilities of simple life forms that have evolved in humans into complex behavioral patterns, such as learning, motivation, and appetitive and hedonic activities, which remain essential as we age. A substantial body of data in animals indicates that dopamine is closely associated with reward processing (1-3), and that midbrain dopamine neurons send reward-related signals to postsynaptic sites, particularly the prefrontal cortex. In humans, although indirect evidence from pharmacological (4, 5) and clinical (6-8) studies also suggests a fundamental role of dopamine in reward processing, there has been no direct demonstration of a link between midbrain dopamine and reward-related neural response. Moreover, although the dopamine system is known to be particularly vulnerable to aging (9, 10), there has been no search for alterations in this predicted relationship in older humans. Here, by using 6-[ 18 F]fluoroDOPA ...

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“…Second, nerve terminals in these regions are known to express L-aromatic amino acid decarboxylase (AADC) to varying degrees (Jaeger et al, 1984;Smith and Kieval, 2000) (cf. Brown et al, 1999;Rakshi et al, 1999;Garcia-Cabezas et al, 2007).…”

Section: Metabolic and Vasomotor Responses To Levodopa Therapymentioning

confidence: 99%

Dissociation of Metabolic and Neurovascular Responses to Levodopa in the Treatment of Parkinson's Disease

Hirano¹,

Asanuma²,

Ma³

et al. 2008

J. Neurosci.

131

218

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We compared the metabolic and neurovascular effects of levodopa (LD) therapy for Parkinson's disease (PD). Eleven PD patients were scanned with both [ O]-H 2 O and [18 F]-fluorodeoxyglucose positron emission tomography in the unmedicated state and during intravenous LD infusion. Images were used to quantify LD-mediated changes in the expression of motor-and cognition-related PD covariance patterns in scans of cerebral blood flow (CBF) and cerebral metabolic rate for glucose (CMR). These changes in network activity were compared with those occurring during subthalamic nucleus (STN) deep brain stimulation (DBS), and those observed in a test-retest PD control group. Separate voxel-based searches were conducted to identify individual regions with dissociated treatment-mediated changes in local cerebral blood flow and metabolism. We found a significant dissociation between CBF and CMR in the modulation of the PD motor-related network by LD treatment ( p Ͻ 0.001). This dissociation was characterized by reductions in network activity in the CMR scans ( p Ͻ 0.003) occurring concurrently with increases in the CBF scans ( p Ͻ 0.01). Flow-metabolism dissociation was also evident at the regional level, with LD-mediated reductions in CMR and increases in CBF in the putamen/globus pallidus, dorsal midbrain/pons, STN, and ventral thalamus. CBF responses to LD in the putamen and pons were relatively greater in patients exhibiting drug-induced dyskinesia. In contrast, flow-metabolism dissociation was not present in the STN DBS treatment group or in the PD control group. These findings suggest that flow-metabolism dissociation is a distinctive feature of LD treatment. This phenomenon may be especially pronounced in patients with LD-induced dyskinesia.

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FluoroDOPA PET shows the nondopaminergic as well as dopaminergic destinations of levodopa

Cited by 79 publications

References 33 publications

Elevated [¹⁸F]Fluorodopamine Turnover in Brain of Patients with Schizophrenia: An [¹⁸F]Fluorodopa/Positron Emission Tomography Study

Elevated [¹⁸F]Fluorodopamine Turnover in Brain of Patients with Schizophrenia: An [¹⁸F]Fluorodopa/Positron Emission Tomography Study

Age-related changes in midbrain dopaminergic regulation of the human reward system

Dissociation of Metabolic and Neurovascular Responses to Levodopa in the Treatment of Parkinson's Disease

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FluoroDOPA PET shows the nondopaminergic as well as dopaminergic destinations of levodopa

Cited by 79 publications

References 33 publications

Elevated [18F]Fluorodopamine Turnover in Brain of Patients with Schizophrenia: An [18F]Fluorodopa/Positron Emission Tomography Study

Elevated [18F]Fluorodopamine Turnover in Brain of Patients with Schizophrenia: An [18F]Fluorodopa/Positron Emission Tomography Study

Age-related changes in midbrain dopaminergic regulation of the human reward system

Dissociation of Metabolic and Neurovascular Responses to Levodopa in the Treatment of Parkinson's Disease

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Elevated [¹⁸F]Fluorodopamine Turnover in Brain of Patients with Schizophrenia: An [¹⁸F]Fluorodopa/Positron Emission Tomography Study

Elevated [¹⁸F]Fluorodopamine Turnover in Brain of Patients with Schizophrenia: An [¹⁸F]Fluorodopa/Positron Emission Tomography Study