Role of Dopaminergic Treatment in Dopamine Receptor Down-regulation in Advanced Parkinson Disease

Thobois, Stéphane; Vingerhoets, François; Fraix, Valérie; Xie‐Brustolin, Jing; Mollion, Hélène; Costes, Nicolas; Mertens, Patrick; Benabid, Alim‐Louis; Pollak, Pierre; Broussolle, Emmanuel

doi:10.1001/archneur.61.11.1705

Cited by 76 publications

(57 citation statements)

References 23 publications

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“…However, in the present study the 11 C-raclopride binding reduction was not statistically different in both YOPD populations: BP D2 values are lower in the parkin group by 9% of normal values in the putamen and 6% in the caudate, but this difference is not significant, suggesting that chronic exposure to dopaminergic drugs is responsible for a downregulation of dopamine receptors in PD independent of the genetic status of the patients (35). In addition, SPM analysis does not reveal any striatal or extra-striatal difference between the 2 groups for D 2 binding.…”

Section: Discussioncontrasting

confidence: 83%

A Multitracer Dopaminergic PET Study of Young-Onset Parkinsonian Patients With and Without Parkin Gene Mutations

Ribeiro

Thobois²,

Lohmann

et al. 2009

J Nucl Med

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The impact of parkin gene mutations on nigrostriatal dopaminergic degeneration is not well established. The purpose of this study was to characterize by PET using 18 F-fluoro-L-3,4-dihydroxyphenylalanine ( 18 F-fluoro-L-DOPA), 11 C-PE2I, and 11 C-raclopride the pattern of dopaminergic lesions in young-onset Parkinson disease (YOPD) patients with or without mutations of the parkin gene and to correlate the clinical and neuropsychologic characteristics of these patients with PET results. Methods: A total of 35 YOPD patients were enrolled (16 with parkin mutation, 19 without). The uptake constant (K i ) of 18 F-fluoro-L-DOPA and the binding potential (BP) of 11 C-PE2I (BP DAT ) and of 11 C-raclopride (BP D2 ) were calculated in the striatum. Comparisons were made between the 2 groups of YOPD and between controls and patients. For each radiotracer, parametric images were obtained, and statistical parametric mapping (SPM) analysis using a voxel-by-voxel statistical t test was performed. Correlations between the cognitive and motor status and PET results were analyzed. Results: In YOPD patients, 18 F-fluoro-L-DOPA K i values were reduced to 68% (caudate) and 40% (putamen) of normal values (P , 0.0001). This decrease was symmetric and comparable for nonparkin and parkin patients. No correlation was found between the K i values and cognitive or motor status. 11 C-PE2I BP DAT values in YOPD patients were decreased to 56% (caudate) and 41% (putamen) of normal values (P , 0.0001) and did not differ between the 2 YOPD populations. The mean 11 C-raclopride BP D2 values were reduced to 72% (caudate) and 84% (putamen) of the normal values (P , 0.02) and did not differ between nonparkin and parkin patients. SPM analyses showed in patients an additional decrease of 11 C-raclopride in the frontal cortex and a decrease of 18 F-fluoro-L-DOPA and 11 C-PE2I uptake in the substantia nigra bilaterally (P , 0.05, false-discovery rate-corrected). Conclusion: Carriers of parkin mutations are indistinguishable on PET markers of dopaminergic dysfunction from other YOPD patients with long disease duration.

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Section: Discussioncontrasting

confidence: 83%

A Multitracer Dopaminergic PET Study of Young-Onset Parkinsonian Patients With and Without Parkin Gene Mutations

Ribeiro

Thobois²,

Lohmann

et al. 2009

J Nucl Med

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“…Increased striatal expression of Drd2a is commonly reported in human postmortem (Hurley and Jenner 2006;Joyce 1993;Piggott et al, 1999;Ryoo et al, 1998) and functional studies (Kim et al, 2002;Thobois et al, 2004) of PD, as well as in animal models (Morissette et al 1998;Guillin et al 2001). We did not identify an absolute increase in Drd2 expression in our ak mice.…”

Section: Discussionmentioning

confidence: 98%

Motor deficits and altered striatal gene expression in aphakia (ak) mice

et al. 2007

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Like humans with Parkinsons disease (PD), the ak mouse lacks the majority of the substantia nigra pars compacta (SNc) and experiences striatal denervation. The purpose of this study was to test whether motor abnormalities in the ak mouse progress over time, and whether motor function could be associated with temporal alterations in the striatal transcriptome. Ak and wt mice (28 to 180 days old) were tested using paradigms sensitive to nigrostriatal dysfunction. Results were analyzed using a linear mixed model. Ak mice significantly underperformed wt controls in rotarod, balance beam, string test, pole test and cotton shred tests at all ages examined. Motor performance in ak mice remained constant over the first 6 months of life, with the exception of the cotton shred test, in which ak mice exhibited marginal decline in performance. Dorsal striatal semi-quantitative RT-PCR for 19 dopaminergic, cholinergic, glutaminergic and catabolic genes was performed in 1 and 6 month old groups of ak and wt mice. Preproenkephalin levels in ak mice were elevated in both age groups. Drd1, 3 and 4 levels declined over time, in contrast to increasing Drd2 expression. Additional findings included decreased Chrnα6 expression and elevated VGluT1 expression at both time points in ak mice, and elevated AchE expression in young ak mice only. Results confirm that motor ability does not decline significantly for the first 6 months of life in ak mice. Their striatal gene expression patterns are consistent with dopaminergic denervation, and change over time, despite relatively unaltered motor performance.

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“…The PD with PG group was taking lower chronic DA agonist doses, along with compensatory increases in levodopa doses, in order to retain benefit to PD symptoms. Since both DA agonists and levodopa effect DA receptor expression (Chernoloz et al, 2009;Kaasinen et al, 2000;Pitts et al, 1995;Subramaniam et al, 1992;Thobois et al, 2004) we chose to match groups on total LEDD, but it must be acknowledged that these differences may have influenced our results.…”

Section: Discussion [11c] Flb-457 Bp In the Midbrainmentioning

confidence: 99%

“…For example, two patients with PG were no longer using DA agonists, and the remainder had DA agonists reduced, with concomitant increases in levodopa (Table 2). Thus, we considered it more important to match patients for total levodopa equivalent doses rather than either levodopa or DA agonists, since both may have an impact on DA receptor expression (Chernoloz et al, 2009;Kaasinen et al, 2000;Pitts et al, 1995;Subramaniam et al, 1992;Thobois et al, 2004).…”

Section: Participants and Experimental Designmentioning

confidence: 99%

Extrastriatal dopaminergic abnormalities of DA homeostasis in Parkinson's patients with medication-induced pathological gambling: A [11C] FLB-457 and PET study

Ray

Miyasaki

Zurowski

et al. 2012

Neurobiology of Disease

121

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Impulse control disorders such as pathological gambling (PG) are a serious and common adverse effect of dopamine (DA) replacement medication in Parkinson's disease (PD). Patients with PG have increased impulsivity and abnormalities in striatal DA, in common with behavioural and substance addictions in the non-PD population. To date, no studies have investigated the role of extrastriatal dopaminergic abnormalities in PD patients with PG. We used the PET radiotracer, [11C] FLB-457, with high-affinity for extrastriatal DA D2/3 receptors. 14 PD patients on DA agonists were imaged while they performed a gambling task involving real monetary reward and a control task. Trait impulsivity was measured with the Barratt Impulsivity Scale (BIS). Seven of the patients had a history of PG that developed subsequent to DA agonist medication. Change in [11C] FLB-457 binding potential (BP) during gambling was reduced in PD with PG patients in the midbrain, where D2/D3 receptors are dominated by autoreceptors. The degree of change in [11C] FLB-457 binding in this region correlated with impulsivity. In the cortex, [11C] FLB-457 BP was significantly greater in the anterior cingulate cortex (ACC) in PD patients with PG during the control task, and binding in this region was also correlated with impulsivity. Our findings provide the first evidence that PD patients with PG have dysfunctional activation of DA autoreceptors in the midbrain and low DA tone in the ACC. Thus, altered striatal and cortical DA homeostasis may incur vulnerability for the development of PG in PD, linked with the impulsive personality trait.

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Role of Dopaminergic Treatment in Dopamine Receptor Down-regulation in Advanced Parkinson Disease

Cited by 76 publications

References 23 publications

A Multitracer Dopaminergic PET Study of Young-Onset Parkinsonian Patients With and Without Parkin Gene Mutations

A Multitracer Dopaminergic PET Study of Young-Onset Parkinsonian Patients With and Without Parkin Gene Mutations

Motor deficits and altered striatal gene expression in aphakia (ak) mice

Extrastriatal dopaminergic abnormalities of DA homeostasis in Parkinson's patients with medication-induced pathological gambling: A [11C] FLB-457 and PET study

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