Longitudinal monitoring of the levodopa concentration‐effect relationship in Parkinson's disease

Contin, Manuela; Riva, R.; Martinelli, Paolo; Cortelli, Pietro; Albani, Fiorenzo; Baruzzi, Agostino

doi:10.1212/wnl.44.7.1287

Cited by 69 publications

(57 citation statements)

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“…In these subjects, levodopa concentrations peaked near the end of the loading dose of levodopa and then stabilized approximately 30 min later [16]. Furthermore, mean levodopa levels remained above levels known to have an antiparkinsonian effect [23] during collection of the on-levodopa fMRI scans. There were no significant differences between groups in levodopa levels at the time of the post-levodopa scans (TD mean=502.8 ng/ml, SD=79.8; C mean=494.8 ng/ml, SD=73.1).…”

Section: Levodopa and Carbidopa Plasma Levelsmentioning

confidence: 82%

Dopaminergic modulation of response inhibition: an fMRI study

HERSHEY

2004

Cognitive Brain Research

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Dopamine has been hypothesized to modulate response inhibition. To test this hypothesis, we used functional magnetic resonance imaging (fMRI) to measure the effects of the dopamine prodrug levodopa on the brain responses to a well-validated response inhibition task (go/no-go, or GNG). Since abnormalities of response inhibition and dopamine have been thought to underlie tics and other symptoms of Tourette syndrome, we studied 8 neuroleptic-naive adults with tic disorders as well as 10 well-matched healthy controls. Subjects were pretreated with the peripheral decarboxylase inhibitor carbidopa, then scanned during GNG and control blocks, both before and during i.v. levodopa infusion. Both groups had similar task performance and task-related regional brain activity before and during levodopa infusion. Levodopa did not affect reaction times or accuracy, so fMRI findings can be interpreted without concern that they simply reflect a performance difference between conditions. Levodopa did affect the magnitude of GNG-related fMRI responses in the right cerebellum and right parietal cortex, significantly reducing both. Pre-levodopa activity in the right cerebellum correlated with reaction times (higher magnitudes associated with faster reaction times), and pre-levodopa activity in the right parietal cortex correlated with false alarm rate (higher magnitudes associated with higher error). In summary, right parietal and cerebellar regions important in mediating specific aspects of the GNG task were modulated by levodopa, suggesting a region-specific role for dopamine in response inhibition. D 2004 Elsevier B.V. All rights reserved.Theme: Neural basis of behavior Topic: Cognition

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Section: Levodopa and Carbidopa Plasma Levelsmentioning

confidence: 82%

Dopaminergic modulation of response inhibition: an fMRI study

HERSHEY

2004

Cognitive Brain Research

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“…The magnitude of clinical response to levodopa was the same for patients with the wearing-off phenomenon, and dopamine agonists have been shown to improve this predictable motor fluctuation [2]. These observations suggest intact D2 receptor densities in patients with the wearing-off phenomenon.…”

Section: Discussionmentioning

confidence: 99%

“…Peripheral levodopa pharmacokinetics has been shown to be less important in the pathogenesis of motor fluctuation [2]. Both presynaptic [3, 4] and postsynaptic [5, 6] mechanisms have been reported to be important in the development of motor fluctuation.…”

Section: Introductionmentioning

confidence: 99%

Downregulation of Striatal Dopamine D2 Receptors in Advanced Parkinson’s Disease Contributes to the Development of Motor Fluctuation

Hwang

Yao²,

Wey³

et al. 2002

Eur Neurol

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The purpose of this study was to evaluate the contribution of the postsynaptic mechanism to the development of motor fluctuation in advanced Parkinson’s disease (PD). We used ¹²³I-iodobenzamide single-photon emission computed tomography to measure the striatal dopamine D2 receptor densities in early levodopa-naïve PD, chronic PD with stable levodopa response, and advanced PD with fluctuating levodopa response. The basal ganglia/frontal cortex ratios at both hemispheres were calculated and averaged. PD patients with fluctuating levodopa response showed a significant decrease in striatal dopamine D2 receptor densities compared to those with early (1.57 ± 0.20 vs. 1.77 ± 0.12, p = 0.009) or chronic stable PD (1.57 ± 0.20 vs. 1.77 ± 0.10, p = 0.024). We conclude that the decreased D2 receptor densities in advanced PD reduced the ‘safety factor’ for synaptic transmission and contributed to the development of motor fluctuation.

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“…For many years, the development of wearing-off has been mainly attributed to a shortening of the SDR over time [13,14] as a result of the progressive reduction in the ability of the nigrostriatal neurons to synthesize and to store dopamine formed from exogenous levodopa [15,16]. However, a number of studies have shown that the magnitude of the SDR and modifications of the LDR during the course of PD also have a critical role in the development of symptom re-emergence [17].…”

Section: Clinical Features Of Wearing-off: the Short- And Long-duratimentioning

confidence: 99%

When Do Levodopa Motor Fluctuations First Appear in Parkinson’s Disease?

2010

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Although levodopa provides therapeutic benefit over the entire course of Parkinson’s disease, most patients eventually notice a decline in the duration of benefit from each dose, a phenomenon termed ‘wearing-off’ or ‘end of dose’ deterioration. This is an important indicator that the patient is entering a more complex phase of the disease. Wearing-off has been classically associated with the later stages of Parkinson’s disease, but it is becoming apparent that patients with early disease, presenting as well controlled, may already be experiencing fluctuations in their response to levodopa. However, neither the pathophysiology nor the clinical relevance of the early emergence of wearing-off has been properly explored. We now review the preclinical and clinical evidence that suggests that even patients who are apparently still in the honeymoon phase of drug treatment may have early fluctuations in their motor response to dopaminergic therapy. It is important that early wearing-off is recognized as it has important consequences for the long-term outcome and for the medication regimens to be used.

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Longitudinal monitoring of the levodopa concentration‐effect relationship in Parkinson's disease

Cited by 69 publications

References 0 publications

Dopaminergic modulation of response inhibition: an fMRI study

Dopaminergic modulation of response inhibition: an fMRI study

Downregulation of Striatal Dopamine D2 Receptors in Advanced Parkinson’s Disease Contributes to the Development of Motor Fluctuation

When Do Levodopa Motor Fluctuations First Appear in Parkinson’s Disease?

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