Levodopa-induced local cerebral blood flow changes in Parkinson's disease and related disorders

doi:10.1016/0022-510X(94)00237-I

Journal of the Neurological Sciences

Volume 128, Issue 2, February 1995, Pages 212-218

https://doi.org/10.1016/0022-510X(94)00237-I Get rights and content

Abstract

Local cerebral blood flow (CBF) in the steady state and after intravenous administration of levodopa (1 mg/kg) was measured by xenon-enhanced computed tomography in patients with Parkinson's disease (PD, n = 16), progressive supranuclear palsy (PSP, n = 6), olivopontocerebellar atrophy (OPCA, n = 5), and arteriosclerotic parkinsonism (AP, n = 7). Three patterns of local CBF changes following levodopa were observed: (1) diffuse CBF increases, especially in striatum and thalamus, as found in patients with PD; (2) no significant changes in CBF, as in patients with OPCA and AP; and (3) CBF reductions in basal ganglia and thalamus, as seen in patients with PSP. The CBF increases after levodopa in PD may be secondary to metabolic activation of the nigrostriatal dopaminergic system. The poor CBF responses in patients with OPCA, AP, and PSP appeared to reflect degeneration of the dopamincrgic neurons and dopamine receptors to various degrees. The CBF increases, especially in striatum and thalamus, tended to be greater (not significant) among responders to oral levodopa therapy. Levodopa-induced CBF measurements may be useful for the differential diagnosis of parkinsonian syndromes of various etiologies, but are not necessarily sufficient for predicting outcomes of long-term levodopa therapy.

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Cited by (34)

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Citation Excerpt :
This supplementary analysis also supports the observation that CBF findings are not being driven by technical variations due to image artifacts, for instance due to variations in labeling efficiency in the pCASL sequence from scan to scan that would manifest as a globally altered CBF measurement. Previous PET and MRI studies investigating the effects of levodopa, the most commonly used dopamine precursor therapy for PD, indicate that treatment alters rCBF in several regions: the striatum and thalamus (Kobari, Fukuuchi, Shinohara, Obara, & Nogawa, 1995), nigrostriatal pathway, occipital cortex, and inferior parietal areas (Chen, Pressman, Simuni, Parrish, & Gitelman, 2015). Both levodopa and DAA augment dopaminergic tone in PD and both appear to increase rCBF in areas associated with PD symptoms, despite the differing mechanisms of action.
Parkinson's disease (PD) is characterized by dysfunction in frontal cortical and striatal networks that regulate action control. We investigated the pharmacological effect of dopamine agonist replacement therapy on frontal cortical activity and motor inhibition. Using Arterial Spin Labeling MRI, we examined 26 PD patients in the off- and on-dopamine agonist medication states to assess the effect of dopamine agonists on frontal cortical regional cerebral blood flow. Motor inhibition was measured by the Simon task in both medication states. We applied the dual process activation suppression model to dissociate fast response impulses from motor inhibition of incorrect responses. General linear regression model analyses determined the medication effect on regional cerebral blood flow and motor inhibition, and the relationship between regional cerebral blood flow and motor inhibitory proficiency. We show that dopamine agonist administration increases frontal cerebral blood flow, particularly in the pre-supplementary motor area (pre-SMA) and the dorsolateral prefrontal cortex (DLPFC). Higher regional blood flow in the pre-SMA, DLPFC and motor cortex was associated with better inhibitory control, suggesting that treatments which improve frontal cortical activity could ameliorate motor inhibition deficiency in PD patients.
Arterial spin labelling reveals prolonged arterial arrival time in idiopathic Parkinson's disease
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Citation Excerpt :
It is possible that differences in NVS might be influential in differing clinical phenotypes of IPD (Lee et al., 2009), however the small sample size in this study meant that phenotype-specific differences could not be explored. LED scores differed between participants, which may confound the results as previous studies have revealed regional blood flow increases with levodopa (Hershey et al., 2003; Kobari et al., 1995). This exploratory work used MRI perfusion and structural measures to investigate NVS in IPD.
Idiopathic Parkinson's disease (IPD) is the second most common neurodegenerative disease, yet effective disease modifying treatments are still lacking. Neurodegeneration involves multiple interacting pathological pathways. The extent to which neurovascular mechanisms are involved is not well defined in IPD. We aimed to determine whether novel magnetic resonance imaging (MRI) techniques, including arterial spin labelling (ASL) quantification of cerebral perfusion, can reveal altered neurovascular status (NVS) in IPD.
Fourteen participants with IPD (mean ± SD age 65.1 ± 5.9 years) and 14 age and cardiovascular risk factor matched control participants (mean ± SD age 64.6 ± 4.2 years) underwent a 3T MRI scan protocol. ASL images were collected before, during and after a 6 minute hypercapnic challenge. FLAIR images were used to determine white matter lesion score. Quantitative images of cerebral blood flow (CBF) and arterial arrival time (AAT) were calculated from the ASL data both at rest and during hypercapnia. Cerebrovascular reactivity (CVR) images were calculated, depicting the change in CBF and AAT relative to the change in end-tidal CO₂.
A significant (p = 0.005) increase in whole brain averaged baseline AAT was observed in IPD participants (mean ± SD age 1532 ± 138 ms) compared to controls (mean ± SD age 1335 ± 165 ms). Voxel-wise analysis revealed this to be widespread across the brain. However, there were no statistically significant differences in white matter lesion score, CBF, or CVR between patients and controls. Regional CBF, but not AAT, in the IPD group was found to correlate positively with Montreal cognitive assessment (MoCA) scores. These findings provide further evidence of alterations in NVS in IPD.
Impairment of cerebral hemodynamic response to the cold pressor test in patients with Parkinson's disease
2009, Parkinsonism and Related Disorders
Citation Excerpt :
All can affect blood pressure and CBFV. According to previous reports [47–49], levodopa, either oral or intravenous, will induce diffuse CBFV increases, especially in the striatum and thalamus, and cause cerebrovascular dilation in patients with PD. But, from other views, these dopaminergic drugs will reduce MAP and blunt the sympathetic response [50,51].
Disturbance of the autonomic nervous system (ANS) is frequently encountered in Parkinson's disease (PD). In this study, we examined changes in systemic and cerebral hemodynamics during the cold pressor test (CPT) to determine whether cerebrovascular reactivity, controlled by the sympathetic nervous system, is intact or impaired in patients with PD.
Forty-nine patients with PD and 49 sex- and age-matched non-PD subjects were evaluated. Measurements were performed in the resting state and over a period of 1 min of CPT. The cerebral blood flow velocity (CBFV) and pulsatility index (PI) of the middle cerebral artery (MCA) were recorded by transcranial color-coded Doppler ultrasonography (TCCS). Mean arterial blood pressure (MAP), heart rate (HR), and end-tidal CO₂ (Et-CO₂) were investigated simultaneously. The resistance of the cerebrovascular bed (CVR) was calculated as the ratio of mean arterial blood pressure to mean cerebral blood flow velocity (Vm). Changes of Vm, PI and CVR in response to the cold pressor test were evaluated.
Baseline values for control and PD subjects showed no statistical difference. CPT induced a significant increase in MAP, HR, and Vm in both groups. Pulsatility index (PI) and CVR were decreased in both groups during CPT. Percent increases of Vm (P < 0.001) and MAP (P = 0.011) were significantly higher while the percent decreases of PI (P = 0.002) and CVR (P = 0.007) were significantly decreased more in the non-PD group.
This study indirectly shows that ANS-mediated cerebrovascular reactivity is impaired in patients with PD. Further investigations are needed to confirm the hypothesis that using the cold pressor test to evaluate cerebrovascular reactivity might be beneficial in early diagnosis of impairment of ANS-mediated cerebrovascular autoregulation in patients with PD.
Intravenous levodopa administration in humans based on a two-compartment kinetic model
2007, Journal of Neuroscience Methods
Levodopa, when combined with a decarboxylase inhibitor, essentially delivers dopamine directly to the brain, with no net effect on brain blood vessels. For future neuroimaging studies of Parkinson disease and Tourette syndrome, we sought to rapidly produce a biologically relevant levodopa concentration in plasma and then maintain that concentration long enough to assess motor, cognitive, emotional, and neuroimaging responses, while minimizing side effects in levodopa-naive individuals. Based on available pharmacokinetic data and a two-compartment model, we designed a decreasing-exponential-rate infusion to meet these goals. This report gives results of double-blind levodopa and placebo infusions in six healthy subjects. Mean plasma levodopa concentrations were within 3% of their 1200 ng/mL target at 20 and 40 min into the infusion, and within 20% between ∼12 and 90 min. Levodopa significantly reduced serum prolactin and raised serum growth hormone concentrations. Volunteers had no significant side effects.
Dopaminergic modulation of response inhibition: An fMRI study
2004, Cognitive Brain Research
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.
Cognitive-pharmacologic functional magnetic resonance imaging in Tourette syndrome: A pilot study
2004, Biological Psychiatry
Dopamine agonists and antagonists can reduce abnormal movements and vocalizations (tics) in Tourette syndrome (TS); however, dopamine-responsive abnormal function in specific brain regions has not been directly demonstrated in TS. We sought to identify dopamine-modulated brain regions that function abnormally in TS by combining functional magnetic resonance imaging (fMRI), a working memory (WM) task, and infusion of the dopamine prodrug levodopa (while blocking dopamine production outside the brain).
We obtained complete fMRI data in 8 neuroleptic-naive adults with a chronic tic disorder and in 10 well-matched tic-free control subjects.
Different task-sensitive brain regions responded differently to the WM task depending on levodopa status and diagnostic group (analysis of variance [ANOVA], p < .001). Four regions showed interactions with diagnosis (ANOVA, p < .001). In TS subjects, the task induced excessive brain activity in parietal cortex, medial frontal gyrus, and thalamus. Levodopa normalized the excess activity. In left parietal cortex, the degree of normalization was greater in patients with higher levodopa plasma concentrations (n = 6; Spearman's r = −.84, p = .04) and a greater degree of diagnostic confidence of TS (r = −.71, p = .05).
These results are consistent with a dopamine-influenced functional abnormality of brain response in TS and suggest testable hypotheses about the mechanism by which dopamine antagonists and agonists alleviate tics.

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Research articleLevodopa-induced local cerebral blood flow changes in Parkinson's disease and related disorders

Abstract

J. Neurol. Sci.

Eur. J. Pharmacol.

Brain Res.

Eur. J. Pharmacol.

Brain Res.

Loss of striatal [76Br]bromos-piperone binding sites demonstrated by positron tomography in progressive supranuclear palsy

J. Cereb. Blood Flow Metab.

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

Ann. Neurol.

Striatal D2 receptor status in patients with Parkinson's disease, striatonigral degeneration, and progressive supranuclear palsy, measured with 11C-raclopride and positron emission tomography

Ann. Neurol.

Amine mechanisms in the cerebral circulation

Pharmacol. Rev.

Nonoxidative glucose consumption during focal physiologic neural activity

Science

Apomorphine test for dopaminergic responsiveness in patients with previously untreated Parkinson's disease

Arch. Neurol.

An investigation on dementia rating scale for the elderly

Seishin Igaku

Challenge tests to predict the dopaminergic response in untreated Parkinson's disease

Neurology

Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico-pathological study

J. Neurol. Neurosurg. Psychiat.

Progressive supranuclear palsy: Clinical features and response to treatment in 16 patients

Ann. Neurol.

The theory and applications of the exchange of inert gas at the lungs and tissues

Pharmacol. Rev.

Research article
Levodopa-induced local cerebral blood flow changes in Parkinson's disease and related disorders

Loss of striatal [⁷⁶Br]bromos-piperone binding sites demonstrated by positron tomography in progressive supranuclear palsy

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

Striatal D₂ receptor status in patients with Parkinson's disease, striatonigral degeneration, and progressive supranuclear palsy, measured with ¹¹C-raclopride and positron emission tomography