In Vivo Evidence for Differential Association of Striatal Dopamine and Midbrain Serotonin Systems With Neuropsychiatric Symptoms in Parkinson's Disease

Murai, Toshiya; Müller, Ulrich; Werheid, Katja; Sorger, Dietlind; Reuter, M.; Becker, Thomas; Cramon, D. Yves von; Barthel, Henryk

doi:10.1176/jnp.13.2.222

Cited by 71 publications

(50 citation statements)

References 24 publications

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“…Images were acquired 24 h after intravenous application of 185 MBq of [ 123 I] ␤ -CIT with a high-resolution (7.5 mm full width at half maximum) brain-dedicated camera system (Ceraspect, DSI, Waltham, Mass., USA) as previously described [29] . SERT-rich areas in the thalamus-hypothalamus, midbrain and brainstem were determined by coregistration of SPECT data with a standard magnetic resonance imaging (MRI) data set [29] ( fi g. 1 a) using the MultiModality software (Hermes Medical Solutions, Stockholm, Sweden). By applying a region of interest (ROI) technique, specifi c-to-nonspecifi c [ 123 I] ␤ -CIT-binding ratios in the target region were calculated using a simplifi ed reference tissue model with the specifi c-to-nondisplaceable partition coeffi cient V 3 (occipital cortex = reference ROI [30] ).…”

Section: Spect Imagingmentioning

confidence: 99%

Serotonin Transporter Imaging with [<sup>123</sup>I]β-CIT SPECT before and after One Year of Citalopram Treatment of Obsessive-Compulsive Disorder

Stengler‐Wenzke

Müller²,

Barthel³

et al. 2006

Neuropsychobiology

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Background: Two thirds of patients with obsessive-compulsive disorder (OCD) respond to treatment with selective serotonin reuptake inhibitors (SSRIs). The neurobiological mechanisms of SSRI action and failure to respond to SSRI treatment remain to be elucidated. Objectives: The aim of this pilot study was to quantify changes in the availability of serotonin transporter (SERT) in the course of SSRI treatment and to relate these changes to improvements of clinical symptoms. Methods: Ten patients with OCD were investigated at baseline and 5 of them after 1 year of SSRI treatment with citalopram 60 mg per day using brain single photon emission computed tomography and [¹²³I]β-CIT. Specific-to-nondisplaceable [¹²³I]β-CIT binding ratios (V₃″) were calculated in SERT-rich brainstem, midbrain and thalamus using a magnetic resonance imaging-based region of interest (ROI) analysis. Symptom severity was evaluated with the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). Results: V₃″ differed significantly between pretreatment and follow-up scans in all three brain regions, thalamus, midbrain as well as in brainstem. In thalamic ROI, differ ences in SERT availability and Y-BOCS ratings correlated. In midbrain, a trend toward a significant association was found. In brainstem, no relationship was revealed. Conclusions: Higher occupancy of SERT by citalopram seems to be associated with better clinical response after 1 year of SSRI treatment of patients with OCD.

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Section: Spect Imagingmentioning

confidence: 99%

Serotonin Transporter Imaging with [<sup>123</sup>I]β-CIT SPECT before and after One Year of Citalopram Treatment of Obsessive-Compulsive Disorder

Stengler‐Wenzke

Müller²,

Barthel³

et al. 2006

Neuropsychobiology

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“…One theory is that the autoregulating function of the DA release is lacking in serotonergic neurons resulting in an un-controlled DA release after levodopa administration and thus causing LID (90)(91)(92). The serotonergic hyperinnervation and the dysregulated DA release in different areas of the brain could also be possible actors in the origination of some NMS in PD, for example impaired cognition, depression and anxiety (8,(93)(94)(95)(96)(97)(98)(99)(100).…”

Section: Discussionmentioning

confidence: 99%

“…One theory is that the autoregulating function of the DA release is lacking in serotonergic neurons resulting in an un-controlled DA release after levodopa administration resulting in pulsatile stimulation of the striatal postsynaptic dopaminergic receptors and thus causing LID (90)(91)(92). There are also several NMS in PD, for example impaired cognition, depression and anxiety (8,(93)(94)(95)(96)(97)(98) and the serotonergic hyperinnervation and the dysregulated DA release in different areas of the brain could be possible actors in the origination of some of them (93,99,100). The pulsatile stimulation of striatal postsynaptic dopaminergic receptors caused by dopaminergic neuron degeneration, intermittent levodopa treatment causing high levodopa peaks (84,85,101,102) and possible involvement of other neurons/astrocytes that convert levodopa to DA, seem to result in modifications of the postsynaptic dopaminergic receptors.…”

Section: Motor Complicationsmentioning

confidence: 99%

Levodopa pharmacokinetics -from stomach to brain : A study on patients with Parkinson’s disease

Nord¹

2017

Linköping University Medical Dissertations

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Parkinson’s disease (PD) is one of the most common neurodegenerative disorders and it is caused by a loss of dopamine (DA) producing neurons in the basal ganglia in the brain. The PD patient suffers from motor symptoms such as tremor, bradykinesia and rigidity and treatment with levodopa (LD), the precursor of DA, has positive effects on these symptoms. Several factors affect the availability of orally given LD. Gastric emptying (GE) is one factor and it has been shown to be delayed in PD patients resulting in impaired levodopa uptake. Different enzymes metabolize LD on its way from the gut to the brain resulting in less LD available in the brain and more side effects from the metabolites. By adding dopa decarboxylase inhibitors (carbidopa or benserazide) or COMT-inhibitors (e.g. entacapone) the bioavailability of LD increases significantly and more LD can pass the blood-brain-barrier and be converted to DA in the brain. It has been considered of importance to avoid high levodopa peaks in the brain because this seems to induce changes in postsynaptic dopaminergic neurons causing disabling motor complications in PD patients. More continuously given LD, e.g. duodenal or intravenous (IV) infusions, has been shown to improve these motor complications. Deep brain stimulation of the subthalamic nucleus (STN DBS) has also been proven to improve motor complications and to make it possible to reduce the LD dosage in PD patients. In this doctoral thesis the main purpose is to study the pharmacokinetics of LD in patients with PD and motor complications; in blood and subcutaneous tissue and study the effect of GE and PD stage on LD uptake and the effect of continuously given LD (CDS) on LD uptake and GE; in blood and cerebrospinal fluid (CSF) when adding the peripheral enzyme inhibitors entacapone and carbidopa to LD infusion IV; in brain during STN DBSand during oral or IV LD treatment. To conclude, LD uptake is more favorable in PD patients with less severe disease and GE is delayed in PD patients. No obvious relation between LD uptake and GE or between GE and PD stage is seen and CDS decreases the LD levels. Entacapone increases the maximal concentration of LD in blood and CSF. This is more evident with additional carbidopa and important to consider in avoiding high LD peaks in brain during PD treatment. LD in brain increases during both oral and IV LD treatment and the DA levels follows LD well indicating that PD patients still have capacity to metabolize LD to DA despite probable pronounced nigral degeneration. STN DBS seems to increase putaminal DA levels and together with IV LD treatment also increases LD in brain possibly explaining why it is possible to decrease LD medication after STN DBS surgery.Parkinsons sjukdom (PS) är en av de vanligaste s.k. neurodegenerativasjukdomarna och orsakas av förlust av dopamin(DA)producerande nervceller i hjärnan. Detta orsakar motoriska symptom såsom skakningar, stelhet och förlångsammade rörelser. Levodopa (LD) är ett ämne, som kan omvandlas till DA i hjärnan och ge symptomlindrin...

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“…It seems to be of importance to avoid high levodopa peaks in brain in PD patients and CDS has been shown effective in reducing LID. The serotonergic hyperinnervation and the dysregu-lated DA release in different areas of the brain could be possible factors in the origination of several non-motor symptoms (NMS), for example impaired cognition, depression and anxiety [48]- [56].…”

Section: Discussionmentioning

confidence: 99%

Levodopa Pharmacokinetics in Brain after Both Oral and Intravenous Levodopa in One Patient with Advanced Parkinson’s Disease

Nord¹,

Zsigmond²,

Kullman³

et al. 2017

APD

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Objective: One patient received oral levodopa during a study aiming for better understanding of the basal ganglia and of the mechanisms of deep brain stimulation of the subthalamic nucleus (STN DBS) with and without intravenous (IV) levodopa infusion in patients with Parkinson's disease (PD). The results from oral and IV levodopa treatment are presented. Methods: Five patients with advanced PD were included in the original study. During planned STN DBS surgery microdialysis probes were implanted in the right putamen and in the right and left globus pallidus interna (Gpi). During the study, microdialysis was performed continuously and STN DBS, with and without IV levodopa infusion, was performed according to a specific protocol. After DBS surgery, but before STN DBS was started, one patient received oral levodopa/ benserazide and entacapone tablets out of protocol due to distressing parkinsonism. Results: The levodopa levels increased prompt in the central nervous system after the first PD medication intakes but declined after the last. Immediately the levodopa seemed to be metabolized to dopamine (DA) since the levels of DA correlated well with levodopa concentrations. Left STN DBS seemed to increase DA levels in left Gpi and right STN DBS seemed to increase DA levels in right Gpi while all STN stimulation seemed to increase the DA levels in right putamen. There was no obvious effect on levodopa levels. Conclusions: The results indicate that PD patients still have capacity to metabolize levodopa to DA despite advanced disease with on-off symptoms and probably pronounced nigral degeneration. STN DBS seems to increase DA levels with a more pronounced effect on ipsilateral structures in striatum.

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In Vivo Evidence for Differential Association of Striatal Dopamine and Midbrain Serotonin Systems With Neuropsychiatric Symptoms in Parkinson's Disease

Cited by 71 publications

References 24 publications

Serotonin Transporter Imaging with [<sup>123</sup>I]β-CIT SPECT before and after One Year of Citalopram Treatment of Obsessive-Compulsive Disorder

Serotonin Transporter Imaging with [<sup>123</sup>I]β-CIT SPECT before and after One Year of Citalopram Treatment of Obsessive-Compulsive Disorder

Levodopa pharmacokinetics -from stomach to brain : A study on patients with Parkinson’s disease

Levodopa Pharmacokinetics in Brain after Both Oral and Intravenous Levodopa in One Patient with Advanced Parkinson’s Disease

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