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Biochemical and pharmacokinetic studies in vivo in Parkinson’s disease
Linköping University, Department of Clinical and Experimental Medicine, Neurosurgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery.
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Parkinson’s disease (PD) is a neurodegenerative disease affecting approximately 25000 people in Sweden. The main cause of the disease is the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) projecting to the striatum. The motor symptoms of PD, due to decreased levels of dopamine, includes bradykinesia, rigidity and tremor.

During the 1960ies oral L-dopa treatment was introduced increasing quality of life for PD patients. In recent decades, enzyme inhibitors have been introduced, increasing bioavailability of L-dopa in plasma. After 5-10 years of L-dopa treatment, 50% of PD patients develop disabling dyskinesias. This can be due to rapid changes in L-dopa conentrations with non physiological stimulation of the dopamine receptor.

For over 20 years deep brain stimulation (DBS) has grown to be a good neurosurgical procedure for improving quality of life in advanced PD with disabling dyskinesias. With stereotactic technique, electrodes are implanted in the brain and connected to a pacemaker sending electrical impulses. The most common target in PD is the subthalamic nucleus (STN). The knowledge about DBS mechanism(s) and its interaction with L-dopa is unsatisfactory.

The aims of this thesis were; to study the effect of the enzyme inhibitor entacapone on the L-dopa concentration over the blood brain barrier (BBB); to study possible interactions between L-dopa and DBS; to study alterations in neurotransmitters during DBS; to visualize microdialysis catheters in anatomical targets and to estimate sampling area of the catheters.

In all four papers the microdialysis technique was used. It is a well-established technique for continuous sampling of small water-soluble molecules within the extracellular fluid space in vivo, allowing studies of pharmaceutical drugs and neurotransmitters.

We showed that entacapone increases the bioavailability of L-dopa in blood with a subsequent increase of L-dopa peak levels in the cerebrospinal fluid. This in turn may cause a larger burden on the dopaminergic neurons causing an increased degeneration rate and worsening of the dyskinesias; we showed that 18% of L-dopa crosses the BBB and that there is a possible interaction between L-dopa and DBS, L-dopa concentrations increase during concomitant STN DBS, which can clarify why its possible to decrease L-dopa medication after DBS surgery. The research has also shown that STN DBS has an effect on various neurotransmitter systems, mainly L-dopa, dopamine and GABA. We showed that STN DBS may have an effect on the SNc, resulting in putaminal dopamine release.

We have shown that with stereotactic technique, it is safe to do microdialysis sampling in specific areas in the human brain. Simulations with the finite element method combined with patient specific preoperative MRI and postoperative CT images gave us exact knowledge about the positions of the catheters and that the studied structures were the intended. The research has given an assumption of the maximum tissue volume that can be sampled around the microdialysis catheters.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2013. , 78 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1345
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-91294ISBN: 978-91-7519-737-1 (print)OAI: oai:DiVA.org:liu-91294DiVA: diva2:616869
Public defence
2013-05-17, Berzeliussalen, Hälsouniversitetet, Campusu US, Linköpings universitet, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2013-04-19 Created: 2013-04-19 Last updated: 2017-04-15Bibliographically approved
List of papers
1. The Effect of Peripheral Enzyme Inhibitors on Levodopa Concentrations in Blood and CSF
Open this publication in new window or tab >>The Effect of Peripheral Enzyme Inhibitors on Levodopa Concentrations in Blood and CSF
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2010 (English)In: Movement Disorders, ISSN 0885-3185, E-ISSN 1531-8257, Vol. 25, no 3, 363-367 p.Article in journal (Refereed) Published
Abstract [en]

Levodopa combined with a dopa-decarboxylase inhibitor, such as carbidopa. shifts the metabolism to the COMT pathway. Adding the peripheral acting COMT inhibitor entacapone provides improvement for patients with PD suffering from motor fluctuations. We studied the effects of the enzyme inhibitors entacapone and carbidopa on the levodopa concentrations in CSF and in blood. Five PD patients with wearing-off underwent lumbar drainage and intravenous microdialysis. Samples were taken 12 h daily for 3 days. Day I; intravenous levodopa was given, day 2; additional oral entacapone 200 mg tid, day 3; additional oral entacapone 200 mg bid and carbidopa 25 mg bid. Levodopa in CSF and in dialysates was analysed. The AUC for levodopa increased both in blood and CSF when additional entacapone was given alone and in combination with carbidopa. The C-max of levodopa in both CSF and blood increased significantly. Additional entacapone to levodopa therapy gives an increase of C-max in CSF and in blood. The increase is more evident when entacapone is combined with carbidopa.

Place, publisher, year, edition, pages
John Wiley & Sons, 2010
Keyword
Parkinsons Disease, levodopa, continuous infusion, COMT
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-54855 (URN)10.1002/mds.22613 (DOI)000276136900016 ()
Available from: 2010-04-16 Created: 2010-04-16 Last updated: 2017-06-19
2. Stereptactic microdialysis of the basal ganglia in Parkinson's disease
Open this publication in new window or tab >>Stereptactic microdialysis of the basal ganglia in Parkinson's disease
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2012 (English)In: Journal of Neuroscience Methods, ISSN 0165-0270, E-ISSN 1872-678X, Vol. 207, no 1, 17-22 p.Article in journal (Refereed) Published
Abstract [en]

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an efficacious treatment in patients with advanced Parkinson's disease, yet the mechanisms of STN DBS are poorly understood. The aims of this study were to develop a useful method for studying neurotransmitter alterations during DBS and for the pharmacokinetics of L-dopa in brain tissue. Ten patients with Parkinson's disease participated, whereof two had no previous L-dopa medication. The electrodes and catheters were placed using MRI-guided stereotaxic targeting. Two microdialysis probes were placed, one in the right internal globus pallidus, and one in a brachial vein. The quadripolar deep brain electrodes were placed in the right STN. Microdialysates from brain tissue and blood were collected in 15-min fractions at baseline and during DBS. After stimulation new baseline fractions were taken and finally three fractions during continuous intravenous infusion of L-dopa. Clinical evaluation showed that both DBS and L-dopa infusion gave good relief of rigidity and tremor in all ten patients. During DBS the L-dopa levels in the brain increased in some of the patients but did not persist during the whole stimulation period. The concentration in brain increased substantially during intravenous L-dopa infusion. A number of catecholamines and their metabolites were analysed with high pressure liquid chromatography (HPLC). With our study we could show that this model is suitable for the monitoring of neurotransmitters and for pharmacokinetic studies in human brain, although we found that the sampling time was too short to follow the possible alterations in brain activity caused by DBS.

Place, publisher, year, edition, pages
Elsevier, 2012
Keyword
Parkinson's disease; Microdialysis; L-dopa; Pharmacokinetics; Stereotaxy; Neurotransmitter
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-89705 (URN)10.1016/j.jneumeth.2012.02.021 (DOI)
Available from: 2013-03-04 Created: 2013-03-04 Last updated: 2017-12-06
3. A model for simulation and patient-specific visualization of the tissue volume of influence during brain microdialysis
Open this publication in new window or tab >>A model for simulation and patient-specific visualization of the tissue volume of influence during brain microdialysis
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2011 (English)In: Medical and Biological Engineering and Computing, ISSN 0140-0118, E-ISSN 1741-0444, Vol. 49, no 12, 1459-1469 p.Article in journal (Refereed) Published
Abstract [en]

Microdialysis can be used in parallel to deep brain stimulation (DBS) to relate biochemical changes to the clinical outcome. The aim of the study was to use the finite element method to predict the tissue volume of influence (TVI(max)) and its cross-sectional radius (r (TVImax)) when using brain microdialysis, and visualize the TVI(max) in relation to patient anatomy. An equation based on Fick's law was used to simulate the TVI(max). Factorial design and regression analysis were used to investigate the impact of the diffusion coefficient, tortuosity and loss rate on the r (TVImax). A calf brain tissue experiment was performed to further evaluate these parameters. The model was implemented with pre-(MRI) and post-(CT) operative patient images for simulation of the TVI(max) for four patients undergoing microdialysis in parallel to DBS. Using physiologically relevant parameter values, the r (TVImax) for analytes with a diffusion coefficient D = 7.5 × 10(-6) cm(2)/s was estimated to 0.85 ± 0.25 mm. The simulations showed agreement with experimental data. Due to an implanted gold thread, the catheter positions were visible in the post-operative images. The TVI(max) was visualized for each catheter. The biochemical changes could thereby be related to their anatomical origin, facilitating interpretation of results.

Place, publisher, year, edition, pages
Springer Publishing Company, 2011
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-72911 (URN)10.1007/s11517-011-0841-0 (DOI)000297550600012 ()22081236 (PubMedID)
Available from: 2011-12-09 Created: 2011-12-09 Last updated: 2017-06-19Bibliographically approved
4. Neurotransmitter levels in basal ganglia during L-dopa and Deep Brain Stimulation treatment in Parkinson’s Disease
Open this publication in new window or tab >>Neurotransmitter levels in basal ganglia during L-dopa and Deep Brain Stimulation treatment in Parkinson’s Disease
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2013 (English)Manuscript (preprint) (Other academic)
Abstract [en]

Background: Bilateral deep brain stimulation of the nucleus subthalamicus (STN DBS) is a wellestablishedtreatment in patients with advanced Parkinson’s disease (PD). The mechanism bywhich STN DBS improves the PD symptoms remains unclear. In a previous perioperativestudy we have shown that there might be alterations of neurotransmitter levels in the Globuspallidum interna (GPi) during STN DBS. In this study we wanted to examine if STN DBSand L-dopa infusion interact and affect the levels of neurotransmitters.

Methods: Five patients with advanced PD took part in the study. During STN surgery microdialysis catheters were inserted bilaterally in the GPi and unilaterally in the right putamen. A study protocol was set up and was followed for three days including STN DBS left side, right side and bilateral. L-dopa infusion with and without concomitant bilateral STN DBS was also performed.

Results: The putaminal dopamine levels increase during STN DBS. In addition an increase of GABA concentrations in the GPi during STN DBS and during L-dopa infusion was found.

Conclusions: These findings can provide evidence that the STN has a direct action on the substantia nigra pars compacta (SNc) and that STN DBS may indirectly release putaminal dopamine. There is also evidence that STN DBS interferes with L-dopa therapy resulting in higher levels of Ldopa in the brain explaining why its possible to decrease L-dopa medication after DBS surgery.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-91293 (URN)
Available from: 2013-04-19 Created: 2013-04-19 Last updated: 2017-06-19Bibliographically approved

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