Parkinson's Research: 2002-2006
     
Clin Neuropharmacol. 2006 Sep-Oct;29(5):292-301.
Apomorphine: a rapid rescue agent for the management of motor fluctuations in advanced Parkinson disease.
Kolls BJ, Stacy M.
Division of Neurology, Duke University Medical School, Durham, NC.

Parkinson disease is one of the most common neurodegenerative diseases in the United States, and the number of late stage patients is rising. In advance-stage disease, fluctuations in motor function, variability in response to dopaminergic therapy, and dyskinesias related to increasing doses of dopamine agonists and levodopa, present a variety of challenges to a managing physician. Traditional methods of treatment have concentrated on therapies to anticipate or prevent states of poor motor function. With the approval of apomorphine as a rapid-acting, subcutaneous injectable anti-Parkinson disease therapy, these off periods may now be treated with apomorphine as a "rescue" medication when they occur. This article reviews the pharmacology of apomorphine, the clinical data that support its use and suggest dosing and methods for initiating therapy in this challenging population of patients with Parkinson disease.

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Arch Neurol. 2006 Sep;63(9):1273-6.
Frequency-dependent reciprocal modulation of verbal fluency and motor functions in subthalamic deep brain stimulation.
Wojtecki L, Timmermann L, Jorgens S, Sudmeyer M, Maarouf M, Treuer H, Gross J, Lehrke R, Koulousakis A, Voges J, Sturm V, Schnitzler A.
Author Affiliations: Department of Neurology, Heinrich Heine University, Dusseldorf, and Department of Stereotactic and Functional Neurosurgery, University of Cologne, Cologne, Germany.

BACKGROUND: High-frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves motor functions in those with Parkinson disease but may worsen frontal functions such as verbal fluency (VF). In contrast, low-frequency DBS leads to deterioration of motor functions. It is not known whether low-frequency STN DBS also has an effect on frontal functions. OBJECTIVE: To examine whether low-frequency STN DBS in contrast to high-frequency STN DBS has a positive effect on frontal functions on the basis of VF test results. DESIGN: A double-blind randomized crossover experiment to compare performance in 4 VF subtests and motor performance at 10 Hz, 130 Hz, and no stimulation. SETTING: University hospitals in Dusseldorf and Cologne, Germany.Patients Twelve patients with Parkinson disease 3 months or more after bilateral electrode implantation into the STN.Main Outcome Measure Mean number of words in VF at different stimulation frequencies. RESULTS: The VF was significantly better at 10 Hz (48.3 words) compared with 130 Hz and showed a nonsignificant trend toward worsening at 130 Hz (42.3 words) compared with no stimulation (43.8 words). These results were consistent across all subtests. CONCLUSIONS: The study provides evidence of a beneficial effect of low-frequency (10 Hz) STN DBS on VF, which may be caused by activating neural pathways projecting to the frontal cortex. In addition, the study reproduces the negative effect of therapeutic high-frequency STN DBS on VF. The study results provide evidence for a frequency-dependent modulation of cognitive circuits involving the STN.

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Mov Disord. 2006 Sep 7; [Epub ahead of print]
Effects of rivastigmine in patients with and without visual hallucinations in dementia associated with Parkinson's disease.
Burn D, Emre M, McKeith I, De Deyn PP, Aarsland D, Hsu C, Lane R.
Regional Neuroscience Center, Newcastle General Hospital, Newcastle-upon-Tyne, United Kingdom.

We aimed to determine prospectively whether rivastigmine, an inhibitor of acetylcholinesterase and butyrylcholinesterase, provided benefits in patients with and without visual hallucinations in a population with dementia associated with Parkinson's disease (PDD). This was a 24-week double-blind placebo-controlled study. Primary efficacy measures were the Alzheimer's Disease Assessment Scale cognitive subscale (ADAS-cog) and Alzheimer's Disease Cooperative Study-Clinician's Global Impression of Change (ADCS-CGIC). Secondary efficacy measures included activities of daily living, behavioral symptoms, and executive and attentional functions. Patients were stratified according to the presence of visual hallucinations at baseline. The study included 188 visual hallucinators (118 on rivastigmine, 70 on placebo) and 348 nonvisual hallucinators (239 on rivastigmine, 109 on placebo). Rivastigmine provided benefits in both visual hallucinators and nonvisual hallucinators. Absolute responses to rivastigmine on the ADAS-cog were comparable over 6 months, although rivastigmine-placebo differences tended to be larger in visual hallucinators (4.27; P = 0.002) than in nonhallucinators (2.09; P = 0.015). On the ADCS-CGIC, differences between rivastigmine and placebo were 0.5 in visual hallucinators (P = 0.030) and 0.3 in nonhallucinators (P = 0.111). Rivastigmine provided benefits on all secondary efficacy measures, and placebo declines and treatment differences were more marked in visual hallucinators. Adverse events were reported more frequently by rivastigmine-treated patients, although this difference was less marked in visual hallucinators. Visual hallucinations appear to predict more rapid decline and possibly greater therapeutic benefit from rivastigmine treatment in PDD. (c) 2006 Movement Disorder Society.

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J Neurol Neurosurg Psychiatry. 2006 Sep 4; [Epub ahead of print]
The effect of levodopa on cognitive function in Parkinson's disease with and without dementia and dementia with Lewy bodies.
Molloy S, Rowan EN, O'brien JT, McKeith IG, Wesnes K, Burn DJ.
Royal Victoria Infirmary, Newcastle, United Kingdom.

BACKGROUND: Levodopa (L-dopa) is the gold standard treatment of Parkinson's disease (PD) but a lack of clear efficacy combined with a perceived liability to neuropsychiatric side effects has limited L-dopa use in patients with parkinsonism and dementia. Therefore, the effect of L-dopa on the cognitive profile of dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD) is unclear. AIM: To ascertain the acute and long-term effects of L-dopa on the cognitive profile of patients with PDD and DLB and compare it to that in PD. METHOD: Baseline cognitive and motor function was assessed off L-dopa in patients with PD (n=22), PDD (n=27) and DLB (n=11) using standard "bedside" measures and a computerised programme detecting reaction times and accuracy. All patients then underwent an acute L- dopa challenge with subsequent subjective and objective analysis of alertness, verbal recall, reaction times and accuracy. The same parameters were measured after three months on L-dopa to assess the prolonged effect. RESULTS: Acute L-dopa challenge significantly improved motor function and subjective alertness in all patients without compromising either reaction times or accuracy but increased fluctuations were noted in both groups with dementia. Neuropsychiatric scores improved in PD patients both with and without dementia on L-dopa at three months. However whilst PD patients also had better global cognitive function at this time, verbal attention and memory deteriorated and PDD patients had slower reaction times in some tests. DLB patients did not experience any adverse cognitive or neuropsychiatric effects after three months of L-dopa therapy. CONCLUSION: The use of L-dopa in patients with parkinsonism with dementia does not adversely affect cognitive function.

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Expert Opin Emerg Drugs. 2006 Sep;11(3):403-17.
Emerging drugs for Parkinson's disease.
Morgan JC, Sethi KD.
Medical College of Georgia, Movement Disorders Program, Department of Neurology, 1429 Harper Street, HF-1121, Augusta, GA 30912, USA. jmorgan@mcg.edu

Parkinson's disease (PD) afflicts millions of people worldwide. There are numerous drugs available for PD; however, levodopa remains the gold standard of pharmacotherapy to which all other therapies are compared. Levodopa is quite effective for many motor symptoms (bradykinesia, tremor, rigidity) of PD; however, non-levodopa-responsive motor symptoms (postural instability) and nonmotor symptoms are frequently the most troublesome in middle and later stages of disease. Although motor symptoms remain an important focus for emerging drugs, current research is largely geared to identify and develop disease-slowing therapies. Another important area of focus has become treatment of the nonmotor symptoms of PD (especially depression and dementia). This review discusses emerging drugs in the management of the motor and nonmotor symptoms of PD and drugs under study as disease-slowing/neuroprotective agents.

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J Neuropsychiatry Clin Neurosci. 2006 Summer;18(3):377-83.
Escitalopram for major depression in Parkinson's disease: an open-label, flexible-dosage study.
Weintraub D, Taraborelli D, Morales KH, Duda JE, Katz IR, Stern MB.
3535 Market St., Rm. 3003, Philadelphia, PA 19104. weintrau@mail.med.upenn.edu.

Depression and antidepressant use are common in Parkinson's disease, but the benefit of selective serotonin reuptake inhibitor (SSRI) treatment in this population has not been established. The authors treated 14 Parkinson's disease patients with major depression with escitalopram in an open-label study. Although treatment was well tolerated and correlated with a significant decrease in Inventory of Depressive Symptomatology score, response and remission rates were only 21% and 14%, respectively. However, half of the subjects met Clinical Global Impression-Improvement criteria for response. In Parkinson's disease, either SSRIs may have limited antidepressant effects, or the use of existing depression diagnostic and rating instruments may be problematic.

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N Engl J Med. 2006 Aug 31;355(9):896-908.
A randomized trial of deep-brain stimulation for Parkinson's disease.
Deuschl G, Schade-Brittinger C, Krack P, Volkmann J, Schafer H, Botzel K, Daniels C, Deutschlander A, Dillmann U, Eisner W, Gruber D, Hamel W, Herzog J, Hilker R, Klebe S, Kloss M, Koy J, Krause M, Kupsch A, Lorenz D, Lorenzl S, Mehdorn HM, Moringlane JR, Oertel W, Pinsker MO, Reichmann H, Reuss A, Schneider GH, Schnitzler A, Steude U, Sturm V, Timmermann L, Tronnier V, Trottenberg T, Wojtecki L, Wolf E, Poewe W, Voges J; German Parkinson Study Group, Neurostimulation Section.
Christian Albrechts University, Kiel, Germany. g.deuschl@neurologie.uni-kiel.de

BACKGROUND: Neurostimulation of the subthalamic nucleus reduces levodopa-related motor complications in advanced Parkinson's disease. We compared this treatment plus medication with medical management. METHODS: In this randomized-pairs trial, we enrolled 156 patients with advanced Parkinson's disease and severe motor symptoms. The primary end points were the changes from baseline to six months in the quality of life, as assessed by the Parkinson's Disease Questionnaire (PDQ-39), and the severity of symptoms without medication, according to the Unified Parkinson's Disease Rating Scale, part III (UPDRS-III). RESULTS: Pairwise comparisons showed that neurostimulation, as compared with medication alone, caused greater improvements from baseline to six months in the PDQ-39 (50 of 78 pairs, P=0.02) and the UPDRS-III (55 of 78, P<0.001), with mean improvements of 9.5 and 19.6 points, respectively. Neurostimulation resulted in improvements of 24 to 38 percent in the PDQ-39 subscales for mobility, activities of daily living, emotional well-being, stigma, and bodily discomfort. Serious adverse events were more common with neurostimulation than with medication alone (13 percent vs. 4 percent, P<0.04) and included a fatal intracerebral hemorrhage. The overall frequency of adverse events was higher in the medication group (64 percent vs. 50 percent, P=0.08). CONCLUSIONS: In this six-month study of patients under 75 years of age with severe motor complications of Parkinson's disease, neurostimulation of the subthalamic nucleus was more effective than medical management alone. (ClinicalTrials.gov number, NCT00196911 [ClinicalTrials.gov].). Copyright 2006 Massachusetts Medical Society.

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Mov Disord. 2006 Aug 28; [Epub ahead of print]
Effect of rivastigmine on tremor in patients with Parkinson's disease and dementia.
Gurevich TY, Shabtai H, Korczyn AD, Simon ES, Giladi N.
Tel-Aviv Medical Center, Department of Neurology, Movement Disorders Unit, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.

The purpose of this study was to assess whether rivastigmine, a cholinergic agent, affects tremor features when given to improve cognition in demented Parkinson's disease (PD) patients. Demented PD patients (n = 26; Mini-Mental State Examination score, 13-25; age, 75.2 +/- 4.9 yr) were given rivastigmine (mean dose, 8.0 mg/day) for 12 weeks. They underwent tremor assessment before and during treatment. Global Tremor Score (GTS) was based on eight items specific to tremor in the Unified Parkinson's Disease Rating Scale. Tremor amplitude was also measured using accelerometers during the ON state in both hands in 19 patients. Drug therapy for other PD symptoms was unchanged. The mean group baseline GTS was 1.2 +/- 1.6 points, increasing to 1.6 +/- 2.4 points after treatment (mean increase, 0.4 +/- 1.2 points; P > 0.05). The GTS increased by 3.2 +/- 1.9 points (range, 1-5) in 7 patients (26.9%) and decreased by 1 +/- 0 points in 3 patients (11.5%). Accelerometric assessment showed a significant increase of the average tremor amplitude in the right hand (0.08 +/- 0.03 xg at baseline; 0.12 +/- 0.02 xg at Week 12 of treatment, P = 0.02). Left-hand tremor amplitude did not change. Rivastigmine caused only slight worsening of tremor in demented PD patients, while improving cognition. (c) 2006 Movement Disorder Society.

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Nat Clin Pract Neurol. 2006 Jul;2(7):382-92.
Drug insight: Continuous dopaminergic stimulation in the treatment of Parkinson's disease.
Olanow CW, Obeso JA, Stocchi F.
Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA. warren.olanow@mssm.edu

Continuous dopaminergic stimulation is a therapeutic strategy for the management of Parkinson's disease, which proposes that dopaminergic agents that provide continuous stimulation of striatal dopamine receptors will delay or prevent the onset of levodopa-related motor complications. Dopaminergic neurons in the basal ganglia normally fire in a random but continuous manner, so that striatal dopamine concentrations are maintained at a relatively constant level. In the dopamine-depleted state, however, intermittent oral doses of levodopa induce discontinuous stimulation of striatal dopamine receptors. This pulsatile stimulation leads to molecular and physiologic changes in basal ganglia neurons and the development of motor complications. These effects are reduced or avoided when dopaminergic therapies are delivered in a more continuous and physiologic manner. Studies in primate models and patients with Parkinson's disease have shown that continuous or long-acting dopaminergic agents are associated with a decreased risk of motor complications compared with short-acting dopamine agonists or levodopa formulations. Continuous dopaminergic stimulation can be achieved with a continuous infusion, but infusion therapies are cumbersome and not likely to be acceptable to patients with early disease. The current challenge is to develop a long-acting oral formulation of levodopa that provides comparable anti-parkinsonian benefits without motor complications.

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Nat Clin Pract Neurol. 2006 Jun;2(6):310-20.
Surgery insight: Deep brain stimulation for movement disorders.
Anderson WS, Lenz FA.
Johns Hopkins University School of Medicine, Baltimore, MA 21287, USA.

Over the past two decades, deep brain stimulation (DBS) has supplanted lesioning techniques for the treatment of movement disorders, and has been shown to be safe and efficacious. The primary therapeutic indications for DBS are essential tremor, dystonia and Parkinson's disease. In the case of Parkinson's disease, DBS is effective for treating the primary symptoms--tremor, bradykinesia and rigidity--as well as the motor complications of drug treatment. Progress has been made in understanding the effects of stimulation at the neuronal level, and this knowledge should eventually improve the effectiveness of this therapy. Preliminary studies also indicate that DBS might be used to treat Tourette's syndrome, obsessive-compulsive disorder, depression and epilepsy. As we will discuss in this review, the success of DBS depends on an appropriate rationale for the procedure, and on collaborations between neurologists and neurosurgeons in defining outcomes.

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Internist (Berl). 2006 Apr 4; [Epub ahead of print]
[Embryonic stem cells : Future perspectives.]
[Article in German]
Groebner M, David R, Franz WM.
Medizinische Klinik und Poliklinik I, Klinikum der Universitat, Munchen-Grosshadern, Marchioninistrasse 15, 81377 , Munchen, Wolfgang.Franz@med.uni-muenchen.de.

Embryonic stem cells (ES cells) are able to differentiate into any cell type, and therefore represent an excellent source for cellular replacement therapies in the case of widespread diseases, for example heart failure, diabetes, Parkinson's disease and spinal cord injury. A major prerequisite for their efficient and safe clinical application is the availability of pure populations for direct cell transplantation or tissue engineering as well as the immunological compatibility of the transplanted cells. The expression of human surface markers under the control of cell type specific promoters represents a promising approach for the selection of cardiomyocytes and other cell types for therapeutic applications. The first human clinical trial using ES cells will start in the United States this year.

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J Neurol. 2006 Apr 20; [Epub ahead of print]
Pramipexole versus sertraline in the treatment of depression in Parkinson's disease : A national multicenter parallel-group randomized study.
Barone P, Scarzella L, Marconi R, Antonini A, Morgante L, Bracco F, Zappia M, Musch B; and the Depression/Parkinson Italian Study Group.
Department of Neurological Sciences, University of Naples Federico II, Via Pansini 5, 80131, Napoli, Italy, barone@unina.it.

In addition to treating the motor symptoms of Parkinson's disease, the dopamine agonist pramipexole has shown an antidepressant effect. The trials, however, included patients with motor complications, raising the question of whether the antidepressant benefit represented only a treatment-related motor improvement. To address this issue, we have conducted a 14-week randomized trial comparing pramipexole with an established antidepressant in patients without motor complications.At seven Italian centers, 67 Parkinsonian outpatients with major depression but no history of motor fluctuations and/or dyskinesia received open-label pramipexole (at 1.5 to 4.5 mg/day) or sertraline (at 50 mg/day). In both groups, the Hamilton Depression Rating Scale (HAM-D) score decreased throughout 12 weeks of treatment, but in the pramipexole group the proportion of patients who recovered, as defined by a final HAM-D score </= 8,was significantly higher, at 60.6% versus 27.3% (p = 0.006). Patients' self-ratings improved in both groups. All adverse events were mild or moderate, but five patients (14.7%) withdrew from the sertraline group. Despite the absence of motor complications, the pramipexole recipients showed improvement on the Unified Parkinson's Disease Rating Scale (UPDRS) motor subscore.We conclude that dopamine agonists may be an alternative to antidepressants in Parkinson's disease.

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Neurology. 2006 Apr 11;66(7):996-1002.
Practice Parameter: evaluation and treatment of depression, psychosis, and dementia in Parkinson disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology.
Miyasaki JM, Shannon K, Voon V, Ravina B, Kleiner-Fisman G, Anderson K, Shulman LM, Gronseth G, Weiner WJ; Quality Standards Subcommittee of the American Academy of Neurology.
University of Toronto, Canada.

OBJECTIVE: To make evidence-based treatment recommendations for patients with Parkinson disease (PD) with dementia, depression, and psychosis based on these questions: 1) What tools are effective to screen for depression, psychosis, and dementia in PD? 2) What are effective treatments for depression and psychosis in PD? 3) What are effective treatments for PD dementia or dementia with Lewy bodies (DLB)? METHODS: A nine-member multispecialty committee evaluated available evidence from a structured literature review using MEDLINE, and the Cochrane Database of Health and Psychosocial Instruments from 1966 to 2004. Additional articles were identified by panel members. RESULTS: The Beck Depression Inventory-I, Hamilton Depression Rating Scale, and Montgomery Asberg Depression Rating Scale should be considered to screen for depression in PD (Level B). The Mini-Mental State Examination and the Cambridge Cognitive Examination should be considered to screen for dementia in PD (Level B). Amitriptyline may be considered to treat depression in PD without dementia (Level C). For psychosis in PD, clozapine should be considered (Level B), quetiapine may be considered (Level C), but olanzapine should not be considered (Level B). Donepezil or rivastigmine should be considered for dementia in PD (Level B) and rivastigmine should be considered for DLB (Level B). CONCLUSIONS: Screening tools are available for depression and dementia in patients with PD, but more specific validated tools are needed. There are no widely used, validated tools for psychosis screening in Parkinson disease (PD). Clozapine successfully treats psychosis in PD. Cholinesterase inhibitors are effective treatments for dementia in PD, but improvement is modest and motor side effects may occur.

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Neurology. 2006 Apr 11;66(7):983-95.
Practice Parameter: treatment of Parkinson disease with motor fluctuations and dyskinesia (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology.
Pahwa R, Factor SA, Lyons KE, Ondo WG, Gronseth G, Bronte-Stewart H, Hallett M, Miyasaki J, Stevens J, Weiner WJ; Quality Standards Subcommittee of the American Academy of Neurology.
University of Kansas Medical Center, Kansas City, USA.

OBJECTIVE: To make evidence-based treatment recommendations for the medical and surgical treatment of patients with Parkinson disease (PD) with levodopa-induced motor fluctuations and dyskinesia. To that end, five questions were addressed. 1. Which medications reduce off time? 2. What is the relative efficacy of medications in reducing off time? 3. Which medications reduce dyskinesia? 4. Does deep brain stimulation (DBS) of the subthalamic nucleus (STN), globus pallidus interna (GPi), or ventral intermediate (VIM) nucleus of the thalamus reduce off time, dyskinesia, and antiparkinsonian medication usage and improve motor function? 5. Which factors predict improvement after DBS? METHODS: A 10-member committee including movement disorder specialists and general neurologists evaluated the available evidence based on a structured literature review including MEDLINE, EMBASE, and Ovid databases from 1965 through June 2004. RESULTS, CONCLUSIONS, AND RECOMMENDATIONS: 1. Entacapone and rasagiline should be offered to reduce off time (Level A). Pergolide, pramipexole, ropinirole, and tolcapone should be considered to reduce off time (Level B). Apomorphine, cabergoline, and selegiline may be considered to reduce off time (Level C). 2. The available evidence does not establish superiority of one medicine over another in reducing off time (Level B). Sustained release carbidopa/levodopa and bromocriptine may be disregarded to reduce off time (Level C). 3. Amantadine may be considered to reduce dyskinesia (Level C). 4. Deep brain stimulation of the STN may be considered to improve motor function and reduce off time, dyskinesia, and medication usage (Level C). There is insufficient evidence to support or refute the efficacy of DBS of the GPi or VIM nucleus of the thalamus in reducing off time, dyskinesia, or medication usage, or to improve motor function. 5. Preoperative response to levodopa predicts better outcome after DBS of the STN (Level B).

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Neurology. 2006 Apr 11;66(7):976-82.
Practice Parameter: neuroprotective strategies and alternative therapies for Parkinson disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology.
Suchowersky O, Gronseth G, Perlmutter J, Reich S, Zesiewicz T, Weiner WJ; Quality Standards Subcommittee of the American Academy of Neurology.
University of Calgary, Calgary, AB, Canada.

OBJECTIVE: To define key issues in the management of Parkinson disease (PD) relating to neuroprotective strategies and alternative treatments, and to make evidence-based treatment recommendations. METHODS: Two clinical questions were identified. 1) In a patient diagnosed with PD, are there any therapies that can slow disease progression? 2) Are there any nonstandard pharmacologic or nonpharmacologic therapies that have been shown to improve motor function in PD? Articles were classified according to a four-tiered level of evidence scheme. Recommendations were based on the evidence. RESULTS AND CONCLUSIONS: 1. Levodopa does not appear to accelerate disease progression. 2. No treatment has been shown to be neuroprotective. 3. There is no evidence that vitamin or food additives can improve motor function in PD. 4. Exercise may be helpful in improving motor function. 5. Speech therapy may be helpful in improving speech volume. 6. No manual therapy has been shown to be helpful in the treatment of motor symptoms, although studies in this area are limited. Further studies using a rigorous scientific method are needed to determine efficacy of alternative therapies.

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Prescrire Int. 2006 Apr;15(82):54-7.
Tolcapone: new drug. In Parkinson's disease: unacceptable risk of severe hepatitis.
[No authors listed]

(1) When patients with Parkinson's disease who are taking levodopa develop motor fluctuations that do not respond to dose adjustments, the standard treatment is the addition of bromocriptine, a dopaminergic agonist. Evaluation of entacapone fails to show whether the risk-benefit balance of this catechol-O-methyltransferase (COMT) inhibitor is at least as favourable as that of bromocriptine. (2) Tolcapone, another COMT inhibitor, is back on the French market after being withdrawn because of serious hepatic effects. The summary of product characteristics (SPC) specifies that tolcapone must only be used when entacapone treatment fails or is poorly tolerated. (3) Renewal of marketing authorisation was based on one clinical trial in which about half the patients were probably not resistant to entacapone. No difference in efficacy was found between tolcapone and entacapone. There is no firm evidence that tolcapone is effective in a significant number of patients in whom entacapone fails. (4) Placebo-controlled trials show that first-line treatment with tolcapone 100 mg to 200 mg 3 times a day reduces the duration of motor freezing ("off") periods, but the global impact of tolcapone on parkinsonism appears to be limited. (5) Unblinded randomised controlled trials have failed to show that tolcapone is more effective than bromocriptine or pergolide. There are no trials assessing the use of tolcapone in combination with dopamine agonists. (6) Adverse effects were frequent during clinical trials. They were mainly neurological and gastrointestinal, and differed from those associated with bromocriptine. In 1988, shortly after worldwide marketing of tolcapone, 3 cases of fatal fulminant hepatitis were reported among about 60 000 patients who had taken this drug. Some countries, including European Union member states, withdrew marketing authorisation. Other countries, including the United States, left tolcapone on the market but required stringent monitoring of liver function. Due to a lack of transparency on the part of both the manufacturer and the health authorities, we do not know if these measures reduced the risk of severe hepatitis. In the trial versus entacapone, one of the 75 patients treated with tolcapone 300 mg/day had an abnormal increase in serum transaminase activity. (7) In practice, tolcapone has a negative risk-benefit balance.

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Annu Rev Neurosci. 2006 Mar 15; [Epub ahead of print]
Deep Brain Stimulation.
Perlmutter JS, Mink JW.
Departments of Neurology, Radiology, Physical Therapy and Anatomy & Neurobiology,Washington University School of Medicine,Washington University in St. Louis, St. Louis, Missouri 63110 joel@npg.wustl.edu.

Deep brain stimulation (DBS) has provided remarkable benefits for people with a variety of neurologic conditions. Stimulation of the ventral intermediate nucleus of the thalamus can dramatically relieve tremor associated with essential tremor or Parkinson disease (PD). Similarly, stimulation of the subthalamic nucleus or the internal segment of the globus pallidus can substantially reduce bradykinesia, rigidity, tremor, and gait difficulties in people with PD. Multiple groups are attempting to extend this mode of treatment to other conditions. Yet, the precise mechanism of action of DBS remains uncertain. Such studies have importance that extends beyond clinical therapeutics. Investigations of the mechanisms of action of DBS have the potential to clarify fundamental issues such as the functional anatomy of selected brain circuits and the relationship between activity in those circuits and behavior. Although we review relevant clinical issues, we emphasize the importance of current and future investigations on these topics. Expected online publication date for the Annual Review of Neuroscience Volume 29 is June 16, 2006. Please see http://www.annualreviews.org/catalog/pub_dates.asp for revised estimates.

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Neurochirurgie. 2006 Feb;52(1):15-25.
[Subthalamic deep brain stimulation for severe idiopathic Parkinson's disease. Location study of the effective contacts.]
[Article in French]
Caire F, Derost P, Coste J, Bonny JM, Durif F, Frenoux E, Villeger A, Lemaire JJ.
Service de Neurochirurgie A, Hopital Gabriel-Montpied, CHU, BP 69, 63003 Clermont-Ferrand Cedex 1.

The subthalamic nucleus (STN) is the main target of deep brain stimulation (DBS) treatment for severe idiopathic Parkinson's disease. But there is still no clear information on the location of the effective contacts (used during the chronic phase of stimulation). Our aim was to assess the anatomical structures of the subthalamic area (STA) involved during chronic DBS. Ten patients successfully treated were included. The surgical procedure was based on direct STN targeting (stereotactic MRI based) pondered by the acute effects of intraoperative stimulation. We used a formaldehyde-fixed human specimen to compare by matching MRI images obtained at 1.5 Tesla (performed in clinical stereotactic conditions) and at very high field at 4.7 Tesla. This allowed accurate analysis of the anatomy of the STA and retrospective precision of the location of the center of effective contacts which were located within the STN in 4 patients, at the interface between the STN and the ZI and/or FF in 13, at the interface between ZI and FF in 2 and between the STN and the substantia nigra in one. These results were consistent with the literature, revealing the implication of neighboring structures, especially the zona incerta and Forel's Field, in the clinical benefit.

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Gen Hosp Psychiatry. 2006 Jan-Feb;28(1):59-64.
Response to 4-month treatment with reboxetine in Parkinson's disease patients with a major depressive episode.
Pintor L, Bailles E, Valldeoriola F, Tolosa E, Marti MJ, de Pablo J.
Servicio de Psiquiatria, Instituto Clinico de Neurociencias, Hospital Clinico de Barcelona, 08036 Barcelona, Spain.

OBJECTIVE: The aim of this study is to evaluate response to reboxetine in a 4-month follow-up study on depression in Parkinson's disease (PD), and to assess its tolerability profile. METHODS: A prospective 4-month follow-up study was performed in 17 PD patients with a major depressive episode. The intensity of depressive symptoms was evaluated mainly with the Hamilton Rating Scale for Depression (HAM-D), and PD was assessed with the Unified Parkinson Disease Rating Scale (UPDRS). RESULTS: Reboxetine causes a progressive decrease in depressive symptoms in PD patients; the initial score of 16.76 (2.68) on HAM-D decreased to 5.85 (2.42) at 4 months (P<.002). Mean UPDRS scores did not show a statistically significant increase: 18.18 (2.6) at the beginning and 18.25 (2.4) at the end of the follow-up period (P=.8). CONCLUSIONS: Reboxetine, as first choice treatment for major depressive episodes in PD patients, seems to be effective in progressively improving depressive symptoms over the first 4 months of treatment until complete remission. Reboxetine does not seem to increase PD symptoms, whereas patients' quality of life improves.

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Acta Neurol Scand. 2006 Jan;113(1):18-24.
Efficacy and safety of high-dose cabergoline in Parkinson's disease.
Odin P, Oehlwein C, Storch A, Polzer U, Werner G, Renner R, Shing M, Ludolph A, Schuler P.
Department of Neurology, Central Hospital, Bremerhaven, Germany.

Objectives - To assess the efficacy and safety of high-dose (up to 20 mg/day) cabergoline in Parkinson's disease (PD) patients with motor fluctuations and/or dyskinesias. Materials and methods - Thirty-four PD patients had cabergoline up-titrated and their levodopa (l-dopa) reduced over a maximum of 20 weeks, followed by at least 6 weeks steady cabergoline dosing. Primary endpoint was change in mean hyperkinesia intensity at the final visit (week 26). Results - Mean (+/- SD) cabergoline was increased from 6.43 +/- 2.66 to 12.78 +/- 5.67 mg/day and mean l-dopa reduced from 606.6 +/- 263.9 to 370.6 +/- 192.5 mg/day. A significant reduction (P < 0.001) in mean hyperkinesia intensity occurred from baseline (day 0) to week 26. Improvements in 'on with dyskinesias', mean dystonia intensity (P < 0.05), time spent in 'severe off' condition, severity of 'off' periods as well as clinical/patient global impression, and health-related quality of life were observed. Twenty-four drug-related adverse events were recorded of which four were regarded as serious. Conclusion - High-dose cabergoline was well tolerated and provided significant improvements in the Parkinson symptomatology and a reduced requirement for l-dopa.

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J Pharmacol Sci. 2006 Jan 13; [Epub ahead of print]
Effect of Clarithromycin on the Pharmacokinetics of Cabergoline in Healthy Controls and in Patients With Parkinson's Disease.
Nakatsuka A, Nagai M, Yabe H, Nishikawa N, Nomura T, Moritoyo H, Moritoyo T, Nomoto M.
Clinical Pharmacology and Therapeutics, Ehime University School of Medicine, Japan.

Cabergoline is used in the treatment of Parkinson's disease (PD). Clarithromycin is a potent inhibitor of CYP3A4 and P-glycoprotein and is often co-administered with cabergoline in usual clinical practice. We studied the effect of clarithromycin co-administration on the blood concentration of cabergoline in healthy male volunteers and in PD patients. Study 1: Ten healthy male volunteers were enrolled and were randomized to take a single oral dose of cabergoline (1 mg/day) for 6 days or a single oral dose of cabergoline plus clarithromycin (400 mg/day) for 6 days. Study 2: Seven PD patients receiving stable cabergoline doses were enrolled. They were evaluated for the plasma cabergoline concentration before and after the addition of clarithromycin 400 mg/day for 6 days, and again 1 month after discontinuation of clarithromycin. The dose and duration of clarithromycin were decided according to usual clinical practice. In healthy male volunteers, mean C(max) and AUC(0-10 h) of cabergoline increased to a similar degree during co-administration of clarithromycin. Mean plasma cabergoline concentration over 10 h post-dosing increased 2.6-fold with clarithromycin co-administration. In PD patients, plasma cabergoline concentration increased 1.7-fold during clarithromycin co-administration. Co-administration with clarithromycin may increase the blood concentration of cabergoline in healthy volunteers and in PD patients.

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NeuroRehabilitation. 2005;20(4):307-22.
The effects of loading and unloading treadmill walking on balance, gait, fall risk, and daily function in Parkinsonism.
Toole T, Maitland CG, Warren E, Hubmann MF, Panton L.
Department of Nutrition, Food & Exercise Sciences, College of Human Sciences, Florida State University, Tallahassee, FL, USA.

Our study aims were: 1) to determine whether assisted weight bearing or additional weight bearing is more beneficial to the improvement of function and increased stability in gait and dynamic balance in patients with Parkinsonism, compared with matched controls (treadmill alone). Twenty-three men and women participants (M +/- SD=74.5 +/- 9.7 yrs; Males=19, Females=4) with Parkinsonism were in the study. Participants staged at 1-7 (M +/- SD=3.96 +/- 1.07) using the Hoehn & Yahr scale. All participants were tested before, after the intervention (within one week), and four weeks later on: 1) dynamic posturography, 2) Berg Balance scale, 3) United Parkinson's Disease Rating Scale (UPDRS), 4) biomechanical assessment of strength and range of motion, and 5) Gaitrite force sensitive gait mat. Group 1 (treadmill control group), received treadmill training with no loading or unloading. Group 2 (unweighted group), walked on the treadmill assisted by the Biodex Unweighing System at a 25% body weight reduction. Group 3 (weighted group), ambulated wearing a weighted scuba-diving belt, which increased their normal body weight by 5%. All subjects walked on the treadmill for 20 minutes per day for 3 days per week for 6 weeks. Improvements in dynamic posturography, falls during balance testing, Berg Balance, UPDRS (Motor Exam), and gait for all groups lead us to believe that neuromuscular regulation can be facilitated in all Parkinson's individuals no matter what treadmill intervention is employed.

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Br J Pharmacol. 2006 Jan;147 Suppl 1:S136-44.
Dopamine: the rewarding years.
Marsden CA.
1School of Biomedical Sciences, Institute of Neuroscience, Medical School, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH.

Dopamine has moved from being an insignificant intermediary in the formation of noradrenaline in 1957 to its present-day position as a major neurotransmitter in the brain. This neurotransmitter is involved in the control of movement and Parkinson's disease, the neurobiology and symptoms of schizophrenia and attention deficit hyperactivity disorder. It is also considered an essential element in the brain reward system and in the action of many drugs of abuse. This evolution reflects the ability of several famous names in neuropharmacology, neurology and psychiatry to apply new techniques to ask and answer the right questions. There is now excellent knowledge about the metabolism of dopamine, dopamine receptor systems and the structural organisation of dopamine pathways in the brain. Less is known about the function of the different receptors and how the various dopamine pathways are organised to produce normal behaviour, which exhibits disruption in the disease states mentioned. In particular, we have very limited information as to why and how the dopamine system dies or becomes abnormal in Parkinson's disease or a neurodevelopmental disorder such as schizophrenia. Dopamine neurones account for less than 1% of the total neuronal population of the brain, but have a profound effect on function. The future challenge is to understand how dopamine is involved in the integration of information to produce a relevant response rather than to study dopamine in isolation from other transmission systems. This integrated approach should lead to greater understanding and improved treatment of diseases involving dopamine.British Journal of Pharmacology (2006) 147, S136-S144. doi:10.1038/sj.bjp.0706473.

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J Neurosurg. 2005 Dec;103(6):956-67.
Deep brain stimulation in Parkinson disease: a metaanalysis of patient outcomes.
Weaver F, Follett K, Hur K, Ippolito D, Stern M.
Midwest Center for Health Services and Policy Research, Edward Hines Jr. VA Hospital, IL 60141-5000, USA. Frances.Weaver@va.gov

OBJECT: Deep brain stimulation (DBS) to treat advanced Parkinson disease (PD) has been focused on one of two anatomical targets: the subthalamic nucleus (STN) and the globus pallidus internus (GPI). Authors of more than 65 articles have reported on bilateral DBS outcomes. With one exception, these studies involved pre- and postintervention comparisons of a single target. Despite the paucity of data directly comparing STN and GPI DBS, many clinicians already consider the STN to be the preferred target site. In this study the authors conducted a metaanalysis of the existing literature on patient outcomes following DBS of the STN and the GPI. METHODS: This metaanalysis includes 31 STN and 14 GPI studies. Motor function improved significantly following stimulation (54% in patients whose STN was targeted and 40% in those whose GPI was stimulated), with effect sizes (ESs) of 2.59 and 2.04, respectively. After controlling for participant and study characteristics, patients who had undergone either STN or GPI DBS experienced comparable improved motor function following surgery (p = 0.094). The performance of activities of daily living improved significantly in patients with either target (40%). Medication requirements were significantly reduced following stimulation of the STN (ES = 1.51) but did not change when the GPI was stimulated (ES = -0.02). CONCLUSIONS: In this analysis the authors highlight the need for uniform, detailed reporting of comprehensive motor and nonmotor DBS outcomes at multiple time points and for a randomized trial of bilateral STN and GPI DBS.

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J Cardiol. 2005 Dec;46(6):221-7.
[Effects of low-dose pergolide therapy on cardiac valves in patients with Parkinson's disease]
[Article in Japanese]
Muraki M, Mikami T, Kitaguchi M, Sugawara T, Isonishi K, Kaneko S, Kashiwaba T, Moriwaka F, Yamada S, Onozuka H, Tsutsui H.
Kashiwaba Neurosurgical Hospital, Sapporo. labo@kashiwaba-nougeka.or.jp

BACKGROUND: Pergolide mesilate is widely used to treat Parkinson's disease in both the USA and Japan, but the maintenance dose is distinctly different between the USA (usually more than 1.5 mg/day) and Japan (usually less than 1.5 mg/day). Although several reports from the USA have suggested that mitral, aortic, and tricuspid valvular lesions were caused by pergolide, it is unclear whether low-dose pergolide therapy causes such valvular lesions. OBJECTIVES: The effects of low-dose pergolide therapy on cardiac valves were studied in Japanese patients with Parkinson's disease. METHODS: One hundred and five consecutive patients with Parkinson's disease approved for our protocol were enrolled in this study. Forty patients were treated with low-dose pergolide (0.05-1.5 mg/day for 2-115 months), and were included in the pergolide group (mean age 71 +/- 6 years). The other 44 patients received no ergot-derived dopamine receptor agonists, and 32 patients acted as age-matched controls (mean age 71 +/- 7 years). Both groups of patients underwent echocardiographic examination to detect organic lesions in cardiac valves such as thickening of the leaflet, annular calcification, restriction of valve motion and valvular tenting, and valvular regurgitation greater than 2 + on the 4-point scale. RESULTS: No significant difference was observed in the incidence of aortic, mitral and pulmonic valve lesions between the pergolide group and the control group. Although no organic lesions were detected in the tricuspid valve, the incidence of tricuspid regurgitation was significantly higher in the pergolide group than in the control group (p < 0.05). CONCLUSIONS: Although low-dose pergolide of less than 1.5 mg/day does not cause serious damage in the left-sided valves, it may induce tricuspid regurgitation.

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Pharmacol Rep. 2005 Nov-Dec;57(6):701-12.
Short review on dopamine agonists: insight into clinical and research studies relevant to Parkinson's disease.
Radad K, Gille G, Rausch WD.
Institute for Medical Chemistry, Veterinary Medical University, Veterinaerplatz 1, A-1210, Vienna, Austria. wolf.rausch@vu.vien.ac.at.

Parkinson's disease (PD) is a chronic and progressive neurological disorder characterized by selective degeneration of dopaminergic neurons (DAergic) in the substantia nigra pars compacta (SNpc) and subsequent decrease in dopamine (DA) levels in the striatum. Although levodopa replacement therapy is initially effective in symptomatic treatment of parkinsonian patients, its effectiveness often declines and various levodopa-related side effects appear after long-term treatment. The disabling side effects of levodopa therapy include motor fluctuations such as the wearing-off or on-off phenomena, dyskinesias and psychiatric symptoms. Nowadays, DA receptor agonists are often regarded as first choice in de novo and young parkinsonian patients to delay the onset of levodopa therapy. In advanced stages of the disease, they are also used as adjunct therapy together with levodopa to retard the development of motor complications. DA receptor agonists mimick the endogenous neurotransmitter, dopamine, and act by direct stimulation of presynaptic (autoreceptors) and postsynaptic DA receptors. Next to their clinical role in treating parkinsonian patients, laboratory studies reported antioxidative and neuron-rescuing effects of DA receptor agonists either in vivo or in vitro. This may involve reduced DA turnover following autoreceptor stimulation and direct free radical scavenging activity. In this review, we focus on and summarize the recently reported effects of the most commonly used DA agonists either in clinical or in research studies relevant to PD treatment.

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CNS Drug Rev. 2005 Fall;11(3):253-72.
Ropinirole, a non-ergoline dopamine agonist.
Jost WH, Angersbach D.
Dept. Neurology, Deutsche Klinik fur Diagnostik, Aukammallee 33, D-65191 Wiesbaden, Germany. jost.neuro@dkd-wiesbaden.de.

Dopamine agonists have become indispensable in the treatment of Parkinson's disease. In every-day practice, however, the decision to select the best compound for an individual patient is rendered difficult because of the large number of substances available on the market. This review article provides a closer look at the experimental and clinical studies with ropinirole published so far. Ropinirole is a non-ergoline dopamine agonist which has been proven to be effective in both, monotherapy and combination therapy of idiopathic Parkinson's disease. In addition to ameliorating bradykinesia, rigor, and tremor, ropinirole facilitates the daily life and improves depressive moods of patients with Parkinson's disease. The long-term complications of levodopa are avoided, and problems commonly associated with levodopa treatment are reduced. Ropinirole appears to have a neuroprotective effect. In addition to Parkinson's disease, ropinirole has also been used successfully in the treatment of restless legs syndrome.

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Adv Neurol. 2005;96:42-55.
Anxiety disorders in Parkinson's disease.
Richard IH.
University of Rochester School of Medicine and Dentistry Rochester, New York, USA.

Anxiety disorders frequently occur in association with PD and may be important causes of morbidity. Actual prevalence rates are uncertain, but estimates suggest that up to 40% of patients with PD experience substantial anxiety. This percentage is greater than expected, particularly for an elderly population. In addition, the age at onset of anxiety in PD (and particularly panic disorder) is later than would be expected from current information regarding the natural course of anxiety disorders. Virtually all of the types of anxiety disorders have been described in PD, but panic disorder, GAD, and social phobia appear to be the ones most commonly encountered. Although most patients with motor fluctuations experience greater anxiety during the "off" phase, this is not a universal phenomenon. Anxiety frequently develops before the motor features do, suggesting that anxiety may not represent psychological and social difficulties in adapting to the illness but rather may be linked to specific neurobiologic processes that occur in PD. Most evidence points to disturbances in central noradrenergic systems, but other neurotransmitters (e.g., serotonin, dopamine) may be involved as well. Studies suggest that right hemispheric disturbances may be particularly important for the genesis of anxiety, especially panic and OCD. Whether antiparkinsonian medications themselves contribute to anxiety needs clarification. Anxiety and depression frequently coexist in PD. It remains to be determined whether anxiety in patients with PD reflects one of the following pathologies: (a) an underlying depressive mood disorder, (b) a particular subtype of depression (atypical depression, anxious or agitated depression), or (c) an independent psychiatric disturbance. The relationship between anxiety and dementia in PD is not clear, but current evidence suggests that cognitive dysfunction is not related to the presence of anxiety symptoms in this disorder. The optimal pharmacologic treatment for anxiety in patients with PD has not been established, nor has the effect of PD surgery on anxiety symptoms.

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Clin Ther. 2005 Nov;27(11):1710-24.
A review of intermittent subcutaneous apomorphineinjections for the rescue management of motor fluctuations associated with advanced Parkinson's disease.
Chen JJ, Obering C.
Movement Disorders Center and School of Pharmacy, Loma Linda University, Loma Linda, California, USA.

BACKGROUND:: As Parkinson's disease (PD) progresses,despite optimized pharmacotherapy, patients experience more frequent fluctuations between symptomatic improvement ("on" times) and the return of motor features ("off" times). Apomorphine, the first injectable dopamine agonist available in the United States, is indicated for the acute treatment of "off" episodes (eg, endof-dose wearing-off episodes, unpredictable "on/off" episodes) in patients with advanced PD who are receiving medically optimal antiparkinsonian therapy. OBJECTIVE:: This article reviews the pharmacology,clinical efficacy, and tolerability of intermittent subcutaneous apomorphine injections for the management of "off" episodes in patients with PD. METHODS:: MEDLINE (1966-July 2005), the CochraneDatabase of Systematic Reviews, and International Pharmaceutical Abstracts (1970-July 2005) were searched for original research and review articles published in English. The search terms were apomorphine and Parkinson's disease. The reference lists of articles were also consulted, as was selected information provided by the manufacturer of apomorphine. All relevant identified studies on intermittent subcutaneous administration of apomorphine were included in the review; trials of continuous subcutaneous infusion and nonsubcutaneous administration of apomorphine were excluded. RESULTS:: Intermittent subcutaneous administrationof apomorphine produced consistent rescue from "of" episodes in patients with advanced PD, with a symptomatic motor improvement between the predose "off" state and postdose "on" state similar to that achieved with levodopa. The onset of effect occurred within 20 minutes, and the duration of effect was approximately 100 minutes. The therapeutic rescue dose ranged from 2 to 6 mg. During the clinical development program for subcutaneously injected apomorphine, patients required a mean of approximately 3 rescue doses per day. Common adverse effects occurring in >/=20% of patients were injection-site reaction, yawning, dyskinesias, drowsiness, nausea and vomiting, dizziness or postural dizziness, and rhinorrhea. CONCLUSIONS:: The available clinical studies indicate that apomorphine is effective in providing prompt and consistent rescue from "off" episodes in patients with PD. Antiemetic prophylaxis and close medical supervision are recommended when initiating apomorphine therapy.

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J Neurol Neurosurg Psychiatry. 2005 Nov;76(11):1472-8.
Present and future drug treatment for Parkinson's disease.
Schapira AH.
University Department of Clinical Neurosciences, Royal Free and University College Medical School, Rowland Hill Street, London NW3 2PF, UK. a.schapira@medsch.ucl.ac.uk.

Considerable advances made in defining the aetiology, pathogenesis, and pathology of Parkinson's disease (PD) have resulted in the development and rapid expansion of the pharmacopoeia available for treatment. Anticholinergics were used before the introduction of levodopa which is now the drug most commonly used. Dopamine agonists are effective when used alone or as an adjunct to levodopa, while monoamine oxidase B inhibitors improve motor function in early and advanced PD. However, treatment mainly addresses the dopaminergic features of the disease and leaves its progressive course unaffected; the drug treatment available for the management of non-motor symptoms is limited. This article seeks to set current treatment options in context, review emerging and novel drug treatments for PD, and assess the prospects for disease modification. Surgical therapies are not considered.

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Kidney Int. 2005 Nov;68(5):1937-9.
Stem cell therapy for human brain disorders.
Lindvall O, Kokaia Z.
Laboratory of Neurogenesis and Cell Therapy, Section of Restorative Neurology, Wallenberg Neuroscience Center, University Hospital, Lund, Sweden.

Stem cell therapy for human brain disorders. Transplantation of stem cells or their derivatives, and mobilization of endogenous stem cells in the adult brain, have been proposed as future therapies for various brain disorders such as Parkinson's disease and stroke. In support, recent progress shows that neurons suitable for transplantation can be generated from stem cells in culture, and that the adult brain produces new neurons from its own stem cells in response to injury. However, from a clinical perspective, the development of stem cell-based therapies for brain diseases is still at an early stage. Many basic issues remain to be solved and we need to move forward with caution and avoid scientifically ill-founded trials in patients. We do not know the best stem cell source, and research on embryonic stem cells and stem cells from embryonic or adult brain or from other tissues should therefore be performed in parallel. We need to understand how to control stem cell proliferation and differentiation into specific cell types, induce their integration into neural networks, and optimize the functional recovery in animal models closely resembling the human disease. All these scientific efforts are clearly justified because, for the first time, there is now real hope that we in the future can offer patients with currently intractable diseases effective cell-based treatments to restore brain function.

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Neurosurgery. 2005 Oct;57(4 Suppl):E402; discussion E402.
Extradural motor cortex stimulation in advanced Parkinson's disease: the Turin experience: technical case report.
Pagni CA, Zeme S, Zenga F, Maina R.
Neurosurgical Clinic, University of Turin, Turin, Italy. carloapagni@virgilio.it

OBJECTIVE AND IMPORTANCE: At our institution, extradural motor cortex stimulation (EMCS) has recently been applied for treating Parkinson's disease symptoms. We report our results and review the literature supporting this application of EMCS. CLINICAL PRESENTATION: Since 1998, six patients affected by advanced Parkinson's disease and not fulfilling inclusion criteria for deep brain stimulation underwent EMCS. INTERVENTION: A quadripolar electrode was introduced in the extradural space over the motor cortex, opposite to the side on which parkinsonian symptoms had begun. Bipolar chronic electrostimulation was delivered at 2.5 to 6 V, 150 to 180 microseconds, and 25 to 40 Hz. Preoperative and postoperative clinical status was assessed by the Unified Parkinson's Disease Rating Scale (UPDRS) and recorded on videotapes. The follow-up of this series varied from 4 months to 2.5 years. After EMCS, the overall UPDRS score decreased by 42 to 62%; Section III UPDRS score (motility evaluation) by 32 to 83%; and Section IV UPDRS score (therapy complications) by 100% in two patients, by 50 to 67% in four patients, and by 33% in one patient. L-Dopa therapy was reduced by 11 to 33% in three patients and by 70 to 73% in the other two patients. No postoperative complications or negative side effects of electrostimulation were recorded, except for a misplacement of the electrodes in one patient. CONCLUSION: Unilateral EMCS relieves, at least partially, but sometimes dramatically, the whole spectrum of symptoms in advanced Parkinson's disease. L-Dopa may be reduced up to 70%. The symptoms of long-term L-dopa syndrome are usually markedly improved. The neurophysiological mechanisms involved are still under debate. Our clinical experience adds favorable data to enlarge the series of parkinsonian patients treated by EMCS.

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Mov Disord. 2005 Oct 14; [Epub ahead of print]
Long-term benefits of rivastigmine in dementia associated with Parkinson's disease: An active treatment extension study.
Poewe W, Wolters E, Emre M, Onofrj M, Hsu C, Tekin S, Lane R.
Innsbruck Medical University, Innsbruck, Austria.

In patients with dementia associated with Parkinson's disease (PD), the efficacy and safety of rivastigmine, an inhibitor of acetylcholinesterase and butyrylcholinesterase, were previously demonstrated in a 24-week double-blind placebo-controlled trial. Our objective was to determine whether benefits were sustained over the long term. Following the double-blind trial, all patients were permitted to enter an active treatment extension study, during which they received rivastigmine 3-12 mg/day. Standard safety assessments were performed. Efficacy assessments included the Alzheimer's Disease Assessment Scale cognitive subscale (ADAS-cog) and other measures of cognition, daily function, neuropsychiatric symptoms, and executive function. Of 433 patients who completed the double-blind trial, 334 entered and 273 completed the active treatment extension. At 48 weeks, the mean ADAS-cog score for the whole group improved by 2 points above baseline. Placebo patients switching to rivastigmine for the active treatment extension experienced a mean cognitive improvement similar to that of the original rivastigmine group during the double-blind trial. The adverse event profile was comparable to that seen in the double-blind trial. Long-term rivastigmine treatment appeared well tolerated and may provide sustained benefits in dementia associated with PD patients who remain on treatment for up to 48 weeks. (c) 2005 Movement Disorder Society.

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Tidsskr Nor Laegeforen. 2005 Oct 6;125(19):2638-40.
[Treatment of advanced Parkinson's disease with intraduodenal levodopa infusion]
[Article in Norwegian]
Lundqvist C, Nystedt T, Reiertsen O, Grotli R, Beiske AG.
Nevrologisk avdeling, Akershus universitetssykehus, 1474 Nordbyhagen. luch@uus.no

BACKGROUND: The advanced stage of Parkinson's disease is characterised by motor fluctuations which are often difficult to control on traditional, peroral levodopa medication. We present our experience and a literature search regarding a method for continuous intraduodenal administration of a levodopa/carbidopa gel (Duodopa). METHODS: In a pilot study based on the compassionate use of continuous intraduodenal levodopa, patients were tested via nasoduodenal administration of the gel and on-off registration. For patients in whom a significant improvement in time in near-normal function per day was seen, permanent administration was started through a permanent duodenal port via percutaneous endoscopic gastrostomy with an inner catheter to the duodenal-jejunal transition. RESULTS AND CONCLUSION: In the nine patients tested, a significant functional improvement over time was seen. Five patients now have a permanent system with lasting good effect. Qualitative evaluation shows maintained good effect over a follow up time of up to 2.5 years (mean 19 months). We conclude that continuous enteral levodopa administration is a good and safe alternative especially for patients not offered deep brain stimulation. Its place among other treatment methods needs further assessment.

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Mov Disord. 2005 Oct 6; [Epub ahead of print]
Placebo-controlled study of rTMS for the treatment of Parkinson's disease.
Lomarev MP, Kanchana S, Bara-Jimenez W, Iyer M, Wassermann EM, Hallett M.
Human Motor Control Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.

The objective of this study is to assess the safety and efficacy of repetitive transcranial magnetic stimulation (rTMS) for gait and bradykinesia in patients with Parkinson's disease (PD). In a double-blind placebo-controlled study, we evaluated the effects of 25 Hz rTMS in 18 PD patients. Eight rTMS sessions were performed over a 4-week period. Four cortical targets (left and right motor and dorsolateral prefrontal cortex) were stimulated in each session, with 300 pulses each, 100% of motor threshold intensity. Left motor cortex (MC) excitability was assessed using motor evoked potentials (MEPs) from the abductor pollicis brevis. During the 4 weeks, times for executing walking and complex hand movements tests gradually decreased. The therapeutic rTMS effect lasted for at least 1 month after treatment ended. Right-hand bradykinesia improvement correlated with increased MEP amplitude evoked by left MC rTMS after individual sessions, but improvement overall did not correlate with MC excitability. rTMS sessions appear to have a cumulative benefit for improving gait, as well as reducing upper limb bradykinesia in PD patients. Although short-term benefit may be due to MC excitability enhancement, the mechanism of cumulative benefit must have another explanation. (c) 2005 Movement Disorder Society.

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Rev Med Suisse. 2005 Sep 21;1(33):2162-4, 2166.
[Novel brain stimulation techniques: therapeutic perspectives in psychiatry]
[Article in French]
Berney A, Vingerhoets F.
Service de psychiatrie de liaison, CHUV, 1011 Lausanne. Alexandre.Berney@chuv.ch

Recent advances have allowed the development of new physical techniques in neurology and psychiatry, such as Transcranial Magnetic Stimulation (TMS), Vagus Nerve Stimulation (VNS), and Deep Brain Stimulation (DBS). These techniques are already recognized as therapeutic approaches in several late stage refractory neurological disorders (Parkinson's disease, tremor, epilepsy), and currently investigated in psychiatric conditions, refractory to medical treatment (obsessive-compulsive disorder, resistant major depression). In Paralell, these new techniques offer a new window to understand the neurobiology of human behavior.

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Neurobiol Aging. 2005 Sep 26; [Epub ahead of print]
The beneficial effects of fruit polyphenols on brain aging.
Lau FC, Shukitt-Hale B, Joseph JA.
Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111, USA.

Brain aging is characterized by the continual concession to battle against insults accumulated over the years. One of the major insults is oxidative stress, which is the inability to balance and to defend against the cellular generation of reactive oxygen species (ROS). These ROS cause oxidative damage to nucleic acid, carbohydrate, protein, and lipids. Oxidative damage is particularly detrimental to the brain, where the neuronal cells are largely post-mitotic. Therefore, damaged neurons cannot be replaced readily via mitosis. During normal aging, the brain undergoes morphological and functional modifications resulting in the observed behavioral declines such as decrements in motor and cognitive performance. These declines are augmented by neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and Parkinson's disease (PD). Research from our laboratory has shown that nutritional antioxidants, such as the polyphenols found in blueberries, can reverse age-related declines in neuronal signal transduction as well as cognitive and motor deficits. Furthermore, we have shown that short-term blueberry (BB) supplementation increases hippocampal plasticity. These findings are briefly reviewed in this paper.

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WMJ. 2005 Aug;104(6):35-8.
Deep brain stimulation of the subthalamic nucleus in Parkinson's disease.
Kawakami N, Jessen H, Bordini B, Gallagher C, Klootwyk J, Garell CP.
Department of Neurological Surgery, University of Wisconsin-Madison, USA.

OBJECTIVE: To evaluate the clinical effects of subthalamic nucleus deep brain stimulation in patients with Parkinson's disease within the first 12 months after surgery. METHODS: We performed a prospective study in 8 patients with Parkinson's disease, in whom electrodes were implanted in the subthalamic nucleus bilaterally. We compared levodopa-equivalents and the scores of the Unified Parkinson's Disease Rating Scale pre- and post-operatively. The post-operative evaluation was done between 3 and 12 months after surgery. RESULTS: Antiparkinsonian medications were reduced post-operatively by a mean of 61.5% (P < 0.01) from a levodopa-equivalent dosage of 1144.9 +/- 572.5 mg/day to 440.9 +/- 172.1 mg/day. Motor scores improved 44.4% (P < 0.01) and activities of daily living scores 38.2% (P < 0.01). Adverse events included a subcutaneous hematoma in 1 patient after internal pulse generator implantation necessitating evacuation. CONCLUSIONS: Bilateral stimulation of the subthalamic nucleus is associated with significant improvement in motor function and reduction of antiparkinsonian medications in patients with Parkinson's disease in the first 12 months after surgery. On-state dyskinesias were greatly reduced, probably due to the reduction of total antiparkinsonian medications. The procedure is well tolerated.

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J Neurosurg. 2005 Aug;103(2):252-5.
Long-term benefits in quality of life provided by bilateral subthalamic stimulation in patients with Parkinson disease.
Lyons KE, Pahwa R.
Department of Neurology, University of Kansas Medical Center, Kansas City, Kansas 66160, USA. lyons.kelly@att.net

OBJECT: The goals of this study were to evaluate long-term benefits in quality of life in patients with Parkinson disease (PD) after bilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) and to evaluate the relationship between improvements in motor function and quality of life. METHODS: Seventy-one patients who received bilateral STN stimulation implants and participated in follow-up review for at least 12 months were included in the study. Fifty-nine patients participated in a 12-month follow-up review and 43 patients in a follow-up review lasting at least 24 months. Patients' symptoms were assessed preoperatively by using the Unified PD Rating Scale (UPDRS) in the "medication-on" and "medication-off' conditions and quality of life was examined using the 39-item PD Questionnaire (PDQ-39). Patient evaluations were repeated postoperatively during periods of stimulation. The UPDRS activities of daily living (ADL) and motor scores as well as the PDQ-39 total, mobility, ADL, emotional well-being, stigma, and bodily discomfort scores were significantly improved at 12 months compared with baseline scores; the UPDRS ADL and motor scores as well as the PDQ-39 total, mobility, ADL, stigma, and bodily discomfort scores were significantly improved at the longest follow-up examination compared with baseline scores. There was a strong correlation between UPDRS motor and ADL scores and the PDQ-39 total, mobility, and ADL scores. Further analyses indicated that improvements in tremor were only correlated with PDQ-39 ADL subscale scores and rigidity was not correlated with any aspect of quality of life. Nevertheless, bradykinesia was strongly correlated with improvements in the PDQ-39 total, mobility, and ADL scores. CONCLUSIONS: Improvements in quality of life following bilateral DBS of the STN are maintained in the long term. These improvements are strongly correlated with improvements in motor function, primarily with regard to bradykinesia.

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Curr Opin Neurol. 2005 Aug;18(4):376-85.
Stem cell treatment for Parkinson's disease: an update for 2005.
Snyder BJ, Olanow CW.
aDepartment of Neurosurgery bDepartment of Neurology and Neuroscience, Mount Sinai School of Medicine, New York, NY, USA.

PURPOSE OF REVIEW: The hallmark pathologic feature of Parkinson's disease is loss of melanized dopaminergic neurons within the substantia nigra pars compacta coupled with depletion of striatal dopamine. This is responsible for the major motor features of the disease. Whereas dopaminergic replacement therapy is effective in the early stages of the illness, chronic treatment is associated with motor complications and development of features that do not respond to levodopa therapy. Development of cellular therapies offers the potential to provide more effective treatment for the disease without motor complications. RECENT FINDINGS: Two clinical trials of fetal nigral transplantation failed to meet their primary endpoint and were complicated by the development of dyskinesia that persisted after withdrawal of levodopa ('off-medication' dyskinesia). However, recent studies suggest that both the limited clinical response and off-medication dyskinesia may be related to partial, but incomplete, dopaminergic reinnervation of the striatum and that both might be improved by transplantation of more dopamine neurons. Stem cells offer the potential to provide a virtually unlimited supply of optimized dopaminergic neurons that can provide enhanced benefits in comparison to fetal mesencephalic transplants. Stem cells have now been shown to be capable of differentiating into dopamine neurons that provide benefits following transplantation in animal models of Parkinson's disease. However, cell survival and behavioral responses are limited. There have been numerous advances in enhancing the yield of dopamine neurons from stem cells, and promoting their survival and consequent clinical effects. SUMMARY: Stem cells offer great promise as a therapy for Parkinson's disease, but numerous hurdles remain to be overcome with stem cell therapy. The adverse event profile of transplantation must be determined, and societal and ethical issues addressed. As Parkinson's disease involves degeneration of both dopaminergic and non-dopaminergic neurons, it also remains to be determined if transplantation of even the ideal dopamine neuron will improve non-dopaminergic features of the disease or provide benefits superior to existing therapies.

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Sleep Med. 2005 Aug 3; [Epub ahead of print]
Melatonin for sleep disturbances in Parkinson's disease.
Dowling GA, Mastick J, Colling E, Carter JH, Singer CM, Aminoff MJ.
Institute on Aging Research Center, 3330 Geary Blvd., San Francisco, and Department of Physiological Nursing, University of California, San Francisco, 2 Koret Way, Room N631, San Francisco, CA 94143-0610, USA.

BACKGROUND AND PURPOSE: Many patients with Parkinson's disease (PD) experience sleep-related symptoms. Studies in other populations indicate that melatonin can increase sleep efficiency, decrease nighttime activity, and shorten sleep latency, but there has been little research on the use of melatonin in PD. The purpose of this study was to compare the effects of two doses of melatonin to placebo on sleep, daytime sleepiness, and level of function in patients with PD who complained of sleep disturbances. PATIENTS AND METHODS: A multi-site double-blind placebo-controlled cross-over trial was employed; 40 subjects completed the 10-week protocol. There was a 2-week screening period, 2-week treatment periods, and 1-week washouts between treatments. Nocturnal sleep was assessed by actigraphy and diaries, whereas daytime sleepiness and function were assessed by the Epworth Sleepiness Scale (ESS), Stanford Sleepiness Scale (SSS), and General Sleep Disturbance Scale (GSDS). RESULTS: Repeated measures analysis of variance revealed a significant improvement in total nighttime sleep time during the 50mg melatonin treatment compared to placebo. There was significant improvement in subjective sleep disturbance, sleep quantity, and daytime sleepiness during the 5mg melatonin treatment compared to placebo as assessed by the GSDS. CONCLUSIONS: Although we found a statistically significant improvement in actigraphically measured total sleep time on 50mg melatonin compared to 5mg or placebo, this small improvement (10min) may not be clinically significant. However, the significant improvement found in subjective sleep disturbance suggests that these modest effects may be clinically relevant in this patient population.

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Mov Disord. 2005 Aug 2; [Epub ahead of print]
Effect of levodopa on pain threshold in Parkinson's disease: A clinical and positron emission tomography study.
Brefel-Courbon C, Payoux P, Thalamas C, Ory F, Quelven I, Chollet F, Montastruc JL, Rascol O.
Service de Pharmacologie Clinique, University Hospital, Toulouse, France.

Patients suffering from Parkinson's disease (PD) frequently experienced painful sensations that could be in part due to central modification of nociception. We compared pain threshold before and after administration of levodopa in PD patients and in controls, and investigated cerebral activity with positron emission tomography (PET) during experimental nociceptive stimulation. Pain threshold was determined using thermal stimulation during two randomized conditions: off and on. We performed H(2) (15)O PET analysis of regional cerebral blood flow on subjects while they received alternate randomized noxious and innocuous stimuli during off and on conditions. In off condition, pain threshold in nine PD patients was significantly lower than in nine controls. Administration of levodopa significantly raised pain threshold in PD patients but not in controls. During off condition, there was a significant increase in pain-induced activation in right insula and prefrontal and left anterior cingulate cortices in PD compared to control group. Levodopa significantly reduced pain-induced activation in these areas in PD. This study shows that pain threshold is lower in PD patients but returns to normal ranges after levodopa administration. Moreover, PD patients have higher pain-induced activation in nociceptive pathways, which can be reduced by levodopa. (c) 2005 Movement Disorder Society.

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Novartis Found Symp. 2005;265:174-86; discussion 187, 204-211.
Cell therapy for Parkinson's disease: problems and prospects.
Bjorklund A.
Wallenberg Neuroscience Center, Division of Neurobiology, Lund University, BMC A11, S 22184 Lund, Sweden.

Cell replacement therapy in Parkinson's disease (PD) has so far been based on the use of primary dopaminergic (DA) neuroblasts obtained from the brain of aborted human fetuses. Clinical trials show that intrastriatal DA neuron transplants can give substantial symptomatic relief in advanced PD patients. Two recent NIH-sponsored placebo-controlled trials, however, have given disappointing results and highlighted a number of critical issues that need to be resolved in order to turn cell transplantation into an acceptable clinical therapy. First, graft survival and clinical outcome has so far been too variable, suggesting that DA neuron grafts may not be equally effective in all PD patients. Secondly, it has become clear that immune mechanisms leading to slowly developing inflammatory responses may compromise long-term graft survival and function. Third, the problems associated with the use of tissue from aborted fetuses make it necessary to develop alternative sources of cells for transplantation. Recent progress in the generation of DA neuroblasts from neural progenitors and embryonic stem cells suggest that these kinds of cell may offer more accessible, defined and standardized sources of cells for clinical transplantation in PD.

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Cochrane Database Syst Rev. 2005 Jul 20;(3):CD004898.
Monoamine oxidase B inhibitors for early Parkinson's disease.
Macleod A, Counsell C, Ives N, Stowe R.

BACKGROUND: It has been postulated that monoamine oxidase B (MAO-B) inhibitors alter disease progression in Parkinson's disease (PD). Clinical trials have produced conflicting results. OBJECTIVES: To assess the evidence from randomized controlled trials for the effectiveness and safety of long-term use of MAO-B inhibitors in early PD. SEARCH STRATEGY: We searched the following electronic databases: Cochrane Central Register of Controlled trials (CENTRAL) (The Cochrane Library Issue 2, 2004), MEDLINE (last searched 18th August 2004) and EMBASE (last searched 18th August 2004). We also handsearched neurology and movement disorders conference proceedings, checked reference lists of relevant studies and contacted other researchers. SELECTION CRITERIA: We sought to include all unconfounded randomized controlled trials that compared a MAO-B inhibitor with control, in the presence or absence of levodopa or dopamine agonists, in patients with early PD and where treatment and follow up lasted at least one year. DATA COLLECTION AND ANALYSIS: Two reviewers independently selected trials for inclusion, assessed the methodological quality, and extracted the data. A small amount of additional data was provided by the original authors. Random-effects models were used to analyse results, where appropriate. MAIN RESULTS: Ten trials were included (a total of 2422 patients), nine using selegiline, one using lazabemide. The methodological quality was reasonable although concealment of allocation was definitely adequate in only four trials. The mean follow up was for 5.8 years. MAO-B inhibitors were not associated with a significant increase in deaths (odds ratio (OR) 1.15; 95% confidence interval (CI) 0.92 to 1.44). They provided small benefits over control in impairment (weighted mean difference (WMD) for change in motor UPDRS score was 3.81 points less with MAO-B inhibitors; 95% CI 2.27 to 5.36) and disability (WMD for change in UPDRS ADL score was 1.50 less; 95% CI 0.48 to 2.53) at one year which, although statistically significant, were not clinically significant. There was a marked levodopa-sparing effect with MAO-B inhibitors which was associated with a significant reduction in motor fluctuations (OR 0.75; 95% CI 0.59 to 0.94) but not dyskinesia (OR 0.97; 95% CI 0.76 to 1.25). The reduction in motor fluctuations was, however, not robust in sensitivity analyses. Although adverse events were generally mild and infrequent, withdrawals due to side-effects were higher (OR 2.36; 95% CI 1.32 to 4.20) with MAO-B inhibitors. AUTHORS' CONCLUSIONS: MAO-B inhibitors do not appear to delay disease progression but may have a beneficial effect on motor fluctuations. There was no statistically significant effect on deaths although the confidence interval does not exclude a small increase with MAO-B inhibitors. At present we do not feel these drugs can be recommended for routine use in the treatment of early Parkinson's disease but further randomized controlled trials should be carried out to clarify, in particular, their effect on deaths and motor complications.

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Arch Gerontol Geriatr. 2005 Jul 16; [Epub ahead of print]
High doses of pergolide improve clinical global impression in advanced Parkinson's disease-A preliminary open label study.
Arnold G, Gasser T, Storch A, Lipp A, Kupsch A, Hundemer HP, Schwarz J.
Department of Neurology, Charite, University Hospital Berlin, Schumannstrasse 20/21, D-10117 Berlin, Germany.

We evaluated the efficacy and safety of high-dose pergolide treatment in patients with moderate to severe Parkinson's disease (PD) in an open-label multicenter clinical trial. The primary objective was to assess the amount of reduction in levodopa, the improvement in Unified Parkinson's Disease Rating Scale (UPDRS) and adverse reactions. We treated 32 patients with PD presenting with motor fluctuations. Pergolide treatment started with a dose escalation period of 12 weeks followed by a 12-week continuation period. Pergolide doses were increased up to a maximum of 12mg/day in combination with a simultaneous decrease of levodopa doses in 100mg steps. Levodopa was reduced from 500mg/day (median) to 250mg/day. Mean UPDRS part III improved significantly (p=0.01). Clinical global impression improved significantly after 24 weeks (p<0.01). Most frequent adverse events were hallucinations, asthenia, anxiety, abdominal pain, and peripheral edema. Twenty-two patients finished the complete study according to protocol. A possible relationship to the study medication was assumed for two serious adverse events reporting psychosis. We conclude that high doses of pergolide are efficacious in advanced stages of PD if given in appropriate regimens.

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J Neurol. 2005 Jul 20; [Epub ahead of print]
Effect of bilateral subthalamic nucleus stimulation on balance and finger control in Parkinson's disease.
Vrancken AM, Allum JH, Peller M, Visser JE, Esselink RA, Speelman JD, Siebner HR, Bloem BR.
Dept. of ORL, University Hospital, Basel, Switzerland.

We aimed to quantify the effects of bilateral subthalamic nucleus (STN) stimulation in Parkinson's disease (PD) on stance and gait ("axial"motor control), and related this to effects on finger movements ("appendicular" motor control). Fourteen PD patients and 20 matched controls participated. Subjects completed several balance and gait tasks (standing with eyes open or closed, on a normal or foam surface; retropulsion test; walking with eyes closed; walking up and down stairs; Get Up and Go test). Postural control was quantified using trunk sway measurements (angle and angular velocity) in the roll and pitch directions. Subjects further performed a pinch grip reaction time task, where we measured isometric grip forces, as well as movement and reaction times. Patients were examined with STN stimulators switched on or off (order randomised across patients), always after a supramaximal levodopa dosage. STN stimulation improved postural control, as reflected by a reduced trunk sway tremor during stance, a reduced duration for all gait tasks, an increased trunk pitch velocity while rising from a chair, and improved roll stability. STN stimulation also improved finger control, as reflected by a reduced time to reach maximum grip force, without altering reaction times and maximum force levels. Improvements in finger control timing did not correlate with reduced task durations during gait. We conclude that STN stimulation affords improvement of postural control in PD, over and above optimal drug treatment. STN stimulation also provides a simultaneous effect on distal and axial motor control. Because improvements in distal and axial motor control were not correlated, we assume that these effects are mediated by stimulation of different structures within the STN.

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Can J Neurol Sci. 2005 May;32(2):213-7.
Inspiratory muscle training and the perception of dyspnea in Parkinson's disease.
Inzelberg R, Peleg N, Nisipeanu P, Magadle R, Carasso RL, Weiner P.
Department of Neurology, Hillel Yaffe Medical Center, Hadera, Israel.

BACKGROUND: Pulmonary and respiratory muscle function impairment are common in patients with Parkinson's disease (PD). Inspiratory muscle training may improve strength, dyspnea and functional capacity in healthy subjects and in those with chronic obstructive pulmonary disease. This study investigated the effect of specific inspiratory muscle training (SIMT) on pulmonary functions, inspiratory muscle performance, dyspnea and quality of life, in patients with PD. PATIENTS AND METHODS: Twenty patients with PD (stage II and III Hoehn and Yahr scale) were recruited for the study and were divided into two groups: (a) ten patients who received SIMT and (b) ten patients who received sham training, for three months. Pulmonary functions, the respiratory muscle strength and endurance, the perception of dyspnea (POD) and the quality of life were studied before and within one week after the training period. All subjects trained daily, six times a week, each session consisting of 1/2 hour, for 12 weeks. RESULTS: Following the training period, there was a significant improvement, in the training group but not in the control group, in the following parameters: inspiratory muscle strength, (PImax, increased from 62.0 +/- 8.2 to 78.0 +/- 7.5 cm of H2O (p < 0.05), inspiratory muscle endurance (increased from 20.0 +/- 2.8 to 29.0 +/- 3.0 cm of H2O (p < 0.05), and the POD (decreased from 17.9 +/- 3.2 to 14.0 +/- 2.4 units (p < 0.05). There was a close correlation between the increase in the inspiratory muscle performance and the decrease in the POD. CONCLUSIONS: The inspiratory muscle performance may be improved by SIMT in patients with PD. This improvement is associated with a significant decrease in their POD.

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Clin Rehabil. 2005 May;19(3):247-54.
Evidence of the efficacy of occupational therapy in different conditions: an overview of systematic reviews.
Steuljens EM, Dekker J, Bouter LM, Leemrijse CJ, van den Ende CH.
Netherlands Institute for Health Services Research, Utrecht, The Netherlands. e.steultjens@ision.nl

OBJECTIVE: To summarize the research evidence available from systematic reviews of the efficacy of occupational therapy (OT) for practitioners, researchers, purchasing organizations and policy-makers. DATA SOURCE: The search for systematic reviews was conducted in PubMed and the Cochrane Library (October 2004). METHODS: The reviews included were those that utilized a systematic search for evidence with regard to OT for specific patient groups. Data were summarized for patient group, interventions, outcome domains, type of study designs included, method of data synthesis and conclusions. RESULTS: Fourteen systematic reviews were included. Three reviews related to rheumatoid arthritis, four reviewed stroke and four focused on elderly people. Reviews of Parkinson's disease, multiple sclerosis, Huntington's disease, cerebral palsy and mental illnesses were also identified. The reviews of rheumatoid arthritis, stroke and elderly people showed evidence of the efficacy of OT in increasing functional abilities. Positive results were presented for quality of life and social participation in elderly people and stroke respectively. The efficacy of OT in all other patient groups is unknown due to insufficient evidence. CONCLUSION: This summary shows that elderly people and people with stroke or rheumatoid arthritis can expect to benefit from comprehensive OT. Evidence of the efficacy of specific interventions is sparse and should be addressed in future research. The evidence that does exist should be incorporated into OT practice. 

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Arch Neurol. 2005 Apr;62(4):554-60.
Pallidal vs subthalamic nucleus deep brain stimulation in Parkinson disease.
Anderson VC, Burchiel KJ, Hogarth P, Favre J, Hammerstad JP.
Department of Neurological Surgery, Oregon Health and Science University, Portland, OR 97201, USA. andersov@ohsu.edu

BACKGROUND: Deep brain stimulation (DBS) of the globus pallidus interna (GPi) and subthalamic nucleus (STN) has been reported to relieve motor symptoms and levodopa-induced dyskinesia in patients with advanced Parkinson disease (PD). Although it has been suggested that stimulation of the STN may be superior to stimulation of the GPi, comparative trials are limited. OBJECTIVE: To extend our randomized, blinded pilot comparison of the safety and efficacy of STN and GPi stimulation in patients with advanced PD. DESIGN: This study represents the combined results from our previously published, randomized, blinded, parallel-group pilot study and additional patients enrolled in our single-center extension study. SETTING: Oregon Health and Science University in Portland.Patients Twenty-three patients with idiopathic PD, levodopa-induced dyskinesia, and response fluctuations were randomized to implantation of bilateral GPi or STN stimulators. Patients and evaluating clinicians were blinded to stimulation site. All patients were tested preoperatively while taking and not taking medications and after 3, 6, and 12 months of DBS. MAIN OUTCOME MEASURES: Postoperatively, response of symptoms to DBS, medication, and combined medication and DBS was evaluated. Twenty patients (10 in the GPi group and 10 in the STN group) completed 12-month follow-up. RESULTS: Off-medication Unified Parkinson's Disease Rating Scale motor scores were improved after 12 months of both GPi and STN stimulation (39% vs 48%). Bradykinesia tended to improve more with STN than GPi stimulation. No improvement in on-medication function was observed in either group. Levodopa dose was reduced by 38% in STN stimulation patients compared with 3% in GPi stimulation patients (P = .08). Dyskinesia was reduced by stimulation at both GPi and STN (89% vs 62%). Cognitive and behavioral complications were observed only in combination with STN stimulation. CONCLUSION: Stimulation of either the GPi or STN improves many features of advanced PD. It is premature to exclude GPi as an appropriate target for DBS in patients with advanced disease.

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Mov Disord. 2005 Apr 27; [Epub ahead of print]
Bilateral stimulation of nucleus subthalamicus in advanced Parkinson's disease: No effects on, and of, autonomic dysfunction.
Holmberg B, Corneliusson O, Elam M.
Institute for Clinical Neuroscience, Sahlgrenska Academy, Gothenburg University, Sweden.

It is not known whether bilateral stimulation of the subthalamic nucleus, performed to improve skeletal motor control in advanced Parkinson's disease, also affects central autonomic regulation of cardiovascular motor function. Furthermore, reduced treatment with dopaminergic and other drugs after bilateral stimulation of the subthalamic nucleus could affect cardiovascular autonomic reflexes and/or other factors controlling blood pressure level. The primary aim of this study was to investigate putative effects of bilateral stimulation of the subthalamic nucleus on the autonomic nervous system, using respiratory heart rate variability and blood pressure responses to tilt as indices. Baseline autonomic tests were performed in 19 patients with Parkinson's disease and 10 matched healthy subjects. Patients were divided in two groups and re-investigated after 1 year of optimized pharmacological treatment (n = 8) or 1 year of bilateral subthalamic nucleus stimulation (n = 11). Both skeletal motor dysfunction and dopaminergic drug treatment were significantly reduced after 1 year of bilateral subthalamic nucleus stimulation. However, heart rate variability as well as blood pressure during tilt was reduced compared to baseline to a similar extent in both patient groups. The number of individual patients showing pathological autonomic test results at 1-year follow-up increased only in the subthalamic nucleus stimulation group. Despite reduced pharmacological treatment and reduced motor disability, bilateral subthalamic nucleus stimulation does not improve cardiovascular autonomic reflex function or protect against development of cardiovascular autonomic failure in Parkinson's disease. Preoperative cardiovascular autonomic reflex dysfunction, conversely, does not exclude an excellent stimulation effect. (c) 2005 Movement Disorder Society.

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Cochrane Database Syst Rev. 2005 Apr 18;(2):CD000269.
Cytidinediphosphocholine (CDP-choline) for cognitive and behavioural disturbances associated with chronic cerebral disorders in the elderly.
Fioravanti M, Yanagi M.
Department of Psychiatric Science and Psychological Medicine, University of Rome "La Sapienza", P.le A. Moro, 5, Rome, ITALY, 00185.

BACKGROUND: CDP-choline (cytidine 5'-diphosphocholine) is a precursor essential for the synthesis of phosphatidylcholine, one of the cell membrane components that is degraded during cerebral ischaemia to free fatty acids and free radicals. Animal studies suggest that CDP-choline may protect cell membranes by accelerating resynthesis of phospholipids. CDP-choline may also attenuate the progression of ischaemic cell damage by suppressing the release of free fatty acids. CDP-choline is the endogenous compound normally produced by the organism. When the same substance is introduced as a drug it can be called citicoline.CDP-choline is mainly used in the treatment of disorders of a cerebrovascular nature. The many years of its presence in the clinical field have caused an evolution in dosage, method of administration, and selection criteria of patients to whom the treatments were given. Modalities of the clinical studies, including length of observation, severity of disturbance, and methodology of evaluation of the results were also heterogeneous. In spite of uncertainties about its efficacy due to these complexities, CDP-choline is a frequently prescribed drug for cognitive impairment in several European countries, especially when the clinical picture is predominantly one of cerebrovascular disease, hence the need for this review.Due to its effects on the adrenergic and dopaminergic activity of the CNS, CDP-choline has also been used as an adjuvant in the treatment of Parkinson's disease. OBJECTIVES: To assess the efficacy of CDP-choline (cytidinediphosphocholine) in the treatment of cognitive, emotional, and behavioural deficits associated with chronic cerebral disorders in the elderly. SEARCH STRATEGY: The trials were identified from a last updated search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 22 April 2004 using the terms CDP-choline, CDP, citicoline, cytidine diphosphate choline or diphosphocholine. The Register contains records from all major health-care databases and many ongoing trials databases and is updated regularly. SELECTION CRITERIA: All relevant unconfounded, double-blind, placebo-controlled, randomized trials of CDP-choline for cognitive impairment due to chronic cerebral disorders were considered for inclusion in the review. DATA COLLECTION AND ANALYSIS: Two reviewers independently reviewed the included studies, extracted the data, and pooled it when appropriate and possible. The pooled odd ratios (95% Confidence Interval (CI)) or the average differences (95% CI) were estimated. No intention-to-treat data were available from the studies included. MAIN RESULTS: Fourteen studies were included in this review. Some of the included studies did not present numerical data suitable for analysis. Description of participants varied over the years and by type of disorders and severity, and ranged from aged individuals with subjective memory disorders to patients with Vascular Cognitive Impairment (mild to moderate), Vascular Dementia or Senile Dementia (mild to moderate). Seven of the included studies observed the subjects for a period between 20 to 30 days, one study was of 6 weeks duration, four studies used periods extending over 2 and 3 months, one study observed continuous administration over 3 months and one study was prolonged, with 12 months of observation. The studies were heterogeneous in dose, modalities of administration, inclusion criteria for subjects, and outcome measures. Results were reported for the domains of attention, memory testing, behavioural rating scales, global clinical impression and tolerability. There was no evidence of a beneficial effect of CDP-choline on attention. There was evidence of benefit of CDP-choline on memory function and behaviour. The drug was well tolerated. AUTHORS' CONCLUSIONS: There was some evidence that CDP-choline has a positive effect on memory and behaviour in at least the short to medium term. The evidence of benefit from global impression was stronger, but is still limited by the duration of the studies. Further research with CDP-choline should focus on longer term studies in subjects who have been diagnosed with currently accepted standardised criteria, especially Vascular Mild Cognitive Impairment (VaMCI) or vascular dementia.

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Mov Disord. 2005 Apr 18; [Epub ahead of print]
Comparison of the effects of a self-supervised home exercise program with a physiotherapist-supervised exercise program on the motor symptoms of Parkinson's disease.
Lun V, Pullan N, Labelle N, Adams C, Suchowersky O.
University of Calgary Sport Medicine Centre, Faculty of Kinesiology, University of Calgary, Calgary, Alberta, Canada.

The effects of a self-supervised home exercise program and a physiotherapist-supervised exercise program on motor symptoms in Parkinson's disease (PD) patients were compared in a prospective single-blinded clinical trial. Nineteen subjects (6 women, 13 men; mean age, 65 +/- 8 years) with Hoehn and Yahr Stages 2 to 3 were recruited. Subjects were self-selected into an 8-week exercise program that was self-supervised (HOME group) or physiotherapist-supervised (PT group). The primary outcome measurement was the Unified Parkinson's Disease Rating Scale (UPDRS) Motor subsection score (UPDRSm). The secondary outcome measurements were the Berg Balance Scale, Timed Up and Go Test, UPDRS Total score, and the Activities-specific Balance Confidence Scale. All outcomes were assessed at baseline and at 8 and 16 weeks after the start of the study. The investigators were blinded to the subject treatment group. Bonferroni-corrected paired Student's t test was used to evaluate the change in the UPDRSm from baseline to 8 weeks. Ninety-five percent confidence intervals (CI) were calculated for the change in the secondary outcome measurements from baseline to 8 weeks. There was statistically significant and equal decrease in the UPDRSm from baseline to 8 weeks in both treatment groups. There was no difference in the 95% CI in the change of the secondary outcome measurements. A self-supervised exercise program was found to have similar effectiveness as a physiotherapist-supervised exercise program in improving motor symptoms in PD patients. This finding is important in the counseling of PD patients regarding adjunctive treatment of motor symptoms of PD with exercise. (c) 2005 Movement Disorder Society.

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Arch Phys Med Rehabil. 2005 Apr;86(4):626-32.
Efficacy of a physical therapy program in patients with Parkinson's disease: a randomized controlled trial.
Ellis T, de Goede CJ, Feldman RG, Wolters EC, Kwakkel G, Wagenaar RC.
Sargent College of Health and Rehabilitation Sciences, Department of Rehabilitation Sciences and Center for Neurorehabilitation, Boston University, MA 02215, USA. tellis@bu.edu

OBJECTIVE: To investigate the effects of a physical therapy (PT) program in groups of people with Parkinson's disease (PD). DESIGN: Randomized controlled trial with a crossover design. SETTING: Two outpatient rehabilitation clinics in Boston and Amsterdam, respectively. PARTICIPANTS: Sixty-eight subjects diagnosed with typical, idiopathic PD, Hoehn and Yahr stage II or III, and stable medication use. INTERVENTION: Group A received PT and medication therapy (MT) for the first 6 weeks, followed by MT only for the second 6 weeks. Group B received only MT for the first 6 weeks and PT and MT for the second 6 weeks. MAIN OUTCOME MEASURES: The Sickness Impact Profile (SIP-68), the mobility portion of the SIP-68, the Unified Parkinson's Disease Rating Scale (UPDRS), and comfortable walking speed (CWS) at baseline, 6-week, 12-week, and 3-month follow-up. RESULTS: At 6 weeks, differences between groups were significant for the SIP mobility ( P =.015; effect size [ES]=.55), for CWS ( P =.012; ES=.49), for the activities of daily living (ADL) section of the UPDRS ( P =.014; ES=.45), and for the total UPDRS ( P =.007; ES=.56). The total SIP and the mentation and motor sections of the UPDRS did not differ significantly between groups. Significant differences were found at 3 months compared with baseline for CWS, the UPDRS ADL, and total scores. CONCLUSIONS: People with PD derive benefits in the short term from PT group treatment, in addition to their MT, for quality of life related to mobility, CWS, and ADLs; long-term benefits were found in CWS, UPDRS ADL, and total scores but varied between groups.

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Neurosurg Rev. 2005 Apr 13; [Epub ahead of print]
Effect of subthalamic stimulation on mood state in Parkinson's disease: evaluation of previous facts and problems.
Takeshita S, Kurisu K, Trop L, Arita K, Akimitsu T, Verhoeff NP.
Kunin-Lunenfeld Applied Research Unit, Baycrest Centre for Geriatric Care, University of Toronto, Toronto, Ontario, Canada.

In an attempt to clarify the effect of deep brain stimulation (DBS) to the subthalamic nucleus (STN) on mood state, previous evidence and problems were evaluated through a systematic literature search. Twenty three articles reported the effect of STN DBS on mood state in Parkinson's disease (PD), and antidepressant, depressant, and mania-induced effects were reported in 16.7-76%, 2-33.3%, and 4.2-8.1% of the patients treated with STN DBS, respectively. Most articles reported larger subgroups showing antidepressant effects than those showing depressant effects. The average depression scale score of all subjects was improved or unchanged after STN DBS. Although there was a limitation due to the varied results, it was suggested that, in general, STN DBS had an antidepressant effect in PD. However, the studies reporting severe depressant symptoms, such as suicidal attempts, after STN DBS indicated the importance of careful attention to mood state as well as to motor symptoms after STN DBS. It may be crucial to reduce the variation in the results by, for example, the use of standardized protocols and the precise verification of the stimulated region in further investigations to address this issue.

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Expert Opin Biol Ther. 2005 Mar;5(3):289-91.
Cell therapies for neurological disease--from bench to clinic to bench.
Harrower T, Barker RA.

The lack of any meaningful regeneration in the adult central nervous system (CNS) subsequent to damage or degeneration stimulated the concept of replacement of the deficient cells by transplantation. Thus, much time and effort has been spent on investigating the potential of cell replacement therapy for repair in a range of conditions of the CNS over the last 25 years. As promising proof of principle basic science results were slowly converted to success in clinical transplantation trials in Parkinson's disease (PD), the future seemed very encouraging for cell therapy. However, the recent randomised, double-blind, placebo-controlled studies of fetal neural transplantation in PD have produced more equivocal results, which has dampened enthusiasm for this approach. However, whilst the translation of cell therapies to the clinic is in limbo, the emergence of stem cells as a source of the replacement tissue has revitalised the laboratory-based studies. This paper attempts to reconcile these disparate views and put forward the authors' view on the future of this form of biological therapy and its implications for related therapies.

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J Neurol Neurosurg Psychiatry. 2005 Feb;76(2):246-8.
Subthalamic nucleus stimulation in tremor dominant parkinsonian patients with previous thalamic surgery.
Fraix V, Pollak P, Moro E, Chabardes S, Xie J, Ardouin C, Benabid AL.
Department of Neurology, Grenoble University Hospital, BP 217, 38043 Grenoble cedex 9, France. valerie.fraix@ujf-grenoble.fr.

Before the introduction of high frequency stimulation of the subthalamic nucleus (STN), many disabled tremor dominant parkinsonian patients underwent lesioning or chronic electrical stimulation of the thalamus. We studied the effects of STN stimulation in patients with previous ventral intermediate nucleus (VIM) surgery whose motor state worsened. Fifteen parkinsonian patients were included in this study: nine with unilateral and two with bilateral VIM stimulation, three with unilateral thalamotomy, and one with both unilateral thalamotomy and contralateral VIM stimulation. The clinical evaluation consisted of a formal motor assessment using the Unified Parkinson's Disease Rating Scale (UPDRS) and neuropsychological tests encompassing a 50 point frontal scale, the Mattis Dementia Rating Scale, and the Beck Depression Inventory. The first surgical procedure was performed a mean (SD) of 8 (5) years after the onset of disease. STN implantation was carried out 10 (4) years later, and duration of follow up after beginning STN stimulation was 24 (20) months. The UPDRS motor score, tremor score, difficulties in performance of activities of daily living, and levodopa equivalent daily dose significantly decreased after STN stimulation. Neither axial symptoms nor neuropsychological status significantly worsened after the implantation of the STN electrodes. The parkinsonian motor state is greatly improved by bilateral STN stimulation even in patients with previous thalamic surgery, and STN stimulation is more effective than VIM stimulation in tremor dominant parkinsonian patients.

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Curr Gene Ther. 2005 Jan;5(1):71-80.
Gene therapy for Parkinson's disease: progress and challenges.
Chen Q, He Y, Yang K.
Department of Neurosurgery, Baylor College of Medicine, Houston, Texas, 77030 USA. qchen1@bcm.tmc.edu.

Therapy for Parkinson's disease (PD), a common neurological disorder characterized by pathological degeneration of the nigrostriatal dopaminergic system, remains unsatisfactory. Gene therapy is considered one of the most promising approaches to developing a novel effective treatment for PD. Among the numerous candidate genes that have been tested as therapeutic agents, those encoding tyrosine hydroxylase, guanosine triphosphate cyclohydrolase I and aromatic L-amino acid decarboxylase all boost dopamine production, while glial cell line-derived neurotrophic factor promotes the survival of dopaminergic neurons and is generally believed to possess the greatest potential for successful restoration of the dopaminergic system. The genes encoding vesicular monoamine trans