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 transporter-2 and glutamic acid decarboxylase have also produced therapeutic effects in animal models of PD. Both viral and non-viral vectors, each with its particular advantages and disadvantages, have been used to deliver these genes into the brain. Whether or not regulatable expression systems are essential to successful gene therapy for PD remains a critical issue in the clinical application of this emerging treatment. Here we review the current status of gene therapy for PD, including the application of control systems for transgene expression in the brain.

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Eur J Neurol. 2005 Jan;12(1):9-15.
Cognitive performance in people with Parkinson's disease and mild or moderate depression: effects of dopamine agonists in an add-on to l-dopa therapy.
Rektorova I, Rektor I, Bares M, Dostal V, Ehler E, Fanfrdlova Z, Fiedler J, Klajblova H, Kulist'ak P, Ressner P, Svatova J, Urbanek K, Veliskova J.
First Department of Neurology, Masaryk University, St Anne's Teaching Hospital, Brno, Czech Republic.

In a randomized prospective multi-centre study, we evaluated the cognitive performances of a group of 41 non-demented patients, all with advanced Parkinson's disease (PD) and a current depressive episode, in whom the effects of pramipexole (PPX) and pergolide (PRG) in an add-on to l-dopa therapy were also studied and published with regard to motor symptoms of PD, motor complications and depression. The Trail Making Test, the Stroop test and four subtests (arithmetic, picture completion, digit symbols and similarities) of the Wechsler Adult Intelligence Scale-Revised were performed prior to and 8 months after the administration of either PPX or PRG. We found no statistically significant difference between the two tested drugs or between the first and the last visit in any of the above-listed neuropsychological tests. All patients' motor outcomes significantly improved and we conclusively demonstrated the anti-depressive effect of PPX. The dissociation of dopaminomimetic effects on the different tested domains indicates that there are different pathological mechanisms of cognitive, motor and affective disturbances in advanced PD patients. In our non-demented group of fluctuating depressed PD subjects, both PPX and PRG administration in combination with l-dopa were safe in terms of the effect on cognitive performance.

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J Neurol Neurosurg Psychiatry. 2005 Jan;76(1):34-9.
Different patterns of medication change after subthalamic or pallidal stimulation for Parkinson's disease: target related effect
or selection bias?
Minguez-Castellanos A, Escamilla-Sevilla F, Katati MJ, Martin-Linares JM, Meersmans M, Ortega-Moreno A, Arjona V.
Servicio de Neurologia, Hospital Virgen de las Nieves, CRT 3 planta, Carretera de Jaen s/n, 18013 Granada, Spain. aminguezc@meditex.es

BACKGROUND: Bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) is favoured over bilateral globus pallidus internus (Gpi) DBS for symptomatic treatment of advanced Parkinson's disease (PD) due to the possibility of reducing medication, despite lack of definitive comparative evidence. OBJECTIVE: To analyse outcomes after one year of bilateral Gpi or STN DBS, with consideration of influence of selection bias on the pattern of postsurgical medication change. METHODS: The first patients to undergo bilateral Gpi (n = 10) or STN (n = 10) DBS at our centre were studied. They were assessed presurgically and one year after surgery (CAPIT protocol). RESULTS: Before surgery the Gpi DBS group had more dyskinesias and received lower doses of medication. At one year, mean reduction in UPDRS off medication score was 35% and 39% in the Gpi and STN groups, respectively (non-significant difference). Dyskinesias reduced in proportion to presurgical severity. The levodopa equivalent dose was significantly reduced only in the STN group (24%). This study high-lights the absence of significant differences between the groups in clinical scales and medication dose at one year. In the multivariate analysis of predictive factors for off-state motor improvement, the presurgical levodopa equivalent dose showed a direct relation in the STN and an inverse relation in the Gpi group. CONCLUSION: Differences in the patterns of medication change after Gpi and STN DBS may be partly due to a patient selection bias. Both procedures may be equally useful for different subgroups of patients with advanced PD, Gpi DBS especially for patients with lower threshold for dyskinesia.

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J Mol Neurosci. 2004;24(3):353-86.
Embryonic and adult stem cells as a source for cell therapy in Parkinson's disease.
Levy YS, Stroomza M, Melamed E, Offen D.
Laboratory of Neurosciences, Felsenstein Medical Research Center, and Department of Neurology, Rabin Medical Center-Beilinson Campus, Petah Tiqva; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

The rationale behind the use of cells as therapeutic modalities for neurodegenerative diseases in general, and in Parkinson's disease (PD) in particular, is that they will improve patient's functioning by replacing the damaged cell population. It is reasoned that these cells will survive, grow neurites, establish functional synapses, integrate best and durably with the host tissue mainly in the striatum, renew the impaired wiring, and lead to meaningful clinical improvement. To increase the generation of dopamine, researchers have already transplanted non-neuronal cells, without any genetic manipulation or after introduction of genes such as tyrosine hydroxylase, in animal models of PD. Because these cells were not of neuronal origin, they developed without control, did not integrate well into the brain parenchyma, and their survival rates were low. Clinical experiments using cell transplantation as a therapy for PD have been conducted since the 1980s. Most of these experiments used fetal dopaminergic cells originating in the ventral mesencephalic tissue obtained from fetuses. Although it was shown that the transplanted cells survived and some patients benefited from this treatment, others suffered from severe dyskinesia, probably caused by the graft's excessive and uncontrolled production and release of dopamine. It is now recognized that cell-replacement strategy will be effective in PD only if the transplanted cells have the same abilities, such as dopamine synthesis and control release, reuptake, and metabolizing dopamine, as the original dopaminergic neurons. Recent studies on embryonic and adult stem cells have demonstrated that cells are able to both self-renew and produce differentiated tissues, including dopaminergic neurons. These new methods offer real hope for tissue replacement in a wide range of diseases, especially PD. In this review we summarize the evidence of dopaminergic neuron generation from embryonic and adult stem cells, and discuss their application for cell therapy in PD.

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Ann Urol (Paris). 2004 Dec;38 Suppl 2:S57-61.
[Bladder sphincter disorders in Parkinson's disease]
[Article in French]
Soler JM, Le Portz B.
Centre de Bouffard-Vercely, Cap Peyrefite, 66290 Cerbere, France. jmsoler66@aol.com

Parkinson's disease related to degeneration of the extrapyramidal structures is characterized in its typical form by the classic triad of tremors, rigidity and akinesia, constituting Parkinson's syndrome. These are combined with neurovegetative disorders, responsible for sexual and bladder sphincter dysfunction. The Latter occurs in from 30% to 90% of cases, depending on the stage of progression of the disease. The dopamine deficiency in the nigrostriataL tract leads to a lifting of the inhibition which is probably the cause of the bladder hyperreflexia. Irritative signs are most frequently observed. The flowmetry data are contradictory, depending on the publication whereas the bladder overactivity, objectified by cystomanometry, is described in most of the studies although certain authors report, on the contrary, bladder hypoactivity. Conflicting data have also been published on bladder sphincter dyssynergia although in most studies, micturition was described as synergic in Parkinson's disease patients. L-dopa, the main drug for Parkinson's disease, has, according to the publication, either no action, or contradictory effects with bladder hypoactivity or hyperactivity. Anticholinergics are effective on overactive bladder, the alphablockers on the urethral hypertonia at the price of a higher risk of arterial hypotension in this diathesis. The indication for prostatic surgery must be carefully considered and preceded by precise clinical, urodynamic and sometimes electromyography evaluation. There is a high risk of post surgical incontinence. Endourethral prostheses provide an attractive alternative in the case of prostatic obstruction.

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N Engl J Med. 2004 Dec 9;351(24):2509-18.
Rivastigmine for dementia associated with Parkinson's disease.
Emre M, Aarsland D, Albanese A, Byrne EJ, Deuschl G, De Deyn PP, Durif F, Kulisevsky J, van Laar T, Lees A, Poewe W, Robillard A, Rosa MM, Wolters E, Quarg P, Tekin S, Lane R.
Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey. muratemre@superonline.com

BACKGROUND: Cholinergic deficits are prominent in patients who have dementia associated with Parkinson's disease. We investigated the effects of the dual cholinesterase inhibitor rivastigmine in such patients. METHODS: Patients in whom mild-to-moderate dementia developed at least 2 years after they received a clinical diagnosis of Parkinson's disease were randomly assigned to receive placebo or 3 to 12 mg of rivastigmine per day for 24 weeks. Primary efficacy variables were the scores for the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog) and Alzheimer's Disease Cooperative Study-Clinician's Global Impression of Change (ADCS-CGIC). Secondary clinical outcomes were the scores for the Alzheimer's Disease Cooperative Study-Activities of Daily Living, the 10-item Neuropsychiatric Inventory, the Mini-Mental State Examination, Cognitive Drug Research power of attention tests, the Verbal Fluency test, and the Ten Point Clock-Drawing test. RESULTS: A total of 541 patients were enrolled, and 410 completed the study. The outcomes were better among patients treated with rivastigmine than among those who received placebo; however, the differences between these two groups were moderate and similar to those reported in trials of rivastigmine for Alzheimer's disease. Rivastigmine-treated patients had a mean improvement of 2.1 points in the score for the 70-point ADAS-cog, from a baseline score of 23.8, as compared with a 0.7-point worsening in the placebo group, from a baseline score of 24.3 (P<0.001). Clinically meaningful improvements in the scores for the ADCS-CGIC were observed in 19.8 percent of patients in the rivastigmine group and 14.5 percent of those in the placebo group, and clinically meaningful worsening was observed in 13.0 percent and 23.1 percent, respectively (mean score at 24 weeks, 3.8 and 4.3, respectively; P=0.007). Significantly better outcomes were seen with rivastigmine with respect to all secondary efficacy variables. The most frequent adverse events were nausea (affecting 29.0 percent of patients in the rivastigmine group and 11.2 percent of those in the placebo group, P<0.001), vomiting (16.6 and 1.7 percent, P<0.001), and tremor (10.2 and 3.9 percent, P=0.01). CONCLUSIONS: In this placebo-controlled study, rivastigmine was associated with moderate improvements in dementia associated with Parkinson's disease but also with higher rates of nausea, vomiting, and tremor. Copyright 2004 Massachusetts Medical Society.

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Rinsho Shinkeigaku. 2004 Nov;44(11):951-3.
[Cell therapy in Parkinson's disease]
[Article in Japanese]
Shingo T.
Department of Neurological Surgery, Okayama University Graduate School of Medicine & Dentistry.

An approach for symptomatic Parkinson's disease (PD) therapy is fetal dopamine neuron transplantation. This approach remains the technical and ethical difficulties in obtaining sufficient and appropriate donor fetal brain tissue. In developments of stem cell biology, neural stem cells exist in the adult brain as well as embryo and have the capacity to regenerate and to give rise to the three cell lineages in the nervous system. Embryonic stem cells (ES cells) and multipotent adult progenitor cells (MAPCs) are pluripotent cells, which give rise to all cells in the organism. Current findings suggest that stem cells but not fetal brain tissues may be suitable for cell replacement therapies in the treatment of neurodegenerative disorders. We will briefly review the current state of cell therapy, and will critically discuss the potential of stem cells for the treatment of PD.

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Rinsho Shinkeigaku. 2004 Nov;44(11):830-2.
[Comment on guidelines for treatment of Parkinson's disease]
[Article in Japanese]
Kondo T.
Department of Neurology, Wakayama Medical University.

The guidelines for the therapy of Parkinson's disease (PD) based on the concept of evidence-based medicine (EBM) were edited by the Japanese Society of Neurology in 2002. The author described his impression of these guidelines from a user's viewpoint after using these guidelines. In the chapter on the therapeutic efficacy and safety of drugs, compared with other antiparkinsonian drugs, levodopa seems to be only briefly described. Because the therapy of PD highly depends on the effect of levodopa, a more detailed description of levodopa will be helpful for neurologists. In the chapter on general and detailed discussions, the use of a dopamine agonist (DA) for young PD patients is recommended because DA prevents motor complications; this is the most emphasized part based on the concept of EBM in the guidelines. Measures of managing various complications based on various lines of evidence and experiences of members of Ad hoc committee for the treatment of PD are well documented in this chapter. In general, since the guidelines are technical ones, they clearly describe how to treat PD patients. For the effective use of these guidelines, neurologists should have the ability to correctly determine PD symptoms, some knowledge about the pharmacology of antiparkinsonian drugs particularly levodopa and DA, and balanced thinking regarding the management of PD patients.

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Int J Clin Pract. 2004 Nov;58(11):1028-32.
Diagnostic and therapeutic value of apomorphine in Parkinsonian patients.
Sharma JC, Macnamara L, Hasoon M, Vassallo M.
Mansfield Community Hospital, Mansfield, Nottinghamshire, UK. jagdish.sharma@sfh-tr.nhs.uk

Apomorphine is a dopamine agonist administered subcutaneously for the management of motor symptoms of Parkinson's disease (PD). Patients with Parkinsonian syndrome underwent an apomorphine challenge for therapeutic efficacy, a positive response being a reduction of > 15% score on motor unified PD rating scale. Of the 42 patients, aged 37-81, disease duration 12 months to 20 years, 36 had a positive response. Six non-responders were later diagnosed as non-PD as compared with only two of the 36 responders. Tremor-predominant patients obtained higher motor response. Few patients demonstrated a delayed positive response. Seven (three idiopathic PD (iPD), four non-PD) suffered adverse reactions of nausea, vomiting or ill-sustained symptomatic fall in BP. Majority of the patients who continued with apomorphine therapy were able to reduce levodopa and achieved an improvement in dyskinesia and motor symptoms. Thirteen responding patients were managed by increasing dopamine agonists. Five patients, intolerant of oral dopamine agonists, were able to beneficially tolerate apomorphine. Age and disease duration did not influence tolerability or efficacy. The patients treated with apomorphine were able to significantly reduce the dose of levodopa, and there was a reduction in dyskinesia, hallucinations and fluctuations (all p < 0.05). In some patients, apomorphine prevented admission to institutions. We also describe the use of apomorphine in acutely ill patients unable to ingest oral medication. Apomorphine seems to have a diagnostic element for iPD. Its use leads to a reduction in dyskinesia, improvement in motor symptoms and prevention of institutional care. Apomorphine test also identifies patients likely to benefit with an increase in oral medication. Age and disease duration should not prevent the use of this valuable drug. Apomorphine also has a role in acutely ill PD patients.

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J Neurol. 2004 Nov;251(11):1370-4.
A 10 year retrospective audit of long-term apomorphine use in Parkinson's disease.
Tyne HL, Parsons J, Sinnott A, Fox SH, Fletcher NA, Steiger MJ.
The University of Liverpool, UK.

OBJECTIVES. Apomorphine is a potent dopamine agonist useful in the treatment of Parkinson's disease patients with disabling motor fluctuations and 'off' periods, not responding to oral medication. It can also be of benefit in reducing dyskinesia by providing more constant dopaminergic stimulation and permitting lower levodopa dosage. However, there is a paucity of information on long-term benefits of apomorphine, including no large-scale phase III trial. We have examined our experience of apomorphine over the last 10 years, to assess indications, pattern of use, efficacy, and side effect profile. METHODS. All patients requiring apomorphine were identified through the Parkinson's disease Nurse Specialist's records. An audit form was produced so that the same information was gathered from all case-notes. RESULTS. There were 107 patients (61 males and 46 females). Mean age of disease onset was 50.9 years, SD+/-9.3 (range 29-78). The mean duration of disease at start of apomorphine treatment was 10 years (SD+/-4.8, range2-29). The most common indications for apomorphine were severe unpredictable 'off' periods (75.7 %), motor fluctuations (18.7 %) and dyskinesia (5.6 %). Most patients (63.6 %) used both intermittent subcutaneous injections and infusion via pump; 25.2% were on intermittent injection, and 11.2 % infusion alone. Mean dose per injection was 3.7mg. Mean infusion dose 69.8mg, running over a mean of 13.5 hours. The mean duration of intermittent apomorphine use was 48.2 months. The mean duration of infusion was 25.1 months. Complications included skin problems in 16 patients, 2 had symptomatic hypotension, 2 worsening confusion, 1 new confusion and 5 new hallucinations (after sometime on apomorphine). Sixteen patients have stopped using apomorphine completely. Thirteen have stopped the pump, but continue on intermittent injections. CONCLUSION. Subcutaneous apomorphine is easy for patients to use, is well tolerated and has a low incidence of side effects, especially confusion.

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Br J Clin Pharmacol. 2004 Nov;58 Suppl 1:41-9.
Concurrent administration of donepezil HCl and levodopa/carbidopa in patients with Parkinson's disease: assessment of pharmacokinetic changes and safety following multiple oral doses.
Okereke CS, Kirby L, Kumar D, Cullen EI, Pratt RD, Hahne WA.
Clinical Pharmacology, Eisai Medical Research Inc., Ridgefield Park, NJ, USA.

Aim The use of acetylcholinesterase inhibitors for the treatment of comorbid Alzheimer's disease in Parkinson's disease (PD) patients stabilized on a levodopa regimen may potentially disrupt cholinergic balance. This randomized, double-blind, crossover study investigated the safety of, and possible drug-drug interaction between, donepezil HCl and levodopa/carbidopa. Methods Twenty-five patients with PD who were taking physician-optimized doses of levodopa/carbidopa (with daytime dosing intervals of 4-8 h) were administered once-daily doses of either donepezil HCl (5 mg) or placebo for 15 days, in two treatment periods, separated by a washout of at least 2 weeks. Some patients took a second dose of levodopa/carbidopa after 4 h, therefore subanalysis of the levodopa/carbidopa data was conducted up to 4 h and 8 h after dosing. Twenty-six healthy matched controls received open-label donepezil HCl only, for a single 15-day period. Blood samples were collected before, during and after the 15 doses of donepezil HCl for pharmacokinetic (PK) assessments. Pharmacokinetic parameters included maximum attained plasma drug concentration (C(max)), time at which C(max) is attained (t(max)), plasma drug concentration at steady state (C(ss)), and area under the drug concentration-time curve over the dosing interval. Safety assessments included monitoring adverse events, and the Unified Parkinson's Disease Rating Scale (UPDRS) motor examination. Results The mean age of all subjects was 72.6 +/- 1.3 years. Donepezil PK assessments of PD patients receiving levodopa/carbidopa were similar to the PK results from healthy controls who received donepezil HCl only (mean AUC(0-12 h)= 281.6 +/- 17.6 and 268.6 +/- 19.9 ng.h ml(-1), respectively). Carbidopa PK were not significantly altered by the concomitant administration of multiple doses of donepezil HCl, compared with when PD patients received placebo (mean AUC(0-8 h)= 921.8 +/- 160 and 821.8 +/- 113 ng.h ml(-1), respectively). Four hours after administration of donepezil HCl in PD patients, AUC(0-4 h), C(max) and C(ss) of levodopa were higher than when PD patients received placebo (P < 0.05). Eight hours after donepezil HCl, however, only C(max) and t(max) were observed to change compared with when PD patients received placebo (mean C(max) = 2652 +/- 429 and 2077 +/- 276 ng ml(-1), respectively; mean t(max) = 1.7 +/- 0.4 and 2.9 +/- 0.5 h, respectively; P</= 0.05). The number of PD patients who experienced at least one adverse event during the study (13/25) was higher when they received donepezil HCl than when they received placebo (5/25), but was the same as healthy subjects who received donepezil HCl only (13/26). There were no significant differences in change from baseline on the UPDRS motor examination parameters in PD patients when they took donepezil HCl and when they took placebo. Conclusions No clinically significant drug-drug interactions between donepezil HCl and levodopa/carbidopa were observed at steady state. The small changes in the pharmacokinetics of levodopa did not result in any change in motor symptoms. Co-administration of the two drugs led to a small increase in adverse events compared with administration of levodopa/carbidopa alone in PD patients. These adverse events, however, were consistent with donepezil's cholinomimetic effect, and their incidence was comparable to that observed following the administration of donepezil HCl alone.

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J Neural Transm. 2004 Oct-Nov;111(10-11):1333-41. Epub 2004 May 12.
Effects of levodopa on cognitive functioning in moderate-to-severe Parkinson's disease (MSPD).
Morrison CE, Borod JC, Brin MF, Halbig TD, Olanow CW.
Comprehensive Epilepsy, New York University Medical Center, New York, NY, USA.

Although improved cognition has been reported in patients with mild Parkinson's disease (PD) following the administration of levodopa, mixed results have been found in moderately-to-severely affected PD patients (MSPD), particularly in studies conducted since 1980. In the present study, 16 MSPD patients were tested on separate days, once following overnight levodopa withdrawal and once while optimally treated. A battery of neuropsychological tests that assess a range of cognitive functions (i.e., attention, language, visuospatial, memory, and executive), as well as a measure of depression, were used. Although patients performed better on a measure of confrontation naming in the untreated than in the treated condition, there were no significant differences for any of the other cognitive variables or for the depression scale variable. Thus, these data suggest that there are generally no adverse or beneficial effects of levodopa therapy on cognition in MSPD patients.

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J Neural Transm. 2004 Oct 22 [Epub ahead of print]
An open-label evaluation of the tolerability and safety of Stalevo(R) (carbidopa, levodopa and entacapone) in Parkinson's disease patients experiencing wearing-off.
Koller W, Guarnieri M, Hubble J, Rabinowicz AL, Silver D.
Mount Sinai Medical Center, New York, NY, USA.

Objectives: To evaluate the tolerability, safety and efficacy of Stalevo(R) (carbidopa, levodopa and entacapone) in Parkinson's disease (PD). Background: Levodopa provides the most effective symptom control for the treatment of Parkinson's disease (PD). However, its long-term use is limited by the development of motor complications such as wearing-off. Catechol-O-methyltransferase (COMT) inhibitors such as entacapone extend the plasma half-life of levodopa and reduce 'off' time. Stalevo is a new levodopa product that combines carbidopa, levodopa and entacapone in one tablet. Clinical studies have not been reported with this compound. Design methods: An open-label, multi-center US trial evaluated 169 consecutive PD patients experiencing end-of-dose wearing-off, with (n = 39) and without (n = 130) mild dyskinesia. Patients were switched from immediate-release carbidopa/levodopa to Stalevo and were treated for four weeks. Assessments included tolerability measures, adverse events profile, the disease-specific quality of life instrument PDQ-39, UPDRS parts II, III, and question 39 and investigator and patient global clinical assessments. Results: 14 subjects (8%) discontinued treatment with Stalevo, of which 12 (7%) were due to adverse events. 11/130 (8.5%) subjects developed new onset dyskinesia and 17/39 (43.6%) of patients with existing dyskinesia reported a worsening in their dyskinesia. However, this was managed by a change in dose in 21.4% of patients and in another 10.7% dyskinesias resolved without any need for dose adjustment. Other side effects were infrequent and mild, the most common being nausea (12.4%) dizziness (6.5%) and somnolence (6.5%). Stalevo treatment resulted in significant improvements in PDQ-39 and UPDRS (II + III) scores (p < 0.001). Assessment of 'off' time demonstrated a reduction in off time in 32% of patients, compared with an increase in 7% of patients. Improvements were noted by both investigator (68.1%) and patient (68.6%) assessments. Conclusions: Switching PD patients experiencing wearing-off from carbidopa/levodopa therapy to Stalevo was safe, well tolerated and resulted in clinical improvement.

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Arch Neurol. 2004 Oct;61(10):1563-8.
Double-blind, Placebo-Controlled Study of Entacapone in Levodopa-Treated Patients With Stable Parkinson Disease.
Olanow CW, Kieburtz K, Stern M, Watts R, Langston JW, Guarnieri M, Hubble J.
Author Affiliations: Department of Neurology, Mount Sinai School of Medicine, New York, NY.

BACKGROUND: The catechol O-methyltransferase inhibitor entacapone acts by extending the elimination half-life of levodopa and is currently approved as an adjunct to levodopa for the treatment of patients with Parkinson disease (PD) with motor fluctuations. OBJECTIVE: To determine if the addition of entacapone administration provides benefit to levodopa-treated PD patients who have a stable response to levodopa and do not experience motor complications. DESIGN: Prospective, double-blind, placebo-controlled trial. SETTING: Outpatient multicenter study.Patients Female and male patients 30 years or older with idiopathic PD receiving stable doses of levodopa or carbidopa with or without other dopaminergic therapies and who did not experience motor fluctuations were eligible for the study. MAIN OUTCOME MEASURES: Parkinsonian function and quality of life. RESULTS: The addition of entacapone did not improve motor scores on the Unified Parkinson's Disease Rating Scale in levodopa-treated PD patients who did not experience motor fluctuations. The mean +/- SE adjusted change between baseline and final treatment visit was -0.9 +/- 0.35 in the entacapone group and -0.8 +/- 0.35 in the placebo group (P = .83). Significant improvement with entacapone treatment was detected in several quality-of-life measures, including the Parkinson Disease Questionnaire 39, the 36-item Short-Form Health Survey, the Parkinson's Symptom Inventory, and investigator and subject Clinical Global Assessments. The drug was well tolerated by patients in this population. CONCLUSIONS: The catechol O-methyltransferase inhibitor entacapone, used as an adjunct to levodopa in PD patients who do not experience motor fluctuations, does not improve Unified Parkinson's Disease Rating Scale motor scores but does improve a variety of quality-of-life measures.

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Nippon Rinsho. 2004 Sep;62(9):1701-8.
[Treatment for patients with early Parkinson's disease]
[Article in Japanese]
Kikuchi S.
Department of Neurology, Hokkaido University Graduate School of Medicine.

Ad hoc committee of Japanese Neurological Society made a guideline for the treatment of Parkinson's disease in 2002. Based on the chapter of treatment for early Parkinson's disease, starting drugs were discussed in this article. Three points should be considered in initiating the drug treatment, that is, neuroprotection, motor complications, and side effects. In order to demonstrate neuroprotection of dopamine agonists by using neuroimaging techniques, CALM-PD CIT study (pramipexole) and REAL-PET study (ropinirole) were done. There are, however, many controversies concerning neuroprotection and no definite conclusion was drawn. On the contrary, the inhibitory effects of dopamine agonists on the appearance of motor complications were clearly elucidated by several large-scale studies. For the present, although the side effects were reported more frequently in those treated by dopamine agonists than by levodopa, starting the treatment by dopamine agonists were recommended except in patients with dementia and in elderly patients, for whom levodopa should be used first.

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Nippon Rinsho. 2004 Sep;62(9):1691-5.
[Indication of surgical therapy for Parkinson's disease]
[Article in Japanese]
Katayama Y, Kobayashi K.
Department of Neurological Surgery, Nihon University School of Medicine and Division of Applied System Neuroscience, Graduate School of Medical Science.

We review the current status of surgical treatment of Parkinson's disease (PD). The advantages of deep brain stimulation (DBS) over ablative surgery include reversibility and controllability of stimulation. In addition, DBS carries a smaller risk of side effects, especially when employed bilaterally. DBS of the thalamus is useful to control tremor which is unresponsive to medication. DBS of the globus pallidus internus (GPi) or the subthalamic nucleus (STN) is useful to control wearing off of motor symptoms which is difficult to manage with medication alone. DBS of STN and GPi improves motor function mainly during the off-period. DBS of STN attenuates levodopa-induced dyskinesia through reduction of dopa requirement, whereas DBS of GPi attenuates dopa-induced dyskinesia directly. DBS of STN is also useful to control symptoms of PD in patients who are intolerant to dopa. However, DBS of either STN or GPi cannot reverse advanced symptoms of PD, which are unresponsive to dopa.

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Nippon Rinsho. 2004 Sep;62(9):1685-90.
[Stereotactic operation for Parkinson's disease]
[Article in Japanese]
Yokochi F.
Department of Neurology, Tokyo Metropolitan Neurological Hospital.

The aim of stereotactic operation for Parkinson's disease is to improve or keep daily activity or quality of life by ablation or improvement of some parkinsonian symptoms. All of parkinsonian symptoms are not improved by stereotactic operation and classify roughly into three categories. The symptoms which are definitely improved are tremor, rigidity, L-dopa-induced dyskinesia, bradykinesia (secondary bradykinesia caused by rigidity) and wearing off phenomenon. Freezing gait, postural instability or postural abnormality is improved in some patients, but not always. Disturbance of speech or swallowing, L-dopa non-responsive akinesia, psychiatric symptoms or autonomic disturbances are not expected to be improved. Before stereotactic operation symptoms which cause disabilities of patients should be carefully examined. Aim of stereotactic operation should make clear and not ambiguous.

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Curr Opin Neurol. 2004 Aug;17(4):399-404.
Dementia in Parkinson's disease: cause and treatment.
Emre M.
Istanbul Faculty of Medicine, Department of Neurology, Behavioral Neurology and Movement Disorders Unit, Capa Istanbul, Turkey.

PURPOSE OF REVIEW: Dementia in Parkinson's disease is increasingly being recognized. A number of studies have recently appeared on the epidemiology, clinical features, pathological correlations and treatment of dementia in Parkinson's disease. The purpose of this article is to provide an overview of recent findings on dementia associated with Parkinson's disease, from February 2003 to the present. RECENT FINDINGS: The cumulative prevalence of dementia in Parkinson's disease can be as high as 78%; dementia is especially prevalent in older patients. The profile of dementia seems to be different from that of Alzheimer's disease and similar to that of dementia with Lewy bodies. Clinicopathological correlation studies have suggested that dementia correlates best with Lewy bodies in certain limbic and cortical areas, but not all patients with sufficient Lewy bodies for a pathological diagnosis of dementia with Lewy bodies are demented. Cholinergic deficits in the cerebral cortex can be shown with in-vivo imaging studies, and seem to be more severe than in Alzheimer's disease. Several small studies with three different cholinesterase inhibitors suggest that these drugs can be effective in the treatment of PD dementia. SUMMARY: Dementia is highly prevalent in Parkinson's disease. The prototype of dementia in Parkinson's disease is a dysexecutive syndrome with impaired attention, executive functions and secondarily impaired memory. Neurochemically the most significant deficit seems to be cholinergic; dementia seems to correlate best with cortical and limbic Lewy bodies. Preliminary evidence suggests that cholinesterase inhibitors may be effective in Parkinson's disease dementia, and the results of large-scale, randomized and controlled studies are awaited to confirm these findings.

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Curr Opin Neurol. 2004 Aug;17(4):393-398.
Dopamine dysregulation syndrome in Parkinson's disease.
Evans AH, Lees AJ.
Reta Lila Weston Institute of Neurological Studies, University College London, The National Hospital for Neurology and Neurosurgery, London, UK.

PURPOSE OF REVIEW: Dopamine replacement therapy in Parkinson's disease ameliorates motor symptoms. However, it has recently been recognized that a small sub-group of patients suffer motor and behavioural disturbances attributable to taking quantities of medication well beyond the dose required to treat their motor disabilities. This review examines the phenomenology of dopamine dysregulation syndrome in relation to the current understanding of basal ganglia function and its impact on long-term management. RECENT FINDINGS: Cortico-striato-thalamic circuits are implicated in the behavioural and motor disturbances associated with compulsive medication use in Parkinson's disease. Advances in understanding of the role of dopamine in psychostimulant addiction are important in helping to understand dopamine dysregulation. SUMMARY: Recognition of dopamine dysregulation syndrome and characterization of its phenomenology supports the notion that the medication used to treat Parkinson's disease can disrupt basal ganglia mediated motor and behavioural functioning. Refinement of clinical strategies to predict, identify and manage this syndrome will aid the future treatment of motor and non-motor complications of Parkinson's disease.

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Exp Neurol. 2004 Aug;188(2):491-4.
Pilot trial of high dosages of coenzyme Q(10) in patients with Parkinson's disease.
Shults CW, Flint Beal M, Song D, Fontaine D.
Department of Neurology and Neuroscience, New York-Presbyterian Hospital, Weill Medical College of Cornell University, New York, NY 10021, USA.

The safety and tolerability of high dosages of coenzyme Q(10) were studied in 17 patients with Parkinson's disease (PD) in an open label study. The subjects received an escalating dosage of coenzyme Q(10)-1200, 1800, 2400, and 3000 mg/day with a stable dosage of vitamin E (alpha-tocopherol) 1200 IU/day. The plasma level of coenzyme Q(10) was measured at each dosage. Thirteen of the subjects achieved the maximal dosage, and adverse events were typically considered to be unrelated to coenzyme Q(10). The plasma level reached a plateau at the 2400 mg/day dosage and did not increase further at the 3000 mg/day dosage. Our data suggest that in future studies of coenzyme Q(10) in PD, a dosage of 2400 mg/day (with vitamin E/alpha-tocopherol 1200 IU/day) is an appropriate highest dosage to be studied.

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Brain. 2004 Jul 7 [Epub ahead of print]
Effects of subthalamic nucleus stimulation and medication on resting and postural tremor in Parkinson's disease.
Sturman MM, Vaillancourt DE, Verhagen Metman L, Bakay RA, Corcos DM.
Department of Movement Sciences, University of Illinois at Chicago, Chicago, IL, USA.

Summary: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) and antiparkinsonian medication have proved to be effective treatments for tremor in Parkinson's disease. To date it is not known how and to what extent STN DBS alone and in combination with antiparkinsonian medication alters the pathophysiology of resting and postural tremor in idiopathic Parkinson's disease. The purpose of this study was to examine the effects of STN DBS and antiparkinsonian medication on the neurophysiological characteristics of resting and postural hand tremor in Parkinson's disease. Resting and postural hand tremor were recorded using accelerometry and surface electromyography (EMG) from 10 Parkinson's disease patients and 10 matched control subjects. The Parkinson's disease subjects were examined under four treatment conditions: (i) off treatment; (ii) STN DBS; (iii) medication; and (iv) medication plus STN DBS. The amplitude, EMG frequency, regularity, and 1-8 Hz tremor-EMG coherence were analysed. Both STN DBS and medication reduced the amplitude, regularity and tremor-EMG coherence, and increased the EMG frequency of resting and postural tremor in Parkinson's disease. STN DBS was more effective than medication in reducing the amplitude and increasing the frequency of resting and postural tremor to healthy physiological levels. These findings provide strong evidence that effective STN DBS normalizes the amplitude and frequency of tremor. The findings suggest that neural activity in the STN is an important modulator of the neural network(s) responsible for both resting and postural tremor genesis in Parkinson's disease.

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Curr Neurol Neurosci Rep. 2004 Jul;4(4):290-5.
Deep brain stimulation in Parkinson's disease.
Lyons KE, Pahwa R.
Department of Neurology, University of Kansas Medical Center, 3599 Rainbow Boulevard, Mailstop 2012, Kansas City, KS 66160, USA. lyons.kelly@att.net

Throughout the past decade, there has been a marked increase in surgical therapies, primarily deep brain stimulation (DBS), for the treatment of advanced Parkinson's disease (PD). DBS of the thalamus has been shown to be effective in reducing parkinsonian tremor; however, it is not the treatment of choice for PD given the progression of other symptoms such as rigidity and bradykinesia. Stimulation of the globus pallidus or the subthalamic nucleus is safe and efficacious in the long-term treatment of all cardinal symptoms of PD, and they are currently the surgeries of choice. Serious adverse events with DBS can occur in 1% to 2% of patients, infection in 5% to 8% of patients, and hardware complications in approximately 25% of patients. Complications associated with DBS are related to the experience of the surgical center. Referring physicians and patients should be aware of the number of surgical procedures and complication rates of any prospective surgical center.

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Curr Neurol Neurosci Rep. 2004 Jul;4(4):277-83.
Neuroprotection in Parkinson's disease: an elusive goal.
Koller WC, Cersosimo MG.
Department of Neurology, The Mount Sinai Medical Center, One Gustave L. Levy Place, Annenberg 1494/Box 1137, New York, NY 10029-6574, USA. william.koller@mssm.edu

Parkinson's disease is a chronic progressive condition that causes disability and reduction of quality of life. Symptomatic treatments are effective in the early disease; however, with time, most patients develop motor complications. Neuroprotective therapies are those that can slow disease progression; unfortunately, these agents are not available. Advances in the knowledge of the possible pathogenic events that can lead to nigral cell death have increased dramatically. These mechanisms include oxidative stress, mitochondrial dysfunction, inflammation, excitotoxicity, alterations in protein degradation, and ultimately apoptosis. Based on these laboratory scientific findings, a number of agents have been studied in clinical trials. However, how to assess disease evolution and establish reliable endpoints is still an unresolved issue. The monoamine oxidase inhibitors selegiline and rasagiline have been shown to be neuroprotective in vitro and in animal models, but so far this property was not demonstrated in clinical trials. Other agents have been studied and still others are undergoing clinical investigation. These include antiexcitotoxicity drugs like riluzole, the bioenergetic agent coenzyme Q10, trophic factors, and antiapoptotic drugs. Laboratory and clinical data suggest that dopamine agonists may have a neuroprotective action, but this has yet to be proven. However, as our basic and clinical knowledge on Parkinson's disease increases, it is likely that a neuroprotective drug will be found.

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Altern Med Rev. 2004 Jun;9(2):211-214.
Withania somnifera - monograph.
[No authors listed]

Withania somnifera, also known as ashwagandha, Indian ginseng, or winter cherry, has been an important herb in the Ayurvedic and indigenous medical systems for over 3000 years. Historically, the plant has been used as an aphrodisiac, liver tonic, anti-inflammatory agent, astringent, and more recently to treat bronchitis, asthma, ulcers, emaciation, insomnia, and senile dementia. Clinical trials and animal research support the use of ashwaganda for anxiety, cognitive and neurological disorders, inflammation, and Parkinson's disease. Ashwaganda's chemopreventive properties make it a potentially useful adjunct for patients undergoing radiation and chemotherapy. Ashwaganda is also used therapeutically as an adaptogen for patients with nervous exhaustion, insomnia, and debility due to stress, and as an immune stimulant in patients with low white blood cell counts.

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Med Sci Monit. 2004 Jun 29;10(7):CR282-CR284. [Epub ahead of print]
Botulinum toxin type B for gait freezing in Parkinson's disease.
Fernandez HH, Lannon MC, Trieschmann ME, Friedman JH.
Department of Clinical Neuroscience, Brown University School of Medicine, Providence, RI, U.S.A.

Background: Freezing of Gait (FOG) can be a serious problem in Parkinson's disease (PD) and is usually refractory to medical treatment. Botulinum toxin (BTX) type A has been reported to relieve FOG in small open label studies. Material/Methods: We performed a double-blind, placebo-controlled, parallel-group study using BTX-B injections on the soleus-gastrocnemius muscle complex of the predominantly affected leg in freezing. Patients were evaluated at baseline and monthly thereafter until endpoint was reached. UPDRS parts II and III, Visual Analog Scale (VAS), Clinical Global Impression Scale (CGIS) and Modified Webster Step-Seconds test were the used to measure efficacy. Results: 14 out of 17 patients screened with idiopathic PD and FOG refractory to medical treatment met inclusion criteria for the study. 9 patients were randomized to 5,000 U of BTX-B treatment and 5 patients to placebo. Our cohort had a mean age of 74 years, and average PD duration of 10 years. Based on the CGIS, 1 patient was much improved, 2 patients had minimal improvement, 9 were unchanged from baseline and 2 were minimally worse. There was no significant difference between the treatment and placebo arms in the number of patients improved versus unchanged. There were no significant differences between the treatment and placebo arms in the UPDRS II and III, VAS, or Modified Webster Step-Seconds scores between the treatment and placebo arms, at baseline and after treatment. Conclusions: 5,000 U of BTX-B injected in one leg did not significantly improve FOG. However, since the power of the study was low, a small beneficial effect may have been missed.

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Sci Aging Knowledge Environ. 2004 Jun 23;2004(25):NF61.
Stem cell savior.
Leslie M.

Stem cells are like the first players picked in the NBA draft—everyone expects wonders from them. A new study reveals a compound that might help stem cells live up to their promise in treating Parkinson's disease (PD). By reducing damage inflicted by a traditional PD treatment, the drug might allow patients to benefit from the standard therapy and stem cells.

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Arch Neurol. 2004 Jun;61(6):886-8.
Postmenopausal estrogen use affects risk for Parkinson disease.
Currie LJ, Harrison MB, Trugman JM, Bennett JP, Wooten GF.
Department of Neurology, School of Medicine, University of Virginia Health System, Charlottesville, VA 22908, USA. ljc3u@virginia.edu

BACKGROUND: Although estrogen therapy has been associated with improved cognitive functioning, a reduced risk of dementia in women with Parkinson disease (PD), and a decreased risk of Alzheimer disease, estrogen therapy has not affected the risk of PD per se. OBJECTIVE: To determine whether postmenopausal women with PD differed from control subjects with regard to estrogen exposure.Design, Setting, and Patients A case-control design was used, abstracting questionnaire data obtained via interview from 133 female PD cases and 128 female controls during routine outpatient clinic visits in 1999 at a mid-Atlantic tertiary care referral center. There were 140 subjects (68 PD cases and 72 controls) who met the inclusion criteria.Main Outcome Measure Use of postmenopausal estrogen therapy. RESULTS: More women in the control group than in the PD group took postmenopausal estrogen (36 [50%] of 72 women vs 17 [25%] of 68 women; P<.003), and women who had taken postmenopausal estrogen were less likely to develop PD than those who had not (odds ratio, 0.40 [95% confidence interval, 0.19-0.84]; P<.02). Among PD cases only, postmenopausal estrogen use was not associated with age of onset. CONCLUSION: Postmenopausal estrogen therapy may be associated with a reduced risk of PD in women.

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Arch Neurol. 2004 Jun;61(6):858-61.
Reaction time and movement time after embryonic cell implantation in Parkinson disease.
Gordon PH, Yu Q, Qualls C, Winfield H, Dillon S, Greene PE, Fahn S, Breeze RE, Freed CR, Pullman SL.
Department of Neurology and Clinical Motor Physiology Laboratory, Columbia-Presbyterian Medical Center, New York, NY 10032, USA.

BACKGROUND: Embryonic nigral cell implants are a novel treatment for Parkinson disease (PD). Reaction time (RT) and movement time (MT) analysis, validated quantitative measures of premovement neural processing and motor execution, can be used as objective physiological markers of motor performance in PD. OBJECTIVES: To gauge the change in motor performance in patients with PD who received implants, and to determine whether the physiological findings correlate with clinical outcome measures after transplantation. DESIGN: Double-blind, placebo-controlled trial.Patients Forty patients with levodopa-responsive, Hoehn and Yahr stage III or greater PD. INTERVENTIONS: Random assignment to embryonic tissue implants or placebo (sham) operation. MAIN OUTCOME MEASURES: Combined RT + MT scores measured preoperatively and at 4 and 12 months postoperatively in the "off" state. RESULTS: The difference in mean RT + MT scores between the sham and implant groups was statistically significant (P =.005) and was greatest in those 60 years or older (P =.003). Changes correlated with Unified Parkinson's Disease Rating Scale off scores at 4 (r = 0.87, P =.001) and 12 (r = 0.75, P =.01) months in those younger than 60 years. There was a significant deterioration in the sham surgery group at 12 months (P =.03) that was thought to be due to worsening in subjects 60 years and older (P<.001). CONCLUSIONS: The physiological measures detected significant changes in patients undergoing embryonic nigral cell implants and correlated directly with clinical outcome measures. Comprehensive analyses of RT paradigms can document subtle changes in motor performance over time, making them useful outcome measures in therapeutic trials of PD. These findings support further research into nigral cell implantation for PD.

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Neurol Res. 2004 Jun;26(4):355-62.
Cell transplantation for Parkinson's disease.
Roitberg B, Urbaniak K, Emborg M.
Department of Neurosurgery, University of Illinois at Chicago, Chicago, Illinois 60612, USA. roitberg@uic.edu

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the degeneration of the dopamine producing neurons projecting from the substantia nigra into the corpus striatum. Current medical therapy is limited and cannot stop or reverse the degeneration. Over the past 30 years, attempts were made to change the course of the disease by replacing the lost neurons with grafts from various sources. Recent controlled clinical trials of fetal cell transplantation for PD have had disappointing results. These events present an opportunity to examine the past developments and future direction of cell transplantation for PD. Copyright 2004 W.S. Maney and Son Ltd

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Neurosci Lett. 2004 Jun 17;363(3):284-7.
Chronic levodopa intake increases levodopa plasma bioavailability in patients with
Parkinson's disease.
Muhlack S, Woitalla D, Welnic J, Twiehaus S, Przuntek H, Muller T.
Department of Neurology, St. Josef Hospital, Ruhr University Bochum, Gudrunstrasse 56, 44791 Bochum, Germany.

Previous pharmacokinetic trials with standard levodopa formulations showed a different behavior of levodopa degradation in plasma of patients with Parkinson's disease (PD) in various advanced stages. The objective of this trial was to compare levodopa plasma metabolism in PD patients with and without previous long-term levodopa intake after oral intake of a dispensable levodopa/benserazide formulation (DLB). The over a 150 min interval computed area under the curve values of levodopa plasma levels after DLB administration were significantly (ANCOVA: F(1,19) = 7.88, P = 0.01) higher in PD patients with chronic levodopa treatment compared to patients without prior levodopa treatment. The maximum plasma levodopa concentration did not differ (ANCOVA: F(1.19) = 1.17, P = 0.29). Long-term levodopa administration results in an increased levodopa plasma bioavailability in PD patients.

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Ann Neurol. 2004 Jun;55(6):871-5.
Long-term results of bilateral pallidal stimulation in Parkinson's disease.
Volkmann J, Allert N, Voges J, Sturm V, Schnitzler A, Freund HJ.
Department of Neurology, Heinrich-Heine-University, Dusseldorf, Cologne, Germany. j.volkmann@neurologie.uni-kiel.de

We followed up 11 patients for up to 5 years after bilateral pallidal deep brain stimulation for advanced Parkinson's disease. Dyskinesias remained significantly reduced until the last assessment. The initial improvement of off-period motor symptoms and fluctuations, however, was not sustained and gradually declined. Beneficial effects of pallidal deep brain stimulation on activities of daily living in the on- and off-period were lost after the first year. Replacement of pallidal electrodes into the subthalamic nucleus in four patients could restore the initial benefit of deep brain stimulation and allowed a significant reduction of dopaminergic drug therapy.

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Nippon Yakurigaku Zasshi. 2004 Jun;123(6):429-40.
[Pharmacological profiles and clinical effects of antiparkinsonian agent, pramipexole]
[Article in Japanese]
Kohno Y, Takeuchi S.
Product Information Department of Marketing Division.

Pramipexole hydrochloride (pramipexole) is a nonergot dopamine D(2) agonist, and the S(-)enantiomer is used for the treatment of Parkinson's disease (PD). Pramipexole possessed the highest affinity with the D(3) subtype among the D(2) receptor subfamily members (D(2), D(3), D(4)), lacking affinity with the D(1) and D(5) subtype. Pramipexole ameliorated the motor disturbances in PD animal models, induced contralateral rotational behavior reflecting post-synaptic D(2) receptor stimulation in the striatum, and showed a variety of neuroprotective effects in vitro and in vivo experimental systems. The neuroprotective effects of pramipexole seemed to be derived from several mechanisms: stimulation of D(2) autoreceptor, stimulation of D(3) receptor, inhibition of oxidative reaction and following radical production, increase of Bcl-2 protein and inhibition of apoptotic cell death, and production of neurotrophic factor. Clinical efficacy of pramipexole both in monotherapy and combined use with L-DOPA were confirmed evaluating by UPDRS (Unified Parkinson's Disease Rating Scale) II (Activities of daily living) and III (Motor), in the results of clinical studies mainly performed in USA and European countries and partly in Japan. In addition, patients initially treated with pramipexole demonstrated reduction in problematic symptoms and in loss of striatal [(123)I]2beta-carboxymethoxy-3beta-(4-idodophenyl)tropan uptake, a marker of dopamine neuron degeneration, compared with those initially treated with L-DOPA.

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J Neural Transm. 2004 Jun;111(6):725-32. Epub 2004 Mar 19.
Usefulness of switching to cabergoline from other dopamine agonists in patients with advanced Parkinson's disease.
Shiraishi M, Kamo T, Hotta M, Nemoto S, Oshima J, Sugihara H, Yasaki S, Kawakami M, Takahashi Y, Shimojo S.
Department of Neurology, St. Marianna University School of Medicine, Kawasaki City, Japan.

Problems associated with long-term treatment of advanced Parkinson's disease (PD) include motor complications and psychotic and autonomic symptoms. We switched patients from bromocriptine (BR) or pergolide (PER) to cabergoline (CB) therapy and investigated CB's usefulness in alleviating such problems. Subjects were 30 patients (mean age 68.2 years; 13 receiving BR, 17 PER) with PD complicated by effects of long-term treatment but in whom their dose of dopamine (DA) agonist was contraindicated due to adverse reactions. Patients were switched to CB over a 2-4-week period. Hoehn-Yahr and Unified Parkinson Disease Rating Scale (UPDRS) I-IV "on" and "off" scores improved in both the BR and PER groups. CB was not discontinued due to adverse reactions in any patient. In conclusion, switching to CB is useful in patients in whom it is problematic to increase their dose of DA agonist due to motor complications or psychotic symptoms of advanced PD.

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J Neurol. 2004 May;251(5):595-8.
Physical therapy in Parkinson's disease: an open long-term rehabilitation trial.
Pellecchia MT, Grasso A, Biancardi LG, Squillante M, Bonavita V, Barone P.
Department of Neurological Sciences, University "Federico II", Ed. 17, Via Pansini 5, 80131, Naples, Italy. foods@katamail.com

The aim of this study was to evaluate the effects of prolonged physical therapy on disability in patients with Parkinson's disease. The study was designed as an open long-term trial over 20 weeks. Twenty slightly to moderately affected parkinsonian patients were included (Hoehn & Yahr stages: 1.5-3). A comprehensive rehabilitation program was applied three times a week in all patients. Pharmacological treatment was kept stable. Evaluations were performed at baseline, at the end of treatment and after 3 months. Following physical rehabilitation, there was a significant improvement in UPDRS (ADL and motor sections) scores, Self-assessment Parkinson's disease Disability Scale, Ten-Meter Walk test and Zung scale for depression. At 3-month follow-up clinical improvements were largely maintained. A sustained improvement of motor skills in PD patients can be achieved with a long-term comprehensive rehabilitation program.

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Expert Opin Drug Saf. 2004 May;3(3):209-20.
Psychotic symptoms in Parkinson's disease: pathophysiology and management.
Bosboom JL, Wolters ECh.
Research Institute Neurosciences Vrije Universiteit, Department of Neurology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands.

Parkinson's disease (PD) is a chronic neurodegenerative disease, in which mainly dopaminergic neurons in the substantia nigra in the brain degenerate, leading to a depletion of dopamine (DA) in the striatum. The most important motor disturbances of the disease are bradykinesia (slowing down of movement), hypokinesia (poverty of movement), rigidity (muscle stiffness), tremor and postural instability. Besides these well-known motor symptoms, non-motor symptoms may develop, such as depression, cognitive impairment and psychosis. Psychotic symptoms constitute a relatively common but nevertheless serious complication, with visual hallucinations and paranoid delusions often being most prominent. These symptoms are important contributors to patient and caregiver distress and are often important risk factors for nursing home placement. Exogenous (related to therapeutic interventions) factors are of major importance but endogenous (related to the disease process itself) factors might also contribute to the development of psychotic symptoms in PD. Therapeutic strategies comprise reduction of antiparkinsonian treatment, cholinesterase inhibitors and atypical antipsychotics. As psychotic symptoms in PD are often influenced by both endogenous and exogenous factors, a combination of strategies may be chosen.

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Arch Neurol. 2004 May;61(5):697-700.
Deep brain stimulation of the subthalamic nucleus improves cognitive flexibility but impairs response inhibition in Parkinson disease.
Witt K, Pulkowski U, Herzog J, Lorenz D, Hamel W, Deuschl G, Krack P.
Department of Neurology, Christian-Albrechts-University Kiel, Kiel, Germany.

BACKGROUND: Deep brain stimulation of the subthalamic nucleus (STN) improves motor symptoms of Parkinson disease. Although several studies have assessed cognitive functions before surgery and after long-term STN stimulation, only a few have assessed patients while stimulation is on and off to more specifically address the short-term cognitive effects of STN deep brain stimulation. OBJECTIVE: To examine the short-term effects of STN stimulation on several tests sensitive to executive function and the long-term effects of STN stimulation on a global cognitive scale. DESIGN: Twenty-three patients with Parkinson disease were tested 6 to 12 months after surgery with STN stimulation switched on and off in a random order while taking their regular medication. The Unified Parkinson's Disease Rating Scale motor score was also rated in the on and off stimulation condition. The neuropsychological battery included digit span, verbal fluency, Stroop color test, and random number generation in a single- and dual-task condition. RESULTS: Short-term stimulation improved the results on the Random Number Generation Task, requiring suppression of habitual responses, but induced more errors in the interference task of the Stroop color test. Digit span, verbal fluency, and dual-task performance results did not change. There was a significant correlation (r = 0.47, P =.02) between improved performance on the Random Number Generation Task and impaired response inhibition in the Stroop interference condition. A preoperative to postoperative comparison showed no changes in global cognitive function with long-term STN deep brain stimulation. CONCLUSIONS: Short-term STN stimulation improves cognitive flexibility (giving up habitual responses) but impairs response inhibition. Long-term STN stimulation does not change global cognitive function.

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Transpl Immunol. 2004 Apr;12(3-4):321-42.
The cellular repair of the brain in Parkinson's disease--past, present and future.
Sayles M, Jain M, Barker RA.
Cambridge Centre for Brain Repair, University of Cambridge, Forvie Site, Robinson Way, Cambridge, CB2 2PY, UK.

Damage to the central nervous system was once considered irreparable. However, there is now growing optimism that neural transplant therapies may one day enable complete circuit reconstruction and thus functional benefit for patients with neurodegenerative conditions such as Parkinson's disease (PD), and perhaps even those with more widespread damage such as stroke patients. Indeed, since the late 1980s hundreds of patients with Parkinson's disease have received allografts of dopamine-rich embryonic human neural tissue. The grafted tissue has been shown to survive and ameliorate many of the symptoms of the disease, both in the clinical setting and in animal models of the disease. However, practical problems associated with tissue procurement and storage, and ethical concerns over using aborted human fetal tissue have fuelled a search for alternative sources of suitable material for grafting. In particular, stem cells and xenogeneic embryonic dopamine-rich neural tissue are being explored, both of which bring their own practical and ethical dilemmas. Here we review the progress made in neural transplantation, both in the laboratory and in the clinic with particular attention to the development of stem cell and xenogeneic tissue based therapy. Copyright 2004 Elsevier B.V.

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J Indian Med Assoc. 2004 Feb;102(2):93-6.
Approach to the problems of the aged.
Thapar GD.
Willingdon Hospital, New Delhi.

In the older age, all body systems show decrements in physiological reserves. Degenerative process starts in this age and complications and sequelae of chronic long-term diseases eg, hypertension and diabetes make their appearance. In the elderly multiple pathologies are often encountered. Common disease conditions found in the elderly are: Parkinson's disease, depression, ischaemic heart disease, chronic obstructive lung disease, tuberculosis and cancer of the lung, osteo-arthritis of various joints, diabetes, hypertension, cataract, hearing loss and so on. While suggesting food for the elderly, one should take into account the small amounts of food with minimum sugar and fats but lots of fresh vegetables and fruits taken in small quantities but more frequently. Physical activity and exercise is good at all ages including old age. Psychological problems frequently arise among the elderly. They result from many factors eg, difficulties with memory, loss of hearing, financial difficulties, feeling of insecurity, chronic unrelieved pain, diffuse atrophy of the brain, etc. Depression is the commonest of the psychological problems of the aged. Alzheimer's disease, dementia are some other problems often arise out of the ageing process. All old people and not-so-old ones should be encouraged to continue stimulating mental activity with the same vigour as we advise them to continue physical activity.

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Curr Opin Neurol. 2003 Dec;16 Suppl 1:S13-9.
Comparing dopamine agonists in Parkinson's disease.
Bonuccelli U.
Department of Neuroscience, University of Pisa, Pisa, Italy. u.bonuccelli@med.unipi.it

Dopamine agonists are effective in the management of both advanced and early-stage Parkinson's disease. Unfortunately, randomized head-to-head comparative studies between the many different dopamine agonists now available are sparse. Indirect comparisons of dopamine agonists show that ergot derivatives, such as pergolide and cabergoline, are as effective as non-ergot derivatives, such as ropinirole and pramipexole, in ameliorating Parkinson's disease symptoms in patients in early or advanced stages of the condition. As far as safety and tolerability are concerned, no significant differences between dopamine agonists are found. However, some specific adverse events, such as somnolence and sleep attacks, seem less frequent in monotherapy studies with pergolide than in those with the non-ergot dopamine agonists; however, because of the lack of direct-comparison studies this cannot be proved conclusively. Randomized, controlled comparative studies between dopamine agonists are necessary to verify any possible differences in their effectiveness and tolerability in the treatment of Parkinson's disease.

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Curr Opin Neurol. 2003 Dec;16 Suppl 1:S27-33.
Rationale for dopamine agonist use as monotherapy in Parkinson's disease.
Schwarz J.
Department of Neurology, University of Leipzig, Germany. johannes@caltech.edu

Dopamine agonists are increasingly being used in the initial treatment of patients with de-novo Parkinson's disease because they provide symptom relief and a low risk of the dyskinesia frequently associated with levodopa. Evidence is also mounting in preclinical models that dopamine agonists protect dopaminergic neurons from the toxic effects of oxidative stress and the by-products of dopamine and L-dopa metabolism. Ergot derivatives, such as pergolide, induce minor side-effects and provide significant and sustained improvements in motor function in patients with early Parkinson's disease. Dopamine agonists also appear to reduce the loss of functional dopamine transporters when used early in the disease course, and these factors combine to build a case for the use of dopamine agonists in early-stage Parkinson's disease.

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Curr Opin Neurol. 2003 Dec;16 Suppl 1:S9-12.
The pharmacokinetics of pergolide in Parkinson's disease.
Blin O.
FRE-CNRS-University 2109, Institute of Physiological and Clinical Neurosciences, CPCET, Hopital de la Timone, Marseille, France. oblin@mail.ap-hm.fr

Three decades of research have led to a fuller understanding of the pharmacokinetics of pergolide. Pergolide is rapidly absorbed following oral dosing, reaching peak plasma concentrations within 2-3 h. It is about 90% protein bound yet has negligible drug interactions. Pergolide undergoes extensive first-pass metabolism and is completely eliminated within 4-5 days. The metabolism/elimination profile varies between patients but is consistent within the individual, highlighting the importance of careful titration to an effective dose. Pergolide has a long half-life of about 21 h; this has interesting implications, as it should produce a more physiological or continuous stimulation of dopamine receptors, avoiding or delaying the induction of dyskinesia.

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Curr Opin Neurol. 2003 Dec;16 Suppl 1:S3-7.
Dopamine agonists, receptor selectivity and dyskinesia induction in Parkinson's disease.
Jenner P.
Neurodegenerative Diseases Research Centre, Guy's, King's, and St Thomas' School of Biomedical Sciences, King's College, London, UK. div.pharm@kcl.ac.uk

Levodopa and the dopamine agonists are effective symptomatic treatments for Parkinson's disease, and all patients receive at least one of these agents during their illness. Long-term use of levodopa is commonly associated with motor complications such as dyskinesia, and both the dosing frequency and total daily dose of levodopa determine the rate of onset and severity. Dopamine agonists have gained popularity as first-line monotherapy in Parkinson's disease, as they effectively reverse motor deficits and reduce the risk of motor complications. Long-acting dopamine agonists providing continuous, rather than pulsatile, dopaminergic stimulation appear able to avoid dyskinesia induction. Current treatments act predominantly on D2 receptors, but drugs acting on both the D1 and D2 receptor families may produce an additive motor response, although this remains to be proven in patients with Parkinson's disease. Most currently used dopamine agonists are selective for D2-like receptors, with only pergolide and apomorphine potentially interacting with D1 receptor populations.

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Arch Neurol. 2004 Jan;61(1):89-96.
Effects of high-frequency stimulation on subthalamic neuronal activity in parkinsonian patients.
Welter ML, Houeto JL, Bonnet AM, Bejjani PB, Mesnage V, Dormont D, Navarro S, Cornu P, Agid Y, Pidoux B.
Centre d'Investigation Clinique, Federation de Neurologie, Institut National de la Sante et de la Recherche Medicale Unit 289, Hopital de la Salpetriere, 47 Boulevard de l'Hopital, 75013 Paris, France.

BACKGROUND: High-frequency stimulation of the subthalamic nucleus (STN) is a neurosurgical alternative to medical treatment in levodopa-responsive forms of Parkinson disease. The mechanism of action of STN stimulation remains controversial, although an inhibition of overactive STN neurons has been postulated. OBJECTIVE: To determine the effects of high-frequency STN stimulation on the neuronal activity of STN neurons in Parkinson disease patients. PATIENTS: Single-unit recordings of the neuronal activity of the STN were obtained before, during, and after the application of intra-STN electrical stimulation in 15 Parkinson disease patients. Changes in firing frequency and pattern were analyzed using various combinations of stimulus frequency (range, 14-140 Hz). RESULTS: Stimulation at a frequency greater than 40 Hz applied within the STN significantly decreased the firing frequency and increased the burst-like activity in the firing pattern of STN neurons. An aftereffect was observed in cells that had been totally inhibited during high-frequency stimulation. CONCLUSION: The beneficial effects of high-frequency stimulation result from a change in the firing pattern of cellular discharge and a blockade of the spontaneous overactivity of STN neurons.

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Neurology. 2004 Jan 13;62(1 Suppl 1):S39-46.
Safety and tolerability of COMT inhibitors.
Brooks DJ.
MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, United Kingdom.

Combining levodopa with the catechol-O-methyltransferase (COMT) inhibitor entacapone has been shown to be an effective strategy in the management of Parkinson's disease (PD) patients experiencing motor fluctuations. Safety and tolerability information has come from postmarketing surveillance studies as well as several randomized, placebo-controlled trials with long-term open-label extension phases specifically investigating the safety and tolerability of levodopa plus entacapone. Results show the most common dopaminergic side effects to be dyskinesia and nausea, which result from the increased bioavailability of levodopa and can be readily managed. Non-dopaminergic side effects include diarrhea and harmless urine discoloration. There is no convincing evidence of hepatic injury with entacapone use, and therefore monitoring of liver enzymes is unnecessary. With over 300,000 patient-years of exposure, levodopa combined with entacapone can be considered safe and well tolerated.

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Ann N Y Acad Sci. 2003 Jun;991:15-21.
Physiology and pathophysiology of Parkinson's disease.
Hamani C, Lozano AM.
Division of Neurosurgery, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada.

The behavior of neurons in the basal ganglia is severely disrupted in Parkinson's disease (PD). In nonhuman parkinsonian primate models, the disturbance in neurons in basal ganglia output structures include increased firing, bursting, an augmented synchrony, correlated activity, and a tendency towards loss of specificity in their receptive fields. This abnormal neuronal behavior, transmitted to the thalamus, cortex and brainstem, is thought to disrupt the functioning of the motor system and underlie the major motor manifestations of PD-tremor, rigidity, akinesia, gait, and postural disturbances. The mainstay of treatment has been to replace the missing dopamine with medication. With time and disease progression, however, dopamine replacement becomes less efficacious and new adverse effects, including the development of motor fluctuations and drug-induced involuntary movements or dyskinesias, emerge. When the patients reach this stage, surgical therapy becomes an option. Most surgical interventions are performed at the level of the thalamus, globus pallidus, and subthalamic nucleus, aiming at the disruption of the pathological activity that accompanies the Parkinson's deficiency state. With this abnormal neuronal activity neutralized, normal movements can in many cases be restored.

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J Neural Transm Suppl. 2003;(64):65-78.
Advances in the pharmacological management of Parkinson disease.
Tolosa E.
Neurology Service, ICMSN, Banco de Tejidos Neurologicos, Hospital Clinico, University of Barcelona, Barcelona, Spain. etolosa@clinic.ub.es

Numerous advances have taken place in the pharmacological management of Parkinson disease (PD) in recent years. Some of the more clinically relevant will be discussed in the text that follows. New drugs have been developed to treat or prevent the motor fluctuations and dyskinesias that occur frequently with the continuous use of levodopa. Such drugs include the catechol-O-methyl-transferase (COMT) inhibitors, such as tolcapone and entecapone, and new dopamine (DA) agonists with long half lives such as cabergoline, pramipexole or ropirinole. Also new, atyical, antipsychotics have appeared which have revolutionized the treatment of PD since they allow us to control hallucinations and other psychotic behaviour without worsening of motor function. Finally preliminary reports suggest that cholinesterase inhibitors, such as rivastigmine, can be usefull in the management of cognitive impairment in PD, one of the most difficult clinical problems encountered in the management of this neurodegenerative disorder.

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Arch Intern Med. 2003 Jul 28;163(14):1650-4.
Neuroprotection in Parkinson disease.
Simpkins N, Jankovic J.
Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, Texas 77030, USA.

Treatment of Parkinson disease has improved dramatically over the past quarter of a century and promising therapies are emerging. Although treatment with levodopa results in marked symptomatic improvement, mortality rates of the disease have remained relatively unchanged. Recent findings of abnormal protein folding, coupled with oxidative stress, provide scientific rationale for novel therapeutic strategies designed to slow disease progression. To be effective, these disease-modifying and neuroprotective therapies must be instituted early in the course of the disease and early diagnosis therefore is critical. Consequently, primary care physicians will play an increasingly important role in early institution of such neuroprotective strategies. This review is designed to highlight some of the recent advances in our understanding of the mechanisms of neurodegeneration and to draw attention to the importance of early recognition and implementation of the new therapeutic interventions.

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J Neurosurg. 2003 Jul;99(1):71-7.
Bilateral subthalamic stimulation in patients with Parkinson disease: long-term follow up.
Pahwa R, Wilkinson SB, Overman J, Lyons KE.
Department of Neurology, University of Kansas Medical Center, Kansas City, Kansas 66160, USA. rpahwa@kumc.edu

OBJECT: Bilateral subthalamic nucleus (STN) stimulation is increasingly used in patients with advanced Parkinson disease (PD). This study was performed to evaluate the long-term efficacy and safety of bilateral STN stimulation in cases of PD. METHODS: The authors performed a prospective, open-label study in patients with PD who underwent bilateral STN stimulation. The authors compared motor scores and activities of daily living (ADL) scores based on the Unified PD Rating Scale (UPDRS) obtained before surgery while patients were in the medication-off state with scores obtained at follow-up evaluations of these patients while in the medication-off/stimulator-on state. Data contained in patient diaries were also compared. Thirty-three patients with PD were evaluated 12 months postoperatively and 19 were evaluated at a mean follow-up time of 28 months. A comparison between UPDRS scores obtained in patients in the medication-off/stimulator-on state and those obtained when patients were in the baseline medication-off state showed a 27% improvement in ADL scores and a 28% improvement in motor scores after surgery. There was a 57% reduction in the use of levodopa-equivalent medication doses. The percentage of the waking day that patients were in the medication-on state increased from 38 to 72%. Surgical complications included seizures (three patients), confusion (five patients), hemiballismus (one patient), and visual disturbance (one patient). Stimulation-related adverse effects were mild. Device-related events included nine lead replacements, seven lead revisions, six extension replacements, and 12 implantable pulse generator (IPG) replacements; one IPG was cleaned and one IPG was placed in a pocket because of the presence of a shunt. CONCLUSIONS: Bilateral STN simulation is associated with a significant improvement in the motor features of PD. Device-related events were common in the first 20 patients who underwent surgery, often requiring repeated surgeries.

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J Neurosurg. 2003 Jul;99(1):78-88.
A waitlist control-group study of cognitive, mood, and quality of life outcome after posteroventral pallidotomy in Parkinson disease.
Carr JA, Honey CR, Sinden M, Phillips AG, Martzke JS.
Division of Neurosurgery, Surgical Centre for Movement Disorders, Vancouver Hospital and Health Sciences Center, Vancouver, British Columbia, Canada.

OBJECT: The aim of this study was to examine neuropsychological outcome from unilateral posteroventral pallidotomy (PVP) in Parkinson disease while controlling for confounding factors such as test practice and disease progression. METHODS: Participants underwent baseline and 2-month follow-up assessments of cognition, quality of life, mood, and motor functioning. The surgery group (22 patients) underwent PVP (15 left, seven right) after baseline assessment. The waitlist group (14 patients) underwent PVP after follow up. At follow up, the left PVP group exhibited a decline on verbal measures of learning, fluency, working memory, and speeded color naming. The incidence of significant decline on these measures after left PVP ranged from 50 to 86%. The right PVP group did not exhibit a significant cognitive decline, but fluency did decline in 71% of patients who underwent right PVP. Participants who underwent PVP reported better bodily pain and social functioning at follow up than participants in the waitlist group. Improved bodily pain was evident for 62% of the surgery group, and social functioning improved for 19%. Surgery did not alter reported physical functioning or mood. Dyskinesia improved after surgery, but there were no improvements in "on-state" manual dexterity or handwriting. CONCLUSIONS: Most patients who underwent left PVP exhibited declines in learning, fluency, working memory, and speeded color naming. Accounting for retesting effects altered the magnitude of these declines by up to one quarter of a standard deviation, but did not increase the breadth of postsurgical neuropsychological decline beyond that typically reported in the literature. It was found that PVP improved dyskinesia, bodily pain, and social functioning, but did not lead to improvement on other objective and self-reported measures of motor functioning.

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J Neurosurg. 2003 Jul;99(1):89-99.
Localization of stimulating electrodes in patients with Parkinson disease by using a three-dimensional atlas-magnetic resonance imaging coregistration method.
Yelnik J, Damier P, Demeret S, Gervais D, Bardinet E, Bejjani BP, Francois C, Houeto JL, Arnule I, Dormont D, Galanaud D, Pidoux B, Cornu P, Agid Y.
Institut National de la Sante et de la Recherche Medicale U289, Hopital de la Salpetriere, Paris, France. yelnik@ccr.jussieu.fr

OBJECT: The aim of this study was to correlate the clinical improvement in patients with Parkinson disease (PD) treated using deep brain stimulation (DBS) of the subthalamic nucleus (STN) with the precise anatomical localization of stimulating electrodes. METHODS: Localization was determined by superimposing figures from an anatomical atlas with postoperative magnetic resonance (MR) images obtained in each patient. This approach was validated by an analysis of experimental and clinical MR images of the electrode, and the development of a three-dimensional (3D) atlas-MR imaging coregistration method. The PD motor score was assessed through two contacts for each of two electrodes implanted in 10 patients: the "therapeutic contact" and the "distant contact" (that is, the next but one to the therapeutic contact). Seventeen therapeutic contacts were located within or on the border of the STN, most of which were associated with significant improvement of the four PD symptoms tested. Therapeutic contacts located in other structures (zona incerta, lenticular fasciculus, or midbrain reticular formation) were also linked to a significant positive effect. Stimulation applied through distant contacts located in the STN improved symptoms of PD, whereas that delivered through distant contacts in the remaining structures had variable effects ranging from worsening of symptoms to their improvement. CONCLUSIONS: The authors have demonstrated that 3D atlas-MR imaging coregistration is a reliable method for the precise localization of DBS electrodes on postoperative MR images. In addition, they have confirmed that although the STN is the main target during DBS treatment for PD, stimulation of surrounding regions, particularly the zona incerta or the lenticular fasciculus, can also improve symptoms of PD.

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Toxicology. 2003 Jul 15;189(1-2):129-46.
Vitamin E therapy in Parkinson's disease.
Fariss MW, Zhang JG.
Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Pullman, WA 99164-6534, USA. fariss@mail.wsu.edu

Though the etiology is not well understood, late-onset Parkinson's disease (PD) appears to result from several key factors including exposure to unknown environmental toxicants, toxic endogenous compounds and genetic alterations. A plethora of scientific evidence suggest that these environmental and endogenous factors cause PD by producing mitochondrial (mito) oxidative stress and damage in the substantia nigra, leading to cell death. Thus assuming a critical role for mito oxidative stress in PD, therapies to treat or prevent PD must target these mito and protect them against oxidative damage. The focus of this article is to briefly review the experimental and clinical evidence for the role of environmental toxicants and mito oxidative stress/damage in PD as well as discuss the potential protective role of mito d-alpha-tocopherol (T) enrichment and vitamin E therapy in PD. New experimental data are presented that supports the enrichment of mito with T as a critical event in cytoprotection against toxic mito-derived oxidative stress. We propose that chronic, high dose vitamin E dietary supplementation or parenteral vitamin E administration (e.g. vitamin E succinate) may serve as a successful therapeutic strategy for the prevention or treatment of PD (by enriching substantia nigra mito with protective levels of T).

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J Neurol Neurosurg Psychiatry. 2003 Jul;74(7):844-51.
Long term treatment and disease severity change brain responses to levodopa in Parkinson's disease.
Hershey T, Black KJ, Carl JL, McGee-Minnich L, Snyder AZ, Perlmutter JS.
Department of Psychiatry, Washington University School of Medicine, USA.

OBJECTIVES: Degeneration of nigrostriatal neurons and subsequent striatal dopamine deficiency produce many of the symptoms of Parkinson disease (PD). Initially restoration of striatal dopamine with oral levodopa provides substantial benefit, but with long term treatment and disease progression, levodopa can elicit additional clinical symptoms, reflecting altered effects of levodopa in the brain. The authors examined whether long term treatment affects the brain's response to levodopa in the absence of these altered clinical responses to levodopa. METHODS: Positron emission tomography (PET) measurements were used of brain-blood flow before and after an acute dose of levodopa in three groups: PD patients treated long term with levodopa without levodopa induced dyskinesias, levodopa naive PD patients, and controls. RESULTS: It was found that the PD group treated long term responded to acute levodopa differently from controls in left sensorimotor and left ventrolateral prefrontal cortex. In both regions, the treated PD group had decreased blood flow whereas the control group had increased blood flow in response to levodopa. Levodopa naive PD patients had little or no response to levodopa in these regions. Within the treated PD group, severity of parkinsonism correlated with the degree of abnormality of the sensorimotor cortex response, but not with the prefrontal response. CONCLUSIONS: It is concluded that long term levodopa treatment and disease severity affect the physiology of dopaminergic pathways, producing altered responses to levodopa in brain regions associated with motor function.

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Cochrane Database Syst Rev. 2003;(2):CD003735.
Anticholinergics for symptomatic management of Parkinson's disease.
Katzenschlager R, Sampaio C, Costa J, Lees A.
National Hospital for Neurology and Neurosurgery, Queen Square, Box 149, London, UK, WC1 N 3BG. r.katzenschlager@ion.ucl.ac.uk

BACKGROUND: Anticholinergics were the first drugs available for the symptomatic treatment of Parkinson's disease and they are still widely used today, both as monotherapy and as part of combination regimes. They are commonly believed to be associated with a less favourable side effect profile than other antiparkinsonian drugs, in particular with respect to neuropsychiatric and cognitive adverse events. They have been claimed to exert a better effect on tremor than on other parkinsonian features. OBJECTIVES: To determine the efficacy and tolerability of anticholinergics in the symptomatic treatment of Parkinson's disease compared to placebo or no treatment. SEARCH STRATEGY: The literature search included electronic searches of the Cochrane Controlled Trials Register (The Cochrane Library, Issue 4, 2001), MEDLINE (1966 to 2001), Old Medline (1960-1965), Index Medicus (1927 - 1959), as well as handsearching the neurology literature including the reference lists of identified articles, other reviews and book chapters. SELECTION CRITERIA: Randomised controlled trials of anticholinergic drugs versus placebo or no treatment in de-novo or advanced Parkinson's disease, either as monotherapy or as an add-on to other antiparkinsonian drugs were included. Trials of anticholinergic drugs that were never in general clinical use were excluded. DATA COLLECTION AND ANALYSIS: Data was abstracted independently by two authors. Differences were settled by discussion among all authors. Data collected included patient characteristics, disease duration and severity, concomitant medication, interventions including duration and dose of anticholinergic treatment, outcome measures, rates of and reasons for withdrawals, and neuropsychiatric and cognitive adverse events. MAIN RESULTS: The initial search yielded 14 potentially eligible studies, five of which were subsequently excluded. In three cases this was because they dealt with substances that had never been marketed or had not been licensed for as far as could be traced back. One trial had been published twice in different languages. One study was excluded based on the assessment of its methodological quality. The remaining nine studies were all of double-blind cross-over design and included 221 patients. Trial duration was between five and 20 weeks and drugs investigated were benzhexol (mean doses: 8 to 20 mg/d), orphenadrine (mean dose not reported), benztropine (mean dose not reported), bornaprine (8 to 8.25 mg/d), benapryzine (200 mg/d), and methixine (45 mg/d). Only one study involved two anticholinergic drugs. Outcome measures varied widely across studies and in many cases, the scales applied were the authors' own and were not defined in detail. Incomplete reporting of methodology and results was frequent. The heterogeneous study designs as well as incomplete reporting precluded combined statistical analysis. Five studies used both tremor and other parkinsonian features as outcome measures. Outcome measures in these five studies were too different for a combined analysis and results varied widely, from a significant improvement in tremor only to significant improvement in other features but not in tremor. All studies except one (dealing with methixine) found a significant improvement from baseline on the anticholinergic drug in at least one outcome measure. The difference between placebo and active drug was reported in four studies and was found to be significant in all cases. No study failed to show superiority of the anticholinergic over placebo. The occurrence of neuropsychiatric and cognitive adverse events was reported in all but three studies (in 35 patients on active drug versus 13 on placebo). The most frequently reported reason for drop-outs from studies was in patients on placebo due to withdrawal from pre-trial anticholinergic treatment. REVIEWER'S CONCLUSIONS: As monotherapy or as an adjunct to other antiparkinsonian drugs, anticholinergics are more effective than placebo in improving motor function in Parkinson's disease. Neuropsychiatric and cognitive adverse events occur more frequently on anticholinergics than on placebo and are a more common reason for withdrawal than lack of efficacy. Results regarding a potentially better effect of the anticholinergic drug on tremor than on other outcome measures are conflicting and data do not strongly support a differential clinical effect on individual parkinsonian features. Data is insufficient to allow comparisons in efficacy or tolerability between individual anticholinergic drugs.

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Cochrane Database Syst Rev. 2003;(2):CD003467.
Amantadine for dyskinesia in Parkinson's disease.
Crosby NJ, Deane KH, Clarke CE.
Department of Neurology, City Hospital NHS Trust, Dudley Road, Birmingham, West Midlands, UK, B18 7QH. c.e.clarke@bham.ac.uk

BACKGROUND: Abnormal involuntary movements known as dyskinesias are amongst the most disabling side-effects of levodopa therapy. It is thought that amantadine, an NMDA-receptor antagonist, may reduce dyskinesias in patients with Parkinson's disease without worsening Parkinsonian symptoms. OBJECTIVES: To compare the efficacy and safety of adjuvant amantadine therapy versus placebo in treating dyskinesia in patients with Parkinson's disease, already established on levodopa, and suffering from motor complications. SEARCH STRATEGY: Electronic searches of The Cochrane Controlled Trials Register (The Cochrane Library Issue 3, 2001), MEDLINE (1966-2001), EMBASE (1974-2001), SCISEARCH (1974-2001), BIOSIS (1993-2001), GEROLIT (1979-2001), OLDMEDLINE (1957-1965), LILACS (1982-2001), MedCarib (17th Century - 2001), PASCAL (1973-2001), JICST-EPLUS (1985-2001), RUSSMED (1973-2001), DISSERTATION ABSTRACTS (2000-2001), SIGLE (1980-2001), ISI-ISTP (1990-2001), Aslib Index to Theses (2001), Clinicaltrials.gov (2001), metaRegister of Controlled Trials (2001), NIDRR (2001) and NRR (2001) were conducted. Grey literature was hand searched and the reference lists of identified studies and reviews examined. The manufacturers of amantadine were contacted. SELECTION CRITERIA: Randomised controlled trials comparing amantadine with placebo in the treatment of dyskinesia in patients with a clinical diagnosis of idiopathic Parkinson's disease. DATA COLLECTION AND ANALYSIS: Data was abstracted independently by NC and KD onto standardised forms and disagreements were resolved by discussion. MAIN RESULTS: Three randomised controlled trials were found comparing amantadine with placebo in the treatment of dyskinesia in patients with idiopathic Parkinson's disease. Three trials were excluded on the basis that they had no control group and a further three did not state whether they randomised the treatment that participants received. The included trials were double-blind cross-over studies involving a total of 53 patients. All three studies failed to present data from the first arm, instead presenting results as combined data from both treatment arms and both placebo arms. Two trials had no wash-out interval between the treatment periods. In view of the risk of a carry-over effect into the second arm, the results of these trials were not analysed. The final trial had a one week wash-out interval but only examined 11 participants. One study reported side-effects of amantadine in 8 of the 18 participants, including confusion and worsening of hallucinations. Another reported reversible edema of both feet in one of eleven participants. REVIEWER'S CONCLUSIONS: Due to lack of evidence it is impossible to determine whether amantadine is a safe and effective form of treatment for levodopa-induced dyskinesias in patients with Parkinson's disease.

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J Neurol. 2003 Jun;250(6):707-13.
Thalamic stimulation for tremor. Subtle changes in episodic memory are related to stimulation per se and not to a microthalamotomy effect.
Loher TJ, Gutbrod K, Fravi NL, Pohle T, Burgunder JM, Krauss JK.
Department of Neurology, University of Berne, Inselspital, Switzerland.

The aim of this study was to investigate the impact of unilateral deep brain stimulation (DBS) of the ventrointermediate (Vim) thalamic nucleus on neuropsychological functioning comparing stimulation-on with stimulation-off conditions. Nine patients [five patients with Parkinson's Disease (PD), two patients with essential tremor (ET) and 2 patients with multiple sclerosis (MS)] underwent comprehensive neuropsychological testing for cognitive functions, including general mental impairment, aphasia, agnosia, executive and constructional abilities, learning, memory, cognitive processing speed and attention as well as depression. The neuropsychological assessments were performed at least 6 months postoperatively (mean 9 months). Testing in the stimulation-on and stimulation-off condition was obtained within a period of 3 to 4 weeks. Unilateral DBS resulted in improvement of tremor in all patients. There were no significant differences between the stimulation-on and the stimulation-off condition with the exception of a decrement of word-recall in the short delay free-recall subtest of the Rey Auditory-Verbal Learning Test (RAVLT). Subgroup analysis indicated that the impairment in word-recall was related to left-sided thalamic stimulation. Our study confirms that chronic unilateral DBS is a safe method with regard to cognitive function. The subtle changes in episodic memory are related to stimulation per se and not to a microthalamotomy effect.

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Clin Neuropharmacol. 2003 May-Jun;26(3):156-63.
Optimizing levodopa pharmacokinetics: intestinal infusion versus oral sustained-release tablets.
Nyholm D, Askmark H, Gomes-Trolin C, Knutson T, Lennernas H, Nystrom C, Aquilonius SM.
Department of Neuroscience, Neurology, Uppsala University, Sweden. dag.nyholm@neurologi.uu.se

Continuous duodenal infusion of carbidopa/levodopa has been shown to control motor fluctuations in advanced Parkinson's disease (PD). The authors compared the pharmacokinetics of levodopa and 3-O-methyldopa in patients with advanced PD after administration of an oral sustained-release levodopa preparation and after continuous intestinal levodopa infusion with a new formulation as a gel suspension. A randomized crossover trial was carried out in 12 patients. Carbidopa/levodopa was administered as an oral sustained-release tablet and by nasoduodenal continuous infusion for 3-week periods for each treatment. Plasma levodopa concentrations and motor performance were evaluated every 30 minutes during 3 test days of each treatment period. The average intraindividual coefficient of variation for the plasma levodopa concentrations after oral therapy was 34% and was significantly lower (14%, p < 0.01) during continuous infusion. Hourly video evaluations showed a significant increase in ON time during infusion and a significant decrease in OFF time and dyskinesia. Continuous intraduodenal delivery of a new carbidopa/levodopa formulation offers a means for markedly improved control of motor fluctuations in late stages of PD.

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Clin Neuropharmacol. 2003 May-Jun;26(3):151-5.
Apomorphine infusion and the long-duration response to levodopa in advanced Parkinson's disease.
Stocchi F, Berardelli A, Vacca L, Barbato L, Monge A, Nordera G, Ruggieri S.
Institute of Neurology IRCCS "NEUROMED," Pozzilli, Rome, Italy. fabrizio.stocchi@tin.it

The authors investigated the long-duration response to levodopa in advanced Parkinson's disease. Eight patients with advanced Parkinson's disease disabled by severe ON/OFF fluctuations treated by chronic daytime subcutaneous apomorphine infusion with supplemental oral levodopa were studied. On day 1, oral levodopa was withdrawn at 4:00 pm and on the following morning subcutaneous apomorphine infusion was continued at the same rate without levodopa therapy. While receiving apomorphine alone, seven of the eight patients turned ON, and their usual dyskinesias returned. The ON phase persisted for 60 to 100 minutes (mean, 185.7 minutes) but then, despite continued, constant-rate apomorphine infusion to stabilize plasma levels, switched to an OFF phase. The authors conclude that the clinical effect of apomorphine is sustained by levodopa long-duration response. This effect is probably the result of postsynaptic mechanisms. In patients with advanced Parkinson's disease, the long-duration response to levodopa is present although slightly diminished.

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Clin Neuropharmacol. 2003 May-Jun;26(3):146-50.
High-dose ropinirole in advanced Parkinson's disease with severe dyskinesias.
Cristina S, Zangaglia R, Mancini F, Martignoni E, Nappi G, Pacchetti C.
Parkinson's Disease and Movement Disorders Unit, Istituto di Ricovero e Cura a Carattere Scientifico IRCCS, C. Mondino, University of Pavia, Italy. claudio.pacchetti@mondino.it

Levodopa (LD) is the gold standard of therapy for Parkinson's disease, but it is commonly associated with motor fluctuations and dyskinesias. Dopamine agonists are often used as adjuncts to LD in an attempt to reduce these complications. In this open-label study the authors investigated the effects of high doses of adjunctive ropinirole in 36 patients with advanced Parkinson's disease and normal cognitive status. The daily dose of ropinirole was increased from 18.4 +/- 3.5 mg to 34.7 +/- 5.5 mg, generally in four separate doses. The daily LD dose was decreased from 734.1 +/- 254.8 mg to 502.8 +/- 228.4 mg. After 12 months 25 patients were still on high doses of ropinirole whereas 11 patients had, after either the emergence of side effects or a worsening of their clinical conditions, decreased or interrupted ropinirole. At 12 months, the daily doses of LD and ropinirole were 489 +/- 243 mg and 34.6 +/- 4.6 mg respectively. There was a significant reduction in the Dyskinesia Rating Scale scores during both ON and OFF periods, indicating a reduction in dyskinesias during ON periods and a reduction in dystonias during OFF periods (p < 0.001). Both the intensity and the hours spent during OFF periods were reduced significantly (p < 0.001). Even though these results need to be confirmed through extended controlled studies, the high-dose dopamine agonist strategy is safe for patients with advanced PD in whom a marked motor response to LD (even at very low doses) is associated with severe dyskinesias, and may be used as a means of delaying surgery or as an alternative to continuous apomorphine infusion.

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Neurol Sci. 2003 May;24 Suppl 1:S38-40.
Surgery of Parkinson's disease: inclusion criteria and follow-up.
Broggi G, Franzini A, Marras C, Romito L, Albanese A.
Department of Neurosurgery, Istituto Nazionale Neurologico C. Besta, Milan, Italy.

Parkinson's disease (PD) is a progressive disturbances of movement that affects mainly the motor system. Prolonged pharmacological administration may result in insufficient control of symptoms and significant side effects. Deep brain stimulation (DBS), targeted at the STN, is a recent surgical procedure that, according to the symptoms response, allows modification of stimulation parameters; its effects are also reversible. In this paper management of surgical patients is reported. It includes patient selection, inclusion and exclusion criteria, postoperative clinical protocol. The evaluation rating scale such as UPDRS, Dyskinesias Rating Scale and Self-Reporting Questionnaire usually administrated on PD patients are analyzed. Surgical inclusion criteria are (1) idiopathic PD, (2) IV or V Hoehn-Yahr stage, (3) severe motor disability, and (4) no dementia or psychiatric abnormalities. Postoperative clinical protocol is analyzed and parameter of stimulation after surgery and at the follow up are reported. Generally DBS allows an improvement of rigidity and tremor; bradykinesia also improves with high frequency stimulation. Results obtained by continuous stimulation show a mean improvement of UPDRS of about 60% and a significant reduction in the drug intake.

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Neurol Sci. 2003 May;24 Suppl 1:S27-9.
Motor complications of Parkinson's disease.
Martignoni E, Riboldazzi G, Calandrella D, Riva N.
Universita del Piemonte Orientale A. Avogadro, Novara, Italy.

Long-term treatment with levodopa in Parkinson's disease results in the development of motor complications, including drug failure, reduced duration of antiparkinsonian action (wearing off phenomenon), sudden shifts between under-treated and over-treated states (on-off phenomenon), freezing and involuntary movements such as levodopainduced dyskinesia. These motor complications can sometimes be solved with changes in the drug regimen, particularly the addition of dopamine agonists and catechol-O-methyltransferase (COMT) inhibitors and/or changes in levodopa dose, formulation and number of doses. Amantadine and selegiline can also be helpful in reducing motor fluctuations.

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Funct Neurol. 2003 Jan-Mar;18(1):11-6.
The influence of rotational exercises on freezing in Parkinson's disease.
Van Vaerenbergh J, Vranken R, Baro F.
Department of Neurorehabilitation, Faculty of Physical Education and Physiotherapy, Catholic University of Leuven, Leuven (Heverlee), Belgium. jo.vanvaerenbergh@cmat.be

The advanced stage of Parkinson's disease (PD) is characterised by complex movement disturbances including freezing. Because freezing is resistant to drug therapy, there has recently been renewed interest in non-pharmacological treatment programmes. In this study the effect of rotational stimulation on freezing was investigated. Eight patients with idiopathic PD and freezing participated in the study. Switching from foot-lifting to 'stand up and walk' provoked freezing in all the tested patients. The mean OPMSP (Onset of Premotor Silence Period) in the EMG of the m. tibialis anterior during the 'foot-lifting' sessions preceding freezing was 124 msec. This value, together with a striking repetition of the EMG discharges in the m. tibialis anterior following the request to 'stand up and walk', was related to the inducement of freezing, as a decrease of 42 msec in the OPMSP (t = 2.61; p < or = 0.01) after rotational stimulation abolished freezing and the concomitant EMG disturbances. Rotational stimulation also reduced freezing frequency during daily life. Freezing periods fell to below 50% of the pre-treatment level the day following rotation (t = 5.58; p < or = 0.001). The OPMSP predicted the short and long-term effects of rotational exercises (R = 0.74; p < or = 0.03). The rather long-lasting effect of the stimulation suggests a possible modulation of neurochemical transmission. Further studies are required to shed more light on the point of action and to elucidate which neurotransmitter might be involved.

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Clin Neurophysiol. 2003 May;114(5):930-7.
Levodopa normalizes exercise related cortico-motoneuron excitability abnormalities in Parkinson's disease.
Lou JS, Benice T, Kearns G, Sexton G, Nutt J.
Department of Neurology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Mail Code CR120, Portland 97201, USA. Louja@ohsu.edu

OBJECTIVES: To measure exercise induced changes in cortico-motoneuron excitability in Parkinson's disease (PD) before and after levodopa. METHODS: Transcranial magnetic stimulation was delivered at 10% above resting motor threshold in 9 PD and 8 control subjects. Each subject performed repetitive isometric wrist extension at 50% of the baseline maximal voluntary contraction (MVC) for 30s with 3s rest between extensions until fatigued, defined as the inability to generate force at more than 25% of the baseline MVC. We recorded motor evoked potentials (MEPs) from the resting extensor carpi radialis muscle before (baseline), during, and after fatiguing exercise. Baseline electromyographic activity was closely monitored. We compared absolute MEP amplitudes between PD and controls, before and after levodopa, during baseline, exercise, and recovery periods. We correlated absolute MEP amplitudes with an objective measure of fatigability. RESULTS: PD subjects in the "off" state had increased absolute MEP amplitudes compared with controls. The effect was present in all 3 exercise periods. These differences disappeared after levodopa. Post-exercise facilitation was clear for PD subjects before and after levodopa, but post-exercise depression was not significant. Absolute MEP amplitude showed negative correlation with objective fatigability for PD subjects before levodopa. CONCLUSIONS: Levodopa normalized the increased cortico-motoneuron excitability in PD patients before, during, and after fatiguing exercise. SIGNIFICANCE: This study demonstrated the abnormal cortico-motoneuron excitability associated with motor fatigue in PD.

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Parkinsonism Relat Disord. 2003 Apr;9 Suppl 1:S31-41.
A collaborative study on the malignant syndrome in Parkinson's disease and related disorders.
Takubo H, Harada T, Hashimoto T, Inaba Y, Kanazawa I, Kuno S, Mizuno Y, Mizuta E, Murata M, Nagatsu T, Nakamura S, Yanagisawa N, Narabayashi H.
Department of Neurology, Tokyo Rinkai Hospital, Tokyo, Japan

We report the results of a collaborative study on malignant syndrome (MS) that developed in patients being treated with levodopa and other anti-parkinsonian drugs. We analyzed clinical features, laboratory findings, precipitating events, and risk factors for poor outcome. The study was conducted in five centers in Japan. Patients who developed MS between January 1991 and December 1997 were included. The enrollment criteria used were the same as those for neuroleptic MS proposed by Levenson et al. (1985).A total of 99 episodes were encountered in 93 patients (72 with Parkinson's disease and 21 with secondary parkinsonism); one patient had four recurrences of MS and three patients had two recurrences. High fever was the most frequent clinical manifestation of MS followed by worsening of parkinsonism, and then altered levels of consciousness. Serum creatine kinase was abnormally elevated in all the patients studied. Life-threatening complications were rhabdomyolysis, disseminated intravascular coagulation, and acute renal failure.The most frequent precipitating event was discontinuation or dose reduction of anti-parkinsonian drugs, particularly levodopa. No drug was the exception in the precipitation of MS. Intercurrent infection was the next most common precipitating event. MS developed without drug withdrawal or infection in some patients. In five patients, severe "wearing off" phenomenon was the only event preceding the onset of MS. Hot weather and dehydration appeared to be the cause in three patients. Among the total of 99 episodes, patients recovered to the pre-MS state following 68 episodes (68.7%); in the remaining 31.3%, patients failed to recover to their previous state. Older age, higher Hoehn and Yahr stage during the symptomatic phase of MS, higher akinesia score, and the absence of wearing off phenomenon prior to developing MS were associated with poor outcome. The most frequently used treatments of MS were intravenous fluid, levodopa, dantrolene sodium, and intragastric bromocriptine. Early introduction of treatment is important. Any elevation of body temperature during the course of anti-parkinsonian drug treatment should be considered as MS until proved otherwise.

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Parkinsonism Relat Disord. 2003 Apr;9 Suppl 1:S3-9.
Malignant syndrome in Parkinson's disease: concept and review of the literature.
Mizuno Y, Takubo H, Mizuta E, Kuno S.
Department of Neurology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo, Tokyo 113-8421, Japan. y_mizuno@med.juntendo.ac.jp

We reviewed literature on malignant syndrome occurring in patients with Parkinson's disease (PD) during the course of drug therapy. Clinical features were high fever, marked rigidity, consciousness disturbance, autonomic dysfunction, and elevation of serum creatine kinase. The clinical features were essentially similar to those of neuroleptic malignant syndrome. The immediate triggering event was, most often, discontinuation or reduction of anti-parkinsonian drugs, particularly of levodopa. But no anti-parkinsonian drug was the exception to the induction of malignant syndrome. Serious complications were severe pneumonia, disseminated intravascular coagulation, and acute renal failure. Early treatment with intravenous fluid infusion and external body cooling are essential for good recovery. Bromocriptine and dantrolene sodium were used frequently. It has been claimed that they are effective; however, randomized controlled studies are needed to explicitly prove the efficacy of these drugs in malignant syndrome associated with PD.

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Acta Neurol Scand. 2003 May;107(5):349-55.
Dihydroergocriptine in Parkinson's disease: clinical efficacy and comparison with other dopamine agonists.
Albanese A, Colosimo C.
Istituto di Neurologia, Universita Cattolica del Sacro Cuore, Rome, Italy.

The present paper reviews clinical studies on the use of dihydroergocriptine (DHEC), an ergot derivative with dopamine agonist activity, for the treatment of Parkinson's disease. This compound is a hydrogenated ergot derivative structurally quite similar to bromocriptine, from which it differs because of the hydrogenation in C9 C10 and the lack of bromine in C2. DHEC has a potent D2-like receptor agonist and a partial D1-like receptor agonist activity; because of this biochemical profile, it has been suggested that DHEC may produce fewer side-effects and have clinical efficacy equal to that of a classical dopamine agonist. Several open-label and double-blind studies indicate that DHEC is an efficacious remedy for parkinsonian signs and symptoms. Further studies are necessary to compare DHEC to new dopamine agonists (pergolide, cabergoline, ropinirole, and pramipexole) which have been more recently marketed.

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Ann Intern Med. 2003 Apr 15;138(8):651-8.
Update on Parkinson disease.
Siderowf A, Stern M.
Parkinson's Disease and Movement Disorders Center, University of Pennsylvania, 330 South 9th Street, Philadelphia, Pennsylvania 19107, USA. adsiderowf@pahosp.com

This Update reviews developments in the pathophysiology and treatment of Parkinson disease during the past several years. In the area of pathophysiology, studies have addressed the contribution of environmental factors such as caffeine and pesticides. Large-scale epidemiologic studies have also expanded the role genetic factors are thought to play. Detailed studies of kindreds with familial Parkinson disease due to alpha-synuclein and parkin have catalyzed basic science investigations into the pathologic mechanisms of the disease. These studies have led to the development of a pathophysiologic model of Parkinson disease that emphasizes abnormal protein aggregation. Studies of treatment have clarified the relative roles of l-dopa and dopamine agonists in early Parkinson disease and shown the potential for surgical interventions, particularly deep-brain stimulation, to relieve the symptoms of advanced, medically refractory disease.

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Can J Neurol Sci. 2003 Mar;30 Suppl 1:S72-82.
Stereotactic neurosurgery for movement disorders.
Abosch A, Lozano A.
Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA 30322, USA.

Stereotactic neurosurgery for the treatment of movement disorders focuses primarily on the treatment of Parkinson's disease (PD), essential tremor (ET), and dystonia. The surgical targets in use are the subthalamic nucleus (STN) and the globus pallidus internus (GPi) for PD, GPi for dystonia, and ventralis intermedius (Vim) nucleus of the thalamus for ET. Following target selection, procedures include the generation of lesions or the placement of deep brain stimulating electrodes in the selected target. Additionally, transplantation has been used in the treatment of PD. The indications, outcomes, and risks of the various procedures are reviewed.

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Can J Neurol Sci. 2003 Mar;30 Suppl 1:S27-33.
Treatment of Parkinson's disease.
Martin WR, Wieler M.
Division of Neurology, University of Alberta, Edmonton, AB, Canada.

Parkinson's disease is a progressive neurodegenerative disorder that demands a holistic approach to treatment. Both pharmacologic and nonpharmacologic interventions play an important role in the comprehensive management of this disorder. While levodopa remains the single most effective medication for symptomatic treatment, dopamine agonists are playing an increasingly important role. Motor complications of dopaminergic therapy are a significant issue, particularly in patients with more advanced disease who have been on levodopa for several years. All therapeutic interventions must be tailored to the individual and modified as the disease progresses, with the goal of minimizing significant functional disability as much as possible.

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Brain. 2003 May;126(Pt 5):1136-45.
Unilateral subthalamotomy in the treatment of Parkinson's disease.
Patel NK, Heywood P, O'Sullivan K, McCarter R, Love S, Gill SS.
Institute of Clinical Neurosciences, Frenchay Hospital, Bristol, UK.

Hyperactivity in the subthalamic nucleus (STN) is seen in animal models of Parkinson's disease, and lesioning of the STN dramatically relieves the animal's parkinsonism. Deep brain stimulation (DBS) of the STN is an effective treatment for patients with advanced Parkinson's disease. We have studied the effects of a unilateral lesion placed in the STN in predominantly hemi-parkinsonian patients. Twenty-one patients with advanced idiopathic Parkinson's disease were studied. Seventeen had asymmetrical tremor-dominant Parkinson's disease and four had bilateral disease. All patients underwent radiofrequency lesioning of the dorsolateral part of the STN under stereotactic guidance. The four patients with bilateral disease had, in addition, an electrode implanted contralaterally in the STN. Twenty-one patients have been followed for a minimum of 12 months. Clinical evaluation included the use of the Unified Parkinson's Disease Rating Scale (UPDRS) before and after surgery. Post-operative high-resolution MRI was performed in each patient to confirm lesion location, and this was correlated with clinical outcome. There was improvement in contralateral tremor, rigidity and bradykinesia in all patients followed for 6, 12 and 24 months, with the effect on tremor being greatest. L-dopa equivalent daily intake was approximately halved, and this resulted in a significant reduction in dyskinesia. Psychometric test scores were mostly unchanged or improved. All lesions were successfully located in the dorsolateral STN. Nineteen of the 21 lesions extended beyond the STN to involve pallidofugal fibres (H2 field of Forel) and the zona incerta (ZI). Lesion-induced dyskinesias were not a management problem except in one patient, whose lesion was confined to the STN. This patient was successfully treated with deep brain stimulator placement in the region of H2/ZI. Unilateral STN lesions can be made safely and are an effective alternative to thalamotomy, pallidotomy and unilateral STN DBS for the treatment of asymmetrical tremor-dominant advanced Parkinson's disease. Com bined lesioning of the dorsolateral STN and H2/ZI is particularly effective.

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Ann Neurol. 2003;53 Suppl 3:S3-12; discussion S12-5.
Limitations of current Parkinson's disease therapy.
Rascol O, Payoux P, Ory F, Ferreira JJ, Brefel-Courbon C, Montastruc JL.
Clinical Investigation Centre and Department of Clinical Pharmacology, Toulouse, University Hospital France.

Levodopa and other dopaminergic medications drastically improve the motor symptoms and quality of life of patients with Parkinson's disease in the early stages of the disease. However, once the "honeymoon" period has waned, usually after a few years of dopaminergic therapy, patients become progressively more disabled despite an ever more complex combination of available antiparkinsonian treatments. Sooner or later, they suffer from "dopa-resistant" motor symptoms (speech impairment, abnormal posture, gait and balance problems), "dopa-resistant" nonmotor signs (autonomic dysfunction, mood and cognitive impairment, sleep problems, pain) and/or drug-related side effects (especially psychosis, motor fluctuations, and dyskinesias). Therefore, the current antiparkinsonian therapy cannot be considered as ideal with regard to both efficacy and safety.

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J Neural Transm. 2003 Mar;110(3):239-51.
Efficacy and tolerability of entacapone in patients with Parkinson's disease treated with levodopa plus a dopamine agonist and experiencing wearing-off motor fluctuations. A randomized, double-blind, multicentre study.
Fenelon G, Gimenez-Roldan S, Montastruc JL, Bermejo F, Durif F, Bourdeix I, Pere JJ, Galiano L, Schadrack J.
Hopital Henri Mondor, Paris, Creteil, France. gfenelon@wanadoo.fr

The efficacy and tolerability of entacapone was investigated in a randomized, double-blind, placebo-controlled, 3-month study of 162 patients with Parkinson's disease (PD) treated with levodopa and a dopamine agonist and experiencing wearing-off motor fluctuations. Patients were randomized in a 3 : 2 ratio to entacapone 200 mg or placebo, administered with each dose of levodopa. Efficacy was judged on the improvement of "on" and "off" time while awake (Patient Diary and UPDRS part IV Item 39), Investigators' Global Assessment, the SF-36 Health Survey, and changes in levodopa dosages. Patients were monitored for adverse events, laboratory safety and vital signs throughout the study. Improvements in "on" time as assessed using patient diary data showed a trend in favour of entacapone, however these did not reach statistical significance. "Off" time while awake (UPDRS part IV Item 39) showed an improvement of at least one category in 36% of entacapone-treated patients, compared with 22% in the control group (p = 0.0038). The proportion of patients showing an improvement at the Investigators' Global Assessment was significantly higher (p = 0.0006) in the entacapone-treated group of patients. Also, the proportion of patients with a reduction in their daily levodopa dose was significantly higher (p = 0.02) in the entacapone group (28%) compared with placebo (13%). As expected, the most frequent adverse events were dopamine-mediated (dyskinesia: entacapone 31% versus placebo 13%), and harmless urinary discoloration. The modest increase in dyskinesias could be readily managed by levodopa down-adjustment, and, at study end there was no significant difference for the UPDRS "overall dyskinesia score" between entacapone and placebo. In conclusion, although the primary efficacy variable did not reach statistical significance, the present results demonstrate that entacapone provides additional antiparkinsonian benefits to levodopa therapy and is well tolerated in levodopa-treated PD patients experiencing wearing-off motor fluctuations despite adjunct dopamine agonist therapy.

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J Neural Transm. 2003 Apr;110(4):373-80.
Pramipexole in comparison to l-dopa: a neuropsychological study.
Brusa L, Bassi A, Stefani A, Pierantozzi M, Peppe A, Caramia MD, Boffa L, Ruggieri S, Stanzione P.
IRCCS Fondazione S. Lucia.

Twenty right-handed patients affected by early/mild Parkinson's disease were evaluated in a randomised study using neuropsychological and clinical assessements during three treatment modalities: when in the off treatment condition, when on pramipexole, and when on l-dopa. In comparison to the off treatment condition, the DA-agonist pramipexole produced a significant impairment of short term verbal memory, attentional-executive functions and verbal fluency, while l-dopa did not. Moreover, pramipexole opposite to l-dopa, failed to improve FAS and Stroop tests. Present findings indicate that pramipexole may worsen cognitive functions although not exceeding normative values.

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J Neurol Neurosurg Psychiatry. 2003 Apr;74(4):519-21.
Surgery for Parkinson's disease: lack of reliable clinical trial evidence.
Stowe RL, Wheatley K, Clarke CE, Ives NJ, Hills RK, Williams AC, Daniels JP, Gray R.
Clinical Trials Unit, University of Birmingham, Park Grange, 1 Somerset Road, Edgbaston, Birmingham B15 2RR, UK. r.l.stowe.1@bham.ac.uk

There has been a striking resurgence of interest in surgery for Parkinson's disease (PD) with new targets identified and new procedures developed. This systematic review identified over 500 studies of surgery for PD published since 1990, including over 10 000 patients. However, the authors were unable to assess the value of PD surgery reliably because only seven randomised trials were identified including just 196 patients. Studies of surgery for PD have generally been of poor quality with too few patients, too short follow up, inappropriate choice of outcome measures, and lack of control groups. Much larger, randomised, controlled trials are needed to assess the longer term effects of surgery on patient rated quality of life and cost effectiveness.

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Nervenarzt. 2003 Mar;74 Suppl 1:S12-21.
[Medicinal treatment of idiopathic Parkinson's disease]
[Article in German]
Klockgether T.
Neurologische Klinik, Universitat Bonn.

Idiopathic Parkinson's disease (IPD) results from a largely selective degeneration of nigrostriatal dopaminergic neurons. Therefore, compounds which strengthen dopaminergic transmission in the striatum are the most important therapeutic approach. These include L-dopa, dopamine receptor agonists, selegeline, and entacapon. Since nigrostriatal degeneration leads to secondary alterations of cholinergic and glutamatergic transmission to the basal ganglia,nondopaminergic compounds such as anticholinergics and N-methyl-D-aspartate (NMDA) receptor antagonists are also used in the management of IPD. L-dopa is the most effective substance but after 3-5 years of L-dopa treatment, approximately half of all IPD patients develop fluctuations. Therefore, initial treatment with a dopamine receptor agonist is recommended.

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Parkinsonism Relat Disord. 2003 Mar;9(4):221-4.
Selegiline in the treatment of Parkinson's disease: its impact on orthostatic hypotension.
Bhattacharya KF, Nouri S, Olanow CW, Yahr MD, Kaufmann H.
Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA.

Less than a consensus exists as to whether chronic treatment with selegiline in combination with levodopa/carbidopa in patients with Parkinson's disease, is associated with more pronounced orthostatic hypotension than treatment with levodopa/carbidopa alone. To resolve this issue, we compared orthostatic tolerance and autonomic reflexes in 95 patients with Parkinson's disease treated chronically with either selegiline alone (n = 10), levodopa/carbidopa alone (n = 49) or both agents combined (n = 36). Supine heart rate and blood pressure, autonomic cardiovascular reflexes and the frequency and magnitude of orthostatic hypotension were similar in all three treatment groups. Copyright 2003 Elsevier Science Ltd.

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Aging Cell. 2002 Oct;1(1):17-21.
Ironing out Parkinson's disease: is therapeutic treatment with iron chelators a real possibility?
Kaur D, Andersen JK.
Buck Institute for Age Research, 8001 Redwood Blvd, Novato, CA 94945, USA.

Levels of iron are increased in the brains of Parkinson's disease (PD) patients compared to age-matched controls. This has been postulated to contribute to progression of the disease via several mechanisms including exacerbation of oxidative stress, initiation of inflammatory responses and triggering of Lewy body formation. In this minireview, we examine the putative role of iron in PD and its pharmacological chelation as a prospective therapeutic for the disease.

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Lancet Neurol. 2002 Aug;1(4):225-31.
Deep brain stimulation for Parkinson's disease: disrupting the disruption.
Lozano AM, Dostrovsky J, Chen R, Ashby P.
Toronto Western Hospital Research Institute, and Department of Surgery, University of Toronto, ON, Canada. lozano@uhnres.utoronto.ca

Many people are disabled by Parkinson's disease (PD) despite the drug treatments that are currently available. For these patients, neurosurgery has the potential to help restore their function. The most effective neurosurgical procedures to date use electrical stimulation--deep brain stimulation (DBS)--of small targets in the brain by use of a pacemaker-like device to deliver constant stimulation. Although these operations can produce striking results, the mechanism by which delivery of electrical stimulation to targets deep in the brain can restore function in the motor system is not clear. This type of surgery probably works by interfering with and shutting down abnormal brain activity in areas where the current is delivered, such as the thalamus, globus pallidus, or the subthalamic nucleus. With this abnormal neuronal activity neutralised, motor areas of the brain can resume their function and normal movements are reinstated. Current research is aimed at elucidating how DBS works and using this information to develop better treatments for patients with PD and other neurological disorders.

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Stereotact Funct Neurosurg. 2002;79(2):75-87.
The effects of posteroventral pallidotomy on balance function in patients with Parkinson's disease.
Westerberg BD, Roberson JB, Stach BA, Silverberg GD, Heit G.
University of British Columbia, Vancouver, Canada.

Parkinson's disease is a chronic, progressive neurodegenerative disorder resulting from dopaminergic cell loss in the pars compacta of the substantia nigra. Conventional treatment of Parkinson's disease consists of pharmacological replacement of dopamine. A treatment alternative, posteroventral pallidotomy (PVP), has been used for medically intractable stages of the disease. The purpose of this study was to evaluate the effects of PVP on balance function, as measured by dynamic posturography, in patients with medically intractable Parkinson's disease. Five subjects were studied within 2 days prior to and within 6 months following PVP. Pretreatment abnormalities were found in vestibular, visual, and somatosensory processing in balance function. Posteroventral pallidotomy resulted in improvement in vestibular compensation of posture in some patients, which may be at least partially due to an improvement in latencies to respond to changes in stance. Dynamic posturography is an effective tool in the evaluation of balance and posture in patients with advanced Parkinson's disease. Copyright 2002 S. Karger AG, Basel.

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