Conference Report
Highlights of the 8th International Congress of Parkinson's Disease and
Movement Disorders
June 13-17, 2004; Rome, Italy
Posted 07/08/2004

Robert A. Hauser, MD, MBA

The 8th International Congress of Parkinson's Disease and Movement
Disorders was held in Rome, Italy, from June 13 to 17, 2004. Herewith are
highlights from this premiere scientific meeting.

Parkinson's Disease


Etiopathogenesis

At the first plenary session, McNaught[1] reviewed information suggesting
that Parkinson's disease (PD) might be caused by dysfunction of the
ubiquitin-proteasome system (UPS) and discussed a rat model of PD induced
by proteasome inhibitors.[2] The UPS is responsible for degradation and
clearance of unwanted proteins. Mutations in parkin and ubiquitin C-terminal
hydrolase L1, components of the UPS, cause rare familial forms of PD. Other
genetic causes of PD, such as mutations or triplications of the alpha-synuclein
gene, might also inhibit the UPS, although direct neuronal toxicity of alpha-
synuclein due to misfolding has also been hypothesized.

On the basis of these observations, it is possible that exposure to
environmental proteasome inhibitors could cause or contribute to the
development of PD. To test this concept, rats were administered proteasome
inhibitors (either epoxomicin or PSI) 6 times over a period of 2 weeks.
Several weeks later, the animals developed progressive parkinsonism that
improved with levodopa or apomorphine. Positron emission tomography
(PET) demonstrated the loss of dopaminergic neurons, and autopsy findings
were similar to those seen in humans with PD, including the presence of
Lewy body-like inclusions. The UPS dysfunction hypothesis represents an
important alternative (or addition) to the synuclein-toxicity hypothesis and
suggests that at least some forms of PD may be caused by environmental
proteasome inhibitors. Possible neuroprotective agents, including those that
help restore the UPS, can be tested in this rat model.


Current Medications

Entacapone

Marin and colleagues[3] reported that levodopa plus entacapone* causes less
dyskinesia than levodopa alone in the 6-hydroxydopamine hemiparkinsonian
rat model of PD. Four weeks after lesioning, rats were treated with levodopa
twice daily, levodopa plus entacapone twice daily, or placebo. Compared
with treatment with levodopa alone, levodopa plus entacapone caused less
dyskinesia. This study confirms similar findings from the MPTP monkey
model of PD and supports the notion that more continuous dopaminergic
stimulation causes less dyskinesia. It raises the issue as to whether catechol-
O-methyltransferase (COMT) inhibitors, such as entacapone, should be
administered from the initial introduction of levodopa in the management of
patients. A study to evaluate the potential of entacapone to delay the onset of
dyskinesia in PD patients is currently in the planning stages.

*Agent not currently approved for the indication discussed

Pergolide
Agarwal and associates[4] presented 2 cases of pergolide-induced fibrosis
and reviewed the literature on this subject. They identified 21 cases in the
literature, with patients having been treated for 1-8 years at a dose of 1-8 mg
of pergolide per day. The most common presenting sign of fibrosis was
dyspnea (13 of 23, including the presenters' cases), and most patients with
pulmonary fibrosis had abnormal chest x-rays. Four patients received
substantial benefit from steroid treatment. Fibrosis should be considered a
possible complication of ergot dopamine agonists (bromocriptine and
pergolide) in patients with new dyspnea, chest pain, weight gain, or dysuria.
Work-up should include electrocardiogram (ECG) and computed
tomographic (CT) scans of the chest, abdomen, and pelvis.

Apomorphine
Trosch and colleagues[5] presented the results of a 6-month study of
intermittent subcutaneous apomorphine for patients with advanced PD.
Patients were premedicated with trimethobenzamide for 3 days to help reduce
nausea and then underwent inpatient dosing of apomorphine. Dosing began at
2 mg and increased in 2-mg increments to a maximum of 10 mg (mean, 5 mg)
to achieve an optimal response. Patients then continued their optimal dose of
apomorphine on an as-needed basis and were evaluated at 1 and 2 weeks as
well as 1, 4, and 6 months. In all, 32 of 56 patients completed 6 months of
treatment. At the 6-month evaluation, benefit in the Unified Parkinson's
Disease Rating Scale (UPDRS) motor scores was observed at 20, 40, and 90
minutes post dose, similar to what had been seen at the beginning of the
study. Adverse events were mild to moderate and included nausea, vomiting,
and injection-site reactions; 17 of 56 patients discontinued treatment because
of adverse events.

This study demonstrates that the benefit of apomorphine injections is
sustained through at least 6 months of treatment, although almost a third of
patients discontinued because of side effects. Apomorphine subcutaneous
injections are now approved in the United States as rescue therapy for
patients with motor fluctuations. It has a relatively rapid onset of action (10-
15 minutes in other studies) and lasts approximately 90 minutes.




Future Medications

Rasagiline
Rascol and colleagues[6] presented the results of a comparative randomized
study of rasagiline* vs placebo or entacapone as an adjunct to levodopa in
patients with motor fluctuations (the LARGO study). Rasagiline is an
irreversible monoamine oxidase type B (MAO-B) inhibitor that is expected to
be approved as once-daily monotherapy for patients with early PD and as an
adjunct to levodopa in those with advanced PD. In this study, both rasagiline
1 mg once daily and entacapone 200 mg, with each levodopa dose, reduced
daily OFF time by approximately 1.2 hours as compared with placebo, which
reduced daily OFF time by 0.4 hours (P < .0001). In clinical practice,
rasagiline and entacapone can be administered concurrently, and it is
anticipated that their benefits together should be greater than either alone
because they have different mechanisms of action.

*Agent not currently approved for the indication discussed

Rotigotine
Watts and coworkers[7] reported the results of a prospective, randomized,
placebo-controlled trial of rotigotine* transdermal patch for patients with
early PD (n = 277). Patients were started at a dose of 4.5 mg/day and titrated
to as much as 13.5 mg/day. They were then followed through a 6-month
maintenance phase. Approximately 80% of patients completed the
maintenance phase, and rotigotine was associated with an improvement in
UPDRS activities of daily living (ADL) plus motor score of approximately
5.3 points as compared with placebo (P < .0001). The most common side
effects (rotigotine vs placebo) were application-site reaction (43% vs 12%),
nausea (41% vs 17%), somnolence (33% vs 19%), and vomiting (95 vs 1%).
The rotigotine transdermal patch is now in phase 3 evaluation as monotherapy
in early disease and as an adjunct to levodopa in advanced disease.

*Agent not currently approved for the indication discussed

Istradefylline
LeWitt and colleagues[8] presented the results of 2 prospective, randomized,
multicenter studies of istradefylline (KW-6002)* as an adjunct to levodopa
for patients with motor fluctuations. Istradefylline is an adenosine A2A
receptor antagonist that improves parkinsonian signs in animal models
without increasing dyskinesia. In 1 of the current studies, 40 mg/day of
istradefylline reduced OFF time by 1.2 hours as compared with placebo (P =
.0006). In the second study, there was a strong trend for a reduction of the
percentage of daily OFF time with 20 mg/day or 60 mg/day of istradefylline
as compared with placebo. When the baseline percentage OFF time was
included as a covariate, these differences were significant (P = .026 and P =
.024, respectively). Istradefylline is now in phase 3 clinical trials as an
adjunct to levodopa. No results are yet available regarding its use as
monotherapy in early disease.

*Agent not currently approved for the indication discussed

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PD -- Interventional Techniques

Subthalamic Nucleus Stimulation
Chronic subthalamic nucleus stimulation is now a widely used treatment for
patients with major disability caused by motor fluctuations. However, some
patients experience inadequate improvement following surgery. Batir and
colleagues[9] evaluated whether reimplantation of electrodes closer to the
target would provide benefit in such patients. They reimplanted electrodes in
6 patients who experienced an inadequate response and found that 5 had
improved substantially. OFF motor scores and Schwab and England activities
of daily living scores improved; levodopa doses were reduced; and major
improvements in dyskinesia and motor fluctuations were observed. The
distance from the electrical contact to the theoretical subthalamic nucleus
target was reduced from 5.7 to 1.7 mm. This experience indicates that
patients with an inadequate response should be evaluated for reimplantation
to move the electrodes closer to the target.

Glial Cell Line-Derived Neurotrophic Factor Infusion
Patel and coworkers[10] presented the 2-year results of their phase 1
evaluation of glial cell line-derived neurotrophic factor * in 5 patients with
advanced PD. They identified no serious side effects. OFF UPDRS motor
scores improved by 57% and ADL scores improved by 63%. PET scans
demonstrated a 60% increase in fluorodopa uptake in the posterior putamen.
Thus, the results of this initial open-label safety study remain very
encouraging through 2 years. A double-blind study is now underway.

*Agent not currently approved for the indication discussed



 =============================================

Best,

Bob




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