Download 2001-2002 - Parkinson Canada

Parkinson Society Canada
National Research Program
for 2001-2002 Cycle
Granting period
January 1, 2001 - December 31, 2002
OPERATING GRANTS
Researcher: Friedman Grant - Parent, Dr. André
Name of Project: Dopamine neurons and fiber pathways in human basal ganglia
Institution: Centre de recherche University Laval
Amount Year One: $40,000
Amount Year Two: $40,000
Total Awarded: $80,000
Lay Summary: The aim of this research program is to elucidate the structural organization of
different aspects of neurons and neural fiber systems that use dopamine (DA) as a neurotransmitter
and are part of the so-called basal ganglia. This set of subcortical structures, which lie at the basis of
the identified neuronal systems to be studied are those that specifically degenerate in Parkinson's
disease (PD). The proposed investigations will be undertaken principally with postmortem brain
material obtained from normal individuals and patients with PD and by using highly specific antibodies
to recognize and label the DA-containing neurons and fibers. In a first set of experiments, anatomical
methods and a computerized image analysis system will be used to obtain a three-dimension picture
of the organization of the entire DA fibers associated by the basal ganglia. These normative data will
then be used to compare the specific alterations that occur in this complex neuronal system in cases
of PD. The second set of experiments will deal with a recently discovered population of DA producing
cells that lie within the one of the major component of the basal ganglia called the striatum. New
knowledge about this cell population could have a major impact on how we see the actual
organization of the forebrain DA systems and how we treat PD patients in whom these systems are
undergoing progressive degeneration.
Researcher: Albert, Dr. Paul R..
Name of Project: Regulation of Dopamine D1 Receptors by Protein Kinase
Institution: University of Ottawa
Amount Year One: $40,000
Amount Year Two: $40,000
Total Awarded: $80,000
Lay Summary: Parkinson's disease is manifest as impaired control of body movement in which the
nerve cells that synthesize dopamine progressively degenerate. Parkinson's disease is treated with lDOPA, a precursor that is converted to dopamine within the surviving dopamine cells. Sadly, the
remarkable recovery of patients on l-DOPA therapy is short-lived. To enhance and stabilize l-DOPA
action, current therapies use dopamine receptor agonists in conjunction with l-DOPA. These
compounds act directly on dopamine D1 and D2 receptors located on cells that mediate dopamine's
actions. However, with prolonged treatment the response to dopamine agonists declines in part
because of a loss of D1 receptor responsiveness (desensitization) that is mediated by proteins called
1
kinases, which inactivate the receptor. We propose to identify the molecular mechanism by which
protein kinase A inactivates the D1 receptor by mutating the specific sites of modification, and then
testing the responsiveness of the mutant D1 receptors. We expect that elimination of these sites will
prevent desensitization of the D1 receptor. By preventing the changes that induce desensitization of
the receptor while enhancing the responsiveness of the receptor, the loss of responsiveness to D1
agonists and l-DOPA therapy should be alleviated.
Researcher:
Blanchet,
Dr.
Pierre
Name of Project: Clinical impact of orphenadrine on the response profile to Levodopa in
Parkinsonian
Patients
Institution:
University
of
Montreal
Amount
Year
One:
$40,000
Amount
Year
Two:
$40,000
Total Awarded: $80,000
Lay Summary: Levodopa (SinemetTM , ProlopaTM ) has been used effectively for over 30 years in
Parkinson's disease (PD) and remains the most potent anti-parkinsonian drug available.
Unfortunately, this revolutionary drug leads to a series of adverse effects in the majority of patients
after a few years of therapy characterized by a shorter response, ineffective doses, or an
unpredictable return of disability during the day, often with abnormal involuntary movements
collectively called "dyskinesias". The research to find effective solutions to improve, reverse or
prevent these adverse events has focused on the development of novel dopaminergic drugs and
surgical strategies. A recent shift in experimental paradigm has been possible after it was discovered
that PD itself and its treatment have an impact on several other chemical messengers in the brain
aside
the
dopamine
loss.
New hope for effective therapy of complications brought about by levodopa has recently focused on
an important excitatory brain chemical called glutamate. In animal models of PD, certain glutamate
pathways seem to work excessively or in a chaotic way following exposure to levodopa. One weak
glutamate blocker, amantadine, has shown efficacy in the relief of response fluctuations and
dyskinesias in a subset of patients. Another glutamate blocker, orphenadrine, may more potently
reduce these complications. The research proposed in this application will test the clinical and
metabolic impact of oprhenadrine in a double blind, placebo-controlled, pilot study. Fifteen patients
will come to the research centre 6 times over 10-12 weeks to receive levodopa intravenously to study
more accurately their clinical response while taking placebo or orphenadrine tablets. The response
will be measured with home diaries, clinical motor scales, motor control tests, neuropsychological
tests, and imaging with nuclear brain scans. Positive results with orphenadrine would be directly
applicable to PD treatment and support its use in a larger patient population, with the hope to improve
the quality of life and delay surgical options to relieve these often disabling response fluctuations.
Researcher: Doering, Dr. Laurie
Name of Project: Stem Cell therapy for Parkinson's
Institution: McMaster University
Amount Year One: $40,000 (one year grant)
Amount Year Two: n/a
Total Awarded: $40,000 (one year grant)
Lay Summary: In recent years, the science of neural transplantation has moved from the laboratory
to the clinical treatment of certain patients with Parkinson's. The hope continues that this and other
neurodegenerative disorders can be corrected by transplanting specific types of cells into the brain.
2
As an alternative to the use of fetal neurons from human embryos, neural stem cells, grown in culture
are now under intense study. Stem cells show remarkable potential to replace cells that die via aging
or injury in the nervous system. It is necessary to fully understand the biology that governs the
survival and death of stem cells that may be used for neural transplants in cases of Parkinson's. The
experiments in this grant will directly compare different types of stem cells in terms of their survival
and potential to correct the functional deficits associated with Parkinson's.
Researcher: Fon, Dr. Edward A
Name of Project: Role of Parkin-Mediated Ubiquitination in Parkinson's Disease
Institution: McGill University
Amount Year One: $40,000
Amount Year Two: $40,000
Total Awarded: $80,000
Lay Summary: Parkinson's disease (PD) involves the death of dopamine neurons in the midbrain
and leads to devastating motor and functional impairment. Although treatment is available, its
effectiveness diminishes over the long term. Hope for a more definitive treatment lies in basic
biomedical research. Already, important advances have been made using molecular and genetic
approaches. Not very long ago, genetics was not thought to be important in PD. However, in the past
four years alone, three genes have been identified which cause familial forms of PD. Of these genes,
"Parkin" accounts for more cases than all the others combined. It is responsible for a young-onset
familial form of the disease as well as certain non-familial cases. My laboratory is interested in
understanding the normal function of Parkin and how defects lead to PD. It appears that Parkin
functions as a key enzyme in the main system fro protein degradation in the cell, the ubiquitin
proteasome pathway. A hypothesis which we are pursuing is that defects in Parkin function might lead
to inefficient protein degradation and the accumulation of potentially toxic proteins within DA neurons.
Understanding Parkin function will undoubtedly enhance our understanding of the mechanisms of
dopamine neuron death in PD.
Researcher: Hagg, Dr. Theodoor
Name of Project: Nigrostriatal recovery using PTP inhibitors and neurotrophic factors
Institution: Dalhousie University
Amount Year One: $40,000
Amount Year Two: $40,000
Total Awarded: $80,000
Lay Summary: Neurotrophic factors are proteins in the brain and we have shown that such factors
can rescue injured adult rat brain cells of a region called the substantia nigra. This region contains the
cells that are lost in Parkinson's disease. Neurotrophic factors "switch on " signaling receptors in the
cell and are "switched off" again by other molecules called protein tyrosine phosphatases (PTPs). We
have tested a chemical that blocks PTPs, as it might cause the trophic receptors to remain "on" for a
longer time. This chemical protected injured dopaminergic brain cells in rats, suggesting that the
survival effects of trophic factors in the brain were potentiated. The PTP inhibitor chemical could also
dramatically increase the rescue ability of infused brain-derived neurotrophic factor. We now wish to
confirm that the trophic factor receptors are "switched on" for longer times after treatment with the
PTP inhibitor using cultured cells and animal models. We also wish to understand how functionrelated molecules can be increased after the treatment. These studies will validate our new treatment
approach for degenerating substantia nigra cells and provide us with research tools to understand
how to improve upon this therapeutic approach. The advantage of this exciting novel approach over
3
that of neurotrophic factors is that it would use small chemicals that readily can reach and diffuse
throughout the brain. This study also will increase our understanding of how dopaminergic neurons
function and is expected to identify new ways to develop treatments for Parkinson's disease.
Researcher: Martin, Dr. Wayne R. & Weiler, Dr. Marguerite
Name of Project: Freezing of Gait in Parkinson's Disease: Potential Benefit from Botox Injection
Institution: University of Alberta
Amount Year One: $26,000
Amount Year Two: $26,000
Total Awarded: $52,000
Lay Summary: Parkinson's disease (PD) is a slowly progressive neurologic disorder. Tremor,
slowness, stiffness, poor balance, and difficulty walking are part of PD. Medications, particularly
levodopa, improve many PD symptoms. However, walking problems often do not respond well to
drugs. One particular problem, freezing of gait (FOG), responds very poorly to drug treatment.
Freezing can occur during walking. The person is suddenly unable to take a step. They often describe
the sensation of the foot suddenly being glued to the ground. Sometimes "tricks", like stepping over a
line or counting out loud, may help them to move again.
There is one treatment that may reduce the frequency and/or severity of freezing episodes. This
involves injecting a small amount of botulinum toxin A - BTX-A (a kind of toxin) into calf muscles. BTXA has been used for many years to treat another condition, dystonia. Dystonia shares some features
with FOG, including temporarily overcoming the problem with "tricks". BTX-A acts directly where a
nerve enters a muscle. This produces temporary muscle weakness. BTX-A may also have effects on
the muscles themselves, producing a long lasting "sensory trick". This indirect effect may explain
improvement in FOG in PD.
This study will look at the effect in 20 subjects receiving BTX-A versus saline injections. Assessments
will obtain objective and subjective information on the effects of the BTX-A versus saline on freezing
and its effect on everyday activities.
Researcher: Rouillard, Dr. Claude & Levesque, Dr. Daniel
Name of Project: Role of dopamine D1, D3 and serotonin receptors in levadopa-induced
sensitization in an animal model of Parkinson's disease
Institution: Laval University
Amount Year One: $40,000
Amount Year Two: $40,000
Total Awarded: $80,000
Lay Summary: Parkinson's disease is characterized by an extensive degeneration of the nigrostriatal
dopamine pathway. Current symptomatic treatment for Parkinson's disease is based largely on
dopamine replacement therapies. Conventional therapy include the use of dopamine precursors such
l-DOPA, the use of dopamine agonists such as bromocriptine, pergolide, pramipexole, ropinirole,
and/or the use of monoamine oxydase inhibitors such as selegiline. However, motor fluctuations and
l-DOPA-induced dyskinesias represent a common and serious problem during chronic treatment of
patients with Parkinson's disease. The fact that the appearance of dyskinesias chronic treatment with
l-DOPA in association to the chronicity of dyskinesia suggest that they result from persistent changes
in the brain leading to behavioural sensitization in response to dopamine stimulation. Recent studies
have provided strong evidence that the dopamine D1 and D3 receptors might be involved in
4
behavioural sensitization in animal models of Parkinson's disease. Two important goals are set in this
grant proposal: 1) to understand the cascade of events leading to behavioural sensitization; and 2) to
determine how serotonin drugs can modulate the processes involved in this phenomenon. Insights
gained may significantly contribute to the design of new therapeutic approaches to treat Parkinson's
disease and help to understand the pathophysiology of dyskinesia.
Researcher: Saint-Cyr, Dr. Jean A., Dostrovsky, Dr. Jonathan & Hutchison, Dr. William
Name of Project: Radiological and Clinical evaluation of STN DBS
Institution: University of Toronto
Amount Year One: $31,000
Amount Year Two: $20,000
Total Awarded: $51,000
Lay Summary: In selected patients with Parkinson's disease in whom pharmacological treatment is
unsatisfactory, surgical treatment aimed at the chronic stimulation of the brain can be very beneficial.
The success of this method depends very much on the correct placement of wires (electrodes) deep
inside the brain. Surgeons rely on scanning (MRI) and electrical recordings during the procedure to
carefully place the electrodes. However, it is not clear what the best location should be. Although we
know that placement must be within or near a small group of cells (subthalamic nucleus), better
results might be had if stimulation was on the edge of this nucleus, near a bundle of fibres. In order to
answer this question and to determine the fastest, most accurate means of placing the electrodes, the
present grant will be aimed at sharpening normal variation of current methods. By the end of the
study, we should know exactly where to stimulate in order to get the best clinical benefit, and perhaps
have new methods to ensure that we can get there efficiently and accurately. It is also possible that
patients with different symptom profiles will require stimulation in specific locations.
BASIC RESEARCH FELLOWSHIPS
Fellow: Fallon, Lara
Field of Training: Neuroscience, cell biology
Institution: McGill University
Amount Year One: $40,000
Amount Year Two: $40,000
Total Awarded: $80,000
Frisch Fellowship
Fellow: Ohta, Shigeki
Field of Training: Neural Stem Cells and Brain Repair, Neural Gene Discovery
Institution: University of Calgary
Amount Year One: $40,000
Amount Year Two: $40,000
Total Awarded: $80,000
5
CLINICAL RESEARCH FELLOWSHIPS
Wherrett Clinical Research Fellowship
Fellow: Stefurak, Taresa L.
Field of Training: Neuropsychiatry of Parkinson's Disease, Functional Neuroimaging
Institution: University of Toronto
Amount Year One: $40,000
Amount Year Two: $40,000
Total Awarded: $80,000
6