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ESI Special
Topics: August 2007
Citing URL: http://esi-topics.com/parkinson/interviews/YvesAgid.html |
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An INTERVIEW with Professor Yves Agid |
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 arkinson’s
disease (PD) is a disorder of the central nervous system that
impairs the sufferer’s speech and motion. These symptoms are
caused when the basal ganglia fail to stimulate the motor cortex
because the action of the neurotransmitter dopamine is impaired.
In North America this widespread disease affects 1-2% of the
population older than 65 years.
According to our Special Topics analysis of
neuroscience research on PD, Yves Agid, who has spent his entire
career at the Pitié-Salpêtrière University Hospital in Paris, is
the top-ranking researcher over the past decade, with 117 papers
cited a total of 5,702 times. In
Essential
Science IndicatorsSM Professor
Agid’s work can be found in the fields of Neuroscience &
Behavior, Clinical Medicine, and Molecular Biology & Genetics.
His most cited paper on PD, "Association between early-onset
Parkinson’s disease and mutations in the parkin gene" (Lücking
CB, et al., New Engl. J. Med., 342, 1560-1567, 2000) has
378 citations to date. In this interview he talks with
correspondent Simon Mitton about his life’s work on the
neuroscience of PD. |
 In
the past decade, the 10 most-cited papers on which you are a co-author
have logged 2,300 citations. The range of topics on which you have
worked is impressively broad, encompassing genetic mutations, deep-brain
stimulation, and the apoptotic death of neurons. And this is research
that you are carrying out in a busy hospital rather than in a detached
research institute. What is the background to this huge research effort
in neurosciences in the heart of Paris?
I am 66 now, and have always wanted to do medical research in the
field of the mechanism of brain function. I had medical training,
M.D., in both neurology and psychiatry, and I also have a Ph.D. in
neurosciences. During my entire professional life I have been a
clinician as well as a real scientist, and that dual role has been
the key to our success.
My guiding principle is that we must have a good clinical
practice, given that we are in such a large hospital (100,000
patients a year). Consequently, we need to provide high-level
teaching to train the doctors of the future, and you only have a
platform for that if you are doing research. This idea of clinical
practice based on teaching, which is itself based on research, is
absolutely crucial to the best practice in a medical university.
My second principle is that our research must have a
multidisciplinary approach, including a continuum between molecular
biology and behavioral research. However this interdisciplinary
approach raises a question that is the same in all countries that I
have visited: clinicians and scientists cannot talk to each other
because they use different languages, and have different methods of
working.
My big idea has been to have intermediaries between the
clinicians and the scientists. I have taken great care to recruit
clinical researchers who are in fact M.D.’s located in the hospital,
both in the wards and the clinical research center. They also have a
good scientific background, normally a Ph.D. Such people can provide
information both to the scientists and to the hands-on clinicians.
How
did you get into the field in the first place?
The history is that after my Ph.D., I left the Collège de France,
and I walked in here with no money or resources for research.
Nothing! The easiest way to get started was to buy human brains,
because at that time they cost 20 cents. We started to do some
biochemistry of the human brain, which was then quite novel. The
only person who had done this with real success was Oleh
Hornykiewicz in Austria, with whom I collaborated.
Since I had a good scientific background, we were able to show,
for example, that in Parkinson’s disease we were dealing with
several types of lesions in the brain, and we found many
impairments. Then we looked at the mechanism of cell death in
Parkinson’s.
Later I migrated towards movement disorders. In my lab we started
in addition to biochemistry, molecular biology. Then we added
neurophysiology in animals (non-human primates) and humans. Right
now in the group we have people working in molecular biology, cell
biology, genetics, neurophysiology, and behavior, with a special
interest in movement disorders.
What
is the international standing of the Institute for Brain and Spinal Cord
Disorders?
When I started out, in 1977, there was almost no research here,
and now our setup, which is a virtual institute, comprises,
altogether, 850 people working in many different laboratories. We
carry out just over 11% of all French research in neuroscience. We
are a center of excellence for both research and patient care.
Could
you describe the background to two of your top papers where the topic is
apoptotic death of dopaminergic neurons (Anglade P, et al., "Apoptosis
and autophagy of nigral neurons of patients with Parkinson’s disease,"
Histol. Histopathol. 12: 25-31, 1997; and Hartmann A, et al.,
"Caspase-3: a vulnerability factor and final effector in apoptotic death
of dopaminergic neurons in Parkinson’s disease," PNAS 97:
2875-80, 2000)?
In the 1980s, we concentrated on biochemical aspects of PD and
related disorders. Then we moved on and were really interested in
the mechanism of nerve cell death. This is where the first paper is
relevant. So, what did we achieve, compared to other researchers?
Three things.
First, our papers show the vulnerability of dopaminergic neurons
in general, which are more susceptible to any kind of attack.
Secondly, we found that in PD the dopaminergic neurons were dying
through apoptosis, or programmed cell death. If you have a
dopaminergic neuron in the brain of a normal person it lives for a
century; it loses its function somewhat over time, but it is still
alive. In PD, some of the neurons are progressively and selectively
dying. Death is slow, but it is more rapid than similar effects due
to natural aging. Among these diseased cells that we have observed a
few of them are dying through apoptosis. Although there are
anti-apoptosis drugs, they don’t do much good. By this stage the
neurons are in a state of agony. If you stop that, the neurons are
nevertheless still diseased, which means we really have to work on
the disease itself.
Our third point was to insist on the different mechanisms of
nerve cell death, including the mitochondria. What was new perhaps
was the role of inflammation, which is highlighted in the PNAS
paper. Etienne Hirsch, who is now head of the laboratory, is a
co-author of this paper, and has done a lot in this field in
relation to cytokines.
A
second front for your group is the molecular genetics of PD. What are
your main findings?
Yes, our second big approach is molecular genetics. This is due
to my colleague Alexis Brice, who was given the lead and who is a
co-author of my most-cited paper in your analysis. The main finding
in that clinical study is that mutations in the parkin gene
are a major cause of early-onset PD.
Our big advantage in genetics research stems from our large
database of patients here. Our patients want to contribute to the
research. Over time we have looked at chronic neuropathy, hereditary
neuropathy (Charcot-Marie-Tooth disease), cerebral ataxia, and
finally Parkinson’s disease.
What
is the third frontier of research on PD?
We’re on to
something entirely new, which is to show that PD is in fact a
neuropsychiatric disorder. It has been known for a century that it
was a motor disorder. But what is less well known is that it is a
cognitive disorder (although this was found to be the case 30 years
ago). Hundreds of papers have been published about the intellectual
state of PD patients, which is different across the various forms of
the disorder.
Right now there are several lines of evidence indicating that PD
is an emotional disorder. My colleague Luc Mallet here has a core
program to study the links between the functioning of the basal
ganglia and psychopathology. We need to know how cognition, motion,
and emotion combine in the basal ganglia. Emotions are very likely
controlled and shaped in the basal ganglia. It is possible to
trigger an acute depression or hypomania just by manipulating the
basal ganglia. And if you keep in mind that the basal ganglia are
the most important brain structure in the pigeon and the snake then
you start to understand that what we call emotion (which can lead to
feelings and passions) probably exist in these animals as well. They
are very old structures in terms of the evolution of animals. This
is the most exciting aspect at the present time.
Finally,
three of your top papers are all on deep-brain stimulation (Obeso JA,
et al., "Deep-brain stimulation of the subthalamic nucleus or the
pars interna of the globus pallidus in Parkinson’s disease," New
Engl. J. Med. 345: 956-63, 2001; Bejjani B, et al., "Pallidal
stimulation for Parkinson's disease—two targets?" Neurology 49:
1564-69, 1997; and Ardouin C, et al., "Bilateral subthalamic or
pallidal stimulation for Parkinson's disease affects neither memory nor
executive functions: A consecutive series of 62 patients," Ann.
Neurol. 46: 217-23, 1999). What are the main findings from these
papers?
We have a lot of experience in treating patients with PD
using deep-brain stimulation. In the past PD would be treated
surgically by making lesions to destroy brain tissue. Naturally
this procedure had many risks. In deep-brain stimulation of the
subthalamic nucleus we simulate the effect of a lesion without
destroying tissue. The results have been dramatic, which is why
the first paper, the result of a huge international
collaboration, is highly cited.
Sometimes it is possible to treat extraordinary emotional
disorders by deep-brain stimulation. In one patient we saw acute
transient depression that started immediately when one electrode
contact was activated, and this disappeared instantly when we
stopped the electrical stimulation. The electrode was located
close to the subthalamic nucleus, actually in the substantia
nigra. In a CAT scan we saw that by stimulating this very
specific contact which triggered a transient depression we were
in fact activating all the limbic systems (known to be
implicated in the control of emotions). This discovery probably
gives psychiatry a new frontier.
Professor Yves Agid, M.D. Ph.D.
INSERM AVENIR Group
CHU Pitié-Salpêtriè
Paris, France
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ESI Special
Topics: August 2007
Citing URL: http://esi-topics.com/parkinson/interviews/YvesAgid.html
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