Following is a transcript of a radio interview with Warren Olanow, =

Professor of Neurology at Mount Sinai School of Medicine in New =

York. The interview was broadcast on The Health Report, Monday, =

15th September, 1997, on ABC Radio National.
--------------------------------------------------------
(c) 1995, 1996, 1997 Australian Broadcasting Corporation

Parkinson's Disease
------------------
(N.S. =3D Dr Norman Swan; Prof. O. =3D Prof. Olanow)

   N.S: And now to a brain disease which, like Alzheimer's is =

uncomfortably =

common as we age. It's Parkinson's. And while there are drugs to treat =

it they are far from ideal. So researchers have been looking at drugs =

which might prevent the disease's progress and even forms of brain =

surgery including transplantation and a technique called 'deep brain =

stimulation'. One of the people who's been involved with all three is =

Warren Olanow, who's Professor of Neurology at Mount Sinai School of =

Medicine in New York.
   Prof. O.: Parkinson's is a disease that is due to degeneration =

of nerve cells in the centre of the brain called the Substantia Nigra. =

When these cells degenerate patients lose a chemical called dopamine. =

And this results in a number of signs and symptoms which include =

tremor, rigidity or stiffness, bradykinesia or slowness, and difficulty =

with walking, tendency to fall, postural instabilities etc.
   N.S: Has it also recently been shown that it's actually =

more widespread than the substantia nigra, large parts of the brain =

are affected and it can affect thinking ability as well?
   Prof. O.: Yes, but half or maybe a third of patients with =

Parkinson's disease eventually will develop problems with cognitive =

function.
   N.S: And before we get into your research in particular, =

do we know what causes this, because there've been famous cases of =

drug induced Parkinson's disease - do we know what causes common =

Parkinson's that affects people in their 60s and 70s.
   Prof. O.: The short answer is no. Approximately five percent =

of cases have an inheritance pattern suggestive of a gene defect. =

It is also suspected that there are environmental factors, perhaps =

toxins or infectious agents that can cause Parkinson's disease, but =

the bottom line is we don't know what causes it.
   N.S: Now you've been looking at ways of trying to =

minimise the damage once somebody's been detected with early =

Parkinson's disease and in different ways of treating Parkinson's =

disease once it's established. Let's start off with this so-called =

neuro-protection because it's been a matter of some debate for some =

years.
   Prof. O.: Yes it has and it's an extraordinarily exciting =

concept. The principle involved is to try to find a treatment that =

will slow, or better yet, stop cell degeneration and progression =

of signs and symptoms. And perhaps most recently we have come to =

suspect that when cells die in disorders like Parkinson's disease, =

they die through a process called apoptosis, which is..
   N.S: Programmed cell death.
   Prof. O.: Right, and it provides us with another series of =

opportunities to interfere with the natural degeneration that =

occurs in these disorders.
   N.S: Now one drug that got a lot of publicity a few =

years ago in terms of neuro protection and preventing the decline =

is actually a form of an old fashioned anti depressant, called a =

Monoamine oxidase inhibitor, one called Deprenyl or selegiline, =

and some people believe it works and some people believe it doesn't =

work. You're one of the people who believes it does work?
   Prof. O.: I do believe that it does work and one has to =

differentiate where one thinks that it may or may not be working. =

We now believe that no protection associated with this drug deals =

with its ability to 'up regulate' if you will, a series of molecules =

that prevent apoptosis from occurring.
   N.S: What happens when you use it experimentally and how =

effective is it when you do look at it in the lab versus the clinic.
   Prof. O.: In the clinic is where the debate is. In the lab =

there is no question, but that the drug is protective. There of =

course we work under very controlled circumstances and we can count =

cells and we can really determine categorically and without question =

that the drug has a protective effect. In the clinic, it is more =

difficult. In our initial study what we did was we evaluated two =

groups of patients who were untreated with Parkinson's disease. =

One group got the drug and one group didn't. And what we looked =

for was to see how long it took until these two groups reached a =

level of disability that we defined as 4N end-point. What we found =

was the group that did not take Deprenyl deteriorated at a much =

faster rate. And this difference between the two groups was highly =

significant.
   N.S: In other words the rate at which they needed the =

heavy duty drugs that you normally use in Parkinson's disease.
   Prof. O.: Right. They developed disability at a faster rate, =

necessitating the introduction of additional help. Now we were =

pretty excited when we first saw that because we assumed that this =

was in fact neuro-protection. But what we came to realise as we =

looked at this more closely was that the drug had a symptomatic =

affect. That means the drug itself..
   N.S: Was actually treating the disease.
   Prof. O.: Well, not treating the disease, but treating the =

symptoms of the disease.
   N.S: Sorry.
   Prof. O.: And what we couldn't tell was whether this delay =

in developing disability was because we were protecting against =

disability or masking disability with a symptomatic drug. And =

that's where all the confusion has been. There are those in the =

camp - there's no question it delays the appearance of disability, =

but some believe it is protecting and that's why it protects, or =

it delays.. And others believe that it is just a minor anti =

Parkinson symptomatic drug and that's why it delays. Now when we =

see protection in the laboratory it makes us hopeful that somewhere =

in there one could tease out a neuro-protective effect. And we =

recently published a series of studies in which we felt that we =

could in fact show that there was a protective component in =

Parkinson patients, but the problem is if you go a number of years =

and you say - okay, let's get right down to the bottom line - =

five/ten years from now do they look any different - and the bottom =

line is they really don't look any different. So the most exciting =

thing about this may be that the drug has opened a crack in the =

previously unknown area of neuro-protection.
   N.S: And buried in there there's some other chemical entity
that will work much better.
   Prof. O.: Right, we might be able to find a way to exploit this. =

Now, what's really been exciting lately is a recent series of =

discoveries from our laboratory in which we have shown that selegiline =

is metabolised to another drug called des-methyl selegiline, and that =

in fact it is the des-methyl selegiline that is the protective =

component not Selegiline. So when you give Selegiline you give both, =

but that comes with good and bad. It comes with the good which is the
protective part, but it also comes with the M.A.O.B. inhibition portion =

which ..
   N.S: ... also has side effects.
   Prof. O.: Has side effects and it limits your ability to be =

able to administer the protective component. Now that we've sorted =

out that it is the des-methyl that appears to be responsible for =

protection. We can now begin a series of treatments where we evaluate =

this drug which hopefully we can push to higher and higher doses =

and not run into limitations because of side effects.
   N.S: There's been a lot of talk about, over the years =

also about transplantation, putting in foetal cells which might =

be able to produce this dopamine, this deficient chemical =

transmitter in Parkinson's disease, and you've been doing a lot =

of work in that - what are the findings so far?
   Prof. O.: Well the findings are very encouraging. With =

our group we've done what's called a pilot study where we've =

studied a small number of patients, we've given them transplants, =

and I'm pleased to tell you that in each instance the patients =

have improved - that it's now been more than two years and in =

each instance the benefit persisted. We measure this with a test =

called fluorodopa uptake on pet scan which is an objective marker
 and what we find is a gradual continual increase in fluorodopa =

uptakes, that's very encouraging.
   N.S: The pet scan being a scan which you can give =

different radioactive chemicals to somebody and see how the brain =

is actually functioning in different parts.
   Prof. O.: Correct, and in our case we use a dopaminergic =

marker that let's us know how the dopamine cells are doing. What's =

been the most exciting part of this is that sadly one of our =

patients passed away approximately a year and a half after the =

transplant procedure. They had enjoyed a remarkable improvement. =

When they died we had the opportunity to examine their brain and =

what we found was that the implanted cells had survived in a =

robust fashion and had re-enervated the target area in virtually =

a normal fashion - almost indistinguishable from what it should =

have looked like. So that gave us enormous enthusiasm for =

continuing this work in the hope that this kind of treatment =

will prove useful.
   N.S: Are these foetal brain cells or foetal adrenal =

cells - this gland above the kidney?
   Prof. O.: These are foetal dopaminergic cells from the =

substantia nigra. The adrenal studies were in vogue for a short =

while - they really never did much either in the laboratory or =

in the clinic and I don't think anyone is doing it now.
   N.S: That was a Mexican group, wasn't it, doing that?
   Prof. O.: It was a Mexican group that argued in favour of =

this procedure and reported very dramatic benefits back in the =

80s, but that never was reproduced in either our work or anyone =

else's that I know of.
   N.S: Now for a long time in the United States there =

was a ban on using foetal tissue for this sort of thing - that =

bans now lifted? And associated with that question if this does =

not expand where are you going to get foetal substantia nigra =

cells - are there ways of growing them in the lab?
   Prof. O.: There was a ban under the Reagan and Bush =

Presidency for the use of foetal cells in patients. There was =

never a ban on experimentation. Under the Clinton administration =

that ban for patients has been lifted and in fact the bulk of our =

funding does come from the Federal Government for these studies. =

On the other hand there is no question that there are societal =

and logistical issues here, and that if we could find an alternate =

source of cells that could provide similar or perhaps enhanced =

benefits it would be preferable. Our group and many others are =

exploring that possibility. One of the things that's very exciting =

as well is that you can take cells today and you can manipulate =

their gene structure so that you can take cells and encourage =

them to produce more dopamine to behave in a more desirable =

fashion, to release trophic factors. And the hope is that we =

will be able to generate a supply of these kinds of cells.
   N.S: So tailored designed for this purpose.
   Prof. O.: Yes, and it will be available for widespread =

use - if it ever turns out to be effective.
   N.S: Because really one doesn't know until you've =

got large numbers of people and you're in this Catch 22 situation =

that you can't really move to huge trials of transplantation =

without the source of material.
   Prof. O.: Well I don't know that it's the source of =

material that's limiting. I think this is one of those issues =

where the work involved is tedious, the data is still very =

preliminary and I think what most people are looking for is more =

conclusive evidence that it really works before it become more =

widely considered.
   N.S: You're reasonably confident?
   Prof. O.: I'm reasonably hopeful. We're currently doing =

a large blinded trial and when that's study's completed then I =

hope we'll be in a better position to comment on it.
   N.S: Oh really, so you're operating on people, but =

some will get foetal tissue and some wont?
   Prof. O.: Well, we're not operating on the people who won't =

get it, we're just blinding so that nobody knows what's happening. =

So one group will get a transplant and one group won't get anything.
   N.S: And see what happens.
   Prof. O.: Right.
   N.S: You've also been experimenting - one of the few =

centres in the world - with this deep brain stimulation. Tell me =

what that is?
   Prof. O.: This is really a fascinating technique that was =

pioneered by a French neurosurgeon by the name of Ben Abbid (sic?), =

and it followed on much of the current enthusiasm with Pallidotomy =

and the older experience with Thalamotomy.
   N.S: Just tell me about Pallidotomy.
   Prof. O.: These are procedures where you make lesions in =

various parts of the basal gangelia complex, which is what controls =

motor function - and it turns out that in diseases like Parkinson's =

disease where the circuitry is altered because of the Dopamine loss. =

If you make a lesion in certain key areas you actually improve =

clinical function. And that was popular back in the 40s and 50s =

and perhaps even 60s, but it fell out of favour in the 70s with =

the advent of L-dopa. But with L-dopa there are many many side =

affects.
   N.S: And just to explain, L-dopa is really the mainstay =

drug for people with severe Parkinson's disease.
   Prof. O.: That's correct. In the brain L-dopa is converted =

to dopamine to replace the dopamine that's deficient. Now because =

of the side effects people have gotten interested once again in =

the surgeries to see if there are ways that one can generate =

improvement. And there has always been this, well, let me start =

by saying some of these surgical procedures are quite effective. =

Pallidotomy for instance is very helpful in getting rid of some =

of the involuntary movements that complicate Levo Dopa. But there =

is something fundamentally unsettling about taking a brain that's =

not working correctly and trying to fix it by making another lesion =

in it. I mean if it works and it's all we have, then we'll do it, =

but there are limitations to that and there are side affects =

associated with the lesion and there are particular side affects =

if you need to do it on both sides. And the other interesting =

thing is if tomorrow we find a cure - will the cure work on =

somebody who has ..
   N.S: is already damaged.
   Prof. O.: Right, who's already damaged now from the treatment. =

So there is this need to do something beyond that. What Ben Abbid =

(sic?) reasoned was that if you put an electrode into the same target =

and you fire the electrode at a very fast rate, about 180-times a =

second - you would functionally reproduce the effects of a lesion. =

But if you stop the stimulation..
   N.S: It's undamaged - you haven't fried it.
   Prof. O.: You haven't fried it and if there are side affects =

they will go away and it allows you to do it bilaterally, and also =

to attack target areas that you wouldn't normally be willing to put =

a lesion in. And what he did then was try this and he hooked up the =

electrode to a pacemaker that was placed over the chest - just like =

you would use for a heart procedure.
   N.S: Except electrodes are in the brain rather than in =

the heart.
   Prof. O.: Exactly. And he found that it was extremely effective. =

He tried it for tremor and reported dramatic benefits in about 80 =

percent of patients. He's now followed some of them for five, six, =

seven years. And they continue to do well.
   N.S: Just explain the technology - do they have multiple =

electrodes and does the patient fire it off himself or herself, or =

is it like a pacemaker, does it kick in of its own accord?
   Prof. O.: There is a series of electrodes that are placed in, =

on a single wire that are in the target region and are connected to =

a pacemaker over the chest, and the pacemaker can be turned on or =

off with a magnet. Generally the pacemaker is left on most of the =

time. And it works. And is very dramatic, you turn the pacemaker =

on and the tremor goes away - you turn it off and it comes back. =

We tried the same experiment in our group and collectively in the =

United States, and our results have been almost identical to those =

of Ben Abbid (sic?) with again about 80 percent having dramatic =

improvement.
   N.S: Just to the tremor?
   Prof. O.: Well we were only looking for tremor placing the =

electrode in a region called the thalamus. But the tremor is a =

minor part of Parkinson's disease. The more important parts are =

the stiffness, the slowness, the gait problems. So we were very =

anxious to see if other target areas might be more effective and =

in particular we're interested in one called the sub-thalamic =

nucleus. And this is an area that no one would be willing to lesion
because it creates a series of problems or side affects that can be =

very serious.
   N.S: Because that has more functions than just this one to =

do with Parkinson's disease?
   Prof. O.: Well it turns out that if you make a lesion there =

they develop wild flailing movements called hemi ballismus. So in =

any event with Ben Abbid (sic?) and our group we began putting =

electrodes in the sub-thalamic nucleus, connecting them to a =

pacemaker and it turns out that preliminarily it would seem that =

patients are very much improved by this procedure. And that it =

is relatively easy to do if you have a group that is experienced =

in stereotaxy and neurophysiology and Parkinson's. So we are very =

anxious to continue to explore this strategy and to see if it will =

allow us to accomplish the same thing or perhaps more than what a =

pallidotomy does, but without the need to make a lesion and with =

the ability to do it on both sides.
   N.S: And the people it works for are they off their drugs, =

or are they still on them.
   Prof. O.: Generally speaking we've kept our patients on drug =

in all of these experimental procedures. The Swedish investigators =

have withdrawn several patients from drug - who have had transplant. =

With the sub-thalamic nucleus stimulation the stimulation effects are =

very similar to the benefit that you get with medication. So it is =

conceivable that you might be able to get away with lowering or even =

stopping drug, although no-one's really pushed that yet.
   N.S: And have you done a double blind study on the one =

person when they don't know whether the electrodes are on or off, and =

the doctor doesn't know. Does that pan out?
   Prof. O.: Yes, we have actually done double blind studies in =

that way. It's not as simple as it sounds because there are little =

electrical buzzes that kind of give you a clue, but the results when =

they work are so dramatic that it's hard to blind someone. I mean if =

somebody is not moving and then they start to move, it's pretty clear =

cut.
   N.S: Warren Olanow, who's Prof. of Neurology at Mount Sinai =

School of Medicine in New York.

References:
Olanow C.W. - GPI Pallidotomy - Have we made a dent in Parkinson's =

Disease? Annals of Neurology 1996; 40:341-343.
Mytilineou C. et al - L-Deprenyl protects mesencephalic dopamine =

neurons from glutamate receptor mediator toxicity in vitro. Journal =

of Neurochemistry 1997; 68: 33-39.
Olanow C.W. et al - Fetal Nigral transplantation as a therapy for =

Parkinson's Disease. Trends in Neuroscience 1996; 19:102-109.
------------------------------------------------------------- =

The Health Report is broadcast at 8.30am and repeated at 8.00pm =

every Monday on Radio National, the Australian Broadcasting =

Corporation's national radio network of ideas.
------------------------------------------------------------- =

Posted by Bruce Wallace, brother of Ken (63/4).