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).