- Most times, when I talk to support groups,
certainly over the last 11 years
that I've been here in Australia,
I have generally steered away from using
that four letter word of cure.
And the reason I've done that is
because I'm a great believer of this sort of balance
between hype and hope.
And really, I think until very recently,
I've not wanted to talk about trying to find a cure
because I think we've really not been
in a position to explore that possibility.
And so I guess, from that perspective,
most of the people in this room
will have heard me talk about exciting things
like constipation, and falls, erectile dysfunction,
and all of the things that really, really matter.
And I still believe they really, really matter.
And the bottom line is
that I'm still happy to talk about all those things.
But what I wanted to do today was to really, I guess,
lay the framework for
what we are, I hope, transitioning towards,
which is the balance of hope and hype
actually sort of colliding in a way that means
that we can actually be sensible
about trying to find a cure,
because many of you will have been on the web
and you will have found snake oil
and you will have found rhubarb baths
and electric shocks to your genitals
as proposed causes that will improve your Parkinson's,
and frankly, none of those are true.
So thank goodness, thank goodness.
So the hope is that we can know,
can actually rationalize things.
I'm delighted to have been invited
by Parkinson's New South Wales, who do some fantastic work,
and I do implore you to try and get involved with them.
Remember, if you're involved with them,
you can help drive the direction as well.
So if you're one of those people
who's dissatisfied or disgruntled,
then naturally you gotta try and be part of the solution
instead of just moaning about it,
and I think that the people in the room
who have ever been involved with any of these organizations
will realize it takes energy and people need help,
so please do get involved.
I'm delighted to see that they're recording the lecture.
I think the fact that they will be able to broadcast this
and we can go out to the Twittersphere and things
is really very good,
because it's more than the people in this room
that we wanna talk to.
And for those of you who aren't so internet-savvy
and all those things,
but you do have smartphones and the like,
there is one slide that you may want to take a photograph,
and it's the last slide.
And that slide will have essentially an internet link
to where you can find the slides,
'cause I've already put them online for you.
It'll also have things like my Twitter handle,
if you want to listen to me twittering away,
asking, telling questions, reporting on things
that I've seen in the world as it were
in the world of Parkinson's.
And it'll also have my website,
and for those of you
who I haven't bored to death about my website,
the website is there as a resource for you.
Essentially there are about a hundred videos of me
just talking to the camera.
There are some videos,
many people will remember last year's speaker
was Roger Barker, my old boss from Cambridge,
and I managed to take the opportunity to interview Roger,
so if you wanted to know more about the things he said
in that lecture on things like stem cells,
there are lectures like that.
There are lectures with me interviewing our nurse
about the NDIS and how the age care system works,
so please use that as a resource.
But what I wanna do now is just, if you like,
double back, ideally get us through this talk,
not at breakneck speed, but crisply,
'cause we have the resource, which is great,
to allow questions, because there may be questions.
I'm sensing there may be questions.
(audience laughing)
All right.
So I think the first thing we have to establish
when we're talking about a cure is
what do we mean by a cure.
Because Parkinson's does not happen overnight.
The bottom line is you don't wake up one day
with Parkinson's, unlike say, a stroke,
where suddenly you've lost
the right side of your body or whatever.
There is a long prodromal period,
often referred to as the non-motor period.
So, period where effectively you don't have the tremor,
you don't have the slowness and the stiffness,
but you do have other features that if we tuned into them,
would allow us to make a diagnosis at an earlier point.
Now we don't know how long that period is,
and it probably is true to say
that it varies between individual patients.
So it may be, people throw around five years,
people talk about 20 years, but effectively we have,
if you like, a window of opportunity.
And then the next question is
what's happening in the brain during that 20 years,
and the answer is cells are dying.
So not all of the cells, not uniformly,
but patterns of cells, and these are the patterns that,
if you like, lead to the symptoms that we see,
the physical symptoms and the non-physical symptoms.
So we can talk about some of those,
if you like, systems a bit later on.
But effectively by the time someone is diagnosed
after this five to 20 years, cells will have died.
And I have to be honest
and say the first question that arises is,
is a cure where we could reincarnate cells.
And the answer is probably not.
The chances of reincarnating a dead cell,
I think are zero, frankly.
And people need to know this
in the context of stem cells as well.
Roger's a great advocate of stem cells,
I'm very happy to talk about stem cells,
but you need to know what we mean about stem cells
compared to what you mean about stem cells.
When I talk about stem cells,
I talk about it from what I've seen in the research world
and what people are doing there
is they are trying to put cells into the brain
that will survive, and physiologically,
that is saying a natural sort of biology kind of way,
make the chemical dopamine,
which is the main chemical that goes missing.
What those cells will never do
is make the 20,000 connections
that the cells used to have that were there.
They are never gonna repair the damage.
They may cover over the cracks,
but they're there to replace your tablets,
they're not gonna stop cells from dying.
And that's, if you like,
our best effort for replacing cells.
But the chance of us bringing cells back to life
that had been dead for maybe 20 years,
I think is zero.
But then that comes to the question of
does a cure need to offer reincarnation.
And I would propose to you probably not.
Because if you've got Parkinson's disease
and you're sitting in this room,
you will know, from what I just said,
that maybe before you got diagnosed,
you may have had a window of opportunity
where you could have been diagnosed
before your walking changed or your tremor started,
your stoop, your shuffle, whatever.
In addition to that, it may be that it's too hard,
and we can talk about diagnosing the disease
before it starts in a minute.
But let's say, for example, you cast yourself back
to that first consultation with the doctor
and your hand was shaking.
If that doctor could say,
I can stop your disease progressing,
stop those cells from dying,
or slow the rate at which they're dying in a way
that means that you will not X, Y, or Z,
end up in a nursing home, end up with dementia,
end up falling over, end up losing your independence,
I would take that deal tomorrow.
And I think probably most people in the room would too.
I would consider that, personally, to be a cure.
And we may not be able to stop the disease.
If we could slow the disease such to the point where,
let's say you're slower when you're walking
but you don't need a walking frame.
That is better than the walking frame,
that's better than if you go into a wheelchair.
And the truth of the matter is
that the bad part of Parkinson's,
this is when people end up in nursing homes,
generally is quite short.
It's generally the last 18 months of life.
But what we'd really like to do
is to stop people going to nursing homes,
stop people from falling over, stop people dementing,
and if we could do that and just keep people healthier
in their own homes,
I would personally take that as close enough to a cure.
And I think the other guy
that would have taken that is this guy.
So this is Muhammad Ali shortly after the 1960 Olympics.
I think it's fair to say he's a bit of an athlete.
He just won a gold medal,
and I think he fancied himself a bit.
(audience laughing)
And this is, of course Atlanta, 1996.
He was diagnosed at the age of 42, this is 1996.
And basically you can see already
the disease has grabbed him, but he's independent.
Now this is London, which I think was 2012,
and you can see now this is him
really unable to mobilize on his own.
He has essentially a carer there who's essentially,
and this is him shortly before his death,
the last appearance that he was videoed,
and died, I think, at the age of 74.
So if we could have taken him, maybe even in 1996,
I reckon he'd have done the deal.
I reckon we all would've done the deal.
And what we're looking at essentially is a disease
that is not static, it is an evolving disease that spreads
and we don't know for sure how it spreads,
but a couple of hypotheses are out there
and probably the most common that people will talk about
is this spread of disease going up through the brain.
And interestingly,
when it's low down there near the spinal cord,
effectively it's not touching the dopamine cells
which you need for the movement,
but it is touching things like the cells
that regulate your sleep, or your mood, or your bowels.
So that's kind of interesting because those are symptoms
that might exist in the premotor phase.
And then as the disease spreads
it'll affect those cells that make the dopamine,
which is the thing that helps us to move,
we'll see more later.
And then it keeps spreading
and gets into the thinking parts of the brain,
the parts of the brain that allow us not to dement,
allow us not to hallucinate.
But of course, over the course of the 10, 20 years,
depending on how old you are when you're diagnosed,
you're really looking at these problems.
What about this spread?
How can this spread possibly happen?
And there is a hypothesis, an hypothesis out there,
and it's called the prion-like hypothesis
and people may not be familiar with the word prion,
but you've all heard of mad cow disease, okay.
So mad cow disease,
the variant of Creutzfeldt-Jakob disease,
where essentially you ingest something,
infected cow, and it then creeps into your body
and spreads through your brain.
And if you look at these features of Parkinson's
that happen before the physical symptoms emerge,
there is often constipation,
and there is often a loss of smell.
So anosmia, losing your sense of smell.
And the idea that maybe something gets into your system,
affects those nerves first
and then just keeps growling up and going up and going up,
maybe perhaps using the nerve that goes up to your stomach,
and then from your stomach goes up to your brain,
'cause there's a nerve that comes down to your brain,
and that's often the place where we see
the first microscope signs of Parkinson's disease,
suggesting that there might be this spread.
And that allows us to think,
well maybe that would tune in to
where there's a window for a cure.
And so this is actually a list of all of the things
that people have looked for that might,
if you like, be associated with your chances of going on
and getting Parkinson's disease.
So if you're an older person
who develops things like losing your sense of smell
or constipation or anxiety
or other problems that are on this list,
as well as some of the other risk factors that we know,
your chances of getting Parkinson's disease go up.
And on the slide there, I think losing your sense of smell
increases your risk by about 3 1/2 times the rate.
So if you're not gonna get Parkinson's, your risk is one,
it goes to about 3 1/2 if you lost your sense of smell,
so it's not a major risk.
But there is one thing that really stands out on this list,
and that's this baby here.
Now, hopefully the video will play.
Video is just taking a little moment.
Ah, there we go.
So this person is asleep the whole way through this film,
he's in a sleep laboratory.
This is courtesy of the Mayo Clinic in America.
He is still asleep, but if you were lying next to him,
you're about to get what I would call a rude awakening.
So hands up, who's been punched in the room.
Yeah, so this is dream enactment behavior,
he's still asleep, by the way.
Dream enactment behavior, REM sleep behavior disorder.
So during the dream stage of sleep,
your body should be paralyzed and not able to move.
But with pathology in Parkinson's
and some of the other diseases that look like Parkinson's,
that gets broken and you can act out your dreams.
Now I mentioned that losing your sense of smell
increased your risk of getting Parkinson's
to about 3 1/2 times, or Parkinson-like diseases.
This guy here is 130 times the risk.
So if you have this in later life
and we can't find another reason
why you might be punching your wife in your sleep,
or punching your husband,
then the chances are you're likely
to go on and get Parkinson's disease,
because, after 15 years,
pretty much everyone who starts like this
ends up getting diagnosed with a brain disease.
Okay.
So, the question then
is whether we can use these patients
as our window to stop the disease ever starting.
And there is work in this space.
So patients often with this condition
will present to the sleep doctors.
They'll present to the sleep doctors
'cause there's a problem in their sleep.
That is they start punching and they start shouting
and they start acting.
And basically what people have done
is to start looking and saying,
well if we collect these patients,
are there clues that could make us more confident
that they're gonna get a brain disease, or pretty confident.
And the answer is yes.
So this is a different set of imaging,
and you'll see in that first column is healthy older people
who don't have a brain disease.
And then in the next column is those people
who act out their dreams, who don't have Parkinson's.
And in the final column on the right
are those people who have Parkinson's.
So if you look at that first panel, the top line,
you'll see those big white arrows
in a normal healthy person showing the bowel lighting up.
And we talked about constipation, the nerves being affected,
and it lights up normally.
But if you look at the next two columns,
it's not lighting up.
So in actual fact, the nerves in the bowel
in these people who have the disease
or at risk of the disease, are already affected.
Similarly, in the next row across
you'll see that big white arrow pointing to the heart,
there's a little shadow of a heart
in a normal, healthy individual.
But in the people who've got the dream behavior,
who are at risk of Parkinson's, and people with Parkinson's,
the scan of the heart, the heart nerves to the heart,
are being affected, presumably by the disease.
The next panel down is a special type of MRI scan
showing those white dots,
which are actually a part of the nervous system
that supply noradrenaline to your brain, not dopamine.
So dopamine isn't the first chemical that's being affected.
But you can see that it's lost in those people
with dream behavior and Parkinson's.
You can also see on the next panel down
the level of serotonin,
a chemical that's important for mood and anxiety.
I said that part of the brainstem
down by the spinal cord, that gets affected,
and you can see the big white arrows there
pointing at two reddish blobs
which aren't there in the guys with the dream behavior
or there in the guys with Parkinson's.
And then finally, we look at the dopamine system.
So my panel on the left,
you've got these two red teardrop-shaped things,
and that's where the dopamine is in the brain,
with those big white arrows
that make it a bit easier to see.
But interestingly, in the guys with the dream behavior,
it's okay, it's still there.
And the guys with Parkinson's, of course, it's gone,
because that's the dopamine system being affected.
So here you have the possibility of saying,
I have a patient, their dopamine system is okay.
They don't yet have
physical symptoms of Parkinson's disease,
but I know that they're going to get it.
So if I had a treatment, then we need to treat 'em now.
So that's what people are looking to do,
and this is the meeting that I was at
earlier this year I think in Germany,
probably about five weeks ago, I lose track,
with all the people from around the world,
there's yours truly,
who are all gathering cases like this.
People who, if we could get a drug to work tomorrow,
we would probably try and put it into these patients
who don't yet have the disease,
and see if we could stop them
from ever getting Parkinson's disease.
Now that may not deal with
all the people who get Parkinson's disease
because not everybody in the room's punching in their sleep,
but it would deal with probably at least a third,
maybe a half of these patients.
So that's a nice idea.
Cute, we might be able to cure the disease
in the sense that we might stop you getting
what we would call Parkinson's.
So maybe there is a hope for a cure.
But that's not really helping the people in this room,
because, effectively,
the majority of people with Parkinson's
we know have already got the damage,
so we need to slow or stop the cell death.
So then we need to know what's causing the cell death,
and that's a problem 'cause we don't know
what's causing the cell death.
But we do have some clues,
and I want to take us through the rest of the talk
into what evidence is out there that might be giving us,
if you like, pointers to what might be
causing the cells to die, or protecting them from dying,
and then say, okay, well how would that lend itself
to a new treatment that might slow or stop
the progression of the disease,
which we'll call, euphemistically, a cure,
which we'd take in a heartbeat.
So we're gonna go back to the dopamine system.
So this is a cartoon of the brain.
The spinal cord goes off the bottom
and then there's the brainstem,
and there's that thing with the black stripe across it,
and it's called the substantia nigra.
Doctors always like to be clever,
we put Os and Es in the middle of words.
Substantia nigra means black substance.
We're not that smart, are we.
And it does look black.
But interestingly, that's where the chemical dopamine
is being made.
These are the cells that are dying,
but it projects up to the red area,
the mission control part of the brain.
These are the basal ganglia.
Those are the bits that were those teardrop shapes
on that other scan.
So we know that that looks
very centrally placed in the brain,
so once you lose dopamine from that area,
effectively you lose mission control.
Your switchboard of the brain is affected
and it causes problems across the physical
and the non-physical symptoms.
So this is a postmortem sample of somebody
with the black stripes intact,
and here's somebody with Parkinson's
where those black cells have died.
But Parkinson's,
doesn't only affect the dopamine system, as I mentioned.
There's this non-dopamine system, so the serotonin system,
happiness, so mood and sleep.
The noradrenaline system,
so the thing that gets us going, gets us concentrated,
gets us focused, also important for mood and sleep.
The cholinergic system,
a system that is more ravaged in Alzheimer's patients,
but also, importantly, ravaged in Parkinson's disease.
Very important for cognition, for memory, hallucinations.
And then just the cells dying
is a clue to the cells going off with this pathology.
And many people will say to me, have I got Lewy bodies.
And of course many of you will remember Unity Walk,
we have Lewis and the Lewy bodies
courtesy of one of my students who came up with that name.
It's one of the best products he's had so far.
And this is what Lewy bodies are.
So this sort of ghostly shadow there is a nerve cell.
And inside it, it looks a bit like poo, doesn't it really,
but brown spheres,
and these spheres are actually tangles of protein
called alpha-synuclein.
Now alpha-synuclein is supposed to be in your brain,
it's a normal protein, but I would equate this to being
if you fold your clothes nicely and you close the drawer,
the drawer will work, no problem.
If, however, you take your clothes off
and you throw them at the drawer
and you tangle like most of us try and avoid doing,
then the drawer won't work.
And this is what we're seeing here,
these are abnormal configurations of this protein,
and they are associated with cell death.
Now what we don't know is
whether they're causing cell death,
whether they were trying to save the cell.
We don't know, but they are associated,
and we know from some of the genetics
that too much of this protein,
so if you have a gene that over-expresses this protein,
means you're more likely to get Parkinson's.
So we think it is pathological,
it may not be the whole story though.
So it's found inside these dying cells
and I say we don't quite know if it's a villain or a hero.
But we gave us a clue,
it gave us that genetics clue
as to what might be driving Parkinson's disease.
And since then, a number of genes have been reported, okay.
And the question is with these genes,
whether they are causative,
or whether they are risk factors for the disease.
So, for example, I have blue eyes.
There is a gene that means I get blue eyes.
They cause the effect.
However, I'm kind of wearing out with hockey
and bits of me are breaking
and people have seen me on crutches,
so there are probably other genes
that are not protecting my joints so well,
and they're probably putting me at risk of arthritis.
I may not get terrible arthritis,
but I'm at risk of arthritis.
So we have these causative and we have these risk genes
in Parkinson's as well,
genes that we absolutely know if you have that gene
you're gonna get the disease,
and genes that we see and say,
aha, with that gene you're likely, more likely than chance,
to get the disease and maybe sooner.
So it gives us, if you like, a steer.
About 10%, five to 10%,
depending on where you are in the world,
of all Parkinson's disease patients at the moment,
we can identify a gene, whether it's a causative gene,
which is very, very small numbers, less than probably 2%,
or a risk gene, which is probably the rest,
those genes that might, if you like, put you at risk.
Most of the causative genes
have got a very strong family history.
There are six members of the family
across three generations.
Mum had it, their mum had it, their children have it.
And that tells you it's a very likely story
that the gene is driving it.
And they're often a young onset,
so people under the age of 30.
And I know many people in this room
consider themselves a young onset Parkinson's patient,
but remember that 5% are under 40,
10, 15%, 40 to 50, so in actual fact
there's quite a proportion of people
who are definitely young.
This is the terms of reference.
If you're on a ward round,
you always say young is younger than the consultant
who's the oldest person on the ward round.
So basically I'm hitting that mark,
so I think it would be young onset.
However, there's this influence of risk genes.
So in the general population,
if we went out on the streets of Sydney at the moment,
we'd find a thousand people,
one of them would have Parkinson's.
In fairness, it wouldn't happen today
'cause you're all in here.
(audience laughing)
But we can play a game.
So if you don't mind exposing your diagnosis,
if you put your hand up if you've got Parkinson's disease.
Okay, now if you have anybody in your family,
a cousin, anybody else, leave your hand up.
And you can see the number is probably
more than it should be than one in a thousand, huh.
So the bottom line is
that some of you might have this very strong,
thank you for that, very strong genes that are causing it,
but most of you probably kinda go, well there was a cousin,
we didn't talk to him, or it was that sort of a deal.
So these are genes that put you at risk,
a bit like cancer genes,
a bit like other genes that we have.
So these risk genes are important.
A lot of people, especially when I started doing research,
were really vexed about what genes could do,
'cause they wanted to know
could I diagnose my Parkinson's by my gene.
And I have to say it is so little
of what we need to do with the genes
is to make the diagnosis, okay.
The reason is this.
If you go to a doctor
to see if you've got Parkinson's disease and they say,
oh, I think you've got Parkinson's disease,
and they test you for a gene, you don't have one,
doesn't mean you don't have Parkinson's disease, okay.
Still got Parkinson's disease.
However, genes do things.
They make proteins, they encode proteins,
a bit like those alpha-synuclein things
that became tangled.
They are the building blocks,
they are enzymes that do things,
like enzymes that digest your food.
If you have too much of them,
maybe the protein becomes tangled,
like you saw with those spheres of brown alpha-synuclein
in the dying neurons.
But it may also be that your genetic mutation means
that you only have, say, one copy of the gene.
Maybe you don't have enough enzyme.
Maybe that enzyme clears garbage from a cell,
and maybe it's the build-up of the garbage,
'cause you don't have enough of the enzyme,
that's killing the cell.
It may also be that the gene is supposed to regulate
other genes or regulate other enzymes,
so in actual fact it's not as simple as
a one-to-one relationship.
Nothing about this disease is simple, my goodness.
It'd be nice if it was once.
But effectively we've got all of these other pathways,
things that can cause cell death.
And one of them I wanna touch on is the commonest gene.
So there is a thing, an enzyme called glucocerebrosidase,
and we're gonna call it GCase for now, okay.
And glucocerebrosidase
essentially clears crap from cells, okay.
Tangled proteins.
So we all, in our cells, have mechanisms
for taking proteins, digesting them, getting rid of them,
thank you very much.
And this enzyme is very important for doing that.
And importantly, for a hundred years we have known
that if you got a faulty gene from mum
and a faulty gene from dad, that is to say you're duff,
you don't have any of this enzyme,
you get a disease called Gaucher's disease
or Gaucher's disease, descending on how posh you are,
or how posh you are.
And this is a rare storage disease
where proteins build up in cells and cause death,
and these children often die very young.
And interestingly, of course, with genes,
if you have a population that is limited,
that is to say, oh, I don't wanna pick on Tasmania,
but it is the obvious local example,
where you can't extend the gene pool,
then you're gonna breed more of these genes in,
because you're not getting Viking stock
and then these other people,
and I guess the population in the world
that gets the biggest hammering
with all of these inherited diseases
are the Ashkenazi Jews, okay.
So the Jewish people in Israel.
The rates of this enzyme problem in the Jewish population
of Parkinson's disease are much higher because of this,
let's say, limited gene pool.
Some might say a Tasmania effect, but a limited gene pool.
I've not yet been to Tasmania, is it great.
- [Audience] Yes.
- Fabulous, I'm going to Tasmania soon, that's great,
let's go book it.
What's interesting about this gene,
and we didn't know it until just a few years ago,
is that actually it's probably the commonest gene
that we find as a risk gene in Parkinson's.
So, in actual fact, about five to 10%
of people with Parkinson's disease
have got one duff copy of this gene.
So either mum gave it to them or dad gave it to them,
so they're half down on the amount of enzyme that they have
that can clear crap from cells, keep the cells healthy.
And that, if you like, is the power
of the genetics part of Parkinson's.
You can say okay, thinking caps on,
I don't want to just diagnose
whether you've got Parkinson's,
I wanna know whether I can help treat Parkinson's disease.
And interestingly, this is some work
that we just had accepted actually in a paper.
And what we did, we took blood,
probably from people in this room,
thank you very much for your help in the research,
that's great, with Parkinson's disease,
and people who didn't have Parkinson's disease,
often their husband or wife.
And the clever scientists that I work with,
people like Nic Dzamko and Glenda Halliday,
were able to, from blood tests,
look at the level of enzyme activity,
not the gene, do you have the gene
or don't you have the gene.
What we did, in actual fact,
was we took the people with the gene out of our analysis.
And what we showed was this.
The people with Parkinson's disease,
without a genetic mutation,
that is to say they've got two good copies.
Mum didn't give 'em a duff one, dad didn't give 'em,
they've got normal copies.
They have not got a genetic mutation.
But the activity of this enzyme
that clears garbage from the cells is down in these patients
compared to people who don't have Parkinson's disease.
And that's kinda cool because, in actual fact,
Gaucher's disease is a horrible disease
that affects children,
which means people have thrown money at it over the years
to try and supplement the enzyme, give people replacements,
stimulate the enzyme, give a genetic primer,
something that would actually encourage.
And there are now studies that are being started
looking to see if we could find people
who have got these enzyme deficits,
to actually try and treat them,
treat their Parkinson's disease by replacing the enzyme
or triggering it some other way.
And that may be, looking at our data,
applicable to all Parkinson's patients,
because it may be that you don't have to have the gene,
the gene just brings it out.
But actually your pathway is down,
your garbage-clearing pathway is down.
So in actual fact, it might apply
to all the patients with Parkinson's.
Which in some ways is cute,
because if this is a blood test,
and let's say we had a treatment
that worked to slow Parkinson's
because it made this garbage better,
that blood test might improve.
So then we could start screening new treatments,
and say, well we don't need a 12-month trial,
we'll just, I don't know, put it in a Petri dish
and see if it makes the enzymes better.
So that's actually a new way of thinking about
how we would do this sort of approach.
So there's the genes.
The other thing that doctors always do
when they don't know what's going on
is they blame the environment.
Let's get a few things straight, okay.
Number one, at the bottom,
please do not stop any of your medications
from what I'm about to say on this slide.
Your doctors have prescribed your medications
with good reason, do not change your medications.
Wherever you are in the world,
the rate of Parkinson's is about the same.
So already those people that come up to me and say,
I think the Mediterranean diet can protect me.
Well, go to the Mediterranean, you'll find a lot of people
who have got Parkinson's disease,
in fact, the same proportion of people
who have got Parkinson's here in Australia.
Mediterranean diet doesn't say it's bad,
but it doesn't necessarily protect you, okay.
Same with saffron, the Indians always, oh, saffron,
very, very good.
And you go, that's fantastic, and it tastes brilliant,
but it's not necessarily gonna protect you.
It may help, but it won't necessarily protect you.
Interestingly, we know there are things
that increase your risk of Parkinson's,
and people, of course I go to Dubbo
and do outreach connection in Dubbo,
everyone there is worried
they got their Parkinson's because of pesticides,
and it was on that list of things
that can increase your risk of getting Parkinson's.
But it might double the risk,
it might just double it. (phone chimes)
Oh, it's not me, I'm so glad, that's great.
Sorry, I thought the hospital was gonna say something,
that's all right.
(phone chimes)
It's okay.
So effectively, people with pesticide exposure
do have an increased risk, but it maybe doubles the risk.
So that's now from one in a thousand to two in 1,000.
So I don't think it's that strong, but interestingly,
if you have one of those risk genes
and you've been exposed to pesticides,
that risk isn't double, it sort of multiplies,
so it might be five times as much.
So in actual fact, you have to look at these things
and say, well maybe they give us a clue.
One of the other pieces of data
that only came out in the last 12 months or so
is that actually there seem to be some medications out there
that increase your risk of developing Parkinson's disease.
And this is the drug not to stop,
so if you're on a beta blocker,
it appears from the Scandinavian registries
as though the risk of Parkinson's in those people
is a little bit higher, okay.
What's cute about that story
is there are also some things that reduce the risk.
So caffeine reduces the risk of getting Parkinson's disease,
and I've, because I'm getting fatter,
I've had to stop having a can of Coke.
Many people will remember me lecturing with a can of Coke
and drinking it just to try and protect myself
from getting Parkinson's disease,
because as you know with doctors,
we all die in our specialty.
The heart doctors die of heart disease,
the bowel doctors, cancer.
I'm gonna retrain as a sex therapist,
I've told you, many of this people.
(audience laughing)
Smoking also reduces your risk of getting Parkinson's.
Please do not go out and start smoking.
It's a bad thing, but it's interesting clues.
But one of the other interesting clues
is that smokers need inhalers.
But interestingly, the Scandinavian registry also found
that those blue inhalers that you take for asthma
seem to be associated with a reduced risk
of getting Parkinson's disease.
The cute part about that is they have exactly the same,
the exact opposite action on the same receptor
as the beta blockers.
So the blood pressure tablets and the inhalers
act at the same point in different ways,
in the opposite direction.
One of them increases your risk,
one of them reduces your risk of getting Parkinson's.
This is interesting because it starts to give us clues.
And what the clever scientists
who did this research looked at was to say,
okay, well what is it that these treatments might do,
and they actually looked at what it did
to the expression of that alpha-synuclein gene,
that synuclein that tangled in the cells that are dying.
And interestingly, the blood pressure tablets
up-regulated the amount of,
sorry, down-regulated the amount of,
the blood pressure tablets up-regulate the amount
of this final protein, and the inhalers reduced it.
So you're getting some actual biological clues as to
what we might think about targeting as a treatment.
Maybe it acts by modulating the genetic expression
of this protein, so that's kinda cute.
So we've had a look at the genes,
we've had a look at the environment,
what about infections.
Doctors always say, well it could be an infection.
And I have an hypothesis that I wanna run by you, okay.
Now many of you will recognize Muhammad Ali.
We saw him earlier, and he had Parkinson's disease.
The guy on the right, does everyone know who that is.
- [Audience] Michael Parkinson.
- That's Michael Parkinson.
I wonder.
(audience laughing)
Hear me out, hear me out.
Michael Parkinson interviewed Muhammad Ali three times.
He interviewed Billy Connolly three or four times.
Michael Redgrave, Sir Michael Redgrave,
another Parkinson's sufferer.
Bob Hoskins another Parkinson's,
Terry Thomas and Robin Williams who had Lewy body dementia.
Now I'm not blaming Michael Parkinson.
(audience laughing)
And it may just be that he interviews older people,
and therefore it's disproportionate.
He interviewed probably about,
maybe he interviewed 6,000 people in his time,
or maybe he interviewed about 3,000 people
who were all older,
and actually the selection bias is there.
But going back to that prion-like hypothesis,
we talked about this before,
the idea that maybe you ingest something,
maybe something gets into your system.
And some of the support for this comes really from
some research that was done a decade ago now,
where we tried to use stem cells to treat Parkinson's.
The idea was to take cells out of aborted fetuses
that were gonna become dopamine cells,
and put them into patients with Parkinson's disease
so they would make dopamine in those patients.
Many people will remember there were two trials,
they were both stopped prematurely
because all of the patients
ended up with runaway dyskinesias,
they couldn't control their body movement,
and they had to have surgery
to stop it and calm it down, okay.
So the trials were stopped because it was dangerous, okay.
But, interestingly, they followed the patients,
and you'll remember the figure on the left,
which is the synuclein.
The figure on the right comes from the postmortem
of some of those patients who've now died.
And interestingly, in those cells that came from the fetus,
that never had Parkinson's disease,
you find these tangles of alpha-synuclein.
Now they're not there in high numbers.
It's not in a region of the brain
that would normally get Parkinson's disease.
But it does raise the question,
could this be that you have infected, transfected,
those cells that you put into the host,
the host being the Parkinson's disease patient.
I've got Parkinson's,
maybe I have something that's prion-like
that will spread from cell to cell to cell,
and it gets in and infects the cells
that never had Parkinson's before.
And there is a lot of energy going into this.
And I do put the caveats
that we don't normally see Lewy bodies
in this part of the brain.
There's very few cells, there are a lot of other things
that can be accounting for these appearances.
But it's become important, because people then think,
well maybe if it's an infection,
we could vaccinate people against it, like whooping cough.
We could give active immunization,
what we call a vaccination program
where effectively what we do is we give you a little bit of,
I don't know, alpha-synuclein,
get your body sensitized to it,
and then you could fight against it later in life.
This would be easier to upscale,
we could have herd immunity,
we could all have our Parkinson's vaccination
with our whooping cough vaccination.
But of course at the moment,
we don't really know if it'll work,
but there are people looking at it.
So in actual fact, what you can do in things like mice,
is give them genetic abnormalities
that will produce too much of those proteins
and give tangles in the brain.
And then what you can do is give those mice
some of that human protein to vaccinate them.
And in actual fact, the mice produce antibodies
against that human abnormal protein
which reduces the accumulation of that protein
in the mouse brain.
I remind you, mice, rats,
no other animal on the planet gets Parkinson's disease.
No mice are in my waiting room waiting to see me.
(audience laughing)
They might be waiting for food,
they might be eating through the cables,
but they're not waiting to see me.
But it does raise the possibility
that perhaps this might be an approach to the future,
and companies are looking at this.
But a more likely route is the idea of
targeted immunotherapy, so passive immunization.
So instead of trying to vaccinate someone
and letting you develop your own antibodies,
we make the antibodies that we think you need.
And these things are already in use
in rheumatoid arthritis, inflammatory bowel disease.
People have got antibodies that have infusions
that fight against, essentially,
what's driving the process in their bodies.
So the question is whether this would work.
If we could give people specific antibodies,
especially if they had advanced disease,
how much is it gonna cost,
how often do you give these treatments.
These are all questions
that we have no idea yet how to answer.
But they are being explored,
and in fact there's lots of different ways to explore this.
Could we break up the protein that's already there?
Could we stop the protein moving
from this cell to that cell?
Could we stop it sort of just aggregating?
So these are all processes that people are exploring
in research today.
And there are, in fact, clinical trials ongoing.
These are some of the register trials that I found.
The numbers and the letters, they bore me to tears.
If you ever go to these meetings they bore you to tears,
but don't worry about that.
The fact is these trials are happening,
but they are only happening at the moment for safety.
So we are not at a stage to tell you
whether this is gonna be an effective treatment.
What we can tell you at the moment is
they haven't killed anyone with these treatments,
which is a good start.
Some treatments do kill people,
and that's a bad thing, okay.
So this is a good thing, but these are baby steps
that we're talking about.
Whether we can actually now move
from these very much safety and tolerability studies
that maybe give us a clue about
how much of the drug to give,
perhaps we have to take blood tests
or maybe spinal fluid and say,
how much is getting into the brain.
How much would you have to give as a dose?
So we're getting some ideas as to
what we might have in the way of a treatment.
And we have lots of these targets,
and there are too many to go through here,
but breaking cells up, the energy resources in the cells,
and basically too many.
In fact, so many I just wrote a paper on it
to try and capture everything.
This is in the Medical Journal of Australia.
It's probably accessible if you wanna go and look it up,
it's there, it'll be in the slide set.
So there are lots of things, too much iron in the brain,
regulating calcium, neuroinflammation stress.
But it really kinda comes down to
whether we can find a golden bullet.
Is there something that will break up the protein?
And this stuff's gonna take big money.
Big Pharma, very expensive, lots of time, a long pipeline.
15 years maybe to get something into the clinic.
Well what about the idea of repurposing?
So this is the idea
that maybe we've seen those cellular processes,
stress on the level of metabolism,
inflammation, too much iron.
Maybe we can get drugs that already exist in humans
that have those effects,
but we don't use them for that reason.
And maybe they have a biological rationale.
Now if we got those to work,
it'd be much cheaper, much quicker.
We could actually say,
well we've done all the safety studies,
we know they're not gonna be, it's good.
And one of the first cabs off the rank was this idea
that maybe diabetes and the cellular process in diabetes,
'cause there's a lot of cell trafficking in diabetes,
a lot of hormone processes
and neuroprotection going on in diabetes,
and we do see this interaction of people with diabetes
having worse Parkinson's.
And this spawned, my old mate Tom Foltynie in London
to do a small trial in his center in London
with 30 patients who got a diabetes treatment,
a treatment that does exist here in Australia,
it's an injection.
I think it's once a week, a drug called exenatide.
And a whole bunch of other 30 patients
injected themselves with placebo.
Saline, probably.
And what they did was they actually took patients
in this study and they said,
okay, for the next 48 weeks you're on treatment,
but after that we're gonna stop the drug for 12 weeks,
because we want the drug to wash out of you,
and we wanna see how your disease progresses, okay.
And what they took was they took patients,
like most the people in this room, who are on medications
and we said, look come in, stop taking your medications,
overnight, come in, you'll look terrible,
you'll feel terrible,
but we'll be able to assess your Parkinson's
and not blame your drugs that you're already on,
the levodopa or whatever else to make you better.
We wanna see if this drug might slow your disease down,
and in 48, no 60 weeks from now when we take the drug away,
if you've been on the drug,
is your progression less than those people
who didn't have the drug, who may have had placebo.
And this is what the guys showed,
and the one I want you to look at is on the right.
And the red line is the people who had the sugar pill,
and the blue line is the people who had the sugar treatment,
so the diabetes drug.
And what you see is
that the red line continues to get worse.
The blue line seems to get a bit better, then plateaus
and when they stopped injecting, it got worse again
but it wasn't as bad as the people who never had the drug.
So this is one of the first studies that we've seen
that might suggest
we could slow the course of the disease down.
Now it's a very small study, it's a very, one center,
but it's encouraging.
But many people in the room would say,
why can't I have exenatide now, doctor,
and the answer is 'cause I asked this guy.
This is Tom.
Tom and I were together in Cambridge.
We generally meet up once a year
at the Movement Disorders Conference,
this is actually two years ago in Vancouver.
And I said him, Tom, what are you doing with your patients.
He said, I'm not giving them exenatide.
He said we need a bigger trial.
We can see these kind of results in small trials.
He said we gotta do a big trial.
So that's what they're gonna do,
and that'll start next year.
Multi-center, around the world.
Mainly in the UK, some sites in America, a couple in Europe.
So we've got this, if you like, a path to a cure.
Hope, hype, hope, hype.
And we've got the idea
that there's maybe some stuff from genetics,
cellular pathways, and we've got people now
talking to each other.
The Linked Clinical Trials Initiative,
where people from all over the world,
including here in Australia, are getting in the same room
as people from London, people from America,
and I know that you've always wanted us to do this.
And the time is coming, it is here.
But what about Australia's role?
Well I'd propose that we're in a really strong position.
Are you bored, you're okay?
I'm not running over time?
I'm here till dinner, so that's fine.
If everyone has buses to catch,
please go and get some buses.
I think Australia is in a really good position because,
number one, I'd suggest we have
a large population of patients,
and I would suggest we're very willing,
and I would say to you that unfortunately,
we've never been able to get you involved
in trials like this before.
So we've always been in the control arm
where we get bugger all treatment,
which is not a good place for us to be.
I'd like to suggest we have a great clinical workforce,
so there are, in fact, people like me,
and thankfully people who are much better than me
seeing Parkinson's patients out there,
and they want to do trials.
We all want the same thing that you want, I promise.
On top of that, Australia has got
some of the smartest scientists that I know,
and they're the smartest scientists on a world stage.
So people I mentioned like Nic Dzamko, Glenda Halliday,
people like Anthony Cooper at the Garvin,
all really important.
And the idea is to have a bit like that trial
that Tom did, but more of it.
So the idea, in actual fact, is not to do one drug,
but to have more than one drug in one protocol
where everyone can get randomized,
and ideally, maybe have the chance
of being on placebo one time,
but the other four means
that you'd have a one-in-five chance
of being on the placebo,
and a four-in-five chance on being on the active drug.
Now there may be four different active drugs, they may be
all repurposed, they may be very different things.
But effectively, Australians love to gamble,
and 80/20 is good odds.
Pretty good odds.
And what we're gonna do,
not only is to run a clinical trial,
because I think running a clinical trial is great,
but what if it doesn't work.
We'll learn that four drugs don't help,
and that's not good enough.
What we really wanna do is
to tap into the clinical scientists,
the basic scientists, and say, can you show us,
we had this drug, we thought it would do X,
maybe it was gonna change inflammation.
Can you measure the inflammatory markers
from this patient's blood sample
before and after they had the drug,
and tell us if it actually did that?
'Cause if it did, and the drug didn't work,
maybe we wouldn't pick another drug like that.
If it didn't, then we'd say,
well the drug was duff from the start.
Similarly, as I showed you
with that blood test that shows the difference
between the enzyme activity in Parkinson's patients
and patients who don't have Parkinson's,
we actually now have some markers
which we believe might show how active a disease is,
'cause these enzymes are also affected in the brain.
So it might be that being exposed to a drug
might change the level of activation of that enzyme,
and allow you to know
whether the drug's gonna work in the future.
And on top of that is the idea of your genetics.
People who have breast cancer in this country
don't all get the same drugs.
They'll get a gene screen,
and they'll say your type of breast cancer
will respond better to this kind of treatment.
And what our study will hope to do
is to actually do that sort of genotyping and say, okay,
maybe 20% of people got better with that drug
and 80% didn't, but what was it about those 20%,
because bloody hell,
maybe we should do the trials in them next time.
So we wanna do smarter trials.
So we're having an issue, and it's across multiple centers,
New South Wales, Victoria, we hope Queensland
and across all of the other states in time.
And the plan will be to get people in and, as I say,
randomize them across four different treatments
and a placebo, see them at baseline,
see them after they've had a drug for a while,
and see them after they've stopped the drug,
and see, just like that study I showed you
on these other slides,
whether we can actually make a difference.
This will not answer the question.
We will have to go on and do those bigger trials,
just like Tom is doing with exenatide right now.
But we have a strategy.
So effectively, we'll pick drugs
that have got different mechanisms of action
so we can try and find things.
We're not gonna do anything clever,
we're not gonna do brain scans, they're too expensive.
We're not gonna do spinal fluid,
it hurts too much and it takes too much time to organize.
We are, however, gonna do clever blood tests
and we've got a panel of things
that we'll be able to look at, including those enzymes,
including the genetics, so we can have a look
and see did we engage targets,
things that we think might relate to the disease,
the production of those alpha-synuclein,
those enzymes that clear junk.
The genotyping, do we know what sort of gene type you are.
This is precision medicine.
Do you have the same treatment as your neighbor
who has the same disease, but for a different reason?
And we're there, we're getting there.
We've already organized who's gonna help run our drug trial
from a company point of view,
we know what sort of drugs we wanna write into a protocol,
we know where we're gonna get our drugs from,
we know which sites are gonna be involved,
we know that we wanna be live to go
in the first half of next year, okay.
So our problem is that we've got a Parkinson's disease
that is growing like an epidemic
'cause we're getting an older population.
However I think we have solutions, things we can try.
We have willing patients, we have good clinicians,
we have great scientists.
We might be able to screen a number of these agents
and maybe take them into international trials.
We might be able to think about smarter trials,
precision medicine approaches.
So we have some steps.
I'm hoping we'll have the patients, the scientists,
the clinicians on board.
The international partners are already there.
And finally, my question to you is, do we have your support.
- [Audience] Yes.
- It wasn't overwhelming.
It wasn't overwhelming.
- No. - And with that,
what I'm gonna do is I'm gonna put up my resources slide,
so if you wanna take photographs,
this has got the website, it's got my email address,
it's got my Twitter handle,
it's got where you can find the slides.
Go for your life, go crazy,
thank you so much for your attention, sorry to ramble on.
- [Man] Thank you,
Professor Simon Lewis.
- No, not at the moment.
I would not do - Thank you.
- genetic testing in my children
because I don't have anything to offer them.
What I would say to them is what I would say to them
if I didn't have Parkinson's in the family,
which is you need to exercise regularly,
you need to eat the right things,
you need to keep your brain active
and be nice to your parents.
(audience laughing)
And I'd be asking,
why did my vasectomy fail so badly.
(audience laughing)
So the bottom line is that we will be advertising,
we'll be advertising in a way
that people can get to know us.
The bottom line is that we will have to be very careful
about who gets into the trials.
It may be that, let's say for example,
we wanted to trial a diabetes drug.
We might actually exclude the people with diabetes
because they're already on a diabetes drug.
So we have to be very careful about who we select, okay.
But the bottom line is
that everyone should reap the benefits,
and remember that trials are exactly that.
We have no idea if they're gonna work.
We may end up giving people more side effects than benefits,
so we need to be careful.
So the answer to your question is it needn't be,
because the bottom line is
those guys are gonna do their thing anyway.
The bottom line is they're already doing their thing.
The question is what do we wanna do,
especially here in Australia.
Watch them doing it while we do nothing?
And the point I'm making is we do have some targets.
People could look at these drugs and say,
I think it will do X, Y, and Z to this part of the system,
therefore we should trial it in Parkinson's.
So it may be that the answer comes from Big Pharma,
but geez, it'd be really funny and really kind of cool
if we got our own answers before they got there.
- [Man] Well that's reassuring.
- And the truth of the matter is that,
let's say two of these drugs work,
not necessarily from our trial.
The next thing we do is what.
Put 'em together.
See if we've got more effect.
So in actual fact,
it doesn't have to be a one-shot deal this.
I think in the interest of brevity,
I'd direct you to my website.
There are about four videos on there
about surgery in the brain,
because it isn't directly related
to the idea of curing the disease.
What you can say is that the American studies,
which have got better data than the Australian studies,
is that the wheat belt regions of America
seem to have more Parkinson's,
and of course, they have higher exposure to pesticides.
And when you bore down on the postcode data,
you realize the people who are closer to the spraying
and the crop fields seem to have higher rates
than the people who are further away.
So I think this is circumstantial evidence,
but I think it's useful
because it sort of led us to toxic models like rotenone,
which is something that we've poisoned rats with in there
to kill their dopamine cells in the past,
so there may be these factors at play.
I don't think they can answer all of it though,
and there's likely to be not one answer,
there's likely to be lots of different answers,
which is why this is hard.
So again, in the interest of brevity,
I would direct you to my website.
There's a couple of videos about medicinal marijuana.
Just to give you a heads up, you look under fake news.
(audience laughing)
- Okay, thank you. - That's the video to watch.
So most people who take marijuana
with advanced Parkinson's disease
drop their blood pressure, pass out, start hallucinating.
Most people who ask me the question have already tried it.
(audience laughing)
The trial will be geared up
so that everybody takes a tablet twice a day.
It may be that one of those tablets is a sugar pill.
It may be that two of those tablets
are a sugar pill.
Bottom line is it seems to be poorly controlled diabetes
results in a more aggressive Parkinson's.
And the reasoning behind that may be
because you need to constrain the energy pathways
in the brain.
If they're overstretched,
because you're trying to deal with your diabetes,
they will be overstretched for your Parkinson's,
so it's bad diabetic control, probably from either source.
- [Woman] Thank you very much.
- Yes, so this is published.
It's nothing to do with the talk we just did,
but impulse control disorder,
where people start gambling, chasing women, spending money,
it does seem to be higher
in people with Parkinson's on medication.
If you're on levodopa alone, the figure is 7%.
If you're on a dopamine agonist on its own,
that's pramipexole, rotigotine, it's said to be 14%.
If you're on both of those drugs, it's about 17%.
So it looks as though the lion's share is being carried
by dopamine agonists.
So mucuna pruriens, the velvet bean,
I would again direct you to the website.
Because they're so common, these questions,
I recorded the answers.
So it's got a natural source of levodopa,
however it's very variable between each bean,
you're better off, A,
because the content of your tablets is much more precise
taking the tablet, and B,
because it's a lot less expensive
than taking mucuna pruriens.
It's much cheaper to just get your prescriptions.
What I mean by that is that people with Parkinson's disease
seem to have different trajectories.
And Parkinson's, unlike things like multiple sclerosis
or stroke disease, tends to run true.
So if your disease is traveling slowly,
it generally travels slowly
the whole way through your course.
If it starts badly it tends to keep going badly.
And in badly what tends to happen is
that people don't respond well to their tablets,
they get more in the way of falls, balance problems,
cognitive problems, and the bottom line is
we don't know what's driving that.
The clues from some of the genetics suggest that
if you have some of the genetic variants of Parkinson's
they seem to have a much worse prognosis
in terms of those features,
but it may well be that some of the other genes
may be protective against that.
Despite the fact you've got Parkinson's,
some of those other genes might protect you
against the progression of the disease.
It comes down to this precision medicine thing.
So I guess the answer to that question is
that the worldwide prevalence of Parkinson's is the same.
So essentially those places
that aren't fighting mosquitoes in that way
would seem to have the same rates of Parkinson's,
so I don't think it should be such a big factor.
And mosquito bites and malaria
have probably killed more people than Parkinson's
in this world,
so you're probably safer having the coils.
Yes, so there are, at the moment,
two therapies that use a pump,
One is an injection that goes under the skin
called apomorphine.
It's a very potent dopamine agonist,
it's actually very effective.
The other is a gel preparation of levodopa
which goes into your stomach, past your stomach in a tube,
and delivers the drug there.
Both of those approaches are trying to get past the fact
that in advanced disease, your stomach doesn't work so well,
your tablets sit there, they get eaten by the acid
and they don't work.
There is a third technique which is currently being trialed
where people are trying to infuse through the skin
levodopa preparations.
Those studies are ongoing and yet to report.
If you forget any of this,
look under duodopa, apomorphine,
device-assisted technologies, advanced therapies,
on my website.
Very common question, and deep brain stimulation
exactly the same.
So I understand by Parkinson's Plus
that people are saying,
look I don't think you have true Parkinson's disease,
you have a mimic of Parkinson's disease.
That is to say that there are diseases out there
that may look clinically like Parkinson's,
so shuffling, slowness, but when you look at the brain,
the pathology is different.
So, for example, if somebody has a lot of strokes,
then they may shuffle and they may look Parkinsonian,
or like a Parkinson Plus.
The commonest ones, when we talk about Parkinson Plus,
are degenerative diseases
that are usually a TLA, three-letter abbreviations,
multiple system atrophy,
MSA, progressive supranuclear palsy,
PSP, corticobasal syndrome, CBS,
and again, on the website you'll find all the videos
'cause these are all the questions
that everybody wants to know the answer to.
Generally don't respond as well to treatments,
generally not so good to have.
This is, in some ways, an impossible question to answer
because as a clinician what you are doing is
what we call deductive reasoning,
which is guessing as well as we can,
where we say well when did it start,
how did it start, what's progressive,
what signs do we see, did it respond to treatment,
what do the investigations show.
So it's a very open question.
But, in actual fact, I mentioned there
some of the Parkinson Plus syndromes.
If you look at the list of things
that can look a bit like Parkinson's,
the bottom line is that they'd fill textbooks,
they'd fill textbooks.
- [Man] And there we will conclude our Q&A,
please thank once again, Simon Lewis.
(audience applauding)
Thank you so much, Simon.
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