Just.

This is Christopher in gold XO d2.

It is eight degrees in my theatre at the moment.

I'm not sure if you can do anything about that,

but I do think that certainly if we work the

incredible work rate in the.

Thank you for joining me.

It's a I grew up in a very home country,

Australia, and I don't think I saw snow until I

was in my mid-twenties.

So for me, it's still awe inspiring to walk through

a white snow field.

So I hope you enjoyed your journey.

And today I am in my place.

But yeah, I'm here.

This is behaviourism.

Yeah, I.

My brain is frozen.

I just.

I hope that's not on, but it's not going to

help us in the next hour, I'm afraid.

So thank you for joining me today.

It's really nice to see you all again.

I'm going to be talking about neurological disorders.

It's a little bit I mean, I have mixed feelings

about giving this lecture.

I always feel a little bit depressed.

But this year I tried to be a to alleviate

my depression a little bit by introducing a couple of

slides illustrating some very recent advances in treating these disorders,

which give me hope at least that we're entering a

period where we might be able to take these on

and generate cures, or at least treatments for people.

Sorry, my brain has actually frozen, so I'll try and

get through this if I put my jacket on.

Well, the problem is if I put my jacket on,

it rustles the volume.

But I see.

Why a neurological disorder is so problematic.

I think what you've learned so far in the course

should give you a bit of a cue to answering

this.

I think the major thing, the first major things, that

nerve cells are not self-renewing, but you're basically born with

the same number of nerve cells you end up with.

And you just lose them.

There's a few that are born maybe in the hippocampus

and the old factory lobe, but most of the neurones

that you have on you now are ones that you

were born with.

And that means that if one of them dies, you're

not going to get replaced.

The second thing is that neurones are excitable cells.

As we've talked a lot.

I like action potentials.

I do a lot of work to try and generate

these action potentials and I can actually be overexcited or

it's a bit of a loose term, but I can

this generating this activity can lead to disorder within the

cells.

So those cells, if they get overexcited, can actually trigger

apoptosis.

That is cell death.

Generating all this activity requires a lot of energy.

It requires a very specific way of getting and be

very, I think, by the way, in the brain of

getting the energy to the right part of the brain.

If we disorder that blood supply, energy supply as we

go through time.

Those neurones also form what we will call what we

have called recurrent circuit.

That is circuits where the axons from one cell connect

to the dendrite to another cell and vice versa and

so forth.

These are very exquisite connections that are both partly genetically

predetermined, but a lot of which is set up by

experience early in life and in later life.

Recapitulating those networks generated in those networks again, or putting

a neurone in that network and asking it to replace

the function of a new one that's already there.

That's effectively impossible.

You would have to recapitulate the experience that those neurones

have had to be able to regenerate that network.

So these for all these reasons, it's very difficult when

the brain starts to be disordered, so start to die.

Treating those disorders is really, really hard.

So in this lecture, I just want to take you

through a couple of different disorders that we know something

about.

And I've chosen these very carefully because there's many disorders

that we do not know much about at all.

In talking about these, I will be talking about disorders

are called intrinsic rather than extrinsic.

Extrinsic ones are ones like, for example, tumours being developing

in the brain.

By the way, since nerve cells and not the actual

part of the tumour because they don't replicate in the

same ways.

Extreme disorders also include traumatic brain injury.

For example, if you have a car accident or if

you get concussed many times as a footballer.

And those kinds of disorders are not a consideration here

because they're really just a result, not just the result

of things that the brain can't do much about.

So we want to talk a little bit about intrinsic

one, things that arise because of the particular structure of

the brain, because of the way the brain works.

I won't be talking about developmental brain abnormalities in this

particular lecture.

What I will be talking about is degenerative disorders, looking

at Alzheimer's disease in particular, and also epileptic seizures.

I'd like to start by talking about seizures.

Seizures?

Does anyone know much about seizures at all?

You come across them.

You may have seen someone having a seizure at some

point in time.

This is quite distressing experience.

I find it's a this is a cause that we'll

find out in.

The second is caused by overly synchronous brain activity, by

synchronous means that the neurones, the nerve cells are all

firing at the same time.

We'll see what the effect of that is in a

second.

About 3% of all people suffer from epilepsy at some

time in life, most commonly in childhood or older age.

I think it's not unexpected because that's the time at

which the brain is changing most and therefore the balance

that is required to prevent seizures, it's most likely to

be disordered.

At least 30% of athletic facilities have some known genetic

basis, whereas about 25% have what we call acquired antecedents

that, for example, rheumatic brain injuries.

So professor of epilepsy, a friend of mine, has suffered

from epilepsy since he had a bike accident 20 years

ago, and he's under treatment for it.

But it's still something that affects his life.

You know that that doesn't add up 100%.

And the other 50% of their bounce that the causes

are known either because there was inadequate record taking at

the time or because they have a complex, multifactorial basis.

We know a lot about seizures since the development of

electroencephalogram, ability to measure the activity of the brain from

the scalp.

On the left hand side to see what would look

like a normal EEG.

And is the traces in the brain due to the

electronic wiggle a little bit that they're not overly wiggly

and they're not overly synchronised between different electrodes.

Two types of seizures as shown on the right here.

The generalised seizure here, which would be part of a

grand mal seizure.

It means that the activity in the brain is synchronised,

basically causing time brain.

And you can see that here because the big wiggles

on the on the electron system, grandma all happen at

the same time.

That means that neurones in each part of the brain

that is generating these EEG signals are firing together at

the same time in big discharge bursts of discharge synchronising

their activity.

Of more interest from a psychological perspective really is the

partial seizures, which is shown in the middle here.

And that is where some parts of the brain start

to synchronise and other bits seem to be untarnished.

We'll be going into that in a second.

We've touched a little bit on brain rhythms over the

course of these lectures.

Rhythms are effectively a natural part of any biological system.

Can anyone tell me one rhythm you can think of?

Circadian rhythm.

That's a daily rhythm in trained by light, but actually

set by pacemaker cells or cells within this whole area

of the brain.

Probably the super charismatic nucleus whose activity varies with over

about a 25 hour cycle.

I think if you take if you if you take

someone and put them in or if you take an

animal and put them in the constant dark, you'll see

they still have a circadian rhythm, but it's not quite

locked to the 24 hour clock.

That's that locking comes from exposure to light, which resets

that pacemaker.

Is there any other rhythms that you can think of?

What am I doing right now?

Well, that's a good one as well.

But that's not a that's actually set by within within

the heart pacemaker activity in the heart.

What am I doing?

What are most of us all doing?

We're all breathing, right?

The breathing is also a rhythm that's set by the

pacemaker cells and a loop part of the brainstem.

I do fact reports, and if I remember rightly, these

activity pulsates, of course, can be modulated.

They can be fast and be slow.

Hold your breath.

It normally would act to inflate the diaphragm.

These kinds of brain rhythms are those are those are

the properties really of individual cells, or at least there's

cycles or rhythms within those individual cells.

The kind of rhythms that get disordered in seizures, though,

are not really properties of individual cells, but properties of

networks of cells.

So what happens is that when you have excitatory cells

talking to each other and then feeding back to each

other, and if you have inhibitory cells helping set that.

These cells.

When you fire an action, potentially send it to another

one and that fires an action potential and sends it

back to you.

That creates a loop and that creates a natural rhythm

from that circuit.

And so depending on the structure of the circuit, you

get different archetypal rhythms emerging.

So this slide here shows you three of the classic

rhythms, the alpha rhythm, the spindle rhythm and the ripple.

They found, or at least are most prominent in particular

brain regions, and they are the result of particular pathways

for communication between brain regions.

So, for example, the rhythm, which is most prominent actually

in the visual cortex at the back of the brain,

is primarily a cortical rhythm.

It's about 12 hertz.

The really prominent rhythm.

It's much stronger when your eyes are closed, when your

eyes are open.

A spindle rhythm is about the interaction between the thalamus

and the cortex.

So neurones in the thalamus send signals to the cortex

to send signals back to the thalamus.

And this loop itself, which is responsible for a large

part of slow wave sleep, also generates what's called spindle

rhythms.

And then these ripple rhythms are the communication between cells

within the hippocampus, which generate a very sharp, very fast

rhythm.

You can see the timescale here is 100 milliseconds as

opposed to one second here.

So this slide also shows this seems to show that

these rhythms are not just a product of something found

in humans.

They're actually found in almost all species that have been

studied.

In fact, all species that have been studied.

You can identify these rhythms if you look in the

right place and search hard enough.

So in humans, in non-human primates, in dogs, cats, bats,

rabbits, rodents.

In other words, you can find these are rhythms.

And it is quite striking that if you look at

the frequency, that is the number of cycles per second

that these rhythms take place over.

As I said, Alpha was about 12 hertz or 12

times per second.

So 12 of these little squiggles per second and the

ripple is about 250 hertz.

If you look across a large range of species, you

find that the rhythms in each of those species are

about the same frequency, even though their brains can vary

in orders of magnitude of number of neurones and all

of the magnitude and numbers of signs.

And that suggests to us that these rhythms are important

for brain function.

What they do is not so clear.

So there's many hypotheses out there, for example, in camera

rhythms, very fast rhythms, about 30 or 50 hertz are

important for consciousness and for propagation of signals between cortical

areas.

Yet there is very little hard evidence that they are

necessary for that those activities.

So, yes.

You can't.

I think it's just been not studied there.

I'm not sure if it's not present.

I'd be willing to know.

I haven't studied all of those animals.

It's you do have to report them in particular ways

and in particular circumstances.

For example, slow way rhythms or any form during sleep.

And so you have to be recording from an animal

during sleep.

So I'm not quite sure if they're missing on this

one a bit older.

So if they're missing because they're absent or missing just

because I haven't studied, it's a good question.

So these rhythms of what is disordered and what a

what prominent about seizure disorders.

This slide just simply classifies the general types of seizures.

We're not going to be talking about the grand mal

seizures, these massive changes to the brain function.

However, what I would like to go through a little

bit is partial seizures, because they tell they're explicit explicable

going from the structure of the brain.

Possible seizures can be either simple or complex.

Complex partial seizures results in a second often involved impairment

or loss of consciousness, or a simple partial seizures.

A person who suffering a seizure suffers no loss of

consciousness during the.

This slide, which is a little bit busy here, but

you can look at in more detail when you feel

like it.

On the top left is a description of some of

the features of a complex partial seizure.

On the bottom right, a simple partial seizure.

Partial seizure complex Partial seizures often start in the temporal

lobe or in the frontal cortex.

And maybe that's why they're actually associated often with a

loss of consciousness, or at least an impairment of consciousness.

The squiggles over here show that the frontal and temple

ones are undergoing large amplified rhythms, whereas the simple ones

are not so prominent.

In this process.

He's a simple, partial Caesar here, however, usually involving the

sensory with the motor cortices.

You can see here that over a typical and a

little bit the motor cortex, some big spikes, but not

so much in the frontal and temporal lobes.

So simple procedures often involve motor disturbances, for example, tremor

that emerge because your motor cortex is being disordered and

cortex is oscillating in a rhythmic fashion.

So your muscles will be oscillating in a rhythmic fashion.

And simple procedures are quite interesting because we can because

someone is conscious and because they're not too problematic, we

can actually track their progression through the cortical structures.

So, for example, I really like this description, and I

should know, by the way, that John Huling Jackson, who

you go introduce you to back in the first lecture

I think was based in Queens where when he made

these discoveries was the one who proposed that the progression

of simple partial seizures reflected the structure of the brain

organisation.

It's a nice description of what might be a typical

seizure.

Is on his right foot, began to shake.

Now a lower leg was shaking than a proper leg

as well.

With horrified fascination, she felt her body begin to shake

and reason with her leg.

Is shaking slowed and then finally stopped.

This is a real case.

A CT scan showed a small white circled spot between

the frontal lobes above the corpus place and a small

tumour.

This woman had a simple procedure that actually progressed to

a complex seizure.

Sometime later.

So this little tumour that emerged in the brain was

up here between the two lobes at the very top

of the motor cortex.

If you remember back to the monthlies that we looked

at when we talked about sensorimotor cortices, the progression of

disease or progression of the disturbances make sense from the

structure that most of us.

A foot is represented at the top of the brain,

near the open close, and the tongue, the face and

head emphasised.

So is the progression of that seizure of that epileptic

form activity move across the cortical surface?

So the shaking in different parts of the body reflected

that among the organisation.

This makes sense for everyone.

This simple partial CS is effectively a travelling wave starting

from a particular point and moving across the surface of

the cortex.

Gradually recruiting different parts of the body that represent or

control the muscles in particular parts of the body.

Some, as I mentioned before, some seizures seem to be

familial, inherited.

I've learned quite a lot about them by studying rare

cases of one of the psychotic twins and looking at

the seizures that they sometimes have.

This is one famous example.

This is a pair of Monozygotic twins, Constance and Catherine,

who have absence epilepsy in this case.

What I want you to take away from this is

electroencephalogram recordings taken from Constance and Catherine, I think at

different times.

Or you should notice the structure of the epileptic form

discharges that are happening on these EEG channels are remarkably

similar across the two twins.

So over here, these these structures, these regions are very

similar over here and so forth.

So the structure of the seizures that they're having seems

to be very similar, seem to have the genetic basis

should be identifiable and seem to control the seizures that

they're having.

Indeed, if we actually look across a large number of

cohort studies and trends, we find a large piecewise concordance

between those two things.

In generalised epilepsies, about 80% of the variance is explained

and even in focal epilepsies, about 40% of the variance

is explained.

This case was concordance goes down substantially if you look

at guys iconic twins rather than monozygotic twins.

So there's something particular about some of the genes in

these individuals that is disrupted.

And remember, back to the first couple of lectures we

had when we talked about the presence of ion channels

in the membranes of nerve cells, it should make sense.

A lot of these disorders are the disorder of specific

kinds of ion channels that are important in regulating neuronal

excitability, particularly sodium channels and potassium channels.

These channels get disordered and therefore the normal structure of

new activity is disrupted and the cells or the circuits

that they are part of become susceptible to the possibility

of being pushed into regimes where they become epileptic form.

Remember, this letter form activity is not just an individual,

so rhythmically discharging its spiking activity across a network of

nerve cells, hundreds of thousands of cells, it suddenly becomes

entrained makes this reverberant circuit of activity.

So normally the activity of really cold, only the activity

of the brain is sufficient to suppress the epileptic form

discharge.

But in people with these channel up with these, as

they called that activity, is that the normal ways of

controlling these these activity, stopping neurones from getting hyper excitable

is disrupted and these people are therefore susceptible to seizures.

She'll also say that you can actually many people are

also sensitive to what's called photosensitive epilepsy.

You're probably all aware of those trigger warnings that come

up often between newspaper.

News reports on the TV saying there will be flash

photography in the upcoming segment.

And the reason those trigger warnings are there is because

if you have sensitive epilepsy, you can be susceptible.

You can be induced to have a seizure response seizure

anyway by the presence of that flickering light from the

flash photography.

It's not exactly clear how or why this this works,

why the light entering the eye in trains, rhythms in

the brain, therefore causes his epileptic seizures.

But about 3% of people suffering from epileptic seizures have

this sort of sensitive epilepsy, generally triggered by lights of

flicker and about 15 to 25 frames per second.

Close to the aphorism that we mentioned over visual cortex,

and maybe that's got something to do with it.

We just don't know.

And can be triggered by ceiling fan, strobe strobe lights,

etc. for anything that makes this rhythmic on 15 to

20 times per second.

Visual image.

The following statement I leave you because I don't actually

really understand.

I wrote it down because I remember this happening.

But who hears what's spoken on?

Are too ashamed to admit?

Or are you just too old to have done that?

Apparently.

Apparently, I've never worked for one in my life.

The 38 episode broadcast on 64th December 1997, includes a

scene where Ash, Ashes and his friends need to go

inside the pokey for whatever that is through any device.

I remember when it happened, I remember it being a

big news story across the world, presumably because a lot

of people watching Pokemon on that stage, I suppose very

few of you actually born then.

But what happened in this thing was the repetitive red,

the blue flicker about five times per second, which ash

was presumably seen and which was transmitted through the TV

screens and induced about 600 to 700 people to have

to go to hospital for photosensitive epilepsy in Japan at

the time.

So this is the reason that we have these trigger

warnings when we see flash photography and the people making

TV and movies now much more aware of the possibility

for sensitive epilepsy.

I want to show you some recent progress actually from

Queen Square.

Again, just as John Houston's Jackson, some from whatever, years

ago.

This is work from a group of people at a

very large epilepsy research group at the Queen Square Institute

of Neurology.

I think this is a really interesting and important innovation.

I'll take you through.

It came out earlier this year.

It also speaks a little bit to some of the

noise that you've picked up over the last few weeks.

The underlying thought from these researchers was the following.

Epileptic activity is this increase in discharge above the normal

rate in nerve cells?

It follows that that increase in discharge triggers some processes,

interestingly, that we might be able to tap into.

In particular, this thing called IED or immediate.

Early gene is something we've known for about 25 years

now that when neurones become more active than normal, that

triggers this expression of this thing called IED.

We don't know exactly what it's doing, but we know

it gets expressed.

And these researchers have the idea.

All right, We know that this stuff only gets expressed

in these regimes of very heightened activity.

So if we can introduce a construct into the cells

that are sensitive to the expression of those immediate early

genes, we might be able to turn down the activity

in the cells that have been over activated.

And so they introduced what's called a form of potassium

channel that actually decreases neuronal excitability and whose expression expression

of this protein was linked to the expression of this

immediate early gene.

So when an epileptic discharge starts, the hypothesis is that

when they discharge start, that increases neural activity, which in

turn drives the production of this immediate early gene.

That immediate early gene production in turn drives the production

of this novel protein that they've been able to introduce

into the cells by means of a virus is otherwise

not destructive to the cells.

And then that that expression of that protein in turn

will drive down the activity and stop the seizure.

That was a hypothesis they wanted to explore.

And the work that I published earlier this year suggests

that this is true and might be a mechanism for

actually treating fungal epilepsies, at least in some patients.

To do this, they induced in a mouse model to

test this hypothesis because epilepsy is a product of brain

networks and not easily reproduced and induced, although they did

do work in vivo before doing this in vivo working

mouse they induced.

There's a standard model of generating epilepsy in mice.

In mice don't suffer too much from this.

They do get seizures, but this doesn't seem to cause

much pain or distress.

After after these seizures were induced, they then measured the

electrical activity by an electrical program electrode placed on the

brain.

And they injected these viruses into the parts of the

brain where the seizures were occurring.

So if they inject this far in the brain, they

can then compare the reduction of seizures in the mice

that have been treated with the control virus or this

virus that produces this particular protein.

And sure enough, they find it was in the control

virus conditions.

Mice continued to have seizures as each of these little

batches shows over the course of several weeks at a

time of a seizure.

They're recording continuously, by the way, from the animals.

They find that in these animals treated with the active

form of the virus, that those ones are stopping the

seizures.

So this opens up the possibility that we might be

able to inject into people who are having intractable epileptic

seizures, at least focal seizures.

We start from particular part of the brain.

We can inject into that part of the brain some

virus that expresses a protein like this, but then in

turn allows that part of the brain to effectively control

production of epileptic discharges.

I showed.

In other words, that I'm not showing here, they showed

that the presence of this virus in doesn't interfere with

normal behaviour, but only really with epileptic seizures.

They're really important and encouraging evidence because people with intractable

epilepsy at the moment, the sole way of trying to

address the seizures is to try and excise from the

brain a little bit of brain tissue to generate the

seizure.

So instead of taking out that piece of brain tissue,

the hope is that we can use a virus that's

otherwise safe but allows the neurones to suppress the epileptic

discharge.

A really important advance from my colleagues over Queensway.

So remember with a simple partial seizures which spread from

a part of the brain down to another, therefore causing

trembling and different things that focal because they start at

a particular point and then they spread like a travelling

wave across the brain, as opposed to generalised epilepsy, which

is a large.

Synchronisation of brain activity across the entire brain.

So this focus on start at particular point and spread.

And because I started at the point you can actually

introduce a virus at that particular point I should have

said that those focal partial seizures, they start from a

reproducible place in the person's brain.

It's not like they start from different places on different

seasons.

They start from the same place each time and spread

across the brain from that same place.

So because the you can then introduce this virus and

try to.

See this as an end or partial.

Or is are there like an off?

I don't think there are.

I think they have to be focal otherwise that generalised.

I don't know whether or not the size of that

focus could be quite variable.

I have a friend who studies epilepsy epileptic patients in

Australia.

He actually a lot of people, as you may know,

a lot of people that have epilepsy have aura associated

with a preceding the epileptic discharge.

And often this aura has structure a bit like the

migraine has associated with migraine has structure and can actually

because of that, people know when they're about to have

or at least some time before they're about to have

an electrical seizure.

And my friend has been studying those people by putting

them in a brain scanner during the seizure, actually.

These are at least four seizures, partial seizures, which don't

have massive consequences for the individuals.

And you can see the progression of this activity in

the brain during during scanning.

Okay, So that's I just want to take through the

seizures that clear result really of probably of mainly of

channel opposites all these disorders of ion channels that regulate

the normal excitability of neurones.

The hope is that we can try and treat these

by effectively resurrecting that normal control of those ion channels.

Seizures are fairly rare and we're going to make a

lot of progress in trying to deal with them.

Other disorders were made much less progress, and one of

the most prominent is Alzheimer's disease, a form of dementia

which is increasingly prevalent.

So there's actually many different types of dementias.

My grandmother had Alzheimer's disease.

Many people's grandparents, I suspect, or even parents will be

suffering from Alzheimer's disease or related dementia.

Alzheimer's disease is by far the largest, most common occurrence.

How?

How well it can be distinguished from other types of

dementia is still a matter of debate.

These dementias have common causes.

It's still quite.

Another common form of dementia is vascular dementia.

That's where three years old strokes, which then allow a

little bit of blood in parts of the brain, turn

triggers the brain to start self-destruction basically in that area.

You can get dementia from having many of these multiple

little strokes, which then have an impact on brain function.

There's also much less common forms of dementia which have

been important, like the one those iconic twins with seizure

disorders.

Those common those rare forms of dementia have been very

important to understanding the potential mechanisms of dementia, because we

can look at some of the genetic contributions of those.

This includes frontotemporal dementia, Pick's disease course for Jakob Disease,

Huntington's disease, Parkinson's dementia and Lewy body disease.

Many of these diseases have other effects as well.

Dementia is a part of the condition, not necessarily the

entire condition.

I got this line from This is the last World

Report from the World from the Outside Disease Foundation.

This just goes to show you the kind of prevalence

of Alzheimer's disease now and predicted prevalence in the future.

About one person around the world becomes diagnosed with dementia

every 3 seconds.

In 2015, there are already 50 million people in the

world who suffering from dementia is projected to be triple

that in 2050.

It's a huge we spend a large amount of resources

that we produce treating people with dementia.

And it's a worldwide phenomenon in particular as life expectancy

increases in the global south.

Dementia is becoming more and more prevalent there as well

and has to date being primarily a ritual disease because

life expectancy is longer in those parts of the world

and Alzheimer's disease or other dimensions.

And we strike older people.

I think the current ratio is something like 20% of

people over the age of 18 will have Alzheimer's disease

or dementia before they die.

The number is much less for people over 65.

So as as life expectancy increases, as more and more

people live over the age of 80, respect dementia, profound

increase around the world.

It's hard for those of us who don't have dementia

to gain some insight into what it feels like, what

it is like to suffer from dementia.

I find this William Autumn Olin's.

Ought to be at least one attempted insight into that.

He was diagnosed with the Alzheimer's disease in 1995.

He actually lived a bit longer than most people who

suffer from Alzheimer's disease.

And he was able as an artist to try and

describe some of the.

Changes in his cognition as he developed Alzheimer's disease, or

at least in the first few years.

This is the first portrait he made when he was

diagnosed, actually a man untethered, someone lost in the world.

As dementia progressed, as his disorder progressed, his his art

takes on particular forms.

You can see that he's a very accomplished artist, very

capable of generating self-portraits.

Back in 1996, in this case, when he's only a

year or so after the diagnosis.

What I hope you notice is that the structure of

these images changes substantially over the next five years.

There's a lot of death, lots of structure.

There's a changing affect.

There's capacity to see and to feel is changing fairly

quickly over these several years.

And really having a disorder of both his representation of

the world, but also his internal representation of himself.

Alzheimer's disease is named after Alois Alzheimer, who was an

Austrian neuropathologist at the turn of the last century.

He made his discoveries by studying data.

Peter Peter, who was one of the unfortunate people who

suffered early onset Alzheimer's disease.

She was only about 50 when she was taken to

his unit by her husband, who was a railway worker,

needed to, couldn't take care of her anymore, and needed

someone else to take care of her and outside to

work with her while she was alive and asked her

questions and so forth.

And then when she died in, I think, 1986 and

performed histopathology on her brain afterwards to see what had

happened to her brain.

And that might be part of the disorder that he

recognised or witnessed in her cognition.

The first thing she said basically when she met him

was that he had lost her so that his wasn't

able to remember who she was, why she was there,

etc..

You remember something?

What is your name?

Augusta.

What's her last name?

Augusta.

Struggling to try and find the elements of her memory

that she could bring to bear to the questions asked.

But she wasn't capable, really, even when he saw her

when she was 50.

Of doing much in life anymore.

And Alzheimer's disease is a very rapid progressive disease.

On average is about eight years.

This is increasing now as our treatments have improved, but

on average about eight years from diagnosis to death.

That's a very rapid.

And for those who suffer a debilitating and disorienting disorder.

One.

One way of thinking about Alzheimer's disease is that it's

a be like development in reverse.

So, for example, if you think about how we develop

over our normal life.

And I think we can hold up ahead off the

one, two, three months.

We can speak a word after year.

We can write sentences.

After about 18 months, we can control and our defaecation

and urine.

After a couple of years, we can shower unaided.

After four or five years, we can handle simple finances.

After about ten years of age and hold it over

for about 12.

And if you look at the progression of the Alzheimer's

disorders like this in reverse, you first lose your capacity

to hold a job with the capacity to handle your

finances, to dress yourself, to actually out of words, and

finally to actually do most of the functions that we

take for granted.

So this is an idea that Alzheimer's disease is a

bit like Retford genesis or development in reverse.

So you probably have seen pictures like this before.

This is a gross pathology of an Alzheimer's disease patient.

On the left is a healthy brain.

On the right is someone with advanced Alzheimer's.

You can see the substantial thinning of the grey matter

in the cortex as a large enlargement of the ventricles,

in this case of very severe hippocampal damage, losing much

of the hippocampus and therefore very much of our capacity

for memory.

On a microscopic level.

This is what Alzheimer found 120 years ago as two

major features that still remain prominent in our understanding of

Alzheimer's disease.

The first is that there are these things called senile

plaques, which are these things about anywhere between about 1/10

and one half of a millimetre in size.

Sometimes you can see them on unaided with the naked

eye.

And these are little disruptions of the brain structure, which

are filled with a protein called amyloid beta.

And on the right here is the other aspect of

pathology that seems to be very prominent people with Alzheimer's

disease.

That's what's called neurofibrillary tangles.

These are basically disordered conglomerations of a protein called Tao

Utown, which has a large number of roles in regulating,

especially transport of substances to the cell.

And there's a lot they organise into long filaments and

somehow they start that filaments start breaking down and start

breaking into what we call tangles.

So these Tao and Amyloid are the two major proteins

associated with Alzheimer's disease.

Yeah.

Does it look like it?

Absolutely.

Yeah.

It's one of the more fundamental proteins in ourselves.

So now the question was, is Tao normally present or

is it just present in in Alzheimer's disease brains?

It is normally present.

It's because of a particular.

Way of how it interacts with other molecules of Tao.

If this gets disordered, it starts to out of the

solution and form these tangles.

And so in Alzheimer's disease is proteins get slightly disordered.

They get called hyper phosphorylated.

Once they are hyper phosphorylated, they can come out of

the solution form these tangles or neurofibrillary tangles within the

cell.

This slide here shows the kind of progression of these

two different proteins, amyloid and TAL, as a function of

time in the progression of Alzheimer's disease.

It's hypothesised, it's not yet clear that there's not a

huge amount of evidence for it.

The amyloid first is causal.

But certainly the case that amyloid emerges early on in

dementia, followed by TAL and then after that followed by

neurodegeneration loss of cells and sinuses, and after that followed

by cognitive decline.

The cognitive decline is probably paralleling the loss of self

and finances, in fact, may even be emerging earlier.

But the overt signs of cognitive decline happened late on

in the season.

The consequence of that means is that by the time

you know that someone is suffering from dementia, from a

cognitive perspective, it's already too late.

Basically, our brain is very capable of making up things

for ourselves and hiding the fact that it's losing its

function.

And by the time we find that someone is demented,

that his pathological calmness, not to mention already too far

gone to do much about it.

We actually know surprisingly little about how amyloid and tal

affect brain function.

One of the reasons for this is it's actually been

surprisingly difficult to generate animal models of Alzheimer's disease.

It's not completely clear why this is.

We can certainly generate animal models where we introduce mutated

forms of amyloid or mutated forms of cow that have

been mutations for which have been deduced from people who

suffer from Alzheimer's disease.

And we can see that those things can lead to

the formation of plants and the formation of these neurofibrillary

tangles.

Often they do not lead to neurodegeneration and they only

have mild effects on the cognitive performance of these animals.

So why it is that it seems to be more

the case in humans and so hard to generate these

animal models of it is unclear.

But the consequence of that is that we actually know

precious little about the functional aspects of neurodegeneration.

However, we do know a little bit.

Whereas in the control condition here, these neurones are healthy

of normal neuronal activity.

This, by the way, is from a view from a

Bush who is in the Dementia Research Institute.

He's based.

100 metres away in the old building.

No critical building site.

Mark is a very prominent researcher in this field.

We've also joined in the last little while.

Be sorry when this app.

This is a particular precursor to more don't worry too

much about this is basically in animals who have this

overproduction of amyloid beta and stand on these plaques.

We often find hyperactivity increased activity in the brain.

Later on when that android over production is joined by

talent misfolding, we find a reduction in activity.

It seems to be the case that this stage of

the amyloid production stage.

We can still rescue some of these phenotypes in mice,

whereas once the towers joined the amyloid and started leading

to hyperactivity, this phenotype seems to be incapable of being

rescued.

But it's still very early days to.

So what do you mean by that?

Is that you can rescue brain function.

Yeah.

Okay.

Sorry.

All right.

Just use the word phenotype.

And unfortunately, you can rescue brain function.

That is, if you stop the production of amyloid, you

can get cells back into the normal healthy state and

stop degeneration.

If you if you leave it later than that, you

get to a stage where you can't seem to stop

this process.

In humans.

We know quite a lot about the progression of Alzheimer's

disease and the and the pathology that's associated with it.

And in the large number of people that we see

in the clinic, Alzheimer's disease is started in the temporal

lobe, in the internal cortex or in the hip around

the hippocampal formation.

So starts this accumulation of talent and amyloid plaque starts

down here and then starts to spread across the rest

of the brain.

It's a fairly slow process.

Why is the temple open?

I'm sorry.

I just want to be see with my face and.

Do have a of.

Yeah, I think I believe the slide from this presentation,

but I think is there in your notes which is

an example where.

PET imaging, positron emission tomography imaging, which can be used

later to visualise the location of radio labelled proteins or

substances we can introduce using PET.

We can detect where this disordered amyloid or disordered pal

is and we can therefore look at the location of

those things in people.

So.

I think your next question would be why can we

therefore say, is this person starting to suffer from dementia

or something like that even before the cognitive symptoms emerge?

That we haven't progressed to that stage yet.

So we know that doing in people who are suffering

from Alzheimer's, dementia, that you can see this structure and

location of these disordered proteins.

But these proteins are present in normal brains as well.

And so in the early stages we can track it

and we can kind of post-hoc reconstruct that this has

happened.

But in terms of being a specific predictor of what

will happen in someone's brain.

We're still not at that stage, if that makes sense.

So we can see the presence of these proteins and

the possibility that someone might be more likely to suffer

from degeneration of dementia.

We can't say on an individual specific basis that you

will suffer from degeneration of dementia.

It's not at that kind of specificity at the moment,

but we can track those proteins at least with p

t, which is very invasive.

It's not something you can scale out to 150 million

people in the world, but it that way.

There is some hope, by the way, that and I

haven't put it here, but we are starting at the

moment.

Other techniques.

So, for example, the electroencephalogram, which, as I showed you,

is very important at picking up seizures.

Turns out there's very characteristic changes in that transfer ground

at some stages of Alzheimer's disease as well.

We'd like to think that maybe if we knew more

about the structure of the circuits involved, also what's happening

to the circuits involved?

Early stages, we might be able to find signatures of

that disorder even earlier on in patients and therefore be

able, since EEG is a very cheap, easy thing to

introduce, might be able to say have that in the

clinic somewhere and just somewhat construe brief EEG study or

something like that, four years age and see whether or

not they're easy activities, predicting that they might be at

risk of these diseases, whether we'll ever move to like

proper predictive, I'm not sure.

But it might be able to pick up some people

from these methods.

If you look at the stages of Alzheimer's disease and

what you know of brain function, Hugo and I and

others have told you over the last few weeks that

the different stages of Alzheimer's disease make sense.

If it starting in the temporal cortex, then the first

stage is going to be hippocampal formation and final cortex.

We know that these areas are important in spatial navigation,

sexual orientation, and it's no surprise, therefore, to discover that

one of the first things to go in Alzheimer's disease

is your capacity to navigate around the world as the

disorder moves up through the brain.

This is just a schematic of that.

For example, in the prior two cortex that you start

to lose your visuospatial kind of organisation as we discuss

the consequence of neglect.

And as it moves more to say, the frontal cortex

and you start to lose your abstract reasoning capacity.

So the structure of the brain, a bit like those

focal seizures, it is travelling wave on a much faster

timescale, moving out across the brain.

So this kind of travelling wave disorder from the temporal

cortex to the rest of the brain has predictable cognitive

consequences.

I won't go through the news this time, but this

is the kind of exam that you might do in

the clinic to try and assess whether someone has dementia.

I encourage you to do it and particularly to try

and do it.

The Where is it?

Serial seventh task count back in seven for 100.

I sometimes think I have to mention when I do

this, I won't go through it now.

What I want.

And I also want to go through a couple of

these hypotheses just in time.

For a long time, we thought that some disruption to

the cognitive system was important in the pathogenesis of dementia.

It doesn't.

Well, it might well be important for treating that.

It doesn't seem to have much effect.

Studies are being made trying to treat the cognitive system

to see whether that has an impact on the occurrence

of dementia.

Very little progress has been made.

By studying rare familial cases of dementia, that is, people

who get early onset dementia.

These tend to be much more genetic link and sporadic

cases that occur later on in life.

And there are some clear genes that are involved, most

of which are related.

Most of the known genes are related to some part

of the amyloid pathway.

And John Hardy, who is at the Institute of Neurology,

is the one who's promoted the idea that amyloid is

important in the pathogenesis of Alzheimer's disease.

This is a slide, I think, from one of his

reviews, but this is his basic hypothesis that there's some

kind of change in how the brain metabolises and like

beta, which in turn leads to all the other steps

that cause degeneration and also the sort of power that

we know happens later on.

I won't go through these in any particular detail.

The point is that this changes in the amyloid beta

metabolism cause the the kinds of inflammation and injury to

nerve cells that we see later on in the disorder

and end up with dementia with plaque and have pathology.

Now, consequence of this hypothesis is that if you were

able to treat the amyloid beta early on, you might

be able to stop the rest of the cascade and

prevent or at least slow down degeneration.

And many of you may be aware of this study

from two weeks ago that came out among eight month

study in collaboration with pharmaceutical companies looking at antibody against

and why beta of people, family beta and immunising people

with that antibody and seeing whether or not it might

protect against Alzheimer's disease.

And this is a figure from that paper which is

cited down here and yet has a doesn't yet have

an issue number.

You can see that in placebo, there's no change in

employee burden.

There's when you immunise with this antibody, you get a

substantial reduction in amyloid burden in the brain.

The top one here.

This shows the the dementia score.

A person might take them to a clinic, but no

one here says one of the performance measures for cognition.

The yellow shows what's happening in patients who are being

treated with this antibody, and the blue shows a placebo.

And the fact that yellow line is above the blue

line means an improvement in performance in those people who

have taken the antibody over placebo.

So this is, I think, something like a 20% improvement

in cognition over this 18 month time period, which if

you're excited, is a great improvement.

If you're not excited, not much.

It all depends which side you see on the fence

there.

I think even the hottest proponents here would say this

is just the first step.

Being able to try and treat Alzheimer's disease.

It's certainly a long way to go.

And it shows it is potentially, theoretically possible to try

and stop Alzheimer's disease by blocking or interfering with this

amyloid beta process early on.

I'm aware that we need to shut up now.

I just want to in the last couple of slides,

just point out to you, we still don't know why

some people suffer from dementia and others don't.

What is it?

Is there a is it just solely divide by genetics?

Is it some kind of combination of genetics and environmental

factors?

What is actually the trigger for the start of degeneration

in those people who have identical genes?

There are several hypotheses about.

I've listened to them in in this.

At the end of this presentation you can go and

read about them and the references there as well.

The fundamental point at the end is that we don't

know why some people are suffering from dementia and why

others are not.

It does seem, though, the most obvious thing to do

for all of you and for me is that exercise,

for whatever reason, seems to slow down dementia or prevent

it.

So I can only encourage you to walk more, run

a bit, and exercise and have will also be here

in about 50 years time.

All right.

Thanks for listening.

Have a good week.

Hope you get the.

Still nine degrees.

As a coach I'm wondering about.

It's a good question.

Should.

That's a very good question.

I don't know what's happening, but what I do is

when I get back to October, I think, you know,

I'm.

I think in the limit you should be able to

be done over at the zoo.

But yeah.

That's a good question because my.

Sorry.

What's that?

You know what I'm saying?

Yeah.

You've got to let it go.

Tell me nothing.

Ever happened to you.

Three.

Yeah.

Yeah.

This is a component from the premise of migraine and.

So from whatever, I think migraine itself is a spreading

depression.

So it's kind of the opposite in terms.

Of so.

The reduction in activity.

I think it's.

Kind of spreading the or the seasonality is pretty significant.

So they're having different effects, but they're both spreading.

They seem to have some link.

And they're both chronic disorders of the normal people.

So I don't know why they should be doing that.

I think I just I know I, me, I oh,

I'm like always like that sort of interesting that you

look at the brain go away and it's like how

like ultimately or mean like sort of like blind spots

and then like, paralysis in the right hand spreading of

the right side.

Yeah.

Yeah.

Yeah.

So and it's I mean, it is interesting.

I know it's not to be treated as a patient

over these things, but it is actually fundamentally interesting for.

I remember seeing a.

Presentation.

A lot of people with migraine or or there's always

structured and ways the leading edge of people often has

these kind of it's clear answers.

Which is the hope was that actually one should be

able to correlate.

Kinds of special circumstances getting on with the part of

the visual cortex that was disrupted at the time.

So it was I believe the early visual cortex had

been disrupted.

Can you see things like.

Edges and stuff like that?

Whereas.

Like a bit of prudence.

Maybe you'd see something, for example.

I think that they hope to do that by.

Because it's such a subjective experience.

You have to be trying to ask people to map

out what you see or represent.

Mm hmm.

Mm hmm.

I don't know what is going to happen to.

Not very strongly, but there was a couple.

All right.

Just a quick question to you.

So do you get.

Partial processes.

Or do you mean that the neurones hiring, that's what's

being asked you, don't you just just that because all

of a sudden.

Yeah, it's a really interesting point.

You can kind of think of like this is one

way of thinking.

The brain is looking with a certain here.

And then that.

And so you get a little disruption here.

The net effect of an isolated incident.

Yes.

And you were talking to each.

Other over and over.

I saw you.

If you get disrupted this little circuit.

I said.

And then just to read this letter by something else.

And that's how and how we keep.

Says the student who was just here.

Not it's not clear when that is on.

At this stage, it doesn't seem like.

It seems like.

To start.

Either that or the disruption of.

To get something to.

And.

And if maybe it triggers.

So that's one possibility.

But this is too.

Important for him to tell what causing.

But I mean, I do think that.

It's very hard and it have to bear in mind

that these are within your own self.

So.