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In diseases such as Alzheimer’s we know that the physical degeneration of the brain makes it difficult to recall things like short-term memories. And so a patient might have trouble recalling a phone number or remembering what they did that day – or remembering someone’s name if the see them. That’s actually because the brain cells used in forming those memories and retrieving them are undergoing changes that are part of the disease. So as well as healthy changes that are part of learning there are also changes that happen because of the diseases – there is an interplay between positive changes that are necessary throughout life – and also effects that make it more difficult to learn. So if you had a computer you were changing the composition of – making changes in the way it is wired – it would affect the ability of the computer to do different operations. What you see as you practice a behavior is actually your brain cells are firing – using electrical messages to talk to each other – and then a second step involved in learning – is these actual building blocks of cells – the proteins or sugars or other elements of any part of the body are being made or restructured so the actual physical membranes of the cells are changing composition. And this translates into differences of how these brain cells fire. So, if a particular brain circuit is useful and helps you remember something – the actual physical structure will change in a way to make it easier for that set of cells to fire. And conversely, if you don’t use brain cells – and you are not learning something there is a degeneration or reduction in the amounts of these particular proteins. Now this is just being understood we know a lot about the physiology of learning – how the brain cells talk to each other when someone learns a particular behavior – we are only just beginning to understand what the actual proteins are involved and the physical and chemical substrates of learning are really only beginning to be deciphered – There is this sort of progressive knowledge that when you learn something it isn’t just in your mind there is also a physical component to this as well. One of the most exciting things about learning and memory and understanding how these things change as you age – is really seeing this in living patients. If you can understand the changes that occur in a patient as they begin to lose their memory or maybe help to save those memory processes – one way you can look at this is brain imaging. Brain imaging is something people are familiar with – you go to a hospital and get a brain scan – it can actually give you a physical picture of how the brain is doing. Now a brain image doesn’t show you individual cells – but it shows you aggregate of millions of millions of cells – you’ll see what is known as gray matter – the thinking part of the brain – and even though it consists of millions of brain cells – looking at that brain scan can give you a lot of information about what those brain cells are doing. So if someone is learning one theory is we see the physical changes in the structure of the brain – one thing that is very easy to see on a brain scan if there are signs of early degeneration of memory areas – for example if a patient is having early memory problems – one of the things we see in their brain scan is the memory areas will actually shrink – there will be volume changes and these are visible at a global level – you could look at your own brain scan and say that “I think – compared to a couple of years ago – these memory areas are shrinking in size”. What that means in terms of the cells is they are actually beginning to die off or changing in size and number – perhaps by atrophy or from a disease process. The brain scan is telling you on the whole is there is evidence that cellular changes taking place. It is a very exciting technology to monitor for early detection of a disease and really understand if the drugs are affecting either our memory or other brain diseases that might be taking place. You can think of brain scanning as a way of getting into the brain – similar to a digital photograph, but really accessing the integrity of the cells rather than the exterior of the body. PDC:
Tell me
about the
animation
of the
Alzheimer’s
disease
process.
PT:
These are
MRI of a
patient
involved
in an
Alzheimer
study -
one
of the
things you
can do
with MRI
is section
the brain
and have a
look at it
from
different
angles.
This is a
three
dimensional
MRI scan
– it
takes
about 8
minutes to
perform
– One of
the things
we are
looking
for in
these
images are
there any
early
signs of
Alzheimer’s
– I’ll
tell you
some of
the areas
that are
important
– these
are fluid
filled
areas here
– they
almost act
like
hydraulics
and
actually
cause a
sort of
buffering
to any
mechanical
sort of
condition
that
happens.
One of the
things you
see as you
age is
that these
fluid
filled
spaces
enlarge.
So often
one of the
first
signs of
Dementia
is if
these
fluid
filled
spaces are
a little
bit bigger
than they
should be.
One of the
reasons
this
happens is
as the
brain
cells
degenerate
– you
actually
get an
increase
in the
size of
these
fluid
filled
spaces.
They are
pretty
complex in
geometry
– it is
like a
labyrinthine
complex
system
that
threads
through
the brain.
One of the
things you
are
looking
for is a
sign that
this is
abnormally
enlarged.
Another
area
I’ll
show you
is the
memory
system.
Here is
the
Hippocampus
–All the
memories
of what
you are
thinking
of doing
today –
or what
your plans
are or
maybe your
remembering
your
schedule
for later
today –
all these
are being
stored in
this tiny
area there
called the
Hippocampus.
This is
another
are you
would look
at in
these
images to
see if
there are
any signs
of change.
Now the
Hippocampus
is really
the size
of a
teaspoon,
It has a
little
handle and
then there
is a
little
piece at
the end
here –
that brain
tissue
changes
very
drastically
in aging
and also
in AD –
One of the
things you
see is
shrinkage
– this
patient
actually
looks like
they are
doing
pretty
well.
Their
Hippocampus
is a good
size. The
fluid that
surrounds
the
Hippocampus
–
doesn’t
look like
there is a
lot of it.
This
actually
looks like
a healthy
brain –
no signs
of serious
deterioration.
One of the
things
you’d
begin to
see is
these
areas here
– a
little
tract of
tissue
called the
Hippocampus
and all
the memory
areas that
begin to
decline in
AD and
Aging –
these are
accompanied
by a
reduction
in volume
of the
structure.
This
structure
is called
the
Hippocampus
and again
we begin
to see a
paring
down of
tissue
structure
here – a
little bit
like the
cells were
dying and
at the
same time
you’d
see an
increase
or
enlargement
of the
fluid that
surrounds
the
Hippocampus
as well.
So this is
really a
target for
Alzheimer’s
therapy -
you are
looking at
the
structure
and trying
to save
the cells
in it –
with drug
you are
trying to
make sure
the rate
of loss of
these
cells is
either
stabilized
or
prevented
by the use
of
therapy.
This
is a
horizontal
section
through
the brain
that has
been taken
with MRI
scanning
– you
can see
the
patient’s
eyes here
and the
nose. One
of the
areas of
AD
research
that we
are really
interested
in is the
Hippocampus
– the
reason for
that is it
is the
structure
that
controls
and lets
in memory
– things
that you
learn –
the brain
tissue is
active in
this
little
area of
the brain.
What
this
scanner is
doing is
actually
accessing
the
physical
intactness
of that
tissue. So
even
though it
is very
tiny –
you can
tell this
looks like
a healthy
subject
– there
is a lot
of tissue
in the
area and
that means
the memory
function
is largely
intact.
This
little
fluid
filled
space here
– that
would be
drastically
increased
in an
Alzheimer’s
patient
– one of
the
reasons
that
happens is
that the
brain
tissue
surrounding
the
Hippocampus
begin to
die off
and as
these
cells die
off you
can see a
corresponding
enlargement
of the
fluid
filled
spaces. So
this is
really the
target for
Alzheimer’s
drug
therapy.
Some of
the drugs
used can
really
save the
cells here
and you
can use
images
like this
to see if
the drugs
are
slowing
down rates of
cell lose.
Also to
see if a
patient is
doing well
– if you
were to
look at
this area
over a
period of
time you
could see
if the
brain
deterioration
which
usually
takes
place
is
happening,
at what
rate it is
happening
and where
in the
brain is
the tissue
being
lost. This animation shows the changes of what happens as a patient develops AD over a year and a half. The red areas that you see here are areas where cells are actually being lost. As AD hits the brain there is this progressive lava flow, which is sort of eating into the brain cells and eliminating them and resulting in the memory decline that you see. One of the earliest areas to be effected in AD is the memory system. One of the things you see is that the red areas – the areas that go into deficit – they are initially only in memory areas. So this makes sense – a patient will have a deficit in memory and learning but not in vision or hearing. As this disease progresses you see this sort of wildfire of tissue loose that spreads across the brain. What this means is that over a year or two year period there is actually a progressive spread of the disease – the brain cells are being lost – not in the whole brain itself but in a sort of slowly spreading sequence. There is some logic as to how this happens – the memory systems are affected first – then the more emotional areas of the brain are affected and ultimately the areas of self-control are being eroded away. One of the things that the brain scan tells us is there is a physical basis for these changes the patient has. If we can use these scans as a record of what is happening in the brain – you can actually see if the physical spread of the disease is being halted or where a drug is slowing it down. So really this animation shows you two things – One is that AD is very selective and there is a sequence of how brain tissue is affected. PDC: That would be valuable information in therapy, are we at a point where the technology is being utilized? PT:
Almost,
memory
areas are
affected,
emotional
areas are
affected
and then
areas of
self-control
are
affected.
The second
thing
these
animations
show that
is much
more
positive
– is
really
they are
telling
you if in
a
particular
patient
the
disease is
being
slowed
down by a
particular
drug –
whether
things
they are
doing are
warding
off the
rate of
changes
happening
here so
even
though
this looks
like
depressing
image –
we are
thinking
in the
near
future
these
changes
could be
decelerated
and these
scans will
give you a
physical
record of
how well
the
patient is
doing. What
happens
when a
patient
gets
Alzheimer’s
disease
– there
are
particular
changes in
their
brain we
are
learning
about. One
of them is
this
molecular
compound
–
beta-amyloid
– a
starchy
substance
that
builds up
in the
brain –
now
amyloid is
not toxic
by itself
– but as
it builds
up in the
brain more
and more
– a lot
of
properties
of the
brain
cells that
allow them
to
function
normally
– begin
to be
impaired.
The first
is the
brain cell
starts to
be
inflamed
– the
reason we
know that
is
anti-inflammatory
drugs –
thing like
Celebrix
or things
like
Aspirin
–
actually
can give a
lot of
benefits
in the
early
stage of
Alzheimer’s. The
reason
they are
helping is
the
inflammation
that is
happening
to those
brain
cells is
actually
being
clamed a
little
bit. Now
on the
other hand
the later
stages of
AD when
the
amyloid
has built
up quite a
lot –
it’s
actually
impairing
the cells
to a
degree so
they
can’t
function
at all. So
you begin
to see
brain
cells
dying –
the
amyloid
starts
killing
off the
brain
cells at a
tremendous
rate and
what you
might see
as much as
5% of the
brain
cells a
year-
being
killed in
the brain
of an
Alzheimer’s
patient.
We know
that that
process is
quite
selective
where
amyloid -
the
molecule
that is
building
up in
Alzheimer’s
– where
that
molecule
is
building
up more
brain
cells
there are
cells
being
killed. It
is almost
like a two
stage
process-
if you can
keep some
of those
brain
cells
healthy in
the brain
– some
of the
degenerative
effects
that you
see as
brain
cells die
– might
be warded
off. PDC:
Isn’t
that the
hope of
pharmaceuticals
and
inoculation
treatment
approach
– to
alter the
chemistry
of the
disease
process
and spoil
it? PT:
Yes, and
imaging
has shown
without a
doubt
there are
a couple
of
different
ways of
warding
this off.
One of the
ways is
drug
treatment
and
obviously
drug
companies
are trying
hard to
keep the
brain
functions
as intact
as
possible.
Really
by beefing
up the
ability of
brain
cells to
talk to
each
other.
So
one of the
drug
treatments
used in
Alzheimer’s
is called
an
inhibitor.
And what
that is
actually
doing is
– you
have
depletion
as these
brain
cells die
- of the
chemicals
that allow
these
brain
cells to
talk to
each
other.
This drug
treatment
is
affecting
the way
this
compound
is being
depleted.
You
actually
have
vacuums in
your brain
that clear
the
chemicals
that let
the brain
cells
speak with
each
other. One
of the
drugs
blocks
these
vacuums
– it is
an
interesting
mechanism
– when
you take
these
drugs your
actually
inhibiting
the
clearance
of the
brain
chemicals
and this
class of
drugs
really
beefs up
the brain
cells
speaking
to each
other. A
second way
that you
can
balance
brain
function
that is
not
through
drug
treatments
-
is
really
just
common
sense. So
anything
you can do
to stay
healthy
things
like
nutrition
or
exercise
– these
are going
to
contribute
to the
physical
health of
the brain.
Now
it is
certainly
known that
your blood
vessels
and
cardiovascular
health is
greatly
improved
with
exercise.
This
is
identical
with the
brain –
the more
people
exercise
the more
the gray
matter of
their
brain is
intact.
This is
the same
tissue
that is at
risk in
things
like AD
– and so
even
though
exercise
doesn’t
directly
prevent
Alzheimer’s
we know
that
anything
you can do
to keep
you brain
tissue
healthy
and intact
– makes
it more
robust it
makes it
less easy
for
disease
like AD or
many
others to
really
take
effect. So
the things
you see
– is the
many
things we
can do –
things
like good
diet,
exercising
or really
having a
healthy
lifestyle
that
isn’t
damaging
brain
cells –
all of
these like
any other
physical
system are
helping to
ward off
the
effects of
ageing as
well as
the more
pathological
effects of
Alzheimer’s
as they
build up. PDC
You are
talking
here about
the
lifestyle
and simple
over the
counter
treatments
that
people can
self-administer
to himself
or herself
right? PT:
Yes, and I
think we
are at a
threshold
point in
imaging
where a
lot of
things are
possible.
One of the
reasons I
say this
is the
imaging
technology
has
undergone
a
revolution
in the
last few
years. We
are now
actually
able to
physically
image the
things
that cause
Alzheimer’s.
Let me
give you
an
example.
The
amyloid
protein
that
builds up
in the
brain has
never
really
been seen
before –
except at
autopsy.
Now that
is
interesting
in terms
of
understanding
the
disease
– but it
doesn’t
help
living
patients. There’s
really
been a
revolution
in imaging
though
that
allows you
to see
where AD
is
spreading
in the
living
brain. So
it not
only these
approaches
that
I’ve
talked
about with
MRI –
that are
looking at
the
intactness
of cells
– but
really a
new window
is created
on the
disease
– partly
because
you can
see these
rouge
chemicals
that are
building
up on the
brain. Now
why would
we want to
do that?
Well one
of the
ways if we
know a
drug or
lifestyle
is
effective
is looking
for a
physical
marker for
the
disease.
Now with
scanning
and
imaging if
someone
has a
tumor or a
broken
blood
vessel -
it is very
easy use
scanning
to detect
that and
see how
that
patient is
doing. With
Alzheimer’s
disease
until
recently
– it
hasn’t
been so
easy.
Alzheimer’s
disease
eliminates
a small
fraction
of your
brain
cells per
year –
but it is
actually
moderately
difficult
to see in
a brain
scan if
someone
has
Alzheimer’s
or not.
One of the
revolutions
in brain
imaging is
we now
have
scanning
in
exquisite
detail –
we can see
changes in
the order
of 1% or
half of a
percent in
the number
of brain
cells per
year –
this lets
you see
the
physical
process of
aging in
unprecedented
detail.
There are
also newer
imaging
technologies
as well
– one
new form
is called
amyloid
imaging
– this
is
relatively
new its
been
developed
over the
past few
years –
and you
can
actually
see the
physical
spread of
the
molecule
causing
Alzheimer’s
- amyloid.
And there
is a lot
of
exciting
ways this
technology
can be
used in
the
future. PDC:
Could the
imaging
technology
be useful
in
verifying
the
effectiveness
of
immunotherapy
– or the
vaccine
approach? PT:
In my
opinion,
yes. In
trials
that are
using
vaccines,
the target
of those
trials is
to eat up
the
amyloid
that is
building
up in the
brain. Now
there is
no better
way than
imaging to
see if a
patient’s
amyloid is
being
cleared.
Now
clearly
the acid
test is at
autopsy to
see if the
plaques
are still
present.
But
certainly
for a
patient
that is
alive who
wants to
know if
the brain
function
or the
pathology
is being
molested
or opposed
–
you’d
want to
use the
best of
imaging
you have
available
– really
to see if
the
hallmarks
of the
disease
– the
physical
signs of
the
disease
– rather
they have
been
cleared or
they are
progressing
as the
disease
evolves. Imaging
is at a
threshold
where we
can see
some of
the
hallmarks
of the
disease
for the
first
time. Some
of the
molecules
we know
that are
implicated
– we
have only
previously
seen at
autopsy.
Now you
can use
imaging to
see these
molecules
in living
patients.
Why that
is useful
is you
really
want a
physical
marker of
the
disease as
patient is
taking
drugs or
really as
people are
doing
things to
slow down
the onset
of the
disease.
These
images
give you a
physical
–
quantitative
measure of
how well
someone is
doing –
have they
averted
the
disease by
doing
particular
things or
in the
case of a
patient
has a drug
treatment
they have
been
having
slowed
down the
disease or
not. PDC:
Do you see
the end of
Alzheimer’s
disease
and the
role
imaging
will play
in that
end? PT:
Well,
there’s
a lot of
ways that
I think
will bring
about the
end of
Alzheimer’s
disease
– some
of them
are
measures
that
anyone can
take that
delay the
onset of
AD –
this buys
time. Some
of the
things we
know are
effective
are
exercise,
cardiovascular
fitness
keeps the
brain in
tact –
and even
healthy
diet and
nutrition
are
important
to keep
the brain
healthy. A
much more
direct
approach
that I
think will
be
revolutionary
is the use
of
vaccines
and other
agents
perhaps
that we
don’t
know about
yet –
but based
on vaccine
technology
that
physically
combat the
causes of
the
disease. As
we said
before, AD
builds up
in the
brain - it
doesn’t
just hit
you
immediately.
It plays
out over a
period of
two to
three
years. Now
even
though
this seems
like bad
news it is
actually a
window of
opportunity
for drug
treatments
like
vaccines
or
vaccines
in concert
with other
drugs. Now
in a sense
AD is a
paradoxical
disease
– there
is a slow
onset –
it sort of
sneaks up
on people
and then
it
doesn’t
hit all at
once. There
is a slow
progression.
One of the
ways that
the
vaccine is
promising
is that
they
physically
target the
cause of
the
disease
– so if
we know
these
rouge
proteins
contribute
to the
memory
decline
and other
symptoms
the
patient
has –
you can
actually
attack the
protein
and some
of the
treatments
that are
experimental
right now
I think
will be
used in
the future
to clear
the brain
of the
physical
source of
these
symptoms.
Now there
are also
other ways
that lead
to an
onset of
symptoms
– even
if we
can’t
clear the
brain of
the
physical
cause of
the
disease we
can
balance
the
function
of brain
cells –
so there
are major
efforts at
the drug
companies
world wide
essentially
to help
the
brain’s
chemicals
communicate
more
effectively
when the
brain is
under
attack.
Rather
than
combating
the
pathology
itself
it’s
really
sort of
mustering
the forces
of the
brain to
keep the
cognitive
function,
as it
should be.
Now since
we know
how brain
cells talk
to each
other and
the
chemicals
are very
well know
– it is
comparatively
straight
forward to
try and
effect
these
chemicals
and beef
up their
functions.
Let me
give you
an example
– if
someone
has
depression,
we know
that
anti-depressants
can be
quite
effective
in
eliminating
or at
least
partially
opposing
depression.
The reason
that works
is that
often in
depression
the
seratonins
or the
dopeamine
systems of
the brain
– these
are
different
chemical
messengers
-
are
altered.
And so the
drugs work
by
restoring
the
imbalance
of those
chemicals
in the
brain. Now
in AD the
case is no
different
- the
brain
cells are
degenerating
in the
brain –
causing a
chemical
imbalance
in the
brain -
and the
way the
brain
cells
communicate
with each
other –
it isn’t
just that
they are
dieing –
but the
existing
cells are
having
difficulty
communicating
with each
other with
these
chemicals. There
are
certain
molecules
– the
pathways
where
there is a
lot of
research
going on.
Where the
chemical
is
depleted
in early
Alzheimer’s
– so one
of the
ways
forward in
drug
therapy in
Alzheimer’s
is to see
if there
are ways
to keep
these
chemicals
around
longer in
the brain
– so not
just
people who
are
worried
about
Alzheimer’s
disease
but also
those who
have it
can keep
their
brain
balanced
for as
long as
possible. One
of the
things we
are
interested
in
understands
which
parts of
the brain
are
affected
in brain
disease.
So let me
give you a
road map
of the
brain and
those
areas
affected
by
diseases.
One of the
things you
see here
is the
overall
structure
of the
brain –
it is
actually
separated
into
regions.
Through a
lot of
research
from many
laboratories
world wide
– we are
now
beginning
to
understand
what these
different
parts do
– this
is an area
just below
the ears
– it’s
just on
the
exterior
surface
– this
area is
involved
in memory
- a
lot of the
thoughts
you are
having
when you
try to
recall a
name or a
telephone
number or
your
interesting
in what
happened
to you
many years
ago –
there is a
processing
going on
here –
it’s
called the
temporal
lobe. This
is
actually a
very
discreet
area of
tissue and
if any
thing
happens to
the brain
in this
tissue
area –
it can
actually
impair
memory
function.
So this is
the area
to first
degenerate
in the
case of
Alzheimer’s. PDC:
How do you
see the
pharmaceutical
industry
and the
imaging
communities
working
together? PT:
I
think the
next few
years will
see a
revolution
in our
ability to
see
understand
how drugs
are
working to
get ride
of
Alzheimer’s
– and
really try
and get
new drugs
on the
market as
fast as
possible.
One way
that
imaging
can help
is that
there are
certain
areas of
the brain
– this
is the
memory
area of
the brain
– where
very very
subtle
changes
take place
early in
Alzheimer’s
– with
imaging
you can
access the
intactness
of this
– you
can look
at
Amyloid,
one of
molecules
involved
in
Alzheimer’s
that’s
building
up here
– and I
think that
a second
revolution
in our
understanding
of
Alzheimer’s
will take
place if
we can see
the
earliest
possible
signs of
AD and
deliver
drugs to
the
patient as
soon as
possible
so this
brain
tissue
stays
intact.
One of the
things I
think we
will see
is the
drug
development
and
imaging
will work
hand in
hand, the
drugs will
actually
combat the
disease
and the
imaging
will give
you the
best
possible
index of
which drug
is working
–
whether
one drug
is better
than
another
– and if
the
physical
spread of
the
disease is
actually
halted in
concert
with the
symptoms.
PDC: What is this beanbag graphic brain image signify? PT: This sort of M&M graphic of the brain is actually a map of how variable the structure of the brain is in a population of people. Just as there isn’t a road map of any one city – everyone’s brain is a little different. In early days surgeons would plan surgeries using an individual brain – this is actually a composite of many many brains – and what the different areas of color are telling you are – the pink areas are areas where your brain and my brain might be quite different – really the structures might be enormously different in those areas. The blue areas are brain regions that are very consistent in the anatomy between subject to subject. Now one of the points of having this is you would like the measure of variance of brain structure is in population. If you have measure of that you can tell if a brain is abnormal. So part of why it’s hard to tell if a brain is abnormal is that there is so much that’s different between normal healthy subjects. It is similar to faces – each face is different from any others – it is difficult to tell if a nose if out of place or something like that – because we don’t have a statistical record of what those features should be. But just looking at this again – the little beans describe regions of space where 95% of the population would have their anatomy. And so the bigger beans are areas that are very variable – the pink areas that you see there with the elongated beans - there is a lot of difference in where people’s brain function is located in those particular areas. But the areas that you see in blue everyone is kind of the same. A surgeon needs this for understanding what the variability is for planning a surgery – and also more practically for more accessing brain abnormalities. If someone’s fissures or groves on the surface of the brain look abnormal – this provides you with a quantities way of measuring if that brain is out of whack at that particular area is it different than the population? So what you can use this for is to give you a map of the abnormality of each brain region by consulting a database of population data. Return to Alzheimer's LifePlan HOME News Room
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