BrainLane.net productions presents –
In April of 2003, I interviewed Dr. Paul Thompson; at the UCLA Laboratory of Neuro Imaging. I was first told of Dr. Thompson’s work by Dr. Wes Ashford, the lead M.D., Ph.D. for the End Alzheimer’s 2012 Task Force and was anxious to see first hand the advances Dr. Thompson was making in computer graphic assisted brain scan and data extrapolated imaging.
And it will tell you if your memory systems or your language systems – all of these different areas of the brain – are active as they should be. These are typically shown as color images, and these are ones where you might see a red area where the brain is very active and a blue area where it is not as active as you would expect it to be. That’s one type of scanning called PET scanning.
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 they 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 negative 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, and we now know a lot about the physiology of learning – how the brain cells talk to each other when someone learns a particular behavior – but we are only just beginning to understand what the actual proteins are, that are involved. 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. 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 that 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: “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 assessing the integrity of the cells rather than the exterior of the body.
PDC: Tell me about the animation of the Alzheimer’s
PT: These are MRIs 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 impact that
happens. One of the things you see as you age is that these fluid filled spaces
enlarge. 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
processed in this tiny area there called the hippocampus. This is another area 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 Alzheimer's Disease. 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 – it 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 a 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 lays down memories –
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 begins 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 loss. 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 these changes, and 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 affected 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 loss 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, second, that 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.
Even though this looks like depressing image – we are thinking in the near
future these changes could be decelerated; 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 always 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 – things like
Celebrex 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 calmed 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 is 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 a cholinesterase 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 you're 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 kept
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 diseases 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
PT: Yes, and I think we are at a threshold point in
imaging where a lot of things are possible for evaluating their effectiveness.
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. And it's 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 now also see these "rogue chemicals" that are building up on the brain. Now
why would we want to do that? Well one of the ways that we can know if 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 arrested 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
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
begin to 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 intact – 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
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 "rogue proteins" contribute to the memory decline and other symptoms
the patient has – you can actually attack the protein. 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 worldwide 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 known
– it is comparatively more straightforward to try and affect 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 serotonins or the dopamine 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 situation 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 dying – but the
existing cells are having difficulty communicating with each other with these
There are certain molecules – the neurotransmitter pathways where there is a
lot of research going on. These chemicals are 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 is to understand 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 worldwide – 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 discrete area
of tissue and if anything happens to the brain in this tissue area – it can
actually impair memory function. So this is the first area to degenerate in the
case of Alzheimer’s.
PDC: How do you see the pharmaceutical industry and
the imaging communities working together?
think the next few years will see a revolution in our ability to see understand
how drugs are working to get rid of Alzheimer’s – and really to 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 also look at Amyloid, one of
molecules involved in Alzheimer’s that’s building up here. 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. We will
see that 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
PDC: What does 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 any one road map of a city, everyone’s brain is a little different. In early days, surgeons would plan surgeries using an individual brain. This image 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 anatomy between subject to subject. Now one of the points of having this is you would like a measure of variance of brain structure in a population. If you have a measure of that, you can tell if a brain is abnormal. 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 normal 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 grooves on the brain surface look abnormal – this provides you with a quantitative 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.