Connie Lee, Angioma Alliance President/CEO: On the morning of June 18, 2002, a
neurosurgeon who had co-edited the only
textbook on CCM received an email from
a mom in Virginia. She was starting a
patient organization and asked for some
direction. That afternoon, the
neurosurgeon wrote her back and offered
to be the new organization's
scientific adviser. The rest, as they say,
is history.
We could not have imagined 17 years ago
where we would be today, but I am honored
that Dr. Awad continues to serve as the
Chair of our Scientific
Advisory Board and that his clinical and
research expertise are focused on our
families and our disease. In addition to
Dr. Awad's brilliance, his dedication, and
the sheer volume of stuff he's able to
do in 24 hours (I don't know if you guys
know this but truly Amy and I just
marvel at this all the time), I
particularly appreciate his patience
with my impatience - there should have
been a cure yesterday, we all know this -
and his willingness to teach at every
level. And by the same token, I appreciate
his impatience, which does show itself
from time to time. As a physician-
scientist, Dr. Awad is on the front line
seeing patients, hearing their pain, and
offering them hope. And he does a very
good job of this.
it is difficult emotional work, and I
know that he too would have liked a cure
yesterday for our families. But we will
get there. Although he's still a young
man, in the last few years I have started
to ask him when he will retire. We all
know how difficult this will be to fill
his shoes in the CCM world, and as a
patient community we worry. Every time I
ask, he tells me, "Not until we have a
treatment," so I am taking him at his word.
I do hope that because of that he gets
to retire sooner rather than later -
because we have a treatment - but I am
relieved that he plans to stay for the
duration. We started this together and
we'll see it
through together.  So now I have the honor
of introducing Dr. Awad as the keynote
speaker for this, our Scientific Meeting's
15th anniversary. He is the University of
Chicago's John Harper Seeley professor
of surgery. He leads the neurovascular
surgery program and co-leads the stroke
and neurovascular care team. He's the
director of our CCM Center of Excellence
as well as the Safadi Center of
Excellence in Clinical and Translational
Neuroscience and the Center of
Excellence for Hereditary Hemorrhagic
Telangiectasia. We are all familiar with
his CCM research. Very little happens in
the US CCM research world that does
not include him. He's held leadership
positions in professional societies in
the US and around the world, including as
president of the Congress of
Neurological Surgeons, Chairman of the
cerebrovascular section of AANS, chairman
of the Congress of Neurological Surgeons,
and on the executive committee of the
American Stroke Association and the
Board of Governors of the American
College of Surgeons. Dr. Awad has
excellent taste in restaurants and wine
and he has professional-level expertise
in telling a good story. So without
further ado, may I present Dr. Awad.
Good morning, thank you. I'm truly, truly
honored and when Connie asked me to
think about giving this address a few
months back, I kind of took a little
time to figure out what is the best way
of telling the big story, the big picture
but yet position us where we are today
on the road ahead. That's
really gonna be the theme of my talk.
This paper we wrote just a couple of
months ago was was meant to be a summary
at the level that a basic clinician can
understand about a lot of the
research that is happening and also the
evidence base. Basically it 
embodies a concept of taking a disease
that neurosurgeons have struggled with
on the technical level of treating a
patient and removing a lesion from their
brain and really deconstructing it using
the tools of modern biology. This has
been really the story of the last 15
years. What I want to share with you
today is basically some glimpses of what
my life taking care of CCM looks like.
That's kind of what it looks like.
It's got faces of patients it's got
colleagues in the lab in the clinic
debating what to do about the case and
it's got connection with scientists
that we sit down and we huddle together
and we ask what can we do together.
I want to start really by reading you
a few verses from a poem by Kahlil
Gibran, written in 1923, talking about
what it is to work with love. "It is to
weave the cloth with threads drawn from
your heart even as if your beloved were
to wear
that cloth. It is to build the house with
affection even as if your beloved were
to dwell in that house. It is to sow
seeds with tenderness and reap the
harvest with joy even as if your beloved
were to eat the fruit. It is to charge
all things you fashion with the breath
of your own spirit and to know that all
the blessed that are standing about and
watching. Work is love made visible." 
With that in mind, we start talking a
little bit about the milestones and the
road ahead. It's a story of collaboration
which means working together - synergy -
which is a little bit different than
collaboration. Synergy is about working
together to create a higher value or a
higher product than each alone can do.
Then cross-fertilization is even
another level beyond synergy where you
create new concepts that would not have
arisen alone by any one endeavor. This
is about community. It's about sprouting
just like we talked about sprouting
blood vessels. It is really starting
with writing a little brochure in 2002
for patients and ending up with what our
website looks like today, with the layers
of and dimensions that we are
dealing with. As I tell a little bit the
story of the science - because this is
what the patient's want to hear they
want us to explain to them what the
sciences about - I want to really
apologize about really the trap of all
keynote addresses. If I fail to
mention all important contributions,
please forgive me. It's very difficult to
do that in a time like this and there is
absolutely no intent to marginalize or
underestimate anyone's
work who I don't mention today. In a
brief history of the CCM, this is about
the story that has spanned just over a
hundred years. In the late 1880s, the
pathologist's were starting to see this
lesion in the brain and they were giving
it different names. The father of
American neurosurgery from the technical
standpoint, Walter Dandy of Johns Hopkins,
had a drawing in one of his books. With
his hand, he made the drawing of a
histology picture of what the cavernous
angioma looked like to him and how it
sat inside the brain. If we go
forward till the era of MRI - about 
80 years later - we could see
almost that same appearance now
with an MRI at high field,
with us starting now to apply the
tools of modern biology to dissect that
lesion. Really nothing happened until
the 1980s when MRI came about and when
the lesion could be seen in vivo [in the brain on MRI] because
before that, it was a pathologic
curiosity. Once we knew that it was seen
in vivo, we knew what the patients were
telling us through their bleeds or
through their autopsies, but now we were
able to see it
even as they survived it. We learned that
the disease had familial features. We
then went on, with many people
in this room, to map the genes and the
familial cases. Early natural history
studies were written.  I will show you
a few of those key papers. In the
next ten years or so, the work got going
to try to understand the function of
those genes. The concept of permeability
disease was presented at one of
these meetings here. Many of us came
here not knowing that concept and
left with an aha moment that this is
probably what this disease is about.
Again, it was the work of biologists who
are in this room - the work on somatic
mutations, the immune response, the
concept of phenotype rescue, and then the
idea of, "what is a hemorrhage?" when
everyone is saying, "did my lesion bleed?
Did my lesion did not bleed?"  Those have led to the
current decade where we are really
hammering away at
mechanisms of lesion genesis - how does that
lesion start? How does it progress? What
are the biomarkers, the natural history,
leading to the threshold of trial
readiness. These are some of the very
very early papers - people describing the
MRI appearance trying to figure out what
what might this lesion
really looked like in the brain based on
the picture we see on MRI. And then, what
we would see on pathology. The group at
the Barrow Institute in Phoenix really
led this effort. Later on, other work came
up, including work from our group in
Cleveland on natural history. These were
very early natural history studies where
we were trying to tell where are the
lesions in the brain. Are they
preferentially in one place or another?
We put needles in the lesions as the
patient was anesthetized and raised
pressure and lowered pressure and
published these things. We tried to
understand what is this lesion about.
Then there was this issue of using the
tools of modern biology to try to start
to understand the lesion. Put an
immunohistochemistry stain on the
classical histology and find out that
there was angiogenesis - that the cells
were actually proliferating in the
lesions. And then when we got stains off
of the junctional proteins, see how
those were lost.
And then when we looked with the
electron microscope and we saw that the
lesion actually was a leaky sieve. All of
those were very early rudimentary. I mean
right now we would roll our eyes as
to how primitive those techniques were.
We even took cells and tried to culture
them, but you know after a after one
particular pass of those cultures
nothing came of it. However nowadays we
are revisiting 20 years later some of
these same efforts. Then collaboration
started and we started getting blood
from families around the country.  I
had the opportunity to work with Rick
Lifton and Murat Gunel, who was at the
time a resident with us.  Rick Lifton,
who is now the president of Rockefeller
University, was the geneticist at Yale. He
was head of the program in genetics.
He said, "If you've got families, we'll
find the genes and sure enough we got in
the game.  I know there were other
people in this room and in France that
were all trying to do this work and
within months and weeks of each other
you started to find that there are three
gene loci that cause the disease, that
there was a founder mutation in the in
the Hispanic Americans of Mexican
descent. These were the first fruits
of collaboration because this could not
have been done by a neurosurgeon alone
or by a geneticist alone. Then
something kind of happened at the
instigation of Connie,  which is, "why don't
you guys get together and talk to each
other?" Doug Marchuk was at the time
leading a lot of these efforts and
and he called a bunch of people and he
said, "Why don't you come down to Duke
University and let's have a first
meeting where we all meet and talk about
it." Amy [Akers] standing there was a
graduate student at the time but you
know she was a leader just like she is
now. And this is what the group
looked like - many faces are still here
who have not missed a single meeting
during the past 15 years. The agenda was
amazing because in all the work we had
done, we've never had a worm guy
and the fish guy and the mouse guy
talked to a neurosurgeon and a
neurologist. We got ideas
from each other. We decided at
the end of that meeting that we should
write a white paper and go to the NIH
and tell them that this is a field worth
investigating. It took about a year, a
year-and-a-half, and then the NINDS
workshop on the biology of vascular
malformations took place. The
late Bill Young and myself were asked to
offer the first talk summarizing AVM and
cavernous malformation biology. Out
of that meeting - many of you
presented at that meeting - a paper came
out that is a white paper about
the research priorities on the biology
of vascular malformations of the brain.
It is sad that Bill is not with us. It
was a friendship that was stolen too
soon.
Here he is in France where we
went to visit the Sorbonne together,
coming to Chicago, or biking together in
Rio de Janeiro and then all of a sudden
he was not there. However, through his
work, the team at UCSF has sprouted with
amazing strength and kept the effort
going.
The layers of collaboration continued
through new initiatives where we are
working with Helen and other
folks involved in that in that effort.
Collaborations turned into synergy and
cross-fertilization. Doug [Marchuk] and Mark [Ginsburg], I
don't know if you remember coming over
to Evanston and sitting together because
we had the 3 Tesla MRI and we had mice
now that developed lesions. We were
wondering what can we do with this
information. Most importantly since
Mark Ginsburg knew what those cells did
when they connected to each other.
Those levels of think tank
communications were happening behind the
scenes and as a result of them
friendships arose. Doug had the room in
my house when he came to Chicago. 
Then, Connie and Amy and I got
together. We visited each other's labs.
I'm trying to illustrate how this type
of community
sprouted. We reached out to the French
group and through a joint grant came the
paper on SWI - double the number of
lesions than on GRE and T2* and
also increasing with age.
Never before had this been done
and this was a collaboration with the
Montpellier group and our group in
Chicago and also work in Rio. The
Canadian connection from the very
beginning was there. The worm was a big
factor in it, but the patients were a
bigger factor. It's amazing what came
out of that including papers that
continued to come out in high impact
journals as a result of these very first
meetings we had together here. Brazil -
they do it in a special way always - and
you know amazing.  That group
motivated again by a patient and her
daughter
and by a dedicated doctor - very, very
similar to the efforts that seem to
happen all over all over the place.
This is what it looked like in
terms of impact and multiplier effect. We
went to the NIH database and we looked
at the funding in number of grants and
then US dollars and you can look at the
years. I know we weren't planning on
it but this is exactly what happened as
a result of this cross-fertilization
coming together. The number of grants
started to come up. There were initially
small grants. Then within about five
years the grants became bigger
grants and a total of 
approximately fifty-six million dollars
have already been awarded by the federal
government. This is excluding American
Heart, excluding Department of Defense
grants, that are helping fuel the
research that is going on. This
wouldn't happen without advocates at the
highest level at NINDS who are
our partners Jim Koenig who is here who
is our program director, and the
NINDS Director who is a
neurologist and who understands very well
the importance of this. I keep
telling them that this money
has given them far more return than
other 55 million have spent on other
fields. It is absolutely true because
you look at the amount of publications
and key publications and impact on
medicine as a whole and on
understanding new medical concept that
arose from cavernous angioma research. The British group had another very
interesting road that they have taken. I
joined them from the very beginning the year
I was in London as their guest in 2008.
What came out of the British
part is really this other character with the
hat over there. This is
Rustam [Salman] of course, who gave the keynote
address last year. Rustam is a
brilliant neurologist neuro-epidemiologist
and trialist, When he
started thinking with us about cavernous
angiomas, I remember sitting and we drew
together these circles of what are the
different manifestations of the disease.
We wrote this evidence-based paper
defining what symptomatic hemorrhage was
and maybe it would mean something. At
the very least it would help
investigators to talk the same language
and patients to talk the same language
as to when a lesion bled. What we didn't
realize is that it would have a very,
very profound impact on natural history.
We had long known - this is a graph
that shows the rates of bleeds in
different studies - and we knew that when
a bleed had happened before, the rate of
bleeding again is higher. Also in the
brainstem, when a bleed 
happened, the rate would be higher.  There
were a lot of people, mostly Canadian
colleagues, who said, "Don't worry cavernous
angioma never does nothing. It doesn't
do anything to you." Then, other people
would say, "No wait a second, if
you really bled before, it's a very
serious disease." As it turns out, 
when Rustam looked at the population
study - as you know in Scotland, they
have Edinburgh and Glasgow and they collect
data throughout the Scottish population.
Whether it be an autopsy or a family
doctor or a hospital admission, they keep
track of it. In that particular
series, it became absolutely evident that
once a lesion bled, it is ten times more
likely to bleed again for the next
several years, and therefore this concept
of cavernous angioma with symptomatic
hemorrhage is a relevant aspect of the
disease, which was previously not
known.
This led us to sit down together,
again at the instigation of Connie and
Amy. "You guys disagree too much with
each other. Why don't you sit down and
tell us what you can agree on? what does
the literature really say?"  It was
about a two-year exercise of reviewing
every publication possibly made in the
field and using standards of evidence
and also very rigorous methodology to
achieve consensus. We don't sit down
and say, "You think the way I do, and I
think the way you do." We actually sent it
anonymously till we all had consensus
with each other and came up with
recommendations. The problem is that even
when we agreed on things, they were not
based on level of evidence, they were not
based on the best evidence that medicine
has today. It left us with a feeling
that there is an intense need for us to
do better in terms of creating evidence
for what we do: whether you should take
aspirin or shouldn't, whether you should
work out or not, whether you should take
vitamin D or not. We just don't have the
evidence that is needed to give you the
answers with the level of certainty that
you deserve. Of course, meanwhile doing
surgery
advanced a great deal and helped many
many patients. This is a lesion being
taken out from the speech area in a
patient with epilepsy. It's not plucking
it out. There are arteries that are
important to preserve. Veins that are important to
preserve. Speech function that is mapped.
These are complicated surgeries, but they
do wonderful things. This person is cured
from both the epilepsy and the cavernoma
as a result of this surgery.
The brain stem is a major
challenge. We all take a lot of pride
when we have these particular perfect
results after we go into the depth of a
patient's brain stem. However, the details
are more complicated than this.
For everyone that looks like this, there
is another one that is left with double
vision, walking with a cane, or having a
problem the rest of their life. This is
what it looks like when we do surgery as
a last resort. This is a lesion that we
couldn't reach it kept bleeding and
bleeding. Eventually we had no
options. This patient was on a ventilator,
was in a coma, and we eventually did
surgery. Now she is going to spend the
rest of her life disabled, but she will
attend her our kids' graduations and
birthdays. Her life is worth living
but with a huge, huge cost. The devil
is in the details. It's not, "take
it out, don't take it out" As it turns
out with brain stem surgery, in
particular, the cost of surgery is very
high. These are the series reported from
the best center, the best chest-beating
Phoenix surgeon, Seattle's surgeon, reporting
their best results. 50% of the patients
in those series have more serious
disability after the operation than they
did before.
In reality in your communities the
results are worse than that. So what have
we learned about disease biology and
will this knowledge really help us treat
cavernous angiomas safer and more
effectively in the future? I'm gonna
run with you through some of 
where the science is. It started with the
three genes and, importantly, one is much
more aggressive than the others. One has
a founder mutation in Hispanics of
American descent, the other in Jewish
families, and now we know in mid-
American families and so forth.
These genetics
research things have helped you
every day as you sit down with your
doctor and make decisions. What do I have?
How does it affect my son or daughter?
Does it skip generations? Does it affect
men and women equally? All of those
things we have answers to that didn't
didn't exist until we knew that
those genes were Mendelian autosomal
dominant. Of course, exceptional
aggressiveness of CCM3 disease is not
only true in patients. It's true in the
mouse. It's true in the cell. It's true in
the worm. Therefore it may hold the
key to trying to understand what disease
aggressiveness is mediated by. What is it
about this gene that does that. The work
of Kevin Whitehead and others showed
us that we are lucky that we only lose
one copy of the gene. If you're born with
both copies gone, you don't even have a
heart. You can't live with
no copies - with two copies gone - so this
gene is not a trivial thing that causes
an occasional lesion in the brain, go on
and live with it, get over it. This gene
has a fundamental biologic importance,
because if the second copy doesn't
happen, you don't even form a heart. This
really woke us all up. There is
something more profound biologically
here about this trivial lesion than we
had ever ever thought. What that
meant is, "what happens for you to form a
lesion?" Since every cell in your body has
one copy that's gone and one copy that's
good, what the hell happens?  Work
took place, many groups dissecting the
lesion and finding ultimately that in
the lesion, both copies of the gene are
mutated so that the lesion looks like
you lost both copies while the body is
lucky not to have lost both copies.
These are the papers that started this.
The work of Amy [Akers] and Doug [Marchuk] showed
that it happens with every particular
one. Then we started to mind the
sporadic lesions that look similar to the
the familial but don't have the
inherited mutation, and lo and behold,
within those same lesions are the same
mutations of the familial case. They just
happen as a fluke in the lesion. What
that means is that the biology of the
gene applies to even the lesions that
are solitary. The familial disease is
not different from the sporadic disease
because ultimately the lesion is a
genetic lesion whether you inherit it or
whether it develops by a mutation. Those
are fundamental findings that led us to
develop these animal models. These are
real cool models - the mouse
brain is the size of a peanut after the mouse has grown up.
With that, we can create cavernous
angiomas that look just like yours.
They look small at the beginning and get big
and they bleed, etc. It actually
allows us now to be able to look deeper
into the lesion and how it develops
using those models. We know that the
mature lesion has inflammation, has
leakage of hemorrhage. That's the
lesion we see on MRI, but yet there are
little tiny lesions you don't even see
on MRI that are mere bubbles in the
capillaries. They have no bleeding,
they have no inflammation, but they
already have the mutation. These are
the seeds of the big lesion.
This is a Paleo CT or a microCT. Almost
all the papers now you see these micro
CT pictures. What you guys don't realize
is that the Paleo CT is developed to
study insect fossils. It is actually in
the basement of the Department of
Organismal Biology and Anatomy
in an ivy-covered building on campus at the
University of Chicago I know at Penn, it
is at the medical school, but at our
place, we just study insects with it. 
We go two afternoons a week, my team, with
it a big plate full of brains
coming from Penn, from Duke, and we
borrow the scanner from them. This
has revolutionized the field, because
we're able to now count how many lesions
and compare treatments and mice and see
the effects of therapy. As a result of
work like this, that signaling aberration
that makes you not form a heart, if it
happens on a brain blood vessel after
you formed your heart so you're lucky to
be alive, it forms a cavernous
malformation. This is a work by Mark
Kahn's
group and this master signaling is
critical. This means, to my knowledge,
this is the first disease ever where the
gene is responsible for such a
fundamental organ formation. 
After the organ has formed, the same gene
in another cell causes a disease. The
downstream signaling of this had been
studied by Mark Ginsberg and others -
Johnson, Whitehead - and realized that the
downstream signaling involves a pathway
of activating rho kinase which
results in unzipping and making the
endothelium leaky. This particular
concept led to the idea that if you
inhibited the way this comes unzipped,
maybe you rescue the disease even if the
gene is still bad. This is a
fundamental concept in genetic medicine.
If you cannot change your genes, you can
change what they do. That's kind of
what that's about. Sure enough, that
proof of concept was true. By inhibiting
Rho kinase,
the lesions in the mouse do not form as much.
These are the early studies based on
really just a few handful of of mice. 
Eventually, this led to work where we
also looked at how statins, which are 
drugs so commonly used, but when you use
them at doses with a drug like
atorvastatin that can cause rho
inhibition, you can have the same effect
as with the rock [rho] inhibitors.  When
you jack up the dose of statin, it is as
if you're giving the drug fasadil
which cannot be given to human being on
a chronic basis, while statin can.
This has led after about eight to ten
years of work to the actual trial many
of you are participating in now, using
statin to try to decrease bleeding. Why
is the brain a favored milieu? We keep 
debating this. Although every cell
in your body is gone occasionally, we
have some lesions in the skin, some
lesions maybe in the testicle or liver,
but they're not big deal for your life.
The big deal is the brain lesion. Why
is that?  One of the big
issues is a lot of the things we study
here it looks like we took away the
cover glass and there are no
inflammatory cells. We look at vessels
coming and going and forming and
unzipping and blood flowing, but this is
happening in the middle of a very, very
strong inflammatory milieu where there
are inflammatory cells that are actually
responding to a very - we have shown this
- responding to a very specific antigen in the lesion.
It's an autoimmune reaction that is
driving this lesion even as the vessel
problems are taking place. We have shown
that using drugs like the ones you use
for psoriasis or chronic ulcerative
colitis or multiple sclerosis
that are immune inhibiting drugs - using
the same drug that is now approved for
MS - actually, lesions in the mouse
do not bleed and do not form
as dramatically. If you look at the
fundamentals of what the genes do, you
have to look at the thousands of genes
affected by the disease gene. When you
have a disease gene, it forms the actual
disease by activating many, many other
partners. It's like one bad note
screwing up the whole symphony.
You want to figure out what is screwed
up and can we fix other things even if
we can't fix the main gene? Doing
this took really a huge effort.
This is something we spent about five
years. We collaborated with Brent [Derry] in
Toronto, with UCSD, giving us cells to
look at the libraries of these thousands
of genes and seeing how are they
different in cavernous angioma from
normal vessels. Lo and behold,
inflammation and the immune response is
a huge thing, even in the worm that
doesn't have white blood cells - doesn't
even have an immune system. They have
genes that are analogues to our immune
system and they're screwed up. 
This is really something that was
telling. What I'm leading at here is
that this led us to start to look at
these pro-inflammatory states, like when
you are Vitamin D deficient, you have a
pro-inflammatory state. Sure enough,
we're seeing now more and more evidence.
Yesterday, Kelly Fleming presented data
that shows what we showed also a few
years ago - that if you are vitamin D
deficient, your disease is more
aggressive. That doesn't mean if I go
pop vitamin D, I'm gonna be cured, but it
may reflect a state of a pro-
inflammation that had favored disease
aggressiveness. Although it doesn't hurt
to take vitamin D - I haven't heard anybody
getting screwed up by vitamin D so you
may as well bet on it. 24 biologic
compounds we looked at because many of
the groups had done research and they
they might be involved in cavernous
angioma disease. These have to do with
inflammation, angiogenesis, permeability,
and extracellular matrix remodeling.
We actually did a systematic
literature review and said, "What proteins
in the blood can we measure that people
said could reflect cavernous angioma?"
Started with that. When we queried
those proteins looking at their levels, a
few of them had some weak correlations.
However when you combine them in a smart
way to look at the smartest combination,
the one that is the most read using very
advanced statistics, that takes every
protein looks at the others, takes every
protein looks at the others and say
"What's the combination that is best?" It
turns out that a combination of four
proteins -
two going up and two going down,  two
inflammatory and two angiogenic - could
actually predict whether you're gonna
bleed next year. That means your body or
your lesion are sending signals in your
blood today as to whether you are ripe
for a bleed. We don't know why. We don't
know if it's you're not eating right. We
don't know if your microbiome is screwed
up. We don't know if you're smoking dope.
We don't know what you're doing, but there is
something that is predisposing you to
bleed next year. The ones that bleed
have a different blood work than the
ones that don't.
This is awaiting multi-site validation,
but we've already revalidated that in
many different independent samples. Many
of you have come to Chicago, given blood,
and this is how we've come up with this.
It has been published in the best journal
Circulation Research etc, so this is
real. Get used to it. This is a blood test.
This is what it looks like. Only one of
the patients that had bled had a blood
test that would not have predicted a
bleed. Unbelievable.
We also saw that the one that has bled a
year before also has signals in the blood .
It's not just the one that's
gonna bleed, but the one that bled
already. The signals from that are a
little bit different. Different proteins
tell you you already bled than the ones
that tell you you're gonna bleed.
This is the very beginning of smart
blood tests. This is not your
grandfather's "I'm gonna go check my
hemoglobin a1c." This is very
smart. This is looking at the mechanisms
of disease, combining it, to try to do an
individualized medicine approach. This is
emerging from cavernous angioma research
and we're writing it in other
medical journals for other fields to
apply. We have people in computational
biology helping us with how to do this
best. Then imaging. I wanna
tell you a little bit how we can squeeze
information out of imaging. You look
at the MRI. We already know that if you
do it really well, like with SWI
sequences, you can count more lesions than
you can otherwise. We can tell you
more accurately your lesion burden. But
has that helped anybody? I mean you just
go out of my office either depressed or
feeling better or whatever, but it hasn't
really changed your life to know what
your lesion burden is. However, if we look
at information within the lesion on MRI,
one of the ways is to look as to whether
the lesion is leaking, how
leaky it is? When we give the dye the
gadolinium instead of just taking a
before and after picture, we take a
picture during the gadolinium phase and
we look at the leak of gadolinium with
serial pictures. We do an equation
and we come up with this colar map that
tells us how leaky your lesion is. As
it turns out, when we look at that, we
find that lesions that bleed
just increase their leakiness 40%.
While the ones that don't bleed or are
recovering, they're leakiness remains a
very steady and, in fact, improves with
time. This is a very interesting
measure. It's beyond what you really look
at MRI for. This looks like what
the FDA calls a monitoring biomarker,
meaning it's a biomarker that can tell
you very accurately, very objectively,
whether you have bled regardless of
whether your doctors disagree or not.
Another one we spend a lot of time on -
about ten years worth of work, more than
two million dollars of research - is on
developing the imaging of how much
iron there is in the lesion. If you
look at the SWI image, the lesion looks
like a black blotch. Right? It's like you
threw ink on the paper. What we try to
do with the QSM imaging is to turn it
into a scale that tells us how much ink
there is in that black blotch. That
becomes a grayscale instead of a black-
and-white. Then you can turn it into
color if you prefer. As a result of
that, we have done very, very careful
studies that show that it effectively
measures in parts-per-million
the amount of iron in your lesion.
When we take a lesion out from a patient
and
we say the amount of iron in that
lesion, it's exactly what the MRI had
predicted. We've shown that. We've shown that in the mice in relation to
the blue stain of iron. Therefore, we can
measure how much your lesion is bleeding
even when you can't tell on black-and-
white whether it did or not. That
turns out to be another way for us to
follow lesions. As it turns out, twice
as many lesions will leak iron than have
symptoms during follow-up. You can
have occult bleeds that are not causing you
symptoms. We also show that yesterday in
another type of study. That means that we
don't have to just do trials on whether
you rebleed. We can do trials that tell
us whether you're changing the rate of
bleeding. Even a 20% change in a rate
of bleeding quantitatively can be
significant in a trial for us to help
choose among drugs, among doses. It may
not answer the definitive question, but
you don't have to do a thousand patient
trials to answer every single question.
This we
published in the Journal of MRI again
telling the radiology community that
"Look guys, you are sitting on something
here that if you measured, look what
happens in trial design." Instead
of having trials that required 300, 100, 90 patients to
count bleeds, you could get an effect
that is meaningful and significant with
30 patients in each group. We were
able to make this argument to the
National Institutes of Health resulting
in five million dollar grant to study
the statin, using for the first
time QSM as a primary endpoint.
For the first time, we are going to
measure whether you bleed more or less.
If it's more, that means statin is bad for
you, get out of it. If we bleed less,
that means statin is good for you. 
That's what we can try to answer.
The list of drugs is amazing. There are
several on the shelf.
Some have already started trials. You saw
that here
Statin, tempol, propranolol. Others are
being developed specifically for CCM.
When they are in the preclinical stage
or first time in man, the road is longer
and therefore we can try to do more
efficient things in between with the
drugs on the shelf, but we are
awaiting the bigger and better ones.
We are constantly trying to tell
Pharma that, "You've got drugs that you've
got patents on that can work for CCM.
Please spend the money to develop them
for CCM." One of those is a multiple
sclerosis drug that's already approved
by Genentech. They have several years
left on the patent, but they're afraid to
test it in CCM because they don't want
to jeopardize the big market in MS.
Believe it or not, that is what we
get told. They don't want a
negative result in CCM to make them not
sell drug for MS. That's the realities
we have to live with. You 
wonder why things are not moving faster.
The obstacles are different on different
parts of this battle. One huge critical
gap, -I'm getting here close  to
wrapping up one - one huge part of the gap
in our advances was trial readiness. Up
till two-three years ago, different
groups would define hemorrhage, would
define the endpoint, differently. They
collect different types of data on
patients and we said, "Guys, we are one
small disease, one small community. We gotto all do it the same way." We got
together the big players in this
group who see a lot of patients - the BVMC
group, the Mayo Clinic group, Utah, the
University of New Mexico because of the
Hispanic population, Barrow, and everybody now is engaged in evaluating trial
readiness, entering data into the same
portal, so that when we are ready to do a
big trial, we're gonna have multiple
institutions able to participate in a
way that was not possible in cavernous
angioma before. This again belongs to
this community. It's several million
dollars spent. This is another five
million dollar grant with direct and
indirect to all these institutions that,
as a result, is a gift to the CCM
community to be able to do research.
The atorvastatin trial is being run on
the side of that because we have an
opportunity to run it. This trial
involves you. It is now a third of
the way done in the enrollment. Of course
we have follow-up ahead of us and these
trials are amazingly complex. 
You heard yesterday about the complexity
in the Italy trial. Here, it's even
worse because we have biomarker and we
have double-blinding and so forth, so we
have safety people, we have monitoring
people.The data people can't be us, so we
like what data, we don't like what data.
This is a very sophisticated approach
but it's teaching us how to do it. This
is something we didn't know in CCM and
now we do it well for CCM. That's kind
of where we are. One of the results of
this again published recently in Journal
of MRI. Do you think CCM would publish in
Journal of MRI?  We're publishing
because we are able to tell them you can
take it to multiple instruments, multiple
institutions, and get the exact same
result using very specific techniques.
That's important. The idea here is
that you can deploy these advanced
methods at multiple institutions. This is
what it's looking like in our enrollment.
We're right on the curve. This
means webinars, this means wearing
t-shirts, this means encouraging each
other. Please do not be apathetic about
it. Be energetic about it. The answer is
worth it. No matter what it is. Yes, good,
Bad, it's good. One answer that's bad is
we can't do trials in CCMs. We're not
gonna allow that. Everybody should
avoid us ending up with an answer that
we can't do trials in CCM.
The patients are all coming. They are of all
kinds -  males, females, ages, etc. We know
what they look like. Future targets -
just
a couple of words. The microbiome. Who
knew that would be important until one
colony in Mark Kahn's group quit
forming CCMs? It was too clean.
it was too clean.
When they got dirty, they formed CCMs again. This led to a nature paper that
shows a relationship between
gram-negative bacteria signals from the
gut and the brain endothelial cells
switches that sends those signals. It
is really a very fundamental story to
medicine. Many groups are talking about
microbiome but few have done it with
this type of mechanistic impact. Again
thanks to CCM researchers, a whole
advance in medicine was opened again.
Where we are now is basically
looking at what the normal brain blood
vessel should look like on the left.
We're stuck with the cavernous angioma
being a dilated vessel. We want
to try to understand the switches that
make that dilated vessel bleed or not
bleed and in the process even understand
switches that could make a normal blood
vessel bleed. We're discovering those
as part of studying a cavernous angioma.
A lot of impressive work is going on
that the fruits of which are just around
the corner. The broader implications are
even cooler you know. I gave a paper
yesterday that says some aged brains
look exactly like a cavernous angioma
brain. I could show it to a
medical student and he wouldn't know if
it's a familial case or an aged brain.
Because cavernous angiomas bleed
prematurely but aged brains bleed. A
lot of the same signals of one apply
to all of us as we age. We talked
yesterday about as we get older all our
brains start to look
like cavernous angiomas. The big picture
is this - team's teaming up and teaming up
bigger and working together to
accomplish greater things. I want to
end with another couple of verses, also
from 1923, but this time from the great
New England poet Robert Frost: "The woods are lovely dark and deep, but I have
promises to keep and miles to go before
I sleep, and miles to go before I sleep."
We all have miles to go before we sleep,
because brains should not bleed. Thank
you very much.
