English language

How to pronounce down syndrome in English?

Full Transcript

[Music]
uh good morning everyone uh it's my
honor to introduce professor elizabeth
head this morning as our speaker uh some
background doctor had obtained her
bachelor's master's and phd at the
university of toronto followed by a
postdoc at uc irvine
she then accepted a position at the
university of kentucky where she stayed
until recently but has now returned back
to us in the uc system at uc irvine
where she is currently a professor and
vice chair of research in the department
of pathology and laboratory medicine uh
professor head also serves as co-pi for
uci's titan t-32 grant which provides
funding and training for the
translational study of alzheimer's
disease and related dementias
dr head has been involved with a vast
amount of research in the alzheimer's
and down syndrome field appearing on
over 200 papers spanning the
establishment of canine models which
those of us who joined in early
heard some discussion and background on
uh for the characterization of aging
as well as the characterization of beta
amyloid plaques and other alzheimer's
and downs related proteins at nearly
every scale of life from biochemical to
behavioral science levels
uh so with that introduction said i'll
now hand it over to dr ed to present
insights from studying down syndrome as
a model for the pathogenesis of
alzheimer's disease
daniel
um so when i heard this uh that you guys
were inviting me for a t32
activity i was i was pretty excited so
i'm hoping you guys are all enjoying
your t-32 experience i think they're
just wonderful mechanisms for training
so i changed my title slightly it's kind
of the same topic
and um what i'd like to do is
go through um
part of the talk that i actually gave at
ucsd a couple years back before the
pandemic hit so i did this in person for
the adrc
and introduce near the end some new data
and introduce you a little bit to my lab
and my trainees and what they're working
on
so just to hopefully inspire you to also
consider maybe going into a little bit
of the down syndrome world
but i did want to start by just saying
that the most important slide in this
whole slide deck is the acknowledgements
and um
to understand that there's a huge amount
of data that
we work on that does span everything
from molecular genetic all the way up to
cognitive and clinical outcome measures
and it takes a village to do this work
and i'm lucky to work with two teams one
at the university of kentucky where i
still am an active collaborator
and also here at uci but most
importantly a lot of this work wouldn't
be possible of course without our
participants
and their families being actively
engaged in this research and they're
very committed so i'm pretty pretty
excited about that and of course it
takes a lot of funding and our more
recent funding is a year 19 and i'll
tell you a little bit about the abcds
program at the end
because the data that we're collecting
on a longitudinal cohort is freely
available to you upon request so i'd
like to encourage you to think about
that
so i'll just kind of get us all up to
speed on what causes down syndrome and
why do i think it's important to study
uh down syndrome in order to understand
alzheimer's disease and what does
alzheimer's disease look like in people
with down syndrome
and then i'm going to spend the kind of
the rest of the half of the talk is
going more deep dive into the areas of
interest that we have here in the lab
and some of these things topics
shouldn't surprise you and i'm i'm
suspecting a lot of you are working on
some of these areas
but we're very interested in
cerebrovascular pathology and down
syndrome and it's links to neural
inflammation
and i'll kind of summarize all that
material and what i think the
implications are moving forward and then
a little smattering of abcds to give you
some insights into what we're doing with
this larger study
so down syndrome uh
in many respects and um my colleague
juan fortia in barcelona spain likes to
say this a lot is the most common
familial form of alzheimer's disease in
other words
uh there are far more people with down
syndrome who develop alzheimer's disease
than there are families with the
standard genetic mutations
that lead to early onset alzheimer's
disease
so
our estimates are there are almost half
a million people in the u.s alone who
have down syndrome
and uh it was originally described in
1887 by jay langdon down who was a
neurologist and this is his first paper
describing the phenotype of people with
down syndrome and a kind of classic
picture of a
baby with down syndrome which we are now
very much more familiar with
and this i think we're on the wrong uh
he's not advancing
it's not advancing okay
let's do
stop share
and
i'm glad you stopped me
all right how does that look
great
as proper slides yeah
okay good we missed the introduction on
the history of downs there yeah okay
okay good thank you
uh even after all the zoom there's
glitches um so this is just i thought
it's fun i i like to know a little bit
about the history of these different
conditions and so here's an image of
what jay lang and down looked like in
his seminal paper in 1887
describing the phenotype of a person
with down syndrome
so what causes down syndrome
it wasn't until in 1959 that the the
genetic um contribution to down syndrome
was identified as an extra copy of
chromosome 21 which is thankfully the
smallest chromosome and has the smallest
number of genes
so that makes life a little bit easier
for us
and it's a really interesting story
on how this was discovered and
it turns out that dr gautier
was the one who actually visualized that
extra copy of chromosome 21
in vitro but she didn't have a
microscope to take a picture of this and
she sent those images or those slides
materials
to dr lejean who took a picture of this
very famous image and subsequently
published a paper and he's credited with
this discovery when actually
when you read the science article about
this it turns out gautier was really the
one who discovered it so it's one of
those kind of
interesting historical again stories
about down syndrome
but it turns out there's actually three
causes of down syndrome and this becomes
important when you think about how we
can learn a lot about alzheimer's
disease from people with down syndrome
so the most common cause of down
syndrome is the full extra copy of
chromosome 21
but there's also
another cause for down syndrome that
accounts for about three to four percent
of people
call translocation and that means only a
tiny piece of chromosome 21 gets carried
on another chromosome and triplicate it
so that's a natural
essentially genetic study where you have
a subset of genes that are triplicated
and you can look at the phenotype of
these people
and see if they develop alzheimer's
disease or not depending on which genes
are overexpressed and there's only two
case reports of that in the literature
so they're very very interesting people
and the third cause is mosaicism and
this is the more challenging one but
kind of interesting as well
in that not every cell in the body has
those full extra three copies of
chromosome 21
only some cells in the body and
i still don't understand if it's tissue
specific or if it's distributed we we
kind of measure this in blood
but you can kind of think about this as
a dose effect in terms of you might have
people who are 10 20 30 mosaicism
and you will see varying degrees of the
phenotype again which could be super
interesting for understanding
alzheimer's disease and there's only one
case report that really describes uh
early onset alzheimer's disease in a
person with down syndrome who was mosaic
and that was by john ringman's group at
ucla
so the good news for people with down
syndrome as they're living much longer
back in in the 50s and 60s it was very
rare for a person with down syndrome to
get much out of childhood and into their
teens
this has progressively improved over the
years and now we have people certainly
in our cohort or in their early 70s
and there's a couple of reasons why we
think this is happening one is much
better management of the congenital
heart defects that happen when they're
little
but also better management of
co-occurring illnesses and access to
a lifestyle that is just like everybody
else which is going to school and going
to work in that case is getting married
okay in some cases getting divorced
um but all of these things are combined
to provide
people with a much longer lifespan
and not surprisingly and just with the
general population the most rapidly
rising cohort of people with down
syndrome are those over 40 years of age
so we also are essentially having a wave
a silver wave i can't remember if that's
what we call it
in that we're seeing much
larger numbers of older people with down
syndrome and that's potentially going to
have a hit on our support systems
because how do we take care of people
with down syndrome when they have
dementia and potentially their parents
are much much older demented themselves
or possibly have passed away
so that's something that we'll need to
think about very very soon
so why should we study alzheimer's and
people with down syndrome what does this
tell us about alzheimer's disease in the
general population
and i love this picture this is ira lot
he's a pediatric neurologist and it was
ira who really set me on this path along
with carl cotman here at uci and he's
just a wonderful clinician very much
adored by our families
but
one of the key reasons for i think um
you know it's important to look at
alzheimer's disease and people with down
syndrome is the fact that on chromosome
21 as many of you well know
we have the amyloid precursor protein
gene
we have a number of other genes that if
you look at that i'm sure you're going
to find some genes relevant to your own
research
one which i'll revisit at the end of the
talk s100 beta which is a protein
associated with astrocytes but we have
mitochondrial genes we have synapse
genes oxidative stress genes
all kinds of goodies in here that might
be very relevant for testing hypotheses
about the role of these genes or protein
pathways in alzheimer's disease
but really
it's the amoled precursor protein story
that's carried the most weight in this
area
for many many decades
and so not surprisingly we see a one and
a half fold over expression and actually
1.4 to 1.5
fold over expression of amyloid
precursor protein and down syndrome
and not surprisingly we see increased
production of beta amyloid
which is also a consistent feature with
familial alzheimer's disease and as you
all well know adelaide has been indeed
you know implicated in the development
of alzheimer's disease now when i talk
about amyloid and app and down syndrome
does not mean i don't think other things
are important
but certainly we have good evidence that
app is critically important for
developing ad and down syndrome and if
you don't have that app over expression
such as in a partial trisomy case
those people tend not to develop
alzheimer's disease so it's important
for this story
and when you look at the brains of
people with down syndrome across their
lifespan
for example in this series i'm showing
you from a 31 year old a 40 year old and
a 54 year old
you see a very
systematic
uh progressive increase in beta amyloid
deposition in the form of plaques and
this is in the frontal cortex
indeed when you
you can quantitate those plaques and
plot them as a function of age
and it's not linear
it's pretty slow gradual increase until
about 40 and then it explodes in an
exponential function
and not surprisingly the tangles start
to follow suit although clearly the
tangles come after the plaques
until by the age of 40 here's a standard
image of the type of pathology we see in
40 year old brains and older
of significant tangles and plaques
so
the the useful thing about
people with down syndrome and studying
their brains and thinking about ad
pathogenesis is we can get a really good
handle on temporal events
and here's an example of what i mean by
this exponential kind of increase
is when you look at the prevalence of
both plaques and tangles in the brains
of people with down syndrome this is
based on some work by david mann in 1993
and i actually took his table data and
plot them instead
but when you look at this what's really
fascinating and i'm sorry about the typo
that's 29 um 30 to 39
that when you hit around 30 things
really accelerate
until by the time you get to the 40s
we're maxing out on the extent of a beta
and tau pathology
and so that raises some interesting
questions about will we have an over
expression system but we're not seeing
plaques really accumulate till about 30
so something
good is happening for many decades that
they can turn this a beta over and it
doesn't accumulate but something breaks
in around the 30s and those plaques
start to hit
and then that goes for probably almost
10 years until something changes again
and the tangles really start to kick in
so if we want to understand what's
contributing to all these different
processes
we can look at this as a function of age
and people with down syndrome whereas we
cannot do this in the general population
because the age of onset of ab is quite
variable
however what's i think to me extremely
fascinating
is that
the signs of dementia in people with
down syndrome if they do occur
don't start to really happen until about
a decade after we see both plaques and
tangles so here's an example of a couple
of papers that have been published
this was work done by nicole at columbia
university where she put together all
the courts that had published data at
the time which is in 2002
and here's the ages of the individuals
being evaluated and what percent of
people
have signs of dementia and
again you can see it's pretty stable
until around 50 and then those numbers
start to exponentially increase
what's fascinating to me though is this
and that is we're not at 100
and indeed what we're learning more and
more is that percentage of people who
get into their late 60s and even early
70s is starting to increase
so we used to estimate it's about 15 it
might be starting to grow
and that gives me great hope because
maybe it is a matter of managing some of
the risk factors like we're learning for
80 in the general population
so even though we have a genetic driver
there's still something happening here
that protects these folks
then there's been a couple of studies
more recently by andre streitem's group
and juan fortia's group where they
looked at the age of onset of changes
and kind of plotted these and what's
striking
is uh andre stratum shows in the united
kingdom that around 55 is the median age
where we see signs of dementia and a
completely separate cohort juan fortia
uh estimated that number to be 53.
and so uh we're looking at our numbers
in our longitudinal court but our
impression is it's around that same age
so that is incredibly powerful when you
think about clinical trials
so when we put this together let's start
assembling a kind of a puzzle
so um
why don't we start thinking about an
x-axis of age and when do these events
happen
and that might give us an idea of maybe
what leads to what and i wouldn't go so
far as to say what causes white but
certainly
what events happen earlier than other
events and that becomes critically
important when we think about clinical
trials and what pathways are we supposed
to target
because they are going to vary as a
function of age
so plaques might be great to target in
the 30s
but they really don't have many tangles
so maybe a tangle intervention is not
critical here
in their 40s maybe it's important to
target both plaques and tangles as an
intervention
so i wanted to kind of start filling in
the gaps of some of
this so one of the gaps that i thought
was really interesting to kind of look
at in down syndrome
was cerebrovascular pathology and and
there's there was really kind of an
interesting tension on this question
and it
is when you look back at the literature
for for many decades this was not an
area of focus in aging and down syndrome
and i'll tell you why that is
and this is why sometimes asking the
questions that you don't
expect to ask but gives you some really
fun new leads to pursue
so people with down syndrome typically
do not develop atherosclerosis they
typically do not develop hypertension
so i think and given their younger ages
most folks in the field
thought that cerebral vascular pathology
was not going to be a feature of people
with down syndrome because they don't
have these vascular risk factors
however
people with down syndrome are prone to
obesity and overweight
they have sleep apnea at a much higher
prevalence than in the general
population
and that's primarily due to the
structure of the throat and the neck
and
they are of expressing beta-amyloid so
you've got to assume there's lots of
this being deposited not only in plaques
but also blood vessels
and that was an area that we started to
kind of map down and it was surprising
there wasn't a whole lot of systematic
information about this in down syndrome
and when you look at cerebral amyloid
angiopathy and the brains of people with
down syndrome and here's just two uh
immunohistochemistry stains one for a
beta 42
and one for a beta 1 to 40 which a beta
1 to 40 being more soluble and typically
more tightly coupled to caa
we can see buckets of plaques but you
can also see these blood vessels with a
beta 42 absolutely caked on them
and when you look at a beta 1 to 40
again tons of blood vessels in the
brains of people with down syndrome have
a beta associated with them in fact
it's just
not only is it pervasive it's really
extensive that you just can't imagine
those blood vessels are able to function
properly that they can't constrict and
dilate properly
and now we have more and more evidence
that that's the case
so the question we asked is what is the
extent this rheumatovascular pathology
in the down syndrome brain
because we have these protective factors
but we also have this increased app
expression
so do they have more or do they have
less or do they have the same as what we
might see in later on said alzheimer's
disease
and the way that we first addressed this
question
was by working with a wonderful
biostatistician michael fallon pictured
here
where we took every single
adrc case we had here at uci
with all their neuropath reports that we
generate for the national alzheimer's
coordinating center or knack
and collated all those data and put in
um
our data from our down syndrome autopsy
cases which by the way are not uploaded
to nike yet but we can talk about that
later
and um so we just for at first blush
just look to see what we had that we
could compare
and we focused on controls non-demented
outflow controls
um
late onset alzheimer's disease and our
our autopsy cases with down syndrome
and something i really want to highlight
which is kind of a
a challenge throughout this research is
of course the brains of people with down
syndrome are much much younger than late
onset alzheimer's disease and control so
we always have this age
issue um that it's hard to control for
age across these groups
but nonetheless we had a pretty good
sample size of 32 autopsy cases with
down syndrome with vascular
data on it and specifically focused on
atherosclerosis in the circle of willis
arteriolar sclerosis and cerebral
amyloid angiopathy and we hypothesized
that atherosclerosis and arterial
sclerosis would be lower in down
syndrome
compared to sporadic alzheimer's disease
but that cerebral amylade angiopathy and
contrast should be higher
than sporadic alzheimer's disease
and it turns out our hypothesis was
correct
so when we look at this these graphs we
have the severity of the pathology so
mild moderate and severe the darker
colors are more severe and here's our
cohort cs ada and controls and each
graph represents a different outcome
measure so atherosclerosis not
surprisingly
less frequent in brains of people with
down syndrome
more frequent in alzheimer's disease and
in our subset anyways we had even more
frequent athero in our controls
arterial sclerosis there was i was
absolutely absent in our down syndrome
cases compared to our 80 and control
cases
and then in contrast cerebral amyloid
angiopathy was far more extensive and
far more severe
in down syndrome when we compare that to
alzheimer's disease and control cases
and then michael kind of plotted this a
different way looking at age of people
with this is just down syndrome
different ages of down syndrome um in
our autopsy cohort and we can see that
the the severity of cerebral amyloid
angiotherapy decreases with age so
i'm sorry we have fewer cases without
caa with age but more strikingly there's
almost a slight linear relationship of
increasing severe angiopathy with
increasing age
so clearly an issue for people with down
syndrome
so the next question we started to ask
and this was with a graduate student in
my lab at kentucky alex hellman was
we're seeing far more bleats i am sorry
we're seeing far more cerebral
angiopathy in the brains of people with
down syndrome compared to sporadic 80
one would suspect um that there might be
more microbleeds in the brains of these
folks so what are the consequences of
this increased caa
and um so alex started doing the studies
back during those years when we were
really having a lot of uh protests about
standing up for science et cetera and
alex um was a very active in this
movement
and what alex did was um she wanted to
look at the frequency of micro
hemorrhages in the brains of people with
down syndrome so she used a classic
stain called prussian blue which uh
identifies hemosiderin deposits
and those are deposits in the brain
here's an example of a blood vessel you
can see this is naturally and here this
blue deposit is hemosiderin
those blue deposits represent iron in
the brain and it should not be in the
brain so the only way you see this is
when there's been a micro bleed
what's really kind of cool about the
stain though is that that bleed could
have happened
decades before we looked at their brains
it doesn't tell us about when that bleed
happened anytime i have a bleed it just
sits there forever and ever i'm sorry
it's kind of a scary thought
but um it's it's really useful for
research purposes so alex did this very
laborious project um where she
identified blood vessels and then
counted microbleeds in a blinded fashion
to the cases
and it was a large study of young
controls who were under 40 years
uh middle age controls 40 to 60 years
you can see here we're trying to pick
controls now that match for the typical
age of our down syndrome cases
and then we had age controls to match
for sporadic ad
and in this case we hit up the nih
neurobio bank for younger control cases
under 40 and those with ad pathology
which were typically over 40 and
compared those to sporadic ads so this
is a big study and here's some
representative images prussian blue is
not a pretty stain when it works it
works extremely well
um so it does take a lot of manual labor
to kind of look at things very carefully
and quantitate them
and what alex found was when we looked
at just the presence of microbleeds
in the brains of controls we see a
little bit of an increase in middle-aged
old controls so i think that's actually
kind of good news considering my own age
when we look at sporadic alzheimer's
disease the average number of
microbleeds and the frontal cortex is
much of course higher so on average
about 32 to 33 bleeds in in the brain
region she examined
and then people with down syndrome were
under 40 without ad pathology you know
we had random infrequent bleeds
and when we look at down syndrome with
alzheimer's disease what's interesting
to me is
and look at the variability we're really
we are not significantly different than
sporadic ad so despite all this extra
caa in down syndrome brain we are not
seeing more bleeds
than what we would typically see in
sporadic alzheimer's disease
so does that suggest to us another
protective event
and it turns out infarcts frank infarcts
if you were down syndrome is not common
so another really cool thing to look at
in some more detail
however
microbleeds are
important and are happening in the
brains of people with down syndrome and
a lot of the neuroimaging approaches
that we're looking at now you can
clearly see these dark
circles these are micro bleeds
by neuroimaging by mri and they tend to
really favor the occipital cortex
but here is a person that came in for a
standard longitudinal visit with us at
the university of kentucky
and
he went he did his clinical evaluation
his neuropsyc evaluation and went into
the scanner and as these scans came down
the pipe we saw he was actively bleeding
so we pulled him out and sent him into
the emergency room
but this is happening in people with
down syndrome and we didn't have any
clinical signs
of that happening
so we can have a fun talk a little bit
later about what the implications of
this might be when we're thinking about
say at a helm or any kind of vaccine or
immunotherapy
targeting any beta and people with down
syndrome because to me this is a serious
concern
and
as i mentioned i'm going to try and
highlight some junior investigators and
students in this talk
i'm really excited that adam brickman at
columbia university who's been doing a
lot of work on vascular pathology by
neuro imaging and adney and other
cohorts
took an interest in down syndrome and
came on board with us
and he had
patrick lau was this graduate student at
patrick's thesis work
was to characterize vascular pathology
by neuroimaging
and people with down syndrome and there
was very little work on this
and uh he did this beautiful job of
characterizing white matter hyper
intensities
perivascular space widening
and also looking at micro bleeds as i
showed you better in a different image
and frank infarcts in a cohort of people
with down syndrome and he published one
of the first papers on this
and this was really surprising to me
these white matter hyperintensities
um because we typically think of those
as being a consequence of hypertension
and we don't see a lot of that in down
syndrome
and certainly in our cohort in kentucky
we didn't see a lot of this
so adam and i have been pushing around
ideas about is this cohort dependent or
is this something else and so
um we have an r01 and submission of
fingers crossed we get to explore this
in a little bit more detail but patrick
did an absolutely gorgeous job on this
paper
so the next question then if we just
keep kind of following the tale and i
i'll be honest with you this tale
actually did not evolve in the beautiful
order i'm telling you it kind of
happened all over the place
but we wanted to know what are the
consequences of all these bleeds in the
brain you would imagine there's all
these proteins in the blood they're
getting into the brain they shouldn't be
in the brain and those are probably
going to be causing inflammation
so i partnered up with donna wilcock um
who's at the university of kentucky with
me we're delighted to recruit her a
couple years after um i arrived there
and donna and i um did a lot of painting
and drinking together
so uh what we did is i was able to
provide her with frozen tissue
again for frontal cortex and asked me
why i always do frontal
um where i was able to give her some
young controls middle-aged controls and
old controls kind of the same design as
i just described
and then eight brains of people under 40
years of age without ad pathology lots
of brains with ad pathology and some
sporadic ad cases
so again here's our ages and our
post-mortem intervals
um you can kind of see who's our adrc
cases which are these shorter postmortem
intervals and the nih neurobiobank by
the nature of how they do these
collections have longer postmortems so
another thing to keep in mind
um that pmi could be potentially a
covariate in these analyses and so donna
at that time this was in 2000 early
2000s i'm sorry it's a little bit dated
but it's surprising there's not a lot of
updates on this
um used rt pcr and a subset of markers
of inflammation that she thought would
be important
and the first thing she did was
she looked at comparison of sporadic 80
compared to their age match controls to
understand
the full changes in rna and these
different markers of inflammation
uh the the dotted line each of these
graphs would represents um no full
change and of course if the bar is lower
it's a decrease in higher it's an
increase
and she clustered these genes into
different classes
which we can talk about later i know
it's not a super favorite nomenclature
to use but it helped here a lot
but we can see in sporadic ad as we see
il-6 il-12 are increased il-10 and tgf
beta
so this is kind of the profile of what
we would expect to see in sporadic ad
so then we just looked at the younger
cases of down syndrome compared to their
younger age match controls
and it was remarkable to see that we
already have huge amount of neural
inflammation in these younger people now
of course they're coming to autopsy for
a reason but this was a pretty
consistent finding that a lot of these
markers were increased
with the exception of cd86 and
fcgr1 beta
similar to what we see in sporadic ad
so now what happens when you have a
brain of a person with down syndrome who
died with alzheimer's disease
it gets worse
so huge amount of increase in
inflammation
and a number of um pro and
anti-inflammatory molecules
but uniquely to down syndrome we see
cd68 and fcgr1 beta increased and this
is not a pattern we see in sporadic ad
it's unique
to down syndrome
so the way donna explained this to me is
if you kind of break it down into these
different classes m1 m2a m2b and 2c
you can get some idea of what the
pathology underlying that profile might
be
and i think really of interest to us
with this m2b phenotype
it's typically associated with immune
complexes forming in the brain and that
was kind of the unique pathway that came
up in our down syndrome cases
so that led us down as you can well
imagine the next path and that is what
do microglia look like and the brains of
people with down syndrome
and again when you looked in the
literature there were scattered reports
of
people looking at microglia and down
syndrome brain
with very small sample sizes two or
three cases they tended to be end stage
cases
so
so far it looked like things were the
same but there really wasn't a good
systematic study of this
and an understanding of how it might
change with age
and so this was another study that alex
took on at university of kentucky
and then when i moved here to uci um i
was delighted to bring alessandra
martini on board
and dr martini was able to kind of wrap
up the study and um
you know offer her interpretations of
what these data meant she brought a nice
background of looking at microglia in
most models with frank leferle's team
and so what we did is a case series of
looking at what are the different
microglial phenotypes that we observe in
the brains of people with down syndrome
and to do this study
a similar type of setup we had young
controls
their age match
cases with down syndrome middle age
controls dsad age controls and
alzheimer's disease and there's our ages
of death
our distribution of males and females in
our post-mortem intervals
and
we use the verse imperial scanner to
scan and digitize all the images that we
had
and then each of these images was
annotated
and then this is where the labor began
uh every single image
the number of microglia that kind of met
each of these phenotypes was counted
i'm hoping there's a better way to do
this going forward because of these
beautiful ai approaches we can use and
and uh
but in this case
um we did this manually and actually
i'll tell you about another way that it
was done
so um alex and alessandra kind of
characterized these microglia by being
ramified which is what we consider the
resting or surveillance microglia
whether or not they're amoeboid which is
apparently represents more of an acute
inflammatory response
hypertrophic which we're all super
familiar with these are active and busy
microglia they're trying to deal with
damage in the brain
uh dystrophic microglia which are
microglia that have these blebs and
their processes are a little bit beaded
and wolfgang stright actually describe
this as part of the lifespan of a
microglia this is their old age
senescence and dying
morphology
and then we have these rod shaped
microglia which are really cool looking
uh i used to see these in the
hippocampus quite a bit and actually
they're positive for c1q complement
um and these are thought to reflect a
more chronic inflammatory state and so
the morphologies are pretty clear that
in terms of you can distinguish these
and um so now those counts were done
and it was absolutely interesting what
came with this it was completely
unexpected
so um when you just and just
trying to represent these data it was
also a little bit of a challenge so if
we just look at the gray matter of
frontal cortex of all these groups of
cases
and we look at
just normal aging across the top young
middle age and age controls and the
proportion
of these different microglial phenotypes
what you can see is with aging the big
blue is dystrophic not surprisingly we
see more dystrophin rights with age
um i'm sorry historically because the
dying ones we see more dying microglia
with age we also see the hypertrophic
which are the ones that responding to
injury in the gray pi slot here
increasing with age
and the number of ramo fighter quote
resting surveillance microglia in the
white decreases with age so that's what
you might expect for normal aging
so now when we look at alzheimer's
disease just focusing on here we're
seeing far more dystrophic
microglia
lower numbers of breast and microglia
sorry breast microwave and
not surprisingly we see lots of
hypertrophic microglia so here's what
surprised us in down syndrome
um when we looked at down younger down
syndrome cases without a.d pathology
they look very similar to young controls
so that was the interesting that was
fine kind of what we expected
but when we looked at down syndrome with
alzheimer's disease we saw a huge number
of dystrophic microglia larger numbers
actually compared to sporadic 80
and a lot you know we lost a lot of
those ramified
but we don't see
as many hypertrophic microglia as what
we see in alzheimer's disease
and so
i'll show this in a different way
when we plot
the individual data points which i think
is super important to do to see if
there's somebody driving this effect
here is uh we're just looking at
ramified microglia so those resting
microglia we don't see a lot of these in
white matter but we do see a lot of
these in gray matter
and we compare just young controls to
down syndrome and middle age controls to
down syndrome with ad
we're seeing not surprisingly
uh a decrease in the number of these
resting microglia and down syndrome with
alzheimer's disease brains so
that's good news
in other words it's similar to what we
see in sporadic 80 however what was
really interesting again is we are
seeing far more dystrophic microglia in
the down syndrome brain
and so um
that might give us a hint that the
microglia and down syndrome brain are
either under a bigger load in terms of
trying to clear up pathology or
they're an unhealthy compared to what we
see in normal aging and those microglia
are really struggling to do their job
and are dying as a consequence of that
and maybe that's a pathway we really
need to look carefully and down syndrome
given these different neural
inflammation phenotypes
and again that has implications for
clinical trials in future
but surprising to me was the lack of
really big increases in hypertrophic
microglia and i think that's because
that phenotype jumps very quickly
dystrophic and we're not seeing a lot of
these busy active taking up um taking up
stuff
and dealing with damage that we would
see in the hypertrophic microglia
and then when ali and alex
published this study i was so happy to
see
that another group independently
essentially uh was doing the same study
and another cohort of brains of people
with down syndrome
in claude coelho's lab in montreal
and uh lisi flores aguilar did this
gorgeous study looking across the life
span
and mapped down a number of pathways
but what she was also seeing here and
i'm just going to highlight is these
changes in the morphology but she had a
beautiful way to kind of quantitate that
that
hopefully she will teach us because
she's now joining us as for a postdoc
and starting now as soon as kobe lets
her come in
so um there's really something to the
story and it's you know i don't know
what the molecular mechanisms behind all
of this are yet but i'm hoping lisa will
take this on and continue to work on it
and it's not only just important to
think about these neural inflammation
markers in brain
and thinking about clinical trials and
treatment
targets
but these neural inflammation markers
also have a biomarker
rule
so melissa peterson who's the junior
faculty member at
university of north texas
has been looking at the plasma of people
with down syndrome
in our abcds study
and uh measuring and doing a proteomics
kind of profile of
protein changes that happen
when we look at people who are
cognitively stable with down syndrome
relative to those who are developing
mild cognitive impairment or the best
that we can assess that in people with
down syndrome and compare those to
people who are frankly um have dementia
and also have down syndrome
and what melissa found in this this kind
of
examination is
um that when she compares people who
have
dementia with down syndrome to those who
are cognitively stable
the biggest hits she sees in terms of
which proteins in the plasma distinguish
those two groups are inflammation a lot
of inflammatory
molecules are engaged here
and similarly when she looks at mild
cognitive impairment and people with
down syndrome and compare those to
people who are cognitively stable
again she sees a lot of inflammatory
proteins kind of distinguishing those
two groups plus some vascular proteins
which is a great lead for us
so
this story about neuroinflammation and
inflammation in people with down
syndrome is a big deal i think and
not only is it important in childhood
and that's a whole different discussion
but certainly
it's happening with age it's happening
with alzheimer's disease and i think to
some extent that pattern's a little bit
different than what we see in sporadic
ed
very important for clinical trials
so let's start kind of putting this all
together and i'll bring this
kind of to a close
so the way i've been kind of
conceptualizing this is to put all of
these neuropath pathways
into an aging
axis type of format
so
here's the original image i showed you
where we're seeing 80 franc 80 pathology
by 40
signs of dementia in their 50s but if we
start kind of slotting in all these
other pathologies i've just told you
about
we can see that there's some early
neuroinflammation that happens before
alzheimer's disease and i i left off
this part of the story entirely
um we start to see cerebral amyloid
angiopathy and microbleeds in the 40s
and 50s and then we see a second kind of
burst of a different profile of neural
inflammation
and then a higher prevalence of these
dying microglia
so again thinking about treatments and
orders and maybe what leads to what this
is kind of a really fun thing to do
when we study down syndrome to
understand alzheimer's disease that we
can't necessarily do easily in the
general um in sporadic or late onset
alzheimer's disease
and indeed kind of what the whole lab is
focused on everybody's contributing a
piece to this project in the lab
is to put this in context of the jack
curve which i'm sure you're all familiar
with which is typically applied for
biomarkers
but i'd love to apply this in the
context of neuropathology and so
ira and i put our heads together and
kind of started this conceptually
to think about you know what ages do we
start to see these different pathways
kind of engage
and we're going to try and now fill
these in about where does
where's the vascular pathology come in
and maybe the different kinds
and when does the inflammation come in
and what kind and try to fill out this
whole jack curve in the context of
neuropath
so what are we working on now
um we've got some really fun projects
going on and i'm just putting a picture
uh drawn by another graduate student
here at uci her name is patol rizvi
she's an incredible artist and so i use
her artwork everywhere i can with
permission
and so she does this beautiful artwork
on in neuroscience
and
we have a couple of really fun projects
that we're trying to start
really dig into this vascular story and
and inflammation story and try to put
these stories all together because we're
using the same set of autopsy cases for
all of our work
so we can
talk about vascular pathology and other
pathologies all in the same set of cases
all on that
x-axis that's going to be the same
so lorena sordo just joined us as a
postdoc from scotland
where lorena actually did a huge amount
of work on the cat model of alzheimer's
disease beautiful work so she's starting
to look at some of the vascular
pathology and of course this has been a
really really exciting area of research
uh in the literature and lots of great
people looking at this and so taking a
lot of hints from these folks
but one of the areas we're looking at is
extravasation of fibrinogen because this
has implications for neuron function in
the proximity of fibrinogen getting into
the brain and these are some pilot
studies we just did for our grants so
um
you can kind of these are like single
two case studies but i think they're
really intriguing
and what what lorena saw was there's
clearly in areas where there are blood
vessels you can see them here where the
spaces are in down syndrome brain with
alzheimer's disease there's clear
fibrinogen leaking out into the brain so
those blood vessels are not doing good
and then we did a study of just
anti-collagen just for
large blood vessels in the brains
of people with alzheimer's
and with down syndrome alzheimer's
disease and sporadic alzheimer's and old
controls and really we just wanted to do
this because we wanted to set the stage
for doing double labels but when we
looked at this the slides we were really
struck
in that you can see these beautiful big
blood vessels and alzheimer's and and
non-demented elderly control brains
but in down syndrome those blood vessels
don't look the same
so um we don't know what this is yet so
this is something we're gonna have a lot
of fun playing around with to see what
this means
and uh of course i've been talking a lot
about microglia but the other big glia
cells that we need to think about are
astrocytes and
given that s 100 beta is overexpressed
in down syndrome astrocytes have got to
be a part of the story
and so um leslie vazquez-rangel as an
undergraduate student is doing gorgeous
work looking at astrocytes labeling them
with different markers to give us an
idea about their function and she's
doing a lot of immunostaining and imaris
quantitation to characterize these
astrocytes in grain white matter and
then shari lapay is another graduate
student in the lab and cherie has landed
on a protein aquaporin iv
which is really fascinating um and
aquaporin4 kind of links the flow of
fluids from the vasculature into the
brain
and there's some work suggesting this
protein receptor
is mislocalized in alzheimer's disease
and we have no idea if that same thing
is happening in down syndrome so she's
going to be hitting up the super
resolution folks here to get a handle on
that so i'm really excited about both of
their projects and they've done a lot of
work to figure this out on their own
so um
let's kind of pull this all together and
i'll finish up with a little bit about
abcds and give time for questions
but i hope i convince you that down
syndrome is associated with early onset
alzheimer's disease pathology
but emily pickers are protein over
expression and
cleavage to beta amyloid is probably
what's leading to more cerebral amyloid
angiopathy
certainly when we see more caa and
there's another paper i didn't tell you
about but alex clearly linked the caa to
the microbleeds
so we think that caa is leading to leaky
blood vessels and or brittle blood
vessels that are breaking and blood is
getting into the brain
and that blood getting if the brain is
bringing in serum proteins may be
causing a different pattern of
neuroinflammation and down syndrome or
certainly is more prominent in down
syndrome brain
and it's
thought to be linked to the formation of
immune complexes in the brain
stimulating microglia
and we looked at microglia we see fewer
resting microglia which is not
unexpected
but what was unexpected which we're
seeing a lot more dying microglia in the
down syndrome brain
and these are linked to um you know
plasma biomarkers as well which is
really fun to think about
and we're going to keep running down
those pathways of looking at vascular
pathology and the neurovascular unit and
the astrocyte story so i'm hoping um
if we get together again in the future
i'll have some more updates on that
so what are the implications of some of
this work
um
and i think really
that they're all multiple targets for
intervention for people with down
syndrome
that might target a beta might target
tau my target's group of vast mythology
neural inflammation maybe we have to
consider and not surprisingly
multiple prone types of approaches
however because we can understand these
different events in the context of aging
and people with down syndrome we might
be able to get a little bit more precise
on based on the age of a person with
down syndrome what the best targets for
intervention would be for that person
and maybe
given the timelines of of how aging and
alzheimer's disease develop in down
syndrome
they might be one of the the early
cohorts that really benefits from a
prevention study
since we kind of know the age of onset
of each of these pathologies
but we can't really you know implement
these clinical trials and prevention
studies super duper well yet because we
still need to figure out what the best
clinical outcome measures are if we're
doing these intervention studies we also
need to understand it just in terms of
aging
and
because i think in future it's going to
be very important to have clinical
trials that are specifically dedicated
to people with down syndrome that takes
into account their unique features
it it does break my heart that almost
all clinical trials for alzheimer's
cities that are running right now
specifically
exclude people with down syndrome
and i think we need to change our
attitude on that and be more inclusive
of people with down syndrome into these
clinical trials
so one of the big efforts to kind of get
us to a point of clinical trials
is the alzheimer's biomarker consortium
for down syndrome
and i put the web link up there pretty
much if you google abcds naa you'll find
our website
where we're following 550 people with
down syndrome over the age of 25 years
we have 18 clinical and research sites
pretty large endeavor
and
in this study we bring people in every
16 months for a clinical examination for
a neuropsychological
exam
and we we pull blood and also
if people are willing we also collect
csf samples
there's extensive neuroimaging in terms
of pet tau and amyloid and also mr lots
of outcome measures with mri
and of those people who consent to brain
donation and we're
trying to encourage people to think
about this a bit more uh we'll follow
that up with neuropathology data when
the time comes
so
these sites are all around the country
we also have a site in the united
kingdom and i'm hoping in the next
iteration of the apcds we'll have more
sites both internationally and
nationally
but this is really exciting and fun
study and all of the data imaging data
proteomics data metabolomics data
genetics data are all deposited into
data warehouses that are accessible by
anybody
you just put in a request and we can
share that data with you so we're
encouraging people to use this data as
much as possible
so um i want to put out a big thanks to
the nih for
supporting all of this research
and also uh the bright focus foundation
which has been helping us with our brain
banks and so
thank you to them
again many thanks to our families and
our participants and i also want to
thank my lab
which is pretty fantastic we have a
great time together and of course when
your mascot's a dog that should tell you
a lot
but our lab is made up of post-talks
graduate students undergraduate students
and high school students we're pretty
inclusive
of folks who are interested in looking
at this in more detail with us so with
that i will end

[Music]

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down syndrome::noun | Spocien Dictionary

down syndrome

noun

a congenital disorder caused by having an extra 21st chromosome; results in a flat face and short stature and mental retardation

Type	Words
Synonyms	down's syndrome, mongolianism, mongolism, trisomy 21
Type of	birth defect, congenital abnormality, congenital anomaly, congenital defect, congenital disorder, trisomy

How to pronounce down syndrome in English?

down syndrome::noun | Spocien Dictionary

abandonment

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