- Welcome, everyone, to
Wednesday Nite @ the Lab.
I'm Tom Zinnen.
I work here at the UW-Madison
Biotechnology Center.
I also work for UW-Extension
Cooperative Extension,
and on behalf of those folks
and our other co-organizers,
Wisconsin Public Television, the
Wisconsin Alumni Association,
and the UW-Madison
Science Alliance.
Thanks again for coming to Wednesday Nite @ the Lab.
We do this every Wednesday
night, 50 times a year.
Tonight it's my pleasure to
introduce to you Kim Mueller.
She's with the Wisconsin
Alzheimer's Institute.
She was born in
Ridgewood, New Jersey,
and went to River Dell
High School, right there.
Then she went 20 miles south?
- 35.
- 35, I stand corrected,
to Rutgers University
for her undergraduate
in psychology.
And then she got a master's in
speech pathology at
Columbia University, across
the river in Manhattan.
And then she came here to
UW-Madison in 2005.
She also did a PhD program,
which she just finished in May.
Way to go.
- Thank you.
[applause]
- Tonight, the topic
is preclinical
Alzheimer's in speech.
She has a longer title,
which she'll give to you.
This is something that
anybody who has parents,
you're watching out for them.
I'm rolling the
odometer over to 60.
I'm watching myself not be able
to pull things up, words.
[laughter]
Like I used to.
[laughter]
So, this is going to be
interesting, and I think
that's why we have such a
great crowd here tonight.
Please join me in
welcoming Kim Mueller
to Wednesday Nite @ the Lab.
[applause]

- What a great introduction. [laughter] Thank you.
Can you hear me okay?
All right. Thank you.
So, the longer title of this
presentation is
"Connected Speech in Early Mild Cognitive Impairment:
"Results from the
Wisconsin Registry
"for Alzheimer's Prevention."
So before I go any further,
I want to tell you what
is connected speech.
And connected speech basically
refers to everyday talking.
It's a kind of technical term.
I was just at a conference and
somebody said, "Well, what would
"my speech sound like
if it was unconnected?"
And the answer is that typically
when we test language,
we do so in a single word way.
We have people look at
pictures and name them.
That's a cat, that's a dog.
But connected speech is
putting words together,
everyday talking, just
like I'm doing now.
So, keep that in mind as we
go forward with this talk.
And, also, I just want to
thank everyone here at
Wednesday Nite @ the Lab,
Tom Zinnen, for having me.
Thank you to Sandy Rotter
for getting me here.
So I really want to thank--
I'm very grateful to
be here tonight.
So, thank you again.
All right, so this is Iris
Murdoch, award-winning novelist,
former president Ronald Reagan,
and novelist Agatha Christie.
So they all had
something in common.
They all had Alzheimer's
disease or, in the case of
Agatha Christie, suspected
Alzheimer's disease.
But they also had
something else in common.
They had a very personal
biomarker or cognitive marker
that was publicly and
is publicly available:
their speech and their language.
And we have this on record
for decades and decades prior
to the diagnosis of
Alzheimer's disease.
So in the case of Iris Murdoch,
she was an
award-winning novelist.
She wrote over 26 novels
in her lifetime.
She died of Alzheimer's disease
at the age of 79 in 1999.
And this was Alzheimer's disease
confirmed by autopsy.
And the last novel that
she wrote was in 1994,
and it was called
"Jackson's Dilemma."
And this novel was very
interesting because it got
really bad reviews,
which was unusual for her.
So in the New York Times book
review, in 1996, this is.
The review goes on to say that
the writing is a mess,
strewn with imprecisions
and blatant redundancies.
The author of this review also
mentioned how she would often
repeat the same phrase,
like now suddenly,
several times within
the same paragraph.
So some researchers then
took Iris Murdoch's novels
and looked at them over time.
So this researcher named
Peter Garrard in London.
And so he looked at her novels
at the beginning of her career,
at the mid-height of her career,
and then this last novel,
"Jackson's Dilemma," and
analyzed the content of her
writing and found that, over
time, by the end of this novel,
her content words decreased, her
lexical, her vocabulary became
more limited, and she did in
fact repeat words and phrases
much more often
by the last novel.
And so the authors argued
that this is evidence
of Alzheimer's disease at
play before the diagnosis,
before symptoms set in.
President Ronald Reagan was
diagnosed with Alzheimer's
disease six years after
he left office.
And some researchers in Arizona,
Berisha and colleagues,
they analyzed Ronald Reagan's
unscripted speeches from
press conferences from
1981 through 1988.
And they found that Ronald
Reagan's speech,
over time, became less fluent.
And that means that he
started to pause more often,
he used more filler words,
like "um," "well," "uh,"
and nonspecific words,
like pronouns,
and words like "thing"
and "that" over time.
And this was a significant
change over time.
So I'm going to play you two
examples from Ronald Reagan's
speeches, and see if you can
hear the difference.
Now, this is extremely
subtle differences,
so it may be difficult
to hear them.
But I'll try to point
them out as we go.

So this first one is his first
press conference in 1981.

- ...detente is possible?

- "Well, so far detente has
been a one-way street
"the Soviet Union has used
to pursue its own aims.
"I don't have to
think of an answer
"as to what I think
their intentions are.
"They have repeated it.
"I know of no leader of the
Soviet Union since the
"revolution and including the
present leadership
"that has not more
than once repeated
"in the various
communist congresses
"they hold their determination
"that their goal must
be the promotion
"of world revolution and a
one-world socialist or
"communist state, whichever
words you want to use."
- Okay, so aside from that
being the longest run-on
sentence in the
history of sentences-- [laughter]
And a lot of embedded clauses, it was a very complex sentence,
it was pretty fluent,
and he kind of knew
where he was going with
what he was saying.
So now we look at
press conference,
an excerpt from six years later.
And this is in 1987.
And this is his 41st
press conference.
- "Secretary of State Schultz
says that he's a good man
"and he can keep his job.
"Is Schultz right?
"Can Elliott Abrams keep
that job as long as he wants?

- "I know the statement made by
the Secretary of State,
"and that is the
administration's position.

"And I know the reference
that you're making to the
particular point
"in which he himself
volunteered that we had
made a misstatement,
"but I accept the Secretary's
statement in this."

- Okay, so this second sample,
very subtly you can
hear some hesitations.
Some "uh" filler
words like that,
which we all use by the way.
We all use these.
You can hear me using them
now throughout this talk.
But from a change, this
is a changed standpoint.
From earlier to later,
the researchers found a change.
Now, they did this in
a very controlled way.
So each press conference they
took a specified number of words
per conference and analyzed it
according to those 100 words
or 200 words, whatever they
used as their standard.
So, relatively speaking,
an increase in filled pauses
and pauses over time.

So, this is the nun study, and
this happened right here in
Wisconsin, in Milwaukee and
other areas of Wisconsin.
These researchers studied
nuns throughout their lives.
And one study of this nun study
found that by examining the
nuns' free-writing samples when
they were in their 20s, they
looked at idea density, so this
means, how many ideas relative
to the total numbers of
words did they express?
How rich were their
writing samples?
So they looked at that, and
nuns with lower idea density
in their 20s predicted
who of those nuns
would go on to develop Alzheimer's disease.
Not only on cognitive tests did
they perform worse 58 years
later, but also it predicted who
would have the brain pathology
of Alzheimer's on autopsy.
So something about linguistic
ability in early life
predicted later life
cognitive function
and Alzheimer's
disease pathology.
So here is a picture
of a hypothetical
mother and daughter.
And the mother in this case
has Alzheimer's disease,
and the daughter
is caring for her.
So my research question is, can
we use that same speech analysis
that was use retrospectively
with Ronald Reagan, Iris
Murdoch, can we use that same
analysis with the daughter while
she is still healthy and
follow that speech over time
to see if it is a
marker for change?
And that's the basis
of my research.
And the Wisconsin Registry
for Alzheimer's Prevention,
or the WRAP study, is going
on here in UW-Madison.
It's been going on since 2001,
and it is a cohort
of individuals who are at
risk for Alzheimer's disease.
So they're in their
late middle age.
They have no symptoms of
Alzheimer's disease.
We don't know who of them is
going to go on to develop the
disease, but they're enriched
for parental family history.
So we are following this group
over time to determine who is
going to get the disease and
what about them is possibly
increasing or decreasing risk?
So, pausing, and to talk about
what is Alzheimer's disease.
So Alzheimer's disease is
defined by the brain pathology.
So the amyloid plaques, which
are hard, sticky substances
which you can see up there in
the yellow areas, and the
neurofibrillary tangles, which
clumps of tau proteins that
eventually cause the neurons
in the brain to die.
And this is the definition
of Alzheimer's disease.
It's the presence of these
plaques and tangles.
Now, Alzheimer's disease
is a cause of dementia.
Often people wonder, well,
what's the difference between
dementia and
Alzheimer's disease?
Dementia is the
set of syndromes,
and Alzheimer's disease is
a cause of that dementia.
Alzheimer's disease is
the most common cause.
There are other causes, like
changes due to vascular changes
from stroke or Lewy
body dementia.
Alzheimer's disease
is the most common.
Currently, there are over 5.5
million Americans living
with Alzheimer's disease
in the US today.
And this number is
expected to triple by 2050
if a cure or prevention
is not found.
Alzheimer's disease is the sixth
leading cause of death in the
United States and is the only
cause of death for which there
is no prevention or known
cure for this disease.
Alzheimer's disease is not
a part of normal aging.
It is not inevitable that people
will get Alzheimer's disease
if they live long enough.
It is an abnormal disease,
and it needs to be understood.
And that's why there is a huge
push to try to understand what's
causing this disease and how
to prevent it or cure it.

So the symptoms of Alzheimer's
dementia are memory loss
that disrupts daily life.
So you can no longer live
independently when you're
diagnosed with
Alzheimer's dementia.
There's a confusion
with time or place,
withdrawal from work
or social activities,
severe challenges in
solving everyday problems.
Things that used to be automatic
are no longer easy to do.
And there's a problem
with words and speaking,
which is my area of interest.
It's generally accepted now that
Alzheimer's disease is on a
continuum and that there is an
asymptomatic phase where the
plaques and tangles are forming
but there are no symptoms.
And this asymptomatic phase
could be occurring decades
and decades prior to
the onset of symptoms.

Mild cognitive impairment is the
precursor to Alzheimer's disease
dementia, or the
intermediary stage between
asymptomatic and dementia.
And the criteria for being
diagnosed in a clinic for mild
cognitive impairment, or MCI, is
that there are cognitive changes
that are concerning to either
oneself or one's family, one or
more cognitive domains are
affected from previous function.
There's a decline from
previous ability,
but a person is
still functional.
A person can still
live independently,
and that's the difference between MCI and AD dementia
is that they're
still functional.
And it's possible that
compensation strategies
can be taught and used
effectively at this MCI phase.
So it's really important that
we diagnose this disease
and this process as
early as possible.

So, what do we know about
speech and language
in Alzheimer's disease and MCI?
Basically, as Tom was
referring to, as we age
problems with word retrieval
are a normal part of aging.
Word retrieval becomes slower
and more difficult as we age.
However, this word retrieval
problem is not, it's a nuisance
but it's not a major
disruption to communication.
You might not be able to
retrieve the word, but it will
come back to you at the most
inopportune time hours later
when it's no longer relevant
but it does come back to you.
Also, it doesn't cause a person
to completely withdraw and feel
so frustrated that they no
longer want to communicate.
This is what it looks like
in mild cognitive impairment
and Alzheimer's disease.
The word retrieval problems are
so intense that they will occur
multiple times within a
sentence or a conversation.
And they disrupt fluency,
like we talked about
with Ronald Reagan.
Also, the word retrieval
problems became so severe that
sentence structure becomes less
complex and disorganized.
And on this slide, that bottom
piece about pragmatics and
discourse, this refers to one's
ability to communicate back
and forth with other people.
And this part becomes affected
in mild Alzheimer's disease,
possibly even in MCI,
because of that frustration
and kind of a quitting of
what you were going to say.
Losing the thread of thought in
conversation and getting to the
point where you change the
topic or you withdraw.
So these are the
things that we see.
We know that in severe
Alzheimer's dementia people can
become completely nonverbal and
lack any means of communication.
So, again, just like I said
earlier, the declines in
language are on a continuum
as well with this disease.

So, connected speech, I told
you what that definition is.
And this is just
an illustration.
Currently in research
studies or in the clinic,
we evaluate language by typically asking people
to name objects or pictures.
So, on the right-hand side, tell
me the name of what you see.
That's a cat. A ladder.
That's not really going to get
at what people are feeling
frustrated with and
are complaining about
in their daily lives.
How can we do that
in a controlled way?
One way is by picture
description tasks.
So, on the left-hand side, this
is a line drawing, a picture,
and some things are
going on there.
And the question is,
tell me everything
you see going on in the picture.
And then that will then elicit
more typical everyday speech
and language than another
kind of task would.
And so that's what I'm
interested in, in my work.
I alluded to this already, but
why would we study connected
speech in this
preclinical phase?
Why is that important?
And this article was
written in 2014.
And it asks the question, if we
have, we have better methods
of identifying the plaques
and tangles now.
We can see plaques and tangles
on PET scans and MRIs.
We can see a lot of information,
more than we ever
could in the past.
So we've made great advances
there, but we haven't made as
much advance in detecting
subtle change in cognition
that actually affects
everyday life.
So if we have a drug trial,
we want to know. "Is the drug
working in everyday life?"
That's the question.
It's not, okay, the
person's staying stable
on this neuropsychological test.
It's more, is it actually having
effect on everyday life?
And so that's my question Can
speech be a possible tool
for that, a tool for screening
or for disease monitoring?
That's one aspect of this
that I think is important.
So, again, this research
question that I'm asking,
can everyday language,
just talking, be a tool
for assessing cognition
and a tool for assessing
a functional activity of
daily living?
That's my question.
So I gave you a definition
of connected speech.
You'll hear me interchanging
language and speech together.
And just as a
speech pathologist,
the word speech refers
to the automatic process
of producing sounds
to form words.
And that's different from
language, which has to do with
the rules of vocabulary
and the rules of grammar.
So these two words are not
quite interchangeable.
They have different meanings.
But in this task I'm actually
looking at both aspects,
mechanical aspects, timing,
as well as the content
of the language.
It's also important that you
keep in mind as I talk about
my study that mild cognitive
impairment, what I talked about
earlier, is a clinical condition
that diagnosed by a doctor.
And that's different from
what I'm going to talk about,
which is early mild
cognitive impairment.
So, something that's not yet
diagnosed by a physician
but something that we see
in a longitudinal study.
So it's almost a pre-mild
cognitive impairment state.
And the last thing is
ecological validity.
This is something that we're
looking for in our tools.
Ecological validity gets at
whether or not a test measures
what it's designed to measure.
So, is speech, is a single
word task going to measure
how someone actually converses?
Or my argument is that connected
speech tasks might actually be
better at measuring
an everyday activity.
So that's ecological validity.
So the first step in doing this
work was to review connected
language tasks in MCI and AD.
What have people done so far,
other than the few studies that
I talked about at the beginning?
And what I found by doing this
review was that most of the
studies of connected speech
were done with people
with Alzheimer's disease
dementia later on.
Very few were done in the
mild cognitive impairment
stage or earlier.
I also found that across studies
there were multiple
measures used.
People looked at percent nouns,
percent pronouns,
number of pronouns divided
by nouns plus pronouns.
I mean, the list went
on and on and on.
And sometimes it was
similar constructs
but different names
for these constructs.
So there was not a
lot of continuity
among all of these studies.
I also found that picture
description was the most common
method of eliciting
connected language.
There are other ways
to elicit language,
such as tell me about
where you grew up.
That's a confounding way of
eliciting that in a memory
impairment kind of disorder
because we don't know then
is it a memory of events
that's getting in the way.
And that's why picture
description is a confined task
with the stimuli right there
in front of the person.
And so memory for events and
things is less of an issue
with a picture description task.
So I want to tell you about one
other study in particular.
This is a study of people
with the inherited form
of Alzheimer's disease.
It's a very rare genetic form.
It's involved with
the presenilin gene,
and it's a very rare form.
Usually the onset of
Alzheimer's disease
happens in a person's 40s
or younger, so very rare.
But there is a
family in Columbia
who have this
genetic form.
It's a rich family for
this genetic form of
Alzheimer's disease.
So what these researchers did
was they studied people who had
the gene and then family members
who did not have the gene
in their early 30s and 40s
before any symptoms of
Alzheimer's disease.
And the people with the gene,
the carriers of the gene,
showed reduced content in
their picture descriptions
of connected speech versus
those who were not carriers.
So this is an asymptomatic
cohort, and already
the researchers were seeing
change in connected speech
prior to the onset of symptoms.

So this cohort that I'm looking
at is the Wisconsin Registry
for Alzheimer's Prevention,
as I mentioned earlier.
I'm going to tell you a little
bit more about this group.
The goals of the WRAP study are
to identify Alzheimer's disease
in its preclinical phase, before
symptoms set in, and to identify
the biological health and
lifestyle factors that might
increase or decrease risk
of Alzheimer's disease.
So, participants, this is
the design of the study.
And the idea, if you look at
this graph, on the bottom is age
and on the Y axis is
cognitive function.
And so the idea is that in
normal aging, you see that black
line, cognitive function will
decrease slightly but not a lot.
But then this other
trajectory in red is the
trajectory of
Alzheimer's disease.
And so we're following
these individuals
when they start at a young age.
The mean age at baseline
was 54 years old.
So they are cognitively healthy,
no problems, they had a parent
with the disease, but that's
about all that we know.
And so we follow them over time.
After the first visit,
they come in four years later
and then two years
every visit thereafter.
Currently, we're on
our sixth wave visit
for many of our participants.

Currently, we have over
1500 people enrolled
in this Wisconsin study.
The last visit the
mean age was 62.5.
There are 70% women
in this group,
and the mean age of
education is 16 years.
So they have at least a
college degree, on average.
A very highly-educated group.
Their average IQ is also high
for average. Above average.
There are 90%
non-Hispanic white.
We are working on increasing
our diversity of this sample.
We have a cohort in Milwaukee. We have a site in La Crosse.
So we're trying to sample
as much diversity
in terms of rural and urban communities as possible.
40% of these people have an
gene that is a risk factor gene
for Alzheimer's disease,
the later onset version.
And this gene is called APOE E4.
And so it's enriched for that,
probably because of this parental family history.
But we don't know whether or not if you had that gene,
you could still go on to not
develop Alzheimer's disease.
So it's a risk factor gene.
Your risk is increased,
but it's not a definitive
like that other study I
was talking about earlier.
72% have a family history
of Alzheimer's disease.
So these participants
are extremely giving.
They come in and spend
about six hours with us.
And they undergo a
fasting blood draw.
So we look at all kinds of
aspects of risk that we know
about in their blood, including
the genetic risk factor.
Their glucose levels,
their insulin levels,
vitamin B, vitamin D.
We're looking at all
kinds of things
that we know about that
may increase risk.
We also get other
physical measures,
like blood pressure and
resting heart rate.
We ask lots and lots
of questions.
They fill out questionnaires
prior to coming in.
It takes them a couple
of hours to fill out
all these questionnaires
about their lifestyle,
their medical history,
their physical activities.
What are they doing?
What are they doing?
If they're retired,
are they volunteering?
Are they doing computer games?
Are they, what are they
doing for their cognition?
Are they in groups?
What is their social support?
So we're looking at all of the
things that you may have heard
about in the news about
increased or decreased
risk of Alzheimer's disease.
And they undergo
two-and-a-half hours
of extremely detailed
cognitive testing.
And these are neural
psychological tests that have
been validated and used
across other studies, and
they look at memory, language,
speed, executive function,
and a global measure
of cognition.

Also, in this WRAP study, I've
cited two articles from the WRAP
study that detail how we go
about determining if someone is
showing signs of this early mild
cognitive impairment, or EMCI.
So this is a construct
that was developed
by establishing robust norms
within the WRAP study.
So that means that we're able
to look at people relative to
themselves and relative to
people in their cohort
and determine if they're
declining over time.
They may not feel like they're
declining, they may not feel
like they have symptoms
of Alzheimer's disease
or of cognitive decline,
but we are seeing this
according to our construct.
And so the people that I'm
interested in are the people
that are circled there in red.
So, people who are cognitively
healthy over several visits.
They're not declining.
In fact, some of them
might even be getting
better on the tests over time.
And the people who are
declining, this EMCI group.

I just want to tell you a
little bit more about WRAP.
This slide is extremely busy
because the WRAP study
is extremely busy.
So there's the main WRAP
study but off-shoots of that
are other studies
that are going on.
And so, because of these other
studies, we're able to collect
biomarkers, like PET scans,
MRIs, cerebral spinal fluid,
where we can really
detect the plaques
and the tangles in
these controlled ways.
And so there's all kinds of
other studies that are going on
that are off-shoots of
the main WRAP study.

Okay, so back to the
connected speech task.
So I'm going to show
you this picture.
This isn't the exact picture
that I'm using in the WRAP
study, but it's
extremely similar.
It's a black and
white line drawing.
It's very simple.
The prompt is tell me
everything you see
going on in this picture.
And we have a very simple $50
digital recorder that we use.
And the participants talk
into this digital recorder.
It's actually a very sensitive
digital recorder, so we can hear
very, very subtle nuances
in their speech.
So a participant might
give a sample like this:
"Well, I see a man stuck up in a tree," and then they laugh,
"while a daughter, um,
I mean a girl," and so on.
And so this is what
we're recording.
After we record that, we come
back and then we transcribe it.
And this is done by a
speech pathology student
or a speech pathologist.
And the transcription is
basically writing verbatim
everything that they say,
including these hesitations and
these filler words, clearing
their throat, laughing, all of
these things are coded in this
Codes for the Human Analysis
of Transcripts, or
the CHAT program.
So it's a specialized coding
method that we then feed
into a natural
language processor.
And this is called Computerized
Language Analysis,
or the CLAN program.
It was developed at
Carnegie Mellon University
by Dr. Brian MacWhinney
and his colleagues.
And what this does is it allows
us to feed these transcripts
in and quickly, automatically,
extract all kinds of measures
about speech and language.
So it's a very quick analysis.
The transcription part, after
training, it takes approximately
15 minutes to transcribe
about a minute of speech.
So 15 minutes to transcribe
about a minute of speech.
And then this part, the
analysis, takes seconds,
basically, to do
multiple data points.
So the first study I did
was kind of a pilot,
a cross-sectional design to see
can we just see anything
with this connected speech task.
And this was done
kind of early on
when we didn't have
a lot collected.
Presently, there are over 2,500
connected speech
samples that we have.
But at the time we didn't
have a lot transcribed.
So we looked at 78 people, and
we used a matched pairs design.
So this means that 39 of them
were determined to cognitively
healthy over time, and 39 of
them were determined to have
early mild cognitive impairment.

And this paper was published in
the Journal of Alzheimer's Disease in 2016.
And what we found was that, in
fact, people with early mild
cognitive impairment in these
one-minute picture description
tasks were producing
less content words
and they showed
lower idea density,
liked I talked about
with that nun study.
So, fewer ideas relative to
the total number of words
that they expressed.
So this is what I found at that
point, that cross-sectional
point, and this was at
their first speech sample.

So I wanted to next address this
question, since we found that
this is working or it's
possible, I wanted to address
that next problem about so many
measures that we can extract.
How do we choose what to look at
when there's so many
measures we can look at?
And so the way that I
approached this problem was by
doing a factor analysis.
And a factor analysis basically
takes all those measures
and distills them down into
these underlying constructs.
And we had a really
impressive number
of transcribed speech samples: 399.
This is a large amount
of transcriptions.
And they were 399 people who
were cognitively stable.
So we wanted to do
that on purpose.
We wanted to look at
these measures in people
who were not declining.
So we separated these 399 people
into two different groups.
One was the exploratory group
and one was the
confirmatory group.
So the exploratory
group had 250 people,
and the other one had 150.
And the two groups were
very similar except that
the confirmatory group had more
people with a family history.
I addressed that problem,
and I'll tell you about
that in a minute.
Basically, we found a
confirmed factor structure,
first in the exploratory group
and then we found it again
in the confirmatory group.
So that says that this
structure is relatively stable.
And, basically, we're
taking all these measures
and we found that they kind of load on four different factors.
And this is what they look like.
There's a lexical factor,
which has to do with the
diversity of vocabulary used.
The content or semantic factor,
which has to do with this
number of content words,
but also this pronoun ratio.
So, how many pronouns
are they using
relative to the number of nouns?
A syntax factor looks at
how complex the
sentence structure is.
And then this fluency factor,
which looks at all of those repetitions and filler words
and pauses in their
speech in an indexed way.

So, now that I confirmed
that factor structure,
I also confirmed that it was
invariant across groups.
So it didn't matter if they
were family history positive,
family history negative,
men versus women.
The factor structure was the
same across those groups.
And I looked at the factor
structure in stable people over
time at two time points
and found that people
who were stable on other
neural psycho measures
were stable on these
factor scores.
So that shows that the factor
structure can possibly be a
reliable way of looking
at speech over time.
And that was my goal
for that study.
So the final study then looked
at those factor scores,
those constructs,
in participants
with language samples
at two time points.
And we had 264 people.
And the question here was, are
declines in memory associated
with declines in
connected language?
So, the results.
First we looked at the
demographics of this group.
And so we just took 264 people
who had language samples
at two time points.
That's all we knew about
them at the outset.
And when we looked further,
we found that 200 of them were
cognitively healthy at several
time points, and 64 of them had
this early MCI construct
at the most recent visit.
So what else we know about
these groups is that
the early MCI group had a
higher percentage of men,
and they were slightly
older in the EMCI group.
Otherwise, and this
is important,
the two groups were the
same in terms of age,
level of education,
their literacy ability
as measured by neural
psychological testing,
and their family history of Alzheimer's disease,
as well as their ethnicity.
So the two groups were similar
except on age and sex.

So I did a linear
mixed effects model,
and so that basically allows
you to look at, over time,
how a person, how a group,
is performing.
And so if you look here,
the dotted line is the
group with the EMCI status.
And the first, the top graph,
the bottom, the X axis is age,
so as they get older, and the Y
axis is that fluency factor.
And you see that the dotted
line, the group with EMCI,
is declining faster on
these measures of fluency.
So they're becoming more and
more disfluent in a faster way
as compared to the
cognitively stable group.
The other piece was that the
semantic factor was also
significantly different in that
the EMCI group in the dotted
line declined faster
over time in content.
And they produced more pronouns
relative to nouns over time.
It's interesting, if you look
at that graph on the bottom,
the EMCI group appears
to start higher
than the cognitively stable group in measures of content
but then declines faster
and more steeply.
I don't have a full explanation
for that at this point in time.

I also did a logistic
regression, and what that says
is can we predict who's going
to have that EMCI status
at the most recent visit.
And that's done by a
logistic regression.
And so what we found was that
that fluency factor, again,
was a significant predictor of
who would go on to be diagnosed
with this EMCI construct
at the most recent visit.
So on the right-hand
side is the EMCI group,
and that's the amount of negative change in fluency
compared to the cognitively healthy group.

Also interestingly found that at
baseline syntax or sentence
structure complexity was a
predictor at baseline of who
would then be diagnosed with
EMCI at the most recent visit.
So this is similar to the
finding of the nun study
where early life
complexity seemed to be
a predictor of later life cognitive function.
I don't know that this
is the same finding,
but it's interesting
anyway at this point.
Other metrics of
the speech sample.
I found that at both visits the
group with EMCI produced shorter
sentences overall, and they
were slower to produce the same
amount of words and ideas as
the cognitively stable group.
So they took longer.
So what does this sound like?
I'm going to show you or play
for you an example of this.
The first is a 62-year-old
participant in 2013, his first
sample, and then that same
participant two years later.
So, this participant,
at time two,
declined significantly
in fluency.
So he becomes less
fluent over time.
He also produces less
content-rich speech over time.
And his lexical diversity,
his word choice,
becomes narrower over time.
So I'm going to
play these samples
and see if you can
hear the difference.
And, again, it's going
to be very subtle,
but you may be able to
detect the difference.
So this is the first time point.
The speech is slightly altered
to protect the
person's identity.

- Tell me everything you see
going on in this picture.
- Okay, I see a family, um,
together in the kitchen
with some possible
potential accidents.
Um, mother is
washing the dishes.
She's daydreaming and the
water is running over
and it's spilling in a way
that might cause her to fall.
And the siblings
are not supervised
because mother's daydreaming.
And they are, the brother
is on a high stool,
which he probably shouldn't
be on, going for the cookies,
and he's just about
to take a tumble.
And sister might be
laughing about that.
There may be some
sibling rivalry there.
- Okay, so that's the
first speech sample.
You do hear some
disfluencies there.
He says "um" a few times,
but now, this next sample,
there are significantly
more filler words
like that and hesitations
and things like that.
So you'll be able
to hear that now.

- I'd like you to
tell me everything
that you see going
on in this picture.
- Okay, so I see a kitchen
scene, um, that's chaotic.
Um, mother has two children who
are not, not given, um, um,
line-of-sight supervision.
And so the children are
reaching for cookies
on the top shelf
and eating away.
Probably overeating on sugar.
And then the boy is about to be
launched from a three-legged
stool that is tipping over.
And then mother appears to be
daydreaming about something.
That looks like a nice daydream
because she's smiling.
Um, so she's kind of ritualistically
cleaning a plate.
Simultaneous, the um, the sink
is overflowing to the floor.
So it looks to me
like it's a scene
that will soon be complete
chaos when the chair tips over.
- If you notice, he
does speak a lot more
the second time around,
but, relative to that
increase in words,
the number of ideas
actually went down.
So he's speaking more, but
conveying less over time.

So, what does this mean?
Well, first, it's really
important to note
that these individuals
have this EMCI construct,
early mild cognitive impairment.
We don't know a lot about that.
We don't know if that is going
to then go on to develop mild
cognitive impairment, go on to
develop Alzheimer's disease.
We don't know that
about this group.
And so that's why it's really
important for my next step
to look at the biomarkers
that we know about.
So the amyloid plaques
and the tangles.
If we have participants who have
evidence of Alzheimer's disease
pathology in their brain and
then these findings stay
and hold, then it will be more
convincing about what that means
for this tool in the future.
The other finding is that this
fluency factor, at least at this
stage, was the most robust
in terms of findings here.
And that, to me, was encouraging
because the other factor
that has been typically
shown, the content,
typically shown to be affected early on in the disease process
is dependent upon the
stimulus that's used.
And if we can detect changes in
everyday speech where we don't
need a particular stimulus but,
rather, it could be a
conversation at the doctor's
office, for example,
or a conversation at home
that we tape record.
This would be even closer to an
ecologically valid measure,
an everyday activity.
This measure, you know, showing
a picture in a confined setting
is closer to everyday speech,
but it's still not quite.
And so if this fluency factor
can be translated to an everyday
activity that's truly an
everyday activity, then it will
be even stronger as a measure
to use in the clinical setting.

Finally, what I found here,
which to my knowledge this is
the largest study of a
preclinical cohort of connected
speech at two time points.
Usually the sample sizes for
this kind of work range
between one and 30 people.
And so this is a large sample,
and we have many more to use.
And it was feasible
to do it this way,
to have manual transcription from a student.
It took 15 minutes per sample.
But now, with technology improving, the next step would
be if we could find an automatic
speech recognition tool
that would eliminate that step
for manual transcription,
that would make this
tool even better.
And so that's another
future direction.
Things here at the UW-Madison
are going on, looking at these
automatic speech recognition
tools and other machine-learning
techniques of doing
this in a faster way.
And so that's also a future
direction for this work.

I want to bring it back and
end with the participants.
So, they are at an
increased risk.
They have seen this
disease firsthand.
They've cared for someone
with Alzheimer's disease.
We have some control subjects
who have no family history,
but they're often spouses of a
person who cared for a parent.
So they have seen the
disease firsthand.
I would bet that almost everyone
in this room has had some
experience with dementia
or Alzheimer's disease.
And so it is not easy to come
in and give up a day and put
yourself on the line and do
these difficult memory tests.
It is not an easy thing to do.
It's an emotional thing to do.
It's an extremely generous
thing to do because,
as you'll hear this sample,
this participant will tell you,
they don't expect to benefit
by their participation.
They do this for
future generations.
They know that they're being
watched over years and that
their contributions are going to
go far, far into the future.
But they don't know
that they'll benefit.
So, again, that makes it even
more heroic what they're doing.
So I just want to play another
part of a speech sample.
So we also collect other
parts for the speech sample.
In addition to that picture
description, we ask open-ended
questions as well, which I plan
to analyze in the future.
But one of them is, "Tell by
about why being involved
"in the WRAP study is
important to you."
And here's the words from
a participant about that.

- You know, when you have a
parent with the disease and you
feel pretty helpless and I
learned about the study, it was
a way that I thought I could do
something by giving my time.
I mean, I don't really know what
I was getting into signing up
for it, quite frankly, but I
think those of us who have the
experience of having a parent
with the disease feel so
helpless in many respects that
being in a study is a way to
contribute, and it helps to kind
of offset that helplessness.
And it also feels like
you're being part of
a potential solution.
Thank you.
- So, my first thank you, then,
goes to our WRAP participants
here in Wisconsin.
They also come from
all over the US.
So I really want to thank
the participants for what
they do for us and our studies.
On this slide are
all kinds of people
who are involved in the
WRAP study and in my work.
And so, special thanks to
Dr. Sterling Johnson,
who is the PI of the WRAP study,
Dr. Lyn Turkstra, who was my
mentor for my dissertation work,
and all of the
faculty and staff
at the Wisconsin
Alzheimer's Institute
and the Wisconsin Alzheimer's Disease Research Center.
Finally, the WRAP study is
funded by the National
Institutes on Aging of the
National Institutes of Health.
So, thank you very much for you
time, and I look forward to
answering your questions.
Thank you.
[applause]