A Visit with Stroke Neurologist Dr. Jeff Saver

In episode 37 of "In the Interim…", Dr. Jeff Saver, Director of the UCLA Comprehensive Stroke and Vascular Neurology Program, details his shift from behavioral neurology to clinical stroke research after early engagement with multicenter trials like TOAST. The discussion covers the biology of acute ischemic stroke, quantifying neuronal loss, and the scientific underpinnings of “time is brain.” Dr. Saver outlines the evolution of endovascular therapy, from early device challenges to current reperfusion success rates exceeding 85%. Key methodological issues in stroke trial analyses are presented, including debate over endpoint selection—dichotomous versus ordinal approaches and the limitations therein. Special focus is placed on the utility-weighted modified Rankin Scale, which assigns empirically derived, patient-centered health values to each disability state, providing a comprehensive measure that captures both benefit and harm. The episode explores regulatory hesitancy, differing analytic preferences within the field, and the design prospects for neuroprotectant interventions. Heterogeneity in patient outcomes and implications for public health and trial methodology are addressed. The episode provides an empirical account of clinical trial endpoint selection, interpretation, and future directions in cerebrovascular research.

Key Highlights

• Early career influences and pivotal trial participation.
• Pathophysiology and quantification of acute stroke injury.
• Endovascular device development and clinical impact.
• Comparative analysis of endpoint methods: dichotomous, ordinal, and utility-weighted approaches.
• Technical derivation and application of utility-weighted mRS.
• Ongoing regulatory and methodological debate.
• Heterogeneity in ischemic vulnerability and future trial directions.

For more, visit us at https://www.berryconsultants.com/

Creators and Guests

Host

Scott Berry

President and a Senior Statistical Scientist at Berry Consultants, LLC

What is In the Interim...?

A podcast on statistical science and clinical trials.

Explore the intricacies of Bayesian statistics and adaptive clinical trials. Uncover methods that push beyond conventional paradigms, ushering in data-driven insights that enhance trial outcomes while ensuring safety and efficacy. Join us as we dive into complex medical challenges and regulatory landscapes, offering innovative solutions tailored for pharma pioneers. Featuring expertise from industry leaders, each episode is crafted to provide clarity, foster debate, and challenge mainstream perspectives, ensuring you remain at the forefront of clinical trial excellence.

Judith: Welcome to Berry's In the
Interim podcast, where we explore the

cutting edge of innovative clinical
trial design for the pharmaceutical and

medical industries, and so much more.

Let's dive in.

Scott Berry: All right.

Welcome everybody back to in the interim.

your host, Scott Berry, and I have
a, uh, distinguished guest today.

I have Jeff Aver, Dr.

Jeff Aver, who is the Carolyn
James Collins distinguished

professor of neurology at the David
Geffen School of Medicine, UCLA.

He is the director of the UCLA
Comprehensive Stroke and Vascular

Neurology Program, and I'll talk more
about his distinguished history as we go.

But welcome to in the interim, Jeff.

Jeff Saver: Thank you, Scott.

It's such a pleasure to be here
with you and your audience.

Scott Berry: Wonderful.

So we're, we're gonna touch on a number
of topics, but, but first, let's, let's

talk about now you're a, a, you're
a distinguished clinical trialist.

You've worked a great deal in stroke.

Quantifying the, the effects of
stroke, things like PFO occlusion,

which I may ask about that as well.

Uh, but, but a good number of things
in stroke and the clinical trials.

But let's talk a little bit about how
you got here, um, uh, within this.

So you went to Harvard as an undergrad.

Interestingly, I think you were
a philosophy and biomedical

sort of double major.

When you went to Harvard as an
undergrad, was, was it always

that you were gonna be a doctor?

Was that the plan?

Jeff Saver: Well, I do
come from a medical family.

My grandfather and father were a medical,
uh, physician, so there was a strong,

uh, push to go into medicine against,
which I, of course, rebelled somewhat.

And, uh, I originally was
going to secretly triumph as a.

Uh, basic scientist with an MD degree.

But after spending a, a summer in, in the
basic science lab deprived of interaction

with people, I realized that wasn't
for me and I was tempted by philosophy.

I actually, uh, applied for and
received a fellowship from Harvard,

uh, in the year after that was
originally to give to the 1890s.

Harvard gentleman, grand tours of Europe.

Of course, the, uh, Harvard, uh, faculty
could no longer allow you to just travel.

So you had to have a, uh, a project.

So my project was interview biologists on
religion and biology and four countries,

England, France, Israel and Japan.

Rent around the world.

Got some, uh, need to be
out there out of my system.

And then.

Went to medical school somewhat
reluctantly, but uh, did go there.

And, uh, and I knew once I arrived
it was, uh, either neurology or

psychiatry, nothing else, you know,
had that deep connection to, uh, uh,

the mind and, and who we are as humans.

Uh, so that's how I got started.

Scott Berry: Was, was, was your family,
your, your father, your grandfather,

was that, were they in, uh, neurology,
neuroscience, uh, in their medicine?

Jeff Saver: No, they were, uh, my
father was an old fashioned, uh, GP

in Boston with, when I was a toddler.

It drove me around on his, uh, home calls,

and my dad was an internist in
the New York City hospital system.

Scott Berry: Okay, so, so you grew up in
New England, uh, hence going to Harvard.

Jeff Saver: Well, I grew up in New
York, but northeast, absolutely.

Scott Berry: Okay.

Okay.

Um, and from there, you, you go to
medical school and you're, you're vascular

neurology and, and you do a number of,
of programs in that, at what point did

clinical trials become interesting to you?

Jeff Saver: Well, I originally set
out to be a cognitive and behavioral

neurologist, and that was my first
post-training fellowship at the

University of Iowa with the theios.

But at, uh, that it was
intellectually fascinating, but we

couldn't do anything for patients.

And in Iowa was the very first
stroke unit in the country.

Harold Adams and Jose Biller doing the.

One of the very first big multicenter
trials in the country, the TOAST

trial of an acute anticoagulant.

And so as I was.

Having, uh, my, uh,
disappointments as well as, uh,

encouragement and neuro behavior.

I saw this alternative approach, uh,
which was much more collaborative,

much more therapeutically oriented, uh,
much more engaged directly, uh, with,

uh, uh, patients on their benefit.

Um, so that's, uh, why I then.

Uh, went on to immediately do a stroke
fellowship at Brown and, and onto the

career, including clinical trials.

I will say, when I set out, uh, part
of my goal was, uh, reason for going

to, uh, clinical trials and stroke
was I didn't anticipate to ever be

writing grants, living on grants, um,
and in clinical trials you could be

a site investigator, contribute to.

Two big trials and, uh, be a cog in a
machine and, uh, and be very helpful.

And that made it very attractive to me.

Uh, and, uh, I was a late bloomer.

I didn't write my first grant until
late Assistant Professor Hood.

Uh, but what happened as I was
doing clinical trials was I

always wanted to understand more
about what we were doing and.

Uh, neurology is, people talk a lot
about burnout in medicine, but I think

for lots of medicine, and especially
for neurology, a big problem is burnout.

It takes such a long time

to acquire the huge.

Knowledge base of neurologic disease.

You don't know if you're gonna be good
until you're in your late thirties, early

forties, and I had a long burn in period.

Uh, but it, it, it was very rewarding
along the long apprenticeship.

And then I eventually took on more and
more leadership roles and ended up writing

grants in the way I never expected to.

Scott Berry: So what, by the way, what
was the result of the TOAST trial?

Um,

Jeff Saver: The TOAST trial was neutral.

Uh, it was done at the same
time as the NMS TPA trials.

They were the two great strides.

Um, and, uh, but the TOAST trial set the,
uh, framework for all trials that fall.

We still used the, um, toast system
for classifying the cause of stroke.

Now, 30 years later.

Scott Berry: Hmm.

Okay, so you're, you're jumping into
stroke, which you, you, you do a lot

of work within stroke, uh, early on,
by the way, I was looking at your, your

various publications and, uh, it's hard
to count your publications, but, uh, 870

at one source, 7 93, and another source.

Uh, but one of the, the, the most
cited of those is called, time is brain

quantified and it talks about stroke.

So you get involved in a great deal
and we're gonna sort of touch on stroke

and we're gonna touch on how to analyze
stroke trials, but, uh, acute stroke.

So, uh, I think given that paper
and, uh, time is brain, what is an

acute stroke and what happens to
the brain during an acute stroke?

Jeff Saver: Sure.

Well there are two main types of stroke.

Um, there.

You know, stroke is injury to
the brain from blockages or.

Ruptures of blood vessels and a blockage
in a blood vessel, usually due to a clot,

is the cause of four out of five strokes.

Um, rupture of a blood vessel
causing a bleeding in the brain.

A hemorrhagic stroke, one out of five,
the blockage stroke, ischemic stroke.

When the blockage occurs, a small
group of nerve cells is deprived

of all blood flow, all nutrients
and dies within a few minutes.

But a much larger, uh, group of
nerve cells has a more moderate,

uh, reduction in blood flow
because there are some collateral

channels still delivering blood.

And the tissue there can last for.

Uh, a few hours to, up to 24 hours
depending, uh, on each patient's anatomy.

Uh, so that is the target of acute
ischemic stroke therapy, the, uh, getting

the, uh, vessel open and restoring blood
flow in time to save those threatened,

but still salvageable brain tissues.

Scott Berry: Okay, so as in,
in my, my naive statistician

view of this within the brain.

Uh, blood flows through the brain
and it serves, delivers oxygen.

I'm sure it does much more than that,
but when a clot occurs that you don't

get the blood flow, the downstream
parts of the brain that are served

by that are no longer served there.

There's, as you say, 1.9

million neurons, 14 billion
synapses, and seven miles.

Of myelinated fibers are destroyed
by the not having blood flow,

Jeff Saver: Every

Scott Berry: And you get
this death every minute.

Jeff Saver: 2 million
nerve cells a minute.

And there's an interesting clinical
trial story behind our, my doing

that article to quantify the speed of
loss of neurocircuitry in the brain.

Uh, when we were doing, uh, acute
stroke trials in the late 90s early

2000s the IRB would ask us to.

Uh, make sure that we had an informed
consent and they, uh, wanted us to

wait an hour to give patients and
families time to think about it before

signing the consent form, which is
absolutely appropriate to maximize the

ethical consideration by the patient.

But the problem is the brain
is dying all that time and your

chance to show benefit of drug is
being lost and also the patient's.

Ability to themselves experience benefit
from the intervention is being lost.

And I couldn't make
that clear to the IRBs.

I said, you can't delay it.

And they said, what?

We're gonna wait an hour.

So I said, alright, I'm going to.

Uh, look at the literature and there was
some interesting stereotaxic literature

on just how many 20 billion brain
cells there are in the brain and the

typical size of an ischemic stroke and
from, and how long it takes to grow.

And from that you could derive that it's
2 million nerve cells lost a minute.

And the rallying cry of time, is
brain had already existed, but.

Being able to quantify it gave
a big kick to that, uh, both in

research but also in clinical care.

Scott Berry: Yeah.

So I, I mean, the analogy would be
sort of, uh, somebody's drowning

and you, you wait for an, you wait
for a period of time to enroll

them in a trial rather than doing
something to fix, to fix the drowning.

Okay.

Uh, so stroke has had, uh, an amazing
in, in your involvement in trials.

That is an amazing history and,
and endovascular therapy, which

you can describe this, but you
go in and you remove the clot.

Restoring blood flow has
been amazingly successful.

Uh, through a history of sort of
figuring out the right patients and

the wrong patients and the right
devices and all of this, but this,

this incredible device that saves
many, many lives in acute stroke.

You were involved in this beginning
of the development of this device.

Sounds like an incredible story.

Jeff Saver: Yeah, it
was a great privilege.

Um, I had the great fortune of being
at UCLA where a French interventional

neurology, Pierre Gobin invented
the very first retrieval devices.

These are devices where the
interventionalists will put.

A wire and small tube into an artery
in the leg and slowly advance it up

into the brain, reach the clot, and
then either, uh, deploy a grabbing

tool to pull the clot out or suction
to pull the clot out and reopen, uh,

the artery and restore blood flow.

Pierre, his design was of a helical coil.

That he would,

uh, put into the clot, uh, and then
pull it out much like a corkscrew

pulling, a cork out of a wine bottle.

It is not an accident that a
French interventional neurologist.

Developed this particular device
as the first device, and he did

the very first animal models.

And then when it came time to go
to humans, I as a non-invasive

stroke neurologist, helped to
design the very first studies and

was able to be involved ever since.

Scott Berry: Wow.

So the, the, the clot, is this
what we think of as, I mean,

what is it you're removing?

Is this.

Coagulated blood, that
that doesn't flow anymore?

Is that what the clot is?

Jeff Saver: Yes, and it, it can
have a variety of, uh, compositions.

It can be mostly red blood
cells, it can be mostly platelet

clumping elements of the blood.

And, you know, it's always
a combination of the two.

But, uh, the same clots that we see on our
skin when we, uh, have a skin break and

we see clots form, uh, this is what forms,
but instead of forming in a useful whale.

Way to heal a broken surface.

It forms within the lumen of the artery
or travels to, uh, forms elsewhere

and travels there and, uh, completely
blocks that artery blood flow.

Scott Berry: Yeah.

Amazing.

And, and just how long does
it take when you start this

procedure to remove the clot?

You described time as brain.

How long would it take for this to happen?

Jeff Saver: Uh, from the time that
the skin puncture occurs to begin the

procedure, uh, these days, uh, the.

They can reach the clot within 25
minutes, often be able to pull it out

with the first pass within 35 minutes.

When we first started doing
this, we got the artery fully

open maybe 25% of the time.

And then, uh, over time there
have been a history of incremental

improvements in the devices.

Now the interventionalists get the
artery open 85, 90% of the time.

Scott Berry: Hmm.

Wow.

Wow.

That's amazing.

Uh, it's, it, it is incredible that the,
the story of this and the impact it's had.

Okay, so now we're, we're involved,
uh, I, you're involved as a, uh,

investigator, uh, primary investigator
in the STEP platform, which is now

looking you, you've, you've identified
people that absolutely benefit by

this endovascular therapy based on
the location, the size of the stroke,

the time since the stroke started.

But the question is, who,
who does this benefit?

So a number of clinical trials, a
number of stroke clinical trials.

And there's been a history of
endpoints in stroke trials.

It seems like, you know, there
was a Scandinavian stroke scale.

There was other things,
but at least it has.

It has come to the endpoint being
the Modified Rankin score, which is

an ordinal score as measuring the
neurological status of a patient.

And, uh, and, uh, I've talked about
this before and maybe we should

talk about that scale, but then how
do you analyze this ordinal scale?

Uh, and we'll sort of come to that.

So to tell our audience what
the MRS Ordinal Scale is.

Jeff Saver: Sure.

So it's now a seven level scale,
going from the best zero recovered to

no symptoms whatsoever to the worst.

Six dead and in between
are different steps.

Uh, one is you have
symptoms, but you can work.

Uh, two is you can't work,
but you can live alone.

Uh, three is you can, uh.

You can't live alone, but you can walk.

Uh, four is you can't walk, and
a five is you're bedridden meet

somebody with you all the time.

So each has a pretty clear step
down, although just how much worse

it is to be able to have symptoms
versus no symptoms versus being able

to walk versus not able to walk.

The value of those steps are
unlikely to be exactly equal.

So it makes this an ranked but
ordinal scale where we don't know

the distance between each level.

Scott Berry: Yeah, I, and, and the,
the last level on this is death.

So, uh, from the
bedridden, then there is a

value that is death.

Um, within that, so you touched
on exactly the issue of this as a

statistician, if we do something like,
uh, we call it the shift analysis or

a proportional odds model, we're we're
analyzing this, that zero is is the

best one is is is next, two is next.

But there's no numerical
difference between them.

We don't say.

One is a little bit better than zero,
more than two is better than one.

And likewise, we don't actually
talk about the utility of

death relative to other scans.

It, it leads to some, uh, challenges
in the interpretation of outcomes if

we rely on a statistical assumption to
dictate what is good clinical outcomes.

So, uh, you were involved and I was
involved in an effort to develop

a different way to analyze this.

Uh, so, so what was an
alternative way to analyze?

Said.

Jeff Saver: So we were part of the group
that developed the utility-weighted

modified Rankin scale, the U-W-M-R-S,
which assigns a health utility value

to each level of the, uh, seven levels,
uh, uh, weight between zero and 1.0,

1.0

being.

Fully healthy, vigorous
zero being, uh, dead.

And the, this is the standard way
to measure the value of health

states in health econometrics.

So what were the value
of each Rankin scale?

We took two approaches to figure that out.

One was, uh, uh.

John Rothwell and the Oxford Group
in Britain had done a large study in

thousands of stroke survivors, uh, scoring
them on the Rankin Scale and having.

Them themselves fill out the European
quality of life scale for their

health related quality of life.

And so they were able to derive
from patients at each level what the

average value of the patients was.

Our group used the World Health
Organization Global Burden of Disease

approach, where they have to assign the
value of every disease known to humans.

And the way they do that
is with the time trade off.

Uh, uh, sorry, person, trade off measure
that if you were a, uh, physician making

health system divisions decisions,
and you could keep, um, either a.

A thousand patients who are completely
healthy, alive for another year, or X

number of patients with whatever disease
state they have alive for a year.

How many patients with that disease
state would you need to be indifferent

as to where you spent the money?

And if it's a nearly completely healthy,
it's not gonna be that many more patients.

If they're really bad, it's
gonna be a lot more patients.

So we, uh.

Uh, did that with, uh, stroke physicians
and nurses from around the world and

came up with the clinician ratings
and we, uh, looked at the two to

take the average between the patient
self-ratings and the clinician ratings.

And it turned out they
were remarkably similar.

They matched almost perfectly,
which was very reassuring.

And we came up with these weights
for each of the seven levels.

Scott Berry: A a as an example
in the, in the numeric values,

you described the zero to one.

So zero is perfect neurological status.

One, you described it there, that there
are, there's some deficit, but you're

fully working, fully independent.

That that's, that is a one
for the value zero and 0.91

for the value one.

So there's a 0.09,

lost going from zero to one.

Likewise, on the far end of the scale,
five and six are actually combined.

So being bed bedridden,
essentially vegetative and

death are combined to have zero.

And stepping up to four is 0.33

unit.

So going from that five to fours
point, three, three units, we're

going from one to zeros 0.09

units.

So it's, it's largely four times as good
to move patients from five, six to four,

that it is from one to zero, and that
goes into the analysis of the input.

Right.

Uh, at the end of the day, and
likewise, there are values across

the scale of these to look at.

this is fantastic and I love
it for multiple reasons.

Um, in some trials and especially
in stroke like endovascular therapy,

you worried you might actually
be doing harm to some patients,

maybe by restoring blood flow.

There isn't much brain to save,
and you actually cause brain, you

cause bleeding, you cause harm.

And if we do an analysis and say,
well, we're looking at efficacy, but

now how do we incorporate safety?

This incorporates it all.

It incorporates the negative outcomes
of this, this endpoint encompasses that

and it weights the, the various values.

So I love this.

It's, I, I think it works great.

What has been the reaction from
the stroke community to the

development of this endpoint?

Jeff Saver: Well, uh, there
have been a range of reaction.

Some people have.

Yes, uh, really loved it.

A, uh, adopted it and
been very happy about it.

Um, others have, well, the
regulators at FDA and elsewhere

across the world have been hesitant.

Uh, they've always already been
hesitant about looking at the rank

and scale as an ordinal outcome.

They've preferred to dichotomize the
rank and scale and say, well, analyze.

Zero to two versus three to six, um,
because that's computationally easier,

but also because then it's easy to derive
and not be needed to treat so clinicians

can understand what they're doing.

Now, of course, this is a completely
mistaken idea because if you just

count improvements in the health
state, transition across one level

of the ranking, you are missing.

Improvements elsewhere.

You're giving misleading clinicians as
to the actual benefit of your therapy.

And the example for lay people I give is,
if you had a new high school educational

in intervention and you wanted to see if
it helped students, would you only count

how many people went from a B to a b plus,
or would you want to count everybody?

Um, so we've, uh.

Have those difficulties,
uh, with the regulators.

And then there are, um, other folks who,
who think, uh, the, uh, appropriately

at that, the, uh, Rankin utility
weights that we derived are based on,

uh, originally patients from Great
Britain plus this international panel.

And.

Every country has its own
tariffs for utility weights, and

they value different outcomes.

Uh, uh, uh, Rankin one in India is
very different than a Rankin one in

the us and that's certainly true.

Uh, but what's also true is that
counting every level of the rank equally

as one is always further off from.

Uh, what people actually
value than comparing one, uh,

country to another country.

Uh, that's always much closer.

Scott Berry: Yeah, I, and, and
in the dichotomous outcome, for

example, you could write down a
utility function, which is 1, 1, 1.

0, 0, 0, 0 and say that let's

use that utility function, which is
one that nobody has, uh, uh, in that

rather than the one that you developed,
uh, that, that represents a population.

Alternatively, even doing
an ordinal analysis.

Imposes a utility upon these states, but
in an unspecified, implicit way that comes

through the proportionality assumption.

Um, so you are still assuming that
everybody in the population has a

particular utility that's just implicit
in the, the statistical algorithm, which

some people seem sort of more comfortable
with than explicitly writing it down?

Um,

Jeff Saver: important to emphasize
that you can't escape putting

weights on each level of the
ranking no matter how you are.

Analyze if you dichotomize, as you say.

You're weighting many
of them as worthless.

If you analyze orally, then
you're implicitly ranking them

in, um, in somewhat obscure
but relatively equal ways.

Um, and if you do it using open
utility weights that are empirically

derived, you're basing it on
real patience and real value.

Scott Berry: Yeah.

And, uh, there, there was, uh, the
Dawn trial used utility weighted MRS.

And Mr.

Clean did not, and Mr.

The Mr.

Clean investigators had a
series that showed up where they

complained about the utility weight.

And it's a, it's a fascinating read
of their, their response to it, our

response back to them, their response
on the, on the various methods.

So this is something that is, uh,
passionate about how to analyze this

endpoint with, with disagreement for sure.

Jeff Saver: Uh, yes.

I just had an exchange three days ago, uh,
about a new analytic project with the Mr.

Clean investigators where
they, again, were objecting to

the utility weighted MRS, so.

Uh, this, uh, controversy has not,
not died down, but I, but I think

we are slowly winning the field.

Scott Berry: So the, the, this
interesting question you brought up

about the number needed to treat on a
dichotomous endpoint is really simple.

Um, you've done work on number
needed to treat for this utility

weighted, um, if that's the thing
that is relevant to clinicians.

Jeff Saver: Yes.

And uh, you know, the first we've
done a lot of work on oral, uh,

derivation of utility to treat,
and there are variety of techniques

that have, we have been developed.

Our groups used a variety of
joint outcome table specification

techniques, uh, and, you know.

Whatever you do, uh, you're estimating
the map needed to treat because parallel

group trials, unlike crossover trials,
won't let you specify it exactly,

um, when you have an ordinal outcome.

Uh, whereas you, uh, will exactly
calculate it with dichotomous.

But there's a, a famous quote, uh, that
it is preferable to have an estimate of a.

Uh, useful outcome than an exact, uh,
quantification of a not useful outcome.

And, uh, and I think we
need to recognize that.

And then the utility weighted MRS
then allows us to convert the value

of these outcomes to health utility
and the not be needed to treat.

And the economic applications that are
used worldwide in health system plan.

Scott Berry: So it, it, it's, um,
uh, and so this, this will continue.

Uh, we will continue to push regulators.

We'll continue to push
better ways to analyze this.

Um, interestingly, so it seems
like a lot of the stroke world.

The work so far and this incredible
work in a clock clearing device

and thrombo, medical thrombolytics
seem to be the same mechanism of

action, of restoring blood flow.

I know there's this huge interest in
neuroprotectants and I guess the idea

behind a neuroprotectant is a, a lot of
this research so far is clearing the clot,

restoring the blood flow, letting the the
human body do the work it's supposed to.

And you talked about synapsis loss.

Um, uh, all the things that dies during
this process is a neuroprotectant,

something that we could give
somebody while this is happening,

that might protect the synapses,
protect the neurons, protect the

myelinated fiber so it doesn't die.

Is that the notion of a neuroprotectant?

Jeff Saver: Yes, the neuroprotective
agents are agents that allow.

Brain tissues to tolerate low blood flow
either while they're still not getting

blood flow so they can last longer
until you can restore the blood flow or

after the blood flow's been restored.

When you get reap profusion
injury or protect them.

Against that.

And it turns out that, you know,
plumbing is easily is easy.

We give lytic drugs like Draino, we
use these devices like rotor Rooter.

Um, and whereas.

Intermediate metabolism of, uh,
the nervous system is complicated.

And so we've tried hundreds
of neuroprotective drugs

that worked in animals.

None have worked so far in humans.

Uh, but we need to get there because, uh.

By the time we get the artery open
with the, uh, thrombectomy devices,

a lot of injury has often occurred.

So being able to give a drug right
at the onset, or even before the

onset that will protect the brain and
deliver more salvageable tissue to the

interventionalist is, is a critical need.

Scott Berry: So for somebody who's
spent so much time on the details of

the brain of what a clot is, uh, the
damage that happens, are you optimistic?

We'll find a neuroprotectant.

Jeff Saver: I am sure
we'll get there eventually.

And I, I, um, there's actually a
stream of trials coming out of China

now, um, where they are able to.

Uh, test large populations much more
quickly than we've been able in the US

that are finally beginning to suggest, uh,
positive results with Neuroprotectants.

And we in, uh, the NH
step group also have, uh.

Neuroprotective agents including,

uh, the uric acid that went
through rigorous, uh, risk, uh, uh,

qualification in preclinical studies
at NIH that we're very hopeful about.

So I, I think in, in the next five
years, we will have a neuroprotectant.

Now I will note this is my 30th
year of saying in the next five

years we'll have a neuroprotectant.

But I am more hopeful than ever.

Scott Berry: Okay.

Okay.

Okay.

I, I assume by the way that humans have.

Different capability to withstand lack
of blood flow for a while, that there's

natural heterogeneity and there may
be protein levels and other things

that just allow one person does much
better, where another does much worse.

Jeff Saver: We are not all that
different in our ability to withstand

low blood flow if exposed to the
same amount of low blood flow.

You know, if we have a cardiac
arrest, just about everybody

only has six minutes at most.

Um, the, uh, but we differ a lot in.

When there's a blockage in one artery,
how much the other arteries can take over.

So that makes for a, a
very heterogeneous pattern.

Some people are fast
progressors with their stroke.

Some people are slow, progressive with
their stroke, but it's, it's due to the

plumbing more than they, than chemistry.

Scott Berry: Hmm.

And, and, and you're, you, you've
done cognitive behavioral work.

Uh, vascular specialist is.

and, and I know Alzheimer's is another
disease where we talk about amyloid

plaque and tau tangles kind of blocking
the, the networking and that's the

loss of memory, the loss of cognition.

Is that similar to a stroke
or are they just completely

different blockage mechanisms?

Vascularly.

Jeff Saver: Um, they are different.

Those are buildup of, uh, precipitated
proteins in nerve cells blocking

the function of the nerve cells as
opposed to the clots that are in

the arteries blocking the passage
of flow through the arteries.

But it is the case that
most, uh, patients with.

Dementia have mixed Alzheimer's
disease and vascular dementia that,

uh, lifelong mild low blood flow injury to
the brain adds to the Alzheimer's disease.

In fact, uh, the.

Age adjusted incidence of dementia
now is half what it was 30 years ago.

And that's because we're so much
better at preventing vascular disease.

We don't realize that 'cause the
population's been getting older,

so more and more people are getting
Alzheimer's prevalence is increasing.

But if we hadn't reduced the.

Age adjusted incidents, it
would've been even worse.

Uh, so it's an untold success,
unrecognized success story that we've

cut the incidents of dementia in half,
but of course we need to do more.

Scott Berry: So what, what
are those vascular things?

Is it, is it metabolic?

Is it, um, uh, obesity,
uh, cardiovascular drugs?

What, what is it that we're doing better?

Vascularly.

Jeff Saver: Uh, it is, uh,
people have stopped smoking.

People exercise more people on
cholesterol lowering medicines.

We have better blood
pressure lowering medicines.

Um, all of those have added together.

Scott Berry: Wow.

Wow, wow.

It's amazing.

Uh, amazing work.

Uh, very interesting stuff.

Uh, can't wait to see more of
these trials in neuroprotectants

using the utility weighted MRS.

Uh, hopefully as we go forward.

So Jeff, I want to thank you
tremendously for being on here.

It's incredibly interesting.

I, I, I love this stuff, so thank you
for joining us here in the interim.

Jeff Saver: Thank you so much.

Thank you for helping our field so much,
and thank you for having me, Scott.

Scott Berry: Appreciate it.

Thanks, Jeff.