1.
Valida'on
of
vascular
permeability
as
preclinical
diagnos'c
tool
for
diabe'c
re'nopathy
using
fluorescein
videoangiography
tracer
kine'cs
Adriane
Walther,
Kenneth
M.
Tichauer,
Jennifer
J.
Kang-­‐Mieler,
BME,
Theme:
Health
Introduc?on
Purpose
Theory
Methods
Results
Diabe?c
re?nopathy
is
characterized
by
abnormal
hemodynamics
in
the
neovasculature
of
the
eye
is
not
detectable
un?l
it
reaches
an
irreversible
stage,
at
least
by
today’s
treatment
standards.
Therefore,
methods
of
detec?on
for
its
onset
are
in
demand.
This
study
aims
to
use
an
adiaba?c
approxima?on
to
?ssue
homogeneity
model
and
tracer
kine?c
modeling
to
validate
the
quan?fica?on
of
vascular
permeability
as
a
“sub-­‐clinical”
diagnos?c
tool
of
diabe?c
re?nopathy.
Re?nal
videoangiographic
data,
using
fluorescein
as
a
radiopaque
tracer,
obtained
from
diabetes
induced
rats
was
evaluated
to
validate
the
capacity
of
vascular
permeability
as
an
early
indicator
of
diabe?c
re?nopathy.
In
this
study,
a
method
for
quan?ta?vely
mapping
volumetric
flow
and
re?nal
permeability
using
fluorescein
videoangiography
is
proposed
using
tracer
kine?c
modeling
and
the
theories
of
linear
systems
theory.
dCf (t)
dt
= −keCf (t)
)()()( thtFCtFC av ∗=
Q(t) = F Ca (u)du−
0
t
∫ F Ca (u)∗h(u)du
0
t
∫
Q(t) = FCa (t)∗ R(t)
R(t) =1− h(u)du
0
t
∫
Adiaba&c
Approxima&on
to
the
Tissue
Homogeneity
Model
The
concentra?on
of
imaging
agent,
Q(t),
was
treated
as
a
black-­‐box
model
with
arterial
input
and
venous
output
func?on.
The
input
is
defined
as
product
of
the
volumetric
flow,
F,
and
the
upflow
of
arterial
blood
flow,
Ca(t),
called
the
arterial
input
func?on
while
the
output
is
defined
as
the
product
of
the
volumetric
flow
and
the
ouRake
of
venous
blood
flow.
where
*
represents
the
convolu?on
operator.
Linear
Systems
Theory
By
linear
systems
theory,
the
output
can
also
be
defined
as
the
convolu?on
of
the
arterial
input
func?on
with
the
func?onal
response
of
the
system
to
a
Dirac
Delta
func?on,
h(t).
Then,
by
the
law
of
conserva?on
of
mass,
the
concentra?on
of
fluorescein
in
the
vessels
is
equal
to
the
difference
of
the
input
and
output
func?ons.
where u represents a dummy integra?on variable. This can then be simplified to:
where
R(t)
is
the
impulse
residue
func?on,
defined
as:
Plug
Flow
Model
Because
the
ini?al
value
of
R(t)
must
equal
1,
because
h(0)=0,
it
can
be
said
that
FR(t)
is
equivalent
to
the
volumetric
blood
flow,
F.
Furthermore,
the
dynamics
of
the
fluorescein
concentra?on
is
used
to
approximate
the
leakage
of
blood
out
of
the
vessels
and
into
extravascular
?ssue,
“extrac?on
frac?on”
E,
by
assuming
a
“plug-­‐flow”
model
sta?ng
that
the
rate
at
which
imagining
agent
is
washed
out
of
the
?ssue
and
back
into
the
blood
stream
can
be
represented
by
a
first
order
equa?on:
where
ke
is
a
constant
rela?ng
the
efflux
back
into
the
vessel.
Streptozocin-­‐induced
Long-­‐Evans
rats
were
anesthe?zed
with
ketamine
(80
mg/kg
BW)
and
xylazine
(10
mg.kg
BW)
through
the
tail
vein
and
videoangiograms
were
recorded
with
a
scanning
laser
ophthalmoscope.
Volumetric
blood
flow
and
vascular
permeability
are
then
determined
using
MATLAB
in
accordance
with
the
mathema?cal
models
named
previously.
Diabetic
a)
b)
Diabetic
a)
b)
In
conclusion,
a
method
for
quan?ta?vely
mapping
volumetric
blood
flow
and
re?nal
permeability
using
fluorescein
videoangiography
is
proposed
as
an
alterna?ve,
noninvasive,
and
clinically
translatable
is
validated.
Since
fluorescein
is
FDA
approved
and
commonly
used
in
ophthalmology,
the
poten?al
for
expedited
clinical
applica?on
providing
early
indica?on
of
diabe?c
re?nopathy.
References
A
future
study
will
use
a
lesser
concentra?on
of
fluorescein
dye
to
alleviate
camera
satura?on,
16-­‐bit
camera
to
increase
sensi?vity
in
local
changes
of
blood
flow,
modifica?on
to
mo?on
correc?on,
and
the
addi?on
of
user
interface
checking
modali?es
for
op?mal
data
selec?on.
Goals
include
the
replica?on
of
this
procedure
with
non-­‐
saturated
videoangiography
data
to
produce
quan?fied
blood
flow
maps
and
extrac?on
frac?on
es?mates,
based
on
the
parameter,
E,
valida?ng
there
use
for
“sub-­‐clinical”
biomarkers
for
diabe?c
re?nopathy.
[1]
K.M.
Tichauer,
M.
Guthrie,
L.
Hones,
L.
Sinha,
K.
St.
Lawrence,
J.J.
Kang-­‐Mieler.
“Quan?ta?ve
re?nal
blood
flow
mapping
from
fluorescein
videoangiography
using
tracer
kine?c
modeling,”
Op?cs
LeRers,
vol.
40,
no.
10,
pp.
1–4.
[2]
K.
S.
St
Lawrence,
and
T.
Y.
Lee,
“An
adiaba?c
approxima?on
to
the
?ssue
homogeneity
model
for
water
exchange
in
the
brain:
II.
Experimental
valida?on,”
J
Cereb
Blood
Flow
Metab,
18(12),
1378-­‐85
(1998).
Future
Work
&
Goals
Conclusion
Figure
1:
Demonstra?on
of
blood
flow
mapping
and
vascular
permiability
for
fluorescein
videoangiography
data
in
the
re?na
with
streptozotocin-­‐induced
diabetes
Arterial
ROI
Venous
ROI
Tissue
ROI
Quan'ta've
Mapping
Selec'on
of
Regions
of
Interest