11/18/2019 1 Blood Vessels and Dementia? Tell Me More Adviye Ergul, MD, PhD, FAHA Department of Pathology & Laboratory Medicine, MUSC & Ralph H Johnson VA Medical Center, Charleston, SC ERFA Vascular Neuroprotection Laboratories Dementia
11182019
1
Blood Vessels and Dementia Tell Me More
Adviye Ergul MD PhD FAHA
Department of Pathology amp Laboratory Medicine MUSC amp
Ralph H Johnson VA Medical Center Charleston SC
ERFA Vascular Neuroprotection Laboratories
Dementia
11182019
2
~86 billion neurons
400 miles of vascular networks
~86 billion
neurons
capillary
within 15
micron
range of a
neuron
WHY
11182019
3
Brain has no energy reserves
Depends on steady blood flow for proper
function
Needs on demand local blood delivery-
functional hyperemia-neurovascular
coupling
Immune trafficking ------Neuroinflammation
Neurovascular Unit
11182019
4
11182019
5
VCID spectrum disorders arise as a result of risk factors that similarly increase the risk
for cerebrovascular disease (stroke) including atrial fibrillation hypertension diabetes
and high cholesterol Forms of VCID include
bullVascular cognitive impairmentdementia
bullPost-stroke cognitive impairmentdementia (PSCI)
bullMulti-infarct dementia
bullCerebral autosomal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy (CADASIL)
bullSubcortical vascular dementia
Vascular contributions to cognitive impairment and
dementia (VCID)
COGNITION
11182019
6
Arterioscler Thromb Vasc Biol 2019 Feb 28ATVBAHA118311906 doi
101161ATVBAHA118311906 [Epub ahead of print]
Brain Vasculature and Cognition
Fouda AY12 Fagan SC32 Ergul A45
Changes in brain blood vessel functionstructure
Decreased blood flowimpaired removal of metabolites
White matter damage
BBB disruption
VCID
(VCIPSCI)
Neuroinflammation
Stroke
Vascular risk factors (hypertensiondiabetes) amp aging
Pathologic new vessel formation
Neurovascular remodeling
ADADRD
ADRD 2019 NIH Summit
11182019
7
Of Mice to WoMen
Translational ADRD Research
Vessel Dysfunction in Diabetes
Cortex Striatum0
50
100
150
200
250
Control (n=12)
Diabetes (n=12)
CB
F (
ml
100g
min
)
Cortex
Striatum
Diabetes
Control
Hardigan T et al Clin Sci 2016
Blood flow to the brain (CBF) is decreased in diabetes
11182019
8
Vessel Dysfunction in Diabetes
Control Diabetes0
20
40
60
(n=4) (n=4)
CB
F i
ncre
ase
( o
f b
aseli
ne)
2 10 18 26 34 42 50 58 66 74 82
-20
0
20
40
60
80
Control (n=4)
Diabetes (n=4)
Stimulation
Time (sec)
Blo
od
flo
w c
han
ge
( o
f b
aseli
ne)
Neurovascular uncoupling
Hardigan T et al Clin Sci 2016
Diabetes Amplifies Post-stroke Inflammation
Diabetes
Control
C o n tr o l D ia b e te s
0
2 0
4 0
6 0
Ce
ll B
od
y S
ize
(u
m)
C o n tr o l D ia b e te s
0
2
4
6
8
Nu
mb
er
of
Pro
tru
sio
ns
Microglia
11182019
9
Diabetes causes cognitive impairment (VCID)
RECOGNITION INDEX
0 0
0 2
0 4
0 6
0 8
1 0
C o n t r o l
D ia b e t e s ( G K r a t s )
2 5 7 1 0 1 4
c
a
ba
aa
a
D a y s a f t e r s t r o k e
Re
co
gn
itio
n i
nd
ex
B L D 1 4
0 0
0 2
0 4
0 6
0 8
d2
In
de
x
p d i a b e t e s lt 0 0 0 0 1
^ p s e x = 0 3 6 8 7
p in te r a c t io n = 0 2 9 9 9
p d i a b e t e s lt 0 0 0 0 1
^ p s e x = 0 2 8 9 2
p in te r a c t io n = 0 4 2 0 8
p lt 0 0 0 1
v s s h a m
p = 0 0 0 7
v s s h a m
Diabetes causes cognitive impairment (VCID)
11182019
10
After Before Control Diabetes + Metformin Control Diabetes
Stroke side of
the brain
0
5
10
15
Ipsilateral Contralateral
Cortex
Control Diabetes Diabetes + Metformin
Sham
p=00009
p=00019
p=00098
p=00019
p=00098
b
b
v
asc
ular
vo
lum
e
Prakash et al Stroke 2013
Diabetes
In Search of Therapies Randomized Blinded Preclinical Trial of Glucose Control
Blood sugar control
0
20
40
60
80
100
0 2 14
Control
Diabetes + MetforminDiabetes
ba
Days after stroke
o
f ti
me s
pen
t in
th
e o
pen
arm
MEMORY amp ANXIETY
(ELEVATED T-MAZE)
00
02
04
06
08
10
Control
Diabetes
Diabetes + Metformin
2 5 7 10 14
c
a
ba
aa
a
Days after stroke
Re
co
gn
itio
n i
nd
ex
MEMORY amp COGNITION
(NOVEL OBJECT RECOGNITION)
15 min delay
AA session AB session
Glucose control attenuates VCID
11182019
11
In Search of Therapies Randomized Blinded Preclinical Trial 2
Stroke Increased bleeding into brain
Death of blood vessel cells
Poor outcomesrecovery PSCI
Iron
Pathological new vessel formation
Diabetes
DFX
In Search of Therapies Randomized Blinded Preclinical Trial 2
Day 14
Ctrl DM00
02
04
06
08
$ $
NO
R i
nd
ex
DFX DFX
Diabetes Stroke Behavior Age 4w 12-14 w Day 14 Post-Stroke
Day 1-7 DFX treatment
DFX treatment has a differential effect on blood vessels in control versus diabetic rats
11182019
12
In Search of Therapies Randomized Blinded Preclinical Trial 2
Diabetes Stroke Behavior Age 4w 12-14 w Day 14 Post-Stroke
Day 1-7 DFX treatment
Day 14
Ctrl DM00
02
04
06
08
$ $
NO
R i
nd
ex
DFX DFX
DFX treatment prevents inflammation
In Search of Therapies Sex Differences
Day 14
Ctrl DM00
02
04
06
08
$
$
NO
R i
nd
ex
DFX DFX
DFX treatment reduces blood vessels in both control and diabetic rats
DFX treatment does not reduce inflammation in females
11182019
13
In Search of Therapies Randomized Blinded Preclinical Trial 3
C21
In Search of Therapies Continued
Diabetes Stroke Behavior Age (w) 4 12-14 W1-8 Post-Stroke
Delayed
Administration
Blinded amp
Randomized
Day 3
C21
11182019
14
In Search of Therapies Randomized Blinded Preclinical Trial 3
BL W1 W2 W4 W802
04
06
08
Time Post- MCAO
T
ime in
No
vel A
rm
2 Trial Ymaze
C C21C Veh
NS
BL W1 W2 W4 W800
02
04
06
08
Time Post- MCAO
T
ime in
No
vel A
rm
2 Trial Ymaze
D C21 D Veh
Interaction Plt005
In Search of Therapies Randomized Blinded Preclinical Trial 3
C21 reduces inflammation improves vascular integrity and prevents cognitive decline
11182019
15
In Search of Therapies for ADRD Of Mice to WoMen
Preclinical animal studies using comorbid disease models commonly found in patients such as diabetes and hypertension are essential to identify mechanisms underlying ADRD to develop new therapies Translational preclinical studies designed like human clinical trials can help us test the efficacy and optimize treatment strategies to modify the disease progression Improving blood vessel integrity and function can help reduce neuron degeneration and inflammation Preclinical and clinical research are integral pieces of an Alzheimerrsquos Disease Research Center (ADRC)
Of Mice to WoMen Translational Dementia Research Labs at MUSC
ERFA Vascular Neuroprotection Laboratories Adviye Ergul MD PhD ergulmuscedu Aging and Senescence Laboratories Gavin Wang MD PhD wangymuscedu Sims-Robinson Lab Metabolic Disorders Brain Aging and AD Catrine Sims-Robinson PhD robinsocmuscedu Christie Heart amp Brain Program Federica del Monte MD PhD delmontemuscedu Onder Albayram PhD albayrammuscedu Carroll A Campbell Jr Neuropathology Laboratories (Brain Bank) Steven Carroll MD PhD Eric D Hamlett PhD hamlettemuscedu
11182019
16
TEAM ERFA VASCULAR NEUROPROTECTION LABORATORIES
YOUR PARTICIPATION AND SUPPORT FOR PRECLINICAL AND CLINICAL RESEARCH IS VITAL FOR SUCCESS IN THE FIGHT AGAINST ADRD
Tell your senators and representatives to keep supporting biomedical
research
We need an Alzheimerrsquos Disease Research Center in South Carolina
THANK YOU
11182019
17
In Search of Therapies for ADRD
Reduce vascular risk factors
Blood pressure control
Blood sugar control
Blood lipid control
ExerciseHealthy Diet
New learning
11182019
2
~86 billion neurons
400 miles of vascular networks
~86 billion
neurons
capillary
within 15
micron
range of a
neuron
WHY
11182019
3
Brain has no energy reserves
Depends on steady blood flow for proper
function
Needs on demand local blood delivery-
functional hyperemia-neurovascular
coupling
Immune trafficking ------Neuroinflammation
Neurovascular Unit
11182019
4
11182019
5
VCID spectrum disorders arise as a result of risk factors that similarly increase the risk
for cerebrovascular disease (stroke) including atrial fibrillation hypertension diabetes
and high cholesterol Forms of VCID include
bullVascular cognitive impairmentdementia
bullPost-stroke cognitive impairmentdementia (PSCI)
bullMulti-infarct dementia
bullCerebral autosomal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy (CADASIL)
bullSubcortical vascular dementia
Vascular contributions to cognitive impairment and
dementia (VCID)
COGNITION
11182019
6
Arterioscler Thromb Vasc Biol 2019 Feb 28ATVBAHA118311906 doi
101161ATVBAHA118311906 [Epub ahead of print]
Brain Vasculature and Cognition
Fouda AY12 Fagan SC32 Ergul A45
Changes in brain blood vessel functionstructure
Decreased blood flowimpaired removal of metabolites
White matter damage
BBB disruption
VCID
(VCIPSCI)
Neuroinflammation
Stroke
Vascular risk factors (hypertensiondiabetes) amp aging
Pathologic new vessel formation
Neurovascular remodeling
ADADRD
ADRD 2019 NIH Summit
11182019
7
Of Mice to WoMen
Translational ADRD Research
Vessel Dysfunction in Diabetes
Cortex Striatum0
50
100
150
200
250
Control (n=12)
Diabetes (n=12)
CB
F (
ml
100g
min
)
Cortex
Striatum
Diabetes
Control
Hardigan T et al Clin Sci 2016
Blood flow to the brain (CBF) is decreased in diabetes
11182019
8
Vessel Dysfunction in Diabetes
Control Diabetes0
20
40
60
(n=4) (n=4)
CB
F i
ncre
ase
( o
f b
aseli
ne)
2 10 18 26 34 42 50 58 66 74 82
-20
0
20
40
60
80
Control (n=4)
Diabetes (n=4)
Stimulation
Time (sec)
Blo
od
flo
w c
han
ge
( o
f b
aseli
ne)
Neurovascular uncoupling
Hardigan T et al Clin Sci 2016
Diabetes Amplifies Post-stroke Inflammation
Diabetes
Control
C o n tr o l D ia b e te s
0
2 0
4 0
6 0
Ce
ll B
od
y S
ize
(u
m)
C o n tr o l D ia b e te s
0
2
4
6
8
Nu
mb
er
of
Pro
tru
sio
ns
Microglia
11182019
9
Diabetes causes cognitive impairment (VCID)
RECOGNITION INDEX
0 0
0 2
0 4
0 6
0 8
1 0
C o n t r o l
D ia b e t e s ( G K r a t s )
2 5 7 1 0 1 4
c
a
ba
aa
a
D a y s a f t e r s t r o k e
Re
co
gn
itio
n i
nd
ex
B L D 1 4
0 0
0 2
0 4
0 6
0 8
d2
In
de
x
p d i a b e t e s lt 0 0 0 0 1
^ p s e x = 0 3 6 8 7
p in te r a c t io n = 0 2 9 9 9
p d i a b e t e s lt 0 0 0 0 1
^ p s e x = 0 2 8 9 2
p in te r a c t io n = 0 4 2 0 8
p lt 0 0 0 1
v s s h a m
p = 0 0 0 7
v s s h a m
Diabetes causes cognitive impairment (VCID)
11182019
10
After Before Control Diabetes + Metformin Control Diabetes
Stroke side of
the brain
0
5
10
15
Ipsilateral Contralateral
Cortex
Control Diabetes Diabetes + Metformin
Sham
p=00009
p=00019
p=00098
p=00019
p=00098
b
b
v
asc
ular
vo
lum
e
Prakash et al Stroke 2013
Diabetes
In Search of Therapies Randomized Blinded Preclinical Trial of Glucose Control
Blood sugar control
0
20
40
60
80
100
0 2 14
Control
Diabetes + MetforminDiabetes
ba
Days after stroke
o
f ti
me s
pen
t in
th
e o
pen
arm
MEMORY amp ANXIETY
(ELEVATED T-MAZE)
00
02
04
06
08
10
Control
Diabetes
Diabetes + Metformin
2 5 7 10 14
c
a
ba
aa
a
Days after stroke
Re
co
gn
itio
n i
nd
ex
MEMORY amp COGNITION
(NOVEL OBJECT RECOGNITION)
15 min delay
AA session AB session
Glucose control attenuates VCID
11182019
11
In Search of Therapies Randomized Blinded Preclinical Trial 2
Stroke Increased bleeding into brain
Death of blood vessel cells
Poor outcomesrecovery PSCI
Iron
Pathological new vessel formation
Diabetes
DFX
In Search of Therapies Randomized Blinded Preclinical Trial 2
Day 14
Ctrl DM00
02
04
06
08
$ $
NO
R i
nd
ex
DFX DFX
Diabetes Stroke Behavior Age 4w 12-14 w Day 14 Post-Stroke
Day 1-7 DFX treatment
DFX treatment has a differential effect on blood vessels in control versus diabetic rats
11182019
12
In Search of Therapies Randomized Blinded Preclinical Trial 2
Diabetes Stroke Behavior Age 4w 12-14 w Day 14 Post-Stroke
Day 1-7 DFX treatment
Day 14
Ctrl DM00
02
04
06
08
$ $
NO
R i
nd
ex
DFX DFX
DFX treatment prevents inflammation
In Search of Therapies Sex Differences
Day 14
Ctrl DM00
02
04
06
08
$
$
NO
R i
nd
ex
DFX DFX
DFX treatment reduces blood vessels in both control and diabetic rats
DFX treatment does not reduce inflammation in females
11182019
13
In Search of Therapies Randomized Blinded Preclinical Trial 3
C21
In Search of Therapies Continued
Diabetes Stroke Behavior Age (w) 4 12-14 W1-8 Post-Stroke
Delayed
Administration
Blinded amp
Randomized
Day 3
C21
11182019
14
In Search of Therapies Randomized Blinded Preclinical Trial 3
BL W1 W2 W4 W802
04
06
08
Time Post- MCAO
T
ime in
No
vel A
rm
2 Trial Ymaze
C C21C Veh
NS
BL W1 W2 W4 W800
02
04
06
08
Time Post- MCAO
T
ime in
No
vel A
rm
2 Trial Ymaze
D C21 D Veh
Interaction Plt005
In Search of Therapies Randomized Blinded Preclinical Trial 3
C21 reduces inflammation improves vascular integrity and prevents cognitive decline
11182019
15
In Search of Therapies for ADRD Of Mice to WoMen
Preclinical animal studies using comorbid disease models commonly found in patients such as diabetes and hypertension are essential to identify mechanisms underlying ADRD to develop new therapies Translational preclinical studies designed like human clinical trials can help us test the efficacy and optimize treatment strategies to modify the disease progression Improving blood vessel integrity and function can help reduce neuron degeneration and inflammation Preclinical and clinical research are integral pieces of an Alzheimerrsquos Disease Research Center (ADRC)
Of Mice to WoMen Translational Dementia Research Labs at MUSC
ERFA Vascular Neuroprotection Laboratories Adviye Ergul MD PhD ergulmuscedu Aging and Senescence Laboratories Gavin Wang MD PhD wangymuscedu Sims-Robinson Lab Metabolic Disorders Brain Aging and AD Catrine Sims-Robinson PhD robinsocmuscedu Christie Heart amp Brain Program Federica del Monte MD PhD delmontemuscedu Onder Albayram PhD albayrammuscedu Carroll A Campbell Jr Neuropathology Laboratories (Brain Bank) Steven Carroll MD PhD Eric D Hamlett PhD hamlettemuscedu
11182019
16
TEAM ERFA VASCULAR NEUROPROTECTION LABORATORIES
YOUR PARTICIPATION AND SUPPORT FOR PRECLINICAL AND CLINICAL RESEARCH IS VITAL FOR SUCCESS IN THE FIGHT AGAINST ADRD
Tell your senators and representatives to keep supporting biomedical
research
We need an Alzheimerrsquos Disease Research Center in South Carolina
THANK YOU
11182019
17
In Search of Therapies for ADRD
Reduce vascular risk factors
Blood pressure control
Blood sugar control
Blood lipid control
ExerciseHealthy Diet
New learning
11182019
3
Brain has no energy reserves
Depends on steady blood flow for proper
function
Needs on demand local blood delivery-
functional hyperemia-neurovascular
coupling
Immune trafficking ------Neuroinflammation
Neurovascular Unit
11182019
4
11182019
5
VCID spectrum disorders arise as a result of risk factors that similarly increase the risk
for cerebrovascular disease (stroke) including atrial fibrillation hypertension diabetes
and high cholesterol Forms of VCID include
bullVascular cognitive impairmentdementia
bullPost-stroke cognitive impairmentdementia (PSCI)
bullMulti-infarct dementia
bullCerebral autosomal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy (CADASIL)
bullSubcortical vascular dementia
Vascular contributions to cognitive impairment and
dementia (VCID)
COGNITION
11182019
6
Arterioscler Thromb Vasc Biol 2019 Feb 28ATVBAHA118311906 doi
101161ATVBAHA118311906 [Epub ahead of print]
Brain Vasculature and Cognition
Fouda AY12 Fagan SC32 Ergul A45
Changes in brain blood vessel functionstructure
Decreased blood flowimpaired removal of metabolites
White matter damage
BBB disruption
VCID
(VCIPSCI)
Neuroinflammation
Stroke
Vascular risk factors (hypertensiondiabetes) amp aging
Pathologic new vessel formation
Neurovascular remodeling
ADADRD
ADRD 2019 NIH Summit
11182019
7
Of Mice to WoMen
Translational ADRD Research
Vessel Dysfunction in Diabetes
Cortex Striatum0
50
100
150
200
250
Control (n=12)
Diabetes (n=12)
CB
F (
ml
100g
min
)
Cortex
Striatum
Diabetes
Control
Hardigan T et al Clin Sci 2016
Blood flow to the brain (CBF) is decreased in diabetes
11182019
8
Vessel Dysfunction in Diabetes
Control Diabetes0
20
40
60
(n=4) (n=4)
CB
F i
ncre
ase
( o
f b
aseli
ne)
2 10 18 26 34 42 50 58 66 74 82
-20
0
20
40
60
80
Control (n=4)
Diabetes (n=4)
Stimulation
Time (sec)
Blo
od
flo
w c
han
ge
( o
f b
aseli
ne)
Neurovascular uncoupling
Hardigan T et al Clin Sci 2016
Diabetes Amplifies Post-stroke Inflammation
Diabetes
Control
C o n tr o l D ia b e te s
0
2 0
4 0
6 0
Ce
ll B
od
y S
ize
(u
m)
C o n tr o l D ia b e te s
0
2
4
6
8
Nu
mb
er
of
Pro
tru
sio
ns
Microglia
11182019
9
Diabetes causes cognitive impairment (VCID)
RECOGNITION INDEX
0 0
0 2
0 4
0 6
0 8
1 0
C o n t r o l
D ia b e t e s ( G K r a t s )
2 5 7 1 0 1 4
c
a
ba
aa
a
D a y s a f t e r s t r o k e
Re
co
gn
itio
n i
nd
ex
B L D 1 4
0 0
0 2
0 4
0 6
0 8
d2
In
de
x
p d i a b e t e s lt 0 0 0 0 1
^ p s e x = 0 3 6 8 7
p in te r a c t io n = 0 2 9 9 9
p d i a b e t e s lt 0 0 0 0 1
^ p s e x = 0 2 8 9 2
p in te r a c t io n = 0 4 2 0 8
p lt 0 0 0 1
v s s h a m
p = 0 0 0 7
v s s h a m
Diabetes causes cognitive impairment (VCID)
11182019
10
After Before Control Diabetes + Metformin Control Diabetes
Stroke side of
the brain
0
5
10
15
Ipsilateral Contralateral
Cortex
Control Diabetes Diabetes + Metformin
Sham
p=00009
p=00019
p=00098
p=00019
p=00098
b
b
v
asc
ular
vo
lum
e
Prakash et al Stroke 2013
Diabetes
In Search of Therapies Randomized Blinded Preclinical Trial of Glucose Control
Blood sugar control
0
20
40
60
80
100
0 2 14
Control
Diabetes + MetforminDiabetes
ba
Days after stroke
o
f ti
me s
pen
t in
th
e o
pen
arm
MEMORY amp ANXIETY
(ELEVATED T-MAZE)
00
02
04
06
08
10
Control
Diabetes
Diabetes + Metformin
2 5 7 10 14
c
a
ba
aa
a
Days after stroke
Re
co
gn
itio
n i
nd
ex
MEMORY amp COGNITION
(NOVEL OBJECT RECOGNITION)
15 min delay
AA session AB session
Glucose control attenuates VCID
11182019
11
In Search of Therapies Randomized Blinded Preclinical Trial 2
Stroke Increased bleeding into brain
Death of blood vessel cells
Poor outcomesrecovery PSCI
Iron
Pathological new vessel formation
Diabetes
DFX
In Search of Therapies Randomized Blinded Preclinical Trial 2
Day 14
Ctrl DM00
02
04
06
08
$ $
NO
R i
nd
ex
DFX DFX
Diabetes Stroke Behavior Age 4w 12-14 w Day 14 Post-Stroke
Day 1-7 DFX treatment
DFX treatment has a differential effect on blood vessels in control versus diabetic rats
11182019
12
In Search of Therapies Randomized Blinded Preclinical Trial 2
Diabetes Stroke Behavior Age 4w 12-14 w Day 14 Post-Stroke
Day 1-7 DFX treatment
Day 14
Ctrl DM00
02
04
06
08
$ $
NO
R i
nd
ex
DFX DFX
DFX treatment prevents inflammation
In Search of Therapies Sex Differences
Day 14
Ctrl DM00
02
04
06
08
$
$
NO
R i
nd
ex
DFX DFX
DFX treatment reduces blood vessels in both control and diabetic rats
DFX treatment does not reduce inflammation in females
11182019
13
In Search of Therapies Randomized Blinded Preclinical Trial 3
C21
In Search of Therapies Continued
Diabetes Stroke Behavior Age (w) 4 12-14 W1-8 Post-Stroke
Delayed
Administration
Blinded amp
Randomized
Day 3
C21
11182019
14
In Search of Therapies Randomized Blinded Preclinical Trial 3
BL W1 W2 W4 W802
04
06
08
Time Post- MCAO
T
ime in
No
vel A
rm
2 Trial Ymaze
C C21C Veh
NS
BL W1 W2 W4 W800
02
04
06
08
Time Post- MCAO
T
ime in
No
vel A
rm
2 Trial Ymaze
D C21 D Veh
Interaction Plt005
In Search of Therapies Randomized Blinded Preclinical Trial 3
C21 reduces inflammation improves vascular integrity and prevents cognitive decline
11182019
15
In Search of Therapies for ADRD Of Mice to WoMen
Preclinical animal studies using comorbid disease models commonly found in patients such as diabetes and hypertension are essential to identify mechanisms underlying ADRD to develop new therapies Translational preclinical studies designed like human clinical trials can help us test the efficacy and optimize treatment strategies to modify the disease progression Improving blood vessel integrity and function can help reduce neuron degeneration and inflammation Preclinical and clinical research are integral pieces of an Alzheimerrsquos Disease Research Center (ADRC)
Of Mice to WoMen Translational Dementia Research Labs at MUSC
ERFA Vascular Neuroprotection Laboratories Adviye Ergul MD PhD ergulmuscedu Aging and Senescence Laboratories Gavin Wang MD PhD wangymuscedu Sims-Robinson Lab Metabolic Disorders Brain Aging and AD Catrine Sims-Robinson PhD robinsocmuscedu Christie Heart amp Brain Program Federica del Monte MD PhD delmontemuscedu Onder Albayram PhD albayrammuscedu Carroll A Campbell Jr Neuropathology Laboratories (Brain Bank) Steven Carroll MD PhD Eric D Hamlett PhD hamlettemuscedu
11182019
16
TEAM ERFA VASCULAR NEUROPROTECTION LABORATORIES
YOUR PARTICIPATION AND SUPPORT FOR PRECLINICAL AND CLINICAL RESEARCH IS VITAL FOR SUCCESS IN THE FIGHT AGAINST ADRD
Tell your senators and representatives to keep supporting biomedical
research
We need an Alzheimerrsquos Disease Research Center in South Carolina
THANK YOU
11182019
17
In Search of Therapies for ADRD
Reduce vascular risk factors
Blood pressure control
Blood sugar control
Blood lipid control
ExerciseHealthy Diet
New learning
11182019
4
11182019
5
VCID spectrum disorders arise as a result of risk factors that similarly increase the risk
for cerebrovascular disease (stroke) including atrial fibrillation hypertension diabetes
and high cholesterol Forms of VCID include
bullVascular cognitive impairmentdementia
bullPost-stroke cognitive impairmentdementia (PSCI)
bullMulti-infarct dementia
bullCerebral autosomal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy (CADASIL)
bullSubcortical vascular dementia
Vascular contributions to cognitive impairment and
dementia (VCID)
COGNITION
11182019
6
Arterioscler Thromb Vasc Biol 2019 Feb 28ATVBAHA118311906 doi
101161ATVBAHA118311906 [Epub ahead of print]
Brain Vasculature and Cognition
Fouda AY12 Fagan SC32 Ergul A45
Changes in brain blood vessel functionstructure
Decreased blood flowimpaired removal of metabolites
White matter damage
BBB disruption
VCID
(VCIPSCI)
Neuroinflammation
Stroke
Vascular risk factors (hypertensiondiabetes) amp aging
Pathologic new vessel formation
Neurovascular remodeling
ADADRD
ADRD 2019 NIH Summit
11182019
7
Of Mice to WoMen
Translational ADRD Research
Vessel Dysfunction in Diabetes
Cortex Striatum0
50
100
150
200
250
Control (n=12)
Diabetes (n=12)
CB
F (
ml
100g
min
)
Cortex
Striatum
Diabetes
Control
Hardigan T et al Clin Sci 2016
Blood flow to the brain (CBF) is decreased in diabetes
11182019
8
Vessel Dysfunction in Diabetes
Control Diabetes0
20
40
60
(n=4) (n=4)
CB
F i
ncre
ase
( o
f b
aseli
ne)
2 10 18 26 34 42 50 58 66 74 82
-20
0
20
40
60
80
Control (n=4)
Diabetes (n=4)
Stimulation
Time (sec)
Blo
od
flo
w c
han
ge
( o
f b
aseli
ne)
Neurovascular uncoupling
Hardigan T et al Clin Sci 2016
Diabetes Amplifies Post-stroke Inflammation
Diabetes
Control
C o n tr o l D ia b e te s
0
2 0
4 0
6 0
Ce
ll B
od
y S
ize
(u
m)
C o n tr o l D ia b e te s
0
2
4
6
8
Nu
mb
er
of
Pro
tru
sio
ns
Microglia
11182019
9
Diabetes causes cognitive impairment (VCID)
RECOGNITION INDEX
0 0
0 2
0 4
0 6
0 8
1 0
C o n t r o l
D ia b e t e s ( G K r a t s )
2 5 7 1 0 1 4
c
a
ba
aa
a
D a y s a f t e r s t r o k e
Re
co
gn
itio
n i
nd
ex
B L D 1 4
0 0
0 2
0 4
0 6
0 8
d2
In
de
x
p d i a b e t e s lt 0 0 0 0 1
^ p s e x = 0 3 6 8 7
p in te r a c t io n = 0 2 9 9 9
p d i a b e t e s lt 0 0 0 0 1
^ p s e x = 0 2 8 9 2
p in te r a c t io n = 0 4 2 0 8
p lt 0 0 0 1
v s s h a m
p = 0 0 0 7
v s s h a m
Diabetes causes cognitive impairment (VCID)
11182019
10
After Before Control Diabetes + Metformin Control Diabetes
Stroke side of
the brain
0
5
10
15
Ipsilateral Contralateral
Cortex
Control Diabetes Diabetes + Metformin
Sham
p=00009
p=00019
p=00098
p=00019
p=00098
b
b
v
asc
ular
vo
lum
e
Prakash et al Stroke 2013
Diabetes
In Search of Therapies Randomized Blinded Preclinical Trial of Glucose Control
Blood sugar control
0
20
40
60
80
100
0 2 14
Control
Diabetes + MetforminDiabetes
ba
Days after stroke
o
f ti
me s
pen
t in
th
e o
pen
arm
MEMORY amp ANXIETY
(ELEVATED T-MAZE)
00
02
04
06
08
10
Control
Diabetes
Diabetes + Metformin
2 5 7 10 14
c
a
ba
aa
a
Days after stroke
Re
co
gn
itio
n i
nd
ex
MEMORY amp COGNITION
(NOVEL OBJECT RECOGNITION)
15 min delay
AA session AB session
Glucose control attenuates VCID
11182019
11
In Search of Therapies Randomized Blinded Preclinical Trial 2
Stroke Increased bleeding into brain
Death of blood vessel cells
Poor outcomesrecovery PSCI
Iron
Pathological new vessel formation
Diabetes
DFX
In Search of Therapies Randomized Blinded Preclinical Trial 2
Day 14
Ctrl DM00
02
04
06
08
$ $
NO
R i
nd
ex
DFX DFX
Diabetes Stroke Behavior Age 4w 12-14 w Day 14 Post-Stroke
Day 1-7 DFX treatment
DFX treatment has a differential effect on blood vessels in control versus diabetic rats
11182019
12
In Search of Therapies Randomized Blinded Preclinical Trial 2
Diabetes Stroke Behavior Age 4w 12-14 w Day 14 Post-Stroke
Day 1-7 DFX treatment
Day 14
Ctrl DM00
02
04
06
08
$ $
NO
R i
nd
ex
DFX DFX
DFX treatment prevents inflammation
In Search of Therapies Sex Differences
Day 14
Ctrl DM00
02
04
06
08
$
$
NO
R i
nd
ex
DFX DFX
DFX treatment reduces blood vessels in both control and diabetic rats
DFX treatment does not reduce inflammation in females
11182019
13
In Search of Therapies Randomized Blinded Preclinical Trial 3
C21
In Search of Therapies Continued
Diabetes Stroke Behavior Age (w) 4 12-14 W1-8 Post-Stroke
Delayed
Administration
Blinded amp
Randomized
Day 3
C21
11182019
14
In Search of Therapies Randomized Blinded Preclinical Trial 3
BL W1 W2 W4 W802
04
06
08
Time Post- MCAO
T
ime in
No
vel A
rm
2 Trial Ymaze
C C21C Veh
NS
BL W1 W2 W4 W800
02
04
06
08
Time Post- MCAO
T
ime in
No
vel A
rm
2 Trial Ymaze
D C21 D Veh
Interaction Plt005
In Search of Therapies Randomized Blinded Preclinical Trial 3
C21 reduces inflammation improves vascular integrity and prevents cognitive decline
11182019
15
In Search of Therapies for ADRD Of Mice to WoMen
Preclinical animal studies using comorbid disease models commonly found in patients such as diabetes and hypertension are essential to identify mechanisms underlying ADRD to develop new therapies Translational preclinical studies designed like human clinical trials can help us test the efficacy and optimize treatment strategies to modify the disease progression Improving blood vessel integrity and function can help reduce neuron degeneration and inflammation Preclinical and clinical research are integral pieces of an Alzheimerrsquos Disease Research Center (ADRC)
Of Mice to WoMen Translational Dementia Research Labs at MUSC
ERFA Vascular Neuroprotection Laboratories Adviye Ergul MD PhD ergulmuscedu Aging and Senescence Laboratories Gavin Wang MD PhD wangymuscedu Sims-Robinson Lab Metabolic Disorders Brain Aging and AD Catrine Sims-Robinson PhD robinsocmuscedu Christie Heart amp Brain Program Federica del Monte MD PhD delmontemuscedu Onder Albayram PhD albayrammuscedu Carroll A Campbell Jr Neuropathology Laboratories (Brain Bank) Steven Carroll MD PhD Eric D Hamlett PhD hamlettemuscedu
11182019
16
TEAM ERFA VASCULAR NEUROPROTECTION LABORATORIES
YOUR PARTICIPATION AND SUPPORT FOR PRECLINICAL AND CLINICAL RESEARCH IS VITAL FOR SUCCESS IN THE FIGHT AGAINST ADRD
Tell your senators and representatives to keep supporting biomedical
research
We need an Alzheimerrsquos Disease Research Center in South Carolina
THANK YOU
11182019
17
In Search of Therapies for ADRD
Reduce vascular risk factors
Blood pressure control
Blood sugar control
Blood lipid control
ExerciseHealthy Diet
New learning
11182019
5
VCID spectrum disorders arise as a result of risk factors that similarly increase the risk
for cerebrovascular disease (stroke) including atrial fibrillation hypertension diabetes
and high cholesterol Forms of VCID include
bullVascular cognitive impairmentdementia
bullPost-stroke cognitive impairmentdementia (PSCI)
bullMulti-infarct dementia
bullCerebral autosomal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy (CADASIL)
bullSubcortical vascular dementia
Vascular contributions to cognitive impairment and
dementia (VCID)
COGNITION
11182019
6
Arterioscler Thromb Vasc Biol 2019 Feb 28ATVBAHA118311906 doi
101161ATVBAHA118311906 [Epub ahead of print]
Brain Vasculature and Cognition
Fouda AY12 Fagan SC32 Ergul A45
Changes in brain blood vessel functionstructure
Decreased blood flowimpaired removal of metabolites
White matter damage
BBB disruption
VCID
(VCIPSCI)
Neuroinflammation
Stroke
Vascular risk factors (hypertensiondiabetes) amp aging
Pathologic new vessel formation
Neurovascular remodeling
ADADRD
ADRD 2019 NIH Summit
11182019
7
Of Mice to WoMen
Translational ADRD Research
Vessel Dysfunction in Diabetes
Cortex Striatum0
50
100
150
200
250
Control (n=12)
Diabetes (n=12)
CB
F (
ml
100g
min
)
Cortex
Striatum
Diabetes
Control
Hardigan T et al Clin Sci 2016
Blood flow to the brain (CBF) is decreased in diabetes
11182019
8
Vessel Dysfunction in Diabetes
Control Diabetes0
20
40
60
(n=4) (n=4)
CB
F i
ncre
ase
( o
f b
aseli
ne)
2 10 18 26 34 42 50 58 66 74 82
-20
0
20
40
60
80
Control (n=4)
Diabetes (n=4)
Stimulation
Time (sec)
Blo
od
flo
w c
han
ge
( o
f b
aseli
ne)
Neurovascular uncoupling
Hardigan T et al Clin Sci 2016
Diabetes Amplifies Post-stroke Inflammation
Diabetes
Control
C o n tr o l D ia b e te s
0
2 0
4 0
6 0
Ce
ll B
od
y S
ize
(u
m)
C o n tr o l D ia b e te s
0
2
4
6
8
Nu
mb
er
of
Pro
tru
sio
ns
Microglia
11182019
9
Diabetes causes cognitive impairment (VCID)
RECOGNITION INDEX
0 0
0 2
0 4
0 6
0 8
1 0
C o n t r o l
D ia b e t e s ( G K r a t s )
2 5 7 1 0 1 4
c
a
ba
aa
a
D a y s a f t e r s t r o k e
Re
co
gn
itio
n i
nd
ex
B L D 1 4
0 0
0 2
0 4
0 6
0 8
d2
In
de
x
p d i a b e t e s lt 0 0 0 0 1
^ p s e x = 0 3 6 8 7
p in te r a c t io n = 0 2 9 9 9
p d i a b e t e s lt 0 0 0 0 1
^ p s e x = 0 2 8 9 2
p in te r a c t io n = 0 4 2 0 8
p lt 0 0 0 1
v s s h a m
p = 0 0 0 7
v s s h a m
Diabetes causes cognitive impairment (VCID)
11182019
10
After Before Control Diabetes + Metformin Control Diabetes
Stroke side of
the brain
0
5
10
15
Ipsilateral Contralateral
Cortex
Control Diabetes Diabetes + Metformin
Sham
p=00009
p=00019
p=00098
p=00019
p=00098
b
b
v
asc
ular
vo
lum
e
Prakash et al Stroke 2013
Diabetes
In Search of Therapies Randomized Blinded Preclinical Trial of Glucose Control
Blood sugar control
0
20
40
60
80
100
0 2 14
Control
Diabetes + MetforminDiabetes
ba
Days after stroke
o
f ti
me s
pen
t in
th
e o
pen
arm
MEMORY amp ANXIETY
(ELEVATED T-MAZE)
00
02
04
06
08
10
Control
Diabetes
Diabetes + Metformin
2 5 7 10 14
c
a
ba
aa
a
Days after stroke
Re
co
gn
itio
n i
nd
ex
MEMORY amp COGNITION
(NOVEL OBJECT RECOGNITION)
15 min delay
AA session AB session
Glucose control attenuates VCID
11182019
11
In Search of Therapies Randomized Blinded Preclinical Trial 2
Stroke Increased bleeding into brain
Death of blood vessel cells
Poor outcomesrecovery PSCI
Iron
Pathological new vessel formation
Diabetes
DFX
In Search of Therapies Randomized Blinded Preclinical Trial 2
Day 14
Ctrl DM00
02
04
06
08
$ $
NO
R i
nd
ex
DFX DFX
Diabetes Stroke Behavior Age 4w 12-14 w Day 14 Post-Stroke
Day 1-7 DFX treatment
DFX treatment has a differential effect on blood vessels in control versus diabetic rats
11182019
12
In Search of Therapies Randomized Blinded Preclinical Trial 2
Diabetes Stroke Behavior Age 4w 12-14 w Day 14 Post-Stroke
Day 1-7 DFX treatment
Day 14
Ctrl DM00
02
04
06
08
$ $
NO
R i
nd
ex
DFX DFX
DFX treatment prevents inflammation
In Search of Therapies Sex Differences
Day 14
Ctrl DM00
02
04
06
08
$
$
NO
R i
nd
ex
DFX DFX
DFX treatment reduces blood vessels in both control and diabetic rats
DFX treatment does not reduce inflammation in females
11182019
13
In Search of Therapies Randomized Blinded Preclinical Trial 3
C21
In Search of Therapies Continued
Diabetes Stroke Behavior Age (w) 4 12-14 W1-8 Post-Stroke
Delayed
Administration
Blinded amp
Randomized
Day 3
C21
11182019
14
In Search of Therapies Randomized Blinded Preclinical Trial 3
BL W1 W2 W4 W802
04
06
08
Time Post- MCAO
T
ime in
No
vel A
rm
2 Trial Ymaze
C C21C Veh
NS
BL W1 W2 W4 W800
02
04
06
08
Time Post- MCAO
T
ime in
No
vel A
rm
2 Trial Ymaze
D C21 D Veh
Interaction Plt005
In Search of Therapies Randomized Blinded Preclinical Trial 3
C21 reduces inflammation improves vascular integrity and prevents cognitive decline
11182019
15
In Search of Therapies for ADRD Of Mice to WoMen
Preclinical animal studies using comorbid disease models commonly found in patients such as diabetes and hypertension are essential to identify mechanisms underlying ADRD to develop new therapies Translational preclinical studies designed like human clinical trials can help us test the efficacy and optimize treatment strategies to modify the disease progression Improving blood vessel integrity and function can help reduce neuron degeneration and inflammation Preclinical and clinical research are integral pieces of an Alzheimerrsquos Disease Research Center (ADRC)
Of Mice to WoMen Translational Dementia Research Labs at MUSC
ERFA Vascular Neuroprotection Laboratories Adviye Ergul MD PhD ergulmuscedu Aging and Senescence Laboratories Gavin Wang MD PhD wangymuscedu Sims-Robinson Lab Metabolic Disorders Brain Aging and AD Catrine Sims-Robinson PhD robinsocmuscedu Christie Heart amp Brain Program Federica del Monte MD PhD delmontemuscedu Onder Albayram PhD albayrammuscedu Carroll A Campbell Jr Neuropathology Laboratories (Brain Bank) Steven Carroll MD PhD Eric D Hamlett PhD hamlettemuscedu
11182019
16
TEAM ERFA VASCULAR NEUROPROTECTION LABORATORIES
YOUR PARTICIPATION AND SUPPORT FOR PRECLINICAL AND CLINICAL RESEARCH IS VITAL FOR SUCCESS IN THE FIGHT AGAINST ADRD
Tell your senators and representatives to keep supporting biomedical
research
We need an Alzheimerrsquos Disease Research Center in South Carolina
THANK YOU
11182019
17
In Search of Therapies for ADRD
Reduce vascular risk factors
Blood pressure control
Blood sugar control
Blood lipid control
ExerciseHealthy Diet
New learning
11182019
6
Arterioscler Thromb Vasc Biol 2019 Feb 28ATVBAHA118311906 doi
101161ATVBAHA118311906 [Epub ahead of print]
Brain Vasculature and Cognition
Fouda AY12 Fagan SC32 Ergul A45
Changes in brain blood vessel functionstructure
Decreased blood flowimpaired removal of metabolites
White matter damage
BBB disruption
VCID
(VCIPSCI)
Neuroinflammation
Stroke
Vascular risk factors (hypertensiondiabetes) amp aging
Pathologic new vessel formation
Neurovascular remodeling
ADADRD
ADRD 2019 NIH Summit
11182019
7
Of Mice to WoMen
Translational ADRD Research
Vessel Dysfunction in Diabetes
Cortex Striatum0
50
100
150
200
250
Control (n=12)
Diabetes (n=12)
CB
F (
ml
100g
min
)
Cortex
Striatum
Diabetes
Control
Hardigan T et al Clin Sci 2016
Blood flow to the brain (CBF) is decreased in diabetes
11182019
8
Vessel Dysfunction in Diabetes
Control Diabetes0
20
40
60
(n=4) (n=4)
CB
F i
ncre
ase
( o
f b
aseli
ne)
2 10 18 26 34 42 50 58 66 74 82
-20
0
20
40
60
80
Control (n=4)
Diabetes (n=4)
Stimulation
Time (sec)
Blo
od
flo
w c
han
ge
( o
f b
aseli
ne)
Neurovascular uncoupling
Hardigan T et al Clin Sci 2016
Diabetes Amplifies Post-stroke Inflammation
Diabetes
Control
C o n tr o l D ia b e te s
0
2 0
4 0
6 0
Ce
ll B
od
y S
ize
(u
m)
C o n tr o l D ia b e te s
0
2
4
6
8
Nu
mb
er
of
Pro
tru
sio
ns
Microglia
11182019
9
Diabetes causes cognitive impairment (VCID)
RECOGNITION INDEX
0 0
0 2
0 4
0 6
0 8
1 0
C o n t r o l
D ia b e t e s ( G K r a t s )
2 5 7 1 0 1 4
c
a
ba
aa
a
D a y s a f t e r s t r o k e
Re
co
gn
itio
n i
nd
ex
B L D 1 4
0 0
0 2
0 4
0 6
0 8
d2
In
de
x
p d i a b e t e s lt 0 0 0 0 1
^ p s e x = 0 3 6 8 7
p in te r a c t io n = 0 2 9 9 9
p d i a b e t e s lt 0 0 0 0 1
^ p s e x = 0 2 8 9 2
p in te r a c t io n = 0 4 2 0 8
p lt 0 0 0 1
v s s h a m
p = 0 0 0 7
v s s h a m
Diabetes causes cognitive impairment (VCID)
11182019
10
After Before Control Diabetes + Metformin Control Diabetes
Stroke side of
the brain
0
5
10
15
Ipsilateral Contralateral
Cortex
Control Diabetes Diabetes + Metformin
Sham
p=00009
p=00019
p=00098
p=00019
p=00098
b
b
v
asc
ular
vo
lum
e
Prakash et al Stroke 2013
Diabetes
In Search of Therapies Randomized Blinded Preclinical Trial of Glucose Control
Blood sugar control
0
20
40
60
80
100
0 2 14
Control
Diabetes + MetforminDiabetes
ba
Days after stroke
o
f ti
me s
pen
t in
th
e o
pen
arm
MEMORY amp ANXIETY
(ELEVATED T-MAZE)
00
02
04
06
08
10
Control
Diabetes
Diabetes + Metformin
2 5 7 10 14
c
a
ba
aa
a
Days after stroke
Re
co
gn
itio
n i
nd
ex
MEMORY amp COGNITION
(NOVEL OBJECT RECOGNITION)
15 min delay
AA session AB session
Glucose control attenuates VCID
11182019
11
In Search of Therapies Randomized Blinded Preclinical Trial 2
Stroke Increased bleeding into brain
Death of blood vessel cells
Poor outcomesrecovery PSCI
Iron
Pathological new vessel formation
Diabetes
DFX
In Search of Therapies Randomized Blinded Preclinical Trial 2
Day 14
Ctrl DM00
02
04
06
08
$ $
NO
R i
nd
ex
DFX DFX
Diabetes Stroke Behavior Age 4w 12-14 w Day 14 Post-Stroke
Day 1-7 DFX treatment
DFX treatment has a differential effect on blood vessels in control versus diabetic rats
11182019
12
In Search of Therapies Randomized Blinded Preclinical Trial 2
Diabetes Stroke Behavior Age 4w 12-14 w Day 14 Post-Stroke
Day 1-7 DFX treatment
Day 14
Ctrl DM00
02
04
06
08
$ $
NO
R i
nd
ex
DFX DFX
DFX treatment prevents inflammation
In Search of Therapies Sex Differences
Day 14
Ctrl DM00
02
04
06
08
$
$
NO
R i
nd
ex
DFX DFX
DFX treatment reduces blood vessels in both control and diabetic rats
DFX treatment does not reduce inflammation in females
11182019
13
In Search of Therapies Randomized Blinded Preclinical Trial 3
C21
In Search of Therapies Continued
Diabetes Stroke Behavior Age (w) 4 12-14 W1-8 Post-Stroke
Delayed
Administration
Blinded amp
Randomized
Day 3
C21
11182019
14
In Search of Therapies Randomized Blinded Preclinical Trial 3
BL W1 W2 W4 W802
04
06
08
Time Post- MCAO
T
ime in
No
vel A
rm
2 Trial Ymaze
C C21C Veh
NS
BL W1 W2 W4 W800
02
04
06
08
Time Post- MCAO
T
ime in
No
vel A
rm
2 Trial Ymaze
D C21 D Veh
Interaction Plt005
In Search of Therapies Randomized Blinded Preclinical Trial 3
C21 reduces inflammation improves vascular integrity and prevents cognitive decline
11182019
15
In Search of Therapies for ADRD Of Mice to WoMen
Preclinical animal studies using comorbid disease models commonly found in patients such as diabetes and hypertension are essential to identify mechanisms underlying ADRD to develop new therapies Translational preclinical studies designed like human clinical trials can help us test the efficacy and optimize treatment strategies to modify the disease progression Improving blood vessel integrity and function can help reduce neuron degeneration and inflammation Preclinical and clinical research are integral pieces of an Alzheimerrsquos Disease Research Center (ADRC)
Of Mice to WoMen Translational Dementia Research Labs at MUSC
ERFA Vascular Neuroprotection Laboratories Adviye Ergul MD PhD ergulmuscedu Aging and Senescence Laboratories Gavin Wang MD PhD wangymuscedu Sims-Robinson Lab Metabolic Disorders Brain Aging and AD Catrine Sims-Robinson PhD robinsocmuscedu Christie Heart amp Brain Program Federica del Monte MD PhD delmontemuscedu Onder Albayram PhD albayrammuscedu Carroll A Campbell Jr Neuropathology Laboratories (Brain Bank) Steven Carroll MD PhD Eric D Hamlett PhD hamlettemuscedu
11182019
16
TEAM ERFA VASCULAR NEUROPROTECTION LABORATORIES
YOUR PARTICIPATION AND SUPPORT FOR PRECLINICAL AND CLINICAL RESEARCH IS VITAL FOR SUCCESS IN THE FIGHT AGAINST ADRD
Tell your senators and representatives to keep supporting biomedical
research
We need an Alzheimerrsquos Disease Research Center in South Carolina
THANK YOU
11182019
17
In Search of Therapies for ADRD
Reduce vascular risk factors
Blood pressure control
Blood sugar control
Blood lipid control
ExerciseHealthy Diet
New learning
11182019
7
Of Mice to WoMen
Translational ADRD Research
Vessel Dysfunction in Diabetes
Cortex Striatum0
50
100
150
200
250
Control (n=12)
Diabetes (n=12)
CB
F (
ml
100g
min
)
Cortex
Striatum
Diabetes
Control
Hardigan T et al Clin Sci 2016
Blood flow to the brain (CBF) is decreased in diabetes
11182019
8
Vessel Dysfunction in Diabetes
Control Diabetes0
20
40
60
(n=4) (n=4)
CB
F i
ncre
ase
( o
f b
aseli
ne)
2 10 18 26 34 42 50 58 66 74 82
-20
0
20
40
60
80
Control (n=4)
Diabetes (n=4)
Stimulation
Time (sec)
Blo
od
flo
w c
han
ge
( o
f b
aseli
ne)
Neurovascular uncoupling
Hardigan T et al Clin Sci 2016
Diabetes Amplifies Post-stroke Inflammation
Diabetes
Control
C o n tr o l D ia b e te s
0
2 0
4 0
6 0
Ce
ll B
od
y S
ize
(u
m)
C o n tr o l D ia b e te s
0
2
4
6
8
Nu
mb
er
of
Pro
tru
sio
ns
Microglia
11182019
9
Diabetes causes cognitive impairment (VCID)
RECOGNITION INDEX
0 0
0 2
0 4
0 6
0 8
1 0
C o n t r o l
D ia b e t e s ( G K r a t s )
2 5 7 1 0 1 4
c
a
ba
aa
a
D a y s a f t e r s t r o k e
Re
co
gn
itio
n i
nd
ex
B L D 1 4
0 0
0 2
0 4
0 6
0 8
d2
In
de
x
p d i a b e t e s lt 0 0 0 0 1
^ p s e x = 0 3 6 8 7
p in te r a c t io n = 0 2 9 9 9
p d i a b e t e s lt 0 0 0 0 1
^ p s e x = 0 2 8 9 2
p in te r a c t io n = 0 4 2 0 8
p lt 0 0 0 1
v s s h a m
p = 0 0 0 7
v s s h a m
Diabetes causes cognitive impairment (VCID)
11182019
10
After Before Control Diabetes + Metformin Control Diabetes
Stroke side of
the brain
0
5
10
15
Ipsilateral Contralateral
Cortex
Control Diabetes Diabetes + Metformin
Sham
p=00009
p=00019
p=00098
p=00019
p=00098
b
b
v
asc
ular
vo
lum
e
Prakash et al Stroke 2013
Diabetes
In Search of Therapies Randomized Blinded Preclinical Trial of Glucose Control
Blood sugar control
0
20
40
60
80
100
0 2 14
Control
Diabetes + MetforminDiabetes
ba
Days after stroke
o
f ti
me s
pen
t in
th
e o
pen
arm
MEMORY amp ANXIETY
(ELEVATED T-MAZE)
00
02
04
06
08
10
Control
Diabetes
Diabetes + Metformin
2 5 7 10 14
c
a
ba
aa
a
Days after stroke
Re
co
gn
itio
n i
nd
ex
MEMORY amp COGNITION
(NOVEL OBJECT RECOGNITION)
15 min delay
AA session AB session
Glucose control attenuates VCID
11182019
11
In Search of Therapies Randomized Blinded Preclinical Trial 2
Stroke Increased bleeding into brain
Death of blood vessel cells
Poor outcomesrecovery PSCI
Iron
Pathological new vessel formation
Diabetes
DFX
In Search of Therapies Randomized Blinded Preclinical Trial 2
Day 14
Ctrl DM00
02
04
06
08
$ $
NO
R i
nd
ex
DFX DFX
Diabetes Stroke Behavior Age 4w 12-14 w Day 14 Post-Stroke
Day 1-7 DFX treatment
DFX treatment has a differential effect on blood vessels in control versus diabetic rats
11182019
12
In Search of Therapies Randomized Blinded Preclinical Trial 2
Diabetes Stroke Behavior Age 4w 12-14 w Day 14 Post-Stroke
Day 1-7 DFX treatment
Day 14
Ctrl DM00
02
04
06
08
$ $
NO
R i
nd
ex
DFX DFX
DFX treatment prevents inflammation
In Search of Therapies Sex Differences
Day 14
Ctrl DM00
02
04
06
08
$
$
NO
R i
nd
ex
DFX DFX
DFX treatment reduces blood vessels in both control and diabetic rats
DFX treatment does not reduce inflammation in females
11182019
13
In Search of Therapies Randomized Blinded Preclinical Trial 3
C21
In Search of Therapies Continued
Diabetes Stroke Behavior Age (w) 4 12-14 W1-8 Post-Stroke
Delayed
Administration
Blinded amp
Randomized
Day 3
C21
11182019
14
In Search of Therapies Randomized Blinded Preclinical Trial 3
BL W1 W2 W4 W802
04
06
08
Time Post- MCAO
T
ime in
No
vel A
rm
2 Trial Ymaze
C C21C Veh
NS
BL W1 W2 W4 W800
02
04
06
08
Time Post- MCAO
T
ime in
No
vel A
rm
2 Trial Ymaze
D C21 D Veh
Interaction Plt005
In Search of Therapies Randomized Blinded Preclinical Trial 3
C21 reduces inflammation improves vascular integrity and prevents cognitive decline
11182019
15
In Search of Therapies for ADRD Of Mice to WoMen
Preclinical animal studies using comorbid disease models commonly found in patients such as diabetes and hypertension are essential to identify mechanisms underlying ADRD to develop new therapies Translational preclinical studies designed like human clinical trials can help us test the efficacy and optimize treatment strategies to modify the disease progression Improving blood vessel integrity and function can help reduce neuron degeneration and inflammation Preclinical and clinical research are integral pieces of an Alzheimerrsquos Disease Research Center (ADRC)
Of Mice to WoMen Translational Dementia Research Labs at MUSC
ERFA Vascular Neuroprotection Laboratories Adviye Ergul MD PhD ergulmuscedu Aging and Senescence Laboratories Gavin Wang MD PhD wangymuscedu Sims-Robinson Lab Metabolic Disorders Brain Aging and AD Catrine Sims-Robinson PhD robinsocmuscedu Christie Heart amp Brain Program Federica del Monte MD PhD delmontemuscedu Onder Albayram PhD albayrammuscedu Carroll A Campbell Jr Neuropathology Laboratories (Brain Bank) Steven Carroll MD PhD Eric D Hamlett PhD hamlettemuscedu
11182019
16
TEAM ERFA VASCULAR NEUROPROTECTION LABORATORIES
YOUR PARTICIPATION AND SUPPORT FOR PRECLINICAL AND CLINICAL RESEARCH IS VITAL FOR SUCCESS IN THE FIGHT AGAINST ADRD
Tell your senators and representatives to keep supporting biomedical
research
We need an Alzheimerrsquos Disease Research Center in South Carolina
THANK YOU
11182019
17
In Search of Therapies for ADRD
Reduce vascular risk factors
Blood pressure control
Blood sugar control
Blood lipid control
ExerciseHealthy Diet
New learning
11182019
8
Vessel Dysfunction in Diabetes
Control Diabetes0
20
40
60
(n=4) (n=4)
CB
F i
ncre
ase
( o
f b
aseli
ne)
2 10 18 26 34 42 50 58 66 74 82
-20
0
20
40
60
80
Control (n=4)
Diabetes (n=4)
Stimulation
Time (sec)
Blo
od
flo
w c
han
ge
( o
f b
aseli
ne)
Neurovascular uncoupling
Hardigan T et al Clin Sci 2016
Diabetes Amplifies Post-stroke Inflammation
Diabetes
Control
C o n tr o l D ia b e te s
0
2 0
4 0
6 0
Ce
ll B
od
y S
ize
(u
m)
C o n tr o l D ia b e te s
0
2
4
6
8
Nu
mb
er
of
Pro
tru
sio
ns
Microglia
11182019
9
Diabetes causes cognitive impairment (VCID)
RECOGNITION INDEX
0 0
0 2
0 4
0 6
0 8
1 0
C o n t r o l
D ia b e t e s ( G K r a t s )
2 5 7 1 0 1 4
c
a
ba
aa
a
D a y s a f t e r s t r o k e
Re
co
gn
itio
n i
nd
ex
B L D 1 4
0 0
0 2
0 4
0 6
0 8
d2
In
de
x
p d i a b e t e s lt 0 0 0 0 1
^ p s e x = 0 3 6 8 7
p in te r a c t io n = 0 2 9 9 9
p d i a b e t e s lt 0 0 0 0 1
^ p s e x = 0 2 8 9 2
p in te r a c t io n = 0 4 2 0 8
p lt 0 0 0 1
v s s h a m
p = 0 0 0 7
v s s h a m
Diabetes causes cognitive impairment (VCID)
11182019
10
After Before Control Diabetes + Metformin Control Diabetes
Stroke side of
the brain
0
5
10
15
Ipsilateral Contralateral
Cortex
Control Diabetes Diabetes + Metformin
Sham
p=00009
p=00019
p=00098
p=00019
p=00098
b
b
v
asc
ular
vo
lum
e
Prakash et al Stroke 2013
Diabetes
In Search of Therapies Randomized Blinded Preclinical Trial of Glucose Control
Blood sugar control
0
20
40
60
80
100
0 2 14
Control
Diabetes + MetforminDiabetes
ba
Days after stroke
o
f ti
me s
pen
t in
th
e o
pen
arm
MEMORY amp ANXIETY
(ELEVATED T-MAZE)
00
02
04
06
08
10
Control
Diabetes
Diabetes + Metformin
2 5 7 10 14
c
a
ba
aa
a
Days after stroke
Re
co
gn
itio
n i
nd
ex
MEMORY amp COGNITION
(NOVEL OBJECT RECOGNITION)
15 min delay
AA session AB session
Glucose control attenuates VCID
11182019
11
In Search of Therapies Randomized Blinded Preclinical Trial 2
Stroke Increased bleeding into brain
Death of blood vessel cells
Poor outcomesrecovery PSCI
Iron
Pathological new vessel formation
Diabetes
DFX
In Search of Therapies Randomized Blinded Preclinical Trial 2
Day 14
Ctrl DM00
02
04
06
08
$ $
NO
R i
nd
ex
DFX DFX
Diabetes Stroke Behavior Age 4w 12-14 w Day 14 Post-Stroke
Day 1-7 DFX treatment
DFX treatment has a differential effect on blood vessels in control versus diabetic rats
11182019
12
In Search of Therapies Randomized Blinded Preclinical Trial 2
Diabetes Stroke Behavior Age 4w 12-14 w Day 14 Post-Stroke
Day 1-7 DFX treatment
Day 14
Ctrl DM00
02
04
06
08
$ $
NO
R i
nd
ex
DFX DFX
DFX treatment prevents inflammation
In Search of Therapies Sex Differences
Day 14
Ctrl DM00
02
04
06
08
$
$
NO
R i
nd
ex
DFX DFX
DFX treatment reduces blood vessels in both control and diabetic rats
DFX treatment does not reduce inflammation in females
11182019
13
In Search of Therapies Randomized Blinded Preclinical Trial 3
C21
In Search of Therapies Continued
Diabetes Stroke Behavior Age (w) 4 12-14 W1-8 Post-Stroke
Delayed
Administration
Blinded amp
Randomized
Day 3
C21
11182019
14
In Search of Therapies Randomized Blinded Preclinical Trial 3
BL W1 W2 W4 W802
04
06
08
Time Post- MCAO
T
ime in
No
vel A
rm
2 Trial Ymaze
C C21C Veh
NS
BL W1 W2 W4 W800
02
04
06
08
Time Post- MCAO
T
ime in
No
vel A
rm
2 Trial Ymaze
D C21 D Veh
Interaction Plt005
In Search of Therapies Randomized Blinded Preclinical Trial 3
C21 reduces inflammation improves vascular integrity and prevents cognitive decline
11182019
15
In Search of Therapies for ADRD Of Mice to WoMen
Preclinical animal studies using comorbid disease models commonly found in patients such as diabetes and hypertension are essential to identify mechanisms underlying ADRD to develop new therapies Translational preclinical studies designed like human clinical trials can help us test the efficacy and optimize treatment strategies to modify the disease progression Improving blood vessel integrity and function can help reduce neuron degeneration and inflammation Preclinical and clinical research are integral pieces of an Alzheimerrsquos Disease Research Center (ADRC)
Of Mice to WoMen Translational Dementia Research Labs at MUSC
ERFA Vascular Neuroprotection Laboratories Adviye Ergul MD PhD ergulmuscedu Aging and Senescence Laboratories Gavin Wang MD PhD wangymuscedu Sims-Robinson Lab Metabolic Disorders Brain Aging and AD Catrine Sims-Robinson PhD robinsocmuscedu Christie Heart amp Brain Program Federica del Monte MD PhD delmontemuscedu Onder Albayram PhD albayrammuscedu Carroll A Campbell Jr Neuropathology Laboratories (Brain Bank) Steven Carroll MD PhD Eric D Hamlett PhD hamlettemuscedu
11182019
16
TEAM ERFA VASCULAR NEUROPROTECTION LABORATORIES
YOUR PARTICIPATION AND SUPPORT FOR PRECLINICAL AND CLINICAL RESEARCH IS VITAL FOR SUCCESS IN THE FIGHT AGAINST ADRD
Tell your senators and representatives to keep supporting biomedical
research
We need an Alzheimerrsquos Disease Research Center in South Carolina
THANK YOU
11182019
17
In Search of Therapies for ADRD
Reduce vascular risk factors
Blood pressure control
Blood sugar control
Blood lipid control
ExerciseHealthy Diet
New learning
11182019
9
Diabetes causes cognitive impairment (VCID)
RECOGNITION INDEX
0 0
0 2
0 4
0 6
0 8
1 0
C o n t r o l
D ia b e t e s ( G K r a t s )
2 5 7 1 0 1 4
c
a
ba
aa
a
D a y s a f t e r s t r o k e
Re
co
gn
itio
n i
nd
ex
B L D 1 4
0 0
0 2
0 4
0 6
0 8
d2
In
de
x
p d i a b e t e s lt 0 0 0 0 1
^ p s e x = 0 3 6 8 7
p in te r a c t io n = 0 2 9 9 9
p d i a b e t e s lt 0 0 0 0 1
^ p s e x = 0 2 8 9 2
p in te r a c t io n = 0 4 2 0 8
p lt 0 0 0 1
v s s h a m
p = 0 0 0 7
v s s h a m
Diabetes causes cognitive impairment (VCID)
11182019
10
After Before Control Diabetes + Metformin Control Diabetes
Stroke side of
the brain
0
5
10
15
Ipsilateral Contralateral
Cortex
Control Diabetes Diabetes + Metformin
Sham
p=00009
p=00019
p=00098
p=00019
p=00098
b
b
v
asc
ular
vo
lum
e
Prakash et al Stroke 2013
Diabetes
In Search of Therapies Randomized Blinded Preclinical Trial of Glucose Control
Blood sugar control
0
20
40
60
80
100
0 2 14
Control
Diabetes + MetforminDiabetes
ba
Days after stroke
o
f ti
me s
pen
t in
th
e o
pen
arm
MEMORY amp ANXIETY
(ELEVATED T-MAZE)
00
02
04
06
08
10
Control
Diabetes
Diabetes + Metformin
2 5 7 10 14
c
a
ba
aa
a
Days after stroke
Re
co
gn
itio
n i
nd
ex
MEMORY amp COGNITION
(NOVEL OBJECT RECOGNITION)
15 min delay
AA session AB session
Glucose control attenuates VCID
11182019
11
In Search of Therapies Randomized Blinded Preclinical Trial 2
Stroke Increased bleeding into brain
Death of blood vessel cells
Poor outcomesrecovery PSCI
Iron
Pathological new vessel formation
Diabetes
DFX
In Search of Therapies Randomized Blinded Preclinical Trial 2
Day 14
Ctrl DM00
02
04
06
08
$ $
NO
R i
nd
ex
DFX DFX
Diabetes Stroke Behavior Age 4w 12-14 w Day 14 Post-Stroke
Day 1-7 DFX treatment
DFX treatment has a differential effect on blood vessels in control versus diabetic rats
11182019
12
In Search of Therapies Randomized Blinded Preclinical Trial 2
Diabetes Stroke Behavior Age 4w 12-14 w Day 14 Post-Stroke
Day 1-7 DFX treatment
Day 14
Ctrl DM00
02
04
06
08
$ $
NO
R i
nd
ex
DFX DFX
DFX treatment prevents inflammation
In Search of Therapies Sex Differences
Day 14
Ctrl DM00
02
04
06
08
$
$
NO
R i
nd
ex
DFX DFX
DFX treatment reduces blood vessels in both control and diabetic rats
DFX treatment does not reduce inflammation in females
11182019
13
In Search of Therapies Randomized Blinded Preclinical Trial 3
C21
In Search of Therapies Continued
Diabetes Stroke Behavior Age (w) 4 12-14 W1-8 Post-Stroke
Delayed
Administration
Blinded amp
Randomized
Day 3
C21
11182019
14
In Search of Therapies Randomized Blinded Preclinical Trial 3
BL W1 W2 W4 W802
04
06
08
Time Post- MCAO
T
ime in
No
vel A
rm
2 Trial Ymaze
C C21C Veh
NS
BL W1 W2 W4 W800
02
04
06
08
Time Post- MCAO
T
ime in
No
vel A
rm
2 Trial Ymaze
D C21 D Veh
Interaction Plt005
In Search of Therapies Randomized Blinded Preclinical Trial 3
C21 reduces inflammation improves vascular integrity and prevents cognitive decline
11182019
15
In Search of Therapies for ADRD Of Mice to WoMen
Preclinical animal studies using comorbid disease models commonly found in patients such as diabetes and hypertension are essential to identify mechanisms underlying ADRD to develop new therapies Translational preclinical studies designed like human clinical trials can help us test the efficacy and optimize treatment strategies to modify the disease progression Improving blood vessel integrity and function can help reduce neuron degeneration and inflammation Preclinical and clinical research are integral pieces of an Alzheimerrsquos Disease Research Center (ADRC)
Of Mice to WoMen Translational Dementia Research Labs at MUSC
ERFA Vascular Neuroprotection Laboratories Adviye Ergul MD PhD ergulmuscedu Aging and Senescence Laboratories Gavin Wang MD PhD wangymuscedu Sims-Robinson Lab Metabolic Disorders Brain Aging and AD Catrine Sims-Robinson PhD robinsocmuscedu Christie Heart amp Brain Program Federica del Monte MD PhD delmontemuscedu Onder Albayram PhD albayrammuscedu Carroll A Campbell Jr Neuropathology Laboratories (Brain Bank) Steven Carroll MD PhD Eric D Hamlett PhD hamlettemuscedu
11182019
16
TEAM ERFA VASCULAR NEUROPROTECTION LABORATORIES
YOUR PARTICIPATION AND SUPPORT FOR PRECLINICAL AND CLINICAL RESEARCH IS VITAL FOR SUCCESS IN THE FIGHT AGAINST ADRD
Tell your senators and representatives to keep supporting biomedical
research
We need an Alzheimerrsquos Disease Research Center in South Carolina
THANK YOU
11182019
17
In Search of Therapies for ADRD
Reduce vascular risk factors
Blood pressure control
Blood sugar control
Blood lipid control
ExerciseHealthy Diet
New learning
11182019
10
After Before Control Diabetes + Metformin Control Diabetes
Stroke side of
the brain
0
5
10
15
Ipsilateral Contralateral
Cortex
Control Diabetes Diabetes + Metformin
Sham
p=00009
p=00019
p=00098
p=00019
p=00098
b
b
v
asc
ular
vo
lum
e
Prakash et al Stroke 2013
Diabetes
In Search of Therapies Randomized Blinded Preclinical Trial of Glucose Control
Blood sugar control
0
20
40
60
80
100
0 2 14
Control
Diabetes + MetforminDiabetes
ba
Days after stroke
o
f ti
me s
pen
t in
th
e o
pen
arm
MEMORY amp ANXIETY
(ELEVATED T-MAZE)
00
02
04
06
08
10
Control
Diabetes
Diabetes + Metformin
2 5 7 10 14
c
a
ba
aa
a
Days after stroke
Re
co
gn
itio
n i
nd
ex
MEMORY amp COGNITION
(NOVEL OBJECT RECOGNITION)
15 min delay
AA session AB session
Glucose control attenuates VCID
11182019
11
In Search of Therapies Randomized Blinded Preclinical Trial 2
Stroke Increased bleeding into brain
Death of blood vessel cells
Poor outcomesrecovery PSCI
Iron
Pathological new vessel formation
Diabetes
DFX
In Search of Therapies Randomized Blinded Preclinical Trial 2
Day 14
Ctrl DM00
02
04
06
08
$ $
NO
R i
nd
ex
DFX DFX
Diabetes Stroke Behavior Age 4w 12-14 w Day 14 Post-Stroke
Day 1-7 DFX treatment
DFX treatment has a differential effect on blood vessels in control versus diabetic rats
11182019
12
In Search of Therapies Randomized Blinded Preclinical Trial 2
Diabetes Stroke Behavior Age 4w 12-14 w Day 14 Post-Stroke
Day 1-7 DFX treatment
Day 14
Ctrl DM00
02
04
06
08
$ $
NO
R i
nd
ex
DFX DFX
DFX treatment prevents inflammation
In Search of Therapies Sex Differences
Day 14
Ctrl DM00
02
04
06
08
$
$
NO
R i
nd
ex
DFX DFX
DFX treatment reduces blood vessels in both control and diabetic rats
DFX treatment does not reduce inflammation in females
11182019
13
In Search of Therapies Randomized Blinded Preclinical Trial 3
C21
In Search of Therapies Continued
Diabetes Stroke Behavior Age (w) 4 12-14 W1-8 Post-Stroke
Delayed
Administration
Blinded amp
Randomized
Day 3
C21
11182019
14
In Search of Therapies Randomized Blinded Preclinical Trial 3
BL W1 W2 W4 W802
04
06
08
Time Post- MCAO
T
ime in
No
vel A
rm
2 Trial Ymaze
C C21C Veh
NS
BL W1 W2 W4 W800
02
04
06
08
Time Post- MCAO
T
ime in
No
vel A
rm
2 Trial Ymaze
D C21 D Veh
Interaction Plt005
In Search of Therapies Randomized Blinded Preclinical Trial 3
C21 reduces inflammation improves vascular integrity and prevents cognitive decline
11182019
15
In Search of Therapies for ADRD Of Mice to WoMen
Preclinical animal studies using comorbid disease models commonly found in patients such as diabetes and hypertension are essential to identify mechanisms underlying ADRD to develop new therapies Translational preclinical studies designed like human clinical trials can help us test the efficacy and optimize treatment strategies to modify the disease progression Improving blood vessel integrity and function can help reduce neuron degeneration and inflammation Preclinical and clinical research are integral pieces of an Alzheimerrsquos Disease Research Center (ADRC)
Of Mice to WoMen Translational Dementia Research Labs at MUSC
ERFA Vascular Neuroprotection Laboratories Adviye Ergul MD PhD ergulmuscedu Aging and Senescence Laboratories Gavin Wang MD PhD wangymuscedu Sims-Robinson Lab Metabolic Disorders Brain Aging and AD Catrine Sims-Robinson PhD robinsocmuscedu Christie Heart amp Brain Program Federica del Monte MD PhD delmontemuscedu Onder Albayram PhD albayrammuscedu Carroll A Campbell Jr Neuropathology Laboratories (Brain Bank) Steven Carroll MD PhD Eric D Hamlett PhD hamlettemuscedu
11182019
16
TEAM ERFA VASCULAR NEUROPROTECTION LABORATORIES
YOUR PARTICIPATION AND SUPPORT FOR PRECLINICAL AND CLINICAL RESEARCH IS VITAL FOR SUCCESS IN THE FIGHT AGAINST ADRD
Tell your senators and representatives to keep supporting biomedical
research
We need an Alzheimerrsquos Disease Research Center in South Carolina
THANK YOU
11182019
17
In Search of Therapies for ADRD
Reduce vascular risk factors
Blood pressure control
Blood sugar control
Blood lipid control
ExerciseHealthy Diet
New learning
11182019
11
In Search of Therapies Randomized Blinded Preclinical Trial 2
Stroke Increased bleeding into brain
Death of blood vessel cells
Poor outcomesrecovery PSCI
Iron
Pathological new vessel formation
Diabetes
DFX
In Search of Therapies Randomized Blinded Preclinical Trial 2
Day 14
Ctrl DM00
02
04
06
08
$ $
NO
R i
nd
ex
DFX DFX
Diabetes Stroke Behavior Age 4w 12-14 w Day 14 Post-Stroke
Day 1-7 DFX treatment
DFX treatment has a differential effect on blood vessels in control versus diabetic rats
11182019
12
In Search of Therapies Randomized Blinded Preclinical Trial 2
Diabetes Stroke Behavior Age 4w 12-14 w Day 14 Post-Stroke
Day 1-7 DFX treatment
Day 14
Ctrl DM00
02
04
06
08
$ $
NO
R i
nd
ex
DFX DFX
DFX treatment prevents inflammation
In Search of Therapies Sex Differences
Day 14
Ctrl DM00
02
04
06
08
$
$
NO
R i
nd
ex
DFX DFX
DFX treatment reduces blood vessels in both control and diabetic rats
DFX treatment does not reduce inflammation in females
11182019
13
In Search of Therapies Randomized Blinded Preclinical Trial 3
C21
In Search of Therapies Continued
Diabetes Stroke Behavior Age (w) 4 12-14 W1-8 Post-Stroke
Delayed
Administration
Blinded amp
Randomized
Day 3
C21
11182019
14
In Search of Therapies Randomized Blinded Preclinical Trial 3
BL W1 W2 W4 W802
04
06
08
Time Post- MCAO
T
ime in
No
vel A
rm
2 Trial Ymaze
C C21C Veh
NS
BL W1 W2 W4 W800
02
04
06
08
Time Post- MCAO
T
ime in
No
vel A
rm
2 Trial Ymaze
D C21 D Veh
Interaction Plt005
In Search of Therapies Randomized Blinded Preclinical Trial 3
C21 reduces inflammation improves vascular integrity and prevents cognitive decline
11182019
15
In Search of Therapies for ADRD Of Mice to WoMen
Preclinical animal studies using comorbid disease models commonly found in patients such as diabetes and hypertension are essential to identify mechanisms underlying ADRD to develop new therapies Translational preclinical studies designed like human clinical trials can help us test the efficacy and optimize treatment strategies to modify the disease progression Improving blood vessel integrity and function can help reduce neuron degeneration and inflammation Preclinical and clinical research are integral pieces of an Alzheimerrsquos Disease Research Center (ADRC)
Of Mice to WoMen Translational Dementia Research Labs at MUSC
ERFA Vascular Neuroprotection Laboratories Adviye Ergul MD PhD ergulmuscedu Aging and Senescence Laboratories Gavin Wang MD PhD wangymuscedu Sims-Robinson Lab Metabolic Disorders Brain Aging and AD Catrine Sims-Robinson PhD robinsocmuscedu Christie Heart amp Brain Program Federica del Monte MD PhD delmontemuscedu Onder Albayram PhD albayrammuscedu Carroll A Campbell Jr Neuropathology Laboratories (Brain Bank) Steven Carroll MD PhD Eric D Hamlett PhD hamlettemuscedu
11182019
16
TEAM ERFA VASCULAR NEUROPROTECTION LABORATORIES
YOUR PARTICIPATION AND SUPPORT FOR PRECLINICAL AND CLINICAL RESEARCH IS VITAL FOR SUCCESS IN THE FIGHT AGAINST ADRD
Tell your senators and representatives to keep supporting biomedical
research
We need an Alzheimerrsquos Disease Research Center in South Carolina
THANK YOU
11182019
17
In Search of Therapies for ADRD
Reduce vascular risk factors
Blood pressure control
Blood sugar control
Blood lipid control
ExerciseHealthy Diet
New learning
11182019
12
In Search of Therapies Randomized Blinded Preclinical Trial 2
Diabetes Stroke Behavior Age 4w 12-14 w Day 14 Post-Stroke
Day 1-7 DFX treatment
Day 14
Ctrl DM00
02
04
06
08
$ $
NO
R i
nd
ex
DFX DFX
DFX treatment prevents inflammation
In Search of Therapies Sex Differences
Day 14
Ctrl DM00
02
04
06
08
$
$
NO
R i
nd
ex
DFX DFX
DFX treatment reduces blood vessels in both control and diabetic rats
DFX treatment does not reduce inflammation in females
11182019
13
In Search of Therapies Randomized Blinded Preclinical Trial 3
C21
In Search of Therapies Continued
Diabetes Stroke Behavior Age (w) 4 12-14 W1-8 Post-Stroke
Delayed
Administration
Blinded amp
Randomized
Day 3
C21
11182019
14
In Search of Therapies Randomized Blinded Preclinical Trial 3
BL W1 W2 W4 W802
04
06
08
Time Post- MCAO
T
ime in
No
vel A
rm
2 Trial Ymaze
C C21C Veh
NS
BL W1 W2 W4 W800
02
04
06
08
Time Post- MCAO
T
ime in
No
vel A
rm
2 Trial Ymaze
D C21 D Veh
Interaction Plt005
In Search of Therapies Randomized Blinded Preclinical Trial 3
C21 reduces inflammation improves vascular integrity and prevents cognitive decline
11182019
15
In Search of Therapies for ADRD Of Mice to WoMen
Preclinical animal studies using comorbid disease models commonly found in patients such as diabetes and hypertension are essential to identify mechanisms underlying ADRD to develop new therapies Translational preclinical studies designed like human clinical trials can help us test the efficacy and optimize treatment strategies to modify the disease progression Improving blood vessel integrity and function can help reduce neuron degeneration and inflammation Preclinical and clinical research are integral pieces of an Alzheimerrsquos Disease Research Center (ADRC)
Of Mice to WoMen Translational Dementia Research Labs at MUSC
ERFA Vascular Neuroprotection Laboratories Adviye Ergul MD PhD ergulmuscedu Aging and Senescence Laboratories Gavin Wang MD PhD wangymuscedu Sims-Robinson Lab Metabolic Disorders Brain Aging and AD Catrine Sims-Robinson PhD robinsocmuscedu Christie Heart amp Brain Program Federica del Monte MD PhD delmontemuscedu Onder Albayram PhD albayrammuscedu Carroll A Campbell Jr Neuropathology Laboratories (Brain Bank) Steven Carroll MD PhD Eric D Hamlett PhD hamlettemuscedu
11182019
16
TEAM ERFA VASCULAR NEUROPROTECTION LABORATORIES
YOUR PARTICIPATION AND SUPPORT FOR PRECLINICAL AND CLINICAL RESEARCH IS VITAL FOR SUCCESS IN THE FIGHT AGAINST ADRD
Tell your senators and representatives to keep supporting biomedical
research
We need an Alzheimerrsquos Disease Research Center in South Carolina
THANK YOU
11182019
17
In Search of Therapies for ADRD
Reduce vascular risk factors
Blood pressure control
Blood sugar control
Blood lipid control
ExerciseHealthy Diet
New learning
11182019
13
In Search of Therapies Randomized Blinded Preclinical Trial 3
C21
In Search of Therapies Continued
Diabetes Stroke Behavior Age (w) 4 12-14 W1-8 Post-Stroke
Delayed
Administration
Blinded amp
Randomized
Day 3
C21
11182019
14
In Search of Therapies Randomized Blinded Preclinical Trial 3
BL W1 W2 W4 W802
04
06
08
Time Post- MCAO
T
ime in
No
vel A
rm
2 Trial Ymaze
C C21C Veh
NS
BL W1 W2 W4 W800
02
04
06
08
Time Post- MCAO
T
ime in
No
vel A
rm
2 Trial Ymaze
D C21 D Veh
Interaction Plt005
In Search of Therapies Randomized Blinded Preclinical Trial 3
C21 reduces inflammation improves vascular integrity and prevents cognitive decline
11182019
15
In Search of Therapies for ADRD Of Mice to WoMen
Preclinical animal studies using comorbid disease models commonly found in patients such as diabetes and hypertension are essential to identify mechanisms underlying ADRD to develop new therapies Translational preclinical studies designed like human clinical trials can help us test the efficacy and optimize treatment strategies to modify the disease progression Improving blood vessel integrity and function can help reduce neuron degeneration and inflammation Preclinical and clinical research are integral pieces of an Alzheimerrsquos Disease Research Center (ADRC)
Of Mice to WoMen Translational Dementia Research Labs at MUSC
ERFA Vascular Neuroprotection Laboratories Adviye Ergul MD PhD ergulmuscedu Aging and Senescence Laboratories Gavin Wang MD PhD wangymuscedu Sims-Robinson Lab Metabolic Disorders Brain Aging and AD Catrine Sims-Robinson PhD robinsocmuscedu Christie Heart amp Brain Program Federica del Monte MD PhD delmontemuscedu Onder Albayram PhD albayrammuscedu Carroll A Campbell Jr Neuropathology Laboratories (Brain Bank) Steven Carroll MD PhD Eric D Hamlett PhD hamlettemuscedu
11182019
16
TEAM ERFA VASCULAR NEUROPROTECTION LABORATORIES
YOUR PARTICIPATION AND SUPPORT FOR PRECLINICAL AND CLINICAL RESEARCH IS VITAL FOR SUCCESS IN THE FIGHT AGAINST ADRD
Tell your senators and representatives to keep supporting biomedical
research
We need an Alzheimerrsquos Disease Research Center in South Carolina
THANK YOU
11182019
17
In Search of Therapies for ADRD
Reduce vascular risk factors
Blood pressure control
Blood sugar control
Blood lipid control
ExerciseHealthy Diet
New learning
11182019
14
In Search of Therapies Randomized Blinded Preclinical Trial 3
BL W1 W2 W4 W802
04
06
08
Time Post- MCAO
T
ime in
No
vel A
rm
2 Trial Ymaze
C C21C Veh
NS
BL W1 W2 W4 W800
02
04
06
08
Time Post- MCAO
T
ime in
No
vel A
rm
2 Trial Ymaze
D C21 D Veh
Interaction Plt005
In Search of Therapies Randomized Blinded Preclinical Trial 3
C21 reduces inflammation improves vascular integrity and prevents cognitive decline
11182019
15
In Search of Therapies for ADRD Of Mice to WoMen
Preclinical animal studies using comorbid disease models commonly found in patients such as diabetes and hypertension are essential to identify mechanisms underlying ADRD to develop new therapies Translational preclinical studies designed like human clinical trials can help us test the efficacy and optimize treatment strategies to modify the disease progression Improving blood vessel integrity and function can help reduce neuron degeneration and inflammation Preclinical and clinical research are integral pieces of an Alzheimerrsquos Disease Research Center (ADRC)
Of Mice to WoMen Translational Dementia Research Labs at MUSC
ERFA Vascular Neuroprotection Laboratories Adviye Ergul MD PhD ergulmuscedu Aging and Senescence Laboratories Gavin Wang MD PhD wangymuscedu Sims-Robinson Lab Metabolic Disorders Brain Aging and AD Catrine Sims-Robinson PhD robinsocmuscedu Christie Heart amp Brain Program Federica del Monte MD PhD delmontemuscedu Onder Albayram PhD albayrammuscedu Carroll A Campbell Jr Neuropathology Laboratories (Brain Bank) Steven Carroll MD PhD Eric D Hamlett PhD hamlettemuscedu
11182019
16
TEAM ERFA VASCULAR NEUROPROTECTION LABORATORIES
YOUR PARTICIPATION AND SUPPORT FOR PRECLINICAL AND CLINICAL RESEARCH IS VITAL FOR SUCCESS IN THE FIGHT AGAINST ADRD
Tell your senators and representatives to keep supporting biomedical
research
We need an Alzheimerrsquos Disease Research Center in South Carolina
THANK YOU
11182019
17
In Search of Therapies for ADRD
Reduce vascular risk factors
Blood pressure control
Blood sugar control
Blood lipid control
ExerciseHealthy Diet
New learning
11182019
15
In Search of Therapies for ADRD Of Mice to WoMen
Preclinical animal studies using comorbid disease models commonly found in patients such as diabetes and hypertension are essential to identify mechanisms underlying ADRD to develop new therapies Translational preclinical studies designed like human clinical trials can help us test the efficacy and optimize treatment strategies to modify the disease progression Improving blood vessel integrity and function can help reduce neuron degeneration and inflammation Preclinical and clinical research are integral pieces of an Alzheimerrsquos Disease Research Center (ADRC)
Of Mice to WoMen Translational Dementia Research Labs at MUSC
ERFA Vascular Neuroprotection Laboratories Adviye Ergul MD PhD ergulmuscedu Aging and Senescence Laboratories Gavin Wang MD PhD wangymuscedu Sims-Robinson Lab Metabolic Disorders Brain Aging and AD Catrine Sims-Robinson PhD robinsocmuscedu Christie Heart amp Brain Program Federica del Monte MD PhD delmontemuscedu Onder Albayram PhD albayrammuscedu Carroll A Campbell Jr Neuropathology Laboratories (Brain Bank) Steven Carroll MD PhD Eric D Hamlett PhD hamlettemuscedu
11182019
16
TEAM ERFA VASCULAR NEUROPROTECTION LABORATORIES
YOUR PARTICIPATION AND SUPPORT FOR PRECLINICAL AND CLINICAL RESEARCH IS VITAL FOR SUCCESS IN THE FIGHT AGAINST ADRD
Tell your senators and representatives to keep supporting biomedical
research
We need an Alzheimerrsquos Disease Research Center in South Carolina
THANK YOU
11182019
17
In Search of Therapies for ADRD
Reduce vascular risk factors
Blood pressure control
Blood sugar control
Blood lipid control
ExerciseHealthy Diet
New learning
11182019
16
TEAM ERFA VASCULAR NEUROPROTECTION LABORATORIES
YOUR PARTICIPATION AND SUPPORT FOR PRECLINICAL AND CLINICAL RESEARCH IS VITAL FOR SUCCESS IN THE FIGHT AGAINST ADRD
Tell your senators and representatives to keep supporting biomedical
research
We need an Alzheimerrsquos Disease Research Center in South Carolina
THANK YOU
11182019
17
In Search of Therapies for ADRD
Reduce vascular risk factors
Blood pressure control
Blood sugar control
Blood lipid control
ExerciseHealthy Diet
New learning
11182019
17
In Search of Therapies for ADRD
Reduce vascular risk factors
Blood pressure control
Blood sugar control
Blood lipid control
ExerciseHealthy Diet
New learning