blood vessels and dementia? tell me more · 11/18/2019 1 blood vessels and dementia? tell me more...

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


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


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)


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


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


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




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


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


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


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



function



coupling


Neurovascular Unit

11182019

4

11182019

5











dementia (VCID)

COGNITION

11182019

6







White matter damage

BBB disruption

VCID

(VCIPSCI)

Neuroinflammation

Stroke




ADADRD


11182019

7

Of Mice to WoMen



Cortex Striatum0

50

100

150

200

250

Control (n=12)

Diabetes (n=12)

CB

F (

ml

100g

min

)

Cortex

Striatum

Diabetes

Control



11182019

8


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)




Diabetes

Control


0

2 0

4 0

6 0

Ce

ll B

od

y S

ize

(u

m)


0

2

4

6

8

Nu

mb

er

of

Pro

tru

sio

ns

Microglia

11182019

9


RECOGNITION INDEX

0 0

0 2

0 4

0 6

0 8

1 0

C o n t r o l


2 5 7 1 0 1 4

c

a

ba

aa

a


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


11182019

10


Stroke side of

the brain

0

5

10

15


Cortex


Sham

p=00009

p=00019

p=00098

p=00019

p=00098

b

b

v

asc

ular

vo

lum

e


Diabetes


Blood sugar control

0

20

40

60

80

100

0 2 14

Control


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


2 5 7 10 14

c

a

ba

aa

a

Days after stroke

Re

co

gn

itio

n i

nd

ex



15 min delay



11182019

11





Iron


Diabetes

DFX


Day 14

Ctrl DM00

02

04

06

08

$ $

NO

R i

nd

ex

DFX DFX




11182019

12




Day 14

Ctrl DM00

02

04

06

08

$ $

NO

R i

nd

ex

DFX DFX



Day 14

Ctrl DM00

02

04

06

08

$

$

NO

R i

nd

ex

DFX DFX



11182019

13


C21



Delayed

Administration

Blinded amp

Randomized

Day 3

C21

11182019

14


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



11182019

15





11182019

16




research


THANK YOU

11182019

17




Blood sugar control

Blood lipid control


New learning

11182019

3



function



coupling


Neurovascular Unit

11182019

4

11182019

5











dementia (VCID)

COGNITION

11182019

6







White matter damage

BBB disruption

VCID

(VCIPSCI)

Neuroinflammation

Stroke




ADADRD


11182019

7

Of Mice to WoMen



Cortex Striatum0

50

100

150

200

250

Control (n=12)

Diabetes (n=12)

CB

F (

ml

100g

min

)

Cortex

Striatum

Diabetes

Control



11182019

8


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)




Diabetes

Control


0

2 0

4 0

6 0

Ce

ll B

od

y S

ize

(u

m)


0

2

4

6

8

Nu

mb

er

of

Pro

tru

sio

ns

Microglia

11182019

9


RECOGNITION INDEX

0 0

0 2

0 4

0 6

0 8

1 0

C o n t r o l


2 5 7 1 0 1 4

c

a

ba

aa

a


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


11182019

10


Stroke side of

the brain

0

5

10

15


Cortex


Sham

p=00009

p=00019

p=00098

p=00019

p=00098

b

b

v

asc

ular

vo

lum

e


Diabetes


Blood sugar control

0

20

40

60

80

100

0 2 14

Control


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


2 5 7 10 14

c

a

ba

aa

a

Days after stroke

Re

co

gn

itio

n i

nd

ex



15 min delay



11182019

11





Iron


Diabetes

DFX


Day 14

Ctrl DM00

02

04

06

08

$ $

NO

R i

nd

ex

DFX DFX




11182019

12




Day 14

Ctrl DM00

02

04

06

08

$ $

NO

R i

nd

ex

DFX DFX



Day 14

Ctrl DM00

02

04

06

08

$

$

NO

R i

nd

ex

DFX DFX



11182019

13


C21



Delayed

Administration

Blinded amp

Randomized

Day 3

C21

11182019

14


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



11182019

15





11182019

16




research


THANK YOU

11182019

17




Blood sugar control

Blood lipid control


New learning

11182019

4

11182019

5











dementia (VCID)

COGNITION

11182019

6







White matter damage

BBB disruption

VCID

(VCIPSCI)

Neuroinflammation

Stroke




ADADRD


11182019

7

Of Mice to WoMen



Cortex Striatum0

50

100

150

200

250

Control (n=12)

Diabetes (n=12)

CB

F (

ml

100g

min

)

Cortex

Striatum

Diabetes

Control



11182019

8


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)




Diabetes

Control


0

2 0

4 0

6 0

Ce

ll B

od

y S

ize

(u

m)


0

2

4

6

8

Nu

mb

er

of

Pro

tru

sio

ns

Microglia

11182019

9


RECOGNITION INDEX

0 0

0 2

0 4

0 6

0 8

1 0

C o n t r o l


2 5 7 1 0 1 4

c

a

ba

aa

a


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


11182019

10


Stroke side of

the brain

0

5

10

15


Cortex


Sham

p=00009

p=00019

p=00098

p=00019

p=00098

b

b

v

asc

ular

vo

lum

e


Diabetes


Blood sugar control

0

20

40

60

80

100

0 2 14

Control


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


2 5 7 10 14

c

a

ba

aa

a

Days after stroke

Re

co

gn

itio

n i

nd

ex



15 min delay



11182019

11





Iron


Diabetes

DFX


Day 14

Ctrl DM00

02

04

06

08

$ $

NO

R i

nd

ex

DFX DFX




11182019

12




Day 14

Ctrl DM00

02

04

06

08

$ $

NO

R i

nd

ex

DFX DFX



Day 14

Ctrl DM00

02

04

06

08

$

$

NO

R i

nd

ex

DFX DFX



11182019

13


C21



Delayed

Administration

Blinded amp

Randomized

Day 3

C21

11182019

14


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



11182019

15





11182019

16




research


THANK YOU

11182019

17




Blood sugar control

Blood lipid control


New learning

11182019

5











dementia (VCID)

COGNITION

11182019

6







White matter damage

BBB disruption

VCID

(VCIPSCI)

Neuroinflammation

Stroke




ADADRD


11182019

7

Of Mice to WoMen



Cortex Striatum0

50

100

150

200

250

Control (n=12)

Diabetes (n=12)

CB

F (

ml

100g

min

)

Cortex

Striatum

Diabetes

Control



11182019

8


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)




Diabetes

Control


0

2 0

4 0

6 0

Ce

ll B

od

y S

ize

(u

m)


0

2

4

6

8

Nu

mb

er

of

Pro

tru

sio

ns

Microglia

11182019

9


RECOGNITION INDEX

0 0

0 2

0 4

0 6

0 8

1 0

C o n t r o l


2 5 7 1 0 1 4

c

a

ba

aa

a


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


11182019

10


Stroke side of

the brain

0

5

10

15


Cortex


Sham

p=00009

p=00019

p=00098

p=00019

p=00098

b

b

v

asc

ular

vo

lum

e


Diabetes


Blood sugar control

0

20

40

60

80

100

0 2 14

Control


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


2 5 7 10 14

c

a

ba

aa

a

Days after stroke

Re

co

gn

itio

n i

nd

ex



15 min delay



11182019

11





Iron


Diabetes

DFX


Day 14

Ctrl DM00

02

04

06

08

$ $

NO

R i

nd

ex

DFX DFX




11182019

12




Day 14

Ctrl DM00

02

04

06

08

$ $

NO

R i

nd

ex

DFX DFX



Day 14

Ctrl DM00

02

04

06

08

$

$

NO

R i

nd

ex

DFX DFX



11182019

13


C21



Delayed

Administration

Blinded amp

Randomized

Day 3

C21

11182019

14


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



11182019

15





11182019

16




research


THANK YOU

11182019

17




Blood sugar control

Blood lipid control


New learning

11182019

6







White matter damage

BBB disruption

VCID

(VCIPSCI)

Neuroinflammation

Stroke




ADADRD


11182019

7

Of Mice to WoMen



Cortex Striatum0

50

100

150

200

250

Control (n=12)

Diabetes (n=12)

CB

F (

ml

100g

min

)

Cortex

Striatum

Diabetes

Control



11182019

8


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)




Diabetes

Control


0

2 0

4 0

6 0

Ce

ll B

od

y S

ize

(u

m)


0

2

4

6

8

Nu

mb

er

of

Pro

tru

sio

ns

Microglia

11182019

9


RECOGNITION INDEX

0 0

0 2

0 4

0 6

0 8

1 0

C o n t r o l


2 5 7 1 0 1 4

c

a

ba

aa

a


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


11182019

10


Stroke side of

the brain

0

5

10

15


Cortex


Sham

p=00009

p=00019

p=00098

p=00019

p=00098

b

b

v

asc

ular

vo

lum

e


Diabetes


Blood sugar control

0

20

40

60

80

100

0 2 14

Control


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


2 5 7 10 14

c

a

ba

aa

a

Days after stroke

Re

co

gn

itio

n i

nd

ex



15 min delay



11182019

11





Iron


Diabetes

DFX


Day 14

Ctrl DM00

02

04

06

08

$ $

NO

R i

nd

ex

DFX DFX




11182019

12




Day 14

Ctrl DM00

02

04

06

08

$ $

NO

R i

nd

ex

DFX DFX



Day 14

Ctrl DM00

02

04

06

08

$

$

NO

R i

nd

ex

DFX DFX



11182019

13


C21



Delayed

Administration

Blinded amp

Randomized

Day 3

C21

11182019

14


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



11182019

15





11182019

16




research


THANK YOU

11182019

17




Blood sugar control

Blood lipid control


New learning

11182019

7

Of Mice to WoMen



Cortex Striatum0

50

100

150

200

250

Control (n=12)

Diabetes (n=12)

CB

F (

ml

100g

min

)

Cortex

Striatum

Diabetes

Control



11182019

8


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)




Diabetes

Control


0

2 0

4 0

6 0

Ce

ll B

od

y S

ize

(u

m)


0

2

4

6

8

Nu

mb

er

of

Pro

tru

sio

ns

Microglia

11182019

9


RECOGNITION INDEX

0 0

0 2

0 4

0 6

0 8

1 0

C o n t r o l


2 5 7 1 0 1 4

c

a

ba

aa

a


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


11182019

10


Stroke side of

the brain

0

5

10

15


Cortex


Sham

p=00009

p=00019

p=00098

p=00019

p=00098

b

b

v

asc

ular

vo

lum

e


Diabetes


Blood sugar control

0

20

40

60

80

100

0 2 14

Control


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


2 5 7 10 14

c

a

ba

aa

a

Days after stroke

Re

co

gn

itio

n i

nd

ex



15 min delay



11182019

11





Iron


Diabetes

DFX


Day 14

Ctrl DM00

02

04

06

08

$ $

NO

R i

nd

ex

DFX DFX




11182019

12




Day 14

Ctrl DM00

02

04

06

08

$ $

NO

R i

nd

ex

DFX DFX



Day 14

Ctrl DM00

02

04

06

08

$

$

NO

R i

nd

ex

DFX DFX



11182019

13


C21



Delayed

Administration

Blinded amp

Randomized

Day 3

C21

11182019

14


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



11182019

15





11182019

16




research


THANK YOU

11182019

17




Blood sugar control

Blood lipid control


New learning

11182019

8


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)




Diabetes

Control


0

2 0

4 0

6 0

Ce

ll B

od

y S

ize

(u

m)


0

2

4

6

8

Nu

mb

er

of

Pro

tru

sio

ns

Microglia

11182019

9


RECOGNITION INDEX

0 0

0 2

0 4

0 6

0 8

1 0

C o n t r o l


2 5 7 1 0 1 4

c

a

ba

aa

a


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


11182019

10


Stroke side of

the brain

0

5

10

15


Cortex


Sham

p=00009

p=00019

p=00098

p=00019

p=00098

b

b

v

asc

ular

vo

lum

e


Diabetes


Blood sugar control

0

20

40

60

80

100

0 2 14

Control


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


2 5 7 10 14

c

a

ba

aa

a

Days after stroke

Re

co

gn

itio

n i

nd

ex



15 min delay



11182019

11





Iron


Diabetes

DFX


Day 14

Ctrl DM00

02

04

06

08

$ $

NO

R i

nd

ex

DFX DFX




11182019

12




Day 14

Ctrl DM00

02

04

06

08

$ $

NO

R i

nd

ex

DFX DFX



Day 14

Ctrl DM00

02

04

06

08

$

$

NO

R i

nd

ex

DFX DFX



11182019

13


C21



Delayed

Administration

Blinded amp

Randomized

Day 3

C21

11182019

14


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



11182019

15





11182019

16




research


THANK YOU

11182019

17




Blood sugar control

Blood lipid control


New learning

11182019

9


RECOGNITION INDEX

0 0

0 2

0 4

0 6

0 8

1 0

C o n t r o l


2 5 7 1 0 1 4

c

a

ba

aa

a


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


11182019

10


Stroke side of

the brain

0

5

10

15


Cortex


Sham

p=00009

p=00019

p=00098

p=00019

p=00098

b

b

v

asc

ular

vo

lum

e


Diabetes


Blood sugar control

0

20

40

60

80

100

0 2 14

Control


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


2 5 7 10 14

c

a

ba

aa

a

Days after stroke

Re

co

gn

itio

n i

nd

ex



15 min delay



11182019

11





Iron


Diabetes

DFX


Day 14

Ctrl DM00

02

04

06

08

$ $

NO

R i

nd

ex

DFX DFX




11182019

12




Day 14

Ctrl DM00

02

04

06

08

$ $

NO

R i

nd

ex

DFX DFX



Day 14

Ctrl DM00

02

04

06

08

$

$

NO

R i

nd

ex

DFX DFX



11182019

13


C21



Delayed

Administration

Blinded amp

Randomized

Day 3

C21

11182019

14


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



11182019

15





11182019

16




research


THANK YOU

11182019

17




Blood sugar control

Blood lipid control


New learning

11182019

10


Stroke side of

the brain

0

5

10

15


Cortex


Sham

p=00009

p=00019

p=00098

p=00019

p=00098

b

b

v

asc

ular

vo

lum

e


Diabetes


Blood sugar control

0

20

40

60

80

100

0 2 14

Control


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


2 5 7 10 14

c

a

ba

aa

a

Days after stroke

Re

co

gn

itio

n i

nd

ex



15 min delay



11182019

11





Iron


Diabetes

DFX


Day 14

Ctrl DM00

02

04

06

08

$ $

NO

R i

nd

ex

DFX DFX




11182019

12




Day 14

Ctrl DM00

02

04

06

08

$ $

NO

R i

nd

ex

DFX DFX



Day 14

Ctrl DM00

02

04

06

08

$

$

NO

R i

nd

ex

DFX DFX



11182019

13


C21



Delayed

Administration

Blinded amp

Randomized

Day 3

C21

11182019

14


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



11182019

15





11182019

16




research


THANK YOU

11182019

17




Blood sugar control

Blood lipid control


New learning

11182019

11





Iron


Diabetes

DFX


Day 14

Ctrl DM00

02

04

06

08

$ $

NO

R i

nd

ex

DFX DFX




11182019

12




Day 14

Ctrl DM00

02

04

06

08

$ $

NO

R i

nd

ex

DFX DFX



Day 14

Ctrl DM00

02

04

06

08

$

$

NO

R i

nd

ex

DFX DFX



11182019

13


C21



Delayed

Administration

Blinded amp

Randomized

Day 3

C21

11182019

14


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



11182019

15





11182019

16




research


THANK YOU

11182019

17




Blood sugar control

Blood lipid control


New learning

11182019

12




Day 14

Ctrl DM00

02

04

06

08

$ $

NO

R i

nd

ex

DFX DFX



Day 14

Ctrl DM00

02

04

06

08

$

$

NO

R i

nd

ex

DFX DFX



11182019

13


C21



Delayed

Administration

Blinded amp

Randomized

Day 3

C21

11182019

14


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



11182019

15





11182019

16




research


THANK YOU

11182019

17




Blood sugar control

Blood lipid control


New learning

11182019

13


C21



Delayed

Administration

Blinded amp

Randomized

Day 3

C21

11182019

14


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



11182019

15





11182019

16




research


THANK YOU

11182019

17




Blood sugar control

Blood lipid control


New learning

11182019

14


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



11182019

15





11182019

16




research


THANK YOU

11182019

17




Blood sugar control

Blood lipid control


New learning

11182019

15





11182019

16




research


THANK YOU

11182019

17




Blood sugar control

Blood lipid control


New learning

11182019

16




research


THANK YOU

11182019

17




Blood sugar control

Blood lipid control


New learning

11182019

17




Blood sugar control

Blood lipid control


New learning

blood vessels and dementia? tell me more · 11/18/2019 1 blood vessels and dementia? tell me more...

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