Vascular Contributions to Dementia

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Vascular Contributions to
Dementia
Ashley Walker, PhD
Assistant Professor
Human Physiology
University of Oregon

Vascular Contributions to Dementia:
Role of Arterial Stiffness
Ashley Walker, PhD
Assistant Professor
University of Oregon
aewalker@uoregon.edu
Vascularlab.uoregon.edu
@Ashley_E_Walker

Images created with Biorender.com

Alzheimer’s disease
Image: Alzheimer’s Association

For individuals diagnosed with Alzheimer’s disease,
how many have AD pathology in their brain?
B. 65%
A. 45% C. 85%

C. 85%
Data from: Kapasi, Acta Neuropathol, 2017, DOI: 10.1007/s00401-017-1717-7
how many have AD pathology in their brain?

how many have other pathology in their brain?
B. 66%
A. 36% C. 96%

how many have other pathology in their brain?
C. 96%

In the brain of patients diagnosed with
Alzheimer’s disease:
*Other pathology: Lewy body,
TDP-43, hippocampal sclerosis
AD pathology
AD + Vascular pathology
Other pathology
No pathology
AD pathology (only)
AD and Other pathology
Other pathology (no AD)
No pathology

Image: Zlokovic, Neurosurgery, 1998

AD pathology
AD + Vascular pathology
Other + Vascular
pathology
Other pathology
No pathology
*Other pathology: Lewy body,
TDP-43, hippocampal sclerosis
AD pathology(only)
Vascular pathology AND
AD pathology
No pathology
Vascular pathology (only)
Other pathology
In the brain of patients diagnosed with
Alzheimer’s disease:

Iturria-Medina, 2016. Nature Communications, DOI: 10.1038/ncomms11934
Vascular dysregulation is the earliest
biomarker for late-onset Alzheimer’s disease
Healthy
control
Early mild
cognitive
impairment
Late mild
cognitive
impairment
Late-onset
Alzheimer's
disease
Biomarker
abnormality

Iturria-Medina, 2016. Nature Communications, DOI: 10.1038/ncomms11934
Vascular dysregulation is the earliest
biomarker for late-onset Alzheimer’s disease
Healthy
Control
Early mild
cognitive
impairment
Biomarker
abnormality

Vascular functions in the brain

Endothelial cells important to brain vascular
functions

Endothelial cells regulated blood flow and the
blood brain barrier

Dysfunctional endothelial cells impair blood flow
and the blood brain barrier

Major Alzheimer's disease risk factors
Aging Cardiovascular Disease

Distance
Time
Carotid
Femoral
Assessing large artery stiffness: aortic pulse wave
velocity (PWV)
Santos-Parker, Advances in Physiology Education, 2014 DOI: 10.1152/advan.00088.2014
PWV= distance
time

Aortic pulse wave velocity increases with age
Mitchell, J Appl Physiol, 2008, DOI: 10.1152/japplphysiol.90549.2008
Stiffer
artery

Why?

With age (and greater large artery stiffness),
the following occurs:
A. Systolic and diastolic blood pressure increase
B. Systolic blood pressure increases, diastolic blood
pressure decreases
C. Systolic blood pressure decreases, diastolic blood
pressure increases
D. Systolic and diastolic blood pressure decrease

Pulse pressure increases with age
Pulse pressure (PP)
Mitchell, J Appl Physiol, 2008, DOI: 10.1152/japplphysiol.90549.2008

Winder, 2021, AJP Heart, DOI: 10.1152/ajpheart.00696.2020

Arteries Capillaries Veins

Arteries Capillaries Veins Arteries Capillaries Veins

Small arteries have fewer elastic lamina and
respond poorly to greater pulsatility
100 um
10 um
Aorta
Cerebral artery
Arteries Capillaries Veins
Capillary

?

Low and high pulse pressure ex vivo in cerebral arteries
Nick Winder, MS
Posterior cerebral
artery (PCA)

Pulse Conditions:
Low Pulse: 75 mmHg/50 mmHg
High Pulse: 87.5 mmHg/37.5 mmHg
400 bpm
Posterior cerebral
artery (PCA)
Low and high pulse pressure ex vivo in cerebral arteries

Smooth muscle
cells
Endothelial
cells
ACh: acetylcholine
eNOS: endothelial nitric oxide synthase
NO: nitric oxide

Blood Flow
Smooth muscle
cells
Endothelial
cells
ACh: acetylcholine
NO: nitric oxide

Blood Flow
ACh: acetylcholine
NO: nitric oxide
Smooth muscle
cells
Endothelial
cells

ACh: acetylcholine
NO: nitric oxide
Smooth muscle
cells
Endothelial
cells
Blood Flow

ACh: acetylcholine
NO: nitric oxide
Smooth muscle
cells
Endothelial
cells
Blood Flow
Endothelium–dependent dilation

Measuring endothelium-dependent dilation in isolated arteries
Courtesy of Seals Lab

Low pulse pressure ex vivo does not affect
endothelial function in cerebral arteries
Acetylcholine [log M]
PRE -9 -8 -7 -6 -5 -4
PCA
Vasodilation
(%)
0
20
40
60
Static Pressure
Low Pulse Pressure
Winder and Walker, In Review

High pulse pressure ex vivo impairs endothelial
function in cerebral arteries
PRE -9 -8 -7 -6 -5 -4
PCA
Vasodilation
(%)
0
20
40
60
Static Pressure
Low Pulse Pressure
High Pulse Pressure
*

PRE -9 -8 -7 -6 -5 -4
PCA
Vasodilation
(%)
0
20
40
60
Static Pressure
Low Pulse Pressure
High Pulse Pressure
*
Winder and Walker, In Review Raignault, JCBFM, 2016 https://doi.org/10.1177/0271678X16629155
function in cerebral arteries

function in cerebral arteries from young, but not old,
mice
PRE -9 -8 -7 -6 -5 -4
PCA
Vasodilation
(%)
0
20
40
60
Young
Young Low Pulse
Young High Pulse
PRE -9 -8 -7 -6 -5 -4
PCA
Vasodilation
(%)
0
20
40
60
Old
Old Low Pulse
Old High Pulse
*

Old cerebral arteries distend less and are
more stiff during high pulse pressure
Young High Pulse Old High Pulse

?
Eln+/-

Eln+/+ Eln+/-
Aorta
Middle
Cerebral
Artery
Elastin heterozygote (Eln+/-) mice as a model of
large artery stiffness
100 um
100 um
10 um 10 um
• Eln+/- mice have lower elastin content in the large arteries, but not small
arteries.
0.0
0.5
1.0
Aortic
Elastin
Content
(AU)
Eln+/+ Eln+/-
0.0
0.5
1.0
MCA
Elastin
Content
(AU)
Eln+/+ Eln+/-
*
Green: elastin, Blue: nuclei
Walker, 2015, J Physiol, DOI: 10.1113/jphysiol.2014.285338

0
200
400
Aortic
Pulse
Wave
Velocity
(cm/s)
Young Old
0
200
400
Aortic
Pulse
Wave
Velocity
(cm/s)
Eln+/+ Eln+/-
*
• Similar difference in PWV as young vs. old mice wildtype mice
*
Dontao, 2013, Aging Cell, DOI: 10.1111/acel.12103

0
200
400
Aortic
Pulse
Wave
Velocity
(cm/s)
Eln+/+ Eln+/-
*
• Eln+/- mice are a model of isolated stiffening of the large arteries.
0
5
10
15
MCA
Beta
Stiffness
Parameter
Eln+/+ Eln+/-

PRE -9 -8 -7 -6 -5 -4
MCA
Vasodilation
(%)
0
10
20
30
40
50
60
Eln
+/+
Eln
+/-
Eln+/- mice have impaired cerebral artery
endothelium-dependent dilation
*
PRE -9 -8 -7 -6 -5 -4
MCA
Vasodilation
(%)
0
20
40
60 Young
Old
• Similar difference in endothelium-dependent dilation as young vs. old wildtype mice
*
Walker, 2014, AGE, DOI: 10.1007/s11357-013-9585-0

PRE -9 -8 -7 -6 -5 -4
MCA
Vasodilation
(%)
0
10
20
30
40
50
60
Eln
+/+
Eln
+/-
Sodium Nitroprusside [log M]
PRE-10 -9 -8 -7 -6 -5 -4
MCA
Vasodilation
(%)
0
20
40
60
80
100
Eln
+/+
Eln
+/-
*
Eln+/- mice have impaired cerebral artery
endothelium-dependent dilation

ACh: acetylcholine
NO: nitric oxide
Smooth muscle
cells
Endothelial
cells L-NAME

PRE -9 -8 -7 -6 -5 -4
MCA
Vasodilation
(%)
-20
0
20
40
60
Eln
+/+
Eln
+/-
Eln
+/+
L-NAME
Eln
+/-
L-NAME
Endothelial dysfunction in Eln+/- results from reduced
nitric oxide bioavailability
*
†
*

Smooth muscle
cells
Endothelial
cells
Endothelial dysfunction with aging:
O2
-: superoxide
ONOO-: peroxynitrite

Smooth muscle
cells
Endothelial
cells
O2
-: superoxide
Nitrotyrosine

0.0
0.5
1.0
1.5
MCA
Nitrotyrosine
Content
(AU)
Eln+/+ Eln+/-
Eln+/- mice have greater cerebral artery oxidative stress
*
Eln+/+ Eln+/-
Nitrotyrosine
Overlay
Red: nitrotyrosine Green: elastin, Blue: nuclei

Smooth muscle
cells
Endothelial
cells
O2
-: superoxide
TEMOPOL

PRE -9 -8 -7 -6 -5 -4
MCA
Vasodilation
(%)
0
20
40
60
Eln+/-
Eln+/- TEMPOL
Oxidative stress contributes to endothelial dysfunction in Eln+/-
cerebral arteries
*
PRE -9 -8 -7 -6 -5 -4
MCA
Vasodilation
(%)
0
20
40
60
Eln+/+
Eln+/+ TEMPOL

Aβ ?

PRE -9 -8 -7 -6 -5 -4
MCA
Vasodilation
(%)
-20
0
20
40
60
Eln+/+
Eln
+/-
Eln+/+
+ Ab
Eln+/-
+ Ab
Amyloid-β and large artery stiffness have an additive
effect on cerebral artery endothelial dysfunction
Walker, unpublished
*†
*
*

?
3xTgAD x

Measuring cerebral perfusion
12T MR Imaging T2-weighted images:
anatomic location
Arterial spin labelling for
perfusion:
2 mm coronal slice
Nick Winder, MS
Marty Pike, PhD Grant Henson, MS
Winder and Walker, unpublished
Nabil Alkayed, MD, PhD

Perfusion
(ml/100
g
tissue/min)
0
50
100
Eln+/+ Eln+/+
3xTgAD
Eln+/- Eln+/-
3xTgAD
Hippocampus Eln+/+
Eln+/-
Eln+/+ x 3xTg-AD
Eln+/- x 3xTg-AD
N=5-12/group
Large artery stiffness and 3xTg-AD do not affect
perfusion when measured for the hippocampus

3xTg-AD leads to decreased perfusion of the
entorhinal cortex, large artery stiffness does not
have an effect
Perfusion
(ml/100
g
tissue/min)
0
50
100
Eln+/+ Eln+/+
3xTgAD
Eln+/- Eln+/-
3xTgAD
*
N=5-12/group, *p<0.05 vs. Eln+/+
Eln+/+
Eln+/-
Eln+/+ x 3xTg-AD
Eln+/- x 3xTg-AD
Entorhinal cortex

Perfusion
(ml/100
g
tissue/min)
0
50
100
150
Eln+/+ Eln+/+
3xTgAD
Eln+/- Eln+/-
3xTgAD
* *
*
Impaired vascular reactivity in the hippocampus
with the combination of greater large artery stiffness
and 3xTg-AD
N=5-12/group, *p<0.05 vs. 100% O2
100% O2
95% O2 / 5% CO2
Eln+/+ Eln+/-
Eln+/+ x 3xTg-AD Eln+/- x 3xTg-AD
100% O2
95% O2,
5% CO2
Hippocampus

3xTgAD x

Large artery stiffness leads to more activated
microglia in the cerebral cortex
Iba1
positive
area
(%)
0.00
0.25
0.50
0.75
Eln+/+ Eln+/+
3xTgAD
Eln+/- Eln+/-
3xTgAD
*
N=4-10/group, *p<0.05 vs. Eln+/+
Eln+/+ Eln+/-
Eln+/+ x 3xTg-AD Eln+/- x 3xTg-AD
Sahana Krishna Kumaran
Krishna Kumaran and Walker, unpublished

Knutsen, 2018, AJP Heart, DOI: 10.1152/ajpheart.00683.2017
Muhire, 2019, J Am Heart Assoc, DOI: 10.1161/JAHA.118.011630
Sadekova, 2013, J Am Heart Assoc, DOI: 10.1161/JAHA.113.000224
Sadekova, 2018, J Hypertension, DOI: 10.1097/HJH.0000000000001557
de Montgolfier, 2019, Hypertension, DOI: 10.1161/HYPERTENSIONAHA.118.12048
Image created with Biorender.com

2/3 of patients
with Alzheimer’s
disease are women
Alzheimer’s Association, Alzheimers Dement, 2013

Females have higher rate of arterial stiffness and
cerebral flow pulsatility increase with aging
Alwatban, 2021, J Appl Physiol, DOI: 10.1152/japplphysiol.00926.2020
Yu, 2020, JACC, DOI: 10.1016/j.jacc.2019.12.039

Acknowledgements
Aging and Vascular Physiology Lab:
Abigail Cullen, PhD
Emily Reeve, MS
Mackenzie Kehmeier, MS
Nick Winder, MS
Grant Henson, MS
Jessica LaFarga, MS
Funding:
National Institutes of Health: National Institute on Aging
Alzheimer’s Association
John L Luvaas Family Fund
Oregon Medical Research Foundation
Oregon Charitable Checkoff Donations for Alzheimer's research
Images created with BioRender
Elise Kronquist
Kerrick Chinen
Jazmin Cole
Sahana Krishna Kumaran
Julia Wolf
Byron Lee
Hanson Pham
Bradley Bedell
Aleena Khurana
Nayantara Arora
Max Braker
Audrey Cannon
Holly D’Amico
Collaborators:
Marty Pike, PhD, OHSU
Nabil Alkayed, MD, PhD, OHSU
Randy Woltjer, MD, PhD, OHSU
Laura Villasanna, PhD, OHSU
Dean Li, MD, PhD, U of Utah
Tony Dontao, PhD, U of Utah
Lisa Lesniewski, PhD, U of Utah

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Vascular Contributions to Dementia

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